Recent advances in organocatalytic asymmetric aza-Michael reactions of amines and amides

Nitrogen-containing scaffolds are ubiquitous in nature and constitute an important class of building blocks in organic synthesis. The asymmetric aza-Michael reaction (aza-MR) alone or in tandem with other organic reaction(s) is an important synthetic tool to form new C–N bond(s) leading to developing new libraries of diverse types of bioactive nitrogen compounds. The synthesis and application of a variety of organocatalysts for accomplishing highly useful organic syntheses without causing environmental pollution in compliance with ‘Green Chemistry” has been a landmark development in the recent past. Application of many of these organocatalysts has been extended to asymmetric aza-MR during the last two decades. The present article overviews the literature published during the last 10 years concerning the asymmetric aza-MR of amines and amides catalysed by organocatalysts. Both types of the organocatalysts, i.e., those acting through non-covalent interactions and those working through covalent bond formation have been applied for the asymmetric aza-MR. Thus, the review includes the examples wherein cinchona alkaloids, squaramides, chiral amines, phase-transfer catalysts and chiral bifunctional thioureas have been used, which activate the substrates through hydrogen bond formation. Most of these reactions are accompanied by high yields and enantiomeric excesses. On the other hand, N-heterocyclic carbenes and chiral pyrrolidine derivatives acting through covalent bond formation such as the iminium ions with the substrates have also been included. Wherever possible, a comparison has been made between the efficacies of various organocatalysts in asymmetric aza-MR.


Introduction
The Michael reaction though discovered about 135 years ago [1,2] continues to attract attention of the chemists owing to its potential of making a vast variety of organic compounds partic-ularly of pharmacological importance accessible. Over the years, its many versions known as aza-Michael, thio-Michael, oxa-Michael, phospha-Michael, etc. have been developed and well exploited for their synthetic applications [3][4][5][6][7]. The reaction involving a nitrogen-based nucleophile as the Michael donor is known as the aza-Michael reaction (aza-MR). In view of its ability to introduce a nitrogen-containing functionality at the β-position of an activated alkenyl-or alkynyl-substrate, over the years, it has developed as an important synthetic strategy for the preparation of a large variety of β-amino carbonyl and similar motifs which are present in many bioactive natural products [8,9], antibiotics [10][11][12] and chiral auxiliaries [13][14][15]. However, the reaction of many nitrogen-nucleophiles, such as aromatic amines, amides, imides, etc. require the use of an appropriate catalyst to undergo a Michael addition with a suitable acceptor. In view of this, chemists endeavoured to develop different types of catalysts, particularly the chiral catalysts to accomplish asymmetric aza-MRs. The development of metal-free small organic molecules as catalysts has been a landmark advancement in organic synthesis in the recent past [16]. MacMillan and co-workers for the first time in the year 2000 termed these catalysts as 'Organocatalysts' [17]. It was followed by intense activity and phenomenal rise in the number of publications in this field. These organocatalysts have been found compatible with many aspects of 'Green Chemistry' on the one hand, and highly selective in many organic syntheses on the other hand [17]. It has an added advantage that a large number of enantiomerically pure organocatalysts can be accessed from the chiral pool. Both types of organocatalysts, namely those acting through non-covalent bonding as well as those working by making covalent bonding have been employed for accomplishing asymmetric aza-MRs.
There are several review articles available on organocatalytic asymmetric aza-MRs, each highlighting a certain aspect of the reaction. While Sánchez-Roselló et al. [18] classified these reactions on the basis of the nature of the substrates, Nayak et al. [19] and Bhanja et al. [20] focused on the stereoselective synthesis of nitrogen heterocycles via Michael cascade reactions. Recently, Vinogradov et al. [21] reviewed the synthesis of pharmacology-relevant nitrogen heterocycles via stereoselective aza-MRs. On the other hand, Enders et al. [22], Wang et al. [23] as well as Krishna et al. [24] highlighted the scope and catalytic performances of some organocatalysts in asymmetric aza-MRs. However, the last three review articles are almost 10 years old and they do not cover the application of many important organocatalysts, such as thioureas and nitrogen heterocyclic carbenes (NHCs) used for the asymmetric aza-MRs. Furthermore, in the last review article [24], the application of organocatalysts is included as a small part of a general review. In view of this, we considered it prudent to compile this mini review exclusively based on the application of all categories of the organocatalysts and highlighting their efficacies covering the literature of the last ten years.

Review
In the present review, the known stereoselective syntheses of pharmacology-oriented nitrogen containing heterocyclic scaffolds via non-covalent bonding and covalent bonding organocatalytic aza-MRs has been systematized. This classification is especially useful for researchers to understand both the noncovalent and covalent organocatalysis.
It is intended to overview the literature of the last 10 years, i.e., from 2011 through 2020 only. Nevertheless, wherever necessary, earlier references may also be cited to maintain coherence. Furthermore, nitrogen nucleophiles comprise a large variety of compounds; however, in order to comply with the requirements of a mini review, additions of amines and amides only will be included.

