Introduction

Organocatalytic allylic substitution of Morita-Baylis-Hillman (MBH) adducts has emerged as a highly versatile synthetic transformation1,2,3,4,5,6,7, allowing the introduction of a wide diversity of nucleophiles into multifunctional molecular frameworks. While activated carbon-nucleophiles have been widely utilized8,9,10,11,12,13,14,15,16,17,18,19,20,21,22, the use of inert C–H nucleophiles, essential for expanding the reaction’s versatility and synthetic utility, remains a major challenge23. Benzylamines are a class of readily accessible primary amines possessing two inert α C(sp3)‒H bonds24. Direct asymmetric organocatalytic α-C(sp3)‒H allylic alkylation of benzylamines with MBH adducts offers a promising strategy for simultaneous formation of a C–C bond and establishment of chiral amine functionality (Fig. 1a), providing an efficient and appealing approach to construