2âAzaallyl Anions, 2âAzaallyl Cations, 2âAzaallyl Radicals, and

Review Cite This: Chem. Rev. 2018, 118, 10393−10457

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2‑Azaallyl Anions, 2‑Azaallyl Cations, 2‑Azaallyl Radicals, and Azomethine Ylides Shaojian Tang,† Xia Zhang,† Jiayue Sun, Dawen Niu,* and Jason J. Chruma*

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Key Laboratory of Green Chemistry & Technology (MOE), College of Chemistry, Sino-British Materials Research Institute, College of Physical Sciences & Technology, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610064, People’s Republic of China ABSTRACT: This review covers the use of 2-azaallyl anions, 2-azaallyl cations, and 2azaallyl radicals in organic synthesis up through June 2018. Particular attention is paid to both foundational studies and recent advances over the past decade involving semistabilized and nonstabilized 2-azaallyl anions as key intermediates in various carbon−carbon and carbon−heteroatom bond-forming processes. Both transitionmetal-catalyzed and transition-metal-free transformations are covered. Azomethine ylides, which have received significant attention elsewhere, are discussed briefly with the primary focus on critical comparisons with 2-azaallyl anions in regard to generation and use.

CONTENTS 1. Introduction 2. 2-Azaallyl Anions 2.1. Reactions of Semistabilized 2-Azaallyl Anions Generated via Direct Deprotonation 2.1.1. 1,3-Proton Shift 2.1.2. Cycloadditions 2.1.3. Nucleophilic Attack 2.1.4. Transition-Metal-Catalyzed Cross-Couplings 2.2. Reactions of Semistabilized 2-Azaallyl Anions Generated via Decarboxylation 2.2.1. Dialkylglycine Decarboxylase Mimics 2.2.2. Transition-Metal-Catalyzed Decarboxylative Alkylations 2.2.3. Direct Decarboxylative Couplings 2.3. Reactions of Nonstabilized 2-Azaallyl Anions Generated via Lithium−Tin Exchange 2.3.1. General Reactivity: Cycloadditions 2.3.2. Applications in Total Synthesis 3. 2-Azaallyl Cations 4. 2-Azaallyl Radicals 5. Azomethine Ylides 5.1. N-Protio and N-Alkyl Azomethine Ylides 5.2. N-Metalated Azomethine Ylides 6. Conclusions and Outlook Author Information Corresponding Authors ORCID Author Contributions Notes Biographies Acknowledgments © 2018 American Chemical Society

Dedication References

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1. INTRODUCTION The 2-azaallyl anion is one of the oldest known synthetic intermediates in organic chemistry (Figure 1). As early as

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Figure 1. 2-Azaallyl anions, azomethine ylides, 2-azaallyl cations, and radicals.

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1899, Emil Erlenmeyer, Jr., proposed the 1,3-diphenyl-2azaallyl anion as an intermediate in the formation of 2-amino1,2-diphenylethan-1-ol via the condensation of benzylamine and benzylaldehyde in aqueous sodium hydroxide (Scheme 1).1 After this seminal report, there have been several waves of investigation focused on the 2-azaallyl anion; the past decade, in particular, has experienced significant renewed interest in the 2-azaallyl anion as a nucleophilic imine umpolung. Similarly, the N-substituted and N-metalated azomethine ylides, which are the zwitterionic cousins of the 2-azaallyl anion, have enjoyed a long history as dipoles for cycloaddition Received: May 30, 2018 Published: October 10, 2018 10393

DOI: 10.1021/acs.chemrev.8b00349 Chem. Rev. 2018, 118, 10393−10457

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Scheme 1. First Appearance of a 2-Azaallyl Anion in the Literature by E. Erlenmeyer, Jr.

Scheme 2. Accessing 2-Azaallyl Anions by Deprotonation of Imines

reactions. In comparison to its anionic counterpart, the 2azaallyl cation has received considerably less attention, but recent advances in transition-metal-mediated C−H activation strategies offer hope for better access to this intriguing class of electrophiles. Finally, reports within the past year that 2azaallyl anions can serve as superelectron donors (SEDs) and that the resulting 2-azaallyl radicals are persistent radical species available for further C−C bond formations have both opened up a whole new world of possibilities for radicalmediated transformations and motivated a reconsideration of the reaction mechanisms underlying the past century of 2azaallyl anion chemistry. Herein, a critical and comprehensive review of 2-azaallyl anions, cations, and radicals in organic synthesis up through June 2018 is provided. Particular attention is paid to new reports within the past decade that have not been reviewed elsewhere. The use of azomethine ylides in organic synthesis has been summarized extensively elsewhere.2−15 Accordingly, our treatment of these species in this review will focus primarily on comparing and contrasting their formation and utilization in organic synthesis with that of 2-azaallyl anions. Before proceeding, several definitions and categories must be established so as to chart the scope of this review. First of all, the 2-azaallyl anion can be segregated into three categories depending on the ancillary substituents and roughly related to the pKa of the conjugate acid (Figure 1). A nonstabilized 2azaallyl anion is one in which the negative charge is sequestered to the three-atom C−N−C network without any possibility for further delocalization. Accordingly, nonstabilized 2-azaallyl anions are extremely basic and possess only alkyl substituents and/or hydrogens on the carbon termini. The most significant contributions to the generation and use of nonstabilized 2-azaallyl anions were made by Pearson and coworkers (see section 2.3).16−33 At the other end of the spectrum are the stabilized 2-azaallyl anions, wherein the negative charge is predominantly associated with an appropriate electron-withdrawing substituent, e.g., carbonyl, nitro, nitrile, phosphate, etc. In contrast to their nonstabilized counterparts, these anionic species are typically stable under aqueous conditions. A quintessential example of stabilized 2azaallyl anions is the benzophenone imine glycinate ester enolates popularized by O’Donnell34 and employed by several others (Scheme 2).35−40 In this particular circumstance, it is more appropriate to consider the anionic species as an αiminoenolate given that the electron density is focused mostly on the enolate oxygen and not the 2-azaallyl framework. Such stabilized 2-azaallyl anions and their role in organic synthesis (particularly in relationship to phase-transfer catalysis) are summarized regularly34,37−40 and, thus, will receive very little attention in this review. Similarly, the related cyclic aromatic azlactone-derived oxazoline anions and their use in organic synthesis will not be addressed in this review.41 In between these two extremes lies the most diverse category of 2-azaallyl anions, namely the semistabilized 2-azaallyl anions, in which the negative charge can partially delocalize into at least one (hetero)aromatic terminal substituent. The range of pKa values

for the corresponding conjugate acids of semistabilized 2azaallyl anions is rather broad and depends on the nature of the aromatic substituents.42 Moreover, semistabilized 2-azaallyl anions are reported to perform both cycloaddition reactions (à la nonstabilized 2-azaallyl anions) and nucleophilic substitutions/additions (à la stabilized 2-azaallyl anions) and thus bridge the gap between the two extremes. Although there has been a flurry of research activity focused on semistabilized 2azaallyl anions in the past decade, this particular class of synthetic intermediates has not been appropriately reviewed.43,44 Accordingly, the majority of this review will be focused on semistabilized 2-azaallyl anions, with particular focus on advances made within the past 10 years up through June 2018. As with semistabilized 2-azaallyl anions, there are no comprehensive and critical reviews focused on 2-azaallyl cations and radicals. Admittedly, there is significantly less research involving these species in comparison to their anionic counterparts, but very recent reports are expected to elicit significant interest from the synthetic community. Accordingly, past efforts involving 2-azaallyl cations and radicals will be summarized thoroughly in this review and critical suggestions and predictions for future exploration also will be provided. Finally, it should be pointed out that the distinction between a 2-azaallyl anion and an N-metalated azomethine ylide is admittedly ambiguous.44 As depicted in Figure 2, there are at

Figure 2. 2-Azaallyl anions versus N-metalated azomethine ylides.

least three different modes by which the 2-azaallyl anion can associate with a cationic metal species and the predominating mode depends on the particular metal (M), solvent, and other reaction conditions. X-ray crystallographic,45 spectroscopic,46 and computational studies47 have provided evidence for each of these species, and they very well may exchange among one another under most reaction conditions. The distinction between N-metalated azomethine ylides (section 5.2) and 10394


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stabilized 2-azaallyl anions is particularly ambiguous given that the former almost always possess a chelating functional group (e.g., R = CO2Me in Figure 2) that stabilizes the N−M coordination via formation of a five-membered metallocycle. For the sake of this review, the observed reactivity will be used as one method to distinguish between the 2-azaallyl intermediate (either η3 or η1 C−M) and the N-metalated azomethine ylide, with the former serving primarily as a nucleophile (substitutions and additions) and the latter serving predominantly as a 1,3-dipole for cycloaddition reactions. For transition metal complexes, this distinction is generally sufficient. It is less clear, however, for complexes of semistabilized 2-azaallyl anions and alkali metals, particularly lithium, in which both nucleophilic and dipolar reactivities have been reported. Moreover, N-metalated azomethine ylides are known, in specific circumstances, to act as nucleophiles in conjugate addition reactions and, very recently, mixed-metal/ dual-catalyst systems have further extended the reactivity of Nmetalated azomethine ylides beyond cycloadditions into transition-metal-catalyzed alkylations. For the sake of this review, complexes of alkali metals and semistabilized 2-azaallyl anions will be included in the section covering 2-azaallyl anions (specifically sections 2.1.1 and 2.3). As mentioned above, there are several reviews focused on the use of azomethine ylides and N-metalated azomethine ylides in organic synthesis.2−15 With this in mind, coverage of these synthetic intermediates in this review will focus primarily on how they relate to their 2-azaallyl anion counterparts, particularly semistabilized 2-azaallyl anion species, in regard to generation, reactivity, and application.

corresponding C−H bond is more acidic with a pKa of 18.7. A change from benzophenone imine 2a to fluorenone imine 2c results in a significantly more acidic C−H bond, with a pKa in DMSO of 14.5. This dramatic change is due to the aromatic stabilization of the resulting fluorenyl anion derived from deprotonation of 2c. In the presence of a substoichiometric amount of KO-t-Bu, imine 2a in DMSO exists in equilibrium with its tautomer 1a, with the latter favored by a factor of 2 (Scheme 2C). With this information, the pKa of 1a is deduced to be 24.4. Given the above features, this route for generating semistabilized 2-azaallyl anions is attractive and most often used. The resulting delocalized semistabilized anions are typically deeply colored anywhere from reddish purple to bluish green, depending on the exact aromatic substituents and solvent. For example, the 2-azaallyllithium of colorless 4phenylbenzylidene benzylamine in THF is a deep blue and can be used for titrating solutions of lithium alkyls and metal amides.49 As an alternative deprotonative method for the generation of 2-azaallyl anions, Kauffmann,50 Vo-Quang,51 and others found that thermolysis of the lithium amide 5, obtained by deprotonation of the N−H bond in aziridine 4, occurred readily at temperatures as low as 40−60 °C to provide the corresponding 1,3-diphenyl-2-azaallyl anion 6a (Scheme 3). Prior to recent advances,52 the relative inaccessibility of N−H aziridines compared with that of imines, however, has limited the utility of this strategy. Scheme 3. Accessing 2-Azaallyllithiums by Deprotonation and Ring-Opening of N−H Aziridines

2. 2-AZAALLYL ANIONS As mentioned in the Introduction, the majority of this review will focus on the generation and use in organic synthesis of semistabilized 2-azaallyl anions, namely, 2-azaallyl anions that possess at least one aromatic substituent on the carbon termini (sections 2.1 and 2.2). Significant attention also will be paid to the use of nonstabilized 2-azaallyl anions in organic synthesis, particularly with regard to the total synthesis of natural products (section 2.3). Stabilized 2-azaallyl anions, as defined in section 1 (see Figure 1), however, will receive very little attention in this review since their role in organic synthesis, particularly in combination with phase-transfer catalysis, has received considerable attention and summary elsewhere.34,37−40

2.1.1. 1,3-Proton Shift. The 1,3-proton shift involved in the interconversion between 1a and 2a (Scheme 2C) resembles a similar process observed in biologically relevant transamination reactions (see section 2.2.1). The equilibrium constant of such a process is heavily dependent on the properties of each species. In fact, researchers have long exploited this base-mediated tautomerization as a means to oxidize amines or to prepare chiral amines. A comprehensive review by Soloshonok and co-workers summarized the progress in this area through 2011.53 Following are provided several examples to illustrate the key features of this process and to introduce the most recent updates of this field. In 1969, Corey and Achiwa disclosed the use of 3,5-di-tertbutyl-1,2-benzoquinone (7) as an oxidizing agent for primary amines (Scheme 4).54 The substitution pattern in 7 is designed to block the nucleophilic attack of an amine group to all but the C1 position. Thus, the condensation of amine 8 with 7 gave imine 9 predominantly. The subsequent conversion of 9 to 9′ is thermodynamically preferred due to aromatic stabilization in the latter. By this method, a variety of amines could be converted to the corresponding ketones (10) in high yields. In another example, Cainelli and co-workers reported the isomerization of α-ketoimine 11 to benzophenone imine 11′ in the presence of KO-t-Bu (Scheme 5).55 In this case, the preferred formation of 11′ is likely due to minimization of dipole interactions. Interestingly, the C−N single bond in 11′ is formed stereoselectively.

2.1. Reactions of Semistabilized 2-Azaallyl Anions Generated via Direct Deprotonation

The most straightforward method to generate semistabilized 2azaallyl anions (3/3′) is arguably by the direct deprotonation of the corresponding imines, such as 1 or 2 (Scheme 2A). Several features of this method are noteworthy. First, the imine starting materials are readily available by the condensation of the corresponding amines and carbonyls. Second, both aldimine 1 and ketimine 2 can, in principle, give the same delocalized 2-azaallyl anion, imparting flexibility in the choice of starting materials. Third, the pKa (and ease of deprotonation) of the relevant C−H bonds can be tuned by altering the steric and electronic natures of substituents in 1 or 2.42 For example, take structure 2a where R1, R2, and R3 are all phenyl groups; the labeled C−H bond in 2a was originally assigned a pKa of 24.3 in DMSO; this value was later corrected due to tautomerization to 24.1 as depicted in Scheme 2B.42,48 When R3 is changed to an ester group, as in glycinate imine 2b, the 10395


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Scheme 4. Generation of Ketones via Imine Isomerization

Scheme 6. Generation of Enantiomerically Enriched Amino Acids by Imine Isomerization

Scheme 5. Generation of Ketones via Imine Isomerization

The 1,3-proton shift also can occur in a catalyst-controlled stereoselective fashion. Remarkable progress has been made in this field since the pioneering studies of Kuzuhara,56 Breslow,57 Berg,58 Zwanenburg,59 and others. In 2011, the Shi group reported the one-pot conversion of α-keto esters 12 to chiral α-amino esters 13 with cinchonine-based catalyst 14 (Scheme 6).60 In this system, the α-keto esters 12 were first converted to the corresponding ketimines, which were then isomerized in situ via the intermediacy of a stabilized 2-azaallyl anion to give the aldimine intermediate (Scheme 6, inset). Several features of this reaction are noteworthy. First, the stoichiometric amount of water generated under the conditions does not interfere with the transformation. Second, the aldimine product is configurationally stable under the conditions. A variety of α-alkyl substituted amino esters could be prepared in decent yields and high enantioselectivities. Similarly, the Deng group has accomplished an asymmetric synthesis of trifluoromethylated amines 16 via enantioselective isomerization of imines 15 by the intermediacy of 2-azaallyl anions (Table 1).61 These authors first examined the influence of the N-substituent on the efficiency of this isomerization event, and found that electron-withdrawing aromatic groups accelerate this transformation dramatically. When a 4-nitrobenzyl group was used (Table 1, entry 4), the reaction was complete within 30 min. Imines with this substituent were then carried forward for the study of enantioselective transformations. The authors identified catalyst 19 to be optimal for the enantioselective isomerization of imines 17 to 18 (Scheme 7). Various α-trifluoromethyl amines could be obtained in decent yields and enantiomeric purities. Imines derived from both aryl and alkyl ketones could be employed as substrates. 2.1.2. Cycloadditions. 2-Azaallyl anions are threecentered, four-electron species and, as such, are suitable participants in various cycloaddition reactions. In the 1970s, Kauffmann and co-workers systematically studied the reactivity of 2-azaallyl anions as 4π components in cycloaddition reactions with unsaturated carbon−carbon bonds. As shown in Scheme 8, they found that the 1,3-diphenyl-2-azaallyl anion 6a, which was accessed via deprotonative ring-opening of

Table 1. Generation of Trifluormethylated Amines via Imine Isomerization

aziridine 4, reacted with trans-stilbene (20), cis-stilbene (22), and acenaphthylene (25).50,62 The relative configurations of the cycloadducts obtained from these reactions provided important mechanistic insights.63 First, according to Woodward−Hoffmann rules, the ring-opening of cis-2,3-diphenylaziridine 4 should occur in a conrotatory fashion to afford Eimine isomer 6a′ as the product. However, the products (21, 23, 24, 26, 27) appeared to result from the W-shaped linear structure 6a, given that the two phenyl groups originating from the 2-azaallyl anion species are syn to each other in the products. This observation indicated that 6a′ and 6a are in 10396


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Scheme 7. Generation of Trifluormethylated Amines via Imine Isomerization

Scheme 9. Ring-Forming Polymerization of 2Azaallyllithiums

contained 35−40 monomers. In 1997, researchers at Boehringer Ingelheim disclosed the use of a [3 + 2] cycloaddition between a semistabilized 2-azaallyl anion and 4-vinylanisole as a means to construct a key intermediate in the synthesis of a trans-2,3-diarylpyrrolidine LTB4 inhibitor.68 Conjugated dienes also react with semistabilized 2-azaallyl anions via cycloaddition. For instance, the reaction of isoprene (29) with 6a gave a mixture of two constitutional isomers 30 and 31 (Scheme 10A).69 Not surprisingly, the more accessible Scheme 10. Cycloaddition between 2-Azaallyllithium 6a and Conjugated Dienes

Scheme 8. Cycloaddition between 2-Azaallyllithium 6a and Alkenes

equilibrium, and the latter is the dominant and/or more reactive species under the reaction conditions.45 In 1982, Young and Ahmad provided spectroscopic evidence for such an isomerization.64 Second, the relative configurations of alkenes were translated to the products with high fidelity, serving as strong support for a concerted [4π + 2π] reaction mechanism. Later, more-detailed studies, however, indicated that a stepwise mechanism is most likely in effect for these cycloaddition reactions.65,66 Interestingly, the reaction between 6a and acenaphthylene gave an approximate 1:1 mixture of two stereoisomers. This poor endo/exo selectivity is presumably a result of contradicting effects of electronic and steric factors. Kauffmann’s group also demonstrated that the cycloaddition between 2-azaallyl anions and styrenes could be extended to a room temperature “ring-forming” polymerization process using imine 1b (Scheme 9).67 In this case, the LDA base could be used as a catalyst, since the lithium amide cycloadduct intermediates also could serve as a base to propagate the reaction. After protic workup, the colorless polymeric product 28 had a molecular weight of ca. 7500−8000, and therefore

monosubstituted double bond reacts preferentially in this reaction to provide 30 as the major cycloadduct. In this case, no product arising from [4 + 3] cycloaddition (32) was observed. Interestingly, in another study by Mayr and coworkers,70 the reaction between 6a and 3,3,4,4,5,5-hexamethyl1,2-bis(methylene)cyclopentane (33) did give a significant amount of the seven-membered azacycle 34, along with ringopened product 35 (Scheme 10B). Since concerted [4π + 4π] cycloadditions are symmetry forbidden by the Woodward− Hoffmann rules, cycloadduct 34 most likely arises via a stepwise reaction mechanism. The isolation of intermediate 35 strengthens this conclusion. Vo-Quang and Vo-Quang investigated the cycloaddition between 1,3-diphenyl-2-azaallyl anion 6a with alkynes and enynes (Scheme 11). When internal alkynes such as 36 reacted with 6a, the corresponding pyrroles 38a and 38b were formed, respectively, presumably following the oxidation of the incipient dihydropyrroles.51 The cycloaddition between 2azaallyllithium 6a and conjugated enyne 37 predominantly 10397


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Scheme 11. Cycloaddition between 2-Azaallyllithium 6a and Alkynes

