Alkenylation of Arenes and Heteroarenes with Alkynes - Chemical

Review pubs.acs.org/CR

Alkenylation of Arenes and Heteroarenes with Alkynes Vadim P. Boyarskiy,† Dmitry S. Ryabukhin,†,‡ Nadezhda A. Bokach,† and Aleksander V. Vasilyev*,†,‡ †

Institute of Chemistry, Saint Petersburg State University, Universitetskaya nab., 7/9, Saint Petersburg 199034, Russia Department of Chemistry, Saint Petersburg State Forest Technical University, Institutsky per. 5, Saint Petersburg 194021, Russia

‡

ABSTRACT: This review is focused on the analysis of current data on new methods of alkenylation of arenes and heteroarenes with alkynes by transition metal catalyzed reactions, Bronsted/Lewis acid promoted transformations, and others. The synthetic potential, scope, limitations, and mechanistic problems of the alkenylation reactions are discussed. The insertion of an alkenyl group into aromatic and heteroaromatic rings by inter- or intramolecular ways provides a synthetic route to derivatives of styrene, stilbene, chalcone, cinnamic acid, various fused carbo- and heterocycles, etc.

CONTENTS 1. Introduction 2. Palladium-Catalyzed Reactions 2.1. Activation of C−H Bonds 2.1.1. Synthesis of Substituted Alkenes and Carbocycles 2.1.2. Synthesis of Benzofuran Derivatives 2.1.3. Synthesis of Benzopyran Derivatives 2.1.4. Synthesis of Indole Derivatives 2.1.5. Synthesis of Quinoline and Isoquinoline Derivatives 2.2. Activation of C−X (X = Cl, Br, I, etc.) Bonds 2.2.1. Synthesis of Substituted Alkenes and Carbocycles 2.2.2. Synthesis of Benzofuran Derivatives 2.2.3. Synthesis of Thiaheterocyclic Derivatives 2.2.4. Synthesis of Indole and Quinoline Derivatives 3. Platinum-Catalyzed Reactions 3.1. Activation of C−H Bonds 3.1.1. Synthesis of Substituted Alkenes 3.1.2. Synthesis of Carbocycles 3.1.3. Synthesis of Benzopyran Derivatives 3.1.4. Synthesis of Quinoline Derivatives 3.1.5. Formation of Other Cyclic Systems 3.2. Activation of C−C Bonds 4. Rhodium-Catalyzed Reactions 4.1. Synthesis of Substituted Alkenes 4.2. Synthesis of Carbocycles 4.3. Synthesis of Oxaheterocycles 4.4. Synthesis of Indole Derivatives 4.5. Synthesis of Quinoline Derivatives 4.6. Synthesis of Isoquinoline Derivatives 4.7. Synthesis of Skeletons Bearing Two Heteroatoms 5. Ruthenium-Catalyzed Reactions 5.1. Synthesis of Substituted Alkenes 5.2. Synthesis of Carbocycles 5.3. Synthesis of Heterocycles

© 2016 American Chemical Society

5.4. Comparison of Reactions Catalyzed by Palladium, Platinum, Rhodium, and Ruthenium 6. Gold-Catalyzed Reactions 6.1. Synthesis of Substituted Alkenes 6.2. Synthesis of Carbocycles 6.3. Synthesis of Benzopyran and Benzofuran Derivatives 6.4. Synthesis of Indole Derivatives 6.5. Synthesis of Quinoline Derivatives 6.6. Formation of other Cyclic Systems 7. Copper-Catalyzed Reactions 7.1. Activation of C−H bonds 7.1.1. Synthesis of Substituted Alkenes 7.1.2. Synthesis of Carbocycles 7.1.3. Synthesis of Quinoline Derivatives 7.2. Activation of C−Hal Bonds 7.3. Activation of C−B bonds 7.4. Related Reactions 8. Iron-Catalyzed Reactions 9. Nickel-Catalyzed Reactions 10. Reactions Catalyzed by Other Metals 10.1. Main Group Metals and Lanthanides 10.2. Transition Metals 10.2.1. Tungsten 10.2.2. Manganese 10.2.3. Rhenium 10.2.4. Cobalt 10.2.5. Iridium 10.2.6. Silver 10.2.7. Mercury 11. Bro̷ nsted-Acid-Promoted Reactions 11.1. Intermolecular Reactions 11.2. Intramolecular Reactions 11.2.1. Carbocyclization 11.2.2. Heterocyclization 12. Reactions Promoted by Electrophiles

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Received: September 5, 2015 Published: April 25, 2016 5894

DOI: 10.1021/acs.chemrev.5b00514 Chem. Rev. 2016, 116, 5894−5986

Chemical Reviews

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Scheme 1. Main Pathways of Alkenylation of (Hetero)Arenes with Alkynes

13. Reactions Promoted by Aluminum-Based Lewis Acids 14. Miscellaneous 15. Summary and Outlook Author Information Corresponding Author Notes Biographies Acknowledgments Abbreviations in Alphabetical Order References

formations (path b). Two other methods are based on the interaction of alkynes with Brønsted acids (path c) or cationic electrophiles (I+, Br+, RS+, RSe+, etc.) (path d), proceeding through the intermediate formation of vinyl cations, which react further with (hetero)arenes. There are several reviews concerning this issue;10−17 however, these cover only some narrow, fragmental, and particular aspects of the whole field of alkenylation reactions of (hetero)arenes by alkynes. The growing number of studies on the subject, especially over the past five to ten years, necessitates a more general review of the field. This review is focused on the analysis of current data on new methods of alkenylation of arenes and heteroarenes with alkynes. The synthetic potential, scope, limitations, and mechanistic problems of the alkenylation reactions are discussed. The review covers literature data mainly from the last ten years, up to the beginning of 2015.

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1. INTRODUCTION Alkynes are widely used to obtain compounds of practical value: monomers for polymerization, nonlinear optics materials, liquid crystals, organic semiconductors and sensors, molecular machines, pharmaceuticals, etc. Alkynes find application in nanotechnology, biology, pharmacology, and medicine. Books1−3 and reviews4−8 on chemistry of acetylene and its derivatives published recently have shown that the further development of the theoretical, synthetic, and applied aspects of this area is very important. In this review, we consider one synthetically important transformation of alkynes, namely alkenylation (vinylation) of arenes and heteroarenes (Scheme 1). This reaction may be also considered as a hydro(or other group)-arylation of the acetylene bond. The insertion of an alkenyl group into aromatic and heteroaromatic rings by inter- or intramolecular methods provides a synthetic route to derivatives of styrene, stilbene, chalcone, cinnamic acid, and various fused carbo- and heterocycles. Many of these compounds are of great importance for organic synthesis and practical applications. This approach is an alternative to the classical (hetero)arene alkenylation by the Heck-Mizoroki, Suzuki-Miyaura, Stille, and Negishi reactions.9 There are four main synthetic strategies for the introduction of the alkenyl group into (hetero)aromatic structures with the use of alkynes (Scheme 1). The first one is transition metal (Pd, Pt, Rh, Ru, etc.) catalyzed reactions (path a). The next route is Lewis-acid [compounds of Al(III), Fe(III), Ga(III), In(III), Sc(III), Zn(IV), Hf(IV), Hg(II), etc.] promoted trans-

Scheme 2. Fujiwara Reaction

2. PALLADIUM-CATALYZED REACTIONS 2.1. Activation of C−H Bonds

2.1.1. Synthesis of Substituted Alkenes and Carbocycles. In 2000, Y. Fujiwara et al. reported on the Pd(II)catalyzed insertion of alkynes 2 into CAr−H bonds of arenes 1 to form alkenylation products 3 in the presence of CF3CO2H (Scheme 2).18−20 Addition of hydrogen and aryl moiety to acetylene bond proceeds mainly in anti-way. 5895


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Scheme 3. Proposed Mechanism of the Fujiwara Reaction

Scheme 6. Fujiwara Reaction of Heterocycles Catalyzed by Chelating Dicarbene Palladium(II) Complexes

Scheme 7. Pentamethylbenzene Alkenylation with Ethyl Propiolate Catalyzed by Chelating Dicarbene Palladium(II) Complexes Scheme 4. Intramolecular Fujiwara Reaction

Scheme 5. Fujiwara Reaction with Chelating Dicarbene Palladium(II) Complexes as Catalysts Scheme 8. (Abnormal NHC−Pd)-Catalyzed Alkenylation of Arenes

Benzene and its derivatives activated with electron-donating substituents (p-xylene, mesitylene, durene, pentamethylbenzene, hydroxy- and alkoxybenzenes, and naphthalene) react easily.18−20 The reaction also takes place with electron-rich heteroarenes, such as pyrroles, indoles, or thiophenes.12,21 Corresponding intramolecular reactions are widely used in the synthesis of heterocycles. The structure of the products of alkenylation of substituted arenes 1 is determined by the SEAr orientation rules. Acetylene components 2 in this reaction are phenylacetylene (forming alkenylation products 3 (R1 = Ph, R2 = H) formally in accord with Markovnikov’s rule), octyne-4, diphenylacetylene, and methyl(phenyl)acetylene (which is characterized by the addition of hydrogen to the acetylene atom C2 such that R1 = Ph, R2 = Me for product 3). Apart from

that, conjugated acetylenic aldehydes, ketones, carboxylic acids, and esters are involved in the alkenylation.18−20 These compounds attach the aryl group at the C3 atom similarly to the Michael reaction. The mechanism of this reaction involves the in situ generation of the electrophilic species 4, viz., a monotrifluoroacetate palladium(II) cation, which then can react via two pathways (Scheme 3).18−21 Pathway A (reaction of intermediate 4 with arene 1) leads to the σ-aryl palladium complex 5 5896


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philic aromatic substitution in arene 1. At the last stage, the group Pd(O2CCF3)+ in structure 7 is replaced by a proton to form the final product 3. Which of the two possible routes this reaction takes, A or B, cannot in all of the cases be unambiguously determined. It is shown by measuring the kinetic isotope effects (H/D) that path B prevails for certain examples of intramolecular alkenylation.14 On the other hand, Gevorgyan and Chernyak reported the cyclization of o-alkynylbiaryls 8 bearing electron-neutral and electron-deficient second aryl rings into the corresponding fluorenes 9 (Scheme 4).22,23 On the basis of the high cyclization efficiency for electron-deficient substrates, the high values of kinetic isotope effects observed, as well as on the exclusive syn-selectivity of cyclization, the authors proposed a mechanism involving the C−H activation (path A, Scheme 3) for this intramolecular reaction. In general, one can assume that electron-rich arenes react through path B under mild conditions (at a temperature close to room temperature) to form the products of anti-addition to the triple bond.18−21 At the same time, benzene14 and arenes having functional groups capable of coordinating palladium atoms at the ortho-position to the reactive C−H bonds22,23 and are activated at elevated temperatures via path A, giving synaddition products. Nowadays, carbene Pd complexes are widely used as catalysts for organic reactions. The Fujiwara reaction is also catalyzed by these active species. Thus, Basato et al.24−27 reported alkenylation of polymethylbenzenes with chelating dicarbene palladium(II) complex catalysts 10, leading to compounds 3 and 11 (Scheme 5). The product yield is higher for more highly methylated arenes (it increases from p-xylene to pentamethylbenzene). Phenylacetylene and substituted phenylacetylenes attach the aryl group of the arene at the PhC atom of the triple bond. Generating a catalyst in situ with weakly coordinating anionic ligands by the addition of 2 equiv of the corresponding silver salt allows the reaction to proceed at room temperature, thus minimizing side reactions such as hydration and polymerization of the alkyne. The use of acids stronger than TFA, such as HBF4 or HOTf, allows a significant reduction of the quantity of acid. When ionic liquids are used as the catalyst-containing phase, the palladium catalyst can be efficiently separated from the reaction mixture and recycled.27 The same complexes can also catalyze alkenylation of electron-rich heterocycles 12 with ethyl 3-phenylpropiolate, leading to compounds 13 and 14 (Scheme 6).28 Thiophenes did not undergo this reaction. Similar chelate NHC-Pd catalysts 15 for alkenylation of pentamethylbenzene with ethyl propiolate were reported by Poyatos and Peris et al. (Scheme 7).29 The formed ethyl pentamethylcinnamate 16 has cis-configuration, which suggests mechanistic path B (Scheme 3). Ethyl pentamethylcinnamate alkenylation product 17 was also obtained as a byproduct. Sankararaman et al.30 used Pd-(abnormal NHC) complex 19 as a catalyst for the stereoselective alkenylation of polyalkyl arenes 18 (Scheme 8). A two-fold excess of 18 (Ar = Mes) allowed the authors to increase the yield of alkenylation product 20 (Ar = Mes, 79%). Compounds 21 are also formed as byproducts. Reaction of phenylacetylene with electron-rich arenes 18, giving 1,1-diarylethenes 23, can be catalyzed by air-stable NHC−Pd complexes 22 in acidic media (Scheme 9).31 The fact that complex 22 also catalyzed a copper-free Sonogashira coupling allowed the authors to develop a

Scheme 9. (NHC−Pd)-Catalyzed Alkenylation of Arenes with Phenylacetylene

Scheme 10. Sequential (NHC−Pd)-Catalyzed Sonogashira/ Hydroarylation Reaction

Scheme 11. Pd-Catalyzed Synthesis of Naphth-1-ols via Oxidative Annulation Reactions

Scheme 12. Plausible Mechanism of Pd-Catalyzed Naphth-1ols Synthesis

followed by reaction with alkyne 2 yielding intermediate 7. An alternative pathway (B) for the formation of the complex 7 is intermediate 4 attaching to the triple bond of alkyne 2 to produce vinyl cationic species 6 and the subsequent electro5897


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Scheme 13. Pd-Catalyzed Iodine-Mediated Electrophilic Annulation of 2-(1-Alkynyl)biphenyls

Scheme 14. Pd-Catalyzed Synthesis of Spiroindenes

Scheme 15. Pd-Catalyzed bis-Annulation Reaction

Scheme 17. Plausible Mechanism of Pd-Catalyzed bisAnnulation

Scheme 16. Pd-Catalyzed bis-Annulation of Unsymmetrical 1-Biaryl-2-(Heteroarylaryl) Alkynes

Scheme 18. Pd-Catalyzed Synthesis of Benzo[b]furans from Phenols and Alkynes sequential Sonogashira/hydroarylation reaction. The process affords diarylalkyl and triaryl ethenes 24 based on arylhalides, terminal alkynes, and arenes (Scheme 10). The mutual arrangement of the substituents at the double bond is fundamentally different depending on whether the alkyl or aryl acetylene is used as the starting compound. The Pd-catalyzed alkenylation of CAr−H bonds is useful for constructing carbocyclic products.32−35 Wang et al.32 developed palladium-catalyzed oxidative annulation reactions of readily available benzoylacetates 25 with internal alkynes 26 as a method for the preparation of substituted naphth-1-ols 27 (Scheme 11). A plausible mechanism involves carbopalladation of 26 followed by intramolecular CAr−H activation of the formed vinyl-Pd intermediate 28 (Scheme 12).

A kinetic isotope effect (KIE) value of kH/kD 3.0 was obtained for 25, thereby suggesting that the rate-determining step involves the cleavage of the CAr−H bond. 5898


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Scheme 19. Pd-Catalyzed Oxidative Annulation of Estrone

Scheme 20. Pd-Catalyzed Benzo[b]furan Synthesis from Phenols and Bromoalkynes

Scheme 21. Plausible Mechanism of the Pd-Catalyzed Reaction between Phenols and Bromoalkynes

Scheme 24. Plausible Mechanism of Pd-Catalyzed Indole Synthesis from N-Aryl Amides and Alkynes

Scheme 25. Pd-Catalyzed Indole Synthesis from Anilines and Alkynes Scheme 22. Pd-Catalyzed Synthesis of Angular Furocoumarin Derivatives via Intramolecular Hydroarylation of 4-Benzofuranyl Alkynoates

disulfides 30 yields 9-thiosubstituted phenanthrenes 32 (Scheme 13).33 The process also proceeds through the intramolecular cyclization of corresponding vinyl-Pd intermediates 31. Lam et al. reported34 the interaction of alkynes with unsymmetrical cyclic 2-aryl-1,3-dicarbonyl compounds 33 (in enol forms) that contain two distinct, nonadjacent sites for the initial C−H functionalization. The selectivity and nature of the cycle formed depend on the catalyst. By the use of the palladium−N-heterocyclic carbene complex PEPPSI-IPr as the catalyst, substrates 33 undergo oxidative annulation with alkynes to provide spiroindenes 34 exclusively (2.5 mol % PEPPSI-IPr, 2.1 equiv Cu(OAc)2, DMF, 120 °C, 2−5 h, 21− 87%) (Scheme 14). The process occurs via the formation of the C−H-activated complex 35. In contrast, a ruthenium-based

Scheme 23. Pd-Catalyzed Indole Synthesis from N-Aryl Amides and Alkynes

Palladium-catalyzed, iodine-mediated electrophilic annulation of 2-(1-alkynyl)biphenyls 29 in the presence of alkyl or aryl 5899


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Scheme 30. Pd-Catalyzed Isoquinoline N-Oxide Synthesis

Scheme 26. Plausible Mechanism of Pd-Catalyzed Indole Synthesis from Anilines and Alkynes in DMF

Scheme 31. Pd-Catalyzed Synthesis of N-Alkoxyl Isoquinolinones

Scheme 27. Pd-Catalyzed Synthesis of Pentaaryl Pyrroles from Anilines and Alkynes

Jin et al. described an interesting bis-annulation reaction.35 The process is a Pd-catalyzed dual C−H activation of bis-biaryl alkynes 36, which produces 9,9′-bifluorenylidene derivatives 37 with a broad range of functional groups. The combination of PdCl2 (10 mol %) as a catalyst with MnO2 (3 equiv) as an oxidant and t-BuCO2H (10 mol %) as a ligand provides high yields of products (Scheme 15). The same process takes place for conversion of unsymmetrical biaryl-(heteroarylaryl) alkynes 38 into structures 39 (Scheme 16). The mechanistic study suggests that this intramolecular arene/alkyne annulation may take place through the unusual dual C−H activation route followed by the annulation with alkynes (Scheme 17). 2.1.2. Synthesis of Benzofuran Derivatives. A one-step synthesis of benzo[b]furans 40 by the Pd-catalyzed oxidative annulation of phenols and unactivated internal alkynes was recently reported by Sahoo et al.36 The reaction proceeds in the presence of N,N-bidentate ligands (1,10-phenanthroline or bathophenanthroline) and Cu(OAc)2·2H2O as an oxidant (Scheme 18). A similar reaction of estrone 41 with diphenylacetylene afforded the corresponding product 42 in 62% after 48 h (Scheme 19). The mechanism of this process has not yet been studied, but it is clear that the activation of the phenol CAr−H bond by Pd(II) plays an important role in the reaction.

Scheme 28. Plausible Mechanism of Pd-Catalyzed Indole Synthesis from Anilines and Alkynes in 1,4-Dioxane

catalyst system gives benzopyrans as the major products (see section 5.3). The authors did not explain the origins of the different selectivities exhibited by palladium- and rutheniumbased catalysts. Scheme 29. Pd-Catalyzed Synthesis of Indole Derivatives

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Scheme 32. Pd-Catalyzed One-Pot Synthesis of Isoquinolinones

The reaction occurs through addition of phenol to the bromoalkyne with subsequent intramolecular Pd-catalyzed cyclization of the intermediate (Z)-2-bromovinyl phenyl ether 44, affording 2-substituted benzo[b]furans 43 (Scheme 21). 2.1.3. Synthesis of Benzopyran Derivatives. Kitamura and Otsubo reported the intramolecular hydroarylation of 4benzofuranyl alkynoates 45 giving angular furocoumarin derivatives 46 in high yields (Scheme 22).38 The reaction mechanism is analogous to path B in Scheme 3, as an intramolecular variant of the Fujiwara reaction. 2.1.4. Synthesis of Indole Derivatives. A Pd-catalyzed synthesis of indoles 48 from N-aryl amides 47 and alkynes was developed by Lu et al. (Scheme 23).39 The key step of the reaction is the aryl C−H activation by Pd(OAc)2 ligated with the amide carbonyl group. The catalytic cycle includes the alkyne insertion followed by the intramolecular N−H activation, reductive elimination, and reoxidation of Pd(0) to Pd(II) with the oxidant [Cu(OTf)2 + Ag2O] (Scheme 24). Indoles 49 are also obtained from arylamines and diarylacetylenes upon heating them with Cu(OAc)2 in the presence of PdCl2 (10 mol %) in DMF (Scheme 25).40 Unsymmetrical diarylacetylenes afforded indoles 49 with no regioselectivity. These authors proposed another plausible mechanism, with the reverse sequence of steps. The first stage involves a nucleophilic addition of aniline to the cationic diarylacetylene complex 50 with subsequent activation of the CAr−H bond resulting in the cationic vinyl complex 51 (Scheme 26). Furthermore, the authors found that the reaction pathway changed upon changing the reaction solvent from DMF to dioxane, whereupon the main products were not indoles 49 but pentaaryl pyrroles 52, indicating the reaction of one molecule of the aniline with two molecules of the diarylacetylene (Scheme 27). Reactions involving unsymmetrical diarylacetylenes gave three kinds of isomers 52, which were formed with no regioselectivity. The reason for the change of the reaction pathway is that in the absence of DMF, ligand cationic complexes are not formed, the CAr−H bond activation is impossible, and the neutral vinyl complex 53 coordinates with another molecule of the alkyne (Scheme 28). A method for the construction of indoles 55 from simple N(alkyn-4-yl)anilines 54 was developed via the Pd-catalyzed domino intramolecular hydroamination and the CAr−H activation (Scheme 29).41,42 Molecular oxygen was used as the sole oxidant to recycle the Pd catalyst. It is curious that two independent groups of authors (Jiao et al. in China41 and Piou, Neuville, and Zhu in France42) reported this reaction not only simultaneously but also in the same issue of Tetrahedron. The reaction conditions used were very similar (5 equiv of PhCO2H, 20 mol % of PhCO2Li, MeCN, 90 °C, 36 h;41 DMA/t-BuCO2H (v/v = 4/1, c 0.16 M)

Scheme 33. Pd-Catalyzed Synthesis of Isoquinolinones

Scheme 34. Pd/Cu-Catalyzed Synthesis of Racemic Ferrocene[1,2-c]pyridine-3(4H)-ones

Scheme 35. Pd-Catalyzed Domino Synthesis of Substituted 4-Acylquinoline

Another approach to obtaining benzofurans 43 is based on the palladium-catalyzed one-pot reaction between phenols and terminal bromoalkynes (Scheme 20).37 5901


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Scheme 36. Proposed Mechanism of the Domino Synthesis of Substituted 4-Acylquinolines from Benzimidoyl Chlorides and Aryl-Substituted Allyl Propargyl Ethers

Scheme 37. Pd-Catalyzed Domino Synthesis of Quinolines or Quinolinones from 2-(Alkynyl)alkenylidene Dibromides and Anilines

oxidation of Pd(0) into Pd(II) by oxygen completes the catalytic cycle. 2.1.5. Synthesis of Quinoline and Isoquinoline Derivatives. The problem of quinoline and isoquinoline synthesis by heterocyclization via the Fujiwara reaction has attracted the attention of many researchers, thus it is considered in detail in contemporary reviews.6,10 Herein, we confine discussion to the consideration of several papers that were not included or mentioned only briefly in these reviews. Huang et al. described a Pd-catalyzed C−H activation/ annulation process for the synthesis of isoquinoline N-oxides.43 An oxime-directed C−H activation−annulation reaction affords the selective synthesis of a range of isoquinoline N-oxides 59 from the corresponding oximes 57 and substituted arylalkyland diarylalkynes 58 (Scheme 30). Both internal and external competition KIE studies showed that the C−H activation process is the limiting step of the proposed catalytic cycle. The further evidence in favor of the pathway through the formation of aryl-palladium complex 60, but not the vinyl palladium cation, is the regioselectivity of the reaction in the case of the interaction with alkynes 58 (R1 = Ph, R2 = Et) and 58 (R1 = 4MeOC6H4, R2 = Ph). The same group also developed a similar process for isoquinolinones synthesis via the C−H activation/annulation reaction of alkynes and N-alkoxyl benzamides (Scheme 31).44,45 It is interesting that the authors used neutral44 or basic45 conditions in these cases, in contrast to the previous method. The reaction under neutral conditions leads to Nalkoxyl isoquinolinones 62 via the N−H and C−H double activation of 61.44 Using basic conditions for this protocol, followed by NaH treatment, gave isoquinolinones 63 an unsubstituted NH group in a one-pot reaction (Scheme 32).45

Scheme 38. Proposed Mechanism of the Domino Synthesis of Quinolines

Scheme 39. Pd-Catalyzed Synthesis of Isoquinolines from 2Aryl Benzimidazoles and Alkynyl Bromides

120 °C, 4 h42). Both groups studied the mechanism and independently showed that the coordination of Pd(II) to the triple bond and carbonyl oxygen of substrate 54, affording intermediate 56, is the first stage of the reaction. This is followed by the aminopalladation of the triple bond, the activation of the neighboring aryl C−H bond, and reductive elimination to provide pyrrolo[1,2-a]indole 55 and Pd(0). The 5902


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Scheme 40. Enantioselective Intramolecular Hydroarylation of the CC Triple Bond in Amides of Acetylene Carboxylic Acids

Scheme 41. Pathway of Pd-Catalyzed Reactions of Alkyl Halides with Alkynes

Scheme 43. Pd-Catalyzed Synthesis of Inden-1-one Derivatives via Addition of 2-Iodobenzaldehyde to Alkynyl Ethers

Scheme 44. Pd-Catalyzed Synthesis of Indeno[1,2c]Dihydrofurans from 1-Alkynyl-2-halobenzenes and Propargylic Alcohols

N-Alkoxylamides of furan or thiophene carboxylic acids react in the same manner.44,45 These authors also reported a similar reaction of N-alkyl or N-aryl benzamides 64, yielding the corresponding N-alkyl or Naryl isoquinolinones 65 (Scheme 33).46 For the reaction mechanism, external competition KIE studies showed that the C−H activation plays an important role in the proposed catalytic cycle (kH/kD ca. 4 for different deuterated/nondeuterated N-substituted benzamides). Also, a competition reaction was conducted using a 1:1 mixture of Nmethyl-3-chlorobenzamide 64 (R = Me, X = 3-Cl) and Nmethyl-3-methoxybenzamide 64 (R = Me, X = 3-MeO). The reaction of the electron-rich arene was favored. These results mean that Ryabov’s concerted metalation−deprotonation mechanism47 with a partial positive charge on the aromatic ring in the transition state may be realized for the C−H activation stage.

Wang et al. developed a synthesis of racemic ferrocene[1,2c]pyridine-3(4H)-ones 67 via Pd/Cu-catalyzed direct dehydrogenative annulations of ferrocene-carboxamides 66 with internal alkynes under air (Scheme 34).48 The reaction also proceeds via C−H activation by amide precoordinated Pd

Scheme 42. Pd-Catalyzed Synthesis of α,β-Disubstituted or β,β-Disubstituted Alkenyl Ethers via Reductive Addition of Organohalides to Alkynyl Ethers

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cyclization to form bicyclic intermediate 76 followed by the unusual removal of the allyl group as propene. A similar electrocyclization is the key step in another one-pot quinoline synthesis. Xi et al. reported the preparation of quinolines 79 from 2-(alkynyl)alkenylidene dibromides 77 and anilines 78 (Scheme 37).50 Acid hydrolysis of 79 afforded quinolinones 80. This efficient domino process includes Pd-catalyzed amination of 77, 1,5-H transfer, annulation of allene intermediate 81 formed via 6-exo-dig-electrophilic cyclization, and Pd-catalyzed alcoholysis (Scheme 38). Li et al. developed yet another tandem method for the construction of the isoquinoline moiety in structures 84 from 2aryl benzimidazoles 82 and alkynyl bromides 83 (Scheme 39).51 The first step of the reaction is the nucleophilic addition of 82 to the triple bond of 83. The oxidative addition of the vinyl C−Br bond to the Pd species and subsequent intramolecular aryl C−H alkenylation then take place, analogously to Scheme 21. Tanaka et al. reported the first enantioselective intramolecular hydroarylation of the CC triple bond in amides 85 to form axially chiral 4-aryl 2-quinolinones 86 as pharmaceutically active compounds and chiral ligands.52 The reaction is catalyzed by the cationic Pd(II) complex [Pd(CH3CN)4](BF4)2 in the presence of the chiral ligand (S)-xylH8-binap and provides the chiral products in moderate to good yields and ee (Scheme 40). The authors proposed the formation of the intermediate alkyne-Pd complex.

