Recent Advances in the Chemistry of Conjugated Nitrosoalkenes and

Review Cite This: Chem. Rev. 2018, 118, 11324−11352

pubs.acs.org/CR

Recent Advances in the Chemistry of Conjugated Nitrosoalkenes and Azoalkenes Susana M. M. Lopes,† Ana L. Cardoso,† Ameŕ ico Lemos,‡ and Teresa M. V. D. Pinho e Melo*,† †

CQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal Centro de Investigaçaõ em Química do Algarve, Faculdade de Ciências e Tecnologia, University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal

Chem. Rev. 2018.118:11324-11352. Downloaded from pubs.acs.org by STOCKHOLM UNIV on 12/19/18. For personal use only.

‡

ABSTRACT: This review aims to present the most recent contributions in the chemistry of nitrosoalkenes and azoalkenes, highlighting the chemical behavior that makes them important and versatile building blocks in organic synthesis. These are heterodienes used in the assembly of a variety of heterocyclic systems, spanning from five- to seven-membered heterocycles, as well as for the functionalization of heterocycles.

CONTENTS 1. Introduction 2. Cycloaddition Reactions of Nitrosoalkenes 2.1. [4 + 2] Cycloaddition Reactions of Nitrosoalkenes 2.2. Asymmetric [4 + 2] Cycloaddition Reactions of Nitrosoalkenes 3. Cycloaddition Reactions of Azoalkenes 3.1. [4 + 2] Cycloaddition Reactions of Azoalkenes 3.2. Asymmetric [4 + 2] Cycloaddition Reactions of Azoalkenes 3.3. Formal [4 + 2] Cycloaddition Reaction of Azoalkenes 3.4. Other Cycloaddition Reactions of Azoalkenes 4. Conjugate Addition of Nitrosoalkenes and Azoalkenes 4.1. Conjugate Addition of Nitrosoalkenes 4.2. Conjugate Addition of Azoalkenes 5. Conclusion Author Information Corresponding Author ORCID Notes Biographies Acknowledgments References

in target-oriented synthesis of naturally occurring and biologically active molecules. These heterodienes have been mainly used as electron-deficient heterodienes in heteroDiels−Alder reactions with electron-rich heterocycles and nucleophilic olefins or as Michael-type acceptors in conjugate 1,4-addition reactions. Nitrosoalkenes and azoalkenes are enolium synthetic equivalents, and their reactivity toward nucleophiles opens the way to umpolung α-functionalization of ketones. Asymmetric versions of these reactions are known, which widen their applicability. Furthermore, azoalkenes also participate in formal [4 + 2] cycloaddition reactions as well as other types of cycloaddition reactions, namely, [4 + 3], [4 + 1], and [3 + 2] cycloadditions. Previously published reviews have addressed nitrosoalkene and azoalkene chemistry separately.1−15 The present work covers the most recent advances in this field since 2010, providing an overview of the use of nitrosoalkenes and azoalkenes as key intermediates in organic synthesis, addressing aspects such as scope, efficiency, and selectivity and giving mechanistic insights that will certainly stimulate further studies.

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2. CYCLOADDITION REACTIONS OF NITROSOALKENES Over the past decades, conjugated nitrosoalkenes (NSA) have consolidated their importance in organic chemistry as extremely valuable intermediates in the synthesis of a vast array of heterocyclic systems.1−7 This is mainly due to the elaboration of a simple and reliable method for their generation from available precursors: the base-mediated dehydrohalogenation of α-halooximes. Although α-halooximes

1. INTRODUCTION The chemistry of conjugated nitrosoalkenes and azoalkenes has been successfully explored, as they are valuable intermediates for the synthesis of a plethora of heterocyclic systems as well as © 2018 American Chemical Society

Received: June 18, 2018 Published: November 29, 2018 11324

DOI: 10.1021/acs.chemrev.8b00375 Chem. Rev. 2018, 118, 11324−11352

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Scheme 1. Overview of Mechanistic Pathwaysa

are the most commonly used precursors of NSA, other synthetic precursors such as α-halooxime silyl ethers,16−18 N,N-bis(silyloxy)enamines,19−21 and N-siloxysulfonamides22,23 have also been described. The most important synthetic application of these highly reactive intermediates is their use as heterodienes in inverse electron demand Diels−Alder reactions with electron-rich heterocycles or nucleophilic olefins, as an effective synthetic methodology to new 1,2-oxazines and openchain oximes. The electrophilic character of the heterodiene is crucial for the efficiency of the cycloaddition, and therefore NSA having electron-withdrawing substituents at 3- and/or 4positions such as aryl, trifluoromethyl, acyl, alkoxycarbonyl, phosphorus, tetrazolyl, and triazolyl groups have been used. These substituted 1,2-oxazines and oximes are valuable synthetic intermediates in the target-oriented synthesis of naturally occurring and biologically active molecules.4,24,25 2.1. [4 + 2] Cycloaddition Reactions of Nitrosoalkenes

Diels−Alder cycloadditions between asymmetrically substituted dienes or heterodienes and/or asymmetrically substituted dienophiles or heterodienophiles occur via highly asymmetric transition states. These reactions are characterized by asynchronous bond formation, with the formation of the first σ-bond between the most electrophilic and nucleophilic centers of the reagents, followed by concomitant ring closure. Recently, quantum chemical calculations were carried out to investigate an extreme case of a polar Diels−Alder reaction involving the reaction of NSA with enamines as highly nucleophilic dienophiles.26−28 The results were consistent with a two-stage, one-step mechanism. The initial C−C bond formation is followed by formation of the C−O bond in the second stage with subsequent ring closure. Two different mechanistic pathways can be involved in the reaction of nucleophiles with α-halooximes: generation of nitrosoalkenes followed by conjugate 1,4-addition or direct substitution of the halogen. Nevertheless, the intermediacy of NSA has been supported in some cases spectroscopically and also by the direct isolation of more stable nitrosoalkenes.1−5,7,29−31 Still, in their pioneering work, Gilchrist et al.32 observed that the reaction of ethyl bromopyruvate oxime with imidazole is faster than with the corresponding O-alkylated oxime, for which dehydrobromination is blocked. The rationalization of these experimental results seems to indicate that the reaction with imidazole proceeds via an elimination−addition mechanism, while with the O-alkylated oxime a direct substitution mechanism occurs. Moreover, imidazole proved to be a strong enough base to eliminate HBr from ethyl bromopyruvate oxime, generating the corresponding NSA. A different pathway was observed in the reaction with less basic azoles (e.g., pyrazole), which proceeds through direct halogen displacement (Scheme 1A). The alkylation of electron-rich heterocycles (e.g., indole, pyrrole) via reaction with α-halooximes is carried out under basic conditions to ensure the generation of NSA. Nevertheless, the reaction pathway can in principle involve either a hetero-Diels−Alder reaction or a conjugate 1,4-addition. In this context, two detailed mechanistic studies from different groups concerning the reactivity of nitrosoalkenes toward pyrrole derivatives have been reported.33,34 Pinho e Melo and co-workers35,36 observed that the chemical behavior of NSA toward pyrrole derivatives is strongly dependent on the substituent in 3-monosubstituted nitrosoalkenes. In fact, conjugated nitrosoalkenes bearing a

a (A) Gilchrist et al.32 (B) Pinho e Melo and co-workers.35,36 (C) Palacios and co-workers.34

tetrazolyl or an ester group at the 3-position reacted with pyrrole and 2,5-dimethylpyrrole via Diels−Alder reaction to give open-chain 2-substituted pyrroles and 5,6-dihydro-4H-1,2oxazines, respectively (Scheme 1B). The formation of these products results from the rearomatization of the initially formed Diels−Alder cycloadducts, the bicyclic 1,2-oxazines. On the other hand, arylnitrosoethylenes [e.g., 1-(pbromophenyl)nitrosoethylene] displayed a different reactivity toward pyrrole, affording two isomeric oximes throught conjugate addition and subsequent rearomatization of the pyrrole ring. In the case of the reaction of this heterodiene with 2,5-dimethylpyrrole, after the initial conjugate addition, an intramolecular O- and N-nucleophilic addition occurs, leading to the corresponding bicyclic oxazine and five-membered cyclic nitrone, respectively. The rationalization of these experimental results was supported by quantum chemical calculations, which 11325


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predicted that the Diels−Alder reaction is favored in the case of ethyl nitrosoacrylate, whereas for 1-(p-bromophenyl)nitrosoethylene an alternative reaction pathway must be involved.33 More recently, Palacios and co-workers34 also reported the reaction of phosphinyl nitrosoalkenes with pyrrole and 2,5dimethylpyrrole, giving rise to the formation of 2-substituted pyrroles and bicyclic oxazines, respectively (Scheme 1C). As in previous results, the quantum chemical calculations showed very good agreement with the experimental data and proposed mechanisms. In this case, the reaction mechanism seems to occur through a concerted asynchronous [4 + 2] cycloaddition process, which is kinetically favored. Therefore, the nature of the NSA substituent at 3- and/or 4-positions has a strong influence on the reaction pathway and outcome of these transformations. Similar calculations were performed to study the chemical behavior of 3-(p-bromophenyl)nitrosoalkene 1 toward indole derivatives, which were in agreement with a process involving hetero-Diels−Alder reaction (Scheme 2).37 Thus, the combination of 3-arylnitrosoalkenes with pyrrole derivatives favors the conjugate addition pathway.

Scheme 3. Synthesis and Reactivity of 3-(1H-Tetrazol-5yl)nitrosoalkenes 5

Scheme 2. Hetero-Diels−Alder Reaction of 1-(pBromophenyl)nitrosoethylene (1) with Indole Derivatives

hetero-Diels−Alder reactions (or conjugate addition) of NSA with pyrroles and indoles, respectively, has been established (Schemes 4 and 5).38−40 The base-mediated dehydrohalogenation of alkyl α,α-dihalooximes 11 in the presence of pyrrole via Diels−Alder reactions (or conjugate addition in the case of 3-arylnitrosoalkenes) afforded 5-substituted dipyrromethanes 13 in good yields (Scheme 4). The reactions were carried out Scheme 4. Synthesis of Dipyrromethanes via Two Consecutive Reactions of Nitrosoalkenes with Pyrrole Pinho e Melo and co-workers35,36 described the first examples of inverse electron demand Diels−Alder reactions of 3-(tetrazol-5-yl)nitrosoalkenes 5, generated in situ from the corresponding tetrazolyl-α-bromooximes 4. By use of the click chemistry approach to build the tetrazole ring, organic azides were reacted with pyruvonitrile to give acetyltetrazole 2, which after bromination with bromine−dioxane complex in diethyl ether and oximation with hydroxylamine hydrochloride gave oximes 4, precursors of the novel 3-(tetrazol-5-yl)nitrosoalkenes 5 (Scheme 3). The reactivity of 3-(tetrazol-5-yl)nitrosoalkenes 5 with electron-rich alkenes and heterocycles was explored, affording in good overall yields new tetrahydro-3-tetrazolyl-1,2-oxazines (e.g., 6−8) and open-chain oximes having the tetrazole functionality (e.g., 9a,b) (Scheme 3).35,36 When acyclic and cyclic ethers were used as dienophiles (e.g., ethyl vinyl ether, 2,3-dihydrofuran, and 2,3-dihydropyran) as well as furan, cycloadducts were isolated, whereas with heterocycles having higher aromatic character, such as pyrrole or indole, openchain oximes were obtained. Moreover, the developed methodology can be applied to the synthesis of tryptophan analogues such as 5-(1-aminoalkyl)-1H-tetrazoles (e.g., 10) via reductive transformations of these adducts. An innovative one-pot synthetic approach to dipyrromethanes and bis(indolyl)methanes based on two consecutive

under on-water conditions, with dichloromethane as solvent or in the absence of solvent (for 13a: no solvent, 66 h, 25% yield vs H2O, 4 h, 74% yield). The on-water reactions allowed the synthesis of the desired products in higher yields, consistently shorter reaction times, and much simpler isolation procedures.38 This broad and versatile methodology was successfully applied to the synthesis of unprecedented 1hydroxyiminomethylbis(indolyl)methanes (e.g., 14) (Scheme 11326


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5).39,40 Thus, a range of alkyl and aryl α,α-dihalooximes (e.g., 11) reacted, under basic conditions, with indole derivatives,

formation of monosubstituted (e.g., 18) or 1,9-disubstituted derivatives (e.g., 19) was attained via reaction stoichiometry control.41 A different outcome was observed in the reaction of 5phenyldipyrromethane (17b) with 3-phenyl-, 3-(p-nitrophenyl)-, 3-(p-fluorophenyl)-, and 3-(1-benzyl-1H-tetrazol-5-yl)nitrosoalkenes, which resulted in the formation of two isomeric oximes 20 and 21 in high overall yield (71−98%).42 In this case, the formation of two isomeric oximes confirms that the reaction pathway involves an initial conjugate addition followed by rearomatization of the pyrrole unit. This synthetic methodology gave access to a variety of new dipyrromethanes, some of which showed interesting biological properties.42 The reactivity of nitrosalkenes toward 2,2-bis(furan-2yl)propane (22) has been described.43,44 Under typical reaction conditions, transient nitrosoalkenes 16 reacted with bis(furan-2-yl)propane 22 to give 1,2-oxazines 23 in good yields. These hetero-Diels−Alder cycloadducts can be efficiently converted to the corresponding open-chain oximes 24 (84−96% yield) by 1,2-oxazine ring-opening and consequent rearomatization of the furan ring, in refluxing dichloromethane or by treatment with trifluoroacetic acid (TFA) at room temperature (Scheme 7).

Scheme 5. Synthesis of Bis(indolyl)methanes from Nitrosoalkenes and Indoles

Scheme 7. Reactivity of Nitrosalkenes toward 2,2-Bis(furan2-yl)propane (22)

giving access to a variety of new bis(indolyl)methanes (BIMs). The H2O/dichloromethane (DCM) solvent system was the most efficient to carry out these transformations, affording BIMs selectively and in good yields (55−78%). Moreover, the reaction of aryl oximes led to the (E)-oximes 14 as single or major product, whereas the reaction of alkyl oximes with indole resulted in the formation of (Z)-oximes as the major product. Modulation of the BIM structure can be easily achieved through appropriate selection of the substitution pattern of the starting oximes and/or indoles. Furthermore, this class of compounds showed promising anti-cancer activity, namely, bis(indolyl)methane 14a, which was identified as a scaffold for the design of new anti-cancer derivatives. The chemistry of nitrosoalkenes was also explored as a new synthetic approach for the functionalization of dipyrromethanes in positions 1 and 9 (Scheme 6).41,42 The heteroDiels−Alder reactions of 5,5′-diethyl- (17a) and 5-phenyldipyrromethanes (17b) with nitrosoalkene 16 (R1 = CO2Et), generated in situ from the corresponding α-bromooxime 15, gave access to dipyrromethanes 18 or 19 with side chains containing oxime groups (Scheme 6). Interestingly, selective

The hetero-Diels−Alder reaction of 3-arylnitrosoalkenes 16 with furan or 2,5-dimethylfuran gave the corresponding furooxazines 25 in good yields (Scheme 8).43,44 Further thermolysis of heterocycles 25 derived from 2,5-dimethylfuran

Scheme 6. Functionalization of Dipyrromethanes via Hetero-Diels−Alder Reaction with Nitrosoalkenes

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with hydroxylamine hydrochloride in DCM/MeOH gave the new α-bromooxime-1,2,3-triazoles 35, precursors of 3triazolylnitrosoalkenes 36. The reaction of nitrosoalkenes 36 with pyrrole afforded the expected open-chain oximes 37 together with the formation of bis-oximes 38 in good overall yields (57−87%). The same behavior was observed in the reaction of nitrosoalkene 36 (R = p-ClC6H4) with 5,5′dipyrromethane, giving mono- and bis-functionalized dipyrromethanes 40 and 41. Compound 39 was obtained from the reaction of nitrosoalkene 36 with indole (R = p-ClC6H4), formed by alkylation of the primarily formed open-chain oxime that resulted from the hetero-Diels−Alder reaction. This outcome indicates that 3-triazolylnitrosoalkenes are more activated heterodienes than nitrosoalkenes bearing an ester, an aryl, or a tetrazolyl group at C-3. On the other hand, openchain oximes were obtained as single isomers, the ones expected from a pathway involving hetero-Diels−Alder reactions. Furthermore, from the reaction of 3-triazolylnitrosoalkene 36 (R = p-ClC6H4) with 2,5-dimethylpyrrole, bicyclic heterocyclic 42 was isolated as a single product, reinforcing that a cycloaddition took place. The antibacterial activity of these new functionalized 1,2,3-triazoles was evaluated and a promising scaffold was identified. In fact, 40 showed high activity against Staphylococcus species including methicillinresistant strains.46 The synthesis of fused 1,2-oxazinedihydropyrrole derivatives (e.g., 46) bearing a phosphorus group via hetero-Diels−Alder of phosphinyl nitrosoalkenes with 2,5-dimethylpyrrole has been described (Scheme 10).34 In this way, the one-pot

Scheme 8. Synthesis and Transformations of Furooxazines

(R1 = Me) in the presence of catalytic amounts of ptoluenesulfonic acid led to the formation of 6H-1,2-oxazines 26 via a furan ring-opening reaction. On the other hand, furooxazines 25 derived from furan (R1 = H) were converted into izoxazoles 29 and open chain oximes 27, by treatment with TFA. However, isoxazoles 29 were obtained in higher yields when the synthetic procedure was carried out in two steps. Thus, furo-oxazines 25 reacted efficiently with TFA (1 equiv) to give the corresponding open-chain oximes 27, which were then converted in good yield into isoxazoles 29 upon treatment with TFA. Faragher and Gilchrist45 have previously described one example of this type of transformation of furooxazines into isoxazoles, involving the generation of spirocyclic intermediate 28 (R = Ph). Recently, the generation and hetero-Diels−Alder reactions of novel 3-triazolylnitrosoalkenes 36 toward heterocycles, as an approach to functionalized 1,2,3-triazoles, has been described (Scheme 9).46 The synthesis of 1,2,3-triazoles 32 was achieved in high yield by the click chemistry approach, reacting organic azides with the terminal alkyne 31 (84−93%). Oxidation of the secondary alcohol of 32 with potassium dichromate, followed by bromination with bromine in acetic acid, gave the expected α-bromoacetyl-1,2,3-triazole 34. Treatment of these triazoles

Scheme 10. Reactivity of Phosphinyl Nitrosoalkenes toward Pyrrole Derivatives

Scheme 9. Synthesis and Hetero-Diels−Alder Reaction of 3Triazolylnitrosoalkenes 36

reaction of phosphinyl α-bromooxime 43a with 2,5-dimethylpyrrole, in dichloromethane and in the presence of sodium carbonate, afforded 1,2-oxazine 46 in 58% yield and in a regioselective fashion. On the other hand, the reaction of phosphinyl nitrosoalkenes with pyrrole led to the formation of open-chain 2-substituted pyrroles 45 in good yields (56−90%). This synthetic approach tolerates several substituents at C-3, as well as other bases, such as anhydrous Na2CO3 or aqueous NaHCO3. In fact, the best results were achieved when the reactions were carried out in saturated aqueous NaHCO3 in the presence of pyrrole. As previously mentioned, the proposed mechanism for these reactions, which were supported by theoretical studies, involves hetero-Diels−Alder cycloaddition as the first step in both cases. The reactivity of phosphinylnitrosoalkenes34 toward indole derivatives has also been reported. 4-Phosphinylnitrosoalkenes 44 bearing a methyl, ethyl, or methoxycarbonyl group at the 311328


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position, generated in situ by treatment of the corresponding α-bromooximes with anhydrous Na2CO3, reacted with indole to form the corresponding open-chain 3-substituted indoles 47 as sole products, in yields ranging from 57% to 75% (Scheme 11).

Scheme 12. [4 + 2] Cycloaddition Reaction of Phosphonyland Phosphinylnitrosoalkenes with Conjugated Cyclic Dienes

Scheme 11. Reactivity of Phosphinylnitrosoalkenes toward Indole Derivatives

Scheme 13. Hetero-Diels−Alder Reactions of Phosphinyl-, Phosphonyl-, and Ethoxycarbonylnitrosoalkenes with Enol Ethers

A surprising tandem process involving an initial heteroDiels−Alder cycloaddition reaction of NSA bearing phosphorus substituents with conjugated cyclic dienes, followed by a [3,3]-sigmatropic rearrangement, has been reported by Palacios and co-workers.47 Moreover, 4-phosphinyl- (48a, R = Ph) and 4-phosphonylnitrosoalkenes (48b, R = OEt) reacted with cyclopentadiene (50) or cyclohexa-1,3-diene (51) to give 2-oxa-3-azabicyclic derivatives 52, instead of the expected hetero-Diels−Alder cycloadducts (Scheme 9). The formation of N-vinyl bicyclic compounds 52 results from a [4 + 2] cycloaddition in which the NSA acts as a heterodienophile, through the nitrogen−oxygen double bond of the nitroso group, while the conjugated cyclic alkene is acting as the 4π electron system. Compounds arising from the reaction of NSA 49 with cyclopentadiene were very unstable and readily converted into the stable 1,2-oxazines 53 via an aza-Cope rearrangement when heated in refluxing chloroform. On the other hand, the reaction of NSA 49 with cyclohexa-1,3-diene also led to cycloadducts 52 in excellent yields, although these derivatives could not be subsequently converted into the corresponding phosphorated 1,2-oxazines 53. A different outcome was observed in the reaction of nitrosoalkenes 49 with 5-(trimethylsilyl)cyclopenta-1,3-diene (54), which under the same reaction conditions afforded a mixture of 1,2-oxazine derivatives 55/56 in a regio- and stereoselective fashion (Scheme 12). Nevertheless, heating the mixture of cycloadducts 55/56 in refluxing chloroform gave rise to the more stable 1,2-oxazines 56 in good yields (Scheme 12). The reactivity of phosphorus NSA toward enol ethers has also been explored (Scheme 13).48 The developed synthetic methodology gave access to functionalized 4-phosphorated 1,2-oxazines 61 via [4 + 2] cycloaddition reaction of transient nitrosoalkenes 58, generated from the α-halooxime precursors 57 in basic conditions, with cyclic and acyclic enol ethers. The scope of this regioselective method includes the reaction of nitrosoalkenes bearing various R1 substituents at C-3 (Me, Et, Ph, and CO2Me) and electron-withdrawing groups (EWG) at C-4 [P(O)Ph2, P(O)(OEt)2, and CO2Et], as well as different basic conditions (NEt3, Na2CO3, and NaHCO3). Depending on the substituents and reaction conditions, a mixture of diastereoisomers 60 and 61 epimeric at C-4 could be obtained. However, the less thermodynamically stable oxazines 60 were

readily converted into the more stable 1,2-oxazines 61 in refluxing chloroform via an imine−enamine tautomeric process. The regio- and stereochemistry of the isolated products has been correctly predicted by density functional theory (DFT)-based reactivity indices.49 Nevertheless, all attempts to prepare 1,2-oxazines bearing a carboxylic acid derivative at C-4 under on-water conditions were unsuccessful. In the past decade, 1,2-oxazine derivatives have been widely used as building blocks for stereoselective synthesis of naturally occurring and biologically active molecules. Therefore, it is not surprising that the key step in some of the reported multistep stereoselective syntheses involves the hetero-Diels−Alder reaction of nitrosoalkenes. In this context, Gallos et al.50,51 have developed a synthetic methodology to prepare enantiomerically pure unnatural hydroxylated pyrrolizidines (e.g., 67) based on a hetero-Diels−Alder reaction of ethyl 2nitrosoacrylate (16) with pent-4-enofuranosides (e.g., 65), followed by a two-step reductive ring opening−ring closure treatment of the corresponding cycloadduct (e.g., 66) (Scheme 14). The process is highly diasteroselective and, for example, spirocycloaduct 66 was obtained as a single product in 62% yield. This synthetic methodology was also used in the synthesis of C-glycoamino acids bearing a variety of sugar moieties.52 Moreover, ethyl 2-nitrosoacrylate (16) underwent cyclo11329


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Scheme 14. Hetero-Diels−Alder Reactions of Nitrosoalkene 16 with Pent-4-enofuranoside and exo-Glycals

addition reaction with electron-rich sugar enol ether 62, yielding spirocyclic oxazine 63 as a single diasteroisomer in 64% yield. Further transformation of this cycloadduct, and others, gave access to several protected C-glycoamino acids with either R or S configuration, namely, unusual amino acids with a spiro-N,O-acetal structure such as 64 (Scheme 14). The stereoselective hetero-Diels−Alder reaction of ethyl 2nitrosoacrylate (16) with D-ribose-derived exo-glycal 68 was successfully applied in the multistep synthesis of a protected trihydroxyindolizidine derivative 70, resulting from a 6-endo epoxide opening, an intermediate formed from the heteroDiels−Alder cycloadduct.53 Thus, treatment of exo-glycal 68 with 2 equiv of ethyl bromopyruvate oxime 15 at room temperature under basic conditions gave rise to the desired precursor, cycloadduct 69, in 56% yield (Scheme 14). Due to their excellent biological activities, (±)-1-deoxy-6epi-castanospermine 72 and (±)-1-deoxy-6,8a-di-epi-castanospermine 73 are considered important synthetic targets. However, the formation of the four contiguous stereocenters is a great challenge, and only a few syntheses have been reported. Recently, these compounds have been prepared via a protection-free synthetic sequence starting from the heteroDiels−Alder cycloadduct 71.54 This precursor was efficiently prepared from the known cycloaddition reaction of ethyl 2nitrosoacrylate (16) with ethyl vinyl ether, which afforded 71 in 99% yield (Scheme 15A). Another interesting example of the usefulness of this chemistry is illustrated in the synthesis of crispine A 77, a potent antitumor agent that has attracted great attention. Among the several synthetic methodologies developed for its preparation, a nine-step synthetic strategy in which the key step involves a NSA hetero-Diels−Alder reaction with ethyl vinyl ether has been reported.55 This strategy has the advantage of starting from easily accessible and inexpensive reagents such as 3,4-dimethoxyphenylacetic acid as a precursor of NSA 75, which undergoes a cycloaddition reaction with ethyl vinyl ether to give cycloadduct 76 in 67% yield.

Scheme 15. Nitrosoalkene Hetero-Diels−Alder Reaction with Ethyl Vinyl Ether

Subsequent simple synthetic transformations led to the target (±)-crispine A in 24% overall yield (Scheme 15B). Under typical reaction conditions, cis-enriched 1-acetoxy-2(benzyloxy)ethene (78) reacted with nitrosoalkenes generated in situ from oximes 15 to give oxygen-substituted 1,2-oxazines 79 in high yields with good trans selectivity (Scheme 16).56 As in previous studies, E-configured alkenes reacted faster than Scheme 16. Synthesis of Oxygen-Substituted 1,2-Oxazines via Hetero-Diels−Alder Reactions

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the corresponding Z-configured alkenes with NSA, leading to the observed trans selectivity. Moreover, the lower trans/cis selectivity observed in the synthesis of 4H-1,2-oxazine 79b seems to result from the higher reactivity of the αnitrosoalkene generated from 15 (R = CO2Et) when compared with the α-nitrosoalkene derived from oxime 15 (R = Ph). These oxygen-substituted 1,2-oxazines 79 are useful intermediates in the preparation of 1,2-aminoalcohols and hydroxyproline derivatives, although the described synthetic methodology does not allow the introduction of substituents at C-4. Thus, hydrogenation followed by acetylation of 1,2oxazine 79a afforded 1,2-aminoalcohol derivative 80 in low yield (31%). On the other hand, the reductive ring contraction of 79b furnished hydroxyproline derivative 81 in 32% yield with low diastereoselectivity. Carrying out this reaction under higher-pressure conditions (50 bar) did not lead to an improvement of the yield or of the cis/trans ratio of 81 (Scheme 16). 6H-1,2-Oxazine derivatives 85 have been prepared in yields ranging from 51% to 68% through [4 + 2] cycloaddition reaction of aryl NSA 84, generated under basic conditions from the corresponding ketoximes 83 by reaction with chloramine T, and terminal acetylenes (Scheme 17).57 This method is tolerant to acetylenes bearing several substituents such as propyl, hydroxymethyl, ester, and phenyl groups.

Scheme 18. Asymmetric Hetero-Diels−Alder Reaction of Indole Derivatives with Nitrosoalkenes

precursors to other chiral heterocyclic scaffolds, some of these tetrahydrooxazinoindoles have shown significant antileishmanial activity.59

Scheme 17. Synthesis of 6H-1,2-Oxazines

3. CYCLOADDITION REACTIONS OF AZOALKENES In recent decades, 1,2-diaza-1,3-butadienes (DAA), also known as azoalkenes, have attracted much interest since they are useful intermediates in the preparation of numerous heterocyclic systems. These heterodienes can participate in both conjugate additions and cycloaddition reactions, namely, hetero-Diels−Alder reactions.7−13 The adducts and cycloadducts formed this way are of extreme importance, not only for their pharmacological properties60 but also as key intermediates in organic synthesis. Conjugated azoalkenes differ in terms of their physical properties and stabilities, which are largely determined by the electron-withdrawing or -donating character of the substituents. Electron-deficient azoalkenes, unsubstituted at the 4position, are very unstable and are typically generated in situ, whereas 1,3,4-substituted azoalkenes are sometimes stable enough to be isolated and characterized. In any case, the most common method for preparation of azoalkenes is dehydrohalogenation of α-halohydrazones. However, azoalkenes can also be generated through the oxidation of hydrazones with 2,2,6,6tetramethylpiperidin-1-yl)oxyl (TEMPO),61 I2, or HgO.62,63 Other methods to generate azoalkenes include the pyrolysis of 1,2,3-thiadiazole dioxides, oxadiazinones,64 or 3-hydroxy-2arylhydrazonoalkanoic acid derivatives.65

2.2. Asymmetric [4 + 2] Cycloaddition Reactions of Nitrosoalkenes

Larionov and co-workers58 reported the first example of a copper-catalyzed asymmetric [4 + 2] annulation of NSA with substituted indoles, which afforded, in one step, up to three new chiral centers in the 1,2-oxazine ring (Scheme 18). Among the several Lewis acids and bisphosphine ligands screened, the Cu[(S)-DM-Binap)]OTf catalyst was the most efficient and, combined with a silver base (Ag2CO3), resulted in a synergistic combination that afforded the desired products 88 with high enantioselectivity (90−96% ee) in good yields (53−85%). Interestingly, this catalytic system allows the presence of several substituents not only in the indoles (in the 3, 4, 5, and 6 positions) but also in the 2-chlorooxime precursors 86, including 2,2-dichlorooximes (R2 = Cl). Thus, a vast range of enantiomerically enriched tetrahydrooxazinoindoles 88 bearing various substituents in the 3, 4, 4a, 5a, 5, and 9 positions were accessed via inverse electron demand [4 + 2] cycloaddition reaction of indole derivatives with nitrosoalkenes generated in situ from α-chlorooximes 86. Besides being excellent

3.1. [4 + 2] Cycloaddition Reactions of Azoalkenes

Ethyl 3-tetrazolyl-1,2-diaza-1,3-butadienes 91, generated from the corresponding α-bromohydrazones 90, were trapped in hetero-Diels−Alder reactions with electron-rich alkenes and heterocycles, as well as with electron-deficient alkenes, giving access to a large variety of 1,4,5,6-tetrahydropyrizadines and open-chain hydrazones bearing a tetrazole moiety (Scheme 19).66 The α-bromohydrazones 90 were obtained through reaction of acetyltetrazole 2 with ethyl carbazate, followed by bromination with N-bromosuccinimide (NBS). The reaction 11331


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Scheme 19. Reactivity of 3-Tetrazolyl-1,2-diaza-1,3-butadiene 91 toward Alkenes and Heterocycles

of DAA 91 with pyrrole and 2,5-dimethylpyrrole led to the formation of open-chain hydrazone 97 (50%) and bicyclic pyridazine 96 (39%), respectively, as final products, as expected. Interestingly, 1,4,5,6-tetrahydropyridazines 98 and 99 were obtained regioselectively in good yields from the reaction of azoalkenes 91 with electron-deficient alkenes. Frontier molecular orbital (FMO) analysis was carried out in order to understand this unusual reactivity pattern. The results indicate that the cycloadditions of 1,2-diaza-1,3-diene 91 (R = Ph) with acrylates as well as with ethyl vinyl ether are controlled by the lowest unoccupied molecular orbital (LUMO) of azoalkene, and consequently, they are inverse electron demand Diels−Alder reactions.66 Nevertheless, Attanasi et al.67,68 have also reported the reactivity of an electron-deficient 1,2-diaza-1,3-butadiene that reacts with both electron-rich and -deficient alkenes, and a report is known describing the Diels−Alder reaction of nitrosoalkenes with acrylonitrile and styrene but also with 1-alkylalkenes.69,70 Furthermore, to rationalize the regioselectivity observed in the Diels−Alder reactions of 1,2-diaza-1,3-diene 91 with 1,2dihydrofuran, quantum chemical calculations were also carried out at the DFT level, showing that the transition state leading to the observed regioisomer is significantly more stable that the one leading to the opposite regioisomer.66 On the other hand, the opposite regioselectivity observed for furan and dihydrofuran is in agreement with the calculated highest occupied molecular orbital (HOMO) coefficients of both dienophiles.71,72 N-Deprotection of the tetrazolyl moiety was also achieved (e.g., 1,4,5,6- tetrahydropyridazines 93c and 99b) in very high yield, by use of ammonium formate as hydrogen transfer agent (Scheme 19).66 Hetero-Diels−Alder reaction of DAA with dipyrromethanes was reported as a synthetic strategy for the functionalization of these heterocycles in positions 1 and 9 (Schemes 20 and 21).41,73 Transient azoalkenes 103, generated in situ by treatment of the corresponding hydrazones with sodium carbonate in either dichloromethane or water/dichloromethane solvent system, were trapped by dipyrromethanes 17 (Scheme 20). When the reaction was carried out with an excess of dipyrromethanes 17, the monofunctionalized dipyrromethanes 104 were obtained as major products. On