Scheme 13. Cycloaddition between 2-Azaallyl Anion 6a and Benzyne

Scheme 14. Intramolecular Cycloadditions

afforded the saturated pyrrolidine 39, indicating that alkenes are inherently more reactive than alkynes in the cycloaddition reactions with 2-azaallyl anions. Allenes also can function as effective 2π components in the trapping of semistabilized 2-azaallyl anions. When investigating the reaction of phenylpropynes 40 with 2-azaallyl anion 6a, Vo-Quang and Vo-Quang generated pyrrolidines with an exocyclic double bond (42) as the major products (Scheme 12).71 The authors proposed that phenylallenes (41) initially Scheme 12. Cycloaddition between 2-Azaallyllithium and Allenes

were formed via base-mediated isomerization of phenylpropynes 40, and these intermediates reacted with the 2azaallyllithium 6a to afford the observed cycloadduct 42. It should be noted that the internal double bond, rather than the terminal double bond, in the allene framework reacted with the 2-azaallyl anion selectively, presumably because the former is activated by conjugation with the aryl ring. Benzynes are among the most reactive 2π components for cycloaddition reactions.72 Indeed, the reaction between benzyne (43, derived from treating chlorobenzene with nBuLi) and 2-azaallyllithium 6a at 20 °C gave, after treatment of the cycloadduct with methyl iodide, N-methylisoindole 44 (Scheme 13).67 Formation of the isolated polyaromatic heterocycle 44 via cycloaddition between benzyne and 6a requires oxidation of the intermediate cycloadduct under the reaction conditions. While semistabilized 2-azaallyl anions readily react with activated alkenes and alkynes at or near room temperature, cycloaddition with unactivated alkenes is more challenging. In 1986, Pearson’s group reported the intramolecular cycloaddition of semistabilized 2-azaallyl anions with unactivated terminal alkenes to give bicyclic pyrrolidines 46 in moderate isolated yields after protic workup (Scheme 14).73 In general, good diastereoselectivities were obtained for a variety of substrates leading to the 5,5-ring system (45a−45d). The

observed diastereoselectivities were not as high, however, in the formation of 6,5-bicyclic ring systems (45e, 45f). To rationalize the observed stereochemical outcome, the authors proposed a model in which the 2-azaallyl anions adopt a Wshaped conformation (Scheme 14, inset), in accord with Kauffmann’s earlier studies.50,62,67 In addition to unsaturated carbon−carbon bonds, semistabilized 2-azaallyl anions can engage with other types of πbonds via cycloaddition reactions. For example, reaction between 6a and diimide 47 in THF at room temperature generated the imidazoline product 48 (Scheme 15).74,75 In this relatively rapid transformation (30 min), one diimide molecule engaged in the cycloaddition reaction while another equivalent was attacked by the resultant N-centered anion to form the guanidinyl group. The reaction between semistabilized 210398


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Scheme 15. Cycloaddition with Carbodiimides, Isocyanates, and Thioisocyanates

Scheme 18. Reaction with Aryl Nitriles

azaallyl anion 6a and phenyl isocyanate (49a) or phenyl thioisocyanate (49b) both gave the corresponding imidazoline cycloadducts 50a and 50b, respectively, without concomitant functionalization of the resultant amine. It is interesting to note that, in both cases, the CN bond participated in this reaction selectively, in preference over the CO or CS bonds. Nevertheless, CS bonds, specifically those found in carbon disulfide, can react with 2-azaallyl anion 6a (Scheme 16). Scheme 16. Double Cycloaddtion with Carbon Disulfide

Scheme 17. Cycloaddition with Imines

enamines 55a and 55b, respectively, in moderate to poor yield. The same 2-azaallyl anion (6b) did undergo formal [3 + 2] cycloaddition, however, with more electron-rich aromatic nitriles to afford the corresponding 2,5-dihydro-1H-imidazoles 56a−56c in moderate yields. Similarly, cycloaddition occurred between benzonitrile and the trisubstituted 2-azaallyl anion 6c to afford cycloadduct 56d, albeit in very low yield. When 1,3diphenyl-2-azaallyllithium (6a) was reacted with various aryl nitriles, oxidation of the initially formed cycloadduct occurred readily under the reaction conditions to afford the corresponding imidazoles 57a−57d. As with aryl nitrile electrophiles, the reaction outcome between semistabilized 2-azaallyl anions and diazo compounds is highly dependent on the structure of each reaction partner.79 For instance, 1,3-diphenyl-2-azaallyl anion (19a) reacts with azobenzene to give the corresponding 1,2,4-triazoline 58 (Figure 3). However, very closely related compounds, such as 4-dimethylaminoazobenzene or 2,2′-azanaphthalenes, are inert under these conditions. On the other hand, 1,1-diphenyl-2-

The reaction between semistabilized 2-azaallyl anions and aromatic nitriles proved to be more complex than other πelectrophiles; the outcome of the reactions, after aqueous workup, were highly dependent on the nature of the 2-azaallyl anion and the aryl nitrile (Scheme 18).77,78 For example, 1,1diphenyl-2-azaallyllithium (6b) performed direct nucleophilic addition and double-bond isomerization, instead of cycloaddition, with either benzonitrile or picolinonitrile to afford

Figure 3. Cycloaddition with diazo compounds.

Toward this end, Kauffmann and co-workers determined that 2 equiv of 6a rapidly reacted twice with 1 equiv of CS2 to afford the bis-cycloadduct 51 as a single diastereomer in 60% isolated yield.74,75 Attempts to isolate the monocycloadduct 52 were unsuccessful, suggesting that the CS bond in 52 is a more reactive 2π component in this reaction. As will be discussed in section 2.1.3, semistabilized 2-azaallyl anions do not react with CO2 via cycloaddition; instead the anions perform nucleophilic addition to afford, after protic workup, α-imino acids.74,76 While reaction between 6a and CS2 provided a single diastereomer, reaction between this same 2-azaallyllithium and benzaldimine 53 afforded a mixture of diastereomeric cycloadducts 54a and 54b in a roughly 2:1 ratio (Scheme 17).67 It was suggested that this poor diastereoselectivity was the result of a stepwise reaction mechanism.

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as HMPA or N,N,N′,N′-pentamethyldiethylenetriamine (PMDETA), favored E2 elimination and deprotonation to afford the corresponding 2-azaallyl anions 6. When this was performed in the presence of an activated olefin, the expected [3 + 2] cycloaddition occurred in moderate-to-high yield and typically in high regio- and diastereoselectivities. Asymmetrical 1,3-diaryl-2-azaallyl anions demonstrated only modest regioselectivity for the cycloaddition with styrene. For example, regioisomeric products 66e and 66e′ were formed in a 2:1 ratio, respectively, but in high combined yield (83%). Even extended azaallyl anions could be formed under these conditions, albeit the isolated yield (20%) for the corresponding cycloadduct 66f was considerably lower than the other reactions. As demonstrated above, semistabilized 2-azaallyl anions can react with a large variety of dipolarophiles via [3 + 2] cycloaddition reactions to afford an equally diverse collection of polysubstituted N-heterocyclic compounds. Surprisingly, there are very few examples beyond the initial reports in which these cycloaddition reactions with semistabilized 2-azaallyl anions play a key role in the construction of more complex compounds, such as natural products, or items of commercial interest, such as drug candidates.68 This is in stark contrast to cycloaddition reactions involving nonstabilized 2-azaallyl anions (section 2.3) and azomethine ylides (section 5). Unlike cycloaddition reactions involving heteroatom-substituted nonstabilized 2-azaallyl anions and N-metalated azomethine ylides, there are currently no enantioselective variants of cycloadditions involving semistabilized 2-azaallyl anions, which may account for the greater popularity of the former method for the construction of value-added cyclic amines. Moreover, in comparison to their semistabilized cousins, both nonstabilized 2-azaallyl anions and azomethine ylides can react with a broader range of olefin substrates and with higher isolated yields of the desired cycloadducts. 2.1.3. Nucleophilic Attack. In addition to being capable dipolar components for cycloaddition reactions (see section 2.1.2), semistabilized 2-azaallyl anions also can serve as potent nucleophiles and react with various types of electrophiles. Indeed, the nucleophilic addition of semistabilized 2-azaallyl anions with aldehyde electrophiles can be traced back to Erlenmeyer’s original report in 1899.1 It was not until 1970, however, when the reactions between 2-azaallyllithiums and ketones received significant attention.82−84 As with the cycloaddition reactions discussed in section 2.1.2, Kauffmann’s group were the pioneers in this field. For example, they reported that the 2-azaallyllithium species generated by deprotonations of N-(diphenylmethylene)methylamine with LDA at −45 °C (19b) could attack a collection of ketones to afford the corresponding imino alcohols 67 in modest isolated yields (Scheme 21). Remarkably, even the poorly electrophilic ketone benzophenone was sensitive to nucleophilic attack from the semistabilized 2-azaallyl anion (cf. 67a). It is worth noting that N-alkyl azomethine ylides (section 5.1) tend to react with ketone and aldehyde carbonyls via 1,3-dipolar cycloaddition instead of the direct nucleophilic attack observed for semistabilized 2-azaallyl anions.85−89 Hydrolysis of the imine functionality in the products 67 was readily achieved in high yield by treatment with aqueous HCl. As an extension of Kauffmann’s seminal investigations, Wolf and Würthwein combined the deeply red colored π-extended 2-azapentadienyllithium 69, generated via deprotonation of allyl benzophenone imine 68 with LDA in THF, with a variety

azaallyl anion (6b) reacts with 1,2-di-p-tolyldiazene to give cycloadduct 60. The same anion, however, reacts with azobenzene under identical conditions to afford the acyclic product 59. It is currently undetermined whether the different products are a result of different reaction mechanisms or if the acyclic product 59 simply represents an unreactive intermediate toward the cycloadducts. In 1995, Couture and co-workers reported a formal [3 + 3] cycloaddition between symmetrical 1,3-diaryl-2-azaallyl anions and o-chloropyridines (Scheme 19).80 For these transScheme 19. Formal [3 + 3] Cycloadditions with oChloropyridines

formations, the semistabilized 2-azaallyllithiums 6 first were generated by deprotonation of the corresponding conjugate acids with LDA in THF and then heated with a solution of ester 61a, nitrile 61b, or ketone 61c in DMPU to afford 1,7naphthyridine analogues 62, 63, or 64, respectively, in isolated yields ranging from 51 to 72%. Presumably, a similar strategy could be employed to construct other nitrogen-containing heterocyclic frameworks. In 2011, Pandiancherri and Lupton introduced an alternative deprotonative strategy to generate semistabilized 2-azaallyl anions for [3 + 2] cycloadditions with styrenes and stilbenes (Scheme 20).81 Specifically, treatment of N-chloroamines 65 with an appropriate base (LDA or KO-t-Bu) and donor, such Scheme 20. 2-Azaallyl Anions from N-Chloroamines

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Scheme 21. Reaction with Ketone Electrophiles

Table 2. Reaction between 2-Azaallylpentadienyllithium 68 and Carbonyl Electrophiles

of aldehydes and ketones (Table 2).90,91 With less reactive ketones such as benzophenone, fluorenone, acetophenone, or tert-butyl methyl ketone, the resulting C-5 alkylated trans-2azadiene products 70a were formed exclusively in 61−83% isolated yields (entries 1−4). Extremely bulky ketones, such as di-tert-butyl ketone, failed to react with the nucleophilic organolithium species 68 (entry 9). More reactive aliphatic ketones such as cyclohexanone (entry 5) or acetone (entry 8) generated a mixture of 70a, cis-alkene 70b, and imino alcohol 71 in a roughly 1:1 ratio of C-5 and C-3 alkylated products. Using cyclohexanone as a test case, the authors determined that changes in the reaction conditions could alter the ratio of C-5 and C-3 alkylated products. For example, addition of HMPA to the reaction mixture favored production of the C-5 alkylated 70a (entry 6), whereas conducting the reaction in hexane at 0 °C shifted the preference toward production of the C-3 alkylated 71. In contrast to ketone electrophiles, aldehydes preferentially were attacked by the C-3 position of the 2azapentadienyl anion to afford α-substituted allylic imines 71 (entries 10, 12, and 13). Addition of HMPA to the reaction mixture, at least in the case of benzaldehyde (entry 11) led to exclusive formation of the trans-2-azadiene 70a. Barrett and coworkers later demonstrated that the 2-azapentadienyllithium 69 was exclusively borylated with (+)-B-chlorodiisopinocamphenylborane [(+)-(Ipc)2BCl], or its enantiomer (not shown), at the C-5 carbon of the extended anion to afford the 2azadiene product 72 (Scheme 22).92,93 The resulting iminefunctionalized allylboranes 72 were readily converted into the corresponding anti-β-imino alcohols 73 with high diastereoand enantioselectivities by reaction with the appropriate aldehydes. In addition to ketones, Kauffman and co-workers investigated the direct alkylation of 1,1-diphenyl-2-azaallyllithium (6b) with a small collection of alkyl bromides (Scheme 23).83 Primary alkyl or allyl bromides afforded the alkylated products 74 in moderately high yields, but significantly lower yields were obtained with secondary alkyl bromides. Interesting results were observed with alkyl dibromides. Treatment of 6b with 1,4-dibromobutane resulted in formation of the iminium bromide salt 75, whereas 1,2-dibromoethane resulted in dimerization of 6b to afford diimine 76 in 31% yield after recrystallization. Two years after these initial reports, Cook and co-workers disclosed their own efforts involving the alkylation of 1,3-diaryl-2-azaallyl anions 78 with alkyl halides (selected examples provided in Table 3).94 In Cook’s studies, particular

Isolated yields. bHMPA added. cConducted at 0 °C in hexanes. Relative yields based on 1H NMR integration. eObtained as a mixture of diastereomers. a

d

Scheme 22. C-5 Borylation of 2-Azapentadienyllithium 69 and Formation of anti-β-Imino Alcohols 73

attention was paid to the factors that controlled the regioselectivity of the C−C bond-forming event. For example, when the 2-azaallylpotassium species generated from the deprotonation of the benzaldimine of 4-chlorobenzylamine 10401


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chloroformate (entry 11). It is worth noting that, in situations where elimination of the halide by the basic 2-azaallyl anion species 78 possibly could be competitive (entries 2, 6, 9, and 10), alkylation of the nucleophilic 78 was the only observed transformation. No mechanistic studies were performed by either Kauffmann’s or Cook’s groups, but a direct SN2-like mechanism would be reasonable. Very recent studies indicate that the alkylations also can occur via single-electron transfer between the 2-azaallyl anion and alkyl halides to afford, after ejection of halide, a 2-azallyl radical and alkyl radical pair that couple with each other (see section 4).95,96 This radicalmediated process most likely dominates for alkylations between 1,1,3-triaryl-2-azaallyl anions and sterically hindered alkyl halides, but further studies still are required to distinguish between anionic and radical reaction pathways for other combinations such as those discussed above. In 2009, Yorimitsu, Oshima, and co-workers provided a more detailed investigation on the alkylation of semistabilized 2-azaallyl anions, with particular attention to the regioselectivity of the C−C bond-forming event.97 In these studies, the authors determined that the allylation of 1,1,3-triphenyl-2azaallylpotassium, generated by deprotonation of ketimine 2a with potassium tert-butoxide, with allyl bromide in THF at ambient temperature afforded, after aqueous workup, a 5.4:1 mixture of mono- and diallylated products (80 and 81, respectively), along with the aldimine isomer 1a (Scheme 24A). For this substrate, allylation happened exclusively at the monoarylated carbon of the 2-azaallyl anion framework. Allylation of the xanthone imine 2d under otherwise identical reaction conditions, however, afforded a nearly 1:1 mixture of regioisomeric products 82 and 83 (65% combined yield), in addition to the aldimine isomer 1d (Scheme 24B). Following the hypothesis that greater steric hindrance would afford higher regioselectivity, the authors next explored the allylation of the di-1-naphthylmethylenimine 2e. As anticipated, allylation of the resultant 2-azaallylpotassium species with allyl bromide only occurred at the less substituted carbon to afford ketimine 84a quantitatively (Scheme 24C). This remarkable regioselectivity and yield extended to a collection

Scheme 23. Alkylation of Semistabilized 2-Azaallyllithium 6b with Alkyl Bromides

with potassium tert-butoxide in DME was exposed to methyl iodide, methylation occurred preferentially at the carbon in the 2-azaallyl anion framework bearing the more electron-withdrawing aromatic substituent (entry 1). This tendency was particularly strong for 4-pyridyl versus phenyl substituents; as shown in entry 2, alkylation with isopropyl iodide occurred exclusively on the carbon bearing the electron-withdrawing 4pyridyl group. Conversely, the addition of electron-donating substituents could “push” the alkylation away from them (entries 3−6), albeit in these situations the stronger base butyllithium was required to form the 2-azaallyl anion intermediate from the less acidic imines 77. Interestingly, Cook’s group also disclosed that steric effects could overcome electronic preferences. Specifically, alkylation of the 2azaallyllithium derived from the (2,4,6-trimethyl)benzaldimine of 4-methoxybenzylamine with isopropyl iodide resulted in the isopropyl group attaching almost exclusively to the carbon bearing the more electron-rich 4-methoxyphenyl moiety and away from the sterically encumbered 2,4,6-trimethylphenyl group (entry 6). As demonstrated in entries 7−9, this trend was quite general. Matching steric and electronic influences led to exclusive functionalization of the carbon bearing the electron-deficient aryl group with a wide variety of electrophiles including cyclic alkyl bromides (entry 10) and ethyl

Table 3. Alkylation of 1,3-Diaryl-2-azaallyl Anions with Alkyl Halides

entry a

1 2a 3b 4b 5b 6c 7c 8b 9b 10b 11b

Ar1

Ar2

Ph 4-pyridyl 4-Me2NC6H4 4-MeOC6H4

4-ClC4H4 Ph Ph 4-ClC4H4

2,4,6-Me3C6H2 2,4,6-Me3C6H2

4-MeOC6H4 Ph

2,4,6-Me3C6H2 2,4,6-Me3C6H2

4-ClC6H4 3,4-Cl2C6H3

R−X

% alkylation

regioisomeric ratio (79a:79b)

Me−I i-Pr−I Me−I Me−I Bn−Br i-Pr−I Me−I Bn−Br i-Pr−I c-C6H11−Br EtO2C−Cl

100 100 83 100 100 100 100 100 100 100 100

65:35 0:100 81:19 82:18 86:14 96:4 86:14 95:5 100:0 100:0 100:0

a

Base, t-BuOK; solvent, DME. bBase, n-BuLi; solvent, THF. cBase, LDA; solvent, THF. 10402


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(85a) or chlorosilanes (85b) followed by either a Wittig-type or Peterson olefination, respectively (Scheme 25).98 A small

Scheme 24. Regioselectivity for the Allylation of 2-Azaallyl Anions

Scheme 25. Enimines via Two-Step Alkylation−Olefination

series of ketones and aldehydes were screened and the resulting 2-azadienes 86 were obtained in 43−92% yields. Very recently, Malcolmson and co-workers employed a slight modification of this strategy using a Horner−Wadsworth− Emmons olefination tactic to construct a series of 2-azadiene starting materials for the copper-catalyzed enantioselective reductive coupling to ketones (see section 2.1.4).99 As mentioned in section 2.1.2 (see Scheme 17), aryl imines tend to react with 1,3-diaryl-2-azaallyl anions via a cycloaddition reaction manifold. The Kobayashi group, however, reported the nucleophilic addition of fluorenone-based 2azaallyl anions toward N-activated imines (Scheme 26).100 In their report, N-9-fluorenylidene aminoalkanes 87 were used as the precursors to semistabilized 2-azaallyl anions. Due to the aromatic stabilization present in the resulting fluorenyl anion, these relatively acidic reagents can be deprotonated with weak bases.42,48,101 In this case, only 5 mol % potassium tertbutoxide in combination with 18-crown-6 was required to effect the transformation. Diphenylphosphoryl (DPP) imines and tert-butylcarbamate (Boc)-protected imines both could be employed as electrophiles. The resulting vicinal diamines 88 and 89 were produced with very high diastereoselectivity favoring the syn isomer in decent yields. Some heterocycles such as furans (88d, 89b, 89f) and thiophenes (88c) were tolerated. Remarkably, aliphatic side chains on the 2-azaallyl anion nucleophile were accommodated (89c−89f), emphasizing the stabilizing impact of the fluorenyl group. Even N-9fluorenylidene aminomethane could be employed under slightly modified conditions (KO-t-Bu + 2,6-dimethylphenol, 89g). The imine electrophile could be derived from both aromatic and aliphatic aldehydes. Potentially competitive electrophilic functional groups such as esters (89e) were tolerated. Importantly, the protecting groups in the products 88 and 89 could be hydrolyzed readily to afford fully unprotected, pharmaceutically important vicinal diamines. Moreover, the authors demonstrated that if the cinchonine derivative 90 was used as a phase-transfer catalyst, the reaction could proceed in high yield with moderate diastereo- and enantioselectivities. In complementary studies, Kobayashi and co-workers demonstrated that the same products could be obtained by reacting N-9-fluorenyl imines with N-diphenylphosphinyl imines in the presence of KOCH2CF3 (Scheme 27).102 Moreover, the 2-azaallyl anion nucleophiles, obtained from either aldimine 1c or ketimine 2c, also could be alkylated by chalcone 91 or benzyl bromide. Interestingly, the regioselectivity of the alkylation event depended on the nature of the alkylating agent. Reaction with the activated imines or Michael acceptor 91 occurred at the less substituted carbon (α) of the semistabilized 2-azaallyl anion framework. Benzyl bromide, on the other hand, benzylated the more substituted carbon (α′) to afford benzaldimine 93. General strategies to control this site

of alkyl halides; the successful coupling with (bromomethyl)cyclopropane to afford 84g in high yield without any ringopening products strongly suggests against a radical mechanism for this particular transformation (see section 4). Kauffmann’s group reported a clever approach to enimines following a two-step procedure involving the alkylation of semistabilized 2-azaallyl anion 6b with phosphoryl chlorides 10403