Scheme 45. Plausible Mechanism of the Pd-Catalyzed Reaction of 1-Alkynyl-2-halobenzenes and Propargylic Alcohols

Scheme 46. Pd-Catalyzed Synthesis of Tetrasubstituted Helical Alkenes

2.2. Activation of C−X (X = Cl, Br, I, etc.) Bonds

As in cross-coupling reactions, aryl halides are more reactive in alkenylation reactions with alkynes than arenes.6 If the Pdcatalyzed activation of C−H bonds in the reactions of arenes can proceed through two mechanisms (see section 2.1.1), and the selection between them is often difficult, then aryl halides can alternatively be used via the formation of aryl palladium complex 87 in the first step by oxidative addition (Scheme 41). Features of such oxidative addition reactions are similar to cross-coupling processes and are well-known (for recent papers on the oxidative addition of C−X bonds to Pd species see refs 53−56). Further, complex 87 interacts with an alkyne yielding the vinyl Pd complex 88 through alkyne insertion (some aspects of alkyne insertion into an CAr−Pd bond were recently studied theoretically by DFT55). Then 88 is converted into the reaction products (as a rule, heterocycles), the structures of which are defined by the substrates used. 2.2.1. Synthesis of Substituted Alkenes and Carbocycles. Zhu et al. developed an effective Pd-catalyzed reductive addition of organohalides, including aryl, alkenyl, and benzyl halides, to ethers 89, affording disubstituted alkenyl ethers 90 or 91 (Scheme 42).56 The regioselectivity of this reaction was determined by the organic halides employed: hydroarylation and hydrovinylation yielded α,β-disubstituted alkenyl ethers 90, while hydrobenzylation gave β,β-disubstituted products 91. The reason for such regioselectivity is the difference in the polarization of Csp2−Pd intermediates 92 and Csp3−Pd intermediates 93. The cyclic products, indenones 94, instead of the desired alkenyl ethers, were obtained from 2iodobenzaldehyde under standard conditions (Scheme 43). Lu, Wang, et al. reported a Pd-catalyzed reaction of 1alkynyl-2-bromo- or 1-alkynyl-2-iodo-benzenes 95 with propargylic alcohols 96, furnishing indeno[1,2-c]dihydrofurans 97 (Scheme 44).57 A plausible mechanism for this cascade

Scheme 47. Pd-Catalyzed Synthesis of Chiral Tetrasubstituted Helical Alkenes

species. The role of the Cu salt is reoxidation in the presence of air oxygen. The basis of several quinoline and isoquinoline syntheses is the intramolecular hydroarylation of alkynes. Thus, Liang et al. reported a Pd-catalyzed domino process for the synthesis of substituted 4-acylquinolines 70 from benzimidoyl chlorides 68 and aryl-substituted allyl propargyl ethers 69 (Scheme 35).49 Use of methyl α-phenylpropargyl ether 69 (R = Me) led to 4(α-methoxybenzyl)quinoline derivative 71. When alkyl-substituted allyl propargyl ethers 72 were explored as substrates, there was no intramolecular cyclization of the corresponding Sonogashira products 73. The quinoline formation pathway includes the Sonogashira coupling of 68 with 69, and the cyclization of intermediate 74 yields quinoline derivatives (Scheme 36). The authors proposed that the C−H activation occurred via the baseassisted propargyl-allenyl isomerization of intermediate 74 giving allene intermediate 75, which undergoes a 6π-electro5904


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Scheme 48. Plausible Mechanism of the Pd-Catalyzed Synthesis of Tetrasubstituted Helical Alkenes

the C−I activation step and gives a tetralin skeleton (Scheme 48). Ma et al. described a one-pot synthesis of dihydrocycloocta[b]indoles 105 from N-sulfonated 2-allyl-3-iodoindoles 103 and substituted propargyl bromides 104, catalyzed by a Pd(II) phosphine complex (Scheme 49).59 Presumably, indium promotes cross-linking of the propargylic bromide fragment of 104 with the alkene double bond of 103. When the reaction was conducted at 60 °C for 6 h, the coupling product 106 was isolated in a yield of 33% (Scheme 50). The cyclization of 106 afforded dihydrocycloocta[b]indole 105a (DMF, 100 °C, 6 h, yield of 61%), thus indicating the intermediacy of species 106 for this transformation. Unfortunately, the authors explained neither the mechanism of the CAr−I bond activation nor details of the aryl-alkyne coupling to form the intermediate 106. Huang, Wen, et al. combined three Pd-catalyzed processes, viz, the Sonogashira reaction, intramolecular internal alkyne carbopalladation, and Suzuki coupling, into an interesting cascade synthesis to obtain methylidenefluorenes 110 from cyclic iodoniums 107, alkynes 108, and boronic acids 109 (Scheme 51).60 No (E/Z)-stereoselectivity was found in the case of the synthesis of unsymmetrical 110. Rao and Dhanorkar reported a synthesis of functionalized symmetrical and unsymmetrical 2,3-diarylindenones 111 directly from 1,1-dibromoalkenes, triarylbismuth reagents, and 2-iodobenzaldehydes (Scheme 52).61 Using 2-bromobenzaldehyde instead of 2-iodobenzaldehyde required increasing the

Scheme 49. Pd-Catalyzed One-Pot Synthesis of Dihydrocycloocta[b]indoles

bicyclization involves the formation of one C−O bond and two C−C bonds in a single step (Scheme 45). Lautens et al. developed a synthesis of sterically crowded tetrasubstituted helical alkenes 100 from iodobenzenes 98 (2 equiv) and 2-(2-arylphenyl)-1-(3-bromopropyl) or (2-bromomethyl) (phenyl)alkynes 99 (Scheme 46).58 The domino reaction of chiral bromoalkyl aryl akynes 101 with 2iodotoluene led to the corresponding chiral helical alkenes 102 in excellent yields and stereoselectivities (Scheme 47). This process is a Pd-catalyzed norbornene-mediated cascade of C−I, C−Br, and C−H activations (Scheme 48). Despite the fact that the intramolecular carbopalladation followed by C−H activation is the basis of the heterocycle formation, the intramolecular alkenylation of the CAr−Pd bond begins with

Scheme 50. Formation of a C−C Coupling Intermediate and Its Cyclization to Dihydrocycloocta[b]indole

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Scheme 51. Pd-Catalyzed Synthesis of Alkylidenefluorenes

Scheme 52. Pd-Catalyzed Synthesis of Functionalized Symmetrical and Unsymmetrical 2,3-Diarylindenones

Scheme 53. Pd-Catalyzed Synthesis of 3-(Diarylmethylene)-2,3-dihydrobenzofurans

carbocyclization/Suzuki coupling of 1-(3-arylprop-2-ynyloxy)2-bromo benzenes 113 and boronic acids to afford 3(diarylmethylene)-2,3-dihydrobenzofuran derivatives 114 (Scheme 53).62 The stereochemistry of these products argues in favor of the syn-insertion of the triple bond into the CAr−Pd bond of the intermediate 115. A domino approach was also developed by Zhang, Wang, et al. to synthesize 3-vinylbenzofurans and 3-vinyl-1-acetylindoles 118 from 3-arylpropargylic derivatives of 2-iodophenols or 2iodoacetanilides 116, respectively, and in situ obtained diazoalkanes 117 (Scheme 54).63 The terminal triple bond in the unsubstituted N-propargylacetanilide decreased the yield to 19%. Excellent stereoselectivity was observed for the CC double bond formation in this reaction. The proposed mechanism includes the oxidative addition to form aryl Pd(II) species 119, from which 5-exo-dig cyclization occurs to afford intermediate 120 (Scheme 55). Its reaction with the in situ formed diazo compound subsequently yields Pd carbene complex 121, followed by carbene insertion to produce allyl

Scheme 54. Pd-Catalyzed Synthesis of 3-Vinylbenzofurans and 3-Vinyl-1-acetylindoles

temperature to 130 °C. The reaction involves the domino synthesis of diarylacetylenes 112 through cross-coupling with triarylbismuth reagents followed by Larock annulations with 2halobenzaldehyde. 2.2.2. Synthesis of Benzofuran Derivatives. Arcadi, Fabrizi, et al. reported Pd-catalyzed domino intramolecular 5906


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Scheme 55. Plausible Mechanism of Pd-Catalyzed 3Vinylbenzofurans and 3-Vinyl-1-acetylindoles Synthesis via Domino Carbocyclization/Carbene Insertion

Scheme 58. Proposed Catalytic Cycle for Larock Heteroannulation

(Scheme 56).64 The reaction of stannanes occurred in a benzene solution at 115 °C; aryl boronic acids required the addition of K3PO4 in a mixture of 2-methyltetrahydrofuran/ water (w/w 98/2) at 130 °C. 2.2.4. Synthesis of Indole and Quinoline Derivatives. The Pd-catalyzed heteroannulation reaction to synthesize indoles from disubstituted alkynes and 2-iodoarene-1-amines was first developed by Richard C. Larock in 199165 and was subsequently named after him. Over the past quarter of a century a number of reviews on Larock synthesis (e.g., Larock’s review66 or the aforementioned recent review15) have appeared. Therefore, we restrict our discussion here to recent works that were not included in these reviews. Chuawong et al. studied the regioselectivity of the Larock heteroannulation for the synthesis of unsymmetrical 1-phenyl2-aryl-substituted phenyl acetylenes 125 in relation to the electronic effects of the substituents (Scheme 57).67 The authors showed that aryl phenyl acetylenes 125 bearing electron-withdrawing groups formed 2,3-diarylindoles 126a with substituted phenyl moieties at the 2 position as major products, while those with electron-donating substituents led preferentially to products 126b with substituted phenyl moieties at the 3 position. The regioisomeric product ratios exhibit an excellent correlation with the corresponding Hammett σ-constants. This fact is in a good agreement with the proposed mechanism of the reaction, wherein the irreversible carbopalladation is the regioselectivity-limiting step (Scheme 58). DFT calculations verified that the activation energy barriers for carbopalladation governed the regioselectivity. Zhang, Wang, et al. used the Larock synthesis as one of the steps in the above-mentioned domino approach to synthesize 3-vinyl-1-acetylindoles 118 (X = AcN) (See Scheme 54).63 Verma et al. reported an efficient Pd-catalyzed cascade synthesis of pyrrolo[3,2,1-d,e]acridones 130 and 131 from iodopyranoquinolines 127 and symmetrical 128 and unsymmetrical 129 internal alkynes, respectively (Scheme 59).68

Scheme 56. Pd-Catalyzed Synthesis of Benzothiolane and Isothiochromane Derivatives

Pd(II) intermediate 122 and (after the haptotropic rearrangement and β-elimination) the title 5-membered heterocycle. 2.2.3. Synthesis of Thiaheterocyclic Derivatives. Gulea, Suffert, et al. described Pd-catalyzed domino intramolecular carbocyclization/Stille or Suzuki coupling of ortho-bromosubstituted phenyl or benzyl sulfides 123 bearing an alkynyl group to synthesize benzothiolanes or isothiochromanes 124

Scheme 57. Larock Synthesis using Unsymmetrical 1-Phenyl-2-(Substituted Phenyl) Acetylenes as Substrates

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Scheme 59. Pd-Catalyzed Cascade Synthesis of Pyrrolo[3,2,1-d,e]acridones

Surprisingly, this Pd-catalyzed reaction is a phosphine-free process, which is rare when Pd(OAc)2 is used as a catalyst. In contrast to the aforementioned reaction with ortho-iodoaniline (Scheme 57),67 unsymmetrical diaryl alkynes 129 reacted with iodopyranoquinolines 127 nonregioselectively, while TMS-(4tolyl)-acetylene 132 yielded only one regioisomer 133 (for each substrate studied) (Scheme 59). Iodopyranopyridine 134 formed pyrroloquinolone 135 under the same conditions (Scheme 60). On the basis of their previous report,69 the authors proposed the mechanism of this complex cascade process that included vinyl Pd intermediate 136 (Scheme 61). Ma and Zhu described a synthesis of N-sulfonated indoles 139 from N-sulfonated 2-iodoanilines 137 and substituted propargyl bromides 138 catalyzed by a Pd(II) phosphine complex (Scheme 62).70 The authors did not propose a catalytic cycle but assumed the formation of aryl allenes 140 as intermediates (similar to intermediate 106 in Scheme 50, section 2.2.1). Jia et al. performed the intramolecular Larock indolization of substituted 2-iodoanilines 141 to obtain 3,4-fused tricyclic indole systems 142 (Scheme 63).71 2-Bromoaniline 143 can be used instead of the corresponding iodo derivative, but it is necessary to add dppe or MePhos as a ligand in this case to obtain a yield of 95% for 144. The authors later reported these results more fully, including the synthesis of 3,5-fused tricyclic indole systems 146 from substrates 145 under the same conditions (Scheme 64).72

Scheme 60. Pd-Catalyzed Cascade Synthesis of Pyrrolo[3,2,1-ij]quinolone

Scheme 61. Proposed Mechanism for Reaction of Iodopyranoquinolines and Internal Alkynes

Scheme 62. Pd-Catalyzed Synthesis of N-Sulfonated Indoles from N-Sulfonated 2-Iodoanilines and Substituted Propargyl Bromides

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Scheme 63. Pd-Catalyzed Synthesis of 3,4-Fused Tricyclic Indole Systems through the Intramolecular Larock Heteroannulation

Scheme 64. Pd-Catalyzed Synthesis of 3,5-Fused Tricyclic Indole Systems through Intramolecular Larock Heteroannulation

Scheme 66. Pd-Catalyzed Synthesis of (E)-4-(Isobenzofuran1(3H)-ylidene)-1,2,3,4-Tetrahydroisoquinolines and Aze/ Oxepinoindoles

Dzhemilev et al. reported a one-step procedure for the synthesis of quinolines 148 and 149 from 2-iodoaniline and N,N-dimethyl-substituted propargyl amines 147 (Scheme 65).73 Quinolines 148 were formed via intermediate indoles 150, but 149 through azepinic intermediates 151. Perumal et al. developed a synthesis of heterocycles 153 and 154 based on Pd-catalyzed cyclization of (2-bromobenzyl)(3arylpropargyl) amines or ethers 152 (Scheme 66).74 The size of the cycle formed depended on the function at the 2 position of the aryl ring of the 3-arylpropargyl fragment. Precursors containing CR2OH groups yielded quinoline products 153 through 6-exo-dig-cyclization of aryl palladium intermediates 155 (Scheme 67). Substrates 152 bearing the NH function in

the arylpropargylic fragment formed seven-membered heterocycles 154 (Scheme 66). The authors explained this difference by the intramolecular nucleophilic attack of group NH on the Pd-coordinated triple bond of the aryl palladium intermediate 156 (Scheme 68).

Scheme 65. Pd-Catalyzed One-Step Procedure for the Synthesis of Quinolines

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Scheme 67. Plausible Mechanism of the Pd-Catalyzed Synthesis of (E)-4-(Isobenzofuran-1(3H)-ylidene)-1,2,3,4Tetrahydroisoquinolines

Scheme 70. Pt-Catalyzed Hydroarylation of Acetylene Carboxylic Acids and Their Esters with Pyrroles and Furans

Scheme 71. Pt-Catalyzed Hydroarylation of Ethyl Propynoates with 2,5-Substituted Pyrroles and Furans

Scheme 68. Plausible Mechanism of the Pd-Catalyzed Synthesis of Aze/Oxepinoindoles

Scheme 72. Pt-Catalyzed Hydroarylation of Acetylene Carboxylic Acids with Phenols, Leading to Coumarins

3. PLATINUM-CATALYZED REACTIONS 3.1. Activation of C−H Bonds

3.1.1. Synthesis of Substituted Alkenes. Similarly to the Pd-catalyzed Fujiwara reaction, Kitamura and Oyamada75−77 reported on the hydroarylation of terminal and internal alkynes, catalyzed by Pt(II) in the presence of trifluoracetic acid. Hydroarylation of propynoic acids and their derivatives by arenes bearing a range of donor substituents results in the formation of cinnamates 157 in good to excellent yields (up to 95%) along with bis-substituted products 158 in low yields (to 16%) (Scheme 69).75 This reaction proceeds more selectively (i.e., without the formation of buta-1,3-diene-1,3-dicarboxylates) than those catalyzed by palladium(II) (see section 2.2.1). Higher reaction temperatures lead to increasing conversion of alkyl propynoates and are accompanied by the hydrolysis of esters 157 and 158 to the corresponding acids. Heteroarenes react with alkyl alkynoates under similar conditions forming products of double hydroarylation 160 in

good yields (50−90%) (Scheme 70) and monohydroarylated products 159 in low yields.77 The monoarylation adduct 159 is formed exclusively in the case of the reaction of N-methylpyrrole (X = NMe, 71%), probably due to steric reasons, and in the reaction with diethyl acetylenedicarboxylate (R1 = CO2Et, 43%), due to electronic factors (i.e., because of the formation of a relatively unreactive electron-deficient alkene). Highly reactive ethyl propynoates react with pyrrole with poor selectivity, giving two 2- and 3substituted regioisomers of the monoadduct 159. The reaction with 2-methylfuran exclusively gives compounds 160. When 2,5-substituted pyrrole and furan are applied, monoadducts E/ Z-161 are obtained as major products (Scheme 71). The double-adduct 160 can be obtained in the reaction with 2,5dimethylfuran when the reaction is carried out at elevated temperature (50 °C).

Scheme 69. Pt-Catalyzed Hydroarylation of Propynoic Acids and Their Esters

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Scheme 73. Plausible Mechanism of Pt-Catalyzed Alkenylation of Acetylene Carboxylic Acids and Their Derivatives

Scheme 75. Plausible Mechanism of Pt-Catalyzed Cyclization

Acetylene carboxylic acids and their ethyl esters react with substituted phenols giving coumarins 162 (Scheme 72, path A).76 These reactions proceed via alkenylation of the phenols followed by the intramolecular cyclization of ortho-hydroxysubstituted cinnamic acids. Dihydrocoumarins 163 (Scheme 72, path B) were also obtained as products of the reaction with alkyl-substituted phenols and 4-bromophenol. Acids with R1 = Ph, n-C5H11 react selectively to give the corresponding coumarins 162 (Scheme 72, Path A). The authors75−77 proposed the following mechanism of these processes: all reactions are catalyzed by platinum(II), and addition of AgOTf improves the reaction yields. The active platinum catalyst is generated from the reaction of the platinum precursor and silver salt, which allows transformation of PtCl2 or K2PtCl4 into a soluble form. An alkynoic acid derivative is activated by the coordination to the active Pt(II) moiety (Scheme 73, A), followed by attack of the arene or heteroarene (B). Alkenylation proceeds via aromatic electrophilic substitution (B and C). The further transformations of alkenylation adducts give products of the cyclization or second addition to the double bond formed. Alkenylation gives mainly products of anti-addition of hydrogen and aryl group to triple bond. 3.1.2. Synthesis of Carbocycles. Platinum-catalyzed intramolecular hydroarylation of ethyl (E)-2-ethynyl/alkynyl cinnamates proceeds selectively with formation of functionalized naphthalenes 164 (Scheme 74).78 Lee et al.78 examined several catalysts using (E)-2-ethynyl cynnamate and determined that Ag(I)/Au(III)-, Pt(0)-, and Pt(II)-based systems demonstrated either no or low-to-moderate catalytic activity, while Pt(IV) in the form of PtCl4 exhibited the greatest activity. The PtCl4-based catalytic system was applied to a wide range of

substrates (Scheme 74), and it was observed that varying the substituents on the phenyl ring did not diminish the efficiency of the reaction. Aryl- and alkyl enynes can also be cyclized under these conditions, while the reaction time is slightly increased (from 30 min for terminal enynes to 2−5 h for substituted examples). A plausible pathway for the cyclization starts with the activation of an alkynyl group by Pt(IV) (Scheme 75 A), followed by 6-endo cyclization to afford the aryl platinum intermediate (B). Aromatization (C) with subsequent protonation (D) provides substituted naphthalenes 164. An additional experiment involving cyclization of (E)-2-ethynyl cynnamate in the presence of D2O (10 mol %) provided 164 with 57% d-incorporation at C3, indicating that the reaction can proceed through the activation of the alkyne by the Pt species (Scheme 75).78 Alcarazo et al.79 applied platinum(II) phosphine complex 165 as a precatalyst in the transformation of ortho-biarylsubstituted alkynes into polycyclic homo- and heteroarenes 166−168 (Scheme 76). Products 166, 167, and 168 were obtained in a 80−100:20−0:0−10 molar ratio, respectively. Complex 165 demonstrated a greater catalytic activity than conventional PtCl2/PR3-based systems (R = Ph, OPh, C6F5) due to the strong π-acceptor character of phosphine ligand [P{C3(NMe2)2}]3+ in the former and, as a consequence, increased π-acidity of Pt in the complex. The addition of an Ag(I) salt to the catalytic system is required for abstraction of one of the chloride ligands, and the highest efficiency was demonstrated with the addition of Ag[CB11H6Cl6], bearing a weakly coordinating anion.

Scheme 74. Pt-Catalyzed Intramolecular Alkenylation of Ethyl (E)-2-Alkynylcinnamates

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Scheme 76. Pt-Catalyzed Synthesis of Polycyclic Homo- and Heteroarenes

the alkyne by the platinum center toward intramolecular attack (Scheme 77, A and B).79 The subsequent opening of the cyclopropane ring (C) and two 1,2-H shifts (D and E) led to pentahelicene. Dimethylsila[7]helicene 169 was synthesized via PtCl2catalyzed double cyclization (Scheme 78).80 This compound exhibits blue luminescence with a quantum yield of 17%. Substituted [5]helicenes were obtained by intramolecular cyclization of alkynes (Scheme 79).81 The reaction led to three products: [5]helicenes 170 and azulene-fused helicenes 171 and 172 (Scheme 79). Yields of side-products 171 and 172 were greater when the synthesis was performed in toluene (2 h, 27 and 5%, respectively) but fell to 7−8% and 0−2% when MeCN (12 h) or MeCN/toluene (7 h, 1:1 v/v) were used as solvents. 3.1.3. Synthesis of Benzopyran Derivatives. Sames et al.82,83 reported the Pt(IV)-catalyzed intramolecular cyclization of propargyl ethers and alkyl alkynoates providing 6-endo products 173 (Scheme 80). PtCl4 exhibits a greater catalytic activity than PtCl2 due to its higher electrophilicity and greater solubility. This reaction can be extended to functionalized substrates, phenols, protected amines, halides and esters, as well as both substituted and terminal alkynes. Electron-releasing groups at the aromatic ring generally increase the reactivity of these substrates; at least one electron-donating group at the aromatic ring is required for the reaction. This strategy was applied for the key step of the PtCl2catalyzed cyclization of an alkyne to form 174 in the six-step synthesis of (±)-deguelin 175 (68%) (Scheme 81), an efficient chemopreventive agent.84 Two catalytic systems, Au(PPh3)Cl/AgSbF6 and PtCl4, were examined in the cyclization of alkynes, leading to complex coumarins 176 in good-to-excellent yields (50−98%) (Scheme 82).85 Au-based systems demonstrated greater activity, and the reaction can be performed at room temperature for variously substituted acetylenic substrates (yields 80−98%). PtCl4 exhibited lower activity (reaction at 80 °C, yields 50−91%). Platinum systems revealed a higher regioselectivity in some examples and allowed reaction with indole substrates lacking substituents at the C3 position, which was unsuccessful with the Au system. This synthetic method was applied for the preparation of a range of neuroimaging agents, FFN511 and PV139 (Figure 1).85

Scheme 77. Pt-Catalyzed Mechanism of Intramolecular Cyclization

Scheme 78. Pt-Catalyzed Synthesis of Dimethylsila[7]Helicene

The scope of the catalytic system was examined on substrates bearing different functional groups, and compounds 166, viz. substituted phenanthrenes, benzophenanthrenes, benzotriphenylenes, substituted benzofurans, and thiophenes, were obtained in good-to-excellent yields.79 DFT calculations, kinetic studies, and deuterium-labeling experiments allowed the study of the reaction mechanism and demonstrated that the reaction proceeded via the activation of 5912


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Scheme 79. Pt-Catalyzed Synthesis of [5]Helicenes

Scheme 80. Pt-Catalyzed Synthesis of Chromenes and Coumarins

To verify the mechanism, the authors86 performed 1H and P MNR monitoring of the stoichiometric reaction between [Pt(Ph) (SPh) (PPh3)2] and alkyne PhCCCO2Et, which confirmed the formation of the product Ph(PhS)CC(Ph)CO2Et, along with the complex [Pt{PhCCCO2Et}(PPh3)2]. In addition, it was demonstrated that the complex [(PPh3)2(pClC6H4S)PtCl] reacted with the alkyne PhCCR (R = CO2Et, CH2OMe) providing the platinum complex [PtCl{C(R1)C(Ph)SC6H4Cl-p}(PPh3)2] bearing a Z-configured vinyl ligand. Both the stereo- and regioselectivity of these reactions confirmed the reaction mechanism postulated (Scheme 87). Thus, the inter- and intramolecular Pt(II)- and Pt(IV)catalyzed alkenylation of (hetero)arenes with alkynes allows the synthesis of a range of alkenes, condensed arenes, and heterohelicenes.

3.1.4. Synthesis of Quinoline Derivatives. Similarly to propargyl esters, propargyl amines undergo PtCl4-catalyzed cyclization, affording dihydroquinolines 177 (Scheme 83).82 3.1.5. Formation of Other Cyclic Systems. N-Alkynylsubstituted pyrroles can be cyclized into dihydroindolizines 178 and 179 via the 6-exo/endo mode depending on the length of their side chain (Scheme 84).82 Fur-2-ylmethyl propargyl ethers yielded either exo-cyclization product 180 (R = CO2Me) or 7-membered oxacycle 181 (R = Me) (Scheme 85), presumably via a tandem rearrangement from the 7-endo cyclization product formed initially.82

4. RHODIUM-CATALYZED REACTIONS The Rh-catalyzed C−H bond activation of arenes was first reported as an example of hydroarylation of internal alkynes in the presence of a metal catalyst (Scheme 88).87 This process occurred in the presence of 1 mol % of Rh4(CO)12 under very harsh conditions [220 °C, CO (>40 bar), 7 h] and afforded only moderate yields of triarylethenes (24−49%) with no regioselectivity. Obviously, this was the reason that interest in rhodium-catalyzed aryl C−H bond activation was lost for almost two decades. There are fewer than ten references of the use of rhodium catalysts in recent reviews on transition-metalcatalyzed hydroarylation of alkynes.14,15 However, in recent years there has been a rapid increase in the number of publications on this topic. This is due to the fact that several functional groups are capable of greatly facilitating the rhodium-catalyzed activation of aryl C−H bonds in the ortho-position. These functional groups include carbonyl (and carbonyl derivatives such as oximes, imines, hydrazones, and nitrones), carboxyl (and carboxyl derivatives such as amides, hydroxamic acids, and amideoximes), and amino, 2-pyridyl, 1-

31

3.2. Activation of C−C Bonds

One work described cis-arylthiolation of unsymmetrical internal alkynes with thioesters ArC(O)SAr1, catalyzed by Pt(PPh3)4, leading to alkenes 182 (Scheme 86).86 The proposed mechanism features initial oxidative addition of ArC(O)SAr1 to the Pt(0) center (Scheme 87, A), followed by CO elimination (B), migratory insertion of the alkyne into the Pt−S bond (C), and reductive elimination of the product (D).

Scheme 81. Pt-Catalyzed Alkyne Cyclization in Synthesis of (±)-Deguelin

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Scheme 82. Pt-Catalyzed Synthesis of Coumarins

Scheme 85. Pt-Catalyzed Cyclization of Fur-2-ylmethyl Propargyl Ethers

Scheme 86. Pt-Catalyzed Arylthiolation of Internal Alkynes

Figure 1. Synthesis of Fluorescent False Neurotransmitters.

Scheme 83. Pt-Catalyzed Synthesis of Dihydroquinolines

Scheme 87. Mechanism of Pt-Catalyzed Arylthiolation of Internal Alkynes

Scheme 84. Pt-Catalyzed Cyclization of N-AlkynylSubstituted Pyrroles

Scheme 88. First Example of Rh-Catalyzed Arene Alkenylation with Internal Alkynes

benzotriazolyl, sulfonyl, and other similar chelating substituents. This promotion has allowed regioselective reactions under milder conditions and without high pressure. There are two general mechanisms of this reaction. One involves a preliminary interaction of an activating functional group with a rhodium(I) catalyst (added to the reaction mixture or formed in situ from a Rh(III) species), followed by the oxidative addition of the metal

onto the ortho-C−H bond, generating the σ-aryl rhodium(III) complex 183 (Scheme 89). The latter reacts with an alkyne yielding the intermediate 184 (protonated or deprotonated), 5914


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Scheme 89. Proposed Mechanism of Rh(I)-Catalyzed Alkenylation of ortho-C−H Bonds of Functionalized Arenes with Internal Alkynes

Scheme 92. Proposed Catalytic Cycle for the Synthesis of Vinyl Heteroarenes

Scheme 90. Proposed Mechanism of Rh(III)-Catalyzed Alkenylation/Cyclization of Functionalized Arenes with Internal Alkynes

Scheme 93. Rh-Catalyzed Reaction of 1Phenylbenzotriazoles and Internal Alkynes

Scheme 94. Rh-Catalyzed Alkenylation of Phenylphosphine Sulfides

Scheme 91. Rh-Catalyzed Reaction of 2-(Pyrid-2yl)heteroarenes and Internal Alkynes

Scheme 95. Rh-Catalyzed Alkenylation of Picolinamides

Scheme 96. Rh-Catalyzed Alkenylation of Sulfones which is converted into a reaction product (a vinyl arene) and a Rh(I) species. This alkenylation proceeds in syn-addtion of hydrogen and aryl moiety to acetylene bond. A second alkenylation pathway was found to occur if the assisting functional group does not only chelate the metal center but can be included in the cyclic moiety of the formed product (annulation reactions). The reaction is catalyzed by a Rh(III) species, usually [Cp*RhCl2]2 or a related species. However, the role of the anionic ligands is important. As a rule, the use of [Cp*RhCl2]2 requires the presence of AgSbF6 in the reaction mixture to form Cp*Rh(SbF6)2 in situ. Also, acetates

or triflates accelerate the process. Bis(carboxylate) complexes are presumably the active catalytic species, usually generated in 5915


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Scheme 97. Rh-Catalyzed Alkenylation of Sulfoxides

Scheme 99. Rh(III)-Catalyzed Reaction of Phenone Derivatives and Internal Alkynes

situ from [Cp*RhCl2]2 by noncoordinating silver salts and/or carboxylate additives. The role of these carboxylate ligands is to facilitate C−H activation.88−90 The mechanism of Rh(III)catalyzed alkenylation of arenes differs from the abovementioned Rh(I)-catalyzed process in the C−H bond activation step, which proceeds via electrophilic substitution at the arene by the prechelated Rh(III) metal center and extrusion of HX (Scheme 90). Other differences are the product formation step and the need for an oxidant to recycle the catalyst. Numerous isotope exchange experiments and KIE measurements indicate that in both pathways [i.e., for Rh(I)- and Rh(III)-catalyzed reactions] the C−H bond activation is reversible in the absence of an alkyne and this activation is the rate-limiting step of the catalytic cycle. The alkyne insertion reactions are less well-studied; however, competition experiments between alkynes indicated that diaryl acetylenes are more active than dialkyl acetylenes and electronrich alkynes react more easily than electron-deficient substrates.91 Data on the regioselectivity of the alkyne insertions are abundant. Most authors argue that the insertion is controlled by steric factors and that sterically less demanding alkyne substituents are ultimately positioned adjacent to the aryl moiety in the product. Unsymmetrical diaryl alkynes are inserted unselectively. Concerning the regioselectivity of the reaction for unsymmetrical alkynes RCCR1, when R is an aryl group and R1 is a nonaryl group, alkenylation takes place at acetylene carbon adjacent to R1 (Schemes 89,90,119, and 120). There is only one report92 wherein the authors suggested a mechanism involving attack of the Rh species at the triple bond (yielding the Rh-substituted vinyl cation), followed by an SEAr step; however, no evidence for such a sequence was provided.

Scheme 100. Proposed Catalytic Cycle for Synthesis of Indenol and Fulvene Derivatives

Scheme 98. Rh-Catalyzed Alkenylation of N-Aryl Anthranilic Acids

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Scheme 105. Rh(III)-Catalyzed Reaction of NBenzoyloxazolidin-2-ones with Internal Alkynes

Scheme 101. Rh(III)-Catalyzed Annulation of Formyl Arenes with Internal Alkynes

Scheme 106. Rh(III)-Catalyzed Reaction of N-Sulfonyl Benzophenone Imine with Diphenyl Acetylene Scheme 102. Plausible Mechanism for the Rh(III)-Catalyzed Synthesis of Indenones

Scheme 107. Rh(III)-Catalyzed Reaction of Cyclic NSulfonyl Ketimines with Internal Alkynes

Scheme 103. Rh(III)-Catalyzed Annulation of Phenone Hydrazones with Internal Alkynes

Scheme 104. Rh(III)-Catalyzed Reaction of Aryl Nitrones with Internal Alkynes

Scheme 108. Rh(III)-Catalyzed Reaction of 5-Aryl-1-Tosyl2,3-Dihydro-1H-Pyrroles with Internal Alkynes

catalyzed reactions of functionalized arenes with internal alkynes. The reason for this is the reaction mechanism (Scheme 89), which requires the participation of sufficiently active functional

4.1. Synthesis of Substituted Alkenes

The alkenylation of arenes, which affords linear products and does not proceed by cyclization, is a rather rare case among Rh5917


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Scheme 109. Rh(III)-Catalyzed Reaction of Azomethine Ylides with Internal Alkynes

Scheme 112. Rh(III)-Catalyzed 1:1 Oxidative Annulation of ortho-Substituted Benzoyl Acetonitriles with Diphenylacetylene

Scheme 113. Rh(III)-Catalyzed Synthesis of Naphthothiophenes

Scheme 110. Plausible Mechanism for the Synthesis of 1Indenyl-Pyrazolidones

Scheme 114. Rh(III)-Catalyzed Synthesis of Axially-Chiral Biaryl Compounds

groups at the ortho position to the activated fragment. As a result, the intermediate 184 has the ability to cyclize further, which usually occurs. Nevertheless, some reports describe the preparation of styrene derivatives using this reaction. Jung, Chang, et al. described a synthesis of vinyl and divinyl derivatives 185 and 186, catalyzed by a Rh(I)-NHC complex formed in situ (Scheme 91).93 Hydroarylation of unsymmetrical alkynes such as hex-2-yne resulted in a mixture of regioisomers. Pyrid-2-yl is an assisting chelating group in this process. Studies of the KIE, the isotope exchange, as well as DFT calculations, allowed the authors to propose a catalytic cycle including the reversible formation of the σ-aryl rhodium(III) hydride complex 187 (Scheme 92). Zhou et al. reported a Rh-catalyzed alkenylation of 1phenylbenzotriazoles 188 (Z = CH) and 1-phenyl-7-aza-benzo1,2,3-triazole 188 (Z = N) with internal alkynes via C−H bond activation, leading to substrates 189 (Scheme 93).94 1-(4Methoxyphenyl)-1,2,3-triazole was also alkenylated with 1,2diphenyl acetylene for 50 h providing a yield of 48%. The

inertness of N-phenylindole, high stereoselectivity (cis-hydroarylation of the alkynes), and a study of the inter- and intramolecular KIE led the authors to the same conclusions on the catalytic cycle and the role of the benzotriazole chelating group as shown in Scheme 92. ortho-Alkenylated phenylphosphine sulfides 191 and picolinamides 193 were synthesized via the alkenylation with internal alkynes at the ortho-position of phenylphosphine sulfides 190 (Scheme 94)95 and picolinamides 192 (Scheme 95),96 respectively. An analogous ortho-directing effect is demonstrated by the SO2 group in the alkenylation of alkyl aryl or diaryl sulfones 194 (Scheme 96)97 and by the SO group in alkyl aryl or diaryl sulfoxides 196 (Scheme 97),98 providing alkenyl derivatives 195 and 197, respectively.

