Recent advances in catalytic asymmetric condensation reactions for the synthesis of nitrogen containing compounds

Abstract

Asymmetric synthesis of functionalized nitrogen-containing compounds has been a hot topic. The condensation of amines with carbonyl compounds presents one of the most efficient methods for the synthesis of nitrogen-containing compounds, such as imines, enamines and α-amino ketones, which have applications in many fields. This review summarizes the most significant concepts and advances in this field, focusing on desymmetrization or dynamic kinetic resolution, the de novo cycloaromatization and the Heyns rearrangement. Additionally, we expect our review to inspire the design of related structures or condensation reactions.

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1. Introduction

The asymmetric synthesis of functionalized nitrogen-containing compounds has been the subject of intensive research, in part because of their importance in synthetic chemistry,¹ pharmacy,² and agriculture³ (Fig. 1). Among the numerous types of nitrogen-containing compounds, imines with different substituent groups have garnered increasing attention due to their potential application in pharmaceuticals, such as antibacterials, antimalarials and antifungals, as well as being useful synthetic intermediates including Schiff bases and sulfinimines. As important synthons, imines conventionally act as electrophiles in a variety of reactions, including reductions, additions, condensations and cycloadditions.⁴ To date, several strategies have been developed for the construction of imines, including the oxidative dehydrogenation of amines,⁵ the oxidative coupling of alcohols with amines,⁶ the hydroamination of alkynes with amines⁷ and miscellaneous reactions.

Fig. 1 Nitrogen-containing compounds exhibiting biological activities and nitrogen-containing chiral ligands/catalysts.

Carbonyl compounds play an indispensable role in various synthetic reactions. The positively charged carbonyl carbon in aldehydes and ketones is vulnerable to attack, forming carbon–carbon or carbon–heteroatom bonds. However, the reactivity of the carbonyl bond is primarily due to the difference in electronegativity between carbon and oxygen, which leads to a significant contribution of the dipolar resonance form, with oxygen being negative and carbon being positive. Carbonyl compounds can be easily attacked by amino compounds owing to such properties. The direct condensation reaction of carbonyls with amines presents the most efficient method for the synthesis of imines in a nearly 100% yield with water as the only by-product.

Normally, the condensation of amines with aldehydes or ketones contributes to the formation of imines or enamines,⁸ which are the key to both organocatalytic and enzymatic cycles,⁹ as well as to various important transformations such as Mannich, Betti, Strecker, Paal–Knorr reactions and so forth.¹⁰ Additionally, α-amino ketones can also be obtained through the direct condensation reaction stepped by the Heyns rearrangement (Scheme 1).¹¹ Notably, the direct condensation reaction is increasingly irreplaceable in the design of chiral ligands and biomimetic catalyst cycles.¹² Given its high atomic efficiency and extensive applications, the direct asymmetric condensation reaction between designed carbonyl compounds and amines is highly worthwhile. However, two significant challenges must be addressed: (1) obtaining stable condensation products to ameliorate the decomposition or racemization of the chiral imines and (2) identifying a suitable amine with basicity and nucleophilicity to avoid quenching of the chiral acidic catalysts or causing serious non-catalytic background reactions.

Scheme 1 The direct condensation reaction of carbonyls and amines.

Our recent efforts have focused on the enantioselective synthesis of atropisomers via the one-step condensation reaction. To the best of our knowledge, no specific review on the construction of chiral nitrogen-containing compounds via the direct carbonyl-amine condensation has been published to date. This review provides a comprehensive overview of catalytic asymmetric condensation reactions, which covers the desymmetrization or dynamic kinetic resolution (DKR), the de novo cycloaromatization and the Heyns rearrangement for the asymmetric synthesis of imines, enamines, or α-amino ketones with their classification based on the methodology. Both one-step condensation and the direct condensation stepped by isomerization or rearrangement are included.