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Scheme 26. Nucleophilic Addition into Activated Imines

Scheme 27. Alternative Alkylation Reactions

Scheme 28. Alkylation by Epoxide Electrophiles

selectivity, as well as compelling mechanistic explanations, remain elusive. In 2017, the Malcolmson group reported the addition of semistabilized 2-azaallyl anions to epoxides (Scheme 28).103 The 2-azaallyl anions generated by deprotonation of the corresponding benzophenone imines 94 with LiN(SiMe3)2 could react with epoxides to give 1,3-amino alcohols 95. This reaction displayed decent substrate scope and functional group tolerance. When trans-1,2-epoxides were employed, the alkylation reaction proceeded with good diastereoselectivity and high regioselectivity with respect to both reaction partners (95a−95h). Since many of these trans-1,2-epoxides are readily accessible in enantiomerically enriched form, this reaction presents a convenient way to prepare enantioenriched 1,3aminoalcohols. Indeed, these results represent one of the few examples of an inherently highly diastereoselective alkylation of 10404


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semistabilized 2-azaallyl anions in the absence of a chiral phase-transfer catalyst. cis-1,2-Epoxides could also be employed, but they proved to be much less reactive, requiring higher reaction temperatures and affording, in general, lower stereoselectivities (95i−95k). With the exception of 2phenyloxirane (95l), mono- and 2,2-disubstituted epoxides were attacked at the less substituted carbon with modest-togood diastereoselectivity (95m−95o). Similarly, Malcolmson and co-workers demonstrated that 2azaallyl anions also could react with N-tosyl aziridines to access various 1,3-diamine derivatives 97 in moderate-to-high diastereoselectivities (Scheme 29).104 Not surprisingly, both

Scheme 30. Carboxylation of Semistabilized 2-Azaallyl Anions

Scheme 29. Alkylation by N-Tosylaziridine Electrophiles

aldimines 96 with a combination of potassium tert-butoxide (1.2 equiv) and 18-crown-6 (1.2 equiv) under a relatively high pressure of CO2 (2.0 MPa) in THF at 25 °C. It is worth noting that the reverse reaction, decarboxylation of α-imino acids, is a powerful strategy for the generation of semistabilized 2-azaallyl anions, as will be discussed in more detail in section 2.2. Semistabilized 2-azaallyl anions can act as Michael donors with α,β-unsaturated carbonyls, as mentioned above (cf. Scheme 27). Toward this end, the Deng group published a series of reports demonstrating that these Michael additions involving semistabilized 2-azaallyl anions can be rendered highly diastereo- and enantioselective in the presence of chiral ammonium phase-transfer catalysts.105−108 In their studies, imines of 4-nitrobenzylamine (99) were used as precursors to the corresponding semistabilized 2-azaallyl anions (Scheme 31). The 4-nitrophenyl substituent lowered the pKa of benzylic C−H bond to an extent that it could be deprotonated with aqueous KOH in the presence of a chiral phase-transfer catalyst (e.g., 102a or 102b). By tuning the properties of the phase-transfer catalyst, in particular the R substituent on the quinuclidine nitrogen, alkylation of the 2-azaallyl anions generated under these conditions by various α,β-unsaturated carbonyl compounds (100) could occur with high enantioand diastereoselectivities.106,108 As summarized in Scheme 31, Deng and co-workers demonstrated that α,β-unsaturated aldehydes could be employed in this reaction, yielding various synthetically versatile γ-amino aldehydes 101. In most cases, only 0.2 mol % of phase-transfer catalyst 102a or 102b was required for efficient transformation. Depending on the substitution pattern of each reaction component, this method could furnish products with a benzylic stereocenter, vicinal tetrasubstituted and tertiary stereogenic centers, or even two nonadjacent stereocenters. Moreover, this transformation demonstrated broad functional group tolerance, with even primary alkyl bromides surviving the alkylation (101h and 101m). Similar to previous studies by Oshima and coworkers,97 the regioselectivities of these reactions are remarkable with essentially exclusive alkylation of the carbon in the 2-azaallyl anion framework furthest from the 4nitrophenyl group (C1 in Scheme 31). This outstanding regioselectivity is experienced even when C1 is disubstituted and, thus, sterically more congested. During the preparation of Michael adducts 101 the authors noted that addition of a cocatalyst 4-chloro-2,6-dimethylphenol was critical for minimizing the amount of side products arising from cyclization, presumably by accelerating the protonation step of the enolate

imine isomers 96 and 94 could be employed as precursors to the corresponding semistabilized 2-azaallyl anions. The enantiopurity of starting aziridines was transferred to the products with high fidelity. The aryl-substituted aziridine electrophilies were preferentially attacked at the benzylic position to afford vicinal stereocenters. Remarkably, this selectivity even extended to 2,2-disubstituted aziridines to furnish a protected 1,3-diamine with a quaternary carbon center (97l), albeit in moderate diastereoselectivity. When the aziridine electrophile is adorned with an ortho-substituted benzene ring, the resulting product (e.g., 97i) is obtained as a single diastereomer. As was introduced in section 2.1.2, the CO bond in carbon dioxide does not undergo cycloaddition with semistabilized 2-azaallyl anions. Instead, the nucleophilic 2-azaallyl anion adds into the π-bond to afford, after protic workup, the corresponding α-imino acid. 74 Zhang and co-workers employed this strategy to convert a collection of diphenylmethaneimines to the corresponding benzophenone imineprotected methyl α-arylglycinates 98 (Scheme 30).76 In this circumstance, the 2-azaallyl anions were generated from 10405


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Scheme 31. Enantioselective Alkylation by Enal Michael Acceptors with Chiral Phase-Transfer Catalysis

a

4-Chloro-2,6-dimethylphenol added as a cocatalyst.

intermediate.108 In addition to enals, Deng and co-workers demonstrated that the less electrophilic enones also could alkylate semistabilized 2-azaallyl anions derived from 4nitrobenzylimines (Scheme 32).107 A slight modification of the chiral phase-transfer catalyst (93c) was necessary, however, to achieve high selectivity profiles in this reaction. Moreover, the authors demonstrated that, by using the pseudoenantiomeric phase-transfer catalyst 105c, the enantiomeric products could be obtained in equally high selectivities. As with the enal electrophiles, the enones reacted at the C1 carbon of the 2azaallyl anion scaffold with good site selectivities. Deng’s group also achieved the asymmetric addition of semistabilized 2-azaallyl anions to α,β-unsaturated N-acyl pyrroles (Scheme 33).107 By using chiral ammonium salt 102d as the phase-transfer catalyst and mesitol as a cocatalyst, products bearing a tetrasubstituted tertiary carbon stereocenter (107a−107c) or a trisubstituted stereocenter (107d) could be accessed in high yields and enantiomeric purities. To prepare Michael adducts with vicinal stereocenters (107e−107h), a nitrile substituent on the pyrrole ring is needed, presumably to enhance the reactivity of the electrophile. Notably, the N-acyl pyrrole moiety could be hydrolyzed readily to afford the corresponding carboxylic acid derivatives. In this work, the authors grew a crystal of the cinchonine cation coordinated with p-nitrophenolate, and found from the X-ray structure that

the 4-nitrophenyl group closely packs with the anthracene groups of the cation, presumably via a π−π interaction. This result supports the notion that π−π interactions between the chiral phase-transfer catalyst and the 4-nitrophenyl group in the 2-azaallyl anion nucleophiles used in Deng’s studies are critical for controlling the site selectivities and enantioselectivities of the above reactions. Wang and co-workers reported the use of isatin-derived imines (108) as precursors to stabilized 2-azaallyl anions and achieved diastereo- and enantioselective allylation of these species (Scheme 34).109 In this circumstance, the active alkylating agent was generated in situ by SN2′ reaction between allyl carbonates 109 and the tertiary amine catalyst βisocupreidine. The resulting tert-butoxide generated from the initial reaction serves as the base to form the requisite 2azaallyl anion nucleophile (111), which then undergoes a second SN2′ reaction to both form the observed alkylated products 110 with high enantio- and diastereoselectivities and regenerate the chiral amine catalyst. Products with vicinal stereocenters were generated in high yields and selectivities. Following a similar mechanistic strategy, but using a chiral phosphine-based catalyst developed by their own group, Zhang and co-workers accomplished the asymmetric allylation of semistabilized 2-azaallyl anions with Morita−Baylis−Hillman carbonates (Scheme 35).110 Similar to Deng’s group, this 10406


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Scheme 32. Enantioselective Alkylation by Enone Michael Acceptors with Chiral Phase-Transfer Catalysis

Scheme 33. Enantioselective Alkylation by N-Acyl Pyrroles with Chiral Phase-Transfer Catalysis

transformation relied on trifluoromethylated imines derived from 4-nitrobenzylamine (99). The resulting chiral αtrifluoromethylated amine derivatives 113 were generally obtained in high yields and with remarkable enantioselectivities. By utilizing a slightly different chiral phosphine catalyst, Zhang’s group also was able to employ allenoates 114 to alkylate the same semistabilized 2-azaallyl anions, affording γ,δunsaturated amino acid derivatives 115 in high yields and enantioselectivities (Scheme 36).110 Importantly, the authors demonstrated that the ketimine precursor 99 could be generated in situ via imine condensation, and the threecomponent reaction proceeds just as efficiently and effectively. 2.1.4. Transition-Metal-Catalyzed Cross-Couplings. Transition-metal-catalyzed cross-coupling reactions have become indispensable tools in organic synthesis. This mode of transformation can activate electrophiles that are otherwise inert under traditional conditions. Appling transition metal catalysis to the functionalization of 2-azaallyl anions can further broaden the scope of accessible products. Building on earlier advances with stabilized 2-azaallyl anions,111−114 the Oshima group reported that pharmaceutically important diarylmethylamines could be accessed by the palladium-catalyzed crosscoupling reaction between N-benzylxanthones 116 and aryl bromides (Scheme 37).97,115 Presumably, N-benzylxanthones 116 underwent deprotonation by CsOH at 140 °C to give the corresponding semistabilized 2-azaallyl anions, which function as nucleophiles in the Pd-catalyzed cross-coupling reactions. PCy3 was found to be the optimal ligand in this reaction. The choice of base also was critical, as Cs2CO3, KOH, or t-BuOK all gave only trace amounts of products. In all cases, arylation

occurred exclusively at the less substituted carbon of the 2azaallyl anion framework. A shortcoming of this reaction, however, is that isomeric imine products 117′ were produced in many cases, which could be due to the high reaction temperatures required. Accordingly, the imine moieties in 117 and 117′ were reduced with NaBH3CN and the resulting amine was then liberated from the xanthine group by acidic hydrolysis to afford the corresponding hydrochloride salts (118). For certain substrates, this amine was treated with benzoyl chloride to afford the corresponding amide (119). The low yield for 119f could be a result of poorer deprotonation of the starting amine due to the electron-donating/pKa raising effects of the 4-methoxy substituent. The Walsh group has made substantial progress in the development of transition-metal-catalyzed functionalizations of semistabilized 2-azaallyl anions. Their initial foray into this field involved a significant improvement to Oshima’s Pdcatalyzed arylation tactic.116,117 A notable difference in these studies was the use of benzophenone imines 94 to afford the requisite semistabilized 2-azaallyl anions. Using a nanoscale high-throughput multivariable reaction screening protocol, Walsh and co-workers identified the ideal reaction conditions to achieve the desired Pd-catalyzed arylation of imines 94 with aryl bromides (Scheme 38). Specifically, deprotonation of ketimines 94 with 3 equiv of NaN(SiMe3)2 in the presence of 3 equiv of aryl bromide plus Pd(OAc)2 (2.5 mol %) and bisphosphine NiXANTPHOS (3.75 mol %) in CPME at room temperature proved to be the optimal reaction conditions. This 10407


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Scheme 34. Chiral Amine Catalyzed Asymmetric Alkylation with Allyl Carbonates

Scheme 35. Phosphine-Catalyzed Asymmetric Alkylation with Allyl Carbonates

Scheme 36. Phosphine-Catalyzed Asymmetric Alkylation with Allenoates

resulting arylation method displayed good scope with respect to both reaction partners. Moreover, the regioselectivity for the reaction was very high and only one imine isomer (111) was generated, representing a potential advantage of the benzophenone imine group over the corresponding xanthone imines. As shown in Scheme 39, slight alterations to the reaction conditions, such as the nature of the base, palladium source, and solvent, allowed for the Pd-catalyzed arylation to proceed in high yield with aryl chlorides, as well.118 Moreover, the authors demonstrated that both the ketimine 94 and the aldimine 96 2-azaallyl anion precursors could be employed and that imine formation and arylation could be telescoped into one reaction vessel. The Nolan group effected a similar transformation using a Ni-based catalyst with the Nheterocyclic carbene ligand IPr (Scheme 40).119 Importantly, the Ni-catalyzed arylation reaction using aryl chlorides also occurred at relatively low temperature. The Buchwald group accomplished a palladium-catalyzed, enantioselective arylation of semistabilized 2-azaallyl anions.120 In their studies, 2-azaallyl anions were produced by deprotonation of N-fluorenyl imines 121 with NaO-t-Bu in cyclohexane. In the presence of chiral monophosphine ligand L1 and [(η-C3H5)PdCl]2, a variety of aryl bromides or triflates could participate in this arylation reaction, furnishing, after reduction of the imine with NaBH4, various benzylic amines 122 in high yields and enantioselectivities (Scheme 41). Notably, aryl chlorides (122d) survive these conditions. Heteroaryl groups such as thiophenes (122g), indoles

(122i), and pyridines (122h) can be accommodated as well. However, ortho-substitution on the aryl bromide led to a dramatic drop in the enantioselectivity (122f). When the alkyl substituent on the 2-azaallyl anion becomes bulky, the arylation event at the more substituted position becomes 10408


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Scheme 37. Pd-Catalyzed Arylation of Xanthone Imine Derived 2-Azaallyl Anions

Scheme 39. Pd-Catalyzed Arylation of 2-Azaallyl Anions with Aryl Chlorides

Scheme 40. Ni-Catalyzed Arylation of 2-Azaallyl Anions with Aryl Chlorides

Scheme 38. Pd-Catalyzed Arylation of Benzophenone Imine Derived 2-Azaallyl Anions

authors determined that exquisite regiocontrol in the arylation event could be achieved with the appropriate choice of ligand and palladium source. When a combination of P-t-Bu3 and {Pd(2-methallyl)Cl}2 were employed as catalyst and KN(SiMe3)2 was used as base in toluene, arylation occurred almost exclusively at the Cα position to afford benzylic imines 125. Exposing the π-extended 2-azaallyl anion generated by deprotonation of 123 with NaN(SiMe 3 ) 2 to a Pd− NiXANTPHOS complex and the same aryl chloride, on the other hand, led to regioselective arylation at the Cγ position producing 2-azadienes 124. Out of the 24 ligands screened, the Cγ regioselectivity was unique to NiXANTPHOS. The authors proposed a model to explain this unique regioselectivity in which the sodium amide complex formed by deprotonation of NiXANTPHOS under the reaction conditions helps template the π-extended anion via cation−π interactions to guide the reaction site (Scheme 42, inset). Niu and co-workers employed the 2-azaallyl anions derived from N-fluorenyl imines 126 in an Ir-catalyzed asymmetric allylic substitution reactions (Scheme 43).101 Similar to

competitive. For example, benzylic amine 122j was produced in nearly a 1:1 mixture with the regioisomeric arylation product 122j′. Wang and co-workers have performed a theoretical study on this reaction, and concluded that the transmetalation step is the key step in determining the enantioand regioselectivities.121 Walsh’s group was able to develop distinct conditions for the regioselective arylation of π-extended azaallyl anionic systems.122 Deprotonation of the diphenylmethane enaldimines 123 results in the formation of a highly delocalized anion in which both the Cα and Cγ positions are potential sites for Pdcatalyzed arylation with aryl chlorides (Scheme 42). The 10409


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Scheme 41. Pd-Catalyzed Enantioselective Arylation of 2Azaallyl Anions

Scheme 42. Regiodivergent Pd-Catalyzed Arylation of Extend Azaallyl Anions

Buchwald’s contributions in this arena (see above), the authors chose N-fluorenyl imines as 2-azaallyl anion precursors because the fluorenyl C−H bond in 126 is fairly acidic and can be deprotonated with a mild base. The use of mild bases could be conducive to the control of enantioselectivity in this reaction due to the potential racemization of the products by stronger bases. Intriguingly, the reaction occurred via a sequence involving the initial highly stereoselective branched-selective allylation of the 2-azaallyl anions at the fluorenyl position, followed by a spontaneous 3,3-sigmatropic rearrangement to afford the homoallylic amine derivatives 127. The regioselectivity of the first C−C bond forming event was notable, presumably due to the inherently softer nature of the fluorenic position. This reaction demonstrated very broad substrate scope. The R1 substituent in the imine could be aryl, heteroaryl, alkenyl, or alkyl. Importantly, various heterocycles are tolerated, including thiazole, imidazole, pyridine, pyrazole, furan, pyrrole, and thiophene. The high tolerance of the R1 substituent could be a result of the reaction mechanism: because the initial bond-forming event occurs at the more substituted fluorenyl carbon of the 2-azaallyl anion, the reaction performance is not impacted dramatically by the nature of the R1 substituent located on the other carbon of the 2-azaallyl anion. This transformation offers a highly versatile

strategy for the preparation of enantioenriched linear 1,4disubstituted homoallylic amines. Recently, the Han group developed a cooperatively catalyzed asymmetric, branch-selective allylation of stabilized 2-azaallyl anions derived from α-imino esters 128 (Scheme 44).123 In this transformation, enantio- and diastereoselectivities are governed by a chiral ligand (L4) on the electrophilic Ir−allyl complex. Amino ester derivatives with two vicinal stereocenters (129) could be generated in good diastereo- and enantioselectivities. Attempts to extend this cooperative catalysis system to semistabilized 2-azaallyl anions, however, have not been forthcoming. Nevertheless, this example provides a good comparison between the different reactivities between stabilized and semistabilized 2-azaallyl anions in regard to Ircatalyzed allylation. Very recently, Malcolmson’s group developed an innovative copper-catalyzed alkylation of semistabilized 2-azaallyl anions with ketones (Scheme 45).99 A remarkable feature of this method is that it generates 2-azaallyl anions under virtually 10410


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Scheme 43. Iridium-Catalyzed Asymmetric Allylation of 2-Azaallyl Anions

neutral conditions. The requisite 2-azaallylcopper species 130 are generated via the enantioselective hydrocupration of 2azadienes 86 in the presence of a chiral bisphophine ligand PhBPE. Importantly, the R1 group in the 2-azaallyl anion precursors 86 are all alkyl groups and, thus, are not able to chelate to the copper and stabilize an N-metallo azomethine ylide intermediate (see section 5.2). The resulting 2azaallylcuprate is then trapped with a ketone electrophile and the requisite copper hydride catalyst is regenerated with the stoichiometric silane reductant. Reductive workup using NaBH4 finally yields α-amino tertiary alcohols 131 in an enantio- and diastereoselective fashion. Remarkably, the copper 2-azaallyl anion complexes 130 are not sufficiently basic to convert the ketone electrophiles into the corresponding enolates. A good diversity of (hetero)aromatic ketones could be used as the electrophiles; those with orthosubstitution generally afforded better diastereoselectivities (131c, 131k−131r). Surprisingly, even alkyl chlorides in the 2-azaallyl anion intermediate survived the reaction conditions; no competitive intramolecular cyclization of the 2-azaallylcuprate was observed in the formation of 131q. Finally, it is worth noting that some of the requisite 2-azadiene starting materials 86 were generated via a Horner−Wadsworth−Emmons modification of the 2-azaallyl anion olefination procedures introduced by Kauffmann and co-workers 40 years prior (see Scheme 25).83

More recently, Malcolmson’s group demonstrated that intermediate 130 could also be trapped by N-diphenylphosphinoyl imines to afford various anti-1,2-diamines 132 in excellent yields and stereoselectivities (Scheme 46).124 Remarkably high diastereo- and enantioselectivities were observed using imine electrophiles derived from both aldehydes (132a−132f) and ketones (132g−132o). As was observed with the carbonyl electrophiles, the functional group tolerance for the imine reagents was equally outstanding; primary alkyl chlorides (132n), boranes (132e), aryl bromides (132c), nitriles (132d), and esters (132o) all survived the transformation. It should be noted that the outstanding stereoselectivities observed by Malcolmson and co-workers for their reactions involving semistabilized 2-azaallyl copper complexes are consistently higher that those exhibited for various Pd-catalyzed transformations (see above and section 2.2.2). 2.2. Reactions of Semistabilized 2-Azaallyl Anions Generated via Decarboxylation

An alternative approach toward the generation of semistabilized 2-azaallyl anions involves the decarboxylation of appropriately substituted α-imino acids. An advantage of this strategy is that it avoids the necessity for strong bases as well as, in many cases, strictly anhydrous and/or anaerobic reaction conditions. While nature has long used this tactic, it has only 10411