Scheme 20. Synthesis of Mono- and Bisfunctionalized Dipyrromethanes

the other hand, bisfunctionalized dipyrromethanes 105 were obtained exclusively and in high yields when an excess of hydrazone (2.3 equiv) was used. When the H2O/DCM solvent system was employed as the reaction medium, the target dipyrromethanes 104 and 105 were obtained in higher yields than when DCM alone was used as solvent.41,73 The same methodology was applied to obtain dipyrromethanes functionalized with a tetrazole moiety (Scheme 21). Scheme 21. Functionalization of Dipyrromethane 17a with 3-Tetrazolylazoalkene 91

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Scheme 22. Synthesis of Dipyrromethanes 111, Bis(indolyl)methanes 112, Bilanes 113, and Calix[4]pyrroles 114

In fact, 3-tetrazolylazoalkene 91 (0.5 equiv) reacts with 5,5′diethyldipyrromethane 17a to give two monofunctionalized dipyrromethanes, 106 and 107. The latter was efficiently converted into the open-chain hydrazone 106 by refluxing in methanol. On the other hand, bisfunctionalized dipyrromethane 109 was obtained from the reaction of azoalkene 91 (2.3 equiv) with dipyrromethane, followed by 1,4,5,6tetrahydropyridazine ring opening of the primarily formed 108. Hetero-Diels−Alder reaction of 3-tetrazolylazoalkenes 91 carried out in DCM gave higher yields than when the H2O/ DCM solvent system was used (Scheme 21). The base-mediated dehydrohalogenation of α,α-dichlorohydrazones 110 in the presence of aromatic heterocycles, such as pyrrole and indole, led to two consecutive Diels−Alder reactions giving dipyrromethanes 111 and bis(indolyl)methanes 112, respectively (Scheme 22).38,40 This one-pot procedure proved to be more efficient in the H2O/DCM solvent system than in DCM alone. The bis-hetero-Diels− Alder approach was also applied to the synthesis of bilanes 113 and calix[4]pyrroles 114 by reacting 5,5′-diethyldipyrromethane (17a) with α,α-dihalohydrazones 110 in the presence of Na2CO3 (Scheme 22).73 Bilanes result from the reaction of monofunctionalized dipyrromethanes with another molecule of dipyrromethane 17a, whereas macrocycles 114 are formed via initial bisfunctionalization followed by a second Diels−Alder reaction with dipyrromethane 17a. Luo and co-workers74 described the synthesis of 1,4,5,6tetrahydropyridazines 117 in good to excellent yields through the [4 + 2] cycloaddition of DAA 116, generated by treatment of α-chlorohydrazones 115 with K2CO3 in dichloromethane in the presence of ethylene (Scheme 23). This procedure was extended to the cycloaddition of heterodiene 116 with other olefins, including styrenes bearing either electron-donating or -withdrawing moieties, including propylene, 2-vinylthiophene, norbornene, and cyclic dienes. The nonsteroidal progesterone receptor regulator 117 could be further converted into the pharmaceutically relevant 1,4-diamine adduct 119 by reduction of the CN bond followed by hexahydropyridazine ring opening. The [4 + 2] cycloaddition reaction of 1,2-diaza-1,3butadienes provides a simple and efficient pathway to obtain novel potentially bioactive 1,2,4-triazines and nonaromatic 1,2,3,4-tetrazines (Scheme 24).75,76 Thus, azoalkenes 121, generated in situ from the α-bromohydrazone 120 upon treatment with base, were trapped by imines to give 2,3,4,5tetrahydro-1,2,4-triazines 122, regioselectively and in good

Scheme 23. Hetero-Diels−Alder Reaction of 1,2-Diaza-1,3butadiene 116 toward Ethylene

Scheme 24. [4 + 2] Cycloaddition of Azoalkene 121 to Imines and Azodicarboxylates

yields. 1,2,3,6-Tetrahydro-1,2,3,4-tetrazines 123 were synthesized by the reaction of 1,2-diaza-1,3-butadiene 121 with azodicarboxylic acid derivatives. Pinho e Melo and co-workers66 described the first example of hetero-Diels−Alder reaction of 1,2-diaza-1,3-butadiene with alkoxyallenes. In fact, the reaction of 3-tetrazolyl-1,2-diaza-1,3butadiene 91 with phenoxyallene gave the 1,4,5,6-tetrahydropyridazine 126 in good yield. Recently, Attanasi et al.77 described the regioselective synthesis of a wide range of 1,4,5,6-tetrahydropyridazines 127, containing a vicinal exocyclic methylene double bond and a cyclic N,O-acetal center, obtained in good yield, from N-alkoxycarbonyl and Naminocarbonyl azoalkenes 125 and methoxyallene. However, attempts to carry out the cycloaddition with methylallene, 11333


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cyclohexenylallene, 4-hydroxybuta-1,2-diene, and ethyl 2,3butadiene were unsuccessful (Scheme 25).

Scheme 27. Reactions of Azoalkenes with 2-Methylfuran and 2,2-Bis(furan-2-yl)propane

Scheme 25. Hetero-Diels−Alder Reaction of Azoalkenes with Alkoxyallenes

diethyl ether by hydrogen chloride, which was intercepted by the protonated 2,3-dihydrofuran ring. Furopyridazine 143, obtained from the reaction of azoalkene 139 with 2methylfuran, was converted into pyrazoles 144 and 145 in the presence of TFA through a spirocyclic intermediate. The [4 + 2] cycloaddition reaction of 1,2-diaza-1,3butadienes 147, generated in situ from the α-chlorohydrazone precursors under basic conditions, with enol diazoacetate 148 produced tetrahydropyridazinyl diazoacetates 149 in good yield. These cycloadducts were transformed into 6-alkylidenetetrahydropyridazines 150 via copper(I)-catalyzed acyl transfer reaction that occurs through an oxazolium salt intermediate. On the other hand, the reaction catalyzed by dirhodium(II) acetate gave bicyclo[4.1.0]tetrahydropyridazines 152 through the generation of donor−acceptor cyclopropene 151, which was trapped in situ by 1,2-diaza-1,3-butadienes 147. Bicyclotetrahydropyridazines 152 underwent ring expansion upon treatment with tetra-n-butylammonium fluoride (TBAF) to give lactam-1,2-azepines 153, an important class of heterocycles whose structure can be found in a plethora of natural products and biologically active molecules (Scheme 29).79 1,2-Diaza-1,3-butadienes, unsubstituted at position C-4, show a tendency to undergo self-condensation in the absence or presence of an unactivated dienophile, giving diazenylsubstituted tetrahydropyridazines.80,81 This chemical behavior can be illustrated by the reaction of 2-halohydrazones 154 in the presence of K2CO3/CsF. The in situ generated 1,2-diaza1,3-butadienes 155 undergo [4 + 2] cyclodimerization to afford diazenyl tetrahydropyridazines 156. An unexpected fluoride-assisted diacylation of heterocycles 156 was observed, followed by nitrogen elimination, giving an unstable carbanion intermediate that led to tetrahydropyridazines 157 after protonation (Scheme 30).80 Generally, 1,2-diaza-1,3-dienes are generated in situ from the dehydrohalogenation of α-halohydrazones. However, Han and co-workers61 developed a new pathway to generate azoalkenes 159 by direct oxidative dehydrogenation of ketohydrazones 158 with TEMPO. These heterodienes were trapped in heteroDiels−Alder reactions with several alkenes, giving tetrahydropyridazine derivatives such as 160 in good to excellent yields (Scheme 31).

Gaonkar and Rai78 described the generation of azoalkenes via oxidation of ketohydrazones 128 with chloramine T of cyclic hydrazones, followed by dehydrohalogenation (Scheme 26). These azoalkenes 130 were trapped by styrene, acrylonitrile, α-methylstyrene, and ethyl acrylate to give fused ring pyridazines 131 in high yield. Scheme 26. Generation and [4 + 2] Cycloadditions of Azoalkenes 130 via Azochlorides 129

The reactivity of DAA toward 2,5-dimethylfuran and 2,2bis(furan-2-yl)propane (22) has been reported. The expected hetero-Diels−Alder adducts 4a,7a-dihydrofuro[3,2-c]pyridazines were obtained in good yields. Cycloadducts 134 and 136 underwent a furan ring opening in the presence of HCl, leading to 1,6-dihydropyridazine derivatives 135 and 137, respectively (Scheme 27).43 Furan, 2-methylfuran, and 2,5-dimethylfuran react with azoalkenes 139 to afford the expected furopyridazines 140 and 143 (Scheme 28).44 The tetrahydrofuro[3,2-c]pyridazines 140 were further functionalized at the 6-position under acid conditions. Thus, when the reaction of cycloadduct 140 (R3 = R4 = H) with H2O was carried out in the presence of TFA, 141 (R5 = H) was obtained as the only product, whereas when methanol was used as the nucleophile, both 141 and 142 (R5 = Me) were obtained. The reaction of furopyridazine 140 (R3 = R4 = Me) with HCl (2 M) in diethyl ether gave both 141 and 142 (R5 = Et), with 141 being the major product. The formation of these furopyridazines was rationalized by the in situ generation of ethanol, resulting from the cleavage of

3.2. Asymmetric [4 + 2] Cycloaddition Reactions of Azoalkenes

Gao et al.82 have described the first example of an asymmetric inverse electron demand hetero-Diels−Alder reaction of the in situ generated 1,2-diaza-1,3-butadienes and enol ethers catalyzed by a chiral copper/bisoxazoline (L1) complex. The chiral tetrahydropyridazines 162 were obtained in good to excellent yields with high enantioselectivity (Scheme 32). 11334


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Scheme 28. Synthesis of Furopyridazines and Pyrazoles

Scheme 29. [4 + 2] Cycloaddition Reactions of 1,2-Diaza1,3-butadiene 147 with Enol Diazoacetate and Subsequent Transformations

Scheme 32. Asymmetric Hetero-Diels−Alder Reaction of Azoalkenes Catalyzed by Copper/Bisoxazoline L1 Complex

Scheme 33. Asymmetric Hetero-Diels−Alder Reactions Catalyzed by Cu/L2 Complex and Subsequent Synthetic Transformations

Scheme 30. Synthesis of Tetrahydropyridazines via SelfCondensation of Azoalkenes Followed by Fluoride-Assisted C−N Bond Cleavage

Scheme 31. Generation and Cycloaddition Reactions of 1,2Diaza-1,3-butadienes 159

bond of cycloadduct 164 (R1 = R2 = Ph), by direct hydrogenation in the presence of catalytic amounts of Pd/C, provides 165 as a single stereoisomer. The N-benzoyl group was easily removed from cycloadduct 164 (R1 = R2 = Ph) under basic conditions to afford 166, with the stereochemical integrity intact. Hetero-Diels−Alder reaction in the presence of the catalytic complex Cu(I)/bisoxazoline L1 of DAA, generated from αchlorohydrazones 115, with 2-methoxyfuran, gave the unexpected tetrahydropyridazines 168, in good yield with high enantioselectivity (Scheme 34). The formation of cycloadducts 168 was explained by considering an initial hetero-Diels−Alder reaction giving the expected cycloadduct 169, followed by nucleophilic addition of water to give 170 and subsequent tetrahydrofuran ring opening. Lactonization of cycloadduct 168 afforded 171, whereas reduction of the ester moiety gave access to the chiral diol 172, without the loss of stereochemical integrity in either case.85

Wang and co-workers83,84 also explored the asymmetric hetero-Diels−Alder reaction of 1,2-diaza-1,3-dienes, generated in situ from the corresponding α-halohydrazones, with enol ethers and indole in the presence of catalytic amounts of Cu/ tBu-Phosferrox L2 complex (Scheme 33). The use of this complex in cycloaddition reactions led to cycloadducts 163 and 164 in excellent yield and high enantioselectivities. Moreover, it was observed that the reduction of the CN 11335


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Scheme 36. Synthesis of α,α-Tetrahydropyridazine Amino Acid Derivatives

Scheme 34. Catalytic Asymmetric Three-Component Cascade Reaction and Further Synthetic Transformations

Recently, Wang and co-workers86 reported the first copper(I)-catalyzed asymmetric desymmetrization of hetero-Diels− Alder reactions (Scheme 35). The reaction of 3-arylazoalkenes Scheme 37. Isothiourea-Catalyzed Formal [4 + 2] Annulation Reactions of Azoalkenes with Arylacetic Acids

Scheme 35. Copper(I)-Catalyzed Asymmetric Desymmetrization

with 5-silylcyclopentadienes 174 occurs via an endo-syn transition state to give the heterocyclic tetrahydropyridazines 175, bearing a unique α-chiral silane motif, in good yield with exclusive diastereoselectivity and excellent enantioselectivity. These heterocycles can be transformed into enantioenriched 1silylcyclopentanes via regioselective hydrogenation without disturbing the optical purity. The hetero-Diels−Alder pathway was confirmed by DFT calculations and by control experiments.

gives isothiouronium enolate II, which undergoes Michael addition to azoalkenes 185, generated in situ from hydrazones 181. Subsequent intramolecular lactamization of intermediate III generates 183, along with the regeneration of DHPB. This strategy was successfully applied to hydrazones substituted with aromatic groups and arylacetic groups. When aryl groups were replaced by alkyl substituents, in 181 or 182, the reaction was unsuccessful.88 Fused and spiropyrrolidinedione derivatives were synthesized by the reaction of maleimides 187 with transient azoalkenes through PPh3-mediated [4 + 2] and [4 + 1] annulations, respectively (Scheme 38). The nucleophilic attack of PPh3 on the electron-deficient double bond in maleimide affords the zwitterionic intermediate I, which in low-polarity solvent, such as 1,2-dichloroethane (DCE), was trapped via Michael addition by azoalkenes 190, giving intermediate II. The subsequent intramolecular cyclization reaction furnishes the fused pyrrolidinediones 188 and regenerates PPh3. On the other hand, in a more polar solvent, such as acetone, and in the presence of a stoichiometric amount of PPh3, the zwitterionic intermediate I gave rise to the more stable phosphorus ylide

3.3. Formal [4 + 2] Cycloaddition Reaction of Azoalkenes

There are a few examples of formal [4 + 2] cycloaddition reactions to obtain highly substituted tetrahydropyridazines that otherwise would not be possible. Thus, reactions of azoalkenes toward dehydroalanine esters,87 arylacetic acids,88 and maleimides89 have been described. Attanasi et al.87 reported the synthesis of functionalized α,αtetrahydropyridazine amino acid derivatives bearing a quaternary carbon center through formal [4 + 2] cycloaddition reaction of azoalkenes with dehydroalanine esters (e.g., Scheme 36). In this way, a new class of conformationally restricted α-amino acid derivatives was obtained. 4,5-Dihydropyridazin-3(2H)-ones 183 were prepared, in moderate to good yields, by the isothiourea-catalyzed formal [4 + 2] annulation reactions of transient azoalkenes, generated in situ from the α-halohydrazones 181, with arylacetic acids 182 (Scheme 37). The catalytic cycle involves the N-acylation of 3,4-dihydro-2H-benzo[4,5]thiazolo[3,2-a]pyrimidine (DHPB) with anhydride 184, formed from arylacetic acids and pivaloyl chloride, affording acylisothiouronium I. Deprotonation of I 11336


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A similar strategy was applied by Guo and co-workers92 in the synthesis of 1,2,4-triazepine derivatives through the [4 + 3] cycloaddition reaction of azoalkenes with phthalazinium dicyanomethanides (Scheme 40). The reaction of hydrazones

Scheme 38. PPh3-Mediated [4 + 2] and [4 + 1] Annulation of Azoalkenes with Maleimides

Scheme 40. Synthesis of 1,2,4-Triazepine Derivatives

197 with dicyanomethamides 198 at room temperature in the presence of Na2CO3 afforded 1,2,4-triazepines 199 in a selective fashion. When Cs2CO3 was used as base, 1,2,4triazepines 200 were obtained by elimination of HCN from the initially formed [4 + 3] cycloadduct. Wang and co-workers developed the asymmetric version of the [4 + 3] cycloaddition reaction of azoalkenes with nitrones93 and azomethine imines94 (Scheme 41). The authors Scheme 41. Asymmetric [4 + 3] Cycloaddition Reactions of Azoalkenes with Nitrones 202 and Azomethine Imines 204

III. Nucleophilic attack of the negatively charged carbon on azoalkenes 190 gave zwitterionic species IV, which underwent [4 + 1] annulation through attack of the negatively charged nitrogen on the phosphine-linked carbon to yield the spiropyrrolidinedione adduct 189.89 3.4. Other Cycloaddition Reactions of Azoalkenes

In addition to participating in hetero-Diels−Alder reactions, DAA also participate in other types of cycloaddition reactions, namely [4 + 3], [4 + 1], and [3 + 2] cycloadditions. [4 + 3] Cycloaddition reactions can be explored as a synthetic strategy to obtain seven-membered heterocycles. In fact, the synthesis of tetrazepine derivatives 194 could be achieved by the reaction of in situ generated 1,2-diaza-1,3butadienes 192 with C,N-cyclic azomethine imines 193,90 whereas the reaction of azoalkenes 192 with nitrones 195 gave access to a wide range of 2,3,4,7-tetrahydro-1,2,4,5-oxatriazepine derivatives 196 (Scheme 39).91

observed that the reaction between azoalkenes 201 (R1 = Me) and nitrones 202, with the Cu(I)/L3 catalytic system, gave 1,2,4,5-oxatriazepanes 203 in good yields with very high enantiomeric excess. However, the cycloaddition of nitrones with an alkyl group instead of a phenyl group was not selective, giving racemic cycloadducts.49 The asymmetric [4 + 3] cycloaddition of azoalkenes 201 (R1 = Ph) with azomethine imine 204 gave 1,2,4,5-tetrazepines 205 in high yield with very good enantiomeric excess, by use of the catalytic system Cu(II)/L1. However, racemic cycloadducts were obtained when alkyl-substituted azoalkenes were used.94 The asymmetric synthesis of spiro-1,2-diazepinones 209, having an oxindole moiety linked to the spirocenter, was achieved through the N-heterocyclic carbene (NHC)-catalyzed formal [4 + 3] cycloaddition of isatin-derived enals 206 with the azoalkenes generated in situ from α-chlorohydrazones 207 (Scheme 42). The precatalyst 208 was converted into carbene 210 by action of base, which adds to the isatin-derived enals forming intermediate I, which in the mesomeric form represents the azolium homoenolate species II. The reaction proceeds via conjugate addition of the in situ generated

Scheme 39. [4 + 3] Cycloaddition of 1,2-Diaza-1,3butadienes with C,N-Cyclic Azomethine Imines 193 and Nitrones 195

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synthesis of 1,2-diazepines and pyrazoles (Scheme 43).96 The reaction mechanism pathway has been theoretically investigated, and it was observed that the NHC is determinant in promoting proton transfer and dehydration.97 The addition of chiral catalyst NHC 1 to aldehyde 212 produces the homoenolate intermediate. This intermediate participates in a 1,4-addition reaction with azoalkenes 216, followed by cyclization and release of the NHC catalyst, affording 1,2diazepines 214 in high enantioselectivity. On the other hand, catalyst NHC 2, with a morpholine backbone, gives the corresponding acyl anion, which reacts with azoalkenes 216 via a Stetter reaction to afford intermediate III. Intramolecular cycloaddition and dehydration give rise to the final [4 + 1] annulation products 215.96,97 The synthesis of optically active dihydropyrazoles 220 was developed through the asymmetric formal [4 + 1] cycloaddition of azoalkenes, generated in situ from α-chlorohydrazones 217, with sulfur ylides 219 (Scheme 44).98 The reaction mediated by a chiral complex, formed in situ from copper(II) triflate and (R)-Tol-BINAP, which coordinates with the azoalkene to give the intermediate 218, results in dihydropyrazoles 220 in good yields with high enantioselectivities. The formal [4 + 1] cycloaddition of azoalkenes with anilines is also a useful strategy for the synthesis of 1,2,3-triazoles, a more ecofriendly azide- and heavy-metal-free methodology.99 This strategy involves the I2/tert-butyl peroxybenzoate (TBPB) oxidative reaction of N-tosylhydrazones 221 with anilines. The proposed mechanism is outlined in Scheme 45, involving the formation of α-iodohydrazones 224 and generation of azoalkenes 225, followed by 1,4-conjugate addition to give intermediate 226. This intermediate is further oxidized under the reaction conditions to give the corresponding radical cation 227. The subsequent intramolecular addition

Scheme 42. Asymmetric Synthesis of Spiro-1,2-diazepinones 209

azoalkene 211 to form the intermediate III, followed by lactamization to produce cycloadducts 209 and release of the NHC catalyst. This strategy leads to spiro-1,2-diazepinones 209 in good yields and high enantioselectivities.95 NHC catalysts were also used in asymmetric formal [4 + 3] and formal [4 + 1] annulations of enals with azoalkenes for the

Scheme 43. N-Heterocyclic Carbene-Catalyzed Formal [4 + 3] and [4 + 1] Cycloadditions

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substituent of the nitrogen to a phenyl group, under the same reaction conditions, leads to the conventional [3 + 2] cycloadducts, pyrrolidines 233.100 Attanasi and Merino and co-workers101 have studied the diastereoselective 1,3-dipolar cycloaddition reaction of azoalkenes 234 with cyclic and acyclic chiral nitrones (e.g., 235 and 237), experimentally and theoretically (Scheme 47). The use

Scheme 44. Asymmetric Formal [4 + 1] Cycloaddition of Azoalkenes with Sulfur Ylides

Scheme 47. 1,3-Dipolar Cycloaddition of Azoalkenes with Acyclic and Cyclic Nitrones

Scheme 45. Mechanism for Formal [4 + 1] Cycloaddition of Azoalkenes to Anilines

of cyclic nitrones afforded only one isomer of 3-substituted-5diazenyl isoxazolines 236 in a regio-, diastereo-, and enantioselective fashion. On the other hand, the reaction with acyclic nitrones led to 1:1 mixtures of isomers 238. Azoalkenes carrying strong electron-withdrawing groups on the terminal carbon and nitrogen atoms of the azo-ene system are required in this reaction, because of their high stability and electrophilicity. DFT studies based on reactivity indices were in agreement with the observed regioselectivity of these cycloaddition reactions.