Reactions catalyzed by chiral cinchona alkaloid derivatives
Cai et al. prepared and used a number of organocatalysts from Cinchona alkaloids for the aza-MR of aniline (1) with chalcone (2) to obtain the adducts 4 in poor to very good yields (24 to >99%) with poor to moderate ee (9 to 55%). A complete reversal of stereoselectivity was observed on introducing a benzoyl group in cinchonine and cinchonidine. It was demonstrated that racemization occurred in suitable solvents under mild conditions due to retro-MR of the initially formed Michael adduct (Scheme 1) [25]. The proposed catalytic cycle involved generation of the active complex through hydrogen bonding between catalyst and aniline followed by interaction with chalcone via π-π stacking of aromatic rings and hydrogen bonding leading to the Michael adduct.
In this case, the role of Ph 3 CCO 2 H as additive is to furnish the conjugate base Ph 3 CO 2 − anion which subsequently deproto-Scheme 1: Asymmetric aza-Michael addition catalyzed by cinchona alkaloid derivatives. nates pyrrole to provide the stronger nucleophilic pyrrolide anion [27].
Similarly, Liu et al. accomplished an asymmetric intramolecular aza-Michael addition of various enone carbamates 10 using a chiral cinchona-based primary-tertiary diamine as catalyst to obtain 2-substituted piperidines 12 in good yields (75-95%) with up to 99% ee. Several sulfonic acids and carboxylic acids were tested as co-catalysts and trifluoroacetic acid (TFA) was found to give the best results [28]. Here the role of the co-catalyst is to assist in the formation of the iminium intermediate ( Table 2) [29]. It appears that in this case, both activation mech-  anisms, namely through hydrogen bonding and iminium ion formation are operating.
Using the same chiral cinchona-based primary-tertiary diamine as catalyst (cat. 11), Zhai et al. developed a highly efficient intramolecular enantioselective aza-Michael addition of carbamates, sulfonamides and acetamides 13 bearing an α,β-unsaturated ketone to synthesize a series of 2-substituted five-and sixmembered heterocycles in good yields (up to 99%) and excellent enantioselectivity (92-97.5% ee) ( Table 3). As in an earlier Scheme 2: Intramolecular 6-exo-trig aza-Michael addition reaction. case [29], several acids were tested as co-catalysts and trifluoroacetic acid and diphenyl hydrogenphosphate (DPP) were found to give the best results [30].
Jakkampudi et al. [33] adopted a different approach for the use of cinchona-based organocatalysts. Instead of using the cinchona derivative alone, they employed a mixture of cinchona derivative and amino acid such as ᴅ-proline, termed as the modularly designed organocatalyst (MDO) for the synthesis of bridged tetrahydroisoquinoline derivatives. It was perceived that the MDO self-assembled in situ from amino acids and cinchona alkaloid derivatives. For example, on reacting (E)-2- in the presence of the MDO 23/24 (quinidinethiourea + ᴅ-proline), instead of the expected domino Mannich/Michael product, the bridged tetrahydroisoquinoline product 25a was obtained in high yield (90%) and excellent dr (94:6) and ee value (99%) ( Table 5). The controlled reactions using 23 and 24 as the catalyst gave the product in very poor yield. It was concluded that the catalytic activity of the MDO was the result of the cooperative action of both constituents. Several examples of such MDOs are included in the paper. The reported yield varies from 56-90% with excellent ee ≈ 99% in all cases.

Reactions catalyzed by chiral squaramide derivatives
Squaramides are related to cinchona alkaloids but are much more effective organocatalysts than the latter due to the ability of dual hydrogen bonding besides a tertiary nitrogen atom of quinuclidine nucleus which may serve both as an H-bond acceptor and a base in asymmetric Michael addition reactions [34,35].
In 2018, Sallio et al. worked on the same reaction by using different PTCs in order to improve yield and diastereomeric excess. They incorporated PTC and chiral auxiliary and reacted