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anions has been applied to organic synthesis. The following sections will review efforts over these past 15 years to mimic enzymatic transformations that involve the decarboxylative generation of 2-azaallyl anions (section 2.2.1) and to develop new C−C bond-forming transformations initiated by the decarboxylative generation of semistabilized 2-azaallyl anions, either with (section 2.2.2) or without (section 2.2.3) the addition of transition metal catalysts. 2.2.1. Dialkylglycine Decarboxylase Mimics. Understanding and mimicking the biosynthesis of enantiopure αamino acids has long attracted the interest of synthetic organic chemists.125 Many naturally abundant enantiopure α-amino acids (134) are generated by the transaminase family of enzymes which effect the enantioselective reductive amination of α-keto acids (133, Scheme 47). A critical cofactor in these enzymes is the amine source pyridoxamine monophosphate (PMP). Upon transamination, the PMP cofactor is converted to the corresponding aldehyde pyridoxal monophosphate (PLP), which must be transformed back to PMP with a sacrificial amino acid to establish catalytic turnover. In the enzymatic systems, regeneration of amine PMP from aldehyde PLP is facilitated by protonation of the pyridine nitrogen with a strategically placed acidic residue. The sacrificial amine source is typically a different α-amino acid than the product. For the dialkylglycine decarboxylase subfamily of transaminase enzymes, however, this role is played by an α,α-disubstituted amino acid (A), typically α-aminoisobutyric acid (Aib, R = Me in Scheme 47).126−128 In this situation, the sacrificial amino acid condenses with PLP to form the corresponding imine B and loss of CO2 affords an ephemeral 2-azaallyl anion intermediate C. Regioselective protonation of 2-azaallyl anion

Scheme 44. Iridium-Catalyzed Asymmetric Allylation of Stabilized 2-Azaallyl Anions

been within the past two decades that the decarboxylative generation and functionalization of semistabilized 2-azaallyl

Scheme 45. Asymmetric Reaction between 2-Azaallylcuprates and Ketones

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Scheme 46. Asymmetric Reaction between 2-Azaallylcuprates and Imines

at the time (TON up to 81 ± 19).129 Specifically, a pyridoximine catalyst adorned with a hydrophobic tail (135) was combined with pyruvic acid as substrate and 2-amino-2phenylpropionic acid (Pmg) as a sacrificial amine source in water buffered to pH 7.5 (Scheme 48). Additionally, a

Scheme 47. General Catalytic Cycle for PMP-Dependent Dialkylglycine Decarboxylase Enzymes

Scheme 48. Dialkylglycine Decarboxylase Mimetic System with Catalyst Turnover

polyethylenimine polymer in which 8.7% of the amines were alkylated with a C12 lauryl chain was added to the reaction mixture to provide a locally hydrophobic general acid−base catalytic system so as to increase the local concentration of the key hydrophobic reactants in the aqueous media. Under these reaction conditions, pyruvic acid was converted to racemic alanine with a turnover frequency (TOF) of 0.42 h−1. Further studies showed that higher turnover frequencies (up to 1.14 h−1) could be obtained by substituting the sacrificial amine source with other α-alkylphenylglycines and by quaternizing the pyridine nitrogen of catalyst 136 with methyl iodide.130 Breslow and co-workers emphasized in their reports that, while many different α-alkylphenylglycines were competent sacrificial amine sources, 2,2-diphenylglycine (Dϕg) was not

C in the active site of the enzyme forms imine D, hydrolysis of which results in regeneration of the essential PMP cofactor. Typically, most attempts to mimic the standard transaminase enzymatic cycle achieve little-to-no catalytic turnover due to the challenge of recapitulating the regeneration of PMP or PMP-like amines from the corresponding aldehydes using a sacrificial α-amino acid.125 In 2004, however, Breslow and coworkers revealed that employing a strategy similar to the dialkylglycine decarboxylases and using an α,α-disubstituted amino acid as the sacrificial amine source afforded the highest turnover numbers (TONs) observed for a transaminase mimic 10413


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suitable for their reaction system.126−129 Specifically, under their reaction conditions, the background reaction in which Dϕg reacted directly with pyruvic acid by tandem decarboxylative imine condensation/hydrolysis to form alanine and benzophenone was significantly faster than the process mediated by catalyst 135. Moreover, the benzophenone imine of 135, which formed via decarboxylative condensation between aldehyde 136 and Dϕg, did not hydrolyze under the reaction conditions, thus killing the catalytic cycle. These results would seem to indicate that Dϕg is not an appropriate sacrificial amine source for dialkylglycine decarboxylase mimics. Zhao and co-workers, however, emphatically showed this to not be the case in a series of reports in 2016.131−134 In screening a collection of different chiral pyridoximine analogues, the best results were observed using 5 mol % of the axially chiral catalyst 137 and 1 equiv of Dϕg in a mixed solvent system (1 equiv of AcOH in 8:2 MeOH−H2O).131,132 Under these conditions, a broad range of aliphatic α-ketoacids were transformed to the corresponding (S)-α-amino acids 134 in good yields and high enantiomeric ratios; representative examples are provided in Scheme 49. Masked aldehydes

keto acid substrate under their reaction conditions. Based on the high enantiomeric ratio (er) values observed, however, this rate is presumably significantly slower in comparison to both the regeneration of the chiral pyridoximine catalyst 137 and the reaction between the catalyst and α-keto acid substrate. The authors do note that the sacrificial amine source Dϕg is poorly soluble under the reaction conditions, which provides a significant rate advantage to the highly soluble catalyst 137 when competing for the substrate. Moreover, 1H NMR analysis of the reaction mixture strongly indicated that, after the initial transamination half-reaction, the resulting amino aldehyde preferentially formed a cyclic iminium species 138. Presumably, the cyclic iminium is substantially more electrophilic than the more abundant α-keto acid substrate, resulting in selective reactivity between Dϕg and 138 to afford, after tandem imine formation/decarboxylation/ketimine hydrolysis, regeneration of the chiral pyridoxamine catalyst 137. Something else which is currently not reported is whether 134, particularly the lessfavored (R) enantiomer, is configurationally stable in the presence of iminium 138. That is, the potential for iminium 138 to serve as a racemase mimic has not been investigated. Nevertheless, these impressive results represent the culmination of several decades of research by many different groups throughout the world to develop a truly catalytic small molecule system for asymmetric biomimetic transamination. It is worth noting that Yuan and Zhao very recently also employed a chiral pyridoxal-based catalyst to enable a highly stereoselective Mannich reaction involving a stabilized 2azaallyl anion intermediate.135 2.2.2. Transition-Metal-Catalyzed Decarboxylative Alkylations. In principle, the fundamental steps within the dialkylglycine decarboxylase catalytic cycle (imine formation, decarboxylative generation of a 2-azaallyl anion, and regioselective functionalization of that 2-azaallyl anion intermediate; see section 2.2.1) could be applied to a broad range of transformations beyond the synthesis of α-amino acids. Toward this end, Burger and Tunge were the first to apply this mechanistic strategy toward a C−C bond-forming process using palladium(0) catalysis.136 As part of a broad and prolific campaign to discover new nucleophilic coupling partners in transition-metal-catalyzed decarboxylative allylations (DcAs),137 Burger and Tunge treated a series of allyl αbenzophenone imino esters (139) with a palladium(0) catalyst to afford regioisomeric products 142 and 143, in which the ketimine 142 always predominated (Scheme 50, top). The regioselectivity and required reaction temperatures were both governed by the nature of the specific imino ester substrate (R1 in 139) and the presence of carbon substituents on the central carbon of the allyl ester (R2 in 139); in regard to the latter, the 2-methallyl esters (R2 = Me) afforded ketimines 142 exclusively. Additionally, the authors noted that, with aliphatic imino esters (R1 = alkyl or benzyl, R2 = H) at high temperatures (102−110 °C), the corresponding N-allylated aziridines 144 were typically the major products (up to >95% yield). Shortly after this initial report, Yeagley and Chruma introduced a complementary Pd-catalyzed DcA approach to homoallylic imines 142 starting from allyl 2,2-diphenylglycinate aryl imines 140 (Scheme 50, middle).138 Seven years later, Zhao and co-workers introduced an “intermolecular” variant starting from various allylacetate (shown), carbonate, or phosphonate pro-electrophiles and lithium 2,2-diphenylglycinate imines 141, the latter of which are relatively stable in protic solvents but decarboxylate in nonprotic coordinating

Scheme 49. Catalytic Asymmetric Biomimetic Transamination

(134a), silyl ethers (134b), primary alkyl halides (134d), and isolated π-bonds (134h) all survived the reaction conditions. Moreover, α-keto acids with preexisting stereogenic centers converted to the corresponding amino acids with outstanding diastereoselectivity in which the newly established nitrogenbearing stereogenic center preferentially adopted the (S) configuration (134i and 134j). In all of their reports,131−134 Zhao and co-workers neglected to report the rate of the background reaction in which Dϕg reacts directly with the α10414


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Scheme 50. Catalytic Asymmetric Biomimetic Transamination

Scheme 51. Asymmetric Pd-Catalyzed DcA of Allyl 2,2Diphenylglycinate Imines

reaction media such as THF or DMSO (Scheme 50, bottom).139 Under otherwise identical reaction conditions (R1, R2, Pd source, ligand, solvent, and temperature), all three approaches afford homoallylic imines 142 and 143 in similar isolated yields and regioisomeric ratios (rr’s, 142:143), strongly suggesting that they all proceed via identical reaction intermediates, namely semistabilized 2-azaallyl anion E and the electrophilic η3-π-allylPd(II) species F. A combination of computational and empirical studies, including crossover experiments, suggested that the turnover-limiting step for these transformations is the decarboxylation of a free carboxylate anion, separated from the corresponding cation by solvent.138,140 Moreover, the C−C bond-forming event appears to occur via an outer-sphere attack of the resultant 2azaallyl anion on the π-allylPd(II) electrophile. In 2014, Chruma and co-workers reported an enantioselective variant of their Pd-catalyzed DcA transformation using Zhang’s ferrocene-derived chiral bisphosphine ligand (S,S)-fbinaphane (Scheme 51).141 The observed enantiomeric ratios (er’s, (S)-142:(R)-142) for this asymmetric transformation demonstrated a positive linear Hammett correlation with respect to the electronic nature of the imine substituent (R in Scheme 51). That is, the highest initial er values were obtained for strongly electron-withdrawing aryl imines (the enantiopurity of many of the ketimine products could be enhanced by single recrystallization). Likewise, the resulting regioisomeric ratios (rr, 142:143) strictly followed a positive linear Hammett correlation with the imine substituent under both the racemic and asymmetric reaction conditions.138,140−142 Chruma and co-workers also determined that Zhao’s intermolecular approach139 could be rendered enantioselective using (S,S)-fbinaphane as a chiral ligand, albeit lower er values were obtained using allyl acetate as the pro-electrophile (Table 4, entries 1 and 2) and lower isolated yields resulted from the corresponding carbonate (entry 3). Moreover, strongly electron-withdrawing imine groups, e.g., 4-nitrobenzaldimine (entry 4), were not viable substrates since the corresponding lithium 2,2-diphenylglycinate imines 141 were not stable and underwent premature decarboxylative protonation. Both the er and rr values for the Pd-catalyzed DcA of allyl 2,2diphenylglycinate imines 140 are significantly influenced by solvent polarity, with highly polar DMSO affording the best results in both regards. This provides further support for the intermediacy of a solvent-separated semistabilized 2-azaallyl

a Initial er (and yield). bIsolated yield and er after single recrystallization from hexanes.

Table 4. Intermolecular Pd-Catalyzed Asymmetric DcA Involving 2-Azaallyl Anions

entry

R

X

solvent

yield (er)

1 2 3 4

H H H NO2

OAc OAc OCO2Me −

THF DMF DMF MeOH

>95% (48:52) >95% (74:26) 57% (85:15) 0%a

a

Parent lithium carboxylate salt (141) decarboxylated upon formation in MeOH.

anion in the reaction mechanism; conditions that better stabilize such an anionic intermediate and associated transition states, such as more polar reaction media, should increase the observed selectivity in the C−C bond-forming event. Additionally, manipulating the electronic and steric factors within the 2,2-diaryl-α-amino acid linchpin should also have a significant influence on the resultant regio- and enantiose10415


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counterparts. Nevertheless, this strategy of combining electronic and steric driving forces holds promise as a general solution to one of the most significant limitations to 2-azaallyl anions as imine umpolung reagents, namely, controlling the regioselectivity in the functionalization of the delocalized anion. The Pd-catalyzed decarboxylative formation of 2-azaallyl anions from allyl 2,2-diphenylglycinate imines proceeds selectively over other well-known Pd-catalyzed transformations. Accordingly, aryl halides are viable substrates (cf. 142d, Scheme 51), allowing for tandem Pd-catalyzed bond-forming reactions initiated by the decarboxylative formation of 2azaallyl anions and π-allylPd(II) electrophiles. Toward this end, Chruma and co-workers reported the successful two-step/ one-pot Pd-catalyzed tandem DcA-microwave-assisted Heck cyclization of o-halo(hetero)aryl imines 151 (Scheme 52).143

lectivities. As mentioned above, Yorimitsu and Oshima investigated the role of steric and electronic factors governing the regioselectivity for the alkylation (see section 2.1.3, Scheme 24) and transition-metal-catalyzed arylation (see section 2.1.4, Scheme 37) of semistabilized 2-azaallyl anions generated via deprotonation.97,115 Similarly, the addition of electrondonating substituents on the 2,2-diarylglycine linchpins for the Pd-catalyzed DcA process should favor allylation of the less substituted carbon in the 2-azaallyl anion intermediate due to increased electron density at this position. Moreover, increasing steric influences in the diarylglycine linchpin should further favor allylation of the less substituted position of the 2azaallyl anion framework. Very recently, Chruma and coworkers provided strong support for these suppositions by comparing the resultant rr values for the Pd-catalyzed DcA of three different allyl 2,2-diarylglycinate arylimino esters.142 As shown in Table 5, switching the 2,2-diaryl-α-amino acid

Scheme 52. Tandem DcA Heck Cyclization of Imino Esters 151

Table 5. Steric and Electronic Effects on Regio- and Enantioselectivities

entry

Ara

R

yield (rr)b

erc

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Ph PMP OMP Ph PMP OMP Ph PMP OMP Ph PMP OMP Ph PMP OMP

CN (a)

91% (>20:1) 96% (>20:1) >98% (>20:1) 96% (6.1:1) 84% (10.1:1) 89% (>20:1) 97% (5.5:1) 79% (6.3:1) >98% (>20:1) 80% (3.1:1) 80% (5.7:1) 88% (>20:1) 52% (2.2:1) 74% (4.1:1) 93% (>20:1)

93.5:6.5 90.6:9.4 89.1:10.9 86.2:13.8 n.d. 83.2:17.1 86.9:13.1 n.d. 77.5:22.5 89.5:10.5 n.d. 80.9:19.1 82.7:17.3 n.d. 87.6:12.4

H (e)

F (i)

Me (f)

MeO (j)

a

Ag2SO4 omitted. bThe initial DcA reaction was run for 15 min (1.5 equiv of Ag2SO4).

a PMP = 4-MeOC6H4; OMP = 2-MeOC6H4. bReaction conditions: Pd(dba)2 (10 mol %), dppf (10 mol %), MeCN, 25 °C. cReaction conditions: Pd2(dba)3 (2.5 mol %), (S,S)-f-binaphane (5 mol %), DMSO, 25 °C.

In most cases, stoichiometric amounts of Ag2SO4 had to be added to the reaction mixture to minimize migration of the double bond into the newly formed five-membered ring during the Heck cyclization. In their preliminary report on the Pd-catalyzed DcA of allyl 2,2-diphenylglycinate imines,138 Yeagley and Chruma revealed that the semistabilized 2-azaallyl anion intermediate could be intercepted by electrophilic aldehydes prior to allylation by the π-allylPd(II) electrophile. For example, exposure of benzaldimine 140e (R = Ph, Scheme 53) and 4-cyanobenzaldehyde in MeCN to 10 mol % Pd(dba)2 at ambient temperature resulted in the formation of the allyl ether 156 as an inseparable mixture of diastereomers in 53% combined yield. Two years later, the same authors noted that arylidene and alkylidene malononitriles, as well as similar Michael acceptors derived from Meldrum’s acid, were also effective electrophiles for such an interceptive decarboxylative allylation (IDcA) protocol (Scheme 53).144 The IDcA products obtained using the malononitrile-based electrophiles (154) were consistently

linchpin from 2,2-diphenylglycine (140) to 2,2-di(4methoxyphenyl)glycine (145) resulted in a consistent improvement in rr values (compare entries 1, 4, 7, 10, and 13 with entries 2, 5, 8, 9, 11, and 14, respectively). Introducing an additional steric influence by shifting the electron-donating methoxy groups to the ortho-positions of the 2,2-diarylglycinate framework (146) completely solved the regioselectivity issue, resulting in exclusive formation of the homoallylic ketimines 149 without any evidence of the aldimine regioisomers 150 (entries 3, 6, 9, 12, and 15). In most cases, however, the use of 2,2-di(2-methoxyphenyl)glycine as an amino acid linchpin for the asymmetric Pd-catalyzed DcA transformation resulted in decreases in the observed enantioselectivities in comparison to the 2,2-diphenylglycinate 10416


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Somewhat surprisingly, the IDcA transformation could be performed in the presence of water without negative impact on the isolated yield (157b), indicating that the interception of the 2-azaallyl anion intermediate by the electrophilic olefins is significantly faster than proton transfer. As with the parent DcA transformation, the Pd-catalyzed IDcA reaction could be relayed into a microwave-assisted Heck cyclization to generate three new C−C bonds and two new stereogenic centers in a single reaction vessel starting from achiral starting materials (Scheme 54).

Scheme 53. Pd-Catalyzed Interceptive DcA Reactions Involving 2-Azaallyl Anions

Scheme 54. Tandem IDcA Heck Cyclization

In addition to allyl 2,2-diphenylglycinate imines, the corresponding benzyl esters are also potential substrates for the Pd-catalyzed decarboxylative generation and alkylation of 2-azallyl anions. Specifically, Fields and Chruma demonstrated that benzylic esters 160 can undergo a microwave-assisted Pdcatalyzed decarboxylative benzylation (DcB) reaction to afford the corresponding 1,2-diaryl-1-iminoethanes 161 in moderateto-good yields (Scheme 55).145 The optimal ligand for this transformation proved to be rac-BINAP; the relatively high reaction temperatures, however, negated the possibility of an asymmetric variant using a single enantiomer of this axially Scheme 55. Pd-Catalyzed Decarboxylative Formation and Benzylation of 2-Azaallyl Anions

a

Reaction conditions: 10 mol % Pd(dba)2, 10 mol % dppf, MeCN, room temperature (rt). bReaction conditions: 10 mol % Pd(PPh3)4, MeCN, 20 °C. cReaction conditions: 10 mol % Pd(PPh3)4, 10 mol % (−)-O-9-allyl-N-(9-anthracenylmethanyl)cinchonidium bromide, PhCH3:H2O, 20 °C. dThe syn diastereomer decomposed on silica gel; the anti diastereomer was recovered exclusively at indicated yield.

obtained as a nearly 1:1 mixture of diastereomers, even in the presence of chiral ammonium salts (157b). The products obtained using the Meldrum’s acid derived electrophilies 155, on the other hand, tended to show preferential formation (diastereomeric ratio (dr) up to 4:1) of the anti diastereomers. Moreover, the corresponding syn-diastereomers of the Meldrum’s acid derived products frequently and selectively decomposed upon purification of the diastereomeric mixture through silica gel, resulting in the exclusive isolation of the anti diastereomers in several cases (158a and 158b, Scheme 52). 10417


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greatly accelerated product formation. Under these reaction conditions, a range of 1,2-diarylethanol imines could be obtained as a mixture of diastereomers (167−169) in modestto-good yields (Scheme 57).147 Careful monitoring of the

chiral biaryl ligand. Unlike the related DcA transformation, significant amounts of the benzylic imines resulting from protonation of the 2-azaallyl anion were formed as side products during the DcB process; the proton source, however, has yet to be determined. Currently, the transition-metal-mediated decarboxylative generation and functionalization of semistabilized 2-azaallyl anions is limited to Pd(0)-based catalysts. As summarized in section 2.1.4, semistabilized 2-azaallyl anions generated by deprotonation of the conjugate acid are viable nucleophilic components for C−C bond-forming reactions mediated by iridium- and nickel-based catalytic systems. Accordingly, these other transition metals hold potential to catalyze similar reactions involving the decarboxylative generation and alkylation of 2-azaallyl anions. That being said, there are very few reports of Ni(0)-catalyzed DcA reactions involving any anionic electrophiles, let alone 2-azaallyl anion intermediates.146 2.2.3. Direct Decarboxylative Couplings. Even though there are several examples of the Pd-mediated decarboxylative generation of semistabilized 2-azaallyl anions (see section 2.2.2), the transition metal catalyst is not required for the decarboxylation of N-imino-2,2-diphenylglycines. The only requirement for the decarboxylative formation of semistabilized 2-azaallyl anions appears to be the ability to form the free carboxylate salt. For example, combining the tetrabutylammonium salt of 2,2-diphenylglycine (TBA·Dϕg) with aromatic aldehyde 162 in toluene at room temperature resulted in the rapid formation (5−50 min) of a complex mixture of 1,2-diaryl-2-iminoethanol derivatives (165 and 166, Scheme 56).147 Presumably, decarboxylation of the imine 163,

Scheme 57. Lewis Acid Catalyzed Decarboxylative Erlenmeyer Coupling

reaction conditions revealed that, at the beginning of the reaction, the anti-diastereomer 167 is formed preferentially. As the reaction progresses, however, the syn-oxazolidine product 169 predominates. Control studies indicated that, under the reaction conditions in which both a Brønsted basic 2-azaallyl anion and a transition-metal-centered Lewis acid are present, the C−C bond-forming event is reversible, resulting in a shift from the kinetically favored anti-diastereomer 167 to the thermodynamically preferred syn-diastereomer 168/169. Accordingly, 2-aryl-2-iminoethanols could also be considered potential precursors to semistabilized 2-azaallyl anions via a retro-Erlenmeyer reaction; this proposition has yet to be further explored experimentally. As mentioned in section 2.2.2, Zhao and co-workers introduced lithium 2,2-diphenylglycinate imines (141) in 2014 as isolable 2-azaallyl anion precursors. As long as the imine substituent (R1) is not too electron-withdrawing, these carboxylate salts are stable in protic media, such as MeOH.139 Prior to Zhao’s reports, Carreira’s group noted that the potassium and cobalt complexes of 3,5-di(tert-butyl)salicylaldimine 171 were also stable in alcohol solvents (Scheme 58, inset); moreover, the cobalt complex (171-Co) is an effective catalyst for the hydrohydrazination and hydroazidation of olefins.148,149 Dissolution of Zhao’s lithium carboxylate salts 141 in nonprotic solvents such as THF, toluene, CH 2 Cl2 , or DMSO, however, results in the decarboxylative formation of the corresponding semistabilized 2-azaallyl anions, presumably after formation of a solventseparated ion pair. This nucleophilic 2-azaallyl anion is now free to react with electrophilic species in the reaction milieu. For example, Zhao’s group first noted that the semistabilized 2azaallyl anions could be intercepted by N-tosyl aryl imines

Scheme 56. Decarboxylative Coupling of TBA·Dϕg with Aldehyde 162

formed by condensation between the amino acid and aldehyde substrates, affords a 2-azaallyl anion intermediate (164) which can attack another equivalent of aldehyde 162. Intramolecular transfer of the acetate group from the phenolic position to the alkoxide oxygen and protonation of the resulting phenoxide upon workup would result in the observed products. This decarboxylative variant of the transformation originally described by Erlenmeyer nearly 120 years prior (see section 1, Scheme 1)1 could be expanded to a series of aromatic aldehydes by changing the solvent to CH2Cl2 and adding molecular sieves to the reaction mixture. Moreover, the addition of a Lewis acid catalyst to the reaction mixture 10418


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Scheme 58. Decarboxylative Coupling of Lithium Salts 141 and N-Tosyl Aryl Iminesa

Scheme 59. Attempted Mannich Addition Reactions with Chiral Sulfinyl Imine 172

a The dr is the ratio of syn:anti 170. bEt3N (20 mol %) added instead of 3-nitrobenzoic acid.