4. CONJUGATE ADDITION OF NITROSOALKENES AND AZOALKENES Conjugation of the azo- or nitroso- substituent with the CC moiety imparts a strong electrophilic character and greatly governs the reactivity of the nitroso and/or azo-ene system. In particular, the terminal carbon C-4 is strongly activated and susceptible to nucleophilic attack. In fact, the electrophilic character of azoalkenes has been evaluated on the basis of kinetics of reactions of azoalkenes 239a−d with malonate or malonate-like stabilized anions 240−244 (Figure 1).102 The results showed that their electrophilic parameters E, ranging from −13.9 to −15.4, are comparable to those of benzylidenemalononitriles 245, 2-benzylideneindan-1,3-diones 246, and benzylidenebarbituric acids 247. Thus, nitrosoalkenes and azoalkenes are enolium synthetic equivalents, and their reactivity toward nucleophiles opens the way to umpolung α-functionalization of ketones (Scheme 48).14 The nature of substituents on the oxaza- or diazadienes will not only tune their reactivity/electrophilicity but also their stability and lifetime. Unsubstituted C-4 systems are unstable and prone to side reactions, as mentioned earlier. The scope and limitations of conjugated nitrosoalkenes, derived from α-halogenated oximes, to act as enolonium ion equivalents have been explored by several groups.14 Likewise, vinylnitroso compounds obtained from cyclic ketones and open-chain aldehydes have been intercepted, in good to very good yields, by diverse enolate ions103 and organocupratestabilized nucleophiles.104 In a similar fashion, ammonia,

followed by an elimination reaction produces triazoles 223 in good yield. Depending on the N-substituent of azoalkene 229, the reaction with azomethine ylide 231, generated in situ from the reaction of sarcosine (230) with paraformaldehyde, gave 1,2,4triazepines 232 or pyrrolidines 233 (Scheme 46). The presence of an electron-withdrawing group at the terminal nitrogen of the azo-ene system stabilizes the anionic intermediate, favoring the formal [4 + 3] cycloaddition reaction which produces 1,2,4-triazepines 232. Changing the Scheme 46. [4 + 3] and [3 + 2] Cycloaddition Reactions of Azoalkenes 229

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Scheme 49. Conjugate Addition of Nucleophiles and Azoles to Nitrosoalkenes

Figure 1. Azoalkenes, nucleophiles, and electrophilicity parameters (E).

Scheme 48. Nitrosoalkenes and Azoalkenes as Enolium Synthetic Equivalents

vinylnitroso intermediates 253 and 256.115 The base-mediated dehydrohalogenation of oximes 252 gives rise to the corresponding reactive NSA 253, which reacted with a first molecule of pyrazole 254 to give the intermediate pyrazole oximes 255. Subsequent dehydrohalogenation produced nitrosoalkenes 256, which reacted with a second molecule of pyrazole to give the desired bis(pyrazolyl)methanes 257 in good yields (43−67%) (Scheme 50). As expected, reaction of the less electron-rich 4-ethoxycarbonylpyrazole with nitrosoalkene 253 was less efficient than the corresponding conjugate addition of pyrazole. However, when imidazole and 2-isopropylimidazole were used as nucleophiles, no isolable products could be obtained under the same reaction conditions. Starting from the chloral oxime (258), it was possible to isolate the tris(pyrazolyl)methane 259 in 87% yield in a onepot procedure (Scheme 51). Sukhorukov and co-workers116 explored the chemistry of nitrosoalkenes for the assembly of β-oximinoalkylamine ligands containing one, two, four, or six oxime groups, and they synthesized the corresponding nickel complexes. Double silylation of 2-nitropropane gave N,N-bis(silyloxy)enamine 260, which reacted with the appropriate amine to afford the target ligands (Scheme 52). The nickel complexes of these βoximinoalkylamine ligands were obtained, and their ability to promote aerobic oxidative transformations was evaluated. It was demonstrated that the bis(oxime) nickel complex was the most efficient promoter of triphenylphosphine oxidation. Due to its relevance, and intrinsic difficulty, the possibility to bring about asymmetric or stereocontrolled conjugate addition was addressed by some groups. Witek and Weinreb117 reported that potassium salts of α-diethyl allylmalonate and N-methyl-p-toluenesulfonamide ions were found to add to acyclic aldehyde-derived nitrosoalkene 266, bearing a chiral carbon at C-5, in a completely anti diastereoselective manner, leading to single stereoisomeric products (Scheme 53A). The extension of this study to cyclic nitrosoalkenes carrying a stereogenic carbon with a bulky substituent, namely, 4-tertbutylnitrosocyclohexene 270, did not produce such good

amines, and optically active amino esters have been added to NSA carrying a phosphine oxide group or a phosphonate group at the C-4 position, producing functionalized α-amino phosphorus compounds.105 4.1. Conjugate Addition of Nitrosoalkenes

During the preparation of this work, a comprehensive review dealing with the conjugate addition of nitrosoalkenes has been released.15 The versatility and scope of the reaction, including the intra- and intermolecular processes and the use of this chemistry for the synthesis of biologically important alkaloid derivatives,21,22,106−112 was widely enlightened in the latter work. Nevertheless, some relevant aspects of this reaction have been elegantly addressed and reported in the literature, which justify including the following selected examples. Sterically hindered conjugated nitrosoalkenes are seldom mentioned in the literature. However, dimeric nitroso chlorides of 2-alkylideneadamantanes 248 or chlorooximes 249 were converted into the transient and reactive nitrosoalkenes 250 and intercepted by a wide range of O- and Nnucleophiles113 and azoles,114 such as tetrazole, imidazole, benzotriazole, and pyrazole (Scheme 49). The yields of the addition products were fair to good. All the oximes obtained were believed to be single geometrical (E)-isomers, due to the concordance of their analytical data with the phenylimidazole adduct, whose structure assignment was made unequivocally by X-ray crystallography. Attempts to extend the reaction to pyrrole and indole derivatives failed, which was rationalized by considering the lower nucleophilicity of these azoles. Previously unknown bis(pyrazolyl)methanes, carrying an αhydroxyiminomethyl functionality at the methylene carbon, were isolated in fair to good yields by an unparalleled and consecutive double 1,4-conjugate addition of pyrazoles to the 11340


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Scheme 50. Synthesis of Bis(pyrazolyl)methanes 257

Scheme 51. Synthesis of Tris(pyrazolyl)methane 259

Scheme 53. Asymmetric or Stereocontrolled Conjugate Addition of Nitrosoalkenes

Scheme 52. Synthesis of β-Oximinoalkylamine Ligands

formed. The survey of phenyl-, aryl-, 2-thienyl-, and azolylthiols, starting oximes, and catalyst led to the conclusion that the best result was obtained by combining thiophenol, cyclohexanone-derived oxime, and tertiary thiourea 274, giving the product in 86% yield and 94:6 enantiomeric ratio (er) (Scheme 54). Subsequent oxidative hydrolysis of the oximes Scheme 54. Catalytic Asymmetric Addition of Thiols (Such as Benzenethiol) to Nitrosoalkenes

results (Scheme 53B).118 In some cases a high degree of stereoselectivity was observed, whereas in other cases mixtures of diastereomeric oximes were isolated. The same authors observed that the addition of C-anion cuprates and N- and S-nucleophiles produced good yields of the corresponding adducts (83−94%), but diverse selectivity was encountered, ranging from very good (in the case of the toluenesulfonyl derivative with a single diastereomer encountered) to geometrical and/or diastereomeric mixtures of oximes (in the case of alkyl cuprates and benzenethiol). An organocatalytic α-sulfenylation of oximes by the asymmetric addition of thiols to nitrosoalkenes, formed in situ from cyclic and acyclic α-chlorooximes 273, was reported.29,119 A chiral thiourea used as auxiliary scaffold was crucial, simultaneously providing the appropriate stereoorganization during bond formation and enabling the intramolecular attack of the nucleophile from the complex so

provided the corresponding nonracemic α-sulfenylketones in good yields. This is an example of α-functionalization of ketones via an umpolung asymmetric process. Recently, it was demonstrated that α-sulfenylation as well as sulfonylation of 2-chlorooximes, via conjugate addition of thiolates or sulfinates to nitrosoalkenes, can be efficiently carried out under more sustainable conditions by using natural 11341


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Scheme 56. Reactivity of N,N-Bis(silyloxy)enamine 260 with HO Acids

deep eutectic solvents (NADES). The L-lactic acid/choline chloride eutectic mixture led to the best results with this NADES, which acted not only as solvent but also as organocatalyst.120 The nucleophilic addition of thiols to nitrosoalkene acetals has been described (Scheme 55). When the reaction is carried Scheme 55. Reactivity of Thiols toward N,NBis(silyloxy)enamine 260

Scheme 57. Synthesis of Bis- and Trihydrazones

out in N,N-dimethylformamide (DMF), the corresponding NSA is formed from N,N-bis(silyloxy)enamines (e.g., 260), followed by S-nucleophile conjugate addition. However, when toluene is used as solvent, an alternative pathway can also occur that involves Brønsted acid-promoted SN′ substitution of the trimethylsilyloxy (TMSO) group. Reactions with aromatic thiols were performed in toluene, whereas with more nucleophilic aliphatic thiols DMF was the selected solvent. The reactivity of enamine 260 toward N-protected L-cysteine and 1,3-propanedithiol was studied and gave the target compounds efficiently.121 The same research group reported a study on the reaction of N,N-bis(silyloxy)enamines with HO acids (carboxylic acids and alcohols). The versatility of this synthetic methodology was demonstrated and the oximinoalkylation of interesting natural molecules, namely, steroidal derivatives and protected amino acids, was reported (Scheme 56).30

trihydrazones 282 were obtained by the reaction of ammonia with 3.1 equiv of hydrazone 280. In an in silico investigation by DFT calculations, the oxime− nitrone isomerization (283 ↔ 284) was studied, and it was determined that this isomerization proceeds via a bimolecular mechanism involving two molecules of oxime.127 The reaction between azoalkenes 285 and oximes 283 in the absence of base, giving products 286, was presented as a practical example to support the oxime−nitrone isomerization (Scheme 58).128 Unlike the usual N-alkylation of oximes to electron-deficient olefins yielding nitrones, the above reaction was considered an exception, and the computational results showed that the experimentally observed O-alkylation, in the absence of base, proceeded via the less stable but more reactive nitrone tautomer. Products 286 could be converted into 1,2,4oxadiazin-5-one derivatives 287 by adding NaH to promote ring closure. Unprecedented Cu(I)-catalyzed addition of Grignard reagents to N-sulfonylazoalkenes was implemented by Hatcher and Coltart.129 Primary, secondary, and tertiary Grignard reagents and different primary, secondary, and tertiary αchloro-N-sulfonylhydrazones, both keto- and aldehyde-derived, efficiently produced the alkylated products. Moreover, α,α-

4.2. Conjugate Addition of Azoalkenes

A vast array of highly functionalized heterocyclic, fused heterocyclic, and open-chain adducts have been obtained via conjugate addition to these motifs that would otherwise be very difficult or impossible to accomplish. This umpolung strategy was well illustrated by the divergent preparation of pyrazoles via base-promoted conjugate addition of Narylhydrazone anions to azoalkenes,122 domino or sequential reactions of azoalkenes with vinyl malononitriles123 and pyridine-like heterocycles,124 and multicomponent reaction with amines and iso(thio)cyanate125 to produce pyrrolo[1,2b]pyrazoles, imidazo[1,2-a]pyridines, imidazo[1,2-a]quinolines, imidazo[1,2-a]isoquinolines, phenyl- or alkyllinked 2-(thio)hydantoin derivatives, and (thio)hydantoins spiro-fused to pyrroline ring derivatives, in good to very good yields. Conjugate addition of amines and ammonia to azoalkenes allowed the preparation of bis-, tri-, and tetrahydrazones in good to excellent yields, as illustrated in Scheme 57.126 The addition of primary amines to azoalkenes gave bishydrazones 281 with 2 equiv of hydrazone 280. By a similar strategy, 11342


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Scheme 58. Reaction of Azoalkenes 285 with Oximes and Nitrones

Scheme 60. Diastereoselective Addition of Grignard Reagents to α-Epoxy-N-sulfonylhydrazones 293

workers (Scheme 61).131 The addition of anilines to azoalkenes 297, mediated by the sterically demanding chiral

bisalkylations were successfully achieved in a one-pot cascade procedure (Scheme 59A). A single-step sequential process of

Scheme 61. Enantioselective Addition of Anilines to Azoalkenes 297 and Synthesis of Enantioenriched Ketones 300

