Norbornene: A Winning Combination for Selective Aromatic

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Pd/Norbornene: A Winning Combination for Selective Aromatic Functionalization via C−H Bond Activation Nicola Della Ca’, Marco Fontana, Elena Motti, and Marta Catellani* Dipartimento di Chimica and CIRCC, Università di Parma, Parco Area delle Scienze 17/A, I-43124 Parma, Italy

CONSPECTUS: Direct C−H bond activation is an important reaction in synthetic organic chemistry. This methodology has the potential to simplify reactions by avoiding the use of prefunctionalized reagents. However, selectivity, especially site selectivity, remains challenging. Sequential reactions, in which different molecules or groups are combined in an ordered sequence, represent a powerful tool for the construction of complex molecules in a single operation. We have discovered and developed a synthetic methodology that combines selective C−H bond activation with sequential reactions. This procedure, which is now known as the “Catellani reaction”, enables the selective functionalization of both the ortho and ipso positions of aryl halides. The desired molecules are obtained with high selectivity from a pool of simple precursors. These molecules are assembled under the control of a palladacycle, which is formed through the joint action of a metal (Pd) and an olefin such as norbornene. These two species act cooperatively with an aryl halide to construct the palladacycle, which is formed through ortho-C−H activation of the original aryl halide. The resulting complex acts as a scaffold to direct the reaction (via Pd(IV)) of other species, such as alkyl or aryl halides and amination or acylation agents, toward the sp2 C−Pd bond. At the end of this process, because of steric hindrance, the scaffold is dismantled by norbornene extrusion. Pd(0) is cleaved from the organic product through C−C, C−H, C−N, C−O, or C−B coupling, in agreement with the well-known reactivity of aryl-Pd complexes. The cycle involves Pd(0), Pd(II), and Pd(IV) species. In particular, our discovery relates to alkylation and arylation reactions. Recently, remarkable progress has been made in the following areas: (a) the installation of an amino or an acyl group at the ortho position of aryl halides, (b) the formation of a C−B bond at the ipso position, (c) the achievement of meta-C−H bond activation of aryl rings bearing a chelating directing group by Pd(II)/Pd(IV)/norbornene catalysis, and (d) the activation of N−H and C− H bonds in sequence for indole 2-alkylation. In this Account, we explain the main features of this methodology, describe its synthetic potential, and illustrate some remarkable progress that has been made, emphasizing the most recent developments and applications in total synthesis.

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ortho positions of aryl halides with complete site selectivity.2 The key to this method is a catalytic system formed by a Pd species and a rigid and strained olefin, such as norbornene. The main feature of this system is its ability to construct a palladacycle by C−H activation using an aryl halide as the substrate. The resulting alkylaromatic palladacycle is extremely effective at directing the construction of complex organic molecules through sequential reactions, in which different molecules or groups react one after the other to attain the selective formation of multiple bonds.3 Therefore, our methodology combines C−H bond activation and sequential reactions,

INTRODUCTION One of the most challenging topics in organometallic chemistry and catalysis is the selective activation and functionalization of inert C−H bonds, which are ubiquitous in organic substances.1 Therefore, this goal has been extensively pursued because it would make many reactions both economical and environmentally friendly. Considerable research has been focused on understanding C−H bond cleavage by transition metals and the efficient transformation of the resulting organometallic complexes to valuable functional groups. However, despite the tremendous progress that has been made, site selectivity remains challenging. In this area, we have discovered and developed a unique way to achieve C−H bond activation and functionalization of the © XXXX American Chemical Society

Received: April 1, 2016

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DOI: 10.1021/acs.accounts.6b00165 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research