(dr 99:1) in 74% isolated yield (Scheme 59C). This high diastereoselectivity and good yield proved consistent throughout a collection of lithium 2,2-diphenylglycinate aryl imines 141 (representative examples provided in Scheme 60).

(Scheme 58).150 The resulting diamine derivatives 170 are formed as a mixture of diastereomers always favoring the syn isomer. The addition of an organic acid (preferentially, 3nitrobenzoic acid) resulted in improved syn-selectivity, whereas the amine base Et3N slightly reduced the preference for the syn isomer. It should be noted that, in contrast to Kobayashi’s related studies for the production of vicinal diamines under deprotonative conditions (section 2.1.3, Scheme 26),100 Zhao and co-workers only focused on the easier to characterize symmetrical products 170 in which both of the aromatic substituents were identical; nonsymmetrical products should be feasible from a mechanistic perspective, however. The specific role of the acid additive is still not clear, especially given that products arising from protonation of the semistabilized 2-azaallyl anion intermediate were not observed under the reaction conditions. When Zhao and co-workers attempted this transformation in MeOH, no product was observed, suggesting that the decarboxylative formation of the 2-azaallyl anion is a seminal step. Han and Soloshonok, however, provided key evidence indicating that decarboxylation may occur concomitantly with, or even after, C−C bond formation in an asymmetric variant of Zhao’s decarboxylative Mannich addition reaction.151 As shown in Scheme 59A, treatment of 1,1,3-triphenyl-2-azaallyl anion (6c), initially formed by deprotonation of the corresponding imine 1a with potassium tert-butoxide in THF, with chiral sulfinyl imine 172 only resulted in the formation of a complex mixture of decomposition products. Premixing benzophenone imine 2a and 172 in THF at −78 °C, followed by addition of n-BuLi as base, on the other hand, led to the formation of diastereomeric vicinal diamine derivatives 173a and 174a in a 63:37 ratio, respectively, and in 32% combined yield (Scheme 59B). Combining the chiral electrophilic imine 172 with Zhao’s lithium carboxylate 141a (R = Ph) in THF with 20 mol % 3nitrobenzoic acid, however, afforded 173a almost exclusively

Scheme 60. Decarboxylative Coupling of Lithium Salts 141 and Chiral Sulfinyl Imine 172

Substitution with alkyl groups, halogens, or methoxy groups at either the ortho (173b and 173c), meta (173d), or para (173e) positions of the aryl imines were all tolerated. Moreover, the cinnamaldimine substrate, which could form a π-extended azaallyl anion system, exclusively formed the αstyrenyl regioisomer 173f. The authors suggested that the requisite decarboxylation could happen concomitantly, or even after, the highly diastereoselective C−C bond formation via the 10419


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(175c), electron-donating groups (175d, 175g), trifluoromethyl groups (175h), heterocycles (175e), and polyaromatic systems (175i). Finally, Zhao and co-workers performed an interesting competition experiment between dialdehyde 176 and Dϕg (Scheme 62).153 In this situation, the amine can condense with

proton-templated transition state G (Scheme 60, inset). Nevertheless, the specific reaction mechanisms for this and related decarboxylative coupling reactions are still under intense scrutiny. In addition to imine-based electrophiles, Zhao and coworkers also demonstrated that the semistabilized 2-azaallyl anions generated by decarboxylation of lithium 2,2-diphenylglycinate imines 141 can also be alkylated with Michael acceptors. For example, when 2-azaallyl anion precursors 141 were treated with O-Boc-protected Morita−Baylis−Hillman adducts 174 and 20 mol % 1,4-diazabicyclo[2.2.2]octane (DABCO) in THF, the resulting α-methylidene-γ-amino acid esters 175 were obtained in excellent yields and good diastereoselectivities favoring the isomer indicated in Scheme 61.152 Presumably, the α,β-unsaturated esters 174 are not

Scheme 62. Intramolecular Alkylation of Extended 2Azaallyl Anions

Scheme 61. Intermolecular Alkylation of 2-Azaallyl Anions with Michael Acceptors

either the benzaldehyde carbonyl or the cinnamaldehyde carbonyl group. Depending on which aldehyde first reacts with Dϕg, after decarboxylation, either a standard semistabilized 2azaallyl anion (I) or a π-extended 2-azaallyl anion (J) will form. When dialdehyde 176 and Dϕg were combined in a 9:1 mixture of THF−H2O, the tricyclic alcohol 177, resulting from intramolecular cyclization of intermediate J, was the only observed product (80% yield). Addition of 20 mol % sodium carbonate reduced the reaction time from 36 to 12 h without impacting the outstanding yield (84%) or the diastereoselectivity that favored the trans adduct exclusively. The authors suggested that the greater steric accessibility of the enal functionality accounts for the remarkable chemoselectivity. The transition-metal-free reaction conditions were applicable to a broad collection of biaryl substrates bearing the critical 2aldehyde-2′-enal dyad, but the diaryl ether 178 (Scheme 62, inset) only afforded a complex mixture of unidentified products. Compared to the decarboxylative generation of azomethine ylides (see section 5.1), the formation and functionalization of semistabilized 2-azaallyl anions via a tandem imine condensation−decarboxylation reaction manifold is relatively unexplored. Nevertheless, as was shown in this section and section 2.2.2, this mechanistic strategy can be a relatively mild and powerful tactic to both introduce amine functionality into a molecular framework and forge new C−C bonds in either an inter- or intramolecular fashion. The amino acid Dϕg and its various salts and esters are particularly attractive precursors to 2-azaallyl anion imine umpolungs as the resulting amine products are protected with the uniquely useful benzophenone imine functionality.154,155 Future advances in this arena could come from both expanding the scope of intercepting electrophiles and identifying appropriate conditions to achieve the critical C−C bond-forming events with high levels of enantioselectivity. There are relatively few direct comparisons between the deprotonative (section 2.1) and decarboxylative (section 2.2)

sufficiently electrophilic to directly alkylate the semistabilized 2-azaallyl anions E, generated by decarboxylation of imines 141. The tertiary amine catalyst, on the other hand, can perform an SN2′ reaction with allyl carbonates 174 to form a more reactive electrophilic species H to intercept the 2-azaallyl anion. The resulting SN2′ reaction between intermediates E and H regenerates the amine catalyst and affords the observed products; representative examples are provided in Scheme 61. The reaction tolerated ortho-substitution on both the 2-azaallyl anion (175f) and electrophilic intermediates (175b). Moreover, the reaction was amenable to the presence of halogens 10420


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in the presence of PPh3. Unfortunately, substitution on the tinbearing carbon was not tolerated by this method due to the instability of the corresponding azides. 2.3.1. General Reactivity: Cycloadditions. The nonstabilized 2-azaallyl anions generated via Li−Sn exchange of imines 170 underwent smooth and extremely fast cycloaddition with relatively activated alkenes (Scheme 65).17 By

generation of semistabilized 2-azaallyl anions. The lack of exogenous base in the Pd-catalyzed DcA reactions discussed in section 2.2.2 obviates the formation of over-allylated side products observed following deprotonative procedures (Scheme 24A).97 While this represents a distinct advantage for decarboxylative generation of semistabilized 2-azaallyl anions versus basic deprotonation, it should be noted that the regioselectivity for the key C−C bond-forming event does not appear to be influenced by the means of generating the delocalized anionic nucleophile. The mechanistic studies performed by Han and Soloshonok for the decarboxylative formation of vicinal diamines (section 2.2.3, Schemes 59 and 60) also represent a situation in which decarboxylative generation of 2-azaallyl anions is superior to deprotonation.151 On the other hand, there are more examples of highly stereoselective transformations involving the deprotonative generation of semistabilized 2-azaallyl anions versus the decarboxylative protocol, particularly in the presence of a chiral phase-transfer catalyst. As will be discussed in section 4, reversible deprotonative generation of semistabilized 2-azaallyl anions with silylazide bases can result in the formation of radical species, presumably by electron transfer between the anion and its conjugate acid. To date, there is no evidence that decarboxylative generation of semistabilized 2-azaallyl anions provides similar access to radical intermediates, but further directed experimentation is required before any conclusions can be made in this regard.

Scheme 65. [3 + 2] Cycloaddition with Conjugated Alkenes

2.3. Reactions of Nonstabilized 2-Azaallyl Anions Generated via Lithium−Tin Exchange

The facile lithium−tin exchange process is a widely adopted strategy to generate carbanions in organic synthesis.156 For over a decade, Pearson’s group applied this tactic toward the generation of nonstabilized 2-azaallyllithiums (180) and systematically investigated the reactivities of these species (Scheme 63). Although the reactivities of 2-azaallyl anions Scheme 63. Generation of Nonstabilized 2-Azaallyl Anions by Lithium−Tin Exchange

using either isomer of stilbene, the authors determined that the cycloaddition reaction was stereospecific with respect to the alkene geometry. The authors also demonstrated the feasibility of intramolecular cycloadditions of 2-azaallyl anions generated by Li−Sn exchange in the production of bicyclic azacycle 184d in high yield and diastereoselectivity. Two regioisomers, 184e and 184e′, were obtained from cycloaddition reactions between 2-azaallyllithiums and styrene. The reaction between trans-stilbene with n-propyl or cyclpropyl-substituted 2-azaallyl anions gave two different stereoisomers (184f/184f′ and 184g/184g′, respectively), suggesting the existence of two different isomers of starting 2-azaallyl anions. Three different isomers (184h−184h″) were obtained when tert-butyl substituted 2-azaallyl anion was used. In this case, the more sterically crowded isomer was formed in a significant amount, indicating the potential for a stepwise mechanism. The reaction could be quenched with either water or methyl iodide to afford pyrrolidine (184) or N-methylpyrrolidine (185) products, respectively. 1,1-Disubstituted 2-azaallyl anions also could participate in the cycloaddition reactions, as evidenced by the production of 184i and 185a. In addition to alkenes, internal alkynes are suitable substrates as well

generated by Li−Sn exchange may not be fundamentally different from those generated by direct deprotonation, the former strategy does allow for access to functionalized 2azaallyl anions that would be difficult to obtain via the latter method. Key to the success of this process was the development of robust methods to prepare the stannyl imine precursors (179). Toward this end, Pearson and co-workers capitalized on a Staudinger-type aza-Wittig reaction to access stannyl imines 179 (Scheme 64).8 Treating the known iodomethyl trialkyl stannanes 181 with NaN3 delivered the required azidomethyl trialkyl stannanes 182, which were available for reductive condensation with ketones or aldehydes Scheme 64. Synthesis of Trialkylstannyl Imines by AzaWittig Reaction

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(185b and 185j). Finally, conjugated enynes underwent cycloaddition with nonstabilized 2-azaallyl anions with their alkene groups exclusively (185c), similar to previous reports involving semistabilized 2-azaallyl anions.51 Unactivated alkenes are not reactive enough to engage these 2-azaallyl anions. The authors noted several different side reactions for the nonstabilized 2-azaallyl anions, including a dimerization pathway (Scheme 66A), the nucleophilic addition of Scheme 66. Observed Side Reaction in [3 + 2] Cycloadditions with 2-Azaallyl Anions Generated by Li−Sn Exchange

Figure 4. Cycloaddition adducts from heteroatom-substituted alkenes.

Scheme 67. 1,3-Dialkyl-2-azaallyl Anions alkyllithiums into the imine precursor with the expulsion of a trialkylstannyl anion (Scheme 66B), and the self-dimerization to give piperazines 189 (Scheme 66C). Apparently, for a productive transformation to occur, the choice of anionophile must enable cycloaddition at a rate that is faster than these decomposition pathways. It should be noted that the observed nucleophilic addition side reactions (Scheme 66B) were later exploited by Pearson’s group to afford a 2-azaallyl dication surrogate (see section 3, Scheme 81). Even though unactivated alkenes were not suitable substrates for cycloadditions with nonstabilized 2-azaallyl anions, Pearson’s group demonstrated that hetereoatom substituted alkenes, such as vinyl sulfides (190, 192), vinyl selenides (191), and vinylsilanes (193, 194) are potent anionophiles in this reaction; representative products are summarized in Figure 4.17 The regio- and stereoselectivities of these reactions are moderate in most cases. However, the heteroatoms inherited in the products serve as versatile handles for further derivatization reactions. Moreover, the sulfide groups, as in cycloadducts 190 and 192, could be removed reductively with Raney nickel to afford, after the two steps, a formal cycloaddition with an unactived alkene. Whereas the azide approach did not allow for the generation of α-alkyl-α-stannyl imines, an alternative phthalimide nucleophile approach afforded, after hydrazinolysis of the phthalimide group, (1-aminoalkyl)stannanes 195.18 Condensation of these amines with carbonyls proferred access to the corresponding imines 196 (Scheme 67). Cycloaddition between the more substituted nonstabilized 2-azaallyl anions generated via Li−Sn exchange of imines 196 and activated alkenes gave the anticipated pyrrolidines 197, albeit with lower diastereoselectivities versus previous studies. Importantly, the substituents at the C-2 and C-5 positions in the pyrrolidine products are always cis to each other, consistent with a reaction occurring via the less sterically congested W-shaped 2-azaallyl

anions. The formation of 197g and 197g′ from cis-stilbene is significant, as it suggests a stepwise cycloaddition mechanism is operating for the cycloaddition event. Using appropriate resinlinked aldehyde precursors, Pearson and Clark adapted this imine condensation/Li−Sn exchange/cycloaddition process to the solid phase, allowing for the rapid production of various polysubstituted pyrrolidines.23 A tandem cycloaddition/intramolecular N-alkylation sequence for o-halo-stannyl imines 198 was also realized, allowing for the effective preparation of substituted indolizidines 201 (Scheme 68).22 Treating stannyl imine 198 with nBuLi resulted in the formation of the corresponding non10422


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alkylated intramolecularly to give the indolizidines 201a and 201b, respectively, in moderate yields. It is worth noting the Li−Sn exchange between 198 and the alkyllithium base appears to be faster than either elimination or substitution of the chlorine substituent. In the same report, the authors noted that heating stannyl imine or the related silyl imine 202 effected the intramolecular N-alkylation and demetalation to give corresponding N-alkyl azomethine ylides 203 which could engage various types of dipolarophiles to give indolizidine skeletons as well (see section 5.1). Under these thermal conditions, the Li−M exchange using alkyllithiums was not required. It would be interesting to compare the selectivity profiles for the reactions involving anion 199 versus those proceeding via azomethine ylide 203; no direct comparisons can be made readily based on the reported data. The generation of heteroatom-substituted 2-azaallyl anions 205 via Li−Sn exchange of the corresponding stannylated species 204 also proved to be viable. Cycloaddition between these heteroatom-substituted 2-azaallyl anions and appropriate alkenes afforded the expected amide anion intermediate 206, from which can be expelled the heteroatom substitutent to finally produce 1-pyrrolines 207 (Table 6).25 Various alkenes, including α-methylstyrene, vinylsilanes, and stilbenes could be

Scheme 68. Tandem Intermolecular Cycloaddition/ Intramolecular Alkylation To Prepare the Indolizine Core

stabilized 2-azaallyl anion 199, which underwent cycloaddition with vinyl sulfide or trans-stilbene to give the corresponding pyrrolidines. The resulting amide anions 191 were then

Table 6. Cycloaddition of Heteroatom-Substituted 2-Azaallyl Anions

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used in this cycloaddition, furnishing polysubstituted 1pyrrolines in good yields. The reaction of 204e with transstilbene and cis-stilbene also gave significant amounts of oxygenated products as byproducts, which presumably arose from oxidation of initial products by oxygen via their enamine tautomers. If the 2-azaallyl anions contain alkyl substituents on both carbons, as in the cases of 204e−204h, their cycloaddition with either vinylsilanes or α-methylstyrene proceeded with high diastereoselectivities. To rationalize this stereochemical outcome, the authors assumed that the 2-azaallyl anions 205 adopted an (E,E)-conformation for steric reasons. With this assumption, they further proposed that the transition structure K′ is energetically more favorable than K due to the steric repulsion between the silyl group and the R group in the latter (Figure 5). For the reaction with α-methylstyrene, they

Table 7. Heteroatom-Substituted Cyclic 2-Azaallyl Anions

Figure 5. Explanation of observed diastereoselectivity.

proposed that structure L is preferred because the phenyl group could adopt a planar conformation to minimize steric repulsion with the R group and potentially stabilize the anionic character by secondary orbital overlap (or by lithium cation−π interaction). The regioselectivities of these reactions were rationalized with the aid of semiempirical calculation of the highest occupied and lowest unoccupied molecular orbitals (HOMO and LUMO) of anions and alkenes. The phenyl or silyl substituents were placed in the 4-position of the pyrroline products to enhance the overlap of the termini with higher coefficients. The regioselectivities could be reinforced for steric reasons. In the transition structures shown in Figure 5, the clash between the more substituted termini of both reactants is avoided. While the structures of most products are consistent with the above prediction, those major regioisomers resulting from the cycloaddition between α-methylstyrene and the 2azaallyl anions derived from 204a and 204d are anomalous. To reconcile this discrepancy, the authors suggested a stepwise mechanism for these two entries. In a stepwise mechanism, the least hindered end of the 2-azaallyl anions attacks the β-carbon of α-methylstyrene initially, followed by ring closure to preferentially give the observed regioisomers. Such a stepwise mechanism may indeed become competitive in these entries, because the 2-azaallyl anions involved in these cases are electronically and sterically distinct from the other nonstabilized 2-azaallyl anions, and α-methylstyrene is more electrophilic than vinylsilanes. In addition to the acyclic starting materials described above, Pearson and Stevens also generated the cyclic imidates 208a and 208b and found these species, after Li−Sn exchange, undergo facile cycloaddition with activated alkenes to furnish the bridged azabicyclic compounds 209 and 210, respectively (Table 7).25 Interestingly, the vinyl sulfide and vinyl selenide

anionophiles, which could not be used in the reaction with acyclic hetereoatom substituted 2-azaallyl anions, had no problems in these transformations. Interestingly, when the Obenzylimidate 208c was subjected to n-BuLi in the presence of 1,2-di(trimethylsilyl)acetylene, the expected cycloaddition reaction did not occur. Instead, the 2-azaallyl anion intermediate underwent an anionic [4,5]-sigmatropic rearrangement to afford, after deprotonation with a second equivalent of n-BuLi benzylic anion 211 which was silylated by the alkyne reagent, lactam 212 (Scheme 69). The successful cycloadditions with heteroatom-substituted 2-azaallyl anions opened up the possibility for stereoinduction by traceless chiral auxiliaries.27 For example, the prolinederived amide (S)-213 could be transformed into the stannylated amidine (S)-204i in two steps (Scheme 70). Treating this amidine with n-BuLi in the presence of αScheme 69. Unexpected Anionic [4,5]-Sigmatropic Rearrangement