Scheme 111. Rh(III)-Catalyzed Synthesis of 4-Azafluorene Compounds

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Scheme 115. Plausible Mechanism for Dual C−H Functionalization/Cycloaromatization of Arylazines with Internal Alkynes

Scheme 117. Rh(III)-Catalyzed 1:2 Oxidative Annulation of Nonactivated Arenes

phenone derivatives 202 and their subsequent coupling with internal alkynes (Scheme 99).100 Unsymmetrically substituted benzophenones were found to react nonregioselectively. Although Cu(OAc)2 is not needed here as a formal oxidant, its stoichiometric presence was found to be essential for good reactivity. The proposed mechanism includes assistance from Cu(OAc)2 during the product formation step of the catalytic cycle (Scheme 100). Cheng et al. reported a Rh(III)-catalyzed annulation of formyl arenes 205 with symmetrical and asymmetrical internal alkynes (1.5 equiv) leading to indenones 206 (Scheme 101).101 The reaction proceeded via in situ formation of acetyl hydrazone 207, which is the chelating group for the metal center in this reaction. Ag2CO3 acts as an oxidant to recycle the active Rh(III) species (Scheme 102). Li et al.102 used the same method to obtain indenes 209 from unsubstituted aceto- and propiophenone hydrazones 208 (Scheme 103) through a pathway similar to that shown in Scheme 102. It is interesting that the use of N,Ndialkylhydrazones as substrates in this reaction affords the alternative products (i.e., isoquinolines) (see section 4.6). Indenones 211 were also synthesized by the Rh(III)catalyzed reaction of aryl nitrones 210 with internal alkynes (Scheme 104).103 Here the nitrones play the role of both substrates and internal oxidants for recycling the catalyst. Electronic effects seems not to be important for the meta

The Rh(I)-catalyzed alkenylation of N-phenyl anthranilic acids 198 in DMF afforded carbazoles 200 as major products via decarboxylation of styryl-Rh intermediates 199 (Scheme 98), while the same reaction in the presence of Rh(III) species in o-xylene yielded isocoumarins 201 (see section 4.3).99 The authors found that different catalytic systems, Rh(I)/ tetraphenyl cyclopentadiene (C5H2Ph4) or Rh(III)Cp, gave different products: 200 and 201, respectively. 4.2. Synthesis of Carbocycles

The formation of a five-membered ring via arene alkenylation requires participation of a neighboring functional group not only for the chelation but also for the cycle construction. Aromatic ketones,100 hydrazones,101,102 nitrones,103 amides,104 N-Ts-imine,105 and arylheterocycles105−108 are effective substrates in this reaction. Glorius et al. described a synthesis of functionalized indenols 203 and fulvenes 204 by the Rh-catalyzed C−H activation of

Scheme 116. Rh(III)-Catalyzed Oxidative 1:1, 1:2, and 1:4 Coupling Reactions of Phenylazoles with Internal Alkynes

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Scheme 118. Rh(III)-Catalyzed Synthesis of Benzofurans

Scheme 119. Rh(III)-Catalyzed 1:2 Oxidative Annulation of Benzoyl Acetonitriles with Internal Alkynes

Scheme 121. Rh(III)-Catalyzed Synthesis of Isochromenes from Tertiary Benzyl Alcohols

Scheme 122. Rh(III)-Catalyzed Synthesis of Isochromenones from Benzoic Acids substituents in the starting nitrones, as nitrones 210 substituted at the 3 position with donor (Me) and acceptor (Br, CF3) groups yielded 6-substituted 1H-inden-1-ones 211. Unsymmetrically substituted acetylenes reacted regioselectively with formation of indenones 211 bearing aryl groups at the 2 position. Shi et al. developed the Rh(III)-catalyzed synthesis of indenones 213 from benzamides and internal alkynes.104 The best results were found when substituted N-benzoyloxazolidin2-ones 212 were used as substrates (Scheme 105). N-Sulfonyl benzophenone imine was found to react with diphenyl acetylene to deliver the [3 + 2] product 214 (Scheme 106).105 Rh(III)-catalyzed reactions of internal alkynes with cyclic Nsulfonyl ketimines 215−217 (Scheme 107)105 and 5-aryl-1-

tosyl-2,3-dihydro-1H-pyrroles 221 (Scheme 108)106 resulted in the formation of spirocyclic sultams 218−220 and spiro[indene-1,2′-pyrrolidines] 222, respectively. Li et al. reported annulative coupling of azomethine ylides 223 with internal alkynes via a Rh(III)-catalyzed C−H activation, leading to compounds 224 (Scheme 109).107 On

Scheme 120. Rh(III)-Catalyzed Reaction of Electron-Deficient Quinones with Internal Alkynes

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Scheme 126. Rh(III)-Catalyzed Synthesis of Indoles from NAcetyl Anilines with Internal Alkynes

Scheme 123. Rh(III)-Catalyzed Synthesis of (4Benzylidene)isochroman-1-ones from 1-Benzoylpyrrolidines

Scheme 127. Rh(III)-Catalyzed Synthesis of Benzoindole Derivatives

Scheme 124. Rh(III)-Catalyzed Intramolecular Syntheses of Chromans from Alkyne Tethered Acetanilides

the basis of studies of H/D exchange, the kH/kD value, and the results of competition reactions, the authors proposed a mechanism for this reaction (Scheme 110) including the reversible cyclometalation of 223 to six-membered rhodacyclic intermediate 225, followed by the coordination and regioselective insertion of the alkyne to generate eight-membered rhodacycle 226. The final product 224 was generated upon protonolysis of the Rh−N bond in the intermediate 227. An intramolecular Rh(III)-catalyzed ortho-alkenylation of the aryl moiety of 3-alkynyl-2-arylpyridines 228 yielded 4azafluorenes 229 (Scheme 111).108 The reaction proceeded with no (E/Z)-stereoselectivity. An unusual feature of this alkenylation/cyclization reaction is that only one of the two alkyne carbon atoms is involved in the formation of the carbocycle. The authors showed that the coordination of the metal center with the nitrogen atom (i.e., not π-coordination of the Rh fragment with the alkyne moiety) assists the aryl C−H bond activation via the formation of the aryl-Rh intermediate 230 (Scheme 111). A six-membered ring synthesized via the Rh-catalyzed alkenylation of an arene can include one109−111 or two112−114

Scheme 128. Rh(III)-Catalyzed Redox-Neutral C−H Activation/Cyclization of 2-Acetyl-1-Arylhydrazines with Internal Alkynes

alkyne molecules. Thus, Wang et al. reported that Rh(III)catalyzed oxidative equimolar annulation of ortho-substituted benzoyl acetonitriles with diphenylacetylene afforded naphthols 231 (Scheme 112).109 Using non ortho-substituted benzoyl acetonitriles and a 2-fold excess of the internal alkynes, the authors obtained the 1:2 coupling products, naphtho[1,8bc]pyrans 251 (see section 4.3, Scheme 119).

Scheme 125. Rh(III)-Catalyzed Intramolecular Synthesis of 4-Halo-3-Chromenes or 4-(Halomethylene)Chromanes

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Scheme 129. Rh(III)-Catalyzed Synthesis of N-Acylamino Indoles from 2-Acyl-1-Arylhydrazines and Internal Alkynes

Scheme 132. Rh(III)-Catalyzed Synthesis of Unprotected Indoles through a Triazene-Directed C−H Annulation

the Rh(I) species after reductive elimination of the product. The role of the catalytic amount of Cs2CO3 is unclear; however, the authors reported that its addition significantly enhanced the reaction efficiency. Recently, the authors extended the range of 3-aryl thiazoles used.111 The same procedure was also reported for a similar oxidative annulation of other aryl-substituted heterocycles (3-phenylbenzoxazole, 2-methyl-4-phenylthiazole, 2,4-diphenylthiazole, 2-methyl-4-phenyloxazole, and 2,4-diphenyloxazole) in yields of 44−98%. The regioisomers that cannot form chelate-assisted aryl-Rh complexes (2-phenylbenzoxazole, 2-methyl-5-phenylthiazole, 2,5-diphenylthiazole, 2-methyl-5phenyloxazole, and 2,5-diphenyloxazole) were found to be inert under the same conditions. You and Zheng reported a synthesis of axially chiral biaryl compounds 235 through the Rh(III)-catalyzed, chelationassisted dual C−H functionalization/cycloaromatization reaction of 1-arylisoquinolines or 2-arylpyridines 234 with internal alkynes (2.2 equiv) (Scheme 114).112 The key feature of substrates 234 is the absence of a C−H bond in the orthoposition to the nitrogen in the heterocyclic moiety, precluding the formation of 1:1 cyclization products analogous to 233. The authors proposed a catalytic cycle involving two sequential electrophilic substitution/alkyne insertion steps through intermediates 236−239 (Scheme 115). This reaction can afford not only 1:2 but also 1:4 cyclization products. Satoh, Miura, et al. described Rh(III)-catalyzed oxidative 1:1, 1:2, and 1:4 coupling reactions of phenylazoles 240 with internal alkynes (Scheme 116).113 The product distribution depends on the reagent ratio and the reaction conditions. The treatment of an excess of 240 (2 equiv) with alkynes (1 equiv) in o-xylene in the presence of a base gives significant amounts of 1:1 coupling products, pyrazolo[1,5a]quinolines 241. When 240 (1 equiv) was treated with alkynes (1−2 equiv) in DMF, 1,2,3,4-tetrasubstituted 1-(naphthalen-5yl)-azoles, or -azine 242 were formed as 1:2 coupling products. Use of larger amounts of alkynes (4-fold excess) afforded 1,2,3,4,5,6,7,8-octasubstituted (anthracen-9-yl) azoles 243 as the 1:4 coupling products. Substrates bearing electron-withdrawing groups underwent the coupling more smoothly. This is consistent with a mechanism involving proton abstraction by the Rh(III) species as the C−H bond activation step (Scheme 115). Cramer and Pham described a similar double C−H activation/cyclization reaction of arenes having no such chelating groups (Scheme 117).114 Harsh reaction conditions (sealed tube, MW, 160 °C, 3 h) and a large excess of the arene in the reaction mixture (2.5−10 mol of arene/1 mol of symmetrical alkyne) allowed the activation of C−H bonds in a range of arenes without ortho-functional group assistance. The reaction with internal alkynes resulted in annulative con-

Scheme 130. Plausible Mechanism for Rh(III)-Catalyzed Annulation 2-Acyl-1-Arylhydrazines

Scheme 131. Rh(III)-Catalyzed Synthesis of Indoles from NAlkyl-N-Aryl Hydrazones and Internal Alkynes

Satoh, Miura, et al. described the Rh(III)-catalyzed reaction of internal alkynes (1 equiv) with an excess of 3-phenylthiophenes 232 (2 equiv), affording the products of the oxidative annulations, viz., variously substituted naphthothiophene derivatives 233 (Scheme 113).110 Cu(OAc)2 reoxidized 5922


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Scheme 133. Rh(III)-Catalyzed Cascade Synthesis of Indolo[2,1-a]Isoquinolines from Aryl Triazenes and Diaryl Alkynes

Scheme 134. Rh(III)-Catalyzed Synthesis of Indoles through a Nitroso-Directed C−H Annulation

Scheme 136. Rh(III)-Catalyzed Intramolecular Syntheses of 3,4-Fused Tricyclic Indoles from Alkyne-Tethered Acetanilides (Method of Xu, Liu et al.121)

Scheme 137. Plausible Mechanism for Rh(III)-Catalyzed Intramolecular Annulation of Alkyne-Tethered Acetanilides

Scheme 135. Proposed Mechanism for Synthesis of Indoles from Nitroso Derivatives

densation to give the homologated arenes 244 in yields of 40− 85%. A substituent, X, was placed at the 5 position of the 1,2,3,4-tetrasubstituted naphthalene, excluding F and CH2OCH2, which gave mixtures of the isomers. 4.3. Synthesis of Oxaheterocycles

To synthesize benzofurans by Rh-catalyzed alkenylation of substituted arenes with internal alkynes, the aromatic substrate has to have an ortho-hydroxyl group with respect to the 5923


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Scheme 138. Rh(III)-Catalyzed Intramolecular Syntheses of 3,4-Fused Tricyclic Indoles from Alkyne-Tethered Acetanilides (Method Jia and Tao131)

Scheme 142. Typical Mechanism for the Rh(III)-Catalyzed Synthesis of Quinolines

Scheme 143. Rh(III)-Catalyzed Synthesis of Aza-Fused Polycyclic Quinolines

Scheme 139. Rh(III)-Catalyzed Intramolecular Syntheses of 3,4-Fused Tricyclic N-Alkyl Indoles from Alkyne-Tethered N-Nitroso-N-Methylanilines

Scheme 140. Rh(III)-Catalyzed Oxidative Annulation of (1Naphthylmethyl)amine with Dialkylacetylenes Scheme 144. Rh(III)-Catalyzed Synthesis of Aza-Fused Polycyclic Quinolines

Scheme 141. Rearrangement of a Vinyl-Rh Intermediate in the Synthesis of 292

followed by alkyne insertion and cyclization of the formed vinyl-Rh intermediate 247. The fused heterocycles 249 and 250 were synthesized in the same manner. Fused six-membered oxaheterocycles can be formed via alkenylation of substrates having C−O bonds at the orthoposition to the activated C−H bond, viz., 1-naphthols,109 1,4-

activated C−H bond. For example, Cheng et al. reported the Rh(III)-catalyzed synthesis of substituted benzofurans 248 by dual direction toward the sterically hindered ortho-C−H bond of phenols 245 bearing an additional chelating group C NOMe (Scheme 118).115 The first step of the reaction is the C−H bond activation, yielding pincer-like intermediate 246 5924


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Scheme 145. Rh(III)/Cu(II)-Catalyzed Cascade Reaction of 1-Aryl Tetrazoles with Internal Alkynes

Scheme 149. Rh(III)-Catalyzed Synthesis of Benzoquinolines

Scheme 146. Rh(III)-Catalyzed Annulation of Imidazolium Salts

Scheme 150. Metal-Charge-Dependent Concurrent Syntheses of Benzoindoles and Benzoquinolines

Scheme 147. Rh(III)-Catalyzed Annulation of N-Carbamoyl Indolines

Scheme 151. Rh(III)-Catalyzed Intramolecular Synthesis of N-(Arenesulfonyl)-4-Halo-1,2-Dihydroquinolines

Scheme 148. Plausible Mechanism for the Rh(III)-Catalyzed Synthesis of Pyrrolinoquinolinones

Scheme 152. Rh(III)-Catalyzed Oxidative Annulation of Aminomethyl Arenes

annulation products (yields of 47% and 23%, respectively), but benzoyl acetone was inert under these conditions. The reaction is a cascade process. The first step of the reaction proceeds through sequential cleavage of C(sp2)−H/C(sp3)−H bonds and annulation with an alkyne, leading to 1-naphthols 231 as intermediate products (see section 4.2, Scheme 112). Subsequently, 231 reacts with the alkyne by cleavage of C(sp2)−H/O−H bonds, affording the 1:2 coupling products

naphthoquinones (which can tautomerize to the corresponding 1-naphthols),116 tertiary benzyl alcohols,117,118 and substituted benzoic acids.99,119 Wang et al. developed a synthesis of substituted naphtho[1,8bc]pyrans 251 by Rh(III)-catalyzed oxidative annulation of benzoyl acetonitriles with internal alkynes (Scheme 119).109 Ethyl benzoyl acetate and 2-benzoyl nitroethane led to similar 5925


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which are catalyzed by [Cp*Rh(MeCN)3][SbF6]2 (4 mol %)117 or [Cp′RhCl2]2 (2.5−5 mol %; Cp′ = 1,3-(CO2Et)2-2,4,5-Me3cyclopentadienyl).118 The latter Rh(III) species bearing an electron-deficient cyclopentadienyl ligand provided the products, isochromenes 256, in good to high yields under very mild conditions (air, acetone, RT, 72 h) (Scheme 121). Reoxidation of the Rh catalyst in this protocol is performed by air oxygen and mediated with the Cu(II)/Cu(I) redox system. As mentioned above (see section 4.1, Scheme 98), the Rh(III)-catalyzed alkenylation of N-phenyl anthranilic acids 198 afforded isocoumarins 201.99 Later, the authors extended this reaction to a range of other electron-donating groups in substituted benzoic acids 257 giving isochromenones 258 (Scheme 122).119 The best yields were obtained if symmetrical diarylacetylenes were used as substrates. PhCCMe furnished a mixture of the regioisomers, and PhCCCMe2OH or nPrCCPr-n required the use of Ag2CO3 (1 equiv) instead of Cu(OAc)2. The reaction begins from the formation of a Rh(III) salt with the substituted benzoic acid followed with intramolecular activation of the neighboring C−H bond. Another approach to the isochromanone moiety was demonstated by Li et al.120 The Rh(III)-catalyzed reaction of 1-benzoylpyrrolidines 259 with propargyl alcohols 260 afforded (4-benzylidene)isochroman-1-ones 261, which includes only one of the triple bond carbon atoms in the formed 6-membered O-heterocycle (Scheme 123). Synthesis of enantioenriched lactones 263 was achieved in good yields (75−92%) and with high ee (94−98%) when optically pure propargyl alcohols 262 were coupled. H/D exchange studies and experiments with Dlabeled 1-benzoylpyrrolidine showed that the C−H activation is reversible in the absence of a propargyl alcohol and irreversible when the alkyne is present. This fact, along with the intermolecular kH/kD value of 3.0, revealed that the aryl C−H cleavage is involved in the rate-limiting step of the catalytic cycle. Xu, Liu, et al. developed the Rh(III)-catalyzed intramolecular syntheses of chromanes 265 from alkyne-tethered acetanilides 264 via aryl C−H bond activation (Scheme 124).121 3,4-Fused tricyclic indoles 266 formed as small impurities, which became the main products in the absence of t-BuCO2H (see section 4.4, Scheme 136). Urabe et al. reported the synthesis of 4-halo-3-chromenes 268 or 4-(halomethylene)chromanes 269 via the regioselective intramolecular hydroarylation of haloacetylenes 267 (n = 1 or 2, respectively) with [Rh2(CF3CO2)4] as a catalyst (Scheme 125).92 Surprisingly, the authors suggested a mechanism involving the Rh species attacking the triple bond (yielding the Rh-substituted vinyl cation) followed by an SEAr step, but they gave no evidence of such a sequence.

Scheme 153. Plausible Mechanism for Rh(III)-Catalyzed Oxidative Annulation of Aminomethyl Arenes

Scheme 154. Rh(III)-Catalyzed Annulation of Phenone Imines

Scheme 155. Rh(III)-Catalyzed One-Pot Synthesis of Isoquinolines and Fused Pyridine Heterocycles using Aryl Ketones

4.4. Synthesis of Indole Derivatives

A range of Rh(III)-catalyzed indole syntheses based on the alkenylation of aryl C−H bonds with internal alkynes were developed over the past few years. Acetanilides,122 arylcarbamates,123 aryl hydrazine derivatives,124−126 triazenes,127,128 and N-nitrosoanilines129,130 are suitable substrates for these reactions. In addition, the C−H bond activation in these reactions is accompanied by the cleavage of N−H or N−N bonds. The typical catalytic cycle includes the reversible electrophilic substitution of a proton in the ortho-position to the directing group with a chelated Rh(III) cationic species, yielding the aryl-Rh complex (ChG = NHZ) (Scheme 90). The coordination and insertion of the alkyne followed by the

251. Thereby, the alkynyl carbon atom of the original alkyne bearing an aryl group, is ultimately bound to oxygen in the product. Zhang et al. developed a Rh(III)-catalyzed process to construct tetracyclic naphthoxazole derivatives 254 by oxidative coupling of electron-deficient quinones 252 with alkynes (Scheme 120).116 A mechanistic study indicated that this one-pot reaction was a domino process. The first reaction includes C−H activation/alkyne insertion/cyclization to fused benzochromenes 253 with a regioisomer ratio of roughly 1:1. Satoh, Miura, et al. described the oxidative annulation of tertiary benzyl alcohols 255 (3 equiv) with internal alkynes, 5926


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Scheme 156. Rh(III)-Catalyzed Synthesis of Isoquinolines from Hydrazones or Azines

Scheme 157. Rh(III)-Catalyzed Synthesis of Naphthyridinone N-Oxides

Scheme 159. Proposed Mechanism for Rh(III)-Catalyzed Multistep Reaction of N-Hydroxy-Benzamidines and Alkynes

Scheme 158. Rh(III)-Catalyzed Synthesis of Highly Substituted Naphthyridine-Based Fused Heteroaromatics

with internal alkynes, which affords indoles 270 (Scheme 126).122 Preliminary mechanistic studies of the H/D exchange showed that a reversible ortho-C−H activation is the first step of the reaction. Jin et al.123 functionalized N-(naphth-1-yl) carbamates 271 regioselectively via an oxidative annulation with internal alkynes using different Rh(III)-catalyst systems. A cationic Rh(III) catalyst system was crucial for the activation of the ortho-C−H bond, which leads to the corresponding benzoindole derivatives 272 (Scheme 127). 1-Pyrenyl carbamate gave the corresponding pentacyclic product in 64%. Reaction of 1,8-naphthalene dicarbamate 273 with an excess of diphenylacetylene (2.4 equiv) yielded product 274 featuring two fused indole moieties. It is important to note that a neutral Rh(III) catalyst system was favorable for the activation of the peri-C−H bond of 271, which gave benzoquinolines 307 with complete chemoselectivity (see section 4.5, Scheme 149). Glorius et al. described a Rh(III)-catalyzed redox-neutral C− H activation/cyclization of 2-acetyl-1-arylhydrazines with internal alkynes to prepare unprotected indoles 275 (Scheme 128).124 The reaction did not require any external oxidant as the N−N bond cleavage occurred with the loss of AcNH2 (Scheme 130, Route A).

electrophilic substitution in the directing group by the metal center afforded the amido vinyl Rh intermediate (Scheme 90). The particular features of alkyne insertion determine the regioselectivity of the reaction: 2-aryl-3-alkyl indoles are formed with the use of alkyl aryl acetylenes as substrates. The reductive elimination and reoxidation of the Rh species are the last two steps of the cycle. Alkynes bearing substituted aniline moieties are able to undergo intramolecular indole formation.121,131,132 Fagnou et al. were the first to develop an approach to indole synthesis based on the Rh(III)-catalyzed alkenylation/cyclyzation. They described an oxidative coupling of N-acetyl anilines 5927


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Scheme 160. Rh(III)-Catalyzed Aerobic Oxidative Annulations of 2-Aryl Pyridines and Related Fused Compounds

yields (61−73%). The difference between this route and the method of Glorius124 was the absence of AcOH in Liu’s reaction mixture, which directed the reaction of intermediate 278 to the other pathway (Scheme 130, Route B). In this case, the recycling of the Rh(III) catalyst required an external oxidant, a role played by 1,3-(NO2)2C6H4 in this case. Matsuda and Tomaru developed a method for the synthesis of 1,2,3-trisubstituted indoles 279 from N-alkyl-N-aryl hydrazones of isobutyric aldehyde and internal alkynes (Scheme 131).126 Hydrazones of propanal gave lower yields of the indoles and pivalic aldehyde, benzaldehyde, and cyclohexanone hydrazones did not afford the desired products. Huang et al. described the synthesis of unprotected indoles 280 through a triazene-directed C−H annulation using alkynes (2.5 equiv) (Scheme 132).127 To probe the reaction mechanism, isotopic labeling experiments were carried out. These indicated that the C−H activation was the ratedetermining step. Later Wu, Zhang, Huang et al. extended this method for the synthesis of indolo[2,1-a]isoquinolines 281 from aryl triazenes and diaryl alkynes using a Rh(III)-catalyzed triple C−H/N−H/ C−H activation−annulation cascade (Scheme 133).128 This transformation utilizes an internally cleavable triazene-directing group. The authors attempted to overcome the limitations associated with the need to use the same alkyne twice. Sequential addition, where the second alkyne was introduced after the first alkyne was consumed, allowed the authors to synthesize “hybrid” indolo[2,1-a]isoquinoline 282 from diphenylacetylene and 1,2-bis(4-bromophenyl)ethyne in 28% yield via the one-pot protocol. The reaction of different NHunsubstituted indoles 283 with alkynes under these conditions gave the desired indolo[2,1-a]isoquinolines 282 in good yields, indicating that indoles 283 are intermediates in this cascade reaction. Huang and Wang129 and Zhu et al.130 simultaneously and independently reported the synthesis of N-alkyl indoles via C− H activation and annulation using a traceless nitroso-directing group in the starting compounds. The first protocol is redoxneutral because the regeneration of the Rh(III) species occurred as a result of the N−N cleavage (Scheme 134, method A). The acetate counterion was critical for efficient catalysis, as other salts failed to promote the reaction. This suggested a concerted metalation−deprotonation (CMD) mechanism for the C−H activation step. The nitroso group tolerated both more electron-rich and more electron-deficient substituents than the analogous triazene reaction (see above), and the yields of 1,2,3-substituted indoles 284 were found to be higher (50−97%). Zhu’s method is also redox-neutral; the authors used t-BuCO2H as an acid (Scheme 134, method B). 3Substituted N-nitrosoanilines reacted unselectively, yielding mixtures of corresponding regioisomers. Use of alkyl aryl

Scheme 161. Rh(III)-Catalyzed Oxidative Annulation of Isoquinolones

Scheme 162. Proposed Mechanism for Rh(III)-Catalyzed Annulation of Isoquinolones

Scheme 163. Rh(III)-Catalyzed Oxidative Annulation of 3Arylpyrazoles

On the other hand, Liu et al. synthesized N-acylaminoindoles 276 from similar precursor acylhydrazines (Scheme 129).125 Diacetylenes gave heteroarylacetylene products 277 in good 5928


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Scheme 164. Rh(III)-Catalyzed Synthesis of Ring-Fused Phenanthroimidazoles

Scheme 165. Proposed Pathway for the Formation of Ring-Fused Phenanthroimidazoles

Scheme 166. Rh(III)-Catalyzed Intramolecular Annulation of Alkyne-Tethered Aryl Hydroxamic Esters

through initial weakening of the C−H bond by the agostic interaction pathway with no buildup of charge in the transition state. A suitable base (e.g., NaOAc) could act as a proton shuttle similar to t-BuCO2H. The next alkyne insertion step is irreversible. The reason for the use of t-BuCO2H as an acid is that stronger acidic conditions afford linear alkenylation products 286 via the fast protonation of vinyl-Rh intermediate 285. Xu, Liu, et al.121 and Jia and Tao131 simultaneously published the Rh-catalyzed intramolecular annulation of alkyne-tethered acetanilides 264 for the synthesis of fused tricyclic indoles 266 via C−H bond activation. Surprisingly, in spite of the similar substrates, the reaction conditions described by both research groups differ greatly. In the first report, the Rh(III)-catalyzed intramolecular syntheses of 3,4-fused tricyclic indoles 266 from alkyne-tethered acetanilides 264 proceeded at an elevated temperature (Scheme 136).121 Chromans 265 are the main

acetylenes gave 2-aryl-3-alkyl indoles in all the cases studied. The authors reported that the replacement of t-BuCO2H with HOAc under otherwise identical conditions led to attenuation of the catalytic activity. Moreover, a substoichiometric amount of NaOAc (0.4 equiv) is sufficient for the transformation under slightly harsher conditions (Scheme 134, method C). A detailed inspection of the mechanism of the catalytic system using isotope exchange, KIE, intermolecular competition techniques, and other methods allowed the authors to propose a mechanism for the reaction (Scheme 135). The exclusive incorporation of deuterium at the ortho-position to the N-nitroso group upon exposure to t-BuCO2D/D2O in the absence of an alkyne, as well as the KIE value (2.9), supported an initial reversible, N-nitroso-directed, turnover-limiting C−H activation step. On the basis of the lack of electronic preference in the competition experiment, the authors suggested concerted metalation-deprotonation (CMD) sequence, presumably 5929


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Scheme 167. Rh(III)-Catalyzed Synthesis of Cinnolines and Cinnolinium Salts

Scheme 168. Rh(III)-Catalyzed Synthesis of Sultones

Scheme 171. Rh(III)-Catalyzed Synthesis of 1,2Benzothiazines

products of the reaction in the presence of t-BuCO2H (see section 4.3, Scheme 124). The authors proposed a reaction mechanism explaining this crucial influence of the acid (Scheme 137). The formation of both products (265 and 266) proceeded via a common intermediate 287. Under acidic conditions, this could be protonated to form chromanes 265 (pathway A, Scheme 137), but in the absence of the acid additive, intermediate 287 underwent reductive elimination to form 3,4-fused tricyclic indoles 266 (pathway B). The other protocol proposed carrying out this reaction under mild conditions (Scheme 138).131 This process employs molecular oxygen as the stoichiometric terminal oxidant. This is presumably the reason for the lower yields of the reaction products 266 using precursor 264 with X = H, due to easier side-chain oxidation of the substrates compared to 264 substituted at the 4 position. Using 4-aminophenol derivatives 288 instead of 3-aminophenol derivatives allowed the synthesis of fused macrocycles 289 in yields of 36−54%. Zhou, Li, et al. reported similar Rh(III)-catalyzed intramolecular syntheses of not only 3,4-fused tricyclic N-acetyl indoles 266 from alkyne-tethered acetanilides 264 in the presence of [Cp*Rh(MeCN)3](SbF6)2 (2.5 mol %) but also 3,4-fused tricyclic N-alkyl indoles 291 from alkyne-tethered Nnitroso-N-alkylanilines 290 (Scheme 139).132 Satoh, Miura, et al. reported an unusual synthetic pathway to 3H-benzo[e]isoindoles 292 based on Rh(III)-catalyzed reactions of ((naphth-1-yl)methyl)amine (2 equiv) with dialkylacetylenes (Scheme 140).133 The authors proposed that the rearrangement of the vinyl-Rh intermediate 293 is the reason for the observation of 3Hbenzo[e]isoindole products (Scheme 141). Diaryl- and arylalkyl acetylenes gave isoquinolines under these conditions (see section 4.6, Scheme 152).