disubstituted vinylarenes 2. Here the process must begin with ortho-substituted iodoarenes.4b Although the reactions are operationally simple, they possibly proceed through a complex catalytic cycle involving a large number of steps that occur in sequence, and Pd complexes in the 0, II, and IV oxidation states are involved (Scheme 1). The cycle is initiated by the oxidative addition of an iodoarene, such as iodobenzene, to Pd(0) to afford the well-known phenylPd(II) species I. Norbornene insertion leads to complex II.5 Because of geometric constraints, this complex is fairly stable toward β-hydrogen elimination,2a which is the most common type of termination step for alkyl-Pd(II) species. However, complex II is quite reactive and affords the alkylaromatic fivemembered palladacycle III through intramolecular ortho-C−H activation in the presence of a base.2a,6 The cyclometalation process is likely facilitated by η2 coordination of the phenyl ring to Pd as in II, placing the metal in close proximity to the ortho position of the aromatic ring.5 The subsequent oxidative addition of the alkyl iodide (R−I) to III gives Pd(IV) metallacycle IV,7 which readily undergoes reductive elimination to yield norbornyl-Pd(II) complex V.7a Then, analogous to III, palladacycle VI is formed through activation of the second ortho-C−H bond. The oxidative addition of another molecule of R−I generates VII, which undergoes reductive elimination to provide VIII, a disubstituted homologue of complex V. At this stage, C−C bond cleavage spontaneously occurs, leading to the o,o′-dialkylated phenyl-Pd(II) iodide IX and norbornene. The latter thus becomes available for a new cycle. Norbornene deinsertion, which is the reversal of the initial insertion step,5 is most likely attributable to the steric effect of the ortho substituents.7a The cycle is terminated by coupling of complex IX with a terminal olefin via a Heck reaction to form compound 1 and Pd(0), thereby beginning a new cycle.2 One of the most intriguing aspects of the reaction course is related to the multiple functions of norbornene in the overall

meeting the requirements of modern chemistry for efficient, economical, and environmentally benign syntheses.

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AROMATIC ALKYLATION The initial breakthrough in Pd/norbornene catalysis occurred in 1997, when a complex catalytic cycle leading to the regioselective synthesis of 1,2,3-trisubstituted arenes was reported (Figure 1A).4a This process involves the one-pot

Figure 1. Symmetrical and unsymmetrical synthesis of 2,6dialkylvinylarenes. DMA, dimethylacetamide; DMF, dimethylformamide.

reaction of iodoarenes, alkyl iodides, and terminal olefins in the presence of a Pd species and norbornene as the catalyst to afford 2,6-disubstituted vinylarenes 1. Notably, in a single transformation three contiguous C−C bonds are formed by exclusive alkylation at the ortho positions and Heck-type olefination at the ipso carbon of the original iodoarene. Figure 1B shows a variant of the process leading to unsymmetrical 2,6-

Scheme 1. Proposed Reaction Pathway for Double ortho-Alkylation (L, Solvent or Coordinating Substrate)

B


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Accounts of Chemical Research process. After insertion into the phenyl-Pd(II) species I, norbornene acts as an ortho-directing group (ortho-DG), facilitating intramolecular C−H bond activation; promotes the reactivity of palladacycle III, leading to the functionalization of both ortho positions; and finally deinserts. Therefore, norbornene acts as a catalyst even though a stoichiometric or superstoichiometric amount is often used to favor the insertion step (Scheme 1). The novelty of this selective aromatic functionalization was recently recognized, and the process is now known as the Catellani reaction.8 This reaction was first named by Tsuji2d and Lautens.2e,f In addition to olefins, a variety of molecules or groups that are good partners for aryl-Pd(II) complexes can be used as terminating agents, and some selected examples are reported in Figure 3. Therefore, the process is very versatile and provides rapid and facile access to multisubstituted aromatic compounds starting from simple and readily available substrates. This work has greatly inspired the research of the Lautens group in Toronto, who have made substantial contributions in this area.2e The use of reactants containing two functional groups enables the facile formation of a large variety of cyclic and polycyclic structures via either intramolecular alkylation and/or termination steps. Carbocycles 4 were synthesized starting from 2-iodotoluene and bromoalkenoates 3, while compounds 6 were obtained from substrates 5, alkyl iodides, and terminal olefins through inter- and intramolecular alkylations followed by Heck coupling (Figure 2).2e,f These

Figure 3. Selected examples of intermolecular and intramolecular ortho-alkylation and termination steps.

Scheme 2. Observed Arylation Reactions Figure 2. Inter- and intramolecular alkylation and termination steps. TFP, tri-2-furylphosphine; EWG, electron-withdrawing group.

reactions were carried out under appropriate modified conditions using a Pd(OAc)2/triarylphosphine as the catalyst and Cs2CO3 as the base in refluxing MeCN or DMF at 80 °C. These conditions have been extensively utilized by Lautens and others.2c,e,g,h Some key synthetic applications are shown in Figure 3.

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AROMATIC ARYLATION Subsequently, the Catellani group reported a new type of Pd/ norbornene reaction involving aromatic arylation.2c This advance required the discovery of another important aspect of the chemistry of alkylaromatic palladacycles: the surprising effect of a substituent at the ortho position of the palladacycle arene moiety. Complex VI (Scheme 2) bearing an ortho substituent on the aromatic ring promoted the attack of haloarenes exclusively on the palladium-bonded aryl group

rather than on the norbornyl one to afford complex X. In the absence of an ortho substituent, as in III, the arylation step was not selective. We termed this remarkable outcome, which is likely attributable to steric factors, the “ortho effect”.2a This novel catalytic reaction allowed access to a biologically and pharmaceutically important class of biphenyls or C


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Accounts of Chemical Research terphenyls. Terphenyl derivatives 7 were readily obtained by the reaction of ortho-substituted iodoarenes and arylboronic acids (Scheme 3).2c This reaction has been proposed to

Scheme 4. Transmetalation Pathway

Scheme 3. ortho-Arylation and Proposed Mechanism

were performed in collaboration with the Derat and Malacria group,14 were in agreement with the proposed arylation of ortho-unsubstituted palladacycles (VI, R = H). However, the arylation of ortho-substituted palladacycle VI (R ≠ H) most likely proceeds through a Pd(IV) mechanism.14 Later, the Vicente group reported the synthesis and X-raydiffraction-based characterization of the first aryl-Pd(IV) complex XVIII, which was obtained by the oxidative addition of 2-iodobenzoic acid to Pd(II) species XVI (Scheme 5).15 The Scheme 5. Pd(IV) Complex of Vicente’s Group

proceed analogously to the previously described alkylation process. The key palladacycle VI, which is formed via oxidative addition, norbornene insertion, and cyclometalation, undergoes oxidative addition with an additional iodoarene molecule to afford Pd(IV) complex XII. Reductive elimination by aryl−aryl coupling and norbornene deinsertion lead to complex XIII, which reacts with arylboronic acid to yield compound 7 and Pd(0). The Pd(IV) intermediate XII was assumed on the basis of the isolation of Pd(IV) complexes containing allyl or benzyl groups in place of the aryl one.7a,2a However, although the model reactions use alkyl halides, the proposed formation of aryl-Pd(IV) metallacycles requires haloarene oxidative addition, which had not yet been observed in reactions of isolated Pd(II) complexes.11 The formation of the Csp2−Csp2 bond (from XII to X; Scheme 3) could alternatively occur through a transmetalation pathway (Scheme 4)12 involving an intermolecular exchange of the aryl and iodo ligands of aryl-Pd(II) complexes VI and XI via a dinuclear intermediate XIV with bridging ligands. The resulting complex XV undergoes reductive elimination to species X by aryl−aryl coupling. Theoretical studies of a simplified system reported by Cardenas and Echavarren13 supported the transmetalation reaction. The results from density functional theory calculations, which

chelating benzoate group replaces the acetato ligand, positioning the iodine atom near the metal center, as in XVII. This arrangement favors subsequent C−I bond cleavage. Therefore, the oxidative addition of haloarenes to Pd(II) species is a feasible pathway, supporting our initial proposal. Previously, the catalytic sequence was achieved using two molecules of the same haloarene to form the initial biphenyl unit. However, we discovered that two different haloarenes could be used to obtain mixed biaryls (Figure 4). To accomplish this goal, accurate tuning of the properties of the two partners was necessary. Iodoarenes containing electrondonating ortho substituents and bromoarenes activated by electron-withdrawing or ortho-chelating groups were necessary to achieve good selectivity.16,17 Under the adopted conditions, the iodoarenes reacted faster with Pd(0) than with the Pd(II) metallacycles, and the bromoarenes preferentially reacted with Pd(II) rather than Pd(0) (Scheme 3). These results allowed us to obtain vinylbiphenyl derivatives 10 substituted with different groups by reacting iodoarenes 8 and bromoarenes 9 with terminal olefins (Figure 4A).16,2c The reaction was readily extended to iodo- and bromoheteroarenes (Figure 4B).2c However, the heteroatom must be in a position that does not favor interaction with Pd in any of the intermediates involved in D


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Figure 4. Unsymmetrical cross-coupling.

the cycle. Thus, although 3- and 4-bromopyridine readily react, 2-bromopyridine hinders the reaction. The mixed aryl coupling reaction provided access to a wide series of condensed aromatics,2c which could be prepared by utilizing bromoarenes bearing suitably placed functional groups that can undergo further transformations. Dibenzopyrans 14 were obtained by reacting iodoarenes, o-bromophenols, and activated olefins via aryl−aryl and Heck couplings followed by cyclization through a Michael-type reaction (Figure 5A).17a

Figure 6. Carbazoles and phenanthridines.

dihydrophenanthridines 17 were formed via a three-component reaction (Figure 6B).20 Similarly, this procedure was also exploited to synthesize phenanthridines 18 (Figure 6C) by employing o-bromo-N-trifluoroacetanilides, iodoarenes, and methyl vinyl ketone. The initially formed dihydrophenanthridines undergo hydrolysis of the trifluoroacetyl group and retroMannich reaction to yield compounds 18 and acetone.21 Direct phenanthridine syntheses were also reported by the Lautens and Malacria groups. The former obtained phenanthridines 20 using o-chloro-N-silylaldimines and -silylketimines 19, which perform better than the corresponding bromides, as suitable partners for iodoarenes (Scheme 6).22 The Malacria Scheme 6. Synthesis of Phenanthridines 20

Figure 5. Dibenzopyrans.

Therefore, electron-rich bromoarenes containing ortho-chelating groups can also be appropriate cross-coupling partners. Through chelation to palladacycle VI (Scheme 3), obromophenol favors breaking the C−Br bond, as reported for o-iodobenzoic acid (Scheme 5). Through the combination of Pd/norbornene and cinchona alkaloid catalysis, the enantioselective synthesis of 6H-dibenzopyrans 14 was achieved in good yields with satisfactory enantioselectivities.17b Dibenzopyrans 15 can be synthesized starting from iodoarenes and tertiary obromobenzyl alcohols. The cyclization step is favored by the presence of the geminal group effect (Figure 5B).18a,b The Pd/norbornene-catalyzed arylation cross-coupling method using N-protected o-bromoanilines was successfully applied to the synthesis of carbazoles and dihydrophenanthridines. The formation of the former proceeds through sequential aryl−aryl and N−aryl couplings, and the formation of the latter occurs according to the previously reported sequence for the synthesis of 6H-dibenzopyrans (Figure 5A). Therefore, N-arylsulfonyl- or N-acetyl-o-bromoanilines and iodoarenes reacted under the reported conditions to afford carbazoles 16 (Figure 6A).19 Starting from activated olefins and the same type of aryl halides,

group synthesized products 20 by employing primary and secondary o-bromobenzylamines 21. The initially formed dihydrophenanthridines undergo Pd(II)-catalyzed oxidative dehydrogenation by dioxygen.23 In contrast to the reactivity of protected o-bromoanilines, which leads to the synthesis of the five-membered ring of carbazoles 16 (Figure 6A), a completely different reaction E


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Accounts of Chemical Research featuring the unexpected formation of a seven-membered nitrogen ring was observed using unprotected o-bromoanilines. Therefore, the one-pot reaction of iodoarenes, free obromoanilines, and norbornene under the reported conditions (Figure 7A) yielded dihydrodibenzoazepines 22 containing the

Figure 8. ortho-Amination/hydrogenolysis.