Scheme 59. (A) α,α-Bisalkylation of α,α-Dichloro-Nsulfonylhydrazones 288 and (B) Sequential Oxidation and Alkylation of N-Sulfonylhydrazones 291

phosphoric acid catalyst 298, was carried out in low-polarity solvents such as benzene. Interestingly, the authors found that the phosphoric acid catalyst performed better than the corresponding Cu(II) phosphate ligand and also that significant enantioenrichment occurred only after the hydrazone addition product was formed. Hydrolysis of adducts 299 promoted by Amberlyst/paraformaldehyde afforded the enantioenriched ketones 300. Sequential one-pot reactions, in which conjugate addition plays a crucial role, afforded polysubstituted pyrroles 304 in a novel solvent- and catalyst-free strategy132 and 1,2-diaminoimidazoles 305 in an elegant 1,4-azide addition, Staudinger, and aza-Wittig reaction sequence (Scheme 62).133 The efficiency, mild reaction conditions, easily available starting materials, and flexibility of substitution pattern are remarkable features of these reactions leading to structurally complex heterocyclic compounds. The synthesis of 1,2,3-triazoles, widely used as synthetic intermediates or as biologically active compounds, has been

oxidation of unhalogenated N-sulfonylhydrazones with phenyltrimethylammonium tribromide (PTAB), followed by catalytic alkylation, was also achieved to give the adducts in high yield (Scheme 59B). The addition of Grignard reagents to sulfonylazoalkenes was brought about with a high degree of diastereoselectivity through the elegant use of α-epoxy N-tosylhydrazones 293, as depicted in Scheme 60.130 Grignard reagents carrying various sp3-, sp2-, and sp-hybridized substituents produced the addition products in good to excellent yields with excellent asymmetric induction; the only exception was the bulky t-butyl derivative, which gave only 3:1 syn/anti selectivity in moderate yield. The resulting hydrazones under CuCl2-catalyzed hydrolysis afforded the corresponding β-hydroxy ketones 296. A strategy culminating in α-arylaminoketones in high enantiomeric excess has been described by Toste and co11343


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Scheme 62. Synthesis of Pyrroles and Imidazoles via Conjugate Addition of Enamines to Azoalkene

Scheme 64. Synthesis of 1,4- and 1,5-Disubstituted 1,2,3Triazoles

mechanism. In the absence of air, running the reaction under argon, or using only 1 equiv of amine, poorer results were obtained. The authors found that arylamine hydrochloride, generated in situ, was fundamental for protonation of the tosyl group in the cyclization step. On the basis of these observations, the authors proposed the mechanism outlined in Scheme 64. A versatile strategy to synthesize triazoles, having a 1,4conjugate addition of azoalkenes as the key step, has also been reported. Copper-catalyzed oxidation of tosylhydrazones 314 afforded the corresponding transient azoalkenes I, which were then intercepted by arylamines. A second copper-catalyzed oxidative cyclization led to the target 1,4-disubstituted or 1,4,5trisubstituted triazoles 316, depending on the starting materials and reaction conditions used (Scheme 65).138

one of the important fields of application of conjugate addition to azo-ene systems. Copper-catalyzed addition of organic azides to azoalkenes in an initial stage, followed by the interception by an alkyne moiety134 or the primary addition of the alkyne functionality to the azoalkene and subsequent cyclization with the organic azide,135 have been reported. Westermann and co-workers136 reported an efficient and stereoselective synthesis of optically active 1,4-disubstituted1,2,3-triazoles from the reaction of α,α-dichlorotosylhydrazones with enantiomerically pure primary amines without the use of toxic organic azides or metals. Among many other examples, the biologically important phytostigmine 307 led to the corresponding triazoles 308 in high yields and without loss of optical purity (Scheme 63).

Scheme 65. Synthesis of 1,4-Disubstituted or 1,4,5Trisubstituted Triazoles

Scheme 63. Construction of the Triazole Ring by Reaction of an Amine with Azoalkenes

Under microwave induction, the conjugate addition (step i) of primary amines to azoalkenes, followed by addition of aldehydes, promoted in situ formation of the corresponding iminium anion I, which underwent 1,5-electrocyclization (step ii) to imidazole-4-carboxylates 319 in moderate to good yields (Scheme 66).139 The strategies described above to construct heterocyclic rings were applied to synthesize bisheterocycles with an indole moiety, namely, indoleimidazoles, indolepyrroles, and indoletriazoles, by use of azoalkenes and tryptamine derivatives as building blocks (Scheme 67).140 Thus, conjugate addition of tryptamines (e.g., 320) to azoalkenes and subsequent treatment with aldehydes produces an iminium ion, which undergoes 1,5-electrocyclization followed by aromatization

A slightly different protocol was envisaged by Wang and coworkers137 under aerobic oxidation and metal- and azide-free conditions. The scope of the reaction was investigated in order to use arylamines and keto- or aldehyde-based tosylhydrazones as precursors of the intermediate azoalkene 313, allowing the selective preparation of 1,4- or 1,5-disubstituted triazoles (Scheme 64). The results obtained were in agreement with the nucleophilicity of the arylamine 310 used. Control experiments were carried out in order to shed some light onto the possible 11344


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Scheme 66. One-Pot Synthesis of Imidazoles via (i) Conjugate Addition and (ii) 1,5-Electrocyclization

Scheme 67. Synthesis of Indole-Containing Imidazoles 321, Pyrroles 322, and Triazoles 325

One-pot procedures are also an interesting strategy to prepare 3a,4-dihydro-1H-pyrrolo[1,2-b]pyrazoles 332 through the reaction of azoalkenes 330 with vinyl malonitriles 331 (Scheme 69).123 This procedure involves the following reactions: (i) vinylogous Michael addition, (ii) aza-Michael cyclization, (iii) azacyclization, and finally (iv) imine−enamine tautomerism, as depicted in Scheme 69. The pursuit of synthetic routes leading to natural products or their analogues constitutes one of the core tasks of organic chemists. In this context, a decisive contribution to synthesis of the isoquinolyl family alkaloid tetrahydroberberine has been reported. This included Michael addition of the enamino functionality of 7,8-dihydroberberine derivatives to azoalkenes,141 as well as the preparation of deaza analogues of the bisindole marine alkaloid Topsentin 335,142 obtained by the addition of 1,3-di(3-indolyl)propan-1,3-diones 333 to azoalkene 334 (Scheme 70). A similar strategy involving a double Michael addition followed by azacyclization of 1,2-diaza-1,3butadienes with 2-oxoindoles,143 barbiturates,144 and rhodanine145 gave 2-oxospiro[indole-3,4′-pyridines], spirobarbiturate pyridines, and 2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridine-1,3,6-triones, respectively. 3-Hydroxy-3,4-dihydro-2H-1,4-thiazines 339 were obtained in quantitative yield by addition of the in situ generated 2-

with elimination of carbamate (electron-withdrawing group, EWG) to furnish indoleimidazole derivatives 321. On the other hand, conjugate addition of tryptamine (e.g., 320) to alkynoate, followed by in situ Michael addition to azoalkenes and then by intramolecular ring closure with elimination of carbazate (EWG), leads to synthesis of the indolepyrrole system 322. Indoletriazole derivatives 325 were synthesized by one-pot addition of tryptamine derivatives (e.g., 320) to azoalkene 324, generated in situ from the α,α-dichlorohydrazone 323, followed by elimination of the tosyl group and subsequent cyclization. The resulting adducts, particularly the ones derived from bis(indolyl)methane amines (325e,f), possessed significant biological activity when tested against two human cancer cell lines, MCF-7 and Caco-2. The domino reaction under solvent-free conditions of azoalkenes 326 with pyridine, quinoline, and isoquinoline produces imidazo[1,2-a]pyridines 327, imidazo[1,2-a]quinolines 328, and imidazo[2,1-a]isoquinoline 329 derivatives, respectively, in good yields (Scheme 68).124 The reaction proceeds as outlined in Scheme 68. Initially, (i) a Michael addition occurs, followed by (ii) generation of a 1,3-dipole, which undergoes (iii) cyclization to afford an imidazoline derivative. Finally, aromatization and elimination of the carbamate residue gives the final product. 11345


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Scheme 68. Reaction of Azoalkenes 326 with Pyridine-like Heterocycles

Scheme 70. Synthesis of Deaza Analogues of the Bisindole Marine Alkaloid Topsentin

Scheme 71. Synthesis of 3-Hydro-3,4-dihydro-2H-1,4thiazines

Scheme 69. Synthesis of Highly Functionalized Pyrrolopyrazoles 332

expedient methodology not only produces the desired products cleanly and quantitatively but also avoids environmental and safety problems due to the employment of volatile and unpleasant-smelling thiols. A scalable, to gram quantity, Cu(II)-catalyzed asymmetric cascade methodology for the preparation of fused butyrolactones 345, with high regioselectivity and excellent stereoselectivity, has been disclosed.147 The addition of 2silyloxyfurans 341 to the in situ formed metalloazoalkene 342 resulted in 343. The appropriate amounts of Cu(II) complex and hexafluoroisopropyl alcohol (HFIPA) protic additive played key roles in establishing the best yields and enantioselectivities (Scheme 72). The scope of the reaction was extended to N-Boc-2-silyloxypyrrole and 2-naphthylderived hydrazones with analogous efficiency and stereoselectivity. The efficient and straightforward asymmetric synthesis of bicyclic 1,8-diazabicyclo[3.3.0]octanes 350 bearing a tetrasubstituted stereogenic center was achieved by the cascade assembly of 1,2-diaza-1,3-butadienes 346 and α,β-unsaturated aldehydes 347 via dienamine activation of chiral amine 348 (Scheme 73).148

mercaptoethanal, from safe and odorless 1,4-dithiane-2,5-diol 336, to azoalkenes 338 (Scheme 71).146 This simple and 11346


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More attention has been paid to the chemistry of azoalkenes, due to the broader scope and generally smoother and more efficient reactions. When compared to nitrosoalkenes, the additional N-substituent at the 1-position of conjugated azoalkenes paves the way to a higher tunability of their electrophilicity and reactivity and constitutes an additional anchorage site for chiral auxiliary or coordination groups, but especially it leads to a much greater versatility for sequential one-pot cascade reactions. However, since cleavage of the C− N bond is more difficult than cleavage of the C−O bond, further transformations of the cycloadducts derived from azoalkenes are harder. On the other hand, there is an added value of the oxime moiety transformations versus the hydrazono functionality in open-chain adducts, affording amino- versus N-amino compounds. These factors may counteract the above-mentioned trend when looking to their utility as synthetic intermediates. It should be emphasized that only a few examples of asymmetric hetero-Diels−Alder or conjugate addition reactions of nitroso- and azoalkenes are reported in the literature. This is an area that should be further explored, since it can be particularly relevant in the target-oriented synthesis of naturally occurring compounds and in the synthesis of biologically active molecules.