Scheme 169. Rh(III)-Catalyzed Synthesis of Benzosultams

Scheme 170. Proposed Mechanism of Rh(III)-Catalyzed Annulation of Acylated Sulfonamides

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Scheme 172. Rh(III)-Catalyzed Synthesis of Phosphaisocoumarins

4.5. Synthesis of Quinoline Derivatives

X = H) and reliably established its structure by single-crystal Xray diffraction study. Recently Loh et al. used N-carbamoyl indolines 305 as substrates for the synthesis of pyrrolinoquinolinones 305 via the Rh(III)-catalyzed redox-neutral C−H alkenylation/annulation with various internal alkynes (Scheme 147).138 It is interesting to note that with the unsymmetrical alkyl aryl substituted alkynes, the reaction proceeded smoothly with high regioselectivity, providing annulation products in which the aryl groups are proximal to the carbonyl group. Unexpectedly, the use of the electronically differentiated diaryl-substituted alkyne (R = 4-BrC6H4, R1 = 4-MeOC6H4) gave 306 (R = 4-BrC6H4, R1 = 4-MeOC6H4) in a highly regioselective manner. The authors proposed the original reaction mechanism (Scheme 148) but did not explain the regioselectivity. As mentioned above, the quinoline skeleton 307 could be obtained by the Rh(III)-catalyzed activation of the peri-C−H bond of naphthylcarbamates 271 (Scheme 149).123 Unlike the synthesis of benzoindole derivatives 272 in the presence of the cationic Rh(III) species (see section 4.4, Scheme 127), the synthesis of benzoquinolines 308 from 273 requires a neutral Rh(III)-catalyst system and a 2-fold excess of the alkyne. The authors explained this feature by the differences of chelation of the cationic and the neutral metal centers with the directing substituent EtO2CNH (Scheme 150). Urabe et al. described the synthesis of N-(arenesulfonyl)-4halo-1,2-dihydroquinolines 310 via the regioselective intramolecular hydroarylation of haloacetylenes 309 with [Rh2(CF3CO2)4], which was found to be superior to traditional Brønsted or Lewis acids (Scheme 151).92 The authors did not study the mechanism of this transformation.

As a rule, N-aryl 1,3-diazoles and related compounds are substrates for the Rh(III)-catalyzed synthesis of quinoline derivatives.134−137 A feature of these substrates is the ease of electrophilic substitution of the hydrogen atom at the 2 position of the heterocyclic moiety. Therefore, the typical mechanism of N-aryl azole annulation with internal alkynes involves heterocyclic C−H bond activation by a Cp*Rh(III) cationic species as an initial step, leading to structure 294 (Scheme 142). The other (aryl) C−H bond is then activated via intramolecular interaction with the metal center. Rhodacyclic intermediate 295 coordinates the alkyne, which inserts to form vinyl intermediate 296. Reductive elimination results in the desired quinoline and Rh(I) species, which reoxidizes to the active Rh(III) complexes with an external oxidant. A variety of aza-fused polycyclic quinolines 298 were synthesized through the Rh(III)-catalyzed annulation of Narylazoles 297 with acetylenes (Scheme 143).134 N-(Thien-2yl)- and N-(pyrid-2-yl)benzimidazoles also reacted with ease. Unsymmetrically disubstituted alkynes gave mixtures of regioisomers. Alkyl aryl acetylenes formed mainly the 3-aryl4-alkyl quinoline moiety, but the methoxycarbonyl(phenyl)acetylene yielded the 4-aryl-3-methoxycarbonyl substituted product. The alkyne containing R = PO(OEt)2 and R1 = Ph gave the only 4-aryl-regioisomer. Later, the authors extended this reaction to the annulation of N-aryl-(2-substituted)azoles, and even some N-arylpyrroles, with diphenylacetylene to obtain compounds 299 (Scheme 144).135 KIE measurements showed that the first stage of the catalytic cycle is the activation of the heteroaryl C−H bond, presumably facilitated by the assistance of the adjacent πsystem. Hua et al. reported a one-pot synthesis of multisubstituted 2aminoquinolines 301 by the cyclization of 1-aryl tetrazoles (2.5 equiv) with internal alkynes through Rh(III)-catalyzed double C−H bond activation followed by Cu(II)-mediated denitrogenation (Scheme 145).136 The process occurred via the formation of tetrazole intermediates 300. The authors studied H/D exchange in tetrazoles in the absence of alkynes. A significant D/H exchange (>85%) at the C5 position of the tetrazole moiety indicated that a reversible Rh(III) insertion occurred initially. The authors obtained further evidence that the reaction begins with heteroaryl C−H bond activation: no significant steric effect was observed with the use of 1-aryl-1Htetrazoles with ortho-, meta-, or para-methyl groups on the phenyl ring as substrates. Ghorai and Choudhury described the catalytic annulation of imidazolium salts 302 (Scheme 146).137 An initial directed C− H activation/insertion/reductive elimination sequence using the NHC−Rh(III) backbone afforded important imidazo[1,2a]quinolinium salts 304 at room temperature. The authors isolated the aryl carbene Rh(III) intermediate 303 (Alk = Me,

4.6. Synthesis of Isoquinoline Derivatives

Rh(III)-catalyzed syntheses of isoquinoline motifs are more common than those of quinolines. The reason for this is that nitrogen atoms in benzyl amines, imines, and other similar aminated carbonyl or carboxyl derivatives, and 2-arylsubstituted azaheterocycles, are good chelating centers for facilitation of the C−H bond activation. Satoh, Miura, et al. reported that benzylamines or ((naphth1-yl)methyl)amine (2 equiv) underwent a Rh(III)-catalyzed oxidative coupling with alkynes accompanied by dehydrogenation and dehydrogenative cyclization to afford isoquinoline derivatives 311 in moderate yields (Scheme 152).133 Unsymmetrical alkyl aryl alkynes reacted regioselectively; only small impurities (3−6%) of the regioisomers were detected in the reaction mixtures. The authors found that the first step of the process was in situ oxidation of the benzylamines to imines (Scheme 153). The reactions of ((naphth-1-yl)methyl)amine with dialkylacetylenes were found to give 3H-benzo[e]isoindole derivatives 292 (see section 4.4, Scheme 140). No benzo[h]isoquinoline-type products could be detected. 5931


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A variety of functional groups on the alkynyl coupling partner were tolerated, including free hydroxyl groups. The Rh(III)-catalyzed synthesis of the isoquinoline skeleton via annulation with alkynes is a powerful method for obtaining highly fused structures. Thus, Chuang, Cheng, et al. developed a simple and effective method for the synthesis of highly substituted naphthyridine-based fused heteroaromatic compounds 318 and 319 from N-hydroxybenzamidines 317 and alkynes (Scheme 158).146 The proposed mechanism involves a Rh(III)-catalyzed multiple C−H bond activation and annulation (Scheme 159). The first step is the coordination of the oxime nitrogen atom of 317 to the metal center, followed by the ortho C−H activation to form five-membered rhodacycle 320. The coordinative insertion of the alkyne into the rhodium−carbon bond gave seven-membered rhodacycle 321. The reductive elimination affords 1-aminoisoquinoline 322. The oxime moiety is an internal oxidant here, therefore, this step does not include Cu(II). The further coordination of the amine nitrogen atom of 322 to the Rh(III) complex, followed by C−H activation, insertion, and reductive elimination affords 318 and a Rh(I) species. The latter is reoxidized by Cu(II) to regenerate the active Rh(III) catalyst. In the case of the arylsubstituted naphthyridine, this sequence repeats once more, yielding 319. The authors confirmed this mechanism by the isolation of the intermediate 322 and preparation of the product 318 from this intermediate and the alkyne under these reaction conditions. This implies that the oxime nitrogen atom coordinates first to the metal center. If pyrid-2-yl is used as a directing group then the corresponding fused isoquinolinium salts are the result of Rh(III)-catalyzed annulations with internal alkynes.140,147 Huang et al. developed the synthesis of isoquinolinium salts 324·OTf from the reaction between arenes 323 and alkynes through Rh-catalyzed aerobic oxidative C−H activation (Scheme 160).140 The process exhibits a high reactivity (TON of up to 740), and thus, it represents the first example of a Rh(III)/O2 catalytic system providing a highly efficient oxidative C−H activation with lower catalyst loading. Alkyl aryl alkynes (R = Ph, R1 = Me, PhCH2) gave the desired products in high yields, revealing that the rhodium selectively attacked the less hindered position of the alkyne. The selectivity was shown to depend on steric, not electronic, factors, as two unsymmetrical diaryl alkyne-bearing aryl groups with different electronic effects (R = Ph, R1 = 4-MeC6H4 or 3,5-(CF3)2C6H3) each gave ca 1:1 mixtures of the corresponding regioisomers. The authors also studied the reaction mechanism, isolating cationic aryl Rh(III) complex 325·OTf and showing that this species is the intermediate. Cheng et al. offered the analogous synthesis of isoquinolinium salts 324·BF4 ([Cp*RhCl2]2 (1 mol %), AgBF4 (10 mol %), or Cu(BF4)2·6H2O (0.5 equiv), O2, DME, 20−65 °C, 22− 36 h or t-AmOH, 100 °C or EtOCH2CH2OH, 120 °C, 48 h; 69−97%).147 The authors also isolated the intermediate cationic 5-membered rhodacycle 325 as its iodide salt. Li, Wang, et al. reported a detailed study of the mechanism of the Rh(III)-catalyzed oxidative annulation of isoquinolones 326 with diphenylacetylene or methyl phenyl acetylene, providing fused cycles 327 and 328 (Scheme 161).148 Methyl phenyl acetylene reacted regioselectively. On the basis of the mechanistic study, the authors proposed a Rh(III)/Rh(I)/ Rh(III) catalytic cycle for the reaction (Scheme 162). The entire set of key intermediates, including the results of acetateassisted C−H activation 329, alkyne insertion of the Rh−C

There are several methods for the Rh(III)-catalyzed annulation of imines and related derivatives.139,140 Cheng et al. described the synthesis of various 1-substituted isoquinolinium salts 312·BF4 from arylketimines and alkynes via Rh(III)catalyzed C−H bond activation (Scheme 154).139 This reaction is not redox-neutral, and Cu(II) is the external oxidant in this case, as in Scheme 153. N-(4-Methoxyphenyl) fluorenone imine also reacted easily, forming the corresponding fused indeno[1,2,3-ij]isoquinoline in 89% yield. An unsymmetrical ketimine, N-(4-methoxyphenyl)-4-bromobenzophenone imine, yielded a mixture (1:1) of isoquinoline and 6-bromoisoquinoline derivatives. Huang et al. developed a Rh-catalyzed synthesis of triflate isoquinolinium salts 312·OTf from the reaction between imines and alkynes using oxygen as an external oxidant.140 Hua et al. developed a route to construct multisubstituted isoquinolines or related fused pyridine heterocycles 313 by using readily available aryl or (hetero)aryl ketones, NH2OH· HCl, and alkynes (Scheme 155).141 The process proceeds efficiently via a cascade reaction involving ketone−hydroxylamine condensation, C−H activation, and intermolecular cyclization in a one-pot process. An oxime plays the role of an internal oxidant. Therefore, the method is “external-oxidantfree” and occurs under moderately mild conditions. Hydrazones and azines 314 are popular starting compounds for annulation to yield isoquinolines 315 (Scheme 156). The reaction conditions are the only difference. Cheng et al. conducted this synthesis under acidic conditions ([Cp*RhCl2]2 (2.5 mol %), Ag2O (20 mol %), AcOH (1 equiv), MeOH, 90 °C, 8−24 h; 21−96%).142 The process is “external-oxidant-free” as the N−N bond acts as an internal oxidant. Xu et al. used neutral conditions and an aprotic solvent ([Cp*Rh (MeCN)3](SbF6)2 (3 mol %), Cu(OAc)2·H2O (2.1 equiv), toluene, 90 °C, 5−29 h; 30−98%).143 In this case, Cu(II) is an external oxidant. Li et al. also used neutral conditions, but a protic solvent ([Cp*RhCl2]2 (5 mol %), AgNO3 (20 mol %), Cu(OAc)2 (1 equiv), EtOH, reflux, 12 h; 50−95%).102 Li, Huang, et al. proposed the mildest reaction conditions for the synthesis of isoquinolines 315 from symmetrical azines 314 ([Cp*Rh(H2O)3](OTf)2 (2−4 mol %), PhCO2H (25 mol %), CH3OH, air, 25 °C, 24−36 h; 36−91%).144 Alkyl aryl alkynes afforded 3-aryl-4-alkyl isoquinolines selectively in all these processes, while using unsymmetrical diarylalkynes led to 1:1 mixtures of the corresponding regioisomers. It is noteworthy that Xu et al.143 reported the selective synthesis of 1-(naphth-1-yl)-3,4-diphenylisoquinoline 315 in a yield of 86% from naphthyl phenyl ketone 314 (Ar = Ph, R2 = naphth-1-yl) in spite of the presence of different aryl C−H bonds near the directing group. The authors did not explain this unexpected selectivity. Huckins, Bercot, et al. reported the Rh(III)-catalyzed C−H activation of nicotinamide N-oxides in the presence of alkynes to afford naphthyridinone N-oxides 316 (Scheme 157).145 The uniqueness of the method lies in the fact that both internal and terminal alkynes can be applied. Reactions with terminal alkyne coupling partners provided products with high selectivity. Along with the ability to use TMS- or TES-substituted alkynes, this allowed the synthesis of naphthyridinone N-oxides with unsubstituted 3 and/or 4 positions, which is impossible to achieve by other Rh(III)-catalyzed annulations. The regioselectivity of the alkyne insertion was consistent with that mentioned above: sterically demanding alkyne substituents were positioned adjacent to the lactam nitrogen in the product. 5932


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position (Scheme 168).153 Interestingly, when the coupling of 4-toluenesulfonic acid (X = 4-Me) with diphenylacetylene was carried out in t-BuOH, naphthalene 346 was obtained in 85% yield, indicating that the reaction selectivity can be controlled. Cramer et al. reported a Rh(III)-catalyzed oxidative C−H activation of simple acylated sulfonamides and subsequent addition of internal alkynes to give access to the benzosultams 347 (Scheme 169).154 The authors showed that the welldefined and highly soluble [Cp*Rh(OAc)2] catalyst was advantageous compared to the commonly utilized [Cp*RhCl2]2 precatalyst. The proposed mechanism involves the coordination of Rh(III) by sulfonamide anions as the first stage of the cycle (Scheme 170). Bolm et al. described a similar process for the synthesis of 1,2-benzothiazines 348 from NH-sulfoximines and alkynes (Scheme 171).155 The intramolecular kinetic isotope effect (KIE) of kH/kD = 2.22, found by using [D1]-sulfoximine (X = H, Y = Me) as a substrate, indicated that the C−H bond cleavage was directly involved in the product-determining cyclometalation step. Beside the new directing group, the novelty of the results lies in the use of Fe(OAc)2 as a mediator for the reoxidation of the Rh catalyst by air. Simultaneously (in the same issue of Organic Letters), Satoh, Miura, et al.156 and Lee and colleagues91 reported syntheses of phosphaisocoumarins 350 through rhodium-catalyzed cyclization with alkynes. Satoh, Miura, et al. used diarylphosphinic acid derivatives 349 (Y = Ar) and phenylphosphonic acid monoethyl ester 349 (Y = OEt) (Scheme 172).156 Use of oxylene, dioxane, or DMF as solvents gave decreased yields. Lee et al. extended the method to other arylphosphonic acid monoesters.91 (Inden-2-yl)- and (thien-2-yl)phosphonic acid monoethyl esters also underwent the annulation. Competition experiments between alkynes indicated that diphenylacetylene was eight times more reactive than dec-5-yne. The reaction of ethyl phenylphosphonate with electron-rich (R = 4-MeOC6H4) and electron-deficient (4-BrC6H4) alkynes afforded mainly the phosphaisocoumarin obtained from the electron-rich alkyne. A significant KIE was detected for 349 (X = H; kH/kD = 5.3), indicating that the C−H bond cleavage at the C2 site is most likely involved in the rate-limiting step.

bond 330, and reductive elimination with formation of C−N bond 331, were isolated, and their structures determined by single-crystal X-ray diffraction. Pyrazoles also reacted with symmetrical internal alkynes in the presence of Rh(III) species, leading to compounds 332 (Scheme 163).149 Alkyl aryl acetylenes yielded mixtures of two regioisomers and the corresponding products with exocyclic double bonds. Deuteration and competition experiments suggested that the C−H activation step is reversible and ratelimiting. DFT calculations indicated the typical mechanism involving sequential N−H and ambiphilic metal−ligandassisted (AMLA)/concerted metalation−deprotonation (CMD) C−H bond activation, HOAc/alkyne exchange, migratory insertion, and C−N reductive coupling. Zheng and Hua described the synthesis of ring-fused phenanthroimidazoles 334 from 2-arylphenanthroimidazoles 333 via Rh(III)-catalyzed C−H activation and alkyne annulation (Scheme 164).150 Interestingly, when methyl phenyl acetylene was explored, two types of products were obtained with the phenyl group at different positions (334 and 335). The authors proposed a possible pathway to form rearrangement product 335 bearing an exocyclic double bond (Scheme 165), which may be triggered by β-elimination of rhodacyclic intermediate 337 to form 338, followed by intramolecular allene insertion. This means that at least during this product formation, the alkyne is inserted into the Rh−N bond of the five-membered rhodacycle 336, instead of the Rh−C bond as in all other reported Rh-catalyzed annulations with alkynes. Wu, Zhang, Huang et al. described the direct Rh(III)catalyzed synthesis of indolo[2,1-a]isoquinolines 318 and 319 from aryl triazenes.128 This reaction has been discussed above (see section 4.4, Scheme 133), as it represents a construction of both indole and isoquinoline moieties. The indolyl substituent formed is a directing group for aryl C−H bond activation on the finished catalytic cycle, leading to the indolo[2,1-a]isoquinolines. This catalytic cycle was investigated by DFT calculations. Park et al. reported that Rh(III)-catalyzed intramolecular annulation of alkyne-tethered aryl hydroxamic esters afforded 3hydroxyalkyl isoquinolones 341 (Scheme 166).151 The reaction proceeded through rhodacyclic intermediates 339 and 340. The author used this method for total syntheses of alkaloids (±)-antofine, (±)-septicine, (±)-tylophorine, and rosettacin.

Scheme 173. First Example of Ru(II)-Catalyzed Arene Alkenylation with Internal Alkynes

4.7. Synthesis of Skeletons Bearing Two Heteroatoms

There exist a few reports describing the construction of heterocycles by Rh-catalyzed alkenylation of arenes with the insertion of two heteroatoms into the forming cycle at once. You et al. developed a method to synthesize cinnolines 342 (64−96%) and cinnolinium salts 343 (71−94%) through the Rh(III)-catalyzed oxidative C−H activation/cyclization of azo compounds with terminal and internal alkynes (Scheme 167).152 The method allowed the installation of versatile functional groups at various positions of the cinnoline ring. The regioselectivity of the reaction with the terminal alkynes (R = nC6H13, Ph, 4-NCC6H4, 3-FC6H4, R1 = H) indicated that the rhodium selectively attacked the substituted position of the alkyne. The catalytic protocol could be extended to prepare the polycyclic cinnolinium salts 344 through two-fold orthodirected C−H activation and cyclization. Li et al. described the synthesis of sultones 345 via the coupling of sulfonic acids with internal alkynes where the sulfonic acid group assisted the C−H activation at the ortho

5. RUTHENIUM-CATALYZED REACTIONS The Ru(II)-catalyzed alkenylation of chelating-group-substituted arenes with internal alkynes is very similar to the Rh(III) variant, both in their explosive growth of interest over the past few years and in the nature of the reagents used.157 In some cases, Ru(II) catalysts are even more active than Rh(III) species,158 while other authors found that [Cp*RhCl2]2 provided the highest yields of products.159 The main difference between complexes of these two metals (besides their cost) is that Rh(III)-catalyzed ortho-alkenylations of functionalized arenes are followed by cyclizations as a rule, while Ru(II)catalyzed reactions often afford linear products. Analogously to 5933


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Scheme 174. Typical Mechanism of Ru(II)-Catalyzed Alkenylation of ortho-C−H Bonds in Functionalized Arenes with Internal Alkynes

Scheme 178. Ru(III)-Catalyzed Alkenylation of Arylpyridines with Terminal Alkynes

Scheme 179. Plausible Mechanism of Ru(III)-Catalyzed Alkenylation of Arylpyridines with Terminal Alkynes

Scheme 175. Ru(II)-Catalyzed Synthesis of Alkenes through the Alkenylation of Pyridines

Scheme 176. Ru(II)-Catalyzed Alkenylation of Pyrroles with Phenyl Acetylene Scheme 180. Ru-Catalyzed Alkenylation of Isoquinolones with Internal Alkynes

Scheme 177. Proposed Mechanism of Ru(II)-Catalyzed Alkenylation of Pyrroles with Phenyl Acetylene 5.1. Synthesis of Substituted Alkenes

The first mini-review on the ruthenium-catalyzed alkenylation of arenes with alkynes appeared only very recently,160 while the first example of this reaction catalyzed by Ru(H)2(CO) (PPh3)3 was reported in 1995 for the reaction of 1-tetralone with internal alkynes, affording alkenylation products (Scheme 173).161 The authors showed that the regio- and stereoselectivity depended on the alkyne substituents. 1-Phenyl-1butyne gave all four possible regio- and stereoisomers, while 1trimethylsilyl-1-propyne afforded only the E-isomer with C−C bond formation exclusively at the silyl-substituted carbon atom in 83% yield. Following the publication of this article nearly 15 years ago, there were no reports on Ru(II)-catalyzed alkenylation with internal alkynes for around a decade. However, interest in these reactions has been rekindled over the past 5 years, with the publication of more than 20 papers devoted to this reaction. A

Rh-catalyzed reactions (section 4), in the case of unsymmetrical alkynes RCCR1, when R is an aryl group and R1 is a nonaryl group, alkenylation takes place regioselectively at the acetylene carbon neighboring R1 (see below Schemes 184, 186, 189, 198, and 200). 5934


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Scheme 181. Ru-Catalyzed Alkenylation of Arenes Bearing N-Containing Substituents as Directing Groups

Scheme 182. Ru-Catalyzed Alkenylation of Aryl Carbamates and Acetanilides with Internal Alkynes

Scheme 184. Ru-Catalyzed Alkenylation of TriazoleSubstituted Arenes with Internal Alkynes

Scheme 183. Ru-Catalyzed Alkenylation of N-(2Pyridyl)Indoles with Internal and Terminal Alkynes

Scheme 185. Ru-Catalyzed Alkenylation of Aromatic Sulfoxides with Internal Alkynes

coordination of the chelating group in the activated arene seems to be the key for the regioselective C−H bond cleavage to form the ruthenacycle intermediate 351 (Scheme 174). Then, alkyne insertion into the resulting aryl−Ru bond forms intermediate 352 and subsequent protonolysis may take place to produce the alkenylation products. Syn-addition of hydrogen and aryl group to triple bond takes place. The last step appears to be promoted by AcOH (or another carboxylic acids; however, Satoh, Miura, et al. showed167 that 1-AdCO2H, t-

typical mechanism for Ru(II)-catalyzed alkenylations of orthoC−H bonds in functionalized arenes with internal alkynes is illustrated in Scheme 174.162−166 An investigation of the effect of various Ru catalysts (RuCl3, Ru3(CO)12, RuH2(CO) (PPh3)2, RuHCl(CO) (PPh3)3, and [RuCl2(p-cymene)]2) indicated that the dimeric species [RuCl2(p-cymene)]2 is the most effective.164 A silver salt added to the reaction mixture (e.g., AgBF4 or AgSbF6) likely removes the Cl− ligand from the Ru complex, giving a cationic ruthenium species. The 5935


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Scheme 186. Ru-Catalyzed Alkenylation of Arylphosphine Oxides with Internal Alkynes

Scheme 190. Ru(II)-NHC-Catalyzed Synthesis of Amino Indenes

Scheme 191. Ru-Catalyzed Oxidative Annulation of Cyclic 2Aryl-1,3-Diketones with Internal Alkynes Scheme 187. Ru-Catalyzed Synthesis of Indenols and Benzofulvenes

Scheme 192. Plausible Mechanism of the Ru(II)-Catalyzed Synthesis of Indenes

Scheme 188. Plausible Mechanism of the Ru(II)-Catalyzed Synthesis of Indenols and Benzofulvenes

Scheme 193. Ru-Catalyzed Oxidative Annulation of 1-Aryl-2Naphthols with Internal Alkynes

Scheme 189. Ru-Catalyzed Synthesis of N-Sulfonyl Aminoindenes

BuCO2H, and 2,6-dimethylbenzoic acid are similarly as effective as AcOH). The first step of the catalytic cycle (C−H bond cleavage) is reversible, but usually the next step (i.e., the alkyne insertion) is fast enough and the equilibrium can be studied only in the absence of alkyne. 5936


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styrylpyridines 353 from pyridines (50 equiv) and trimethylsilyl-protected alkynes (Scheme 175).168 The reaction selectivity resulted in the substitution at the 2-position of the pyridines, and only the E-isomers of 353 were obtained. The authors proposed the reaction of intermediately formed terminal alkynes with the cationic Ru species, yielding the vinylidene complexes 354. An intramolecular coupling between the coordinated pyridine and the vinylidene ligand was proposed to be the key step in the formation of the product. This reaction has many drawbacks, such as the large excess of the aromatic substrate, the high catalyst loading, and the drastic conditions. Lynam, Slattery, et al. reported Ru(II)-promoted (but not Ru(II)-catalyzed!) formation of 2-styrylpyridine derivatives via direct coupling of terminal arylacetylenes ArCCH with pyridine under mild conditions in quantitative yields ([CpRu(Py)2PPh3]PF6 (1 equiv), 50 °C, 24 h).169 The authors studied the mechanism of the reaction with isotope experiments and DFT calculations. Experimental and theoretical data confirmed that [CpRu(Py)2PPh3]+ was the active species for the direct C−H functionalization of pyridine by terminal alkynes, and that the first step of the reaction mechanism is the formation of the vinylidene complex. Fan et al. described a Ru(II)-catalyzed alkenylation of Nmethyl pyrrole (X = Me, 10 equiv) with phenyl acetylene to yield hydroarylation product 355 (Scheme 176).170 Alkyl acetylenes afforded the desired alkenylation products in trace amounts. The pyrrole (X = H) gave the double addition product 356 (X = H) in 91% yield. This reaction is an example of Markovnikov addition. The authors proposed that the mechanism of the reaction was consistent with an electrophilic activation of the alkyne followed by the nucleophilic addition of pyrrole (Scheme 177). In constrast, Zhang et al. reported a Ru(III)-catalyzed C−H functionalization process in which arylpyridines 357 could undergo alkenylation with terminal alkynes in equimolar amounts leading to compounds 358 (Scheme 178).171 2Phenylpyrimidine and 2-phenylpyrazine also reacted with phenyl acetylene under the same conditions in yields of 47− 49%. The authors proposed a typical mechanism for the alkenylation involving a proton abstraction by the benzoic anion coordinated to ruthenium, resulting in the species 359 and 360 and the exchange of benzoic acid with terminal alkynes to form the intermediate 361 (Scheme 179). The subsequent migratory insertion led to the intermediate 362, which liberated the alkenylated product and the Ru catalyst by protodemetalation. A variety of arene substituents can play the role of the directing groups in Ru-catalyzed C−H activation. Li et al. reported the alkenylation of both NH and N-methyl isoquinolones at the 8-position using internal alkynes, giving compounds 363 (Scheme 180).158 The neighboring CO-group facilitated the C−H activation here similarly to those of Rh(III)-catalyzed alkenylations (see section 5.1). However, the authors showed that RhCp* complexes were less effective catalysts for this alkenylation. The alkyne insertion was regioand stereoselective, presumably due to steric reasons. NH isoquinolones can also be alkenylated, albeit with a lower efficiency than N-protected derivatives. In contrast, no coupling was achieved when dialkyl alkynes were applied. Satoh, Miura, et al. described the Ru-catalyzed reactions of internal alkynes (2 equiv) with aryl C−H bonds activated by

Scheme 194. Ru(II)-Catalyzed Synthesis of Isochromenes

Scheme 195. Plausible Mechanism of Ru(II)-Catalyzed Oxidative Alkyne Annulations with Tertiary Benzylic Alcohols

Scheme 196. Ru(II)-Catalyzed Synthesis of 4-Alkyl-2Quinolinones

Scheme 197. Typical Mechanism of the Ru(II)-Catalyzed Construction of the Isoquinoline Skeleton

The Ru-catalyzed alkenylation of activated arenes with terminal alkynes is a much more rare process, and the mechanism of such alkenylation is more debatable. In 2003, Murakami and Hori demonstrated that [CpRuCl(PPh3)2] in the presence of NaPF6 was able to catalyze the formation of 25937


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Scheme 198. Ru(II)-Catalyzed Synthesis of Isoquinolines from Benzylamines

Scheme 199. Ru(II)-Catalyzed Synthesis of Isoquinolones from N-Quinolin-8-yl-Benzamides

Scheme 200. Ru(II)-Catalyzed Synthesis of Isoquinolones from Nitriles

Scheme 202. Ru(II)-Catalyzed Synthesis of Isoquinolinones from NH-Unsubstituted Hydroxamic Acids

Scheme 201. Ru(II)-Catalyzed Synthesis of Isoquinolinones from N-Aroylated Sulfoximines and Diphenylacetylene

the authors (and most other research groups) usually choose [Ru(p-cymene)Cl2]2 as an alkenylation catalyst. The ortho-carbamate174 and ortho-acetamide groups163 also assisted in the alkenylation of corresponding substituted arenes 373 with alkynes, giving compounds 375 under similar conditions (Scheme 182). Arenes with substituents at the 3 position reacted regioselectively at the less hindered ortho-C− H bond. The alkyne insertion was also regioselective. Phenyl trimethylsilyl acetylene gave the corresponding desilylated product. The reaction mechanism included coordination of the carbonyl group of 373 to the Ru cationic species followed by ortho-metalation, affording six-membered ruthenacycle intermediate 374. A deuterium labeling experiment indicated that the C−H bond cleavage with the formation of sixmembered ruthenacycle species 374 is a reversible process. Zeng et al. reported the alkenylation of C2−H bonds in N(2-pyridyl)indoles with both internal and terminal alkynes, leading to compounds 376 (Scheme 183).164 All indole substrates and all alkynes exhibited complete stereoselectivity yielding the alkenylation products with E-stereochemistry, but the regioselectivity was dependent on the alkyne substituents.

different N-containing ortho substituents as donor groups. Among these, alkenylation of 2-aminobiphenyls 364,172 cumylamine 365,172 benzamides 366,162,173 and arylazoles 367,162,173 gave alkenylated products 368−372 (Scheme 181). The reaction of 366 (Y2 = Me2) with phenyl trimethylsilyl acetylene yielded desilylated product 370 (Y2 = Me2, R = H, R1 = Ph) in 63% yield. The terminal trimethylsilyl acetylene afforded very low yields of alkenylation products. The use of [Ru(benzene)Cl2]2 in place of [Ru(p-cymene)Cl2]2 slightly improved the yield of the products, but despite this, 5938


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Scheme 203. Plausible Mechanism of Ru(II)-Catalyzed Annulations of NH-Unsubstituted Hydroxamic Acids