to selectivity control. The importance of arylamines and the remarkable performance of N-benzoyloxyamines have spurred other groups to investigate this subject, and some examples are reported in Figure 9. The Chen group described the synthesis of alkenyl anilines 28 in gram quantities using N-benzoyloxyamines 27 as the partners for iodoarenes and activated olefins (Figure 9A).28 Chen also applied a similar protocol for the synthesis of biaryl amines 31, replacing olefins with pinacol boronates 30 (Figure 9B).29 Liang and Xu reported an ortho-amination reaction using N-benzoyloxyamines 27 followed by alkenylation at the ipso carbon by a Pd carbene generated from tosylhydrazone 32. The resulting ortho-aminated vinylarenes 33 (Figure 9C) were also prepared on a gram scale.30 Ritter reported the first example of intermolecular C−heteroatom bond formation at the ipso carbon in Pd/norbornene catalysis.31 In that work, orthoaminated arylboronate esters 35 were prepared starting from iodoarenes, N-benzoyloxyamines 25, and bis(pinacolato)diboron (34) (Figure 9D). The C−B bond of the resulting products 35 was easily converted into C−C, C−N, C−O, and C−halogen bonds, affording access to a wide variety of valuable intermediates. Gu32 and, subsequently, Chen and Wu33 reported the synthesis of 2-alkynylanilines 37 via ortho-C−H amination and ipso-alkynylation (Figure 9E,F). Both research groups employed cyclic and acyclic N-benzoyloxyamines 25 and aliphatic or aromatic alkyne precursors, such as alkynyl carboxylic acids 36 or alkynols 38. The latter performed better than terminal alkynes and avoided byproduct formation.

Figure 7. Dihydrodibenzoazepines and dibenzoazepines.

norbornane skeleton. When norbornadiene was used as a reactant, the corresponding dihydrodibenzoazepines 23 were formed and directly converted into unsaturated dibenzoazepines 24 through a retro-Diels−Alder reaction (Figure 7B).24 According to theoretical calculations, the unusual reactivity of free o-bromoaniline is most likely attributable to its chelation ability, which neutralizes the “ortho effect” and directs the migration of the Pd-bonded aryl ring toward the norbornyl carbon (Scheme 2).24,25

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RECENT PROGRESS In recent years, various research groups have made remarkable and fascinating progress regarding the synthetic potential offered by Pd/norbornene-based methodologies. Valuable procedures have been developed to (a) introduce an amino or an acyl group at the ortho position of aryl halides, (b) form a C−B bond at the ipso position, (c) achieve consecutive orthoand meta-C−H bond activation of aryl rings bearing a DG, and (d) sequentially activate N−H and C−H bonds for the 2alkylation of indoles. Moreover, the utility of this reaction has been demonstrated in natural product total synthesis.

Aromatic Acylation

Because aromatic ketones are valuable intermediates in the fine chemical industry, efficient alternatives to conventional methodologies are of great interest. In this area, Liang and colleagues34 published the first example of Pd/norbornenecatalyzed ortho-acylation of haloarenes followed by ipsoalkenylation. At nearly the same time, Dong35 and Gu36 concurrently reported similar ortho-acylations terminated by hydrogenolysis and Heck coupling, respectively (Figure 10). The three-component ortho-acylation processes reported by Liang34 and Gu36 (Figure 10A) refer to the synthesis of orthoacylated vinylarenes 40 starting from iodoarenes, acid anhydrides, or chlorides 39, and activated olefins. Both reactions tolerate a variety of functional groups and some heteroarenes and have been scaled-up to gram quantities. Importantly, anhydrides offer an advantage over chlorides by avoiding the formation of HCl. The key to the success of the Dong procedure generating ketones 42 (Figure 10B) is the use of anhydrides 41, which efficiently control the reactivity of the isopropoxide group. A large variety of functional groups are tolerated, and iodoheteroarenes are suitable substrates.35 A substituted norbornene (i.e., endo-5-N-methylaminocarbonyl-2norbornene) positively affects the yields.

Aromatic Amination

Because of the importance of arylamines, substantial interest is focused on developing new methodologies that are complementary to the widely used Buchwald−Hartwig reaction,26 which enables amination at the ipso carbon of haloarenes. In this area, the Dong group developed the first Pd/norbornenecatalyzed ortho-amination reaction of iodoarenes (Figure 8).27 The synthesis of anilines 26 was achieved starting from iodoarenes, N-benzoyloxyamines 25, and isopropanol and was easily scaled up. The reaction was proposed to proceed either through oxidative addition to form a Pd(IV) intermediate or direct electrophilic substitution. Notably, a well-matched reaction was reported in which three reactants were used in a nearly equimolar ratio with norbornene present in a substoichiometric amount; these conditions would contribute F


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Figure 9. ortho-Amination reactions. Bz, benzoyl; BPin, pinacol boronate; Ts, 4-toluenesulfonyl.