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bicyclic imines 216 and 216′ as a 1:1 mixture. Reaction of the same anion with 2,3-dimethyl-1,3-butadiene afforded cycloadduct 217 as a single diastereomer. The use of cycloheptadiene did not give appreciable amounts of products. The authors propose that this is because cycloheptadiene has a decreased degree of conjugation as compared with cyclohexadiene, and thus lower reactivity toward cycloaddition reactions. As can be seen from Table 8, the cyclic 2-azaallyl anions underwent highly stereoselective (endo-selective) cycloaddition with cyclohexadiene, but the acyclic counterparts gave the cycloadducts in low endo/exo selectivities. The transition state structures shown in Figure 6 were invoked to rationalize these

Scheme 70. Chiral Auxiliaries for Enantioselective [3 + 2] Cycloadditions

methylstyrene gave 1-pyrroline 207o in 46% yield and 99.1:0.9 er, along with two other isomers obtained in 13% combined yield. To rationalize this remarkable stereochemical outcome, Pearson and co-workers proposed a transition state structure in which the interaction of the methoxy group in the auxiliary with the lithium cation plays a critical role in determining both the geometry of the starting 2-azaallyl anions and the facial selectivity of the cycloaddition (Scheme 70, inset). Such a model is reminiscent of that involved in Enders’ SAMP hydrazone chemistry.157 As a follow-up to their pioneering work in the field, Pearson’s group systematically investigated the reactions between heteroatom-substituted 2-azaallyl anions generated by Li−Sn exchange with conjugated polyenes.29 For example, the heteroatom-substituted cyclic 2-azaallyl anions from 208b and 208a underwent [4π + 2π] cycloaddition with cyclohexadiene to afford azabicyclic compounds 214 and 215/215′, respectively, in decent yields and selectivities (Table 8). The corresponding acyclic 2-azaallyl anion from 204a could also react with conjugate dienes. For example, this acyclic 2-azaallyl anion combined with cyclohexadiene to give diastereomeric

Figure 6. Explanation for observed diastereoselectivity.

results. For the cyclic 2-azaallyl anions, the transition state structure of the exo-selective mode would incur a significant clash between the ethylene backbones of each component. On the other hand, in the endo-selective mode, the unfavorable interaction is between the ethylene backbone of cyclohexadiene and the THF solvated lithium cation. It is unclear which of the two steric interactions is more severe, but in the endo-selective mode, favorable secondary orbital overlap also exists. For the acyclic 2-azaallyl anions, the steric repulsion present in the exo-selective mode is less severe, and therefore energetically competitive. The final general contribution from Pearson’s group in this arena involves the reaction between heteroatom-substituted 2azaallyl anions with cycloheptatrienes (Table 9).28,29 Treatment of the acyclic stannyl imidate 204e with n-BuLi in the presence of cycloheptatriene afforded the cycloadducts 218, 218′, and 219 in 78% combined yield with a 11:1:3 ratio, respectively. Importantly, cycloadducts 218 and 218′ result from a formal [6π + 4π] cycloaddition, and 219 results via a more familiar [4π + 2π] cycloaddition. For this conjugated cyclic polyene substrate, the [6π + 4π] cycloaddition processes predominated. When the six-membered cyclic stannyl imidate 208a was subjected to the identical reaction conditions, a 1.2:1 mixture of cycloadducts 220 and 221 was formed in 51% yield, the former arising from [6π + 4π] cycloaddition, and the latter from [4π + 2π] cycloaddition. The drastic change of the periselectivity from acyclic to cyclic 2-azaallyl anion species is rather intriguing. Lastly, under identical conditions, the fivemembered cyclic stannyl imidate gave a 1.3:1 mixture of 222 and 223, with the latter arising from anionic 1,2-addition of the corresponding 2-azaallyl anion. All the [6π + 4π] cycloadditions involving heteroatomsubstituted 2-azaallyl anions in the above examples occurred in

Table 8. Cycloadditions with Conjugated Dienes

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Table 9. Cycloaddition with Conjugated Cycloheptatrienes

Scheme 71. Total Synthesis of Mesembrane and transMesembrane

an endo-selective fashion. To rationalize this stereo outcome, it was proposed by the authors that the anionic character in the nitrogen atom could be stabilized by secondary orbital overlap with the double bonds in the endo-selective transition structure but not in the exo-selective transition state. However, such secondary orbital overlap in [6π + 4π] cycloadditions is considered to be repulsive, consistent with the fact that [6π + 4π] cycloadditions between dienes and heptatrienes often occur in an exo-selective manner. The unusual stereoselectivity in the formation of 218 and 222 may be explained better from a steric perspective in which a clash between the methylene group in the cycloheptatriene and the solvated lithium ion in the exo-selective transtition state is avoided. Alternatively, the reaction may proceed in a stepwise, rather than concerted manner, and the endo-selectivity is due to cation−π interactions as suggested in Figure 7.

Scheme 72. Toward 6a-Epippretazettine and 6aEpiprecriwelline

possible transition state structure M that can provide an explanation for the observed stereoselectivity is one in which the methoxylmethoxy substituent adopts a pseudoequatorial position. The judiciously placed silyl group in 227 was planned as a masked precursor to the hydroxyl groups in the natural product targets. Unfortunately, attempts to convert this silyl group to an oxygen failed under various conditions. The intramolecular cyclization of the nonsilylated analogue of 228, however, gave 229 in high yield, and this cycloadduct could be further converted to the (±)-6-epicrinine and (±)-crinine in two to five steps (Scheme 73).158 By using a slightly modified stannyl imine, Pearson and Lian accomplished the total synthesis of (+)-coccinine (Scheme 74).159 Specifically, treatment of stannane 230 with n-BuLi followed by aqueous workup gave the perhydroindole 231, which was subjected to Pictet−Spengler cyclization conditions to generate 232. Elimination of the sulfoxide group (233) followed by inversion of the hydroxyl group gave the desired alkaloid (+)-coccinine. Following a similar strategy, Pearson and Lovering achieved short, efficient syntheses of the Amaryllidaceae alkaloids (−)-amabiline and (−)-augustamine.24 The commercially available lactone 224 could be converted in five high-yielding steps to give the key stannyl imine 235 (Scheme 75). Treating stannane 235 with n-BuLi at −78 °C effected an intramolecular cycloaddition of the

Figure 7. Explanation for observed diastereoselectivity.

2.3.2. Applications in Total Synthesis. Pyrrolidine rings are ubiquitous in naturally occurring products. As a means to access this common alkaloid motif, Pearson’s group championed the cycloaddition of nonstabilized 2-azaallyl anions generated by Li−Sn exchange as a key step in the syntheses of many natural products. For example, the Li−Sn exchange of imine 224 induced an intramolecular [3 + 2] cycloaddition to give, after N-methylation with MeI, two indolines 225 and 225′ in a 3:1 ratio and a 65% combined yield (Scheme 71).17 Upon reduction of the C−S bond by Raney Ni, sulfides 225 and 225′ were smoothly converted to mesembrane (64%) and trans-mesembrane (74%), respectively. In another report,19 Pearson and Postich treated stannyl imine 226 with n-BuLi at −78 °C to effect an intramolecular cycloaddition, furnishing 227 as a core structure of 6aepipretazettine and 6a-epiprecriwelline (Scheme 72). A 10426


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Scheme 73. Total Synthesis of 6-Epicrinine and Crinine

Scheme 75. Total Synthesis of (−)-Augustamine and (−)-Amabiline

Scheme 74. Total Synthesis of Coccinine

Scheme 76. Toward Cylindricine C and Lepadiformine

corresponding nonstabilized 2-azaallyl anion to give, depending on the workup procedures, either 236 and 236′ or the Nmethylated analogues 237 and 237′ in high yields and reasonable diastereoselectivities (4.3−5:1). The major products 236 and 237 have the appropriate relative stereochemistry to allow for rapid conversion to (−)-amabiline and (−)-augustamine, respectively. A transition state structure such as N, in which the anionic character might be stabilized by the aryl ring via secondary orbital overlap, can be invoked to rationalize the observed stereoselectivity. Pearson’s group also attempted to use an intramolecular cycloaddition of 2-azaallyl anions as a key step toward the alkaloids cylidricine C and lepadiformine.21,26 Toward this end, cyclohexanone was converted to the key stannyl imine 238 in nine steps (Scheme 76). Generation of the corresponding nonstabilized 2-azaallyl anion via Li−Sn exchange in the presence of vinyl sulfide provided cycloadduct 239 in decent yield. The stereochemistry, however, at the Cα position did not match the configuration of the corresponding stereocenters in the natural products. The authors reasoned that the 2azaallyl anion resulting from 238 adopts an E-conformation (O′) rather than the Z-conformation (O). Approach of the

vinyl sulfide to the top face of the 2-azaallyl anion would give the observed cycloadduct 239. This intermediate was converted in six steps to tricyclic amine 241 via sulfoxide 240 whose absolute stereochemistry was confirmed by X-ray crystallographic analysis. At the time that Pearson’s group began their attempts toward the total synthesis of lepadiformine, the relative stereochemistry of the marine alkaloid was not determined; later studies by another research group confirmed the relative and absolute configuration to be the one shown in Scheme 76.160 10427


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to that of the heavily investigated family of electrophilic imines. Nevertheless, there are certain situations where a 2-azaallyl cation or 2-azaallyl cation equivalent offers unique reactivity not readily accessible from imine electrophiles. Early progress in this arena emerged from the O’Donnell group, who focused on Schiff base acetate 249a and related compounds as glycine cation equivalents.162 As outlined in Scheme 79, preliminary

An intermolecular cycloaddition of a nonstabilized 2-azaallyl anion with vinyl sulfide was successfully applied in the total synthesis of lapidilectine B (Scheme 77).32 Advanced ketone Scheme 77. Total Synthesis of Lapidilectine B

Scheme 79. Preliminary Studies with Glycine Cation Equivalent 249a

242 was converted to stannylated imine 243 by AlMe3mediated imine condensation. Intermediate 243 was then converted to the 2-azaallyl anion by treatment with n-BuLi in the presence of vinyl sulfide to give cycloadduct 244 in 75% yield, with the correct stereochemical configuration at C13a. Pyrrolidine 244 was readily converted to lapidilectine B following further functional group manipulations. While the lion’s share of natural product syntheses involving nonstabilized 2-azaallyl anions generated via Li−Sn exchange emanated from Pearson’s group, others have also adopted this powerful strategy. For example, She and co-workers described the rapid construction of the [6-6-6-5] tetracyclic skeleton of daphenylline (248) starting from the acyclic stannyl imine 245 (Scheme 78).161 Treatment of stannyl imine 245 with n-BuLi

a

NuH = MeOH, reflux, 1 h. bNuH = EtOH, reflux, 24 h. cNuH = iPrOH, AcOH (1 equiv), reflux, 96 h. dNuH = PhSH in Et2O, rt, 1 h.

studies identified a small collection of heteroatomic nucleophiles that could react with acetate 249a to afford the corresponding nucleophilic substitution products 250 in goodto-high yield. Several related nucleophiles, such as sodium ethoxide, tert-butyl alcohol, and dimethylamine, all resulted in decomposition of 249a to benzophenone instead of the desired substitution products. Follow-up studies identified several different strategies to react 2-azaallyl cation equivalent 249a with different carbon nucleophiles to afford the corresponding α-amino ester Schiff bases. For example, higher order mixed cuprates readily displaced the acetate leaving group to afford αsubstituted glycine derivatives 251 in moderate isolated yields (Scheme 80).163 Later studies indicated that nucleophilic

Scheme 78. She’s Approach to the Tetracyclic Core of Daphenylline

Scheme 80. Reaction between Glycine Cation Equivalent 249a and Organocuprates

generated the corresponding 2-azaallyl anion (246) which rapidly underwent intramolecular cycloaddition to form, after aqueous workup, the desired pyrrolidine 247 as a single diastereomer in 60% isolated yield. Hydrolysis of the silyl ether following intramolecular N-alkylation via the corresponding bromide generated the desired tetracyclic core 248.

aromatic systems such as furan, anisole, indole, and 1,3dimethoxybenzene, as well as allyl silanes and silyl enol ethers, all could serve as appropriate nucleophiles to displace the acetate leaving group in glycine cation equivalent 249a in the presence of 1−2 equiv of titanium tetrachloride in dichloromethane, albeit in low-to-modest isolated yields (Scheme 81).164 Finally, O’Donnell and Falmagne demonstrated that 2azaallyl cation equivalent 249a could be alkylated in good yields with B-alkyl-9-BBN organoboranes in the presence of

3. 2-AZAALLYL CATIONS In comparison with their anionic and zwitterionic counterparts, there is relatively little information regarding 2-azaallyl cations as intermediates in organic synthesis. One possible explanation for this is that, unlike the umpolung reactivity of 2-azaallyl anions, electrophilic 2-azaallyl cations exhibit reactivity similar 10428


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that could be reductively alkylated with C-centered malonate ester enolates in a manner akin to the traditional Tsuji−Trost protocol (Scheme 83).167 Specifically, Schiff base acetate 249b

Scheme 81. Lewis Acid Mediated Nucleophilic Alkylation of 2-Azaallyl Cation Equivalent 249a

Scheme 83. Generation and Alkylation of a Cationic 2-Azaπ-allylPd(II) Electrophile

was combined with sodium dimethyl malonate and Pd(PPh3)4 as a catalyst to afford the coupled product 252 in 79% yield. The presumed electrophilic intermediate for this alkylation is the η3-bound 2-azaallyl cation−Pd(II) complex P. When the reaction was conducted using a combination of 5 mol % Pd(OAc)2 and 10 mol % of the bidentate ligand 1,4bis(diphenylphosphino)butane (dppb), the isolated yield of 252 improved to 87%.168 This Pd-catalyzed generation and alkylation of a 2-azaallyl cation species could be rendered enantioselective by employing chiral bidentate bisphosphine ligands.168−170 Using tert-butyl ester 249c as substrate and (R)-BINAP as the chiral ligand at 0 °C effected the highest levels of asymmetric induction, affording the corresponding triester (S)-253 in 77% isolated yield and 93:7 er (Scheme 84).170 As is frequently the case for chiral compounds Scheme 84. Asymmetric Alkylation of a 2-Aza-π-allylPd(II) Electrophile

potassium 2,6-di-tert-butyl-4-methylphenoxide in THF (Scheme 82).165 Under these reaction conditions, however, Scheme 82. Reaction between 2-Azaallyl Cation Equivalent 249a and Organoboranes

possessing a benzophenone imine moiety, the enantiopurity of (S)-253 could be improved (97.75:2.25 er) via a single recrystallization. Switching to the potassium salt of the malonate nucleophile resulted in an improved isolated yield (90%) at the expense of enantiopurity (89.5:10.5 er when conducted at room temperature). Although limited in scope, O’Donnell’s strategy represents the first example of a Pdcatalyzed asymmetric allylic alkylation reaction involving a 2aza-π-allyl palladium intermediate. In addition to malonate nucleophiles, O’Donnell’s group also disclosed that vinylalanes readily coupled with the 2-aza-πallylPd(II) intermediates generated from α-acetoglycinate 249b (Table 10).171 The requisite vinylalane reagents were first generated by the zirconium-catalyzed syn-methylalumination of various terminal (entries 1−4) or symmetrical internal (entry 5) alkynes with Me3Al before combining with 2-azaallyl cation precursor 249b and Pd(PPh3)4 as a catalyst. Whereas the polar aprotic solvent acetonitrile was optimal for the transformations involving malonate nucleophiles, the Pdcatalyzed vinylation of 249b performed best in the nonpolar solvent 1,4-dioxane. In general, the resulting vinylglycine derivatives 254 were obtained in moderate yield (50−68%). The transformation failed, however, when tert-butylacetylene was employed (entry 4). Presumably, the sterically demanding

the hindered phenoxide most likely serves as a base to deprotonate 249a and the resulting stabilized 2-azaallyl anion first attacks the organoborane. Intramolecular rearrangement of the resulting tetraalkylborate eventually affords the formal nucleophilic substitution product 250. O’Donnell’s group enacted a similar strategy for the functionalization of an αaminophosphonate cation equivalent.166 In addition to these studies involving 2-azaallyl cation equivalents, O’Donnell and co-workers also were the first to report the generation of a cationic 2-aza-π-allylPd(II) complex 10429


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Table 10. Pd-Catalyzed Generation and Vinylation of 2Azaallyl Cations

entry

R1

R2

yield (%)

1 2 3 4 5

n-hexyl Ph n-propyl t-Bu Et

H H H H Et

68 50 60 0 54

Scheme 86. Synthesis of Tetrahydroazepines via 2-Azaallyl Dication Surrogates

tert-butyl substituent prohibited the initial carboalumination event. In 2001, Pearson demonstrated that (2-azaallyl)stannanes could serve as 2-azaallyl dication surrogates (Scheme 85).172 Scheme 85. (2-Azaallyl)stannanes as 2-Azaallyl Dication Equivalents

a

Quenched with ClCO2Ph. bQuenched with ClCO2Bn. cQuenched with HCO2Ac.

Scheme 87. (2-Azaallyl)nitriles as 2-Azaallyl Dication Equivalents

Previous reports from Pearson’s group advanced (2-azaallyl)stannanes as relatively stable precursors to nonstabilized 2azaallyl anions via lithium−tin exchange (see section 2.3). Depending on the organometallic reagent employed, the solvent, and specific characteristics of the (2-azaallyl)stannane reagents, nucleophilic addition into the imine moiety proved to be an alternative reaction pathway. Elimination of the tributyltin moiety from the resultant amide anion then affords a second imine electrophile available to react with another equivalent of the organometallic nucleophile. Accordingly, it was reported that Grignard reagents, such as allyl magnesium bromide, are appropriate nucleophiles for such a process involving (2-azaallyl)stannanes 196 as 2-azaallyl dication equivalents. As summarized in Scheme 86, quenching the reaction with an appropriate reactive formate ester afforded the double addition products 258, which can then be converted to the corresponding 2,3,6,7-tetrahydroazepines 259 via Rucatalyzed ring-closing metathesis.172,173 Further investigations determined that (2-azaallyl)nitriles 260 are also effective 2-azaallyl dication surrogates.173 In contrast to (2-azaallyl)stannanes 196, allyl lithium (instead of allyl magnesium bromide) can be used as a nucleophilic species with nitriles 260, since there is no longer a possibility for lithium−tin exchange to compete with the desired nucleophilic addition (Scheme 87). In most cases, however, the Grignard reagents proved superior. For example, bisallylated carbamate 261f was only observed in trace quantities when allyl lithium was the nucleophilic reagent,

a

Quenched with H2O. bQuenched with HCO2Ac. cQuenched with ClCO2Me.

but the same product could be obtained from the corresponding (2-azaallyl)nitrile in 65% yield and as a 1.7:1 ratio of diastereomers using allyl magnesium bromide in CH2Cl2. One particular advantage of the (2-azaallyl)nitriles 260 over the stannanes 196 as 2-azaallyl dication equivalents was seen in the diastereoselectivity for specific transformations. For example, the diisopropyl product 261a was obtained as essentially a single diastereomer (the relative stereochemistry of which was not determined) starting from the requisite (2azaallyl)nitrile and using either allyl lithium or allyl magnesium bromide. That same product 261a was obtained in a similar yield (67%), but significantly reduced diastereoselectivity (5.3:1 dr) starting from the corresponding (2-azaallyl)stannane. In addition to stannanes and cyanides, Katritzky and co-workers demonstrated that the benzotriazole group also 10430


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is an appropriate leaving group for the double alkylation of 2azaallyl dication equivalents with Grignard reagents.174 These advances from Pearson and Katritzky involving 2azaallyl dication equivalents notwithstanding, it would be 21 years after O’Donnell’s preliminary report of a 2-azaallyl cation−Pd(II) complex before any other group proposed a 2azaallyl cation, or metalated complex thereof, as a plausible intermediate in organic synthesis. Specifically, Han, Yu, and coworkers suggested that the 2-azaallyl cation species R is a critical reactive intermediate in their tandem imine condensation/oxidative cyclization tactic toward 2-aryl quinazolines S (Scheme 88).175 The proposed rate-determining step