Scheme 204. Ru(II)-Catalyzed Synthesis of Pyrazolo[5,1a]isoquinolines from 5-Aryl-Substituted 1H-Pyrazoles and Internal Alkynes

Scheme 207. Ru(II)-Catalyzed Synthesis of Phosphaisocoumarins

Scheme 205. Ru(II)-Catalyzed Synthesis of Benzimidazoisoquinolines from 2-Aryl-Substituted Benzimidazoles

Scheme 208. Ru-Catalyzed Synthesis of Fused Tricyclic Heteroarenes from Benzocyclic Amines and Terminal Alkynes

N-(Pyridin-2-yl)pyrrole and N-(pyrimidin-2-yl)indole also gave the corresponding alkenylation products. The authors investigated the effect of various Ru catalysts (RuCl3, Ru3(CO)12, RuH2(CO) (PPh3)2, RuHCl(CO) (PPh3)3, [RuCl2(p-cymene)]2) and found that of these the dimeric species [RuCl2(p-cymene)]2 gave the best performance. It is interesting to note that the need for Ag salt addition (e.g., AgBF4, AgSbF6, or AgSbF6) depended on the solvent. When the reaction was carried out in 1,4-dioxane, only a trace of the alkenylation products could be observed in the absence of any Ag salt, whereas the reaction in DMF did not require such an addition. Liu et al. developed a Ru-catalyzed alkenylation of triazolesubstituted arenes with internal alkynes through 1,2,3-triazoledirected C−H activation, giving compounds 377 (Scheme 184).165 If both ortho-positions to the triazolyl substituents are unoccupied, bis(alkenylated) products were obtained. The proposed mechanism (which is common for Ru-catalyzed

Scheme 206. Ru-Catalyzed Synthesis of Fused Tetracyclic Heteroarenes

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formed from indenols 380 under these reaction conditions in the presence of AgSbF6 (20 mol %). A plausible reaction mechanism is given in Scheme 188. The coordination of the carbonyl oxygen of the aromatic ketone to the Ru cationic species (formed from [Ru(p-cymene)Cl2]2 with Ag+), followed by ortho-C−H bond metalation and coordinative insertion of the alkyne, provides the intermediate 382. This sequence of steps is common for Ru-catalyzed C−H alkenylation reactions. The key feature of the mechanism is the intramolecular [1,2]-insertion of the CO group into the Ru− alkenyl bond of 382, affording the five-membered ruthenium alkoxide intermediate 383. The exact role of the copper source in the reaction is not clear, but the authors proposed that Cu(OAc)2·H2O provided the AcOH source to accelerate the ortho-metalation and also to release the product and recycle the active Ru species by protonation of 383. The authors reported did not comment on the use of AcOH instead of Cu(OAc)2· H2O. Li et al. reported a Ru(II)-catalyzed annulative coupling of Nsulfonyl imines of benzaldehydes with internal alkynes leading to N-sulfonyl indenamines 384, which occurred via ortho-C−H bond activation (Scheme 189).176 The addition of primary sulfonamides plays an important role in activating the imine substrates toward cyclometalation. Use of NHC-Ru(II) species as catalysts allowed carbocyclization of benzophenone imines (Y = Ar) and internal alkynes without additional activation under extremely mild conditions, providing indenes 385 (Scheme 190).177 Valerophenone imines (Y = n-Bu) reacted under similar conditions at elevated temperatures (60 °C). A benzophenone/diphenylacetylene annulation was also achieved via NHC-Ru(II) catalysis in the presence of NaOAc, giving 1,2,3-triphenylinden-1-ol in an excellent yield. Concerning the regioselectivity of the reactions in Schemes 187, 189, and 190, insertion of alkyl(aryl)alkynes is typical for carbometalation; thus the alkyl-bearing acetylene carbon atom is connected with the aromatic ring in the hydroarylation products. Lam et al. described a new mode of Ru(II)-catalyzed oxidative annulation of cyclic 2-aryl-1,3-diketones 386 with internal alkynes involving the (formal) functionalization of one of the Csp3−H bonds and one of the Csp2−H bonds and resulting in the formation of indenes 387 (Scheme 191).159 Although the authors found that [Cp*RhCl2]2 provided the highest yield of the indenes, [Ru(p-cymene)Cl2]2 was used in the study due to its lower cost. In certain cases, the addition of K2CO3 (2.5 equiv) afforded higher yields of the reaction products. The regioselectivity was high with unsymmetrical alkyl aryl alkynes, with the initial Caryl−Cvinyl bond formation occurring at the alkyne carbon atom bearing the alkyl substituent. The mechanism is depicted in Scheme 192. Cu(OAc)2 performs a triple role here: first, it facilitates the formation of a cationic ruthenium complex; second, it is a source of acetate ions to form complex 388; and third, it oxidizes intermediate 389 during the final step of the cycle. A similar reaction occurs with the 1-aryl-2-naphthols in the same manner as for 2-aryl-1,3-diketones 386 and by the same mechanism (Scheme 193).178 This reaction of 1-aryl-2naphthols provides facile access to a class of highly functionalized spirocyclic compounds 390. The authors carried out a scale-up experiment (3 mmol of 1-aryl-2-naphthol, X = H, Ar = 4-CF3C6H4 with 4.5 mmol of phenyl methyl acetylene) and

Scheme 209. Plausible Mechanism of Ru(II)-Catalyzed Annulations with Terminal Alkynes

alkenylations, see Scheme 184) suggested that Cu(OAc)2·H2O formed AcOH (required as proton source for the product formation) in the reaction mixture. The authors did not explain why they used Cu(OAc)2·H2O instead of AcOH. Not only N-containing but also other heteroatom-bearing fragments are able to act as directing groups for the C−H activation in the Ru-catalyzed alkenylation reaction. Padala and Jeganmohan reported Ru-catalyzed regio- and stereoselective hydroarylation of aromatic sulfoxides with alkynes, providing trisubstituted alkene derivatives 378 (Scheme 185).166 The catalytic reaction proceeds via the coordination of the oxygen atom of sulfoxides to a cationic ruthenium species followed by ortho-metalation, coordinative selective insertion of the alkyne into the formed C−Ru bond, and protonation of the vinyl C− Ru bond by pivalic acid (accordingly with the mechanism indicated in Scheme 184). Pivalic acid plays a dual role in the reaction. It acts as an carboxylate source for the deprotonation of the ortho-C−H bond of arene sulfoxides and as a proton source followed by the regeneration of the active catalyst. Satoh, Miura, et al. described Ru-catalyzed ortho-alkenylation of various arylphosphine oxides with internal alkynes through PO-group-directed C−H bond cleavage (Scheme 186).167 It was necessary to use a large excess of arylphosphine oxides 379 (5 equiv) to avoid formation of multiply alkenylated products. Other acids, such as 1-AdCO2H, t-BuCO2H, and 2,6dimethylbenzoic acid, were found to be similarly as effective as AcOH. Alkyl aryl acetylenes were inserted with high regioselectivity; phenyl trimethylsilyl acetylene yielded the corresponding desilylated product (as in all other cases mentioned above). 5.2. Synthesis of Carbocycles

Chinnagolla and Jeganmohan developed a regioselective Ru(II)-catalyzed cyclization of substituted aromatic ketones with internal alkynes that occurs by C−H bond activation (Scheme 187).175 This methodology offers a simple and mild method for the synthesis of indenols 380 (in yields of 69−88%) or benzofulvenes 381 (in yields of 75−93%), depending on the reaction conditions. The amount of the silver salt used determined the nature of the product. In the presence of 8 mol % of AgSbF6, indenols 380 were the reaction products, whereas benzofulvenes 381 were obtained with 20 mol % of the silver salt. The authors showed that the latter compounds were 5940


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obtained the corresponding spiro compound in 90% yield (1.08 g) with >19:1 regioselectivity.

Most of the works devoted to the synthesis of heterocycles via Ru(II)-catalyzed arenes annulations with internal alkynes are targeted toward the isoquinoline skeleton. Arenes bearing aryl−CXY−NHZ groups (aryl−CRH−NH2,187 aryl−CO− NHR,188 aryl−CN,189 aryl−CNH−NHR,190 aryl−CNH− NHSOMePh, 191 aryl−CNH−NHOH, 192 and aryl−azaHet193−195) are suitable substrates for such reactions. All of these syntheses proceed through the common plausible mechanism (Scheme 197), including cycloruthenation with formation of the five-membered ruthena-aza cyclic intermediate 395 (facilitated and directed by the C−N substituent) followed by the coordinative insertion of an alkyne and reductive elimination of the desired isoquinoline. Reoxidation of the catalyst takes place by an external oxidant [e.g., Cu(OAc)2187−190,193−195] or due to reduction of the directing group.191,192 Reactions of benzylamines 396 bearing a HetCYHNH2 group with internal alkynes gave not only isoquinolines 397 but also double alkenylated products 398 (for R = Ph) or 399 (Scheme 198).187 Formation of 398 is due to a second alkyne insertion at the ortho-position of the 5-phenyl ring in the intermediate 397 (R = Ph). Allu and Swamy reported the synthesis of isoquinolones 402 via the Ru-catalyzed oxidative annulation of N-quinolin-8-ylbenzamides 400 with internal alkynes in air (Scheme 199).188 N-quinolin-8-yl-(heteroaryl)amides also reacted easily. The 8aminoquinoline moiety acted as a bidentate directing group in this reaction, which proceeded through Ru-polycyclic intermediate 401. The authors showed that the regioselectivity of the coordinative insertion of alkynes was controlled by steric, and not electronic, factors of the alkyne. Jeganmohan et al. described the Ru-catalyzed synthesis isoquinolones 404 from aromatic and heteroaromatic nitriles using air oxygen as an external oxidant with Cu(II) mediation (Scheme 200).189 The amide group (formed in situ from the cyano substituent) in compounds 403 acts as the directing group in this reaction. Ackermann et al. used the same system for the synthesis of N-substituted 1-amino-isoquinolines from N-substituted amidines and an excess of internal alkynes (2.4 equiv) ([Ru(pcymene)Cl2]2 (5 mol %), KPF6 (30 mol %), Cu(OAc)2·H2O (2 equiv), DME, air, 120−140 °C, 22 h; 42−79%).190 4Methoxybenzyl-substituted benzamidine furnished the tricyclic product (the corresponding substituted benzo[d,e][1,8]naphthyridine) through a 2-fold C−H/N−H-bond functionalization. Detailed mechanistic studies of the developed method were indicative of a reversible C−H-bond activation step. Sahoo et al. described the Ru(II)-catalyzed synthesis of isoquinolinones 405 from N-aroylated sulfoximines and diphenylacetylene (Scheme 201).191 This ortho-C−H alkenylation/annulation occurred with the aid of reusable methyl phenyl sulfoximine as the directing group. Yang and Ackermann reported efficient dehydrative alkyne annulations by NH-unsubstituted hydroxamic acids in water, leading to heterocycles 406 (Scheme 202).192 Ru(II) biscarboxylate catalyst 407 is generated in situ from the anion of the electron-deficient carboxylic acid 3-CF3C6H4CO2H. Detailed mechanistic studies provided strong support for an initial kinetically relevant C−H ruthenation along with a subsequent alkyne insertion. The proposed catalytic cycle furthermore features a reductive elimination and an intramolecular N−OH oxidative addition (Scheme 203).

5.3. Synthesis of Heterocycles

The synthesis of heterocycles through a Ru(II)-catalyzed annulation with internal alkynes has been studied more comprehensively than the aforementioned syntheses of linear alkenylation products. A 2012 review157 devoted to Rucatalyzed C−H bond activation and functionalization included about ten papers on this subject. Several scientific groups have worked intensively in this field, primarily that of Jeganmohan175,179,180 (who used a catalytic system they had developed earlier for oxidative alkenylation with alkenes 181) and Ackermann.182−184 In 2014, Ackermann also published a review on ruthenium-catalyzed alkyne annulations.11 Taking into account the existence of two reviews,11,157 we confine our discussion to work that is not included in these reviews. Ackermann et al. reported Ru(II)-catalyzed oxidative alkyne annulations with tertiary benzylic alcohols 391 by hydroxyldirected oxidative C−H activation to form isochromenes 392 (Scheme 194).185 Terminal alkynes could not be employed for the proposed oxidative annulations. The reaction of unsymmetrically substituted alkynes occurred with moderate to high regioselectivity, furnishing predominantly isomers featuring their aromatic moiety proximal to the oxygen atom of the isochromene ring. The functionalization of meta-methylsubstituted 391 (X = 3-Me) proceeded selectively at the less sterically hindered C−H bond yielding isochromene 392 (X = 7-Me). In contrast, the use of the substrates 391 [X = 3-F and X = 3,4-(CH2OCH2)] gave exclusively compounds 392 [X = 5F and X = 5,6-(CH2OCH2)], corresponding to the activation of the kinetically more acidic C−H bonds. The reaction was also found to be applicable for the heteroaromatic substrate 2(thiophen-3-yl)propan-2-ol (32%). In this case, the C−H activation occurred again at the more kinetically acidic site (the 2 position of the thiophene moiety) with excellent selectivity. Unfortunately, substrates with primary or secondary benzylic alcohols furnished unsatisfactory results. On the basis of D/H exchange experiments and the resulting KIE value (kH/kD = 5.3), the authors proposed a Ru(II)catalyzed oxidative annulation mechanism (Scheme 195). The first step is an acetate-assisted irreversible cycloruthenation under the reaction conditions used, followed by the coordinative regioselective insertion of the alkyne and reductive elimination, furnishing the desired isochromene. Manikandan and Jeganmohan demonstrated a Ru-catalyzed synthesis of 4-alkyl-2-quinolinones 394 via cyclization of acetanilides with alkyl-substituted propynoates in the presence of carboxylic acids (Scheme 196).186 Ethyl phenylpropynoate also reacted with acetanilide (X = 3,4-(MeO)2), providing 4aryl-substituted quinolinone 394 (X = 3,4-(MeO)2, R = Ph) in 41% yield. However, in the reaction, the alternative alkyne insertion product 393 was observed in 32% yield. In the reaction of a terminal alkyne (ethyl propynoate), the corresponding quinolinone derivative was observed only in a 10% yield. The authors proposed that the cyclic products obtained via linear intermediates 393 were formed through the cyclometalation pathway (Scheme 184), which is typical for Ru(II)catalyzed alkenylations of ortho-C−H bonds in functionalized arenes with internal alkynes. The formed linear intermediates 393 cyclized into 4-alkyl-2-quinolinones 394 under the acidic reaction conditions. 5941


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5.4. Comparison of Reactions Catalyzed by Palladium, Platinum, Rhodium, and Ruthenium

Ackermann et al. described the Ru-catalyzed synthesis of fused bis-heterocyclic frameworks, pyrazolo[5,1-a]isoquinolines 408, through the oxidative annulations of aryl- and alkyldisubstituted alkynes by 5-aryl- or 5-heteroaryl-substituted 1Hpyrazoles (Scheme 204).193 Detailed mechanistic studies provided strong support for a reversible C−H bond metalation step with the cationic Ru(II) catalyst. Chandrasekhar et al. reported that a similar annulation of different azoles (2-arylbenzimidazoles 409) using 1 equiv of diphenylacetylene or ethyl phenyl propiolate gave good yields of the benzimidazoisoquinolines 410 in refluxing toluene, or even at room temperature in PEG-400/H2O, without the silver salt addition (Scheme 205).194 2-(Fur-2-yl)- and 2-(thien-2-yl)benzimidazoles also provided in good yields (69−81%) both in the toluene and the water solutions. Use of a precursor featuring a chloro substituent at the 3 position of the phenyl ring (409, X = 3-Cl) gave a mixture of two regioisomers. At the same time, the regioselectivity of the unsymmetrical acetylene (ethyl phenylpropiolate) insertion was very high. Peng et al. described a Ru(II)-catalyzed synthesis of other fused tetracyclic heteroarenes 411 through the oxidative crosscoupling/cyclization of quinazolinones with internal alkynes (Scheme 206).195 The regioselectivities were evaluated by substitution at the 3′-position of the 2-aryl quinazolinone and by using unsymmetrical alkynes. In the case of quinazolinones with X = 3-Me, only a single regioisomer was detected, presumably due to the difference in the steric hindrance. When unsymmetrical alkynes (R/R1 = Ph/Me, R/R1 = 4-MeOC6H4/ Ph) were utilized, moderate regioselectivities of 3:1 and 6:1, respectively, were obtained (Scheme 206 indicates the major isomers in these cases). When the directing amide group was blocked by the methyl group (N-Me-quinazolinone instead of NH-quinazolinone), the reaction could not proceed any further. Moreover, 2-alkyl-substituted quinazolinone underwent coupling with diphenylacetylene to provide the NH-alkenylation product in a moderate yield. This fact indicated that activation of the N−H bond in the directing group is the first step of the catalytic transformation. Lee et al. demonstrated the Ru(II)-catalyzed oxidative cyclization of phosphonic acid monoesters (412, Y = OEt) or phosphinic acids (412, Y = Ar) with internal alkynes for the synthesis of a wide range of phosphaisocoumarins 414 under aerobic conditions (Scheme 207).196 Competition experiments between diaryl- and dialkylalkynes, and between diarylacetylenes bearing 4-methoxy- and 4-chloro- groups, suggested that the oxidative cyclizations were not affected by the electronic effects of the alkynes. Mechanistic studies revealed that the C−H bond metalation of the formed phosphonic or phosphinic acid (intermediate 413) by the Ru-salt was the ratelimiting step. Only one report of Ru-catalyzed synthesis of heterocycles by annulation with terminal alkynes has been published over the last 15 years. Yi et al. reported a method for the synthesis of tricyclic quinoline derivatives 416 via the C−H bond activation of benzocyclic amines 415 with a huge excess (7−14 equiv) of terminal alkynes (Scheme 208).197 This reaction is very unusual for the Ru-catalyzed aryl C−H bond alkenylation/annulation, as the proposed mechanism included not a cyclometalation step but the formation of a RuH+ cationic species as the first step of the transformation, and its subsequent attack at the alkyne, leading to 417 (Scheme 209).

At present, complexes of four of the six platinum-group metals (ruthenium, rhodium, palladium, and platinum) are widely used as alkenylation catalysts. These complexes have similar catalytic properties and tend to catalyze the chemical transformations in the same manner. As a whole, one can conclude that all four metals considered are good catalysts for alkenylation. Palladium catalysis is the most well-studied, perhaps due to the great number of palladium-catalyzed cross-coupling reactions carried out over the last 30 years. However, it should be taken into consideration that palladium catalysts are quite universal. Depending on the substrates used, such catalysts allow the synthesis of both linear and cyclic products, and the latter can be the result of not only intramolecular but also intermolecular cascade reactions, because of the ability of palladium complexes to catalyze other cross-coupling reactions. This universality is due to the possibility of alkenylation by two different mechanisms, viz., through the formation of arylpalladium complexes or vinylpalladium cations (Scheme 3, pathway A or B, respectively). Platinum compounds are used as catalysts of alkenylation much less frequently, and arguably do not have any advantages, when compared to palladium complexes. They are less universal, since (unlike palladium particles) they do not catalyze intermolecular processes that proceed through metalation of an arene. These catalytic cycles always feature the preliminary coordination of the platinum cation to the triple bond (Scheme 73). However, platinum catalysts only began to be studied relatively recently (during the past decade), and it is possible that all active platinum-catalyzed alkenylation reactions have not been disclosed in full. In this respect, rhodium catalysts provide significant contrast to platinum catalysts. Reactions of ortho-metalation are common for Rh catalysts (Schemes 89 and 90). Since intermediates with mutual ortho-orientation of a chelating group and the rhodium-vinyl substituent are usually formed (Scheme 90), the further cyclization occurs very easily. Because of this, rhodium catalysts are only rarely used for the synthesis of linear alkenylation products; however, they are quite effective for the preparation of carbo- and (especially) heterocycles. Ruthenium complexes may soon replace not only those of rhodium but also palladium, as the former are just as effective in the synthesis of cyclic structures, and they allow the preparation of linear products. At the same time, ruthenium is 20 times cheaper than rhodium and 15 times cheaper than palladium, which gives its compounds a significant competitive advantage. Unsurprisingly, several research groups have realized this, since the number of papers devoted to ruthenium-catalyzed alkenylation has grown rapidly over the past few years.

6. GOLD-CATALYZED REACTIONS 6.1. Synthesis of Substituted Alkenes

Reetz and Sommer198 reported on the alkenylation of arenes with alkynes catalyzed by Au(I and III) complexes. The authors found that AuCl3 in combination with AgSbF6 catalyzes the reaction between excess arenes and aryl-substituted alkynes under mild and neutral conditions (Scheme 210, A).198 Electron-rich arenes (e.g., X = Me3, 1,3,5-Me3-2-OH) lead to good-to-excellent yields of product 418 (70−95%), while less activated ones (e.g., X = 1,3,5-Me3-2-Br) gave moderate yields 5942


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Scheme 210. Au-Catalyzed Alkenylation of Arenes

Scheme 214. Au-Catalyzed Formation of Substituted Indenes

(30−60%). Anisole resulted in low yields (9%) due to the formation of unidentified side-products. The reaction with internal alkynes gave lower yields (R = Ph, 5%) due to steric hindrance. Terminal alkynes bearing electron-withdrawing groups reacted with an excess of arenes with a reversed regioselectivity (Scheme 210, B).198 Both Au(I)- and Au(III)-based systems catalyze this reaction, and the PPh3AuCl/BF3·Et2O system was found to be optimal (Scheme 210, B). Products 419 were obtained as a mixture of E-/Z-isomers with the E-form being predominant; the E-derivative is formed from the initially generated Z-form, due to fast isomerization under the reaction conditions. Furan and 2-methylfuran can also be alkenylated under these conditions. The authors suggested that the mechanism of the reaction includes the activation of the alkyne by Au-π complexation followed by nucelophilic attack.198 He and Shi199 investigated the Au(III)-catalyzed reaction between electron-rich arenes and terminal alkynes, leading to alkenylation products E/Z-420 (Scheme 211). Most often cisconfigured (Z-) products were obtained under the reaction conditions, while trans-arylalkenes were also isolated in some reactions (e.g., for R = COMe, X = Me5; R = CO2Et, X = 2,3benzo; temperature = 50 °C). Intermolecular arene-alkyne addition (e.g., between HCCCO2Et and Me5C6H) was also performed under solvent-free conditions and took less time (ca. 1 h vs 48 h in C2H4Cl2). There is an example of the reaction which was only possible under these solvent-free conditions (for PhCCCO2Et and 1,3,5-(MeO)3C6H3; the yield of the corresponding alkenylation product was 97%). Biffis et al.200 studied alkyne hydroarylation catalyzed by gold N-heterocyclic carbene complexes. This group tested several Au(I and III) complexes (Figure 2) in alkenylation reactions (Scheme 212) and found that 421, activated by AgBF4 and in the presence of acid (HBF4), was most effective. The authors noticed that the nature and amount of acid have a strong influence on the catalytic efficiency; changing the acid from HBF4 to TfOH or performing the reaction under neutral conditions led to decreased yields (e.g., for the HCCCO2Et/ Me5C6H pair: from 99% to 51 and 15%, respectively). Hashmi and Blanco201 reported the formation of 2-fold addition product 422 in the reaction of 2-substituted furans with alkynes (Scheme 213). The presumed intermediate, an arylated alkene, was not detected.

Scheme 211. Au(III)-Catalyzed Alkenylation of Arenes

Figure 2. Au(I and III) complexes employed in a catalytic study.

Scheme 212. Au(I and III)/Ag-Catalyzed Alkenylation of Arenes

Scheme 213. Au-Catalyzed Double Hydroarylation of Alkynes

6.2. Synthesis of Carbocycles

The catalyzed formation of substituted indenes 423 and 424 from aryl propargyl acetates was described by Nolan et al. (Scheme 214).202 The authors checked several catalytic systems of the form [AuCl(L)]/AgX (L = PPh3 and NHC − Nheterocyclic carbene, X = BF4, PF6) and found that [AuCl(IPr)]/AgBF4 was the most effective.202 Interestingly, [AuCl(IPr)] or AuCl alone were found to be inactive in the reaction, 5943


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Scheme 215. Mechanism of Au-Catalyzed Indene Formation

Scheme 216. Au(I)-Catalyzed Synthesis of Naphthol Derivatives

and the reaction of alkyne n-BuCCCH(OAc)Ph with AgBF4 resulted in formation of allene n-BuC(OAc)CCHPh. Both electron-poor and electron-rich arenes can be employed in the reaction to give products 423, while ortho-substituted arenes (X = 2-Me, 2,3-benzo) yielded 424 as a minor product. The authors proposed the following reaction mechanism (Scheme 215). The formation of major products 423 proceeds via two 1,2-migrations (or single 1,3-migration) of the acetate group.202 Substituted naphtholes 425 were synthesized using the Au(I)-catalyzed intramolecular cyclization of furan/ynes (Scheme 216).203 Products 425 were obtained as a mixture of isomers with Z-/E ratios varying from 33:1 to 11:1 (R1 = H), while furan/ynes with R1 = Me or Ph gave exclusively Zconfigured substrates 425. The latter can be converted into functionalized benzocoumarins in a one-pot procedure. The proposed mechanism of the reaction includes the initial coordination of the acetylene triple bond to Au(I) complex 425a followed by an intramolecular nucleophilic attack by the furan moiety.203 Ye et al.204 reported the synthesis of anthracenes 426 through the Au(I)-catalyzed cyclization of 2-alkynyldiarylmethanes (Scheme 217). The authors screened a number of different catalysts, mostly Au(I) phosphine complexes both in the presence of and without an acid, and found the system Et3PAuNTf2/HNTf2 to be most efficient.204 Interestingly, under similar conditions (0.5 equiv HNTf2, C2H4Cl2, 80 °C, section 3.1.2), PtCl2 promotes the transformation of 2alkynyldiphenylmethane into a substituted indene.204 The reaction can be applied both to terminal and internal acetylenes and demonstrated a tolerance toward various functional groups (see Y in 426). The authors suggested that the mechanism of the reaction could proceed via the vinyl gold intermediate A, which then transformed into B (Scheme 218).204 An alternative pathway involves a gold-catalyzed hydration followed by an acid-catalyzed cyclodehydration. Intermediate B was detected via 1H NMR monitoring of the cyclization. Ketone C was formed as a byproduct of the reaction, and it was confirmed that C could be transformed into 426 in the presence of an acid. Aryl phenantrenyl selenides 427 and 428 were obtained in the metal-catalyzed [Au(I) and In(III)] cyclization of

Scheme 217. Au(I)-Catalyzed Synthesis of Anthracene Derivatives

Scheme 218. Mechanism of the Au-Catalyzed Anthracene Synthesis

Scheme 219. Au- and In-Catalyzed Syntheses of Phenanthryl Selenides

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Scheme 220. Au-Catalyzed Synthesis of Phenanthrenes

Scheme 221. Au- or Ga-Catalyzed Synthesis of Fluoranthrenes

Scheme 222. Au(I)-Catalyzed Synthesis of NH-Carbazoles

Scheme 223. Plausible Mechanism of Au(I)-Catalyzed NHCarbazole Formation substituted arylalkynes (Scheme 219).205 Au(I)- and In(III)based catalytic (see also section 10.1) systems exhibit the opposite regioselectivity, providing either 427 or 428, respectively. The authors proposed that the Au-catalyzed reaction proceeds via the formation of gold-vinylidene intermediates.205 An Au(I) complex bearing a cationic phosphorus-based ligand, exhibited great activity in the cyclization of alkynylbiphenyls into phenanthrenes 429 (Scheme 220).206 The authors demonstrated the application of this catalyst for the synthesis of several naturally occurring polyoxygenated phenanthrenes and phenanthropyrones (e.g., bulbophylantrin, marylaurencinol, ochrolide, and coeloginin).206 Fluoranthrenes 430 were synthesized by the intramolecular hydroarylation of alkynes, catalyzed either by Au(I) or GaCl3 (Scheme 221).207 Both catalysts could be used for hydroarylation of aryl-substituted substrates bearing electrondonating (e.g., R = 4-MeC6H4, 2-MeOC6H4) and electronwithdrawing (e.g., R = 4-NCC6H4, 4-NO2C6H4) groups; however, GaCl3 gave better yields (e.g., 71 vs 28% for R = 4ClC6H4). The advantage of the Au catalyst is its greater tolerance toward Br substituents.

Two diacenaphtho[1,2-j;1′,2′-1]fluoranthenes 431 (Figure 3) were synthesized in accordance with this methodology via triple alkenylation, catalyzed by a Au complex [(i) 15 mol %, CH2Cl2, RT, 7h; (ii) DDQ, toluene, Δ].207 Kundu et al.208 reports six-membered ring formation in the Au(I)-catalyzed intermolecular hydroarylation of alkynes and 2-

Figure 3. Diacenaphtho[1,2-j;1′,2′-1]fluoranthenes. Bonds formed in the alkenylation are marked in bold. 5945


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substrates with X = O and Y = CH2, CO in the starting material, benzopyrans (Y = CH2) and coumarins (Y = CO) 434 were obtained as main products. In several cases, benzofurans 435 were formed as byproducts (X = O, Y = CH2; R = 3,4(OMe)2, 2-CO2Me, 2-NO2, 3,4-benzo) or single products (X = O, Y = CH2; R = 2,3-benzo). Products of 6-endo cyclization 436 were obtained via Au(I)or Ag(I)-catalyzed (section 10.2.6) intramolecular reactions of internal alkynes (Scheme 226).212 The outcome of the Agcatalyzed reactions demonstrated sensitivity toward the substituent, thereby electron-withdrawing group X hampered the reaction (X = 4-Ac, 4-Ph). The Au catalyst demonstrated activity even for substrates bearing electron-withdrawing groups in both aryl rings (e.g., X = Y = Ac, yield of 436 was 98% with Au catalyst and 0% with Ag catalyst). The Au-based catalyst also demonstrated a greater regioselectivity, only 4-Mesubstituted compounds 436 were obtained for alkynes with X = 3-Me.212 Applying AgOTf yielded two isomers, viz., 4-Meand 2-Me-substituted 436, in a ca. 1:1 ratio. Stratakis et al.213 used gold nanoparticles supported on TiO2 for the cyclization of propargyl ethers (Scheme 227). Dimers of chromenes 437 were formed as byproducts with terminal alkynes (R = H), for which the yield was decreased when the reaction was performed under argon atmosphere. Naturally occurring pyranocoumarins (xanthyletin and seselin) were synthesized from their corresponding alkyne precursors by this protocol (Figure 4).213 Complex [{Au(PPh3)}3O][BF4] was explored in the synthesis of dihydropyrano[3,2-e]indoles 438 from 5-propargyloxyindoles (Scheme 228).214 The authors demonstrated that the Au-catalyzed formation of products 438 from 5-propargyloxyindoles proceeds at lower temperatures and with slightly greater yields of target compounds than the terminal Claisen rearrangement/cyclization (101 °C and yields of 50−80% vs 156 °C and yields of 0−84%). An Au(III)/Ag(I)-based system was applied for the intramolecular cyclization yielding coumarins 439 (Scheme 229).199 Coumarin-containing natural products pimpinellin and fraxetin (Figure 5) were synthesized from corresponding propiolate esters by Au(I)-catalyzed intramolecular hydroarylation (CH2Cl2, 25 °C, 0.5 h); complex [Au(NCMe){P(naphth-2-yl)(t-Bu)2}][SbF6] (5 mol %) was used as a catalyst.215 Intramolecular Au(III)-catalyzed alkenylation resulting in latent fluorophore 440 (Scheme 230) has found application in the design of highly selective and sensitive fluorescence turn-on probes for gold(III), which could be applied for fluorescence microscopic imaging.216 The authors217 studied the cyclization of p-methoxysubstituted aryl alkynoates catalyzed by a Au(I)/Ag(I) system and discovered that in anhydrous conditions the reaction proceeded as an ortho-cyclization process yielding coumarins 441 (Scheme 231, A), while in the presence of 1 equiv of H2O,

Scheme 224. Synthesis of Carbazoles via the Au(III)Catalyzed Intramolecular Cyclization

Scheme 225. Au(I)-Catalyzed Intramolecular Cyclization

Scheme 226. Au(I)-Catalyzed and Ag(I)-Catalyzed Intramolecular Cyclization of 3-Phenoxyprop-1-ynes

alkynyl indoles (Scheme 222), furnishing NH-carbazoles 432. A plausible mechanism is depicted in Scheme 223. Carbazoles 433 were also prepared by the AuCl3-catalyzed intramolecular cyclization of 1-(indol-2-yl)-3-alkyn-1-ols (Scheme 224).209 The reaction includes Au-catalyzed sixmembered ring formation via the intramolecular C−H alkenylation and subsequent aromatization with the loss of H2O. Hashmi210 published a mini-review article in which was described dual gold catalysis in the carbocycle formation reactions, including inter- and intramolecular cyclizations of 1,2-dialkynyl-substituted (hetero)arenes. This work discusses in detail the experimental and computational results of (NHC)gold(I)-catalyzed cyclization reactions and explains their mechanisms. Therefore, we will not discuss these reactions and instead direct readers to this well-written review.210 6.3. Synthesis of Benzopyran and Benzofuran Derivatives

Bandwell et al.211 reported Au(I)-catalyzed intramolecular cyclization of terminal alkynes bearing different spacer groups XY (X = O, NZ; Y = CH2, CO) (Scheme 225). Complex 425a (see Scheme 216) was applied as the catalyst. For

Scheme 227. Cyclization of Propargyl Ethers Catalyzed by Gold Nanoparticles

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Figure 4. Naturally occurring pyranocoumarins obtained by Au-catalyzed reactions.