Figure 10. Acylation procedures.

meta-Selective C−H Bond Activation

Scheme 7. Design for meta-C−H Activation

One of the most versatile approaches for ortho-C−H activation relies on arenes containing a DG that is able to coordinate a metal and place it near an ortho-C−H bond. Therefore, the C− H activation step readily occurs via cyclometalation.37 In contrast, meta-C−H bond activation of electron-rich arenes remains challenging.37b Recently, Yu38 and, subsequently, Dong39 reported a new strategy for achieving the metaactivation of electronically unbiased arenes by combining chelation-assisted Pd(II) ortho-C−H activation and Pd(II)/ Pd(IV) norbornene chemistry. As shown in Scheme 7, the ortho-C−H bond activation of compound 43 is achieved by a tethered DG, which delivers the metallacycle XIX. Norbornene insertion affords intermediate XX, in which the metal is near the original meta-C−H bond, facilitating the cyclometalation step to generate palladacycle XXI. Complex XXI readily reacts with its coupling partner RX, and the reaction proceeds as previously described (Scheme 1) up to the formation of intermediate XXII, which undergoes protodemetalation to form G


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Accounts of Chemical Research Scheme 8. Yu’s meta-C−H Functionalization

meta-functionalized arene 44 and regenerate the Pd(II) catalyst. The net result of the two consecutive ortho-C−H activation steps is meta-functionalization. Scheme 8 shows two approaches developed by Yu.38 The meta-alkylated products 46 (R = alkyl; way a) were obtained by reacting amide 45 with alkyl halides containing no β-hydrogen atoms. In addition, meta-arylated products 46 (R = aryl) were primarily formed using iodoarenes bearing weak ortho-chelating groups.38a Although this transformation provides a proof of concept that meta-functionalization can be achieved using ortho-DGs and norbornene, it suffers from some limitations. However, the authors successfully combined 2-carbomethoxynorbornene and quinoline-based ligand L2 (way b).38b A variety of primary alkyl and aryl iodides were successfully employed to convert substrates 45 into meta-alkylated or -arylated products 46. The meta-alkylation was also applied to tetralone, dihydrobenzofuran, and indoline substrates. The electronic and steric effects of 2-carbomethoxynorbornene and L2 are crucial for controlling the numerous pitfalls encountered in the process. Interestingly, under these conditions iodobenzene was arylated at both ortho positions. Dong accomplished the synthesis of biaryls 48 by the meta-arylation of benzylamines 47 (Figure 11).39 The reaction tolerates a variety of R1

Scheme 9. 2-Alkylation of Free Indoles

cyclopalladation to afford the N-norbornane-type Pd(II) metallacycle XXV. The reaction proceeds as previously described (Scheme 1) up to the formation of intermediate XXVI. The hydrolysis of XXVI affords 2-alkylindole 49 and the Pd(II) catalyst. The phenanthroline-stabilized palladacycle XXV was characterized by X-ray crystallography.40b

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SELECTED APPLICATIONS IN TOTAL SYNTHESIS Bach applied the indole 2-alkylation method to the total synthesis of two Aspidosperma alkaloids (Scheme 10).40b (±)-Aspidospermidine was synthesized in nine steps starting from indole and bromide 50. (±)-Goniomitine was generated in seven steps from protected tryptophol 52 and iodide 53. The Lautens group reported the enantioselective total synthesis of (+)-linoxepin (Scheme 11).41 In a single reaction, precursor 57, which contained all of the carbon atoms required for the construction of the target molecule, was obtained from iodoarene 55, iodolactone 56, and tert-butyl acrylate in very high yield on a gram scale. This remarkable result enabled the synthesis of (+)-linoxepin in only eight steps with an overall yield of 30%. The Gu group published the rapid synthesis of (±)-rhazinal, which is a potent antitumor alkaloid (Scheme 12).42 Under Pd/ norbornene control, precursor 59 was obtained by sequential ortho-arylation and Heck cyclization of iodopyrrole 58 using 1bromo-2-nitrobenzene as the efficient cross-coupling partner.