Scheme 89. Formation of 2-Aza-π-allylPd(II) Species by C− H Insertion

reductive alkylation, N-allyl imines 262 were readily converted to the corresponding β-imino esters 264 in high yield and good diastereoselectivity in the presence of only 3 mol % Pd(OAc)2 and 6 mol % PPh3; an illustrative set of examples is provided in Scheme 90. The authors noted that the high diastereomeric ratios observed for the Pd-catalyzed C−C bond formation stood in stark contrast to the negligible levels of diastereoselectivity observed in related Mannich-type alkylations of N-acyl imines in the presence of Lewis acids. The resultant dr values were sensitive, however, to steric factors in the aldimines 262; p-nitro-substituted benzylimine 264g was obtained in 86% and 11:1 dr, whereas the more hindered ortho-substituted derivative 264i was produced with significantly lower diastereoselectivity (3.3:1 dr), albeit in higher yield (94%). Similarly, the cyclohexyl-substituted 264r was obtained in significantly lower yield (53%) and diastereomeric purity (5.3:1 dr) in comparison to the phenyl analogue 264a (93%, 13:1 dr). In all cases, esters 263 with alkyl substituents on the α-carbon (R1 = Me, n-hexyl, i-Pr, allyl, or Bn) only formed the 1-aza-1,3-diene products 264; these products most likely arose from preferential attack on central allylic carbon of the 2-aza-πallylPd(II) intermediate T. The more stable anionic nucleophile generated by deprotonation of α-phenylester 265 displayed different regioselectivity, preferring to attack the terminal carbon of the η3-π-allylPd(II) intermediate (e.g., U) to give 2-aza-1,3-dienes 266 exclusively and in good yield (Scheme 91). In both transformations, C(sp2)−halogen bonds survived the relatively mild reaction conditions and heteroaromatic substituents were tolerated. In addition to this initial report, Trost’s group also was able to achieve a Pd-catalyzed asymmetric allylic alkylation involving 2-azaallyl cations generated via C−H activation of N-allyl imines 262.177 In this case, the enolates of the benzophenone imine protected glycine esters popularized by O’Donnell (2b)34 served as the reactive nucleophiles, affording a collection of differentially protected vicinal diamines 267 with typically good diastereoselectivity favoring the syn diastereomers. After careful screening of the reaction conditions, the authors settled on the chiral bisphosphine (S,S)-Cy DIOP in toluene as the preferred ligand/solvent combination; representative examples of this transformation are provided in Scheme 92. In contrast to other asymmetric C−C bond-forming reactions involving benzophenone imine protected glycinate enolates,34−36 methyl ester 2b typically affords higher levels of enantioselectivity than the corresponding tert-butyl ester 2b′. Similar to the racemic reaction conditions using PPh3, ortho-substituted benzaldimines presented lower diastereoselectivities in comparison to the corresponding para-substituted analogues (5:1 dr for 267f versus 8:1 for 267d) when (S,S)-Cy DIOP was used as ligand. The level of asymmetric induction provided by this chiral ligand, however, was not greatly influenced by the position of

Scheme 88. Synthesis of 2-Aryl Quinazolines via the Intermediacy of 2-Azaallyl Cations

for the overall transformation is the oxidative formation of the 2-azaallyl radical species Q (see section 4) using 4-hydroxy2,2,6,6-tetramethylpiperidine-1-oxyl radical (4-OH-TEMPO); a second single-electron transfer between radical Q and another equivalent of 4-OH-TEMPO could afford the crucial 2-azaallyl cation intermediate R. This proposal is unique in that it represents both the first suggested example of a non-glycinederived 2-azaallyl cation intermediate and the only reported example of a “free” 2-azaallyl cation (not complexed to a metal). In 2015, Trost and co-workers reported that 2-aza-πallylPd(II) electrophiles could be generated by Pd-catalyzed C(sp3)−H activation of N-allyl imines.176 For example, treatment of benzaldimine 262a with a stoichiometric amount of palladium acetate and triphenylphosphine resulted in initial formation of 2-azaallyl cation−Pd(II) complex T, which eventually equilibrated to a mixture with the η3-π-allylPd(II) complex U, as determined by 1H NMR analysis of the reaction mixture (Scheme 89). The N-allyl moiety proved critical for the Pd-mediated C−H activation; N-benzylimine 1e was inert under the reaction conditions and N-propargyl-substituted 1f decomposed. In the presence of a suitable nucleophile and oxidant, the C−H activation event was rendered catalytic. Specifically, using the anions of α-cyanoesters 263, generated in situ with a bulky amine base, as nucleophiles and 2,6dimethylbenzoquinone (2,6-DMBQ) as a stoichiometric oxidant to regenerate the necessary Pd(II) catalyst after 10431


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Scheme 90. Pd-Catalyzed Allylic Alkylation of N-Allyl Imines

powdered 4 Å molecular sieves to absorb the water produced upon imine condensation; essentially identical dr and er values for the vicinal diimines 267 were obtained for this one-pot protocol. These limited studies involving 2-azaallyl cations already suggest a few situations where they possess potential advantages over their nucleophilic 2-azaallyl anion counterparts. For example, the electronic nature of the imine component in N-allyl imine 2-azaallyl cation precursors 262 appears to have less of an impact on the outcome of the coupling reactions in comparison to the corresponding 2azaallyl anions; no obvious Hammett relationships with yield or stereoselectivity are seen for the 2-azaallylation of αcyanoesters 261 and 263 (Schemes 90 and 91, respectively) and glycinate imine 2b (Scheme 92). This is in stark contrast to the strong positive linear Hammett correlations with regioselectivity and enantioselectivity observed for the Pdcatalyzed allylic alkylations of 2-azaallyl anions (see section 2.2.2). Whereas the regioselectivity for the reductive alkylation of 2-aza-π-allyl palladium intermediates is somewhat sensitive to the nature of the attacking nucleophile (compare Scheme 90 with Scheme 91), it is still not as complicated and challenging as controlling the regioselectivities for the alkylation and arylation of 2-azaallyl anions (see sections 2.1.4 and 2.2.2). Possibly the most dramatic difference between Pd-bound 2azaallyl cations and the corresponding anions is the significantly higher levels of diastereoselectivity observed for the alkylation of the former with prochiral nucleophiles. Indeed, palladium-catalyzed nucleophilic additions involving semistabilized 2-azaallyl anions typically do not display inherently high diastereoselectivities (>5:1 dr) even in the presence of chiral ligands. For example, essentially no diastereoselectivity was observed for the Pd-catalyzed coupling between nucleophilic 2-azaallyl anions and electrophilic olefins (IDcA, see section 2.2.2). Trost and co-workers, however, typically observed good diastereoselectivities (up to 13:1 dr) for the Pd-catalyzed alkylation of electrophilic 2-azaallyl

Scheme 91. Pd-Catalyzed Formation of 2-Aza-1,3-dienes

the substituent on the benzaldimine moiety (92.5:7.5 er for pfluoro 267d, 90.5:9.5 er for m-fluoro 267e, and 93:7 er for ofluoro 267f). Electron-withdrawing groups (267c), halogens (267d−267g), electron-donating groups (267h), heterocycles (267j, 267k), and alkenes (267l) were all tolerated under the reaction conditions, with isolated yields ranging from 61 to 84%. It should be noted that the highest level of enantioinduction observed (93:7 er for 267f) is exactly the same as that reported by O’Donnell and co-workers for the asymmetric allylic alkylation with sodium dimethyl malonate using a glycine-derived 2-aza-π-allylPd(II) and (R)-BINAP as chiral ligand (Scheme 84).170 The chiral bisphosphine (R)BINAP, however, failed to generate the vicinal diamino derivatives 267 following the C−H activation reaction manifold. A one-pot procedure combining formation of the imines 262 by condensation between N-allylamine and the appropriate aldehydes with the C−H activation/asymmetric allylic alkylation was also realized. The only significant difference for the one-pot procedure was the addition of 10432


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Scheme 92. Pd-Catalyzed Asymmetric Allylic Alkylation involving 2-Aza-π-allyl Palladium Intermediates

In 1,4-dioxane. bAt rt. cAt −4 °C.

a

cations with C-centered anionic nucleophiles. A reasonable explanation for this difference is that while 2-azaallyl anions most likely form tight ion pairs with cationic Pd(II) species,140 the 2-azaallyl cations are directly η3-bound to the palladium center, thus limiting conformational flexibility in the framework of the organic electrophile and providing significant steric influence from the other Pd-bound ligands. It should be noted that the recently reported additions of 2-azaallylcuprates into carbonyls and imines by Malcolmson and co-workers (see section 2.1.4)99,124 offer evidence that highly diastereoselective transition-metal-catalyzed transformations involving 2-azaallyl anionic intermediates (or equivalents thereof) are attainable. O’Donnell’s foundational studies verified 2-azaallyl cations, particularly in the form of 2-aza-π-allylPd(II) species, as reasonable intermediates in organic synthesis. The discovery that 2-azaallyl cations can be generated by Pd-catalyzed C−H activation of N-allyl imines has opened up the field, with only a small fraction of the potential nucleophilic coupling partners having been explored. The identification of alternatives to the N-allyl moiety as a directing group for the C−H activation would expand the scope of 2-azaallyl cation chemistry even further. Additionally, direct oxidative generation of 2-azaallyl cations from the corresponding neutral species, as proposed by Han, Yu, and co-workers (Scheme 86), is a potentially fruitful but currently unexplored general strategy. Of course, 2-azaallyl cations exhibit the same polarity as electrophilic imines, for which there is a deep trove of highly stereoselecitve transformations. Future studies in this field should focus on situations where direct nucleophilic addition into imines is not a competitive alternative for the resultant bond formations.

Scheme 93. 2-Azaallyl Radicals: Early Studies

dihydro-N-heterocycles could be converted to the corresponding heterocyclic 2-azaallyl radicals by either γ irradiation of crystals (270 and 273)180−182 or light-mediated H atom abstraction in solution (271 and 272);183 the resulting radical species were thoroughly characterized by ESR and ENDOR spectroscopies (Scheme 93B). Additionally, it was determined that γ irradiation of aziridines (4) resulted in ring-opening to form 2-azaallyl radical cations 274 (Scheme 93C).184−186 Acyclic 2-azaallyl radicals also have been proposed as transient intermediates in certain cyclization reactions. As mentioned in section 3, a 2-azaallyl radical was suggested as a precursor to a critical 2-azaallyl cation toward the oxidative cyclization of oaminobenzaldimines to the corresponding 2-aryl quinazolines

4. 2-AZAALLYL RADICALS Prior to very recent revolutionary studies,95,96 2-azaallyl radicals were primarily treated as theoretical curiosities. The earliest efforts toward 2-azaallyl radicals were those of Kuhn and Neugebauer in which a persistent highly conjugated 2azaallyl radical 269 was generated by oxidation of the corresponding anion 268 with potassium ferricyanide (Scheme 93A).178 Using this strategy, Watanabe performed detailed ESR spectroscopic analysis of 2-azaallyl radical 269 and related compounds.179 Later investigations revealed that various 10433


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S (section 3, Scheme 87).175 2-Azaallyl radicals were also proposed as initial intermediates in the flash vacuum thermolysis (FVT) of various tert-butyl imines.187 For example, FVT of imine 275 generated indole 275, in addition to several other products, and the preliminary intermediate was suggested to be the 2-azaallyl radical formed by ejection of a methyl radical from the tert-butyl group (Scheme 93D). Moreover, there is significant evidence for the intermediacy of complexes between 2-azaallyl radicals and various transition metals (Ti, Cr, and Ni), in specialized ligand dimerization transformations.188,189 Retrospectively, the dimerization of 2-azaallyl anion 6b in the presence of 1,2-dibromoethane reported by Kauffmann and co-workers in 1977 could be viewed as the earliest potential evidence for the synthetically useful generation of 2-azaallyl radicals (see section 2.1.3, Scheme 23).83 In this case, single electron transfer (SET) could occur between the 2-azaallyl anion and the alkyl bromide. After ejection of a bromide anion, the initially formed α-bromo alkyl radical can undergo elimination of a bromine atom to generate unreactive ethylene (Scheme 94). The remaining 2-azaallyl radicals present in the

Scheme 95. Transition-Metal-Free Regioselective Vinylation of 2-Azaallyl Anions

Scheme 94. Potential Explanation for Dimerization of 6b with 1,2-Dibromoethane

a

Three equiv of NaN(SiMe3)2 used as base.

Scheme 96. Possible Mechanisms for the Transition-MetalFree Vinylation of 2-Azaallyls

reaction mixture then could dimerize with each other to form the observed product 76. It should be noted that the authors offered no explanation for the formation of 76 under their reaction conditions and this unique observation was largely ignored by the rest of the scientific community, as well. It was not until 2017 that the 2-azaallyl radical emerged as a viable synthetic intermediate under ambient reaction conditions. As mentioned in section 2.1.3, there are several reports describing transition-metal-catalyzed arylations of semistabilized 2-azaallyl anions with (hetero)aryl halides. In 2017, Walsh and co-workers reported an unexpected result when they tried to extend this methodology toward cross-coupling with vinyl bromides.95 Namely, it was discovered that semistabilized 2-azaallyl anions, generated by deprotonation of the conjugate acids 94 with LiN(SiMe3)2, coupled directly with a collection of vinyl bromides 277 in high yield and remarkable regioselectivity without the addition of transition metal catalysts; representative examples are provided in Scheme 95. A wide selection of α-bromostyrenes and 2,2dialkylvinyl bromides readily coupled with 2-azallyl anions, albeit the latter tended to afford the resulting vinylated products 278 in lower relative yield (compare 278e with 278a−278d). Electron-withdrawing groups, electron-donating groups, and fluorine were all tolerated on either the vinyl bromide 277 or 2-azaallyl anion precursor 94. In all cases, only one regioisomeric product, in which vinylation occurred at the less substituted carbon of the 2-azaallyl anion framework, was reported. A combination of computational and empirical studies narrowed the possibilities for the mechanism of the observed transition-metal-free vinylation of 2-azaallyl anions with vinyl bromides to two different options (Scheme 96). The first

possibility was direct nucleophilic vinyl substitution (SNV); the steric requirements in the transition state for such a process adequately account for the observed high regioselectivities (Scheme 96A). An alternative mechanistic possibility involved the intermediacy of a 2-azaallyl radical. Treatment of 2-azaallyl anion precursor 2a with a silylazide base would establish an equilibrium mixture of the 2-azaallyl anion 6c and the conjugate acid 2a, and this combination could disproportionate via single electron transfer (SET) to afford 2-azaallyl 10434


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contrast to the transition-metal-catalyzed arylations of semistabilized 2-azaallyl anions discussed in section 2.1.4;97,115−122 in those transformations only the regioisomer corresponding to 120 was reported. For the transition-metal-free arylations, substitution at the ortho position of the aryl iodide was tolerated (120o), but bis-ortho substitution led to formation of a single regioisomer in which arylation occurred exclusively at the less substituted carbon (120p). Sterically hindered alkyl iodides such as neopentyl iodide, tert-butyl iodide, and 1adamantyl iodide, also coupled nicely with 2-azaallyls under slightly modified reaction conditions (0.1 M in MTBE) to afford the corresponding alkylated products 281a−281f in moderate-to-excellent isolated yields and as single regioisomers. In some cases, it was found that the alkylated product also could be obtained from the corresponding alkyl bromide, albeit in reduced isolated yield (e.g., 61% for 281c using 1-adamantyl bromide). Electron-donating groups (281d), electron-withdrawing groups (281e), and heterocycles (281f) in the 2-azaallyl component 94 were all tolerated for the alkylation event. With regard to the reaction mechanism for these transitionmetal-free arylations and alkylations, the successful coupling with sterically hindered alkyl halides strongly suggests against a purely anionic C−C bond formation event. Additionally, formation of the bis-ortho-methylated product 120p excludes the necessity of a benzyne intermediate in the arylation mechanism. To probe the possibility of radical intermediates in the transformations, radical clocks 283a and 283b were coupled with ketimine 2a under the arylation or alkylation reaction conditions, respectively (Scheme 98A). Singleelectron reduction of iodides 283a or 283b, followed by ejection of the halide anion, would afford a radical intermediate that could cyclize with the pendant olefin (e.g., X → Y, Scheme 98A, inset) prior to intermolecular coupling to the 2-azaallyl species. Indeed, cyclized products 284a and 284b were both

radical 279a and ketimine radical anion V (Scheme 96B). Low temperature (190 K) electron paramagnetic resonance (EPR) studies of a frozen solution of ketimine 2a and NaN(SiMe3)2 in a DME glass revealed the presence of an unidentified radical species, providing support for such a proposal. Moreover, very recent studies confirmed the facile generation of ketimine radical anions such as V under photoredox conditions.190 The resulting 2-azaallyl radical 279a is then free to react with the vinyl bromide to afford radical intermediate W. A second SET process between radical W and ketimine radical anion V would both regenerate the 2-azaallyl anion precursor 2a and afford a β-bromo carbanion (not shown) which rapidly eliminates a bromide ion to afford the observed product 278a (Scheme 96C). As with the SNV pathway, steric considerations would govern the regioselectivity of the C−C bond-forming event in such a radical-mediated process. Further support for the presence of 2-azaallyl radicals as coupling partners was provided in the arylation and alkylation of semistabilized 2-azaallyls with aryl iodides and hindered alkyl bromides/iodides, respectively (Scheme 97).96 Under Scheme 97. Transition-Metal-Free Arylation and Alkylation of 2-Azaallyls

Scheme 98. Mechanistic Studies Support Radical Intermediates

a Isolated yield for the major regioisomer 120/281 shown; regioisomeric ratio (rr) is the ratio of 120/281:282 isolated yields. b DME (0.2 M) used as solvent. cMTBE (0.1 M) used as solvent.

conditions similar to those used for the transition-metal-free vinylation process [3 equiv of NaN(SiMe3)2, DME (0.2 M), rt], benzophenone imines 94 could be arylated with a variety of aryl iodides 280 in moderate isolated yields. Electron-rich substituents (120l, 120d, 120o−120p) and other halogens (120n) were all tolerated on the aryl iodide coupling partner. Unlike the vinylation reaction,95 the arylation event typically generated a mixture of regioisomers (120/281 and 282), in which arylation at the less substituted carbon of the 2-azaallyl framework (120) always predominated. This production of two regioisomers (120/280 and 282) also stands in stark 10435


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Table 11. Arylation of 2-Azaallyl Anions with Electron-Deficient Aryl Bromides, Chlorides (Table 8); Pd-Catalyzed Generation and Vinylation of 2-Azaallyl Cations and Fluorides

mediated arylation of semistabilized 2-azaallyl anions also could employ aryl bromides and even electron-rich aryl chlorides with appropriate alterations to the reaction conditions.192 As was discussed in section 2.1.4, previous attempts to arylate semistabilized 2-azaallyl anions with aryl bromides or chlorides required the mediation of a transition metal catalyst.97,115−122 As would be expected for a process where oxidative addition into the aryl halide bond is critical, electron-rich aryl halides typically outperformed their electrondeficient counterparts under these transition-metal-catalyzed reaction conditions. For a radical-mediated process, however, electron-deficient aryl halides should be easier to reduce via SET from the 2-azaallyl anion electron donor. Accordingly, Poznik and Chruma initiated their studies by arylating the 1,1,3-triphenyl-2-azaallyl anion derived from 2a with pchloroacetophenone as a relatively electron-deficient aryl chloride. When these reagents were combined under conditions previously demonstrated to be suitable for the transition-metal-free arylation with aryl iodides (2 equiv of LiN(SiMe3)2 in THF at ambient temperature),96 no arylation products were observed (Table 11, entry 1). Conducting the reaction in the highly polar solvent DMSO, which is known to facilitate radical reactions, afforded the desired arylated product 120q as a single regioisomer but in low yield (13%, entry 2). Further optimization of the reaction conditions such as changing the base to NaH (1.5 equiv) and increasing the reaction concentration (0.3 M) improved the isolated yield of

obtained in essentially quantitative yield as a 1:1 mixture of diastereomers, providing strong support for a radical-mediated reaction mechanism. Additionally, the most prevalent side product for the arylation and alkylation reactions involving ketimine 2a was a diastereomeric mixture of diimines 285 (Scheme 98A, inset), which could arise via dimerization of a 2azaallyl radical intermediate (see above, e.g., Scheme 94). Based on these observations, a general reaction mechanism for the transition-metal-free coupling reactions was proposed as shown in Scheme 98B. Initially, formation of a 2-azaallyl anion occurs by deprotonation of the ketimine starting material with the silylazide base. This anionic intermediate serves as a superelectron donor (SED) and undergoes SET with the aryl iodide or alkyl halide to afford, after ejection of the halide anion, a 2-azaallyl radical and aryl/alkyl radical pair. Direct coupling between these two radical species leads to formation of regioisomeric products 120/281 and 282, in which steric factors primarily determine the resulting regioselectivity. Another possible reaction pathway is an SRN1 mechanism in which the aryl radical combines with the more prevalent 2azaallyl anion species to form a radical anion intermediate followed by another SET event (not shown); the successful coupling with p-haloaryl iodides without loss of the other halogen atom (cf. 120n, Scheme 97), however, strongly suggests against such a possibility.191 Poznik and Chruma, in continued collaboration with Walsh’s group, very recently demonstrated that the radical10436


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absorption of UV light enhanced the reducing power of highly reactive neutral SEDs,193−196 the authors reasoned that irradiation of the deep reddish-purple-colored solution of the anion of 2a in DMSO could similarly enhance the reduction potential of the anionic SED. After significant adjustments to the reaction conditions such as changing the base to 2 equiv of butyllithium, decreasing the concentration to 0.1 M, and employing a large excess of the relatively inexpensive aryl halide reagents (up to 10 equiv), 2-azaallyl anion precursor 2a could be arylated with electron-rich aryl bromides and chlorides upon irradiation of the reaction mixture with green (or blue) LEDs (Table 12). As was observed with the electron-

120q to 82% (entry 3). These reaction conditions proved relatively general for a collection of electron-deficient aryl chlorides and bromides (entries 4−7, 9, 11, 12, 14, and 15). Surprisingly, even electron-deficient aryl fluorides could serve as suitable arylating agents under these reaction conditions (entries 6 and 11). For certain aryl halides, using LiN(SiMe3)2 as the base instead of NaH resulted in a doubling of the isolated yields (entries 8, 10, and 13). Where comparisons are available, these transition-metal-free conditions tended to be as good as or superior to the Pd-catalyzed arylations involving electron-deficient aryl halides (compare Table 11, entries 8, 10, 13, and 14 with section 2.1.4, Scheme 38). This arylation process also was applied to the late-stage modification of the marketed pharmaceutical agent fenofibrate and bromonaphthaleneimide chromophore 287 (Scheme 99).