Catalysis by chiral bifunctional thioureas
Thioureas constitute one of the most important class of organocatalysts [49]. In an interesting report, five organocatalysts belonging to three categories, namely cinchona alkaloid bases, bifunctional squaramides and thioureas were screened for the enantioselective N-alkylation of isoxazolin-5-ones via a 1,6-aza-Michael addition of isoxazolin-5-ones 64 to p-quinone methides (p-QMs) 65 to give isoxazolin-5-ones 67 bearing a chiral diarylmethyl moiety attached to the N atom. The best result in terms of enantioselectivity (85% ee) was obtained with quinine-derived thiourea in dichloroethane as the solvent. The scope of the reaction was also investigated vis-a-vis the effect of the substitution on the isoxazolinone ring and p-quinone methide (p-QM) partner. (Table 15) [51].
Takemoto and co-workers investigated three catalytic systems, namely arylboronic acid alone, its dual combination with chiral thiourea and integrated catalyst having boronic acid functionality in the chiral thiourea molecule. The dual combination of arylboronic acid with chiral thiourea was found as effective as arylboronic acid alone for the intermolecular asymmetric Michael addition of alk-2-enoic acids 68 with O-benzyl-hydroxylamine (69) giving racemic mixture of the product in poor yield. However, the integrated catalyst having boronic acid functionality in the chiral thiourea molecule gave the desired β-benzyloxyamino acid as the single product in a satisfactory yield. Thus, a series of these catalysts was screened. The best results in term of the yield (83%) and ee (90%) were obtained while using the catalyst having a p-nitrophenyl group on the other side of thiourea moiety in CCl 4 in the presence of 4 Å molecular sieves (Table 16). The yields ranged 57-89% with ee 70-97% [52].
A similar chiral multifunctional thiourea/boronic acid was used as an organocatalyst by Michigami et al. for the enantioselective synthesis of N-hydroxyaspartic acid derivatives 76 with perfect regioselectivity and high enantioselectivity (Table 17) [53].
Likewise, Miyaji et al. reported an efficient method for the synthesis of 2-substituted indolines 79 via intramolecular aza-Michael addition of α,β-unsaturated carboxylic acid derivatives 77 in the presence of bifunctional thiourea organocatalysts (cat. (Table 18). The product was obtained in moderate to good yield of 53-99% with an ee of 74-93% [54].

Catalysis by chiral pyrrolidine derivatives
Chiral pyrrolidine derivatives, such as (S)-proline are widely used as organocatalysts [54,64].     106) and using PhCO 2 H as the acid additive. Desired products were obtained in good yields ≈78% with excellent enantioselectivities of up to 93% (Table 24) [65]. The role of the additive is to assist in the formation of the iminium intermediate from the reaction of pyrrolidine with the aldehyde group.
Following a similar approach, Guo et al. accomplished the first organocatalytic asymmetric aza-Michael addition of purine bases 108 to aliphatic α,β-unsaturated aldehydes 109 and synthesized biologically active acyclonucleoside 110 via an iminium-ion activation mechanism. The initially formed prod-uct was reduced in situ to afford the final product in 82-89% yield and 89-96% ee (   Recently, the synthesis of axially chiral 4-naphthylquinoline-3carbaldehydes 117 has been reported via Michael/Aldol cascade reaction of alkynals 116 with N-(2-(1-naphthoyl)phenyl)benzenesulfonamides 115 using the same pyrrolidine catalyst 113. The products were obtained in excellent yields and enantioselectivities (Table 27) [68]. In this context, the presence of a strong electron-withdrawing sulfonyl group was found to be essential. On comparing efficacies of different sulfonyl [69]. The reaction with secondary amines occurred via the formation of HOMO raised dearomative aza-dienamine-type intermediates, which undergo direct aza-Michael addition to β-trifluoromethyl enones to afford N-functionalized heteroarenes 121 efficiently in moderate to excellent yields, albeit with low to fair enantioselectivity. However, asymmetric aza-Michael additions of these heteroarenes with crotonaldehyde yielded the adducts in moderate to good enantioselectivity under dual catalysis of chiral amines (Scheme 5) [69].

Conclusion
The asymmetric aza-Michael reaction being a useful synthetic strategy for constructing C-N bonds to make a variety of nitrogen-containing chiral scaffolds of wide applications in the fields of pharmaceuticals, organic synthesis building blocks and accessible catalysis continues to attract attention of the chemists. During the last two decades, many new chiral organocatalysts have been developed for accomplishing these reactions with the nitrogen nucleophiles, such as aromatic amines and amides which are otherwise averse to reacting. The organocatalysts have emerged as catalysts of choice due to various reasons, such as their compatibility with the 'Green Chemistry' and possibility of tailoring them according to the requirements. Efforts are directed towards enhancing not only the yields of the products but also enantio-and diastereoselectivities of the aza-Michael reactions. New strategies have been adopted while making optimum utilization of the efficacies of the catalysts. Of these strategies, cascade reactions of the Michael addition in conjunction with one or more reactions leading to overall very high yields and ee are noteworthy. Another strategy of interest appears to be the generation of organocatalysts of enhanced efficacy in situ by mixing squaramides with amino acids again giving >99% ee. It may be perceived that in the coming years, more sophisticated methodologies will be developed with the advent of new organocatalysts to accomplish asymmetric aza-Michael reactions of even the so far unexplored and obstinate amines and amides substrates.