2. Desymmetrization or dynamic kinetic resolution

The establishment of central chirality during the condensation process is contingent upon the design of specific reactions, as the reactive site does not allow for the generation of new stereocenters. Significant advances have been made in the desymmetrization or DKR of prochiral substrates for use in asymmetric condensation reactions. In 2017, Antilla and co-workers achieved the first efficient catalytic asymmetric reaction for the synthesis of chiral cyclohexylidene oxime ethers 4–5 via the desymmetrization or DKR of 4-phenyl cyclohexanones 1–2 with hydroxylamine 3 (Scheme 2),¹³ which showed an obvious temperature dependence. A lower yield was obtained, which might be attributed to the decomposition of the starting hydroxylamine by the subdued kinetics of the condensation process at lower temperature. A poor stereogenic effect also occurred when the temperature was increased. Notably, the above problems could be solved through the introduction of a Lewis acid, with the reaction catalyzed by Sr(C1) instead of C1. Substituents at the para position of the phenyl ring of 3 gave the corresponding products in excellent yields with good enantioselectivities. In contrast, only racemic products were afforded by using aliphatic oxyamines, which indicated the pivotal role of the phenyl group of 3 in the enantiomeric induction process. 4-Substituted cyclohexanones with electron-donating or electron-withdrawing groups on the phenyl group were well tolerated (Scheme 2a). Besides, a variety of substrates 2 were synthesized. Both electron-donating groups and electron-withdrawing groups at the ortho position of the carbonyl were tolerated, leading to the expected products in good yields and enantioselectivities (Scheme 2b). A computational study of the desymmetrization reaction was also carried out, which was in excellent agreement with the obtained experimental ee values, and the dehydration of the intermediate alcohol in the presence of chiral phosphoric acid (CPA) was demonstrated as the stereocontrolling step, providing insight into the mode of stereoinduction.

Scheme 2 Asymmetric synthesis of chiral cyclohexylidene oxime ethers from cyclohexanones.

The desymmetrization of readily available meso 1,3-diones has a wide range of applications in the synthesis of chiral ketones en route to significant natural products.¹⁴ As demonstrated by Mukherjee's research, the formation of enantioselective hydrazones is theoretically possible in the presence of chiral Brønsted acids. However, achieving high enantioselectivity remains a challenge in such a process. The direct condensation product, hydrazones 8′, was obtained with poor ee via the direct approach combining 2,2-disubstituted cyclopentane-1,3-diones 6 with N-protected phenylhydrazines 7, catalyzed by (S)-C2 (Scheme 3a). In this condensation process, no final product 8 was formed at 40 °C. Interestingly, cyclopenta[b]indolones 8 with good to excellent enantioselectivities could be produced in significant quantities when the condensation product 8′ was exposed to (S)-C2 and ZnCl₂ in the presence of Amberlite-IR120, a strongly acidic cation exchange resin, at 80 °C. The observation indicated that the condensation product, hydrazones 8′, was reversible and the subsequent products 8 proceeded through the DKR of the initially formed enantiomeric hydrazones 8′. Notably, the cation exchange resin plays an important role in maintaining a balance between the background reactions and making the reaction catalytic by removing the stoichiometric by-product ammonia.¹⁵

Scheme 3 Enantioselective synthesis of cyclic and acyclic keto-hydrazones.

Almost simultaneously, Zhao's group developed an unprecedented desymmetrization of meso 1,3-diones 10–11 through enantioselective intermolecular condensation, which was catalyzed by CPA (R)-C3 (Scheme 3b).¹⁶ Various 1,3-diones with differing cyclic skeletons were subjected to the direct condensation reaction, including meso 1,3-cyclopentanediones, 1,3-cyclohexanediones and acyclic 1,3-diones. Cyclic and acyclic keto-hydrazones 12 and 13 bearing an all-carbon quaternary center were synthesized with high efficiency and enantioselectivity using a range of readily available 1,3-diones and hydrazines 9. A series of control experiments were carried out by the authors. It was demonstrated that the second condensation step worked as a kinetic resolution (KR) to help enhance the enantioselectivity of the desired products. DFT calculations were performed to elaborate the mechanism. The results revealed that the formation of the keto-hydrazone was a reversible process, which was consistent with the need for molecular sieves in the current system. Moreover, the dehydration process was found to be both rate- and enantio-determining, and whether the nucleophilic attack step contributed to the enantiocontrol of such a reaction could not be excluded.

Most well-developed axially chiral compounds contain a rotationally restricted bond linking (hetero)arenes. In pursuit of diverse frameworks, Tan's group explored the axial chirality of cyclohexadienylidene compounds by breaking the symmetry of the substituted cyclohexadienone 14 (Scheme 4a).¹⁷ The hydrazone and oxime derivatives could be furnished via the dearomatization of azobenzenes and the condensation of cyclohexadienones. A complementary route toward axially chiral cyclohexadienylidene structures was achieved via an enantioselective condensation reaction, motivated by the successful establishment of a catalytic asymmetric dearomatization strategy. Condensation products bearing diverse groups at the para position of cyclohexadienone could be obtained with good to excellent enantioselectivity and regioselectivity in the presence of phosphoric acid C4–C6. These findings would significantly improve the structural diversity and application range of axially chiral compounds.