Scheme 228. Au-Catalyzed Synthesis of Dihydropyrano[3,2e]indoles

Scheme 231. Au(I)-Catalyzed Cyclization of Aryl Alkynolates

Scheme 229. Au(III)/Ag(I)-Catalyzed Synthesis of Coumarins

alkenyl). On the basis of experiments with deuterium-labeled substrates, the authors concluded that the reaction most likely involves an electrophilic aromatic substitution process.218 The direct coupling of anilines and alkynes in the presence of an Au(I) catalyst and under visible light irradiation leads to functionalized indoles 444 (Scheme 234).219 The reaction proceeds selectively when aniline bears an electron-withdrawing group at Ar (X = NO2, CO2Me, etc.). Interestingly, the reaction between aniline 4NO2C6H4NHMe and alkyne PhCCCO2Et performed under the same conditions, but in the absence of visible light leads to enamine 4-NO2C6H4N(Me)C(Ph)C(H)CO2Et (95%), which then converts into 444 (86%) in the presence of O2 and visible light irradiation. Therefore, this reaction could proceed via hydroamination of alkyne followed by a lightinduced radical cyclization.219

Figure 5. Naturally occurring compounds obtained by Au-catalyzed alkenylation. New bonds are marked in bold.

Scheme 230. Au(III)-Catalyzed Formation of Latent Fluorophore

6.5. Synthesis of Quinoline Derivatives

N-Substituted (N-tosyl and N-nitrobenzenesulfonyl) dihydroquinolines 434 were obtained via Au(I)-catalyzed intramolecular cyclization of propargyl amines (Scheme 225, X = NTs, NNs).211 Tanaka et al.220 applied Au(I)/(R)-DTMB-Segphos or (R)BINAP systems for selective alkenylation leading to chiral 4aryl-1H-quinolin-2-ones and 4-aryl-coumarins 445 (Scheme 235). Wang et al.221 studied the Au(I)-catalyzed cyclization of Npropargylamino quinones providing the azaanthraquinone skeleton 446 (Scheme 236). The Au(I)-catalyzed alkenylation was applied for the synthesis of S-shaped double azahelicenes 447 (Scheme 237).222 These species exhibit circularly polarized luminescence activity.

the reaction gave spirocycles 442 via dearomative ipsocyclization (Scheme 231, B). It was found that a bulky R substituent hampered the reaction (yield of 442 is 25% after 20 h for R = TMS, no 442 was produced for R = t-Bu). The authors217 proposed mechanism is shown in Scheme 232. The presence of 4-OMe substituent and 1 equiv H2O are crucial for the spirocycle formation. 6.4. Synthesis of Indole Derivatives

6.6. Formation of other Cyclic Systems

The Au(I)/Ag(I)-based system efficiently catalyzes cyclization of N-aryl amides of propynoic acids into 3-acyloxindoles 443 in the presence of 2-bromopyridine N-oxide, which is required as an oxidant (Scheme 233).218 This reaction works well even with functionalized substrates (e.g., R1 = All; R = thien-2-yl,

Au(I) and Au(III) catalyze the annulation of indoles bearing acetylene moieties in their side-chains to six- to eightmembered rings (Schemes 238 and 239).223 Complex 425a (see Scheme 216) efficiently catalyzes the cyclization to seven5947


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Scheme 232. Mechanism of Au-Catalyzed Spirocyclization

Scheme 233. Au-Catalyzed Cyclization of N-Aryl Amides of Propynoic Acids

Scheme 235. Au(I)/Chiral Biarylphosphine-Catalyzed Alkenylation

Scheme 234. Au(I)-Catalyzed Synthesis of Indoles Scheme 236. Au(I)-Catalyzed Synthesis of Azaanthraquinones

(448) and six-membered (450 and 451) rings (Schemes 238 and 239). AuCl3 promotes the formation of indoloazocynes 449 and 448 (Scheme 238). Wan et al.224 performed Au(I)-catalyzed alkenylation reactions of alkynyl-substituted pyrroles into seven-membered cycles 452 (Scheme 240). The intermolecular Au(I)-catalyzed reaction of pyrroles with alkynes gives functionalized pyrrole derivatives 453 and 454 (Scheme 240). There are a few reports of Au-catalyzed reactions of C−H arenes with internal alkynes leading to substituted naphthalenes, these reactions having mechanisms other than C−H alkenylation. In one case, 1-arylnaphthalenes were obtained via Au(III)-catalyzed intra- and intermolecular epoxide rearrangement from internal alkynes and epoxides.225 Another report is devoted to gold film-catalyzed benzannulation reactions of

terminal alkynes with alkynylbenzaldehydes yielding carbonylsubstituted naphthalenes.226 In contrast to Au-catalyzed C−H alkenylation reactions, C− X alkenylation is less common in recent reports. Thus, oxidative cross-coupling of propargyl acetates R(AcO)CHCCR1 (R = Ph, i-Pr, Me, Cy, PhCH2CH2, 4-BrC6H4, AcOCH2CH2, H; R1 = n-Bu, Ph, MeOCH2CH2, Cy) and arylboronic acids ArB(OH)2 (Ar = Ph, 4-MeC6H4, 4-MeCO2C6H4, 4-ClC6H4, 3-MeCO2C6H4), catalyzed by [AuCl(PPh3)] (5 mol %, MeCN/H2O, [FN(CH2)3NCH2Cl](BF4)2 − Selectfluor, 80 °C, 15−30 min) gave α-arylenones (45−70%).227 5948


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the gold catalyst. In the majority of these works, where mechanisms are discussed, it is supposed that gold acts as a Lewis acid, activating the acetylene triple bond.

Scheme 237. Au(I)-Catalyzed Synthesis of Azahelicenes

7. COPPER-CATALYZED REACTIONS 7.1. Activation of C−H bonds

7.1.1. Synthesis of Substituted Alkenes. The Cu(OTf)2/TfOH-catalyzed CH-alkenylation of arenes by terminal alkynes gives 1,1-diarylethylenes in moderate to good yields (Scheme 241). 228 Excluding any one of the catalyst components (Cu(II) or acid) leads to either decreased yields of 455 or no reaction. The authors228 proposed that the mechanism of the reaction could involve metalation of the arene by the Cu(II) catalyst and coordination of acetylene, followed by intramolecular rearrangement to a vinyl species and protonation by TfOH, affording compounds 455. Bis(indolyl)alkanes 456 were obtained in the reaction of indoles and acetylene sulfones (in a 2:1 molar ratio) (Scheme 242, A).229 Interestingly, the reaction of 2-methylindole with (1-phenyl-2-tosyl)ethyne gave only a monoaddition product 457 (Scheme 242, B), presumably due to the steric hindrance of the 2-methyl substituent. A plausible mechanism for this reaction includes alkyne coordination to a Cu(II) center, addition of the indole to an activated acetylene affording a vinyl copper complex, and release of the indolylalkene by protonation.229 This indolylalkene undergoes addition of the second indole moiety under a similar way. The authors229 also succeeded in obtaining bis(pyrrolyl)alkanes (in yields of 68−80%) in the Cu(II)catalyzed reaction of pyrrole with acetylenic sulfones R1C CSO2R2 (R1 = n-C5H11, Ph, 4-MeC6H4, 4-MeOC6H4; R2 = Ph, 4-MeC6H4, 4-ClC6H4). 7.1.2. Synthesis of Carbocycles. Naphthalene-1,3-diamines 458 were prepared from the Cu-catalyzed reaction of terminal haloalkynes with amines (Scheme 243).230 This reaction involves two consecutive processes: the formation of ynamines R1C6H4CCNR2R3 and Cu-catalyzed dimerization of ynamines. Although the mechanism of the reaction was not discussed, the possibility of Cu(II)-catalyzed arene alkenylation as one of the steps of the reaction should not be ruled out. 7.1.3. Synthesis of Quinoline Derivatives. 1,2Dihydrobenzo[g]quinoline-2,10-diones 459 were obtained by the Cu(OTf)2-catalyzed intramolecular cyclization of Npropargylamino naphthoquinones (Scheme 244).231 2,4-Disubstituted quinolines 460 were synthesized in moderate yields in three-component reactions from aryl amines, aldehydes, and terminal alkynes in the presence of CuCl as a catalyst (Scheme 245).232 Substituted benzylamines 461 were also obtained as byproducts. Substituted propargylamines 462 (from traces to 15%) were formed in the reaction mixture and were proposed as one of the intermediates of the reaction leading to 460. In a separate experiment, the authors showed that 462 could be transformed to 460 in the presence of CuCl.232 Terminal alkynes react with 2-aminobenzaldehydes in the presence of CuI and amine (pyrrolidine) affording 2substituted quinolines 463 (Scheme 246).233 A broad range of alkynes and aminobenzaldehydes with electron-donating and -withdrawing groups could be utilized in the reaction (Scheme 246). A number of biologically active compounds were synthesized using this protocol (e.g., 463 with R1 = R2 = R3 = H, R = n-Pr). The authors proposed a joint action of CuI and

Scheme 238. Au(I and III)-Catalyzed Cyclization of AlkynylSubstituted Indoles

Scheme 239. Au(I)-Catalyzed Cyclization of AlkynylSubstituted Indoles

In summary, gold-catalyzed C−H alkenylation in both intraand intermolecular modes allows access to a broad range of acyclic, carbocyclic and heterocyclic products. Both Au(I) and Au(III) complexes are suitable as catalysts, depending on the nature of the substrates. In some cases, a cocatalyst [e.g., a silver(I) salt] is required to obtain the active “naked” form of 5949


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Scheme 240. Au(I)-Catalyzed Intramolecular Alkenylation of Pyrroles and Intermolecular Alkenylation of Pyrroles with Alkynes

Scheme 241. Cu-Catalyzed Reactions of Arenes with Alkynes

Scheme 244. Cu-Catalyzed Synthesis of 1,2Dihydrobenzo[g]quinoline-2,10-diones

Scheme 242. Cu-Catalyzed Reaction of Indoles with Acetylene Sulfones

Scheme 245. Cu-Catalyzed Synthesis of Quinolines

Scheme 246. Cu-Catalyzed Synthesis of 2-Substituted Quinolines

Scheme 243. Cu-Catalyzed Synthesis of Naphthalene-1,3diamines Quinoline-2-carboxylates 464 were obtained via the Cu(II)catalyzed reaction of alkynes with imines (Scheme 248).234 This reaction is favored with aryl-substituted alkynes but gives lower yields of 464 with aliphatic alkynes (R = PhCH2, 52%). The authors234 also succeeded in synthesizing quinoline-2carboxylates 464 (Scheme 249) via a three-component reaction (see similar in Scheme 245). The proposed mechanism of the reaction includes the formation of propargylic amines, which undergo Cu-catalyzed intramolecular cyclization. 7.2. Activation of C−Hal Bonds

pyrrolidine in the reaction mechanism (Scheme 247).233 The use of either catalysts (either CuI or amine) alone does not give 463.

The Cu-catalyzed reaction of 3-iodo-indole-2-carboxylic acids with alkynes led to indolo-[2,3-c]pyrane-1-ones 465 (Scheme 5950


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Scheme 247. Proposed Mechanism of Joint Catalysis of CuI and Pyrrolidine in the Synthesis of 2-Substituted Quinolines

Scheme 251. Cu-Catalyzed Synthesis of 2-Arylindoles

2-Aryl-substituted indoles 466 were obtained via Cucatalyzed decarboxylative coupling of aryl(alkyl)propynoic acids and 2-iodotrifluoracetanilides (Scheme 251).236 The Cu-catalyzed carboarylation of alkynes with diaryliodonium triflate, in the presence of 2,6-di-tert-butylpyridine (DTBP) as a base, can (at least formally) be considered as an alkenylation of a C−I bond (Scheme 252).237 It was also demonstrated237 that carboarylation could be performed as an intermolecular reaction, involving Ph2I(OTf), alkyne, and anisole as an external nucleophile. A plausible mechanism for this reaction includes the activation of the diaryliodonium salt by Cu(I), followed by the formation of a trisubstituted vinyl cation, which undergoes further reactions (Scheme 253).237 Gaunt et al.238 reported on Cu-catalyzed (CuCl 10 mol %, (tBuO)2, CH2Cl2, 50 °C, 2−6 h) arylative rearrangement of propargylic alcohols R1R2(HO)CCCR3 in reactions with Ar2I(OTf), leading to tetrasubstituted olefins R1R2CC(Ar)COR3 (38−89%). This reaction was applied for the synthesis of heterocycles with medicinal and biological applications. Qu et al.239 performed the Cu-catalyzed intramolecular aryletherification of alkynes bearing alkoxy groups with diaryliodonium salts (Scheme 254). The reaction starts with the formation of the vinyl cation, which then undergoes Cucatalyzed alkoxylation. Dihydropyrans 467a, dihydrofurans 467b, and benzofurans 467c could be synthesized by this method.

Scheme 248. Cu-Catalyzed Synthesis of Quinolone-2carboxylates

Scheme 249. Cu-Catalyzed Three-Component Synthesis of Quinolone-2-carboxylates

7.3. Activation of C−B bonds

Yamamoto et al.240 reported the Cu-catalyzed addition of arylboronic acids to the triple bond of alkynoates 468 (Scheme 255). A range of variously substituted aryl boronic acids and internal propynoates could be utilized in the reaction. The authors240 studied the reaction in MeOD and obtained monodeuterated (74% D) 468. They proposed that the hydroxyl group of methanol behaved as a proton donor. The following mechanism was proposed for the reaction (Scheme 256). 4-Arylcoumarins 469 were obtained via the Cu-catalyzed hydroarylation/cyclization of 2-MOMO-substituted arylpropynoates and arylboronic acids (Scheme 257).241 Several naturally occurring substances were synthesized according to this protocol (Scheme 257). Brown et al.242 studied the copper-catalyzed carboboration of alkynes affording substituted vinylboranes 470 (Scheme 258). Unsymmetrically substituted alkynes gave two regioisomers of 470 in the reaction (only the major isomer is depicted in Scheme 258). The authors demonstrated that the reaction could be applied for the synthesis of estrogen receptor antagonist Tamoxifen. The mechanism of the reaction involves the insertion of an alkyne into the Cu−B bond, giving a vinylcopper intermediate, subsequent reaction with an aryl halide yields 470.

Scheme 250. Cu-Catalyzed Synthesis of Indolo-[2,3-c]pyran1-ones

250).235 The authors235 demonstrated that the iodo group in indole-2-carboxylic acids (X = H, R3 = Me) could be substituted with bromide, leading to the same product 465 with a small decrease in the yield (42%). 3-Iodo-thiophene-2carboxylic acids react with MeO2CCCCO2Me under these reaction conditions giving thieno[2,3-c]pyrane-7-one (61%). The mechanism was not discussed. 5951


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Scheme 252. Cu-Catalyzed Intramolecular Carboarylation of Alkynes

Scheme 253. Plausible Mechanism for the Carboarylation of Alkynes

Scheme 256. Proposed Mechanism for Reaction of Arylboronic acids with Alkynoates

Scheme 254. Cu-Catalyzed Intramolecular ArylEtherification

Scheme 257. Cu-Catalyzed Synthesis of 4-Arylcoumarins

complexes could be applied as precatalysts, and in some instances, strong acid (e.g., TfOH) is used to activate the catalyst. Intra- and intermolecular variants of the reaction are known, giving various acyclic and cyclic products.

Scheme 255. Cu-Catalyzed Reaction of Arylboronic Acids with Alkynoates

7.4. Related Reactions

There are several works devoted to Cu-catalyzed intra- and intermolecular reactions of alkynes with C−H(X)-substituted (hetero)arenes, but these reactions have different mechanisms from those discussed in previous sections. Despite the absence of the C−H(X) bond alkenylation step in (hetero)arenes, these reactions can be formally compared (in terms of starting materials, catalysts, and/or products) with the reactions considered in this review, thus we provide a brief overview of these reactions. A variety of CF3-substituted dihydronaphthalenes and chromenes were obtained via the copper-catalyzed carbotrifluoromethylation of a carbon−carbon triple bond.243,244 Benzofurans were synthesized by the CuI-catalyzed domino coupling of terminal acetylenes with bromobenzyl tertiary alcohols,245 and also from phenols and internal alkynes in the

Thus, copper catalyzes both C−H and C−X bond alkenylation processes. For C−H alkenylation, it is commonly supposed that Cu acts as an alkyne activator, while in C−X reactions, the Cu center first reacts with the Ar(HetAr)−X substrate to give Ar(HetAr)−Cu, followed by alkyne insertion into the Ar(HetAr)−Cu bond. Both Cu(I) and Cu(II) salts and 5952


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Scheme 258. Cu-Catalyzed Carboboration of Alkynes

presence of a catalytic amount of Cu(OTf)2.246 CuCl2 was found to catalyze the cyclization of 2-halobenzoic acids with internal alkynes yielding isocoumarins.247 The reaction of 2haloanilines with acetylenic sulfones, ynoates, and ynones in the presence of Cu(OAc)2 afforded variously substituted indoles.248 Pyrazolo[5,1-a]isoquinolines were obtained in copper-catalyzed reactions of ortho-alkynylsubstituted bromobenzenes and pyrazoles.249 1,7- and 3,9-dideazapurines were synthesized from 2-amino-3-iodo- and 3-amino-4-iodopyridines and internal alkynes via addition and copper-catalyzed intramolecular arylation.250 The reaction of aryliodonium salts with nitriles and internal alkynes in the presence of Cu(OTf)2 allowed access to quinolines.251,252 4-Sulfonamidoquinolines were prepared via CuI-catalyzed cascade reactions of sulfonylazides with alkynyl

reaction are high catalyst selectivity under mild reaction conditions, and the possibility of regeneration and multiple use of the catalyst. The presence of a donor substituent in the strating arylacetylene (R2 = Me) allows a reduction of the reaction time. Not only the above-mentioned aluminosilicate complex of iron, but also Y-zeolite HSZ-360 catalyzes regioselective orthoalkenylation of arenes and phenols with phenylacetylene leading to analogous 1,1-diarylalkenes 471.257 In two reports,258,259 Friedel−Crafts alkenylation of electrondonating arenes with alkynes was studied under the action of a catalytic amount of FeCl3 leading to the formation of isomeric 1,1-diarylalkenes E/Z-472 (Scheme 260). The presence of an electron-donating methoxyl group in the arenes gave products of double hydroarylation 473.259 Here, in addition to the catalyst, AgOTf was used as an additive to form the more reactive Fe(OTf)3 in situ, increasing the yields of the target compounds. Aryl lithium derivatives 474 bearing alkyl substituents at the ortho-position of an aromatic ring interact with alkynes under the action of Fe(acac)3 with generation of intermediate A (Scheme 261).260 The decomposition of the latter by electrophilic agents [MeOH, PhCHO, and (CH2)2Br2] leads to the product 475. The presence of the ortho-SiMe3 group in the compound 474a under analogous reaction conditions gives a mixture of isomeric benzosilols 476a and 476b. The authors showed that the reaction of the Fe(III) complex with 10 equiv of the aryllithium compound 474 leads to tetraarylferrate B, which is not able to participate in the coordination with alkynes (Scheme 262).260 The use of 6 equiv of 474 gives triarylferrate C, which is able to coordinate with alkynes and ultimately lead to complex A. Arylindium reagents 477 undergo annulation with the participation of two molecules of acetylene under the action of the FeCl3-dppbz system (Scheme 263).261 Unsymmetrical alkynes lead to a mixture of isomeric naphthalenes 478, while alkyl aryl acetylenes selectively give products with alkyl substituents at the α-position. Indium reagent 477 is too unreactive to give any addition products with FeCl3, thus the

Scheme 259. Fe-Catalyzed Alkenylation of Phenols with Alkynes

imines.253 Quinoxalines were obtained from benzene-1,2diamine and terminal alkynes in the presence of Cu(OAc)2.254 Tandem Cu-catalyzed reactions, CuAAC and Ullmann coupling, provided substituted 1,2,3-triazoles from N-(2haloaryl)-propiolamides.255

8. IRON-CATALYZED REACTIONS In general, a number of iron compounds act as Lewis acids activating acetylene triple bonds or other electron-donating groups in organic molecules, and then these activated organic moieties behave as electrophilic centers. One report256 describes the alkenylation of 4-substituted phenols with arylacetylenes catalyzed by mesoporous aluminosilicate complex Fe−Al-MCM-41, leading to 1,1-diarylalkenes 471 (Scheme 259). The unusual features of this

Scheme 260. FeCl3−Catalyzed Alkenylation of Arenes with Alkynes

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Scheme 261. Fe(acac)3-Catalyzed Alkenylation of Aryl Lithium Derivatives with Alkynes

Scheme 262. Proposed Mechanism for Alkenylation of Aryl Lithium Derivatives with Alkynes

Scheme 265. FeCl3-Catalyzed Synthesis of Naphthalenes from Aryl (Naphthyl) Acetaldehydes and Alkynes

It is pointed out in the original article261 that the mechanism of this reaction is not quite clear; however, the authors proposed a possible catalytic cycle (Scheme 264). Thus, the interaction of the catalyst with the arylindium derivative 477 gives species A, which reacts with the alkyne leading to the intermediate B. Then two pathways are possible. The first is the intramolecular activation of the ortho- C−H bond of the aromatic ring and generation of the ferrocycle C, the addition of the aromatic ring to which gives the naphthalene 478. An alternative pathway for the formation of compound 478 includes the addition of the alkyne to B with formation of intermediate D, which further undergoes cyclization into naphthalene 478. Because of the absence of an external oxidant, the generation of the A occurs as a result of transmetalation of iron hydride E and complex 477. On the basis of the regioselectivity of products 478, the authors chose the first route as the most probable one.261 Hydroarylation of internal acetylenes with aryl- and naphthyl acetaldehydes gives regioselectively substituted naphthalenes and phenanthrenes 479 (Scheme 265).262 The reaction of these aldehydes with terminal alkynes does not proceed. However, in case of the trimethylsilyl group attached to the triple bond, it is possible to split Me3SiOH in the course of the reaction and obtain products 479a with R3 = H. On the basis of the X-ray data obtained, which showed that the bulkiest substituent R2 is found at the α-position of the naphthalene, the authors proposed a plausible mechanism of the reaction (Scheme 266).262 Initially, the coordination of FeCl3 at the oxygen atom of the carbonyl group takes place with formation of the intermediate A. Further, the electrophilic attack of the arylacetylene with the intermediate A occurs, accompanied by the generation of a new carbon−carbon bond in the vinyl cation B, which is stabilized by aryl substituent. As a result of the Friedel−Crafts reaction, intramolecular cyclization into the dihydronaphthalene structure C proceeds. Further elimination of the active species and aromatization afford the final product 479a. If R3 = SiMe3, the 1,5-H shift is possible

Scheme 263. FeCl3-dppbz-Catalyzed Synthesis of Naphthalenes

Scheme 264. Plausible Mechanism of FeCl3-dppbz-Catalyzed Synthesis of Naphthalenes

authors261 envisioned that the reactivity of compound 477 might be modified by transmetalation with a Grignard reagent bearing a nontransferable trimethylsilylmethyl group. 5954


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Scheme 266. Mechanism of the FeCl3-Catalyzed Synthesis of Naphthalenes

Scheme 267. FeCl3-Catalyzed Intramolecular Hydroarylation of Propargyl Alcohols

Scheme 268. Fe(III)-Catalyzed Intramolecular Cyclization of Substituted Biaryls into Phenanthrenes

481 (Scheme 267).263,264 However, the immediate increase of the temperature leads directly to compounds 481 without intermediate isolation of allenes 480. Iron(III) salts are able to catalyze the intramolecular synthesis of 9,10-substituted phenanthrenes 482 from various

with the extrusion of Me3SiOH or Me3SiOSiMe3 from intermediate D, leading to naphthalenes 479a. Friedel−Crafts intramolecular alkenylation of propargyl alcohols under the action of aqueous FeCl3 gives cycles 480, and additional workup at 60 °C leads to isomerization products 5955


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Scheme 269. Fe(III)-Catalyzed Intramolecular Cyclization of Alkynes

Scheme 270. Fe(III)-Catalyzed Intramolecular Synthesis of Coumarin and Quinoline Derivatives

proceeds via 6-endo-dig cyclization as a result of the coordination of iron(III) complexes at basic centers of the precursor molecules followed by the ring closure.267−270 Measurement of the H/D KIE showed that the Friedel−Crafts reaction is the key step of the process.267 In addition to intramolecular cyclizations,267−270 reactions of alkynylarenes 485 with diorganyl diselenides were developed, leading to the formation of organoselenyl coumarins and quinolones 486a,b271 and carboarylation of alkynyl arenes 485 with N,O-acetales272 under the action of iron salts (Scheme 270). FeCl3 is able to catalyze cascade processes, including reaction of ynone 487 with 2-aminoaryl ketones and aldehydes via Michael addition followed by further cyclization into substituted quinolines 488 (Scheme 271).273 The authors showed that the conjugated addition of a triple bond to an amino group is the limiting step of this process. In such a way, the condensation product A was obtained, which was cyclized into the quinoline 488.273 Intermolecular reactions of hydroxylamines with alkynes in the presence of the iron complex Fe(Pc) resulted in the formation of 3-arylindoles 489 (Scheme 272).274 Imines 490, in reactions with alkynes bearing donor275 or acceptor276 groups, give 4- or 3-substituted quinolines, respectively, in the presence of catalyst FeCl3 (Scheme 273).

Scheme 271. FeCl3-Catalyzed Synthesis of Quinolines from 2-Aminoaryl Ketones and Ynones

alkynyl biaryls bearing carbonyl265 or 1-hydroxyalkyl266 substituents (Scheme 268). As the authors pointed out, they were unable to determine the role of the catalyst and only gave a probable mechanism of the reaction. This includes the formation of the benzyl-type carbocation A (Scheme 268) and its 6-exo-dig cyclization with the acetylenic fragment, which leads to the oxetene intermediate B.265 The further cycloreversion of the oxeten B gives phenanthrene 482. Only internal alkenes interact in such a way. In a number of reports,267−270 the intramolecular alkenylation of acetylenic substrates 483 leading to various carbo- and heterocycles 484 is proposed (Scheme 269). The reaction Scheme 272. Fe-Catalyzed Synthesis of Indoles

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Scheme 273. FeCl3-Catalyzed Synthesis of Quinolines from Imines and Alkynes

Scheme 274. Fe3O4-Promoted Interaction of Naphthoyl Chlorides with Alkynes

Scheme 275. Plausible Mechanism of the Fe3O4-Promoted Reaction of Naphthoyl Chlorides with Alkynes

Scheme 276. FeCl3-Catalyzed Synthesis of Indenes

surface of the magnetite and cleavage of the carbon-chlorine bond with the formation of the acyl cation A (Scheme 275). Addition of acetylene gives vinyl cation B that further undergoes electrophilic aromatic substitution forming the intermediate C, while deprotonation of the latter gives target compounds 491. Another example of the synthesis of indene derivatives 494 under the action of Fe(III) is the reaction of Nbenzylsulphonamides with internal alkynes (Scheme 276).277,278 Under the action of FeCl3, the generation of a benzyl cation from a sulfonamide takes place. This cation further attacks the alkyne. The intermediate formed in such a way cyclizes with the formation of the final indene.

In addition to iron salts and other complexes, iron oxides such as magnetite are capable of catalyzing alkenylation reactions of arenes with alkynes (Scheme 274).277 Naphthoyl chloride interacting with unsymmetrical aryl acetylenes leads to the corresponding condensed indenones 491. The reaction with alkyl acetylenes gives compounds 492 as a result of a simple isomerization of cyclopentanaphthalene-1-ones formed under the reaction conditions. The authors also showed the preparation of the compound 493 from 3,3-dimethylbut-2-yne. In this case, the migration of the methyl group takes place, as described earlier for other Lewis acids.277 The authors277 proposed a plausible reaction mechanism consisting of the adsorption of naphthoyl chloride on the 5957


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[Ni(cod)2] affording (hetero)aryl alkene nitriles 498 (Scheme 281).284,285 For unsymmetrical alkynes, the regioselectivety depends on the nature of the substituent, ranging from >99:1 for R1/R2 Me/t-Bu to 37:63 for n-Pr/CH2OMe. Arylcyanation was also performed in an intramolecular manner with 2NCC6H4CH2CH2CCMe (conditions I, Scheme 281) giving the corresponding alkene.284 The addition of a Lewis acid, viz., AlMe3 or AlMe2Cl, increased the efficiency of the reaction.285 It was proposed that the oxidative addition of the C−CN bond to the nickel center is one of the first steps, and Lewis acids facilitate this step via coordination with the cyano group. Selective arylcyanation of alkynes R1CCR2 (R1 = Alk, Ar, H; R2 = Alk, Ar) with polyfluoro benzonitriles C6HnF(5−n)CN was performed in the presence of [Ni(cod)2] (2−3 mol %), DPEphos (2−3 mol %), and BPh3 (8−12 mol %) (cyclopentylmethyl ether, 100 °C, 8−52 h).286 Only alkene nitriles were obtained (55−98%), and no products of C−H or C−F cleavage were observed. A mechanistic study of the reaction allowed the detection of the intermediate complex [Ni(CN· BPh3) (Ar) (DPEphos)] in the reaction mixture of ArCN with a stoichiometric amount of [Ni(cod)2], DPEphos, and BPh3; the former gave the product 498 and complex [Ni(DPEphos)(η2-(n-Pr)CC(n-Pr))] when reacted with alkyne (n-Pr)C C(n-Pr).286 2-Quinolones 499 were synthesized via a [Ni(cod)2]catalyzed reaction of 2-cyanophenyl benzamide derivatives with alkynes (Scheme 282).287 The reaction is an arylcyanation and is accomplished via elimination of the nitrile group in the form of PhCN. Decarbonylative C−C alkenylation of phthalic anhydride with alkynes, catalyzed by [Ni(cod)2], led to isocoumarins 500 (Scheme 283).288 The reaction of alkyne (n-Pr)CC(n-Pr) with 2,3-naphthalene dicarboxylic anhydride and 3-Mesubstituted phthalic anhydride proceeded similarly.288 The proposed mechanism consists of the oxidative addition of the O−CO bond to nickel, subsequent decarbonylation, and insertion of the alkyne into the Ni−Ar bond. Later, mechanisms of Ni- and Pd-catalyzed reactions of phthalic anhydride with alkynes, leading to isocoumarins and naphthalenes, respectively, were studied by DFT calculations.289 The different activities of nickel and palladium

Scheme 277. Ni-Catalyzed Alkenylation of Fluoroarenes

9. NICKEL-CATALYZED REACTIONS Several reports describe intramolecular alkenylation of (hetero)arenes with alkynes, catalyzed by [Ni(cod)2], leading to substituted olefins 495 (Scheme 277).279−282 Thus, Ni(0) catalyzes the alkenylation of polyfluoroarenes, and C−H activation is preferred over C−F activation.279 In some cases, products of double alkenylation were obtained (e.g., for arenes such as 1,2,3,5- and 1,2,4,5-C6H2F4). The proposed mechanism includes an oxidative addition of the C−H bond in one of the first steps.279 Heteroarenes, viz., triazolopyridines and imidazolo[1,5-a]pyridines, were alkenylated with internal alkynes in the presence of [Ni(cod)2] (Scheme 278).279,281 In the case of imidazolo[1,5-a]pyridines, the regioselecivity of the C−H alkenylation is determined by the presence or absence of AlMe3 in the system (Scheme 278).281 Various heteroarenes were alkenylated with internal alkynes in the presence of [Ni(cod)2] giving heteroaryl-substituted alkenes 496 (Scheme 279).282 [Ni(cod)2] catalyzes annulation of alkynes with N-arylpyrimidin-2-amines leading to indoles 497 (Scheme 280).283 The directing group, pyrimidyl, could be removed by the treatment of 497 with NaOEt. The reaction includes steps involving the reversible C−H/N−H activation of aniline. Nickel complexes catalyze alkenylation of arene and heteroarene substrates, accompanied by the cleavage of C−C single bonds. Several works describe the alkyne insertion into the C−CN moiety. Thus, (hetero)aryl cyanides react with internal alkynes in the presence of a catalytic amount of Scheme 278. Ni-Catalyzed Alkenylation of Heteroarenes

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Scheme 279. Ni-Catalyzed Alkenylation of Heteroarenes

Scheme 280. Ni-Catalyzed Synthesis of Indoles

Scheme 283. Ni-Catalyzed Synthesis of Isocoumarins from Phthalic Anhydride and Alkynes

Scheme 281. Ni-Catalyzed Arylcyanation of Alkynes Scheme 284. Ni-Catalyzed Synthesis of Isoquinolones and Isoindolones from Phthalimides and Alkynes

Scheme 282. Ni-Catalyzed Synthesis of Quinolones

alkyne substituents (Scheme 284).290,291 In both cases, the reaction starts with N−CO oxidative addition followed by decarbonylation. Substituted indenes 503 and quinolines 504 were obtained via the Ni(II)-catalyzed cyclization of 2-halide-substituted anilines or benzyl zinc bromides with alkynes (Scheme 285).292,293 The proposed mechanism involves the formation of an Ar−Ni intermediate due to the oxidative addition of an Ar−Hal bond to the nickel center. One of the subsequent steps could involve alkyne insertion into the Ni−C bond.

catalysts were explained by differences in metal−C bonds, arising from the relativistic effect of late transition metals. Kurahashi and Matsubara also demonstrated that the Nicatalyzed decarbonylative addition of phthalimides to alkynes gave isoquinolones 501 and isoindolones 502, depending on the presence of a Lewis acid in the system and the nature of the 5959


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Scheme 285. Ni-Catalyzed Alkenylation of C−Halide Bonds

Scheme 286. In-Catalyzed Intramolecular Alkenylation of Indoles Bearing Alkynyl Substituents

shorter reaction times (122 h).296 This protocol ([bmim][SbF6], methylcyclohexane, 85 °C) was applied in Hf(OTf)3catalyzed (10 mol %) intramolecular cyclizations of arylpropiolates and amides of phenylpropiolic acid, forming 4coumarins (51−89%) and 2-quinolinones (72%), respectively.296 2-H-Chromenes (12 examples, 30−97%) were obtained via the intramolecular cyclization of aryl propargyl ethers ArOCH2CCR (toluene, RT−100 °C, 1−6 h), catalyzed by InI3 (5 mol %). The reaction is promoted by the activation of the alkyne via coordination to the In(III) center via electrophilic aromatic substitution.297 In(OTf)3 (10 mol %) was applied as a catalyst for the hydroarylation (toluene, MW at 120 °C, 30 psi, 30−40 min) of terminal alkynes 4-RC6H4CCH (R = H, Me, OMe) with 2naphtholes (unsubstituted and 7-methoxy), achieving 1-vinyl-2naphthols (85−95%), which were further applied in the synthesis of 2,3-diarylnaphthofurans.298 3-Aryl and 3-heteroarylindoles react with propargyl ethers HCCCH(R)OZ under indium-catalyzed conditions, yielding regioisomers 505 and 506 (Figure 6).299 The regioselectivity of the reaction depends strongly on the leaving group of the propargyl ether. Products 505 were obtained as a single isomer in the reaction with HCCCH(R)OZ (R = H, Me, n-C5H11; Z = H, Me, TMS) and 506 as the major isomer (90−94%) in the reaction with HCCCH2OCO2Et. 3-Heteroarylindoles (thien-3-yl, benzothien-3-yl, and indol-3-yl) react with propargyl ethers in a similar way. The difference in the regioselectivity could be explained by the difference in one of the first steps of the reaction.299 In the case of the formation of 505, the reaction starts with the addition of the indolyl C−H bond to the In-activated CC bond, followed by intramolecular cyclization and aromatization. For the substrate HCCCH2OCO2Et, containing the good leaving group OCO2Et, the substitution of the indolyl C−H bond with the CH2CCH moiety is proposed as the first step, with further cyclization and aromatization achieving 506.

Internal acetylenes, viz., ArCCAr′ and ArCCAlk, react with arylmagnesium bromide (toluene, room temparature, 1 h) in the presence of NiCl2·6H2O (1 mol %) affording, after the treatment with H2O, substituted alkenes (24 examples, 63− 99%).294 In summary, nickel complexes catalyze alkenylation of a range of different bonds, including C−H, C−Hal, and even C− C, the latter being rather rare in organic synthesis. Commonly, complexes of Ni(0) are applied as the precatalyst (i.e., [Ni(cod)2]). When Ni(II) complexes are used as the precatalyst, the reaction system requires an additional reductant (e.g., Zn or organozinc compounds). The mechanism of the alkenylation includes C−X bond activation, which proceeds via oxidative addition to a low oxidation state nickel center. Both intra- and intermolecular alkenylation reactions are known, leading to polysubstituted alkenes and carbocycles. Alkenylation followed by other reactions allows the synthesis of a range of heterocyclic products (e.g., indoles, isoindoles, quinolones, isoquinolines, and isocoumarins).

10. REACTIONS CATALYZED BY OTHER METALS In this section, we provide an overview of reactions catalyzed by other metals that are not covered by the previous chapters. 10.1. Main Group Metals and Lanthanides

Indium has steadily increased in popularity as a catalyst in recent years. Shirakawa et al. applied metal triflates M(OTf)n (M = In, Sc, n = 3; M = Zr, n = 4) as catalysts (10 mol %) for alkenylation (85 °C, 2−186 h) of arenes (C6H6, PhMe, 1,4Me2C6H4, PhOMe, 1,4-(MeO)2C6H4, PhBr, PhCl) with internal and terminal alkynes R1CCR2 (R1 = Ph, 4MeOC6H4, 4-ClC6H4, 4-CF3C6H4; R2 = H, Me, Ph) leading to corresponding alkenes (28−92%).295 M(OTf)3-catalyzed (10 mol %, M = Sc, In, Hf) alkenylation of arenes was performed (85 °C) in hydrophobic ionic liquids ([bmim]X: bmim =1-n-butyl-3-methylimidazolium, X = PF6, SbF6) with

Figure 6. Products of In(III)-catalyzed annulation of 3-arylindoles with propargyl ethers. 5960


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Scheme 287. Mn-Catalyzed Alkenylation of 2-Aryl Pyridines with Terminal Alkynes

10 mol %, 2,2′-bipyridine 20 mol %) to obtain substituted fluorenes (18 examples, 51−82%).306

Scheme 288. Co-Catalyzed Alkenylation of Aromatic Ketones and Imines

10.2. Transition Metals

10.2.1. Tungsten. 2-Arylated quinolines were obtained in yields of 45−82% from alkynyl imines, which underwent [4 + 2] electrocyclization [(i) THF, reflux, 1−3 h; (ii) Nmethylmorpholine N-oxide, CH2Cl2, RT, 1 h] in the presence of [W(CO)5(THF)] (20 mol %).307 It is proposed that tungsten activates the CC bond with the initial formation of a vinylidene complex. 10.2.2. Manganese. Complex [MnBr(CO)5] and base Cy2NH catalyze C−H alkenylation of 2-arylpyridines with terminal alkynes (Et2O, 80 °C, 6 h) (Scheme 287).308 The reaction is initiated by the deprotonative C−H activation of coordinated arylpyridine with the formation of a five-membered metallacycle and alkyne insertion into the Mn−C bond. Wang et al. reported the manganese-catalyzed ([MnBr(CO)5] 15 mol %) [4 + 2] annulation of aryl-substituted NH imines with internal alkynes (1,4-dioxane, 105 °C, 12 h) providing isoquinolines (51−97%).309 The proposed mechanism includes C−H activation via cyclomanganation of the imine, followed by the insertion of the alkyne into the Mn− CAryl bond. 10.2.3. Rhenium. The tandem Re/Mg-catalyzed ([ReBr(CO)5] 2.5 mol %, PhMgBr 30 mol %) alkenylation/cyclization of benzamides and alkynes (THF, 120−150 °C, 18−48 h) yields cis- and trans-3,4-dihydroisoquinolinones (58−90%).310 Complex [ReBr(CO)5] (5 mol %) also catalyzes the reaction of acetal PhCH2CH(OMe)2 with acetylenes ArCCR (R = H, Alk, Ar) (1 equiv H2O, C2H4Cl2, 80 °C, 20 h) with the formation of 1,2-disubstituted naphthalenes (14−78%).311 10.2.4. Cobalt. Yoshikai et al. reported312,313 on orthoalkenylation of arenes with alkynes in the presence of CoBr2 (Scheme 288). This reaction affords ortho-alkenylated aldehydes, ketones (X = O), or imines (X = NR) that can be utilized in further transformations. The catalytic cycle includes an ortho-C−H activation step via the formation of a (C,N)cobaltocycle. The Co-catalyzed (CoBr2 10 mol %, PR3 10 mol %, tBuCH 2MgBr 60 mol %) alkenylation of N-pyrimidylsubstituted indoles with alkynes (THF, 20 °C, 12 h) proceeds similarly and affords 2-alkenyl-substituted indoles (61− 93%).314 The selective indole C-2 alkenylation/annulation (KOAc 20 mol %, C2H4Cl2, 130 °C, 20 h) proceeds in the presence of [Co(Cp*)(C6H6)][PF6]2 (5 mol %), yielding pyrroloindolines (58−89%).315 The mechanism of the reaction, which is supported by experimental studies, includes cyclocobaltation of the indole and alkyne insertion into the Co−C bond.

Scheme 289. Annulative Coupling of 2-Arylbenzoyl Chlorides and Alkynes to Form Phenanthrenes

2-Propargyl biaryls undergo InCl3-catalyzed (10 mol %) intramolecular 6-exo-dig hydroarylation (C2H4Cl2, 80 °C, 1−20 h) leading to functionalized phenanthrenes (80−99%).300 Propargylic alcohols R1R2C(OH)CCR3 (R1/R2 = Alk/Alk, Alk/Ar, Ar/Ar; R3 = Ph, heteroaryl, Alk) react with 2-naphthol (solvent-free, ball milling 30 Hz, RT, 1 h) in the presence of InCl3·4H2O (20 mol %) yielding naphthopyrans (76−97%).301 4-Arylquinoline-2-thiones (12−99%) were synthesized via In(III)-mediated (In(OTf)3, 100 mol % or InBr3 150 mol %) tandem alkenylation/cyclization (ArH, 150 °C, 1−10 h) of 2alkynylphenyl isothiocyanates with ArH (Ar = Ph, 4-PhOC6H4, 4-MeC6H4, 4-BrC6H4, 2-MeO-5-BrC6H3, 2,5-(MeO)2C6H3, and 2,4,6-Me3C6H2).302 An intramolecular hydroarylation of Ugi adducts leads to either azepinoindolones 507 or azocinoindolones 508 (Scheme 286), depending on the catalyst applied, either In(III) or Au(I) (see Section 6), respectively.303 InBr3 (100 mol %) promotes the dimerization of 2-ethynyl aniline derivatives (MeOH, reflux, 24 h) into substituted quinolones (56−89%).304 Indium activates the acetylene bond, leading to the intermolecular cyclization. Ce(OTf)3 (10 mol %) catalyzes the cascade cyclization/ aromatization (toluene, reflux, 2−12 h) of ferrocenyl acetylene, aldehydes, and anilines with the formation of 4-ferrocenylsubstituted quinolines (26 examples, 22−75%).305 (Z)-Pent-2-en-4-yl acetates react with ethynylarenes (MeNO2, 80 °C, 6−12 h) in the presence of Bi(III) (BiBr3 5961


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Scheme 290. TfOH-Promoted Reactions of Ethynyl- and Propargyl-Substituted Nitrogen-Containing Heterocycles with Benzene

1,2,3,4-Substituted naphthalenes (16 examples, 10−87%) were synthesized via cobalt-catalyzed (CoBr2/PPh3 10/10 mol %) C−I alkenylation/cyclization of aryl iodides and 2 equiv of alkynes AlkCCAlk (2 equiv of Mn, MeCN, 25 °C, 3−8 h).316 Presumably, CoBr2, initially reduced by Mn, reacts with aryl iodides to afford Ar−[Co]−I, which undergoes the double alkyne insertion. A similar process, viz., carbocyclization of 2iodophenylketones and aldehydes with internal alkynes (Zn, MeCN, 80 °C, 24−48 h), catalyzed by [CoI2(dppe)]/dppe (5/ 5 mol %), affords indenols (32 examples, 46−99%).317 ortho-Alkenylaryl zinc complexes were generated via the [CoCl2(Xantphos)]-catalyzed [5 mol %, Xantphos (4,5-bis(diphenylphosphino)-9,9-bimethylxanthene)] reaction of aryl zincates and internal alkynes (THF, 60 °C, 4 h).318,319 They were then converted in situ either to ortho-alkenylaryl iodides (82%, treatment with I2) or to benzo[b]thiophenes (38−76%, CuI 1,5 equiv, S, 90 °C, 4 h), or benzo[b]phosphole derivatives [35−67%, (i) CuCN·2LiCl 20 mol %, PCl3 and ArMgBr (or PhPCl2), 60 °C, 12−18 h and (ii) H2O2 or S8, RT]. 10.2.5. Iridium. 2-Arylbenzoyl chlorides react with internal alkynes in the presence of the catalyst [IrCl(cod)]2/P(t-Bu)3 to form phenanthrene derivatives (Scheme 289).320 The reaction starts with an oxidative addition to the Ir(I) center followed by decarbonylation to give an aryliridium species, which interacts with the alkyne. The phosphine acts both as a base in the metalcatalyzed C−H activation step of the reaction and as a ligand. The complex [IrCl(cod)]2 (5 mol %) catalyzes annulation of ketimines ArC(N = R)R1 with internal and terminal alkynes (NaBArF4 10 mol %, toluene, 80 °C, 20 h), which proceeds via C−H activation to give aminoindene derivatives (16 examples, 52−96%).321 10.2.6. Silver. A number of silver-catalyzed reactions that are related to C−H alkenylation, but have a different mechanism, should be mentioned: AgOTf-catalyzed iminoannulation of indole-3-carbonyl derivatives with propargylic alcohols,322 AgOAc-catalyzed dehydrogenative annulation of arylphosphine oxides with alkynes producing benzophosphole oxides,323,324 and AgBF4-catalyzed cascade cyclization of 1,6diyn-4-en-3-ols to form benzo[a]fluorenols.325 10.2.7. Mercury. Hg(OTf)2 (5 mol %) catalyzes the intermolecular alkenylation of tryptamines (3-substituted indoles) with alkynes (CH2Cl2, room temperature, 3 h), affording gem-2-vinyl-substituted tryptamines (79−86%).326

The solid-supported Hg catalyst, viz., silaphenylmercuric triflate (10 mol %), was explored in the intramolecular cyclization of alkynes (CH2Cl2 or MeCN, room temperature to 90 °C, 1−4 h).327 In conclusion, metals that catalyze (hetero)aryl alkenylation should be divided into two groups: the first group act as CC Scheme 291. TfOH-Promoted Reactions of EthynylSubstituted Aniline and Phosphonium Salts with Benzene

bond activators (e.g., indium, lanthanides and mercury), and the second group activates the C−H bond via formation of the C−M intermediate (e.g., manganese, rhenium, cobalt, and iridium). Both intra- and intermolecular reactions are possible, affording substituted alkenes, carbocycles, and heterocycles.

11. BRO̷ NSTED-ACID-PROMOTED REACTIONS Protonation of the acetylene bond by Brønsted acids gives vinyl cations, which may alkenylate arenes and heteroarenes. Due to high protonation ability and extremely low nucleophilicity, Brønsted superacids are the most effective agents for these transformations. The superacidity allows generation of highly reactive dicationic, tricationic, and even more highly (positively) charged species. On the other hand, the low nucleophilicity of the superacidic medium suppresses the interaction of vinyl cations with acid counterions and directs reactions of the cations with aromatic π-nucleophiles in new carbon−carbon bond-forming manners. Various Brønsted and conjugate Brønsted-Lewis (super)acids, TfOH, FSO3H, HF, H2SO4, CF3CO2H, TfOH-SbF5, FSO3H-SbF5, HF-SbF5, etc., have been found to protonate triple bonds with further alkenylation of (hetero)arenes. The most widely used acid for 5962


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Scheme 292. Tf2NH-Promoted Reactions of Amino Alkynes with Indoles

Scheme 293. TfOH-Promoted Reactions of Amino Alkynes with Indoles and Furans

Scheme 295. Dimerization of Acetylene Substrates in Superacids

291). When a trimethylsilyl-substituted alkyne is used, this group is replaced by a proton during the reaction. A general method for the introduction of aminoalkenyl groups in heteroaromatic systems of indole, pyrrole, and furan was developed by Zhang, based on reactions of these heterocycles with amino alkynes under the action of Tf2NH.330 Stereoselective syn-hydroarylation of the acetylene bond takes place. 3-Substituted derivatives 525 with Zconfigured CC double bonds are the only products regioselectively formed from indoles (Scheme 292). Upon reaction with N-n-butyl-N-oct-1-ynyl-p-toluenesulfone amide 526 under similar conditions, pyrroles yield mixtures of isomers 527, bearing an alkenyl group at the 2- or 3-position, while 2-methyl- and 2,3-dimethylfurans are alkenylated at their vacant 5-position, affording compounds 528a,b (Scheme 293).330 A general approach to the alkenylation of arenes with aryl acetylenes conjugated with electron-withdrawing groups, under superacidic conditions, was presented in a series of reports.331−338 Vinyl dications 530, generated upon protonation of the electron-withdrawing substituent and the CC triple bond of compounds 529, react with arenes, furnishing

this purpose is triflic acid CF3SO3H (TfOH) and its derivatives (e.g., Tf2NH and MeOTf.) 11.1. Intermolecular Reactions

Klumpp et al. showed that the protonation of ethynyl and propargyl-substituted nitrogen-containing heterocycles 509− 511 in TfOH affords reactive dications 512−514 that react with benzene, leading to intermediate alkenes 515−517, respectively. The latter compounds add one more benzene molecule to the carbon−carbon double bond, ultimately delivering compounds 518−520 (Scheme 290).328 In the same way, ethynyl-substituted aniline 521 and propargyl phosphonium salts 523a,b yield products of bishydrophenylation of triple bond 522328 and 524a,b,329 respectively, when reacted with benzene in TfOH (Scheme

Scheme 294. Superacid-Promoted Alkenylation of Arenes with Arylacetylenes Bearing Electron Withdrawing Groups

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Scheme 296. Hydroarylation of Trifluoromethyl Acetylenes under Superacidic Conditions

Scheme 297. Intermolecular Hydroarylation and Intramolecular Heterocyclization of 2-Alkynyl Phenylisothiocyanates under the Action of TfOH

Scheme 298. Transformation of Arylisothiocyanates and Alkynes into Quinolones under the Action of MeOTf

COCF3,337 and PO(OEt)2,333,337 may be utilized in this reaction. Hydroarylation may be performed in different superacidic systems [HSO3F, TfOH, HF-SbF5, HSO3F-SbF5, TfOH-SbF5, and HX-AlX3 (X = Cl, Br)] at temperatures ranging from −75 to 25 °C over the course of 0.25−2 h. The total yields of the reaction products range from 70% to 98%.331−338 Various aromatic compounds, including benzene, alkylbenzenes (mono- to tetra-substituted examples), hydroxy-, monoand dimethoxybenzenes, halogenated arenes, arylammonium ions, N-arylacetamides, and polymethylated arenes with electron-withdrawing groups (such as 1-acetyl-2,3,5,6-tetramethylbenzene, 2,3,5,6-tetramethyl-1-fluorosulfonylbenzene, 2,3,5,6-tetramethyl-1-cyanobenzene, etc.) can be alkenylated by this method.331−338

Scheme 299. MeOTf-Promoted Synthesis of Indenones from Arylnitriles and Arylalkynes

products of arene alkenylation 531, as E- or Z-isomers (Scheme 294). Aryl acetylene substrates 529, having a range of different electron-withdrawing groups such as X = CO2Alk,331−336 CO2H,333 CN,333 COMe,335−337 COAr,337 C(O)CO2Et,337,338

Scheme 300. TfOH-Promoted Synthesis of Quinolines From Anilines, Aromatic Aldehydes, and Terminal Alkynes

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Scheme 301. Three-Component Reaction of Benzylic Alcohols, Arylacetylenes, and Arenes

Scheme 302. Acid-Promoted Alkenylation of Indoles with Propargyl Alcohols

Scheme 303. Intramolecular Cyclization of 1,3Diarylpropynones into 3-Arylindenones in Superacids

Scheme 306. Cyclization of 1,4-Enynes into Benzocycloheptenes in H2SO4

Scheme 307. Acid-Promoted Cyclization of Derivatives of 3Arylpropynoic Acids Scheme 304. Formation of the 1,2-Dihydronaphthalene Skeleton via Acid-Promoted Intramolecular Cyclization of Acetylene Derivatives

Scheme 308. TfOH-Promoted Cyclization of Se- and TeSubstituted Propargyl Alcohols or Amines

Scheme 305. TfOH-Catalyzed Cascade Cyclization of 1,7Enynes into Indenes

(−50 to 25 °C), the syn-adducts are converted to products of anti-addition.333,335−337 Arylacetylenes 529 with an aromatic ring comprising at least one methyl group, are rather reactive π-nucleophiles per se. Thus, in FSO3H, dications 530 attack the aromatic system of the parent compounds 529 in the absence of arenes, as external π-nucleophiles, leading to dimers E/Z-532 (Scheme 295).331,337

Hydroarylation proceeds at −75 °C as syn-addition of proton and aryl moieties to the acetylene bond. At higher temperatures 5965


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Scheme 309. TfOH-Promoted Cyclization and Hydrophenylation of (Benzyl)propargylamines

formation of cationic species 546 and 547, affording substituted quinolines 548 (Scheme 298).342 The same group (Xi et al.) reported the MeOTf-promoted synthesis of indenones 549 from aryl nitriles and aryl alkynes (Scheme 299).343 In this case, the initial activation of the nitrile group by methylation with MeOTf takes place, followed by reaction with an alkyne. The synthesis of quinolines 550 was carried out by a TfOHcatalyzed three-component reaction of anilines, aromatic aldehydes, and terminal alkynes (Scheme 300).344 Substrates with both electron-donating and electron-withdrawing substituents were found to be suitable for this transformation. The reaction mechanism includes the initial formation of an imine from aniline and aldehyde, and then the N-protonated form of the imine reacts with a terminal acetylene, followed by the ring closure. A three-component reaction of benzylic alcohols, terminal aryl acetylenes, and polymethylated arenes under the action of TfOH, Tf2NH, or Tf2O-FeCl3−AgNO2 affords E/Z-isomeric alkenes 554 (Scheme 301).345 The best results (higher reaction product yields and greater variability in the substrates tolerated) was achieved with the system Tf2O-FeCl3−AgNO2. In this transformation, the carbocation 552 is generated from the alcohol 551. This cation then reacts with arylacetylene, giving the vinyl cation 553, which finally alkenylates the arene molecule. Stereochemistry of the obtained alkenes 554 depends strongly on the reaction temperature: between −20 and −10 °C, the main reaction product contains group Ar2 in the synposition to the proton at the double bond, but at 80 °C, the major isomer has an anti-configuration. Propargyl alcohols have been explored for alkenylation.346−348 Dehydroxylation of these alcohols in acidic media gives propargyl cations, which alkenylate (hetero)arenes through their allenyl resonance form. Thus, the TfOHpromoted reaction of indoles 555 with various propargyl alcohols initially affords 3-allenyl indoles 556, which undergo subsequent carbocyclization into compounds 557 under acidic conditions (Scheme 302).346 Incorporation of other indoles in the reaction with methyl-phenyl-substituted propargyl alcohols under the action of TsOH gave 3-(buta-1,3-dien-1-yl)indoles 558 (Scheme 302).347 In this case, due to the presence of a methyl group, the rearrangement of the allenyl substituent into a butadienyl group occurs in the intermediate allenyl indols.

Scheme 310. Reaction of Alkynes with Phosphorus-Based Electrophiles

Protonation of CF3-alkynes 533 in TfOH or FSO3H gives vinyl cations 534, which are able to effectively alkenylate a range of arenes (benzene and alkyl-, methoxy-, and halogensubstituted arenes), affording alkenes 535 (Scheme 296).339,340 However, under superacidic reaction conditions, the latter alkenes are protonated to form tertiary carbocations 536. These species are extremely stable in TfOH even at room temperature and were fully characterized by means of NMR.339,340 Finally, upon quenching the reaction solution, cations 536 are either deprotonated or hydrated to afford E/Z-alkenes 535 or alcohols 537, respectively. Quenching with anhydrous MeCN or MeOH/MeONa gave alkenes 535 only. Workup of the reaction mixture in water or aqueous solutions of mineral acids or bases leads to the formation of mixtures of compounds 535 and 537. Otani and Saito showed that the acetylene CC triple bond participates in intermolecular alkenylation and intramolecular heterocyclization reactions.341 2-Alkynyl phenylisothiocyanates 538 were found to be examples that react via two different routes depending on their structure and the reaction temperature (Scheme 297). Substrates 538 were protonated in TfOH at −40 °C at the nitrogen atom of the isothiocyanate moiety, affording cations 539, which cyclize forming the carbocations 540. The latter react with arenes to give indole derivatives 541. At a higher temperature (0 °C), cations 539 are further protonated at the triple bond. The reaction of dications 542 with arenes gives ions 543, undergoing the intramolecular cyclization to 4-arylquinoline-2-thiones 544. When R = H, t-Bu, and SiMe3, the elimination of this group at the double bond takes place in the terminal step of the formation of structures 544. In a similar way, arylisothiocyanates 545 react with alkynes under the action of alkyl triflates, through intermediate 5966


Chemical Reviews

Review

Scheme 311. Alkenylation of Arenes with Alkynes under the Action of Electrophiles

= O) or amines (X = NTs) into cycloalkenyl selenides (Y = SePh) and tellurides (Y = TePh) 570 (Scheme 308).357 In this case, only a catalytic amount of TfOH (5 mol %) is necessary for cyclization. Tandem reactions involving intramolecular cyclization with vinyl cations, followed by hydrophenylation of the formed C C bond, were described.328 In this manner, compounds 572, 574, and 576a,b were obtained in benzene-TfOH using (benzyl)propargylamines 571, 573, 575a,b, respectively, as precursors (Scheme 309).328 Transformation of optically active amines 575a,b resulted in the formation of diastereomers 576a,b in 29% de. Acid (Tf2NH or 4-nitrobenzenesulfonic acid)-promoted cyclization of amino acetylenes (ynamides) was used for the synthesis of a series of polycyclic nitrogen-containing heterocycles.356 Thus, Brønsted (super)acids are quite effective media and reagents to carry out inter- and intramolecular alkenylation reactions of (hetero)arenes with alkynes. By varying the

The same synthetic methodology was used to obtain indenes and inden-2-ones from 1,1,4,4-tetraarylbut-2-ene-1,4-diols and 1- or 2-naphthols catalyzed by p-TsOH348 and for alkenylation of arenes with the trimethylsilyl ether of 1-amino-substituted propargyl alcohol in the presence of MeOTf.349 11.2. Intramolecular Reactions

Vinyl cations comprising (hetero)aromatic moieties may attack these structural fragments in an intramolecular fashion, yielding products of carbo- or heterocyclization. 11.2.1. Carbocyclization. The transformation of 1,3diarylpropynones to 3-arylindenones 559 has been demonstrated in different superacids (TfOH, HSO3F, TfOH-SbF5, and HF-SbF5) (Scheme 303).350−353 Under the reaction conditions, the formed indenones are protonated at the carbonyl oxygen and the CC bond, giving stable dications that were characterized by NMR.352,353 The hydrolytic decomposition of the superacidic reaction solutions afforded reaction products 559. Several approaches were developed for the synthesis of 1,2dihydronaphthalenes 561 based on the 6-endo intramolecular cyclization of acetylenes 560 (Scheme 304). Tf2NH was effectively explored for transformations of siloxy- (X = OSi(iPr)3)354,355 and amino- (X = N(n-Bu)Ts)356 alkynes. Catalytic amounts of TfOH promoted the fast cyclization of seleno- (X = SePh) and telluro- (X = TePh) derivatives.357 TfOH-catalyzed cascade cyclization of 1,7-enynes 562, proceeding through the intermediate formation of cations 563 and 564, yields indenes 565 (Scheme 305).358 1,4-Enynes 566 undergo intramolecular cyclization into benzocycloheptenes 567 with sulfuric acid (Scheme 306).359 This reaction is highly regioselective: due to the electronwithdrawing group CO2Me at the CC bond, the protonation of the acetylene C−C bond occurs exclusively, followed by formation of the seven-membered ring. The intramolecular carbocyclization of various acetylene derivatives in TFA360 or TfOH361 were used in the synthesis of fused polycyclic aromatics. Shubin et al. studied intramolecular cyclization of 10,10-dimethyl-9-phenylethynyl-9,10-dihydrophenanthren-9-ol in the system FSO3H-SbF5−SO2ClF by means of NMR (at −28 °C) and DFT calculations and showed the formation of stable dications of the phenanthrene series.362 11.2.2. Heterocyclization. N-Arylamides,363−368 esters,369 or thioesters370 of 3-arylpropynoic acids 568 have been converted into derivatives of quinolone (X = NH), coumarin (X = O), or thiocoumarin (X = S) 569, respectively, under the action of various acids (e.g., TfOH,363−367 FSO3H,369 H2SO4,367,370 or acidic zeolites363,368) (Scheme 307). Significant changes in the substituents of the starting substrates 568, variations of the acidic agents, the reaction temperature (−75 to 130 °C), and time (0.5 to 100 h) allowed the authors to achieve the highest yields of the target compounds 569. A similar approach was applied by Lee et al. for transformation of Se- and Te-substituted propargyl ethers (X

Scheme 312. Electrophile-Promoted Intramolecular Cyclization of Propargyl Derivatives

Scheme 313. Trifluoromethylation/Cyclization of Aryl Propynoates

Scheme 314. Electrophilic Cyclization of 2-Alkynyl Biaryls into Phenanthrenes

substituents of the starting alkynes, one can change the triple bond basicity and the reactivity of the corresponding vinyl 5967


Chemical Reviews

Review

Scheme 315. Iodospirocyclization of 2-Alkynyl-4′-methoxy Biaryls

Scheme 316. Iodocyclization of 2-Alkynylcarbonyl Biaryls

para to the endocyclic oxygen atom of the oxaphosphorinine heterocycle take place. While the mechanism of the reaction is rather complicated, the authors were able to determine its main features.371−379 In cases where a halide is present in the benzo fragment of the initial phosphorole, a second halide is incorporated ortho to the first halide and para to the oxygen atom of the resulting annulated O,P-heterocycle. If positions 5 and 6 in the benzophosphole are occupied by bromide, the introduction of a third halogen atom does not occur. However, the partial ipsosubstitution of bromide by chloride takes place. Compounds 578, depending on the desired synthetic goal, may easily undergo hydrolysis, alcoholysis, aminolysis, fluorination, thermolysis, etc.371 Friedel−Crafts alkenylation of arenes, with the participation of the ionic liquid [bmim][Sb2F11] (Scheme 311), leads to a mixture of E/Z-isomers 579.380 Iodo-arylation of aryl acetylenes with the participation of electron-rich arenes under the action of molecular iodine occurs regio- and stereoselectively leading to the trans-1,1-diaryl-2-iodoethanes 579.381 As a result of the intramolecular 6-endo-dig cyclization of propargyl derivatives 580, various 3-substituted naphthalenes,382 chromenes,383,384 and quinolines 581385−387 were obtained (Scheme 312). This fruitful approach was developed by Larock and other research groups.382−387 Thus, 3-halogen-, seleno-, telluro-, and sulfur-derivatives of compounds 581 were obtained under mild conditions under the action of various electrophilic agents. 1-Azido-2-(2-propynyl)arenes undergo similar transformations into 3-halo- or 3-H-quinolines in the presence of electrophiles (I2, Br2, ICl, NBS, NIS, etc.).385−388

Scheme 317. Double Iodocyclization of Butadiynes

cations, providing a number of variations of this reaction. In many cases, catalytic amounts of acid may be used for the reactions.

12. REACTIONS PROMOTED BY ELECTROPHILES Addition of electrophilic species other than protons to the acetylene triple bond generates reactive vinyl cations that participate in inter- and intramolecular alkenylation of arenes. Various P-, I-, S-, Se-, Te-, and C-centered electrophiles have been applied for these purposes. The potential introduction of iodide at the C−C double bond has particular synthetic value, due to further possible transformations of this functionality in a number of cross-coupling processes, such as Heck, Suzuki, Sonogashira, and Negishi reactions. In a series of reports,371−379 addition of phosphorus-based electrophiles to alkynes was studied by Mironov et al. Thus, phenylene dioxatrihalogen phosphoranes 577 react with terminal alkyl and aryl acetylenes with formation of benzo[e]1,2-oxaphosphorin-3-enones 578 (Scheme 310). In the course of this reaction, under mild conditions, the ipso-substitution of the oxygen atom, formation of P−C and PO bonds, as well as the regioselective halogenations of the phenylene fragment 5968


Chemical Reviews

Review

Scheme 318. Electrophilic Cyclization of Diaryl Di(arylethynyl) Arenes

Scheme 319. Double Iodocyclization of Bis-Propargyl Ethers

Scheme 321. Alkenylation under the Action of the Trityl Cation

The highly elecrophilic trifluoromethyl radical was generated from hypervalent iodo derivative 582 and aryl propynoates in a reaction catalyzed by Cu(OAc)2 giving coumarins 583 (Scheme 313).389 The presence of substituents at the meta-position of the O-aryl ring of the aryl propynoate leads to a mixture of isomers 583, depending on which of the two ortho positions of the O-aryl fragment undergoes reaction. The intramolecular alkenylation of 2-alkynyl biaryls in substituted phenanthrenes takes place under the action of different electrophilic agents (Scheme 314).390,391 Precursor biaryls containing both donor and acceptor substituents at their aromatic rings interact in a similar way, and both polycyclic and heterocyclic rings can be utilized in the reaction. 2-Alkynyl-4′-methoxy biaryls 584 were shown to undergo ipso-cyclization into spirocyclohexadienes 585 under the action of ICl (Scheme 315).392 In a solution of methanol-sulfuric acid, these spiroketones 585 undergo rearrangement into iodophenanthrenes 586 through a selective 1,2-alkenyl migration. The more complex alkynes 584a participate in an analogous spirocyclization.392 The isomerization of ketones 585a by

sulfuric acid leads to iodophenanthrenes that may produce dibenzo[g,p]chrysenes 587 by a Pd-catalyzed reaction. Alkynones 588, depending on substituents R1 and R2, undergo electrophilic iodocyclization into products of 6-endodig ipso-cyclization 589 or 7-endo-dig ortho-electrophilic aromatic substitution 590 (Scheme 316).393 In this work, the influence of substituents on the cyclization direction was studied in detail. The influence of R3 on the course of the reaction was found to be insignificant. ICl promotes the double electrophilic intramolecular cyclization of butadiynes bearing aryl moieties, with the formation of substituted carbo- and heterocyclic compounds 591 (Scheme 317).394 In a continuation of the synthesis of polycyclic compounds by electrophilic cyclization, reactions of substrates 592a−592c having a central aromatic ring with two (n-alkoxyphenyl)ethynyl and two aromatic substituents should be noted

Scheme 320. Electrophilic Alkenylation of N-Methoxy Benzamides with Alkynes

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Chemical Reviews

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Scheme 322. Interaction of Alkynes with Electrophilic Phosphonium-Iodonium Ylides

Scheme 323. Al2O3-Activated Alkenylation of Pyrroles, Indoles, and 4,5,6,7-Tetrahydroindoles with Terminal Haloacetylenes

Scheme 324. Transformations of Acetylene Carbonyl Compounds and Propargyl Alcohols into Indenes under the Action of AlX3 (X = Cl, Br)

(Scheme 318).360,395 Only symmetrical compounds 592a− 592c, in which aryl fragments were located in para-592a, meta592b, and ortho-592c positions, respectively, were considered. The double intramolecular cyclization is induced by I(Py)2BF4 with formation of bisaryl[a,h]anthracenes 593a and bisaryl[a,j]anthracenes 593b. It is noteworthy that the ortho-arylsubstituted compounds 592c were transformed mainly into the

monocyclic derivative 594, and a small amount (20%) of helicene 593c was obtained.360 Molecular iodine also facilitates the double regioselective 6endo-dig cyclization of bis-propargyl ethers of ortho-dioxybenzene into bis-substituted benzo-2H-pyrans 595 (Scheme 319).396 Bis-propargyl ethers of various dioxynaphthalenes undergo analogous transformations. 5970


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Table 1. List of Synthesized Structures (Depending on Catalysts or Promoters) catalysts or promoters formed skeletons alkenes or alkanes carbocycles benzofurans benzopyrans indoles or isoindoles quinolines isoquinolines other heterocycles

Pd complexes sec 2.1.1; sec 2.2.1 sec 2.1.1; sec 2.2.1 sec 2.1.2; sec 2.2.2 sec 2.1.3 sec 2.1.4; sec 2.2.4 sec 2.1.5; sec 2.2.4 sec 2.1.5; sec 2.2.4 sec 2.2.3; sec 2.2.4

Pt complexes sec 3.1.1; sec 3.2 sec 3.1.2 − sec 3.1.3 − sec 3.1.4 − sec 3.1.5

Rh complexes

Ru complexes

Au complexes

Cu complexes

sec 4.1

sec 5.1

sec 6.1

sec 7.1.1; sec 7.3

sec 4.1

sec 5.2

sec 6.2

sec 7.1.2; sec 7.4

sec 4.3

−

sec 6.3

sec 7.2; sec 7.4

sec 4.3

sec 5.3

sec 6.3

sec 4.4

−

sec 6.4

sec 4.5

sec 5.3

sec 6.5

sec 4.6

sec 5.3

−

sec 4.7

sec 5.3

sec 6.6

other transition metal complexes

Brønsted acids

Lewis acids

sec 8; sec 9; sec 10.2.2; sec 10.2.4; sec 10.2.7 sec 8; sec 10.2.3; sec 10.2.4; sec 10.2.5; sec 10.2.6 −

sec 11.1 sec 11.1; sec 11.2.1 −

sec 12; sec 13 sec 12; sec 13 −

sec 7.2; sec 7.3; sec 7.4 sec 7.2; sec 7.4

sec 9

sec 11.2.2

sec 12

sec 8; sec 9; sec 10.2.4

sec 11.1

sec 7.1.3; sec 7.2; sec 7.4 sec 7.4

sec 8; sec 9; sec 10.2.1

sec 12

sec 8; sec 10.2.3

sec 11.1; sec 11.2.2 sec 11.2.2

sec 7.1.2; sec 7.4

sec 10.2.6

sec 11.2.2

sec 12

−

sec 12

process was alkenylation of substrates 601 with the formation of alkenes 603 (Scheme 323).407−411 The latter may react in two concurrent pathways, leading to alkynes 604 or bis(heteroaryl) alkenes 605. The ratio of the reaction products 604 and 605 depends on the groups X and Y in structures 602 and substituents in heterocycles 601. Aluminum halogenide (AlX3, X = Cl, Br)-promoted transformations of acetylene carbonyl compounds 606 and propargyl alcohols 608 with arenes have been widely studied (Scheme 324).412−415 Coordination of AlX3 at the carbonyl oxygen of substrates 606 activates the carbonyl carbon C1. This electrophilic center reacts with arenes leading to species 607, which are transformed into propargyl cations 609.412,414,415 The latter may also be generated from the corresponding propargyl alcohols 608.413,415 Cations 609 have the allenyl mesomeric form 610. These two resonance species 609 and 610 have two different reactive, electrophilic carbon centers (C1 and C3, respectively) that in reactions with arenes give two different products, viz., alkyne 611 or allene 612 (Scheme 324). The further protonation of compounds 611 and 612 affords the corresponding cations 613 and 614 (with the mesomeric form 615 for the latter). Intramolecular cyclization of 613−615 leads to isomeric indenes 616−619. In this work,415 the influence of the electronic character of the substituents in mesomeric cations 609 and 610 on their consequent transformations was thoroughly analyzed. It was shown that electron-donating substituents Ar, Ar′, and R capable of delocalizing positive charge favored the activation of the neighboring electrophilic center (C1 in 609 and C3 in 610) that guides the reaction via paths a or b, respectively (Scheme 324).

The oxidative cycloaddition of substituted benzamides with alkynes under the action of iodonium electrophiles leads to a range of isoquinolines 596 (Scheme 320).397 Analogous transformations are achieved for benzamides and acetylenes with the use of peroxyacetic acid and iodobenzene.398 The participation of unsymmetrical alkynes in the reactions leads to a mixture of isomers 596 with the substituents R2 and R3 at the 3- and 4-positions of the isoquinoline skeleton. A method for preparation of 1,2-dihydro-2-silanaphthalenes 597 from dialkylbenzylsilanes and acetylenes under the action of trityl tetrakis(pentafluorophenyl)borate has been described399 (Scheme 321). The reaction of phosphonium-iodonium ylide 598 with terminal acetylenes gives phosphonolines 599 or furans 600 (Scheme 322).400 Electron-rich substituents at the triple bond led to the predomination of 1,3-dipole cycloaddition, with an increase of the yield of furans 600, while less electron-rich substituents shift the reaction toward phosphonolines 599. The replacement of benzoyl or carbonylethoxyl fragments in the ylide 598 by a cyano group leads to complete exclusion of furan derivatives. Boron-based electrophiles also were found to induce alkenylation of arenes by acetylenes. Thereby, condensation of phenols with 1,1-disubstituted propargyl alcohols under the action of BF3·Et2O led to 2,2-disubstituted-2H-chromenes.401 The oxidative benzannulation of enamines and acetylenes with (PhIO)n-BF3·Et2O gave polysubstituted 1-aminonaphthalenes.402 One more approach based on cyclization of ortho-(alka-1,3diynyl)-substituted functionalized arenes (Alk−CC−CC− Ar) to form cinnolines,403,404 benzothiophenes, benzofuranes, and indoles405 under the action of various electrophiles (I2, N2+R, etc.) was developed by Balova et al.

14. MISCELLANEOUS This section contains data on miscellaneous transformations leading to products of alkenylation of (hetero)arenes with alkynes. A number of methods416−422 were based on the generation of reactive vinyl radicals by the addition of various free radical species to the acetylene bond. These reactive vinyl radicals are able to attack (hetero)aromatic rings to afford alkenylation products. In this way, construction of carbo-416,417 and heterocycles418−421 and styryl quinazolines422 was carried out by inter-416,419−422 or intra-417,418 molecular reactions.

13. REACTIONS PROMOTED BY ALUMINUM-BASED LEWIS ACIDS Analogously to Brønsted acids (see section 11), aluminum halogenides AlX3 (X = Cl, Br) promote the intra-364,367,369,370 (see Scheme 307) and intermolecular406 alkenylation of arenes. In a study of the formal “inverse Sonogashira coupling” between terminal haloacetylenes 602 and pyrroles, indoles or 4,5,6,7-tetrahydroindoles 601, under the action of Al2O3 and without solvent, Trofimov et al. found that the first step in this 5971


sec 4.6; sec 11.2.2

sec 5.3; sec 6.5; sec 12

other heterocycles

sec 2.2.4

indoles or isoindoles

isoquinolines

sec 3.1.3; sec 4.3; sec 6.3

benzopyrans

sec 2.1.5; sec 3.1.4; sec 6.3; sec 6.5; sec 7.1.3; sec 8; sec 9; sec 11.1

sec 6.3

benzofurans

quinolines

sec 2.2.1; sec 9; sec 10.1; sec 10.2.5

carbocycles

HCCAlk

sec 2.1.1; sec 5.1; sec 6.1; sec 6.5; sec 11.1

alkenes or alkanes

formed skeletons

sec 2.1.3; sec 6.3; sec 7.2

−

5972

sec 5.3; sec 12

sec 4.6

sec 7.1.3; sec 8; sec 9; sec 11.1

sec 10.1

sec 4.6

sec 8; sec 9

−

−

−

sec 8; sec 11.1

sec 2.1.1; sec 3.1.1; sec 5.1; sec 6.1; sec 6.5; sec 8; sec 12 sec 2.2.1; sec 3.1.2; sec 9

HCCCOX, X = Alk, Ar, OAlk

sec 2.1.1; sec 5.1; sec 6.1; sec 6.5; sec 8; sec 10.2.2; sec 11.1; sec 12 sec 2.2.1; sec 3.1.2; sec 4.2; sec 6.2; sec 9 sec 10.2.5

HCCAr

terminal alkynes

sec 2.2.3; sec 3.1.5; sec 4.7; sec 5.3; sec 6.5; sec 8; sec 12

sec 2.1.5; sec 4.6; sec 5.3; sec 8; sec 9

sec 2.2.4; sec 3.1.4; sec 4.5; sec 6.5; sec 7.1.3; sec 8; sec 9; sec 11.1; sec 12

sec 3.1.3; sec 4.1; sec 4.3; sec 5.3; sec 6.3; sec 8; sec 9; sec 12 sec 2.1.4; sec 2.2.4; sec 4.4; sec 11.1

sec 2.1.2; sec 4.3

sec 2.1.1; sec 2.2.1; sec 4.2; sec 5.2; sec 6.2; sec 8; sec 9; sec 10.2.5; sec 11.1; sec 12

sec 2.1.1; sec 3.2; sec 4.1; sec 5.1; sec 7.3; sec 8; sec 9; sec 10.2.4

AlkCCAlk′

sec 2.2.3; sec 2.2.4; sec 4.7; sec 5.3; sec 8

sec 2.1.5; sec 2.2.4; sec 4.6; sec 5.3

sec 3.1.4; sec 4.5; sec 6.5; sec 7.2; sec 8; sec 9; sec 11.1; sec 12

sec 2.2.2; sec 2.2.4; sec 4.4; sec 8

sec 2.1.2; sec 2.2.2; sec 4.3; sec 7.2; sec 8 sec 3.1.3; sec 4.1; sec 4.3; sec 5.3; sec 6.3; sec 7.2; sec 8; sec 12

sec 2.1.1; sec 2.2.1; sec 3.2; sec 4.1; sec 5.1; sec 6.1; sec 7.1.1; sec 7.3; sec 8; sec 9; sec 10.2.4; sec 11.1; sec 12 sec 2.1.1; sec 2.2.1; sec 4.2; sec 5.2; sec 6.2; sec 7.2; sec 8; sec 9; sec 10.2.5; sec 11.1; sec 12

AlkCCAr

Table 2. List of Synthesized Structures (Depending on Starting Acetylene Compounds)

ArCCAr′

sec 2.1.5; sec 4.6; sec 5.3; sec 9; sec 12 sec 4.7; sec 5.3; sec 8; sec 12

sec 4.5; sec 9; sec 11.1

sec 2.1.4; sec 2.2.4; sec 4.4

sec 2.1.2; sec 4.3; sec 7.2 sec 4.1; sec 4.3; sec 5.3; sec 9

sec 2.1.1; sec 4.2; sec 5.2; sec 6.2; sec 8; sec 9; sec 10.2.5; sec 11.1; sec 12

sec 2.1.1; sec 4.1; sec 5.1; sec 6.1; sec 7.3; sec 8; sec 9; sec 10.2.4

sec 3.1.5; sec 10.1

sec 4.6

sec 2.1.3; sec 3.1.3; sec 6.3; sec 12 sec 2.1.4; sec 6.4; sec 7.2 sec 5.3; sec 11.1

−

sec 2.1.1; sec 3.1.1; sec 3.2; sec 5.1; sec 7.3 sec 3.1.2; sec 4.2; sec 12

AlkC CCOX, X = Alk, Ar, OH, OAlk

internal alkynes

sec 4.7

sec 2.1.5; sec 4.6; sec 5.3

sec 4.5; sec 5.3; sec 6.5; sec 8; sec 9; sec 11.1; sec 11.2.2

sec 4.4; sec 6.4; sec 7.2

sec 2.1.3; sec 3.1.3; sec 6.3; sec 7.3; sec 11.2.2; sec 12

sec 6.5

sec 2.1.1; sec 3.1.2; sec 4.2; sec 8; sec 9; sec 10.2.5; sec 11.2.1; sec 12; sec 13

sec 2.1.1; sec 3.1.1; sec 3.2; sec 5.1; sec 5.3; sec 7.3; sec 8; sec 11.1

ArCCOX, X = Alk, Ar, OH, OAlk, NRR′

sec 4.6; sec 11.2.2 sec 2.2.3; sec 12

− −

sec 4.5; sec 8

sec 2.2.4; sec 4.4; sec 11.1 sec 5.3; sec 9; sec 11.1; sec 12

sec 9; sec 12

sec 5.2; sec 8; sec 9; sec 10.2.5; sec 12 −

sec 5.1; sec 9; sec 11.1

RC CSiAlk3, R = Alk, Ar

sec 2.1.4

sec 7.2

−

sec 2.2.1; sec 4.2

sec 3.1.1

XCOC CCOX, X = Alk, Ar, OAlk

−

sec 2.1.5

−

sec 2.1.5; sec 4.5; sec 9; sec 12 −

sec 4.4

−

sec 4.5; sec 11.2.2; sec 12

sec 12

sec 2.2.1; sec 7.2; sec 8; sec 12 −

sec 5.1

enynes or diynes

sec 4.3; sec 11.2.2; sec 12

sec 2.1.2

sec 2.2.1; sec 6.2; sec 7.1.2; sec 7.2; sec 8; sec 11.2.1; sec 12

sec 2.1.1; sec 11.1; sec 13

RCCX, R = Alk, Ar; X = Cl, Br, OR, NRR′, SePh, PO(OEt)2

Chemical Reviews Review


Chemical Reviews

Review

AUTHOR INFORMATION

Direct nucleophilic addition of imidazoles to alkynes gave Nalkenylated derivatives of this heterocycle.423,424 Nucleophilic addition of pyridine to the dimethyl ester of acetylene dicarboxylic acid was explored as a key step in the synthesis of quinolizines.425 In the series of papers,426−428 Durandetti, Maddaluno, et al. developed intramolecular alkenylation of (hetero)arenes bearing ortho bromides or iodides, based on carbolithiation of acetylenes with n-BuLi in THF at −78 °C. In a similar work,429 carbocupration of N-aryl ynamides with the system t-BuLiCuCN in THF at −78 °C was used for the synthesis of indoles. Pericyclic processes have also been effectively applied in inter- and intramolecular alkenylation reactions of (hetero)arenes by alkynes (e.g., the Diels−Alder reaction,430−432 its Povarov imino modification, 433−436 Claisen rearrangements,437,438 and [2 + 2] cycloaddition) (for the synthesis of fullerene dimers).439

Corresponding Author

*E-mail: [email protected] and [email protected]. Notes

The authors declare no competing financial interest. Biographies Vadim Pavlovich Boyarskiy is a native of Saint Petersburg (was born in 1964), Russia (ex. Leningrad, USSR). He graduated from Leningrad State University with an M.S. degree in Chemistry (1986) and obtained his Ph.D. in industrial organic chemistry from Leningrad Technological Institute (1990). After four years at the oil refining and oil chemistry oriented VNIINEFTECHIM Institute (Saint Petersburg), he began his career at the Saint Petersburg State University as a senior researcher (1994), whereupon he joined the faculty as an Assistant Professor (1997). He obtained his posthabilitation D.Sc. degree and was appointed as full Professor of the Saint Petersburg State University in 2010. During association with VNIINEFTECHIM Institute, he conducted research on cobalt carbonyl complexes and their catalytic activity in aryl halide carbonylation. In addition, he was involved in phenol tar utilization and PCBs remediation. Also, he was interested in organic synthesis, particularly, in obtaining multicolor and caged fluorescent dyes. Currently, his interests cover all aspects of aryl halides activation by Co, Cu, and Pd complexes, including synthesis of the catalysts and studying tandem processes.

15. SUMMARY AND OUTLOOK The alkenylation of (hetero)arenes with alkynes is a useful protocol in organic synthesis. It can potentially provide new synthetic strategies that are unavailable by traditional methods of carbon−carbon bond construction. In this review, we have discussed recent achievements in this area of acetylene chemistry. The variety of starting materials [alkynes, (hetero)arenes] and catalysts (metal complexes) or activators (Brønsted and Lewis acids) used in these reactions allows the synthesis of a diverse range of alkenes and unsaturated carbo- and heterocycles with specific structures (see lists of synthesized compounds, starting alkynes, and a type of catalyst or activator with cross-references between sections in Tables 1 and 2). Many examples of activation of C−H or C−X (X = Hal, C, B, S, etc.) bonds in (hetero)arenes by transition-metal complexes have been reported in these alkenylation reactions. These catalysts are quite tolerant to substituents in starting materials, allowing very broad reaction scopes. There exist many examples of electrophilic activation of the acetylene triple bond by Brønsted or Lewis acids for the subsequent reaction with (hetero)arenes. The various proposed mechanisms for all these transformations have been discussed herein. One may notice some distinct trends in this field. Despite the extremely important role of palladium-based catalysts in contemporary organic synthesis,440−445 the use of other metals as catalysts is also increasing. One of the observed tendencies in alkenylation reactions is an active intrusion of rhodium and ruthenium complexes into the realm of “classical” palladiumcatalyzed reactions. There has been a rapid recent growth in the number of publications on the use of rhodium and ruthenium catalysts for the alkenylation of (hetero)arenes with alkynes. In addition, compounds of copper, iron, and nickel are very competitive alkenylation catalysts in terms of efficiency and cost. It should be also noted that there are many metal-free procedures for alkenylation based on the use of Brønsted acids and acidic zeolites. Some of these methods may be applicable in industry for the synthesis of valuable substances such as drugs, bioactive compounds, organic sensors, light-sensitive materials, etc. Thus, despite the existing challenges, one may expect further development in the alkenylation of (hetero)arenes with alkynes. We hope that this review will stimulate interest and further advances in this field.

Dmitry Sergeevich Ryabukhin was born in Novocherkassk, Russia (1986). He graduated from Saint Petersburg State Forest Technical University (Saint Petersburg, Russia) with an M.S. degree in Chemical Technology (2009). He did a Ph.D. study (2009−2011) under the supervision of Professor Aleksander V. Vasilyev at the Department of Organic Chemistry at Saint Petersburg State Forest Technical University and obtained his Ph.D. in Organic Chemistry in 2011. He did Postdoctoral Fellowships at the Moscow State University with Professor Valentine G. Nenajdenko (2012 and 2013) then with Professor Aleksander V. Vasilyev at the Saint Petersburg State University (2013−2015, Russia) and now, in 2016, with Professor Gérard Audran and Sylvain Marque at the Aix-Marseille Université (Institut de Chimie Radicalaire, Marseille, France). His research interests are chemistry of acetylene compounds and superelectrophilic activation of organic compounds. Nadezhda Arsenievna Bokach was born in Vologda, Russia (1976). She studied biology and chemistry at Vologda State Pedagogical University and graduated with distinction in 1998. She received her Ph.D. in inorganic chemistry from Saint Petersburg Technological Institute (2002), followed by postdoctoral work at Instituto Superior Técnico in Lisbon, Portugal (2003−2004). Prof. Bokach simultaneously held a researcher position at Saint Petersburg University starting from 2002 and was appointed associate professor in 2007. She received her posthabilitation D.Sc. degree in organometallic chemistry in 2012 and was awarded full professorship in 2014. She is a recipient of Academia Europea’s award for young Russian scientists (2002), National L’Oreal Award for Woman in Science (2007), Leonard Euler Prize from the Government of Saint Petersburg (2010), and the Presidential Award for Young Scientists (2012), the highest official honor for young Russian researchers. Prof. Bokach is an author and coauthor of more than 80 original papers and 6 reviews. Her research interests include transition metals coordination chemistry, ligand reactivity, metal-mediated synthesis, and metal-involving reactions of carbon−heteroatom multiple bonds. Aleksander Victorovich Vasilyev was born in Leningrad (now Saint Petersburg), Russia (1970). He graduated from Saint Petersburg State 5973


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DMF DPEPhos dppe dppf DTBMP IPr Et Fmoc KIE MAD Me MePhos Mes MOM MS MW NHC Ox OxAdd Pc PDMS PePPSI-IPr

University (Saint Petersburg, Russia) with an M.S. degree in Chemistry (1992). He did a Ph.D. study (1992−1996) under the supervision of Professor Andrey P. Rudenko at the Department of Organic Chemistry at Saint Petersburg State Forest Technical University and obtained his Ph.D. in Organic Chemistry in 1996. Since 1994, he has worked at Saint Petersburg State Forest Technical University successively holding the positions of Scientific Researcher, Lecturer, Senior Lecturer, Assistant Professor, Associate Professor, Full Professor of the Department of Organic Chemistry, Head of the Department of Chemistry, and since 2015, Director of Institute of Chemical Processing of Wood Biomass and Technosphere Safety. He obtained his posthabilitation D.Sc. degree in 2010. Since 2011, he has had a collaborative post of Full Professor at the Department of Organic Chemistry of Institute of Chemistry at Saint Petersburg State University. He did PostDoc Fellowships with Professor Jay K. Kochi at the University of Houston (Houston, Texas) (2000−2001) then with Professor Jean Sommer and Professor Patrick Pale at the University of Louis Pasteur, Strasbourg (France) (2003). He was an Invited Professor at the University of Louis Pasteur, Strasbourg (France) (2007), and at Saimaa University of Applied Sciences (Finland) (2012). He is an author and coauthor of more than 80 original research papers and 2 reviews. His research interests are chemistry of acetylene compounds, superelectrophilic activation of organic compounds, organic radical-cations and charge-transfer complexes, methods of carbon−carbon bond formation, and chemistry of renewable wood and plant resources.

Ph Phen Phth PIFA Pr PyH Py Red RedEI RT TBAB TBS TBDMS TES Tf TFA TFP THF TMS Tol TON Ts Xyl

ACKNOWLEDGMENTS Financial support from Saint Petersburg State University (Saint Petersburg, Russia) Grants 12.38.195.2014 (for sections 3 and 6−14), and 12.37.214.2016 (for sections 2, 4, and 5) is greatly appreciated. ABBREVIATIONS IN ALPHABETICAL ORDER Ac acetyl acac acetylacetonate Ad adamantyl Alk alkyl All allyl AMLA ambiphilic metal−ligand assisted Ar aryl Bathophen 4,7-diphenyl-1,10-phenanthroline bipy 2,2′-bipyridyl binap 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl bmim 1-butyl-3-methylimidazolium Boc tert-butoxycarbonyl Bz benzoyl Bu butyl COD cycloocta-1,5-diene ChG chelating group CMD concerted metalation-deprotonation Cp cyclopentadienyl Cp* pentamethylcyclopentadienyl Cy cyclohexyl dba dibenzilydeneacetone DABCO 1,4-diazabicyclo[2.2.2]octane DCE dichloroethane DCM dichloromethane DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DFT density functional theory DMA dimethylacetamide DME dimethoxyethane

dimethylformamide bis(2-diphenylphosphinophenyl)ether 1,2-bis(diphenylphosphine)ethane 1,1′-bis(diphenylphosphino)ferrocene 2,6-di-tert-butyl-4-methylpyridine N,N′-bis(2,6-diisopropylphenyl)imidazol-2-ylidene ethyl fluorenylmethyloxycarbonyl kinetic isotope effect (CH3)Al(OC6H2-2,6-(t-Bu)2-4-Me)2 methyl 2-methyl-2′-dicyclohexylphosphinobiphenyl 2,4,6-trimethylphenyl methoxymethyl molecular sieves microwave N-heterocyclic carbene oxidant oxidative addition phthalocyanine polydimethylsiloxane [1,3-bis(2,6-diisopropylphenyl)imidazol-2ylidene](3-chloropyridyl)palladium(II) dichloride phenyl phenanthroline phthalocyanyl (bis(trifluoracetoxy)iodo)benzene propyl pyridine pyridyl reductant reductive elimination room temperature tetra(n-butyl)ammonium bromide tri(n-butyl)silyl tert-butyldimethylsilyl triethylsilyl trifluoromethane sulfonyl trifluoracetic acid tri(fur-2-yl)phosphine tetrahydrofuran trimethylsilyl 4-methylphenyl turnover number 4-MeC6H4SO2 2,6-dimethylphenyl

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