Figure 11. Dong’s meta-C−H functionalization.

substituents and is applicable to N-substituted pyrrole- and pyridine-derived substrates, but only ortho-electron-withdrawing groups (R2) in the iodoarene afforded positive results. AsPh3 was the ligand of choice, and a “cocktail” of acetate salts in acetic acid was required to increase the reaction rate. 2-Alkylation of Unprotected N-Indoles

The Bach group developed an elegant procedure involving Pd(II)/Pd(IV)/norbornene catalysis for the synthesis of 2alkylated indoles 49 starting from N-unprotected indoles and primary alkyl bromides (Scheme 9).40 The free ligand reaction tolerates a large range of functional groups on both reagents. In addition, electron-poor pyrroles were good substrates for this transformation.40c The proposed pathway involves N−H activation by Pd(II) followed by norbornene insertion and H


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Accounts of Chemical Research Scheme 10. 2-Alkylated Indoles 51 and 54

Scheme 11. Three-Component Synthesis of 57

Scheme 12. Synthesis of 59, a Key Intermediate for (±)-Rhazinal

products, which are typically complex molecules that are difficult to prepare by alternative approaches. We expect many new developments in these areas.

Our research group developed a direct synthetic route to antibiotic carbazomicin A (63) and D (64) through aryl−aryl and N−aryl coupling starting from iodoarene 60 and bromoarene 61 or 62, respectively (Scheme 13).19,43

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CONCLUSIONS The Pd/norbornene combination is a unique catalytic system for selective reactions via C−H activation. A large variety of highly functionalized aromatic compounds can be prepared in a simple and straightforward fashion through this process. The extraordinary developments in recent years have enhanced and expanded the synthetic potential of this methodology. This type of chemistry, which encompasses organometallic, catalysis, and organic chemistry, offers numerous opportunities, and many breakthroughs have been achieved, generating starting points for new and fascinating developments. Each new reaction pathway described above can be further extended to other substrates or more complex sequences and to new applications. Detailed mechanistic studies are needed to gain additional insight into the reaction pathways and reveal the nature of the coupling steps that occur on Pd. Extremely important synthetic consequences can be expected from these studies. For example, the preliminary results reported by Yu demonstrate that the use of 2-carbomethoxynorbornene rather than unsubstituted norbornene allows selective aromatic arylation of ortho-

Scheme 13. Carbazomycins A and D

Dong reported the rapid synthesis of ketoprofen, a wellknown nonsteroidal anti-inflammatory agent (Scheme 14).35 The key step leading to arylpropionic ester 66 involves the ortho-acylation of iodoarene 65 by reactant 41 followed by hydrogen transfer at the ipso position. These examples illustrate the utility and potential of the Pd/ norbornene catalytic system for the total synthesis of natural I


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Accounts of Chemical Research Scheme 14. Direct Synthesis of (±)-Ketoprofen

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unsubstituted haloarenes. Therefore, sterically hindered olefins may be used to replace norbornene to avoid the ortho substituent. Another fascinating topic related to asymmetric catalysis and Pd/norbornene chemistry is the possibility of creating asymmetric sequences with exciting applications.

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AUTHOR INFORMATION

Notes

The authors declare no competing financial interest. Biographies Nicola Della Ca’ received his Ph.D. in 2004 from Parma University, where he became a Research Associate after studying with Prof. Larock at Iowa State University. His research interests are primarily focused on the synthesis of heterocycles by transition-metal-catalyzed reactions involving C−H activation. Marco Fontana received his Ph.D. in Chemical Sciences in 2015 from Parma University. He performed his research under the supervision of Prof. Catellani and worked on palladium/norbornene chemistry and C−H activation. Elena Motti completed her Ph.D. in 2001 at Parma University, where she is now an Associate Professor. She spent part of her doctoral studies at ETH Zurich working in the group of Prof. Pregosin. Her research is primarily focused on multistep and multicomponent palladium-catalyzed processes via C−H activation. Marta Catellani obtained her Italian Laurea in Chemistry in 1971 and then began investigating catalytic processes in Prof. Chiusoli’s group. After a postdoctoral appointment with Prof. Halpern in Chicago, she joined Parma University in 1981. Her research interests are focused on the catalysis of multicomponent organo−palladium reactions via C−H activation.

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ACKNOWLEDGMENTS We thank MIUR - Project 2008A7P7YJ, for supporting our programs. We are deeply indebted to all of the students and colleagues who are cited in the references for their intellectual and experimental contributions.

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DEDICATION This Account is dedicated to the memory of Gian Paolo Chiusoli, commemorating the third year of his death. REFERENCES

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Norbornene: A Winning Combination for Selective Aromatic

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