Scheme 4 Enantioselective synthesis of axially chiral cyclohexadienylidene and anthrone-based skeletons.

As mentioned previously, novel axially chiral cyclohexanone and cyclohexadienone structures were synthesized through the catalytic asymmetric condensation reaction or dearomatization of azo-substituted benzenes. An efficient and stereoselective protocol for obtaining axially chiral anthrone-based compounds was achieved by the same group via the oxime functionalization of symmetric anthrones 16 (Scheme 4b). A spiro chiral phosphoric acid (SPA) C7 was used to control the E/Z configuration of oxime effectively and confer the axial chirality significantly. Combined with previous literature reports, the authors pointed out that the stereoinduction of this condensation reaction should occur at the dehydration step where the SPA catalyst establishes hydrogen bonding interactions with the NH group and protonates the hydroxyl group for water elimination. A series of enantioenriched axially chiral anthrone-based oximes 17 were obtained with considerable modulations on the anthrones and hydroxyl amines. In addition, optical seven-membered dibenzazepinones 18 were acquired via the Beckmann rearrangement with axial-to-point chirality conversion.¹⁸

The concept of inherent chirality was initially defined as the isomerism in calixarene frameworks. Over time, this definition has been extended to represent chirality derived from the rigid structure of medium- or large-sized ring systems.¹⁹ Interestingly, a CPA-catalyzed condensation reaction of seven-membered cyclic ketones 19 with hydroxylamines was developed by Liu and colleagues.²⁰ A series of tribenzocycloheptene type oxime ethers 20 bearing inherent chirality were synthesized in good yields with excellent enantioselectivities. Tropinone-based chiral oxime ethers 21 could also be obtained in the presence of DCE instead of CCl₄. Moreover, O-benzyl hydroxylamine, tosylhydrazide and N-amino indole were also tolerated under slightly modified reaction conditions, affording the seven-membered inherently chiral products in moderate ee values (Scheme 5).

Scheme 5 Enantioselective synthesis of axially chiral tropinone-based chiral oxime ethers.

Recently, our group developed the phosphoric acid catalyzed atroposelective synthesis of axially chiral heterobiaryl oxime ethers through the one-step condensation reaction of configurationally labile aldehydes 22 with hydroxylamines (Scheme 6). Various axially chiral heterobiaryl oxime ethers 23 were obtained with good to excellent chemical yields and enantioselectivities. DFT calculations were carried out to further elucidate the mechanism of the reaction as a DKR route, of which the racemization of azabiaryl aldehyde could proceed well via the hemiacetal intermediate generated in situ by the intramolecular n → π* interaction. Moreover, a scale-up reaction and significant derivatizations were conducted. The late-stage transformation of the C–N bond in the products, including the synthesis of chiral catalysts/ligands and the modification of chiral drugs, provided access to a variety of structurally diverse and novel atropisomers, which well demonstrated the wide applications of this study.²¹

Scheme 6 Enantioselective synthesis of axially chiral hetero-biaryl oxime ethers.

The method has been applied to the synthesis of enamines. In addition, KR is a practical method to afford products with high enantiomeric excess and recover starting materials from simple racemic starting materials.²² In particular, the KR of racemic amines with carbonyls has been developed for the synthesis of chiral nitrogen-containing compounds through condensation reactions. In 2022, the synthesis of enamines with cyclobutanes via the direct condensation reaction was developed by Zeng and coworkers.²³ As shown in Scheme 7, the enantioselective condensation of 2,2-disubstituted cyclobutane-1,3-diones 24 with a primary amine 25 was achieved in the presence of CPA C1. This reaction provided a mild and efficient protocol for constructing quaternary carbon-containing cyclobutanes 26 in good to high yields and enantioselectivities.

Scheme 7 Enantioselective synthesis of stable alkyl-substituted enamines.

Among them, benzyl groups, allyl and other linear aliphatic substituents were also well tolerated. It was demonstrated that the introduction of an electron-donating or electron-withdrawing group at the ortho or meta position of the benzyl group (R¹) had no significant effect on the enantioselectivities of the reaction, whereas the existence of steric substituents at the para position could slightly improve the ee values. Furthermore, the synthesis of chiral enamines en route to a series of fully substituted cyclobutenone derivatives was conducted in a manner that preserves the enantioselectivities.