Table 12. Visible-Light Enanbled Arylation of 2-Azaallyl Anions with Electron-Rich Aryl Bromides and Chlorides

Scheme 99. Late-Stage Functionalization of Fenofibrate and Chromophore 286

Mechanistic studies akin to those performed in the previous transition-metal-free arylation report (see Scheme 98A)96 indicated that the electron-deficient aryl chlorides and bromides arylated the 2-azaallyl anions via a similar radicalmediated process involving the generation of and coupling to a 2-azaallyl radical intermediate. The electron-deficient aryl fluorides (Table 11, entries 6 and 11), on the other hand, directly arylated the 2-azaallyl anions via a two-electron SNAr process. These results emphasize that semistabilized 2-azaallyl anions can participate in both one-electron and two-electron reaction mechanisms for the same type of reaction depending on the nature of the reagents and other reaction conditions. Accordingly, care should be taken in future studies to conduct the appropriate experiments before proposing reaction mechanisms for transformations involving 2-azaallyl anion intermediates. Whereas the modified reaction conditions outlined in Table 11 were suitable for the transition-metal-free arylation of semistabilized 2-azaallyl anions with electron-deficient aryl chlorides and bromides, relatively electron-rich aryl bromides, e.g., 4-tert-butylbromobenzene, still failed to react (Table 11, entry 15). Presumably the reducing power of the 2-azaallyl anion derived from 2a was not sufficient to perform the initial SET with the electron-rich aryl bromide. Encouraged by several reports from Murphy and collaborators in which the

rich aryl iodides (Scheme 97), and in contrast to the electrondeficient aryl halides (Table 11), a mixture of regioisomers 120 and 282 were isolated in most cases under the photoirradiated reaction conditions. The observed regioisomeric ratios did not depend dramatically on the nature of the halide or the reaction conditions (e.g., compare Table 12, entries 2 and 3, with Scheme 97, 120m). The resulting isolated yields, however, were significantly poorer for the photoirradiated reaction conditions with electron-rich aryl bromides and chlorides versus the nonirradiated procedures employing aryl iodides; the remainder of the 2-azaallyl anion reagent was consumed by 10437


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Scheme 100. General Overview of Strategies for Generating N-Protio and N-Alkyl Azomethine Ylides

Scheme 101. Formation of Azomethine Ylides from NOxides

dimerization to diastereomeric diimines 285 (see Scheme 98). Nevertheless, these studies demonstrated that irradiating semistabilized 2-azaallyl anions with visible light could enhance their reducing power so as to even couple with 4-chloroanisole, which has a reported reduction potential (vs SCE) as low at −2.77 V (Table 12, entry 7). The discovery that semistabilized 2-azaallyl anions can serve as organic electron donors is revolutionary and provides a new mechanistic consideration for reactions (both transition metal catalyzed and transition metal free) involving these anionic intermediates. This is particularly the case for cycloadditions and cross-couplings between 2-azaallyls and functional groups with relatively accessible reduction potentials (e.g., imines, nitriles, etc.; section 2.1.2). The discovery that the reducing power of the deeply colored 2-azaallyl anionic species can be enhanced by irradiation with visible light opens up possibilities for unique photoinitiated electron transfer cascades. Moreover, there are several currently unexplored functional groups whose reduction potentials mark them as possible coupling partners for 2-azaallyl anion SEDs via radical-mediated processes while being immune to ionic reaction mechanisms. The overall generality and scope of 2-azaallyl radicals as viable coupling partners in organic synthesis, however, will depend on the development of strategies to both improve the observed regioselectivity for such radical-mediated bond formations and to reduce the prevalence of undesired side reactions such as dimerization.

Scheme 102. Redox Neutral C−C Bond Formations with Transient Azomethine Ylides

Scheme 103. Formation of Pyrrolidinofullerenes via the “Prato Reaction”

5. AZOMETHINE YLIDES The azomethine ylide as an intermediate in synthetic transformations has an even deeper history than the venerable 2-azaallyl anion, going as far back as 1862 when Strecker first reported the decarboxylative degradation of α-amino acids with carbonyl compounds.197,198 With few and notable exceptions, azomethine ylides are used synthetically as 4π components for 1,3-dipolar cycloadditions. There is even 10438


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5.1. N-Protio and N-Alkyl Azomethine Ylides

Scheme 104. Decarboxylative Generation and RedoxNeutral Functionalization of Azomethine Ylides

As outlined in Scheme 100, there are several different synthetic strategies for the generation of N-protonated azomethine ylides (289) and their N-alkylated cousins (290) including (1) ring-opening reactions, (2) deprotonation, (3) 1,2-prototropic rearrangement, (4) decarboxylation, (5) disilylation/destannylation, and (6) via carbenes and carbenoids. The most classical method involves the thermal (or photochemical) retropericyclic ring opening of aziridines (291).200−224 The mechanism of this ring-opening process and the ensuing 1,3dipolar cycloaddtions have been investigated thoroughly.225−233 More recent innovations include the use of Lewis acids to mediate the ring-opening of aziridines to azomethine ylides at lower temperatures.234−239 Dihydrooxazoles (292, X = O),205,240−245 dihydrothiazoles (292, X = S),246 and related heterocycles221,247,248 also can produce Nalkyl azomethine ylide dipoles via ring-opening processes. The most direct method for the formation of N-alkyl azomethine ylides (290) is the deprotonation of the corresponding iminium 293 (Scheme 100) using an appropriate base (which could be the water generated upon iminium condensation).249−277 Treatment of N-oxides with LDA also was proposed to generate azomethine ylide intermediates (Scheme 101).278 While direct deprotonation of imines 294 (R1 = H) typically affords a 2-azaallyl anion, the corresponding N-protonated azomethine ylides (289) can be accessed via a 1,2-prototropic rearrangement of imines 294, as was pioneered by Grigg279−284 and utilized by many others (Scheme 100).285−289 Other prototropic events, such as 1,5and 1,6-shifts, also can lead to the generation of reactive azomethine ylides.290,291 In the presence of chiral Brønsted acid catalysts, this 1,2-protropic event and the ensuing cycloaddition with appropriate dipolarophiles can be rendered highly diastereo- and enantioselective.291−300 Similarly, proline-based organocatalysts which activate α,β-unsaturated carbonyl dipolarophiles can affect a highly asymmetric 1,3dipolar cycloaddition with azomethine ylides generated via 1,2prototropy or deprotonation.301−315 A special situation championed by Seidel involves the carboxylate-mediated transient generation of an azomethine ylide as part of imine isomerization event.316−318 For example, condensing pyrrolidine with 2,6-dichlorobenzaldehyde in the presence of terminal alkynes and a Cu(II) dicarboxylate catalyst resulted in the near-exclusive formation of 2-alkynylpyrrolidine derivatives 301 (Scheme 102). As was introduced in section 2.2, decarboxylation is a relatively mild and powerful strategy for the generation of semistabilized 2-azaallyl anions. Similarly, the tandem iminium condensation/thermal decarboxylation reaction manifold (via carboxylic acids 278, Scheme 100) is a popular method for in situ preparation of N-alkyl azomethine ylides.319−363 In 1993, Prato and co-workers demonstrated that C60 could be converted to the corresponding pyrrolidine by 1,3-dipolar cycloaddition with the N-methyl azomethine ylide generated via thermal decarboxylation of the iminium formed by condensation between sarcosine (N-methlyglycine) and formaldehyde (Scheme 103).364 This so-called “Prato reaction”, and variations thereof, have since been applied toward the functionalization of fullerenes,365−395 graphene and singlewalled carbon nanotubes and nanohorns,396−416 as well as chlorins and other polyaromatic heterocycles.417−419 Interestingly, the retro-[3 + 2] process for pyrrolidinofullerenes is also thermally accessible, providing an explanation for the isomer-

Scheme 105. N-Alkyl Azomethine Ylides from Dihalocarbenes

Scheme 106. Tungsten-Catalyzed Generation and Cycloaddition of Azomethine Ylides

evidence that the cycloaddition between a cyclic N-alkyl azomethine ylide and an aldehyde is a critical step in the biosynthesis of the oxapenam ring in clavaminic acid.199 In contrast to the azaallyl species discussed in sections 2, 3, and 4, there are several comprehensive reviews of azomethine ylides in organic synthesis, particularly in relation to 1,3-dipolar cycloadditions.2−15 Accordingly, this section will simply provide a general overview of the field with an emphasis on some recent advances as well as critical comparisons to semistabilized 2-azaallyl anion chemistry. We have divided the rich field of azomethine ylide chemistry into two roughly equivalent categories: N-protio/alkyl azomethine ylides (section 5.1) and their N-metalated counterparts (section 5.2). 10439


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Scheme 107. Stereodivergent [3 + 2] Cycloadditions

precursors for the fluoride-mediated generation of highly reactive N-alkyl azomethine ylides.447−457 The final general strategy for the generation of N-alkyl azomethine ylides (290a) is the reaction between imines (302) and carbenes (300) 458−462 or metal carbenoid (301)463−467 species (Scheme 100) For example, dihalocarbenes (300, X = Cl or F) can condense with imines (302) to afford the corresponding gem-dihalogenated azomethine ylide dipole (308) which can undergo either inter- or intramolecular cycloaddition with appropriate dipolarophiles. As shown in Scheme 105, the transient α,α-dihaloamine products 309 readily convert to the corresponding lactams 310 upon aqueous workup. Rhodium, copper, and gold carbenoids have all been reported to react with imines to afford the corresponding azomethine ylide intermediates. One interesting variation out of several468 on this general strategy is shown in Scheme 106. Iwasawa and co-workers determined that treatment of imine functionalized o-ethynylanilines (311) with a π-acidic tungsten carbonyl catalyst in the presence of light (to dissociate a ligand from the tungsten catalyst) resulted in the transient formation of an azomethine ylide−tungsten carbene hybrid 312. The resulting organometallic intermediate 312 then could perform cycloaddition reactions with various alkenes followed by 1,2-hydride migration to form polycyclic indoles 313 and regenerate the tungsten catalyst. There are also other unusual transition-metal-mediated strategies for generating N-alkyl azomethine ylide-like species that do not fit neatly into the catergories outlined in Scheme 100,469 but these are typically isolated reports. In comparison to 2-azaallyl anions (section 2), there are significantly more strategies available for the generation of N-

ization of these species412−424 and offering a rather esoteric source of N-alkyl azomethine ylides for further 1,3-dipolar cycloadditions with other dipolarophiles.420,421 Seidel and co-workers have introduced a decarboxylative variant to the redox-neutral iminium alkylation reactions discussed above (cf. Scheme 102). For example, condensation between proline and various aryl aldehydes at high temperature results in the decarboxylative formation of the resulting azomethine ylide 290a. Similar to their previoius studies, Seidel’s group demonstrated that these azomethine ylides can serve as transient species in imine isomerizations followed by nucleophilic attack from relatively acidic pro-nucleophiles such as naphthols (304), indoles (305), terminal alkynes (306), and nitroalkanes (307) (Scheme 104).425,426 Accordingly, the azomethine ylide intermediate serves as a base to deprotonate and further activate the nucleophilic species. In these C−C bond-forming reactions, the nucleophile preferentially attacks the nonbenzylic iminium tautomer to afford the substituted pyrrolidines 304−307 in moderate-to-good yields. Lithium−tin exchange is a powerful method for the generation of nonstabilized 2-azaallyl anions, as was discussed in section 2.3. Similarly, N-alkyl azomethine ylides can be generated from the corresponding stannylated precursors 297 via lithium−tin exchange (Scheme 100).427−432 A far superior related strategy for the generation of N-protonated and N-alkyl azomethine ylides, which is not as effective for the production of nonstabilized 2-azaallyl anions,17,433 is the fluoride-mediated desilylation of α-trimethylsilyl imines and iminiums (298), respectively.434−443 Vedejs444 and Tsuge433,444−446 were both early proponents of this synthetic strategy. The O-methyl aminal 299 and related compounds have arisen as stable 10440


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Scheme 108. Regiodivergent Cu-Catalyzed Dipolar Cycloadditions

covering stereodivergent transformations.470 In view of this significant coverage, only a few very recent highlights representing the forefront of the field will be presented herein. As with their purely organic counterparts, N-metalated azomethine ylides are powerful substrates for dipolar cycloaddition transformations. In the past two years, some advances in the [3 + 2] cycloaddition of N-metalated azomethine ylides are worth noting. For instance, new strategies to control the diastereo- and regioselectivities of these transformations have emerged. The Xiao group471 reported a copper-catalyzed, stereodivergent [3 + 2] cycloaddition with nitroalkenes (Scheme 107). By using two distinct P,S-ligands developed in their group (L5 and L6), the authors achieved excellent control of both the absolute and the relative configurations of pyrrolidine products 314 and 315, respectively. Similarly, Zhang and co-workers accomplished a regiodivergent coppercatalyzed [3 + 2] cycloaddition of azomethine ylides with α,βunsaturated enones (Scheme 108).472 Depending on the ligand employed (L7 or L8), either pyrrolines with two vicinal (316) or with two nonadjacent quarternary stereocenters (317)

protonated and N-alkyl azomethine ylides. Nevertheless, 2azaallyl anions are suitable for a broad range of transformations, whereas azomethine ylides have generally been limited to cycloaddition reactions. The redox-neutral C−C bond-forming reactions being introduced by Seidel and coworkers, however, suggest that the diversity of transformations involving azomethine ylide intermediates could possibly rival that of 2-azaallyl anions. 5.2. N-Metalated Azomethine Ylides

As mentioned in the Introduction, a near-universal feature of N-metalated azomethine ylides that functionally distinguishes them from semi- and nonstabilized 2-azaallyl anions is the presence of a chelating functional group, such as a carbonyl moiety, that stabilizes the N−M bond via formation of a fivemembered metallacycle. In the presence of suitable chiral ligands, the formation of such conformationally constrained metallacycles allows for the development of highly stereoselective transformations involving N-metalated azomethine ylides. Accordingly, N-metalated azomethine ylides have been used extensively in asymmetric organic synthesis and they have been reviewed extensively, including a very recent report 10441


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Scheme 109. Pd-Catalyzed Asymmetric Allylation of Cu−Azomethine Ylides

Scheme 110. Ir-Catalyzed Asymmetric Allylation of Cu−Azomethine Ylides

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ORCID

could be obtained in high regio-, diastereo-, and enantioselectivities. While N-metalated azomethine ylides are frequently employed as dipoles for cycloaddition reactions, recent advances have expanded their utility toward transition-metalcatalyzed cross-couplings. For example, the Zhang472,473 and Wang474,475 groups have each reported the use of azomethine ylides in the palladium-catalyzed (Scheme 109) and iridiumcatalyzed (Scheme 110) asymmetric allylic substitution reactions, furnishing the corresponding amino acid derivatives 318 (Scheme 109), 319, and 320 (Scheme 110) in high enantiomeric purity. Presumably, the palladium or iridium catalyst activates the allyl carbonate electrophiles, whereas the copper catalyst generates the cupracyclic azomethine ylide intermediates. These reactions demonstrated broad substrate scope. Remarkably, in the Ir/Cu cocatalytic reactions (Scheme 110), the authors used two individual ligands (L9 and L10) to complex with each metal to achieve separate control of the two stereocenters. As a result, this strategy allows for the synthesis of all four possible stereoisomers. The high degree of stereochemical and regiomeric control provided by reactions involving N-metalated azomethine ylides is a distinct advantage for this synthetic intermediate over 2azaallyl anions. Whereas 2-azaallyl anions have the advantage of participating in a broader range of tranformations, the impressive results involving the transition-metal-catalyzed asymmetric allylation of azomethine ylides indicate that this advantage is waning. Of course, the necessity for a carbonyl substituent or similar coordinating moiety for the N-metalated azomethine ylides still limits the scope of readily accessible scaffolds; this is not a limitation for 2-azaallyl anions, cations, and radicals.

Jason J. Chruma: 0000-0002-3669-4863 Author Contributions †

S.T. and X.Z.: These authors contributed equally to the review. Notes

The authors declare no competing financial interest. Biographies Shaojian Tang received his B.S. (2013) from the College of Chemistry at Sichuan University, where he performed research on the total synthesis of trisodium L-isocitrate in the research group of Prof. Jason J. Chruma. In 2013, he continued his graduate studies with Prof. Chruma at Sichuan University focusing on the development of new reactions involving the decarboxylative generation and functionalization of semistabilized 2-azaallyl anions. Mr. Tang expects to earn his Ph.D. in chemistry from Sichuan University in the near future. Xia Zhang earned her B.S. from China Pharmaceutical University (2006) and a Ph.D. degree at the University of Minnesota (2014) under the guidance of Prof. Elizabeth A. Amin. She has been working in the State Key Laborotary of Biotherapy at Sichuan University since 2015. Her research interests are on the design, synthesis, and evaluation of bioactive compounds. Jiayue “Jasmine” Sun received her B.S. (2015) from the College of Chemistry at Sichuan University, where she performed research on the palladium-catalyzed decarboxylative generation and asymmetric allylation of semistabilized 2-azaallyl anions under the supervision of Prof. J. J. Chruma. She recently earned her M.A. in chemistry from the University of Virginia and currently works for the Peking University Institution of Ocean. Dawen Niu received his B.E. (2002−2006) from Southeast University at Nanjing, China. He then moved to the University of Minnesota to pursue his Ph.D. degree (2008−2013) under the tutelage of Prof. Thomas R. Hoye, where he focused on the biomimetic total synthesis of okilactomycins and on the hexadehydro-Diels−Alder reactions. After completing a postdoctoral study with Prof. Stephen L. Buchwald at MIT (2013−2015), he started his independent career at Sichuan University as a 1000 Talents program professor. Currently, the research activities in the Niu group include the development of unconventional (umpolung) approaches for making amines, as well as methods to achieve site-selective modification of polyhydroxylated natural products, such as glycosides. http://niugroup.com.

6. CONCLUSIONS AND OUTLOOK Throughout this review, effort has been made to provide conclusions and suggestions for future investigations at the end of each section. Nevertheless, there is still room for a general summary and outlook. The 2-azaallyl anion and azomethine ylide intermediates trace their heritages back to the beginnings of organic chemistry as a distinct field of science. Despite this deep history, significant and novel advances using these species for organic synthesis continue to be made on a regular basis. The recent discovery that semistabilized 2-azaallyl anions can serve as organic electron donors to generate radical species has envigorated the field and mandates a broader scope of mechanistic considerations for reactions involving 2-azaallyl anions. Similarly, the relatively recent discovery of transitionmetal-catalyzed C−H activation as a means to generate 2azaallyl cationic species finally offers a more general approach to these intriguing reactive species. Finally, the use of transition metal catalysis for transformations involving semistabilized 2azaallyl anions and radicals is still a relatively nascent field and is ripe for further conquest. Of particular interest is the development of C−C bond-forming reactions involving 2azaallyl species that elicit the same outstanding levels of stereocontrol and regiocontrol as seen with N-metalated azomethine ylides.

Jason J. Chruma received his B.S. with Honors (1997) from the University of Arizona, where he carried out research on the synthesis of alkaloids with Prof. Robin Polt. Under the guidance of Prof. Amos B. Smith, III, he obtained his Ph.D. (2002) from the University of Pennsylvania pursuing studies focused on the synthesis of natural and designed small molecule HIV-1 viral entry inhibitors. After completing an NIH postdoctoral fellowship with the late Prof. Ronald C. Breslow at Columbia University in 2005, he initiated his independent career as an assistant professor at the University of Virginia. In 2012, he moved to Sichuan University, where he is currently a professor and Assistant to Dean in the College of Chemistry. Research in Prof. Chruma’s laboratory has been dedicated primarily to the decarboxylative generation and alkylation of 2-azaallyl anions with recent entrance into 2-azaallyl radical chemistry; other research activities include the total synthesis of bioactive natural products and structural analogues, medicinal chemistry, and the design and synthesis of functional/luminescent organic materials. http://chem.scu.edu.cn/En/J.Chruma

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected] (D.N.). *E-mail: [email protected] (J.J.C.). 10443


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