Scheme 72. Catalytic Asymmetric Cascade Vinylogous Mukaiyama 1,6-Michael/Michael Addition of 2Silyloxyfurans to Azoalkenes and Further Transformations

Scheme 73. Synthesis of Bicyclic 1,8Diazabicyclo[3.3.0]octanes

AUTHOR INFORMATION Corresponding Author

*E-mail [email protected]. ORCID

Susana M. M. Lopes: 0000-0002-1580-5667 Ana L. Cardoso: 0000-0003-0551-7255 Américo Lemos: 0000-0001-9588-4555 Teresa M. V. D. Pinho e Melo: 0000-0003-3256-4954 Notes

The authors declare no competing financial interest. Biographies Susana M. M. Lopes was born in Portugal in 1981. She received her B.Sc. in industrial chemistry in 2004 at the University of Coimbra and her M.Sc. in 2007 and her Ph.D. in organic chemistry in 2012, working under the leadership of Professor Teresa M. V. D. Pinho e Melo. Presently she is carrying out postdoctoral research in the organic chemistry group at the University of Coimbra and her research interests are focused on the reactivity of nitrosoalkenes and azoalkenes and the development of new steroid derivatives. Ana L. Cardoso earned her master’s degree in 2003 at University of Coimbra; then she received her doctorate in organic synthesis from University of Coimbra in 2009. Currently, she is a postdoc under the supervision of Professor Pinho e Melo. Her current research focuses on the chemistry of small-ring heterocycles and the development of synthetic routes to new therapeutic agents against amyloid diseases by transthyretin.

5. CONCLUSION This review deals with the chemistry of nitrosoalkenes and azoalkenes as valuable scaffolds in organic synthesis. The key feature of these heterodienes, that greatly governs their reactivity, is their strong electrophilic character, in particular at the terminal carbon C-4, as a result of conjugation of the nitroso or azo substituent with the CC moiety. The reactions that were presented and discussed illustrate the versatility of these building blocks for the synthesis and functionalization of a wide range of heterocycles, including chiral derivatives.

Américo Lemos was born in Fafe, Portugal. He obtained his degree in chemistry in 1988 from the University of Coimbra. After working in Professor António D’A. Rocha Gonsalves’ organic structural and synthetic group (1988−1989), he carried out research work under the supervision of Dr. Thomas L. Gilchrist at the University of Liverpool, U.K., receiving his Ph.D. with the thesis New amino acids from pyrrole (1989−1992). He then joined the Portuguese Companhia Industrial Produtora de Antibioticos (CIPAN) as head director of the 11347


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Along with Bioorthogonal and Material Sciences Applications. Curr. Org. Chem. 2016, 20, 2136−2160. (13) Belskaya, N. P.; Eliseeva, A. I.; Bakulev, V. A. Hydrazones as Substrates for Cycloaddition Reactions. Russ. Chem. Rev. 2015, 84, 1226−1257. (14) Miyata, O.; Miyoshi, T.; Ueda, M. Umpolung Reactions at the α-Carbon Position of Carbonyl Compounds. Arkivoc 2013, 2013 (2), 60−81. (15) Boyko, Y. D.; Dorokhov, V. S.; Sukhorukov, A. Y.; Ioffe, S. L. Conjugated Nitrosoalkenes as Michael Acceptors in Carbon−Carbon Bond Forming Reactions: a Review and Perspective. Beilstein J. Org. Chem. 2017, 13, 2214−2234. (16) Denmark, S. E.; Dappen, M. S. α-Chloro Ketoximes as Precursors of Nitrosoalkenes - Preparation, Stereochemistry, and Conformation. J. Org. Chem. 1984, 49, 798−806. (17) Denmark, S. E.; Dappen, M. S.; Sear, N. L.; Jacobs, R. T. The Vinylogous Anomeric Effect in 3-Alkyl-2-chlorocyclohexanone Oximes and Oxime Ethers. J. Am. Chem. Soc. 1990, 112, 3466−3474. (18) Denmark, S. E.; Dappen, M. S.; Sternberg, J. A. Intramolecular [4 + 2] Cycloadditions of Nitrosoalkenes with Olefins. J. Org. Chem. 1984, 49, 4741−4743. (19) Dilman, A. D.; Tishkov, A. A.; Lyapkalo, I. M.; Ioffe, S. L.; Strelenko, Y. A.; Tartakovsky, V. A. Novel Convenient Method for the Synthesis of N,N-Bis(trimethylsilyloxy)enamines. Synthesis 1998, 1998, 181−185. (20) Lesiv, A. V.; Ioffe, S. L.; Strelenko, Y. A.; Tartakovsky, V. A. Chemistry of N,N-Bis(silyloxy)enamines - Part 5 - Interaction with NTrialkylsilylated Azoles. Convenient Method for the Synthesis of αAzolyl-Substituted Oximes. Helv. Chim. Acta 2002, 85, 3489−3507. (21) Zhmurov, P. A.; Khoroshutina, Y. A.; Novikov, R. A.; Golovanov, I. S.; Sukhorukov, A. Y.; Ioffe, S. L. Divergent Reactivity of in situ Generated Metal Azides: Reaction with N,N-Bis(oxy)enamines as a Case Study. Chem. - Eur. J. 2017, 23, 4570−4578. (22) Tanimoto, H.; Yokoyama, K.; Mizutani, Y.; Shitaoka, T.; Morimoto, T.; Nishiyama, Y.; Kakiuchi, K. Synthesis of α-Substituted Enoximes with Nucleophiles via Nitrosoallenes. J. Org. Chem. 2016, 81, 559−574. (23) Tanimoto, H.; Shitaoka, T.; Yokoyama, K.; Morimoto, T.; Nishiyama, Y.; Kakiuchi, K. Formal [3 + 2] Cycloaddition of Nitrosoallenes with Carbonyl and Nitrile Compounds to Form Functional Cyclic Nitrones. J. Org. Chem. 2016, 81, 8722−8735. (24) Jans, P. E.; Mfuh, A. M.; Arman, H. D.; Shaffer, C. V.; Larionov, O. V.; Mooberry, S. L. Cytotoxicity and Mechanism of Action of the Marine-Derived Fungal Metabolite Trichodermamide B and Synthetic Analogues. J. Nat. Prod. 2017, 80, 676−683. (25) Nirvanappa, A. C.; Mohan, C. D.; Rangappa, S.; Ananda, H.; Sukhorukov, A. Y.; Shanmugam, M. K.; Sundaram, M. S.; Nayaka, S. C.; Girish, K. S.; Chinnathambi, A.; Zayed, M. E.; Alharbi, S. A.; Sethi, G.; Basappa; Rangappa, K. S. Novel Synthetic Oxazines Target NF-κB in Colon Cancer In Vitro and Inflammatory Bowel Disease In Vivo. PLoS One 2016, 11, No. e0163209. (26) Domingo, L. R.; Pérez, P.; Sáez, J. A. Understanding the Regioselectivity in Hetero Diels-Alder Reactions. An ELF Analysis of the Reaction between Nitrosoethylene and 1-Vinylpyrrolidine. Tetrahedron 2013, 69, 107−114. (27) Domingo, L. R.; Pérez, P.; Sáez, J. A. Understanding the Local Reactivity in Polar Organic Reactions through Electrophilic and Nucleophilic Parr Functions. RSC Adv. 2013, 3, 1486−1494. (28) Domingo, L. R.; Picher, M. T.; Arroyo, P. Towards an Understanding of the Polar Diels-Alder Reactions of Nitrosoalkenes with Enamines: a Theoretical Study. Eur. J. Org. Chem. 2006, 2006, 2570−2580. (29) Hatcher, J. M.; Kohler, M. C.; Coltart, D. M. Catalytic Asymmetric Addition of Thiols to Nitrosoalkenes Leading to Chiral Non-Racemic α-Sulfenyl Ketones. Org. Lett. 2011, 13, 3810−3813. (30) Naumovich, Y. A.; Golovanov, I. S.; Sukhorukov, A. Y.; Ioffe, S. L. Addition of HO-Acids to N,N-Bis(oxy)enamines: Mechanism, Scope and Application to the Synthesis of Pharmaceuticals. Eur. J. Org. Chem. 2017, 2017, 6209−6227.

laboratories of chemical synthesis and new products, also coordinating research projects on the synthesis and development of new compounds (1992−1995). After working at the Regional Laboratory of Veterinaryand Food Safety and University of Madeira, in 1998 he becamea professor at the University of Algarve. His research interests are focused on the synthesis of heterocycles with potential synthetic and/or biological interest. Teresa M. V. D. Pinho e Melo studied chemistry at the University of Coimbra, where she graduated in 1985, got her M.Sc. in 1991 and her Ph.D. in organic chemistry in 1995. She was a research fellow at the University of Liverpool (1992−1993). She received her habilitation in organic chemistry in 2003. She is currently an associate professor with habilitation at the University of Coimbra. Her research interests are mainly in the area of synthetic and mechanistic heterocyclic organic chemistry and medicinal chemistry. She is particularly concerned with the development of synthetic routes to new bioactive molecules.

ACKNOWLEDGMENTS The Coimbra Chemistry Centre (CQC) is supported by the Portuguese Agency for Scientific Research, the Fundaçaõ para a Ciência e a Tecnologia (FCT), through Project POCI-010145-FEDER-007630, cofunded by Compete 2020-UE. We also acknowledge FCT for funding project POCI-01-0145FEDER-PTDC/QEQ-MED/0262/2014, which was cofunded by FEDER through Compete 2020-UE, and for the fellowship SFRH/BPD/84423/2012. REFERENCES (1) Gilchrist, T. L. Nitroso-alkenes and Nitroso-alkynes. Chem. Soc. Rev. 1983, 12, 53−73. (2) Gilchrist, T. L.; Wood, J. E. 1,2-Oxazines and their Benzo Derivatives. In Comprehensive Heterocyclic Chemistry II; Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, U.K., 1996; Vol. 6, Module 6.04, pp 279−299; DOI: 10.1016/B978-008096518-5.00120-9. (3) Reissig, H.-U.; Zimmer, R. 1-Nitrosoalkenes. In Science of Synthesis; 2007 ed.; Molander, G. A., Ed.; Georg Thieme Verlag: Stuttgart, Germany, 2007; Vol. 33, pp 371−389. (4) Sukhorukov, A. Y.; Ioffe, S. L. Chemistry of Six-Membered Cyclic Oxime Ethers. Application in the Synthesis of Bioactive Compounds. Chem. Rev. 2011, 111, 5004−5041. (5) Lyapkalo, I. M.; Ioffe, S. L. Conjugated Nitrosoalkenes. Russ. Chem. Rev. 1998, 67, 467−484. (6) de los Santos, J. M.; Vicario, J.; Alonso, C.; Palacios, F. Hydroxyimino Phosphorus Derivatives. An Efficient Tool in Organic Synthesis. Curr. Org. Chem. 2011, 15, 1644−1660. (7) Blond, G.; Gulea, M.; Mamane, V. Recent Contributions to Hetero Diels-Alder Reactions. Curr. Org. Chem. 2016, 20, 2161− 2210. (8) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone, P.; Mantellini, F.; Perrulli, F. R.; Santeusanio, S. Cultivating the Passion to Build Heterocycles from 1,2-Diaza-1,3-dienes: the Force of Imagination. Eur. J. Org. Chem. 2009, 2009, 3109−3127. (9) Attanasi, O. A.; De Crescentini, L.; Filippone, P.; Mantellini, F.; Santeusanio, S. 1,2-Diaza-1,3-butadienes: Just a Nice Class of Compounds, or Powerful Tools in Organic Chemistry? Reviewing an Experience. Arkivoc 2002, 2002 (11), 274−292. (10) Attanasi, O. A.; Filippone, P. Working Twenty Years on Conjugated Azo-alkenes (and environs) to find New Entries in Organic Synthesis. Synlett 1997, 1997, 1128−1140. (11) Lemos, A. Cycloaddition Reactions of Conjugated Azoalkenes. In Targets in Heterocyclic Systems: Chemistry and Properties; Attanasi, O. A., Spinelli, D., Eds.; Soc Chimica Italiana: Rome, 2010; Vol. 14, pp 1−18. (12) Brachet, E.; Belmont, P. Inverse Electron Demand Diels-Alder (IEDDA) Reactions: Synthesis of Heterocycles and Natural Products 11348


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