In 2017, List's group reported a KR of primary amines via the condensation reaction between a carbonyl compound and an amine in the presence of CPA C8 (Scheme 8). The 1,3-diketones 27 reacted with the racemic α-branched amine 28, affording the corresponding enantiomerically enriched enamine ketones 29 and the recovered raw material successfully.²⁴ A broad range of rac-benzylic amines with different electronic substituents at different ring positions gave significantly enhanced selectivity factors. Aliphatic primary amines could also be afforded by this method with good to excellent selectivities. A gram scale experiment was also carried out, of which the reaction with only 1 mol% of catalyst (S)-C8 proceeded smoothly with a satisfactory s-factor, giving (R)-29′ in 41% yield with an 88% ee value. The chiral amine (S)-28′′ derived from rac-28 was isolated in 46% yield with a 90% ee value (Scheme 8). This method represents the first catalytic KR of aliphatic amines, which provided a general concept for enantioselective catalytic amine-carbonyl condensations and might be widely applicable to other transformations.

Scheme 8 Enantioselective synthesis of chiral α-branched enamine ketones.

Then the construction of chiral cycloimines with a stereogenic center via the intramolecular asymmetric condensation reaction followed by an isomerization step was reported. In 2022, Yang and coworkers developed a CPA-catalyzed intramolecular dehydrative cyclization for the asymmetric synthesis of hydroquinazolines bearing C4-tetrasubstituted stereocenters via the KR of 2-amido α-tertiary benzylamines 30 (Scheme 9).²⁵ A series of aryl and alkyl substitutions at the benzylic position, N-aryl groups, and substitutions at the benzene ring were investigated under the standard conditions, giving both the recovered α-tertiary benzylamines and hydroquinazolines with high enantioselectivities. However, the KR of the corresponding α-secondary amine using this method surprisingly afforded an extremely low s-factor, and only moderate KR performance was obtained after screening modified CPA as the optimal catalyst. A plausible explanation was proposed by the researchers, suggesting that the disubstitutions at the benzylic position of these substrates give rise to the Thorpe–Ingold effect.²⁶ Moreover, an intriguing restricted rotation of the C–N bond was observed for the hydroquinazolines with crowded C4-tetrasubstituted stereocenters, providing ideas for the design of axially chiral compounds.

Scheme 9 Intramolecular asymmetric synthesis of hydroquinazolines bearing C4-tetrasubstituted stereocenters.

3. De novo cycloaromatization

The imine or enamine nature of the products obtained from the carbonyl-amine condensation allowed them to undergo various transformations to construct a series of nitrogen-containing compounds. Among them, the carbonyl-amine condensation followed by a simple isomerization step or the continued carbonyl-amine condensation contributes to the de novo cycloaromatization, which paves an important way to the enantioselective synthesis of atropisomers. Notably, the condensation reaction stepped by oxidation²⁷ for the synthesis of axially chiral nitrogen-containing compounds is excluded in this review considering the structural integrity of the article.

Catalytic reactions that address both stereogenic carbon and an element of axial chirality have rarely been developed. In 2018, Miller's group realized that (R)-C1 catalysts could efficiently control the enantioselectivity of the cyclodehydration process, leading to highly enantioenriched benzimidazoles 33 bearing a stereogenic C–N bond axis (Scheme 10).²⁸ In general, centrally chiral compounds 32 were initially formed via the metal–peptide catalyzed enantioselective C–N cross-coupling, the molecular outputs of which were then found to undergo cyclodehydration reactions in the presence of CPA, affording the axially chiral C–N atropisomers 33. Interestingly, biologically inspired pThr-containing peptidyl catalysts were found to catalyze the relative reactions efficiently, which laid the foundation for the subsequent asymmetric condensation cyclization reaction.

Scheme 10 Atroposelective synthesis of axially chiral C–N atropisomers via cyclodehydration.

Based on the above research in Scheme 10, an atropisomeric enantioselective cyclodehydration reaction of 34 was achieved by the same group (Scheme 11).²⁹ In this study, the steric effects of relatively large groups on the catalyst and substrate appear to determine the enantioselective control of C9. A pThr-type C10 was also introduced to the catalytic enantioselective reaction. It was shown that the pThr-type catalyst appeared to work through another enantiomerically induced mode, in which conformational adaptation might limit the repulsive interaction. It is noteworthy that cyclodehydrations proceed efficiently with both catalysts, which exhibited approximately the same catalytic capabilities with different substrates. The descriptive classification of these asymmetric catalysts reveals an increasingly broad set of catalyst types operating with different mechanistic characteristics, opening new opportunities for extensive and complementary application of catalyst supports in different matrix spaces.

Scheme 11 Disparate catalytic scaffolds for atroposelective cyclodehydration.

Due to the instability of the imine structure, especially the one furnished with α-alkyl groups, the imine intermediate generated via the first condensation tends to react with another carbonyl group. Such continued carbonyl-amine condensation reactions enable the formation of stable five-membered heterocyclic compounds or six-membered heterocyclic compounds. The atropisomers can be obtained via the de novo cycloaromatization, including the asymmetric synthesis of axially chiral heterobiaryls via the typical reactions such as Paal–Knorr and Friedländer reactions, which have been intensively explored.

The pyrrole moiety is among the fundamental building blocks in organic synthesis, which appears frequently in natural products and pharmaceuticals, with many advanced research studies being recently reported on this moiety.³⁰ The Knorr pyrrole reaction is used for the synthesis of pyrrole and substituted pyrrole, which involves the condensation of α-aminoketones with other ketones or compounds containing an electron-withdrawing group.³¹ The enantioselective atropisomers furnished with a C–N axis or N–N axis can be efficiently obtained based on the design of starting materials. In 2017, enantiomerically pure arylpyrroles 38 were significantly synthesized by Tan and colleagues via the catalytic asymmetric Paal–Knorr reaction of 1,4-diketones 36 and primary aryl-amines 37 for the first time (Scheme 12).³² It was suggested that CPA might be capable of facilitating the transformation enantioselectively by accelerating the intramolecular nucleophilic addition to form hemiaminal. Arylpyrroles with good yields and ee values could be obtained under the combined acid system of a Lewis acid and CPA, which played an important role in improving the enantioselectivities via the synergistic interaction between the substrates and the catalysts. Furthermore, the absolute configuration of the obtained arylpyrroles could be reversed by only changing the solvent from CCl₄ to MeOH. Various 1,4-diketones and aromatic amines exhibiting different electronic properties and positions of the aromatic ring were also tolerated under the current catalytic system.

Scheme 12 Atroposelective synthesis of arylpyrroles by the Paal–Knorr reaction.

Subsequently, in 2019, an efficient organocatalytic atroposelective three-component cascade reaction of 2,3-diketoesters 39, aromatic amines 37 and 1,3-cyclohexanediones 40 was developed by Lin's group (Scheme 13).³³ The feature of this method for the highly enantioselective synthesis of axially chiral N-arylindoles 41 was highlighted by using a newly developed second-generation SPA (R)-C12, which was the key to improving the enantioselectivity. As illustrated in Scheme 13, the SPA was supposed to catalyze the aldol reaction, thereby generating a stereocenter. This would then afford the axially chiral arylindoles through the central chirality to axial chirality transformation during the dehydration/aromatization step. A variety of axially chiral arylindoles were obtained in high yields with good to excellent enantioselectivities. The chiral products, which showed potential as chiral ligands or organocatalysts in asymmetric catalysis, could be employed for the synthesis of an axially chiral monophosphorus ligand 41′.

Scheme 13 Atroposelective three-component cascade reaction of axially chiral N-arylindoles during the dehydration/aromatization step.

In 2022, Zhao and co-workers employed the organocatalytic asymmetric Paal–Knorr reaction to develop a highly efficient atroposelective synthesis of axially chiral 1,1′-bipyrroles 43 bearing an N–N linkage in the presence of SPA.³⁴ Through continued carbonyl-amine condensation, readily available hydrazines 42 and 1,4-diones 36 could be transformed into target compounds. Interestingly, the addition of Fe(OTf)₃ to the reaction resulted in a switch to the enantiomeric products with high efficiency and enantiopurity. Variations on the ester moiety and different substituents on the aryl unit of 1,4-diones were also tolerated. Notably, the β-ketoester moiety provides a valid reason for the enamine tautomerization en route to the desired pyrroles (Scheme 14).

Scheme 14 Atroposelective synthesis of 1,1′-bipyrroles bearing a chiral N–N axis via the asymmetric Paal–Knorr reaction.

Simultaneously, Shi's group developed a highly atroposelective synthesis of N-pyrrolylindoles 45 through the well-designed N-aminoindoles 44 with 1,4-diketones 36 (Scheme 15).³⁵ They also proposed a possible reaction pathway for the formation of the N–N axially chiral product, which could be further verified by clearly observing the imine intermediate in the reaction system with the reaction temperature lowering to 0 °C. Additionally, the strategy was proved to be applicable for the atroposelective synthesis of N–N axially chiral bispyrroles, resulting in a range of bispyrroles in high yields with excellent atroposelectivities. Of which, the bispyrrole product could be transformed into an N–N axially chiral amide-tertiary amine catalyst 45′, which served as a new type of chiral organocatalyst for asymmetric catalysis by the [2 + 4] cyclization of 2-benzothiazolimine with homophthalic anhydride.

Scheme 15 Atroposelective synthesis of N–N axially chiral products by de novo ring formation.

The primary amines involved in the Paal–Knorr reaction process can be transformed to form axially chiral compounds with different structures. Recently, the catalytic asymmetric Paal–Knorr reactions of amide hydrazines with 1,4-diketones were developed for the synthesis of monoheteroaryl N–N atropisomers. The de novo cyclization reaction catalyzed by phosphoric acid with a C₆F₅ substituent C14 contributed to a diverse array of N–N amide–pyrrole atropisomers with excellent yields and enantioselectivities. To confirm the configurational stability of these N–N axially chiral products, racemization experiments and DFT calculations were carried out. As shown in Scheme 16, the different substituents on the carbonyl side or the nitrogen side of phenylhydrazines 46 exerted a considerable influence on the rotational barrier. Further gram-scale reactions and synthetic transformations were performed to evaluate the potential of the current catalytic system (Scheme 16).³⁶

Scheme 16 Enantioselective synthesis of N–N amide–pyrrole atropisomers via the de novo cyclization reaction.

The Friedländer reaction represents another classical approach for the synthesis of chiral heterocyclic compounds. It is typically conducted through the condensation of α-aminoaldehydes or α-aminoketones with another aldehyde or ketone or α-methylene compounds, containing at least one carbonyl group to form substituted quinolines.³⁷ Additionally, the reaction can be promoted by acids, bases or heating. Early in 2010, Seidel's group reported the first catalytic enantioselective Friedländer reaction catalyzed by a trans-4-hydroxyproline derivative C15, realizing a quinoline compound with a remote stereogenic center.³⁸ The desymmetrization of remote cyclohexanones upon reaction with o-aminobenzaldehydes 48 allows for the synthesis of quinolines with remote stereogenic centers (Scheme 17).

Scheme 17 Synthesis of quinoline compounds with a remote stereogenic center via the Friedländer reaction.

Later, the asymmetric Friedländer reaction was developed for the synthesis of axially chiral heterobiaryls. In 2019, Cheng and coworkers developed an atroposelective Friedländer hetero-annulation reaction of 2-aminoaryl ketones 50 with α-methylene carbonyl derivatives 51 to construct enantioenriched axially chiral polysubstituted 4-arylquinoline architectures 52 catalyzed by CPA (R)-C11 (Scheme 18a).³⁹ The addition of a primary amine, namely glycine tert-butyl ester, played an important role in accelerating the reaction rate, while no negative effect on the enantioselectivity had been observed. In a contemporaneous development, the chiral BINOL-derived CPA catalyzed asymmetric Friedländer reaction of 2-aminoaryl ketones 50 and acetylacetones was reported by Jiang and coworkers, affording the optically active biaryl quinolines in good to excellent yields and enantioselectivities (Scheme 18b).⁴⁰

Scheme 18 Asymmetric Friedländer reaction of axially chiral polysubstituted 4-arylquinoline architectures.

The mechanism of the Friedländer reaction catalyzed by CPA was addressed as follows: in the promotion by phosphoric acid, 2-aminobenzophenone 50 condensed with α-methylene carbonyl derivatives 51 to afford an imine intermediate 52i-2, which was then converted into the nucleophilic enamine intermediate 52i-3. Subsequently, a CPA-catalyzed intramolecular aldol reaction occurred, resulting in the formation of a dihydroquinoline bearing a tertiary alcohol in enantioenriched form. Ultimately, the resulting dihydroquinoline eliminated a molecule of H₂O to produce the desired atropoisomeric quinolines 52 in an optically enriched way (Scheme 19).

Scheme 19 Mechanism of the Friedländer reaction catalyzed by CPA.

In 2020, Cheng's group developed the enantioselective synthesis of atropisomeric 9-aryltetrahydroacridines 54 through the condensation of 2-aminoaryl ketones 50 with alicyclic ketones 53 under the combined catalytic system of CPA and an achiral primary amine promoter (Scheme 20).⁴¹ The introduction of 4-substituted cyclohexanones into the catalytic system resulted in the simultaneous occurrence of cycloaromatization and desymmetrization, giving the hexatomic N-heterobiaryls bearing both axial and central chirality in 3 : 1–9 : 1 dr values with moderate to good yields and enantioselectivities.

Scheme 20 Asymmetric synthesis of 9-aryltetrahydroacridines via cycloaromatization and desymmetrization.

4. Heyns rearrangement

Traditionally, reducing sugars can be an important kind of carbonyl compound that participates in the condensation with amines by acid or base catalysis, resulting in the generation of a Schiff base, which is called Amadori–Heyns rearrangements.⁴² Among these processes, Heyns rearrangement is currently understood to be a classical reaction that produces a stable α-amino carbonyl adduct from ketones through a sequence of rearrangements.⁴³ The direct asymmetric condensation reaction followed by Heyns rearrangement is an effective tool to achieve the chiral structure of α-aminoketones.

Chiral α-aminocyclobutanes have been identified in diverse natural products and have emerged as valuable intermediates in organic synthesis, facilitating the preparation of numerous chemically and biologically significant synthetic compounds owing to their inherent cyclic strain and rigidity.⁴⁴ The popularity of α-aminocyclobutane derivatives renders the quest for effective methods for their preparation intriguing and warrants meticulous design. In some way, the catalytic enantioselective electrophilic α-amination of ketones is an important and widely applied strategy for the construction of these moieties.⁴⁵ However, this approach often encounters challenges due to the generation of polyaminated by-products and, particularly in the case of unsymmetrical ketones, inadequate control over regioselectivity. The study of the catalytic enantioselective α-amination of ketones is thought of as underdeveloped.

The application of the asymmetric α-amination of ketones has been reported since 2014. The racemic α-hydroxycyclobutanone 55 and a selection of N-alkylanilines 56 were used in the tandem condensation/keto–enol tautomerization process reminiscent of the Heyns rearrangements (Scheme 21a).⁴⁶ α-Arylaminocyclobutanones 57 with moderate to high enantioselectivities were obtained using a series of N-alkylanilines furnished with various ring-substituents. The comparison revealed that the cyclic secondary amines gave much better results. On the basis of this example, the method can subsequently be better broadened in its applicability.

Scheme 21 Enantioselective synthesis of α-arylaminocyclobutanones via the asymmetric Heyns rearrangement catalyzed by cinchona alkaloid derivatives.

Benzylamine poses a significant challenge in achieving enantioselective control due to its high reactivity. In contrast to previous studies on weakly nucleophilic anilines, the heightened nucleophilicity of benzyl amine gives rise to a competitive uncatalyzed reaction pathway. In 2015, Frongia and coworkers applied the synthetic methodology to the enantioselective construction of fully aliphatic α-(benzylamino)cyclobutanones (Scheme 21b).⁴⁷ The reaction sequence began from readily available racemic α-hydroxycyclobutanones 55 and benzylamines 58, which were catalyzed by cinchona alkaloid derivatives C17, affording the desired products in good to high yields with moderate to high stereoselectivities.

The development of efficient methods for the construction of optically active α-amino ketone derivatives remains a significant challenge in the field of organic chemistry. In 2014, Caboni and colleagues subsequently conducted the condensation reaction of hydroxycyclobutanone 55 with optically active α-amino acid esters 60, albeit with a reduced number of successfully tested substrates (Scheme 21c).⁴⁸ Consistently, the cinchona alkaloids played an important role in the organocatalytic asymmetric condensation reactions.

In addition to the above-mentioned asymmetric synthesis of cyclic α-amino ketones, acyclic ones have also been developed via the direct condensation stopped with imine formation, isomerization of the imine to an enamine, and a proton-transfer reaction of an enol. Early in 2013, Sanna developed the first enantioselective catalytic Heyns rearrangement for the synthesis of α-aryl-amino ketones (Scheme 22).⁴⁹ Using the catalysis of cinchona alkaloid C19, the optically active α-amino ketones 63 were obtained through an in situ generation of 1,2-enaminol from 62 and 56 followed by the enantioselective enol–keto tautomerization. The products had been isolated in good to high yields with enantioselectivities up to 81%. However, substrates were limited to aromatic amines with the R¹, R² groups addressed as alkyls.

Scheme 22 Enantioselective Heyns rearrangement of α-aryl-amino ketones in the presence of cinchona alkaloids.

Zhu's group reported the first method to afford synthetically valuable chiral α-aryl-α-aminoketones with a chiral acid catalyst, which could not be obtained by means of previously reported Heyns rearrangements (Scheme 23).⁵⁰ The target products as well as some biologically active molecules were synthesized efficiently via the asymmetric reaction of anilines 56 with α-hydroxy aromatic ketones 62 bearing variously substituted phenyl groups. Reactions of anilines with electron-donating groups and weakly electron-withdrawing groups gave good results, but aliphatic amines showed low reactivity, mainly because of their higher basicity, which was incompatible with the acid catalyst. According to the study of the reaction mechanism, the acid catalyst could promote the condensation of the ketone and the amine to form an imine followed by the isomerization of the imine to an enamine. Then the chiral products were generated through the asymmetric proton-transfer step via an eight-membered cyclic transition state as a chiral proton-transfer shuttle.

Scheme 23 Enantioselective Heyns rearrangement catalyzed by a chiral Brønsted acid.

The consecutive Heyns rearrangement is different from the classical Heyns rearrangement in that the α-amino ketones were obtained without the shift of the carbonyl group, which can be seen as the SN-type substitution of the hydroxyl group with an amine group.⁵¹ Recently, Li disclosed a new catalytic asymmetric tandem reaction based on the consecutive Heyns rearrangement for the synthesis of chiral α-amino ketones with readily available substrates (Scheme 24).⁵² The catalyst selectively reacted with ketone 62 via the Heyns rearrangement to afford an imine intermediate which could react with an aromatic amine 56 to afford ketone imine under mild reaction conditions without an acid catalyst. Then the ketone imine isomerizes to enamines, which afford the final product through enantioselective protonation. The key to success was using chiral primary amine C20 as a catalyst by mimicking glucosamine-6-phosphate synthase in catalyzing the efficient Heyns rearrangement in organisms.

Scheme 24 Enantioselective consecutive Heyns rearrangement of chiral α-amino ketones catalyzed by a chiral primary amine.

Interrupted rearrangements allow for the rapid assembly of complex molecular scaffolds with the formation of new carbon–carbon or carbon–heteroatom bonds. Cui's group reported the transformation involved [3 + 2] heteroannulation/interrupted Heyns rearrangement which used CPA as a catalyst for the de novo organocatalyzed enantioselective construction of α-amino ketonel-like compounds 66 (Scheme 25).⁵³ The interrupted rearrangement smoothly proceeded via a proton-transfer process involving a reactive enol intermediate. The CPA served as a chiral proton-transfer shuttle to control the enantioselective proton-transfer step via a ten-membered cyclic transition state. This effective, mild, and practical protocol started from simple and readily available ureas 64 and glyoxals 65 producing water as the sole by-product.

Scheme 25 Enantioselective annulation/interrupted Heyns rearrangement for the construction of substituted hydantoins.

5. Conclusions

In conclusion, considering a green and efficient strategy, we focused on the direct amine-carbonyl condensation reaction to construct diverse functionalized molecules with water as the only by-product. However, it is necessary to develop special reaction designs for the construction of chiral nitrogen-containing compounds since there are no new stereocenters at the reaction site. We concluded with three main categories: desymmetrization or DKR, the de novo cycloaromatization and the Heyns rearrangement.

Nevertheless, the direct condensation reaction faces many challenges, such as severe background reactions under acidic or basic conditions based on the fact that the amine-carbonyl condensation makes it difficult to control the stereoselectivity. Among them, the synthesis of axially chiral compounds by direct condensation reactions remains underdeveloped. Hence the extensive exploration of the enantioselective condensation is of great importance as condensation reactions contribute to diverse functionalized compounds, including imines, enamines and α-amino ketones. Here we propose the following prospects for the asymmetric synthesis of novel structures via the direct condensation reaction: (1) exploring more one-step classical reactions, such as Knoevenagel condensation, the Wittig reaction and HWE reactions, which have rarely been developed, especially for the construction of axially chiral compounds; (2) constructing novel structures with different chirality, such as compounds with planar chirality or spiro chirality; and (3) broadening the catalytic system with the use of metal or biocatalytic enzymes. We hope this review can effectively guide the development of more active compounds and enrich the synthesis methods of functionalized molecules containing double bonds.

Author contributions

Jifan Jia: writing – original draft. Qianqian Xu: writing – original draft. Haitong Fan: writing – original draft. Yunpeng Lv: writing – original draft. Dan Li: writing – review & editing, supervision, funding acquisition, and conceptualization.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Conflicts of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

Our research in this field has been generously supported by the Beijing Municipal Natural Science Foundation (2244066) and the Key Project at the Central Government Level: the ability establishment of sustainable use for valuable Chinese medicine resources (2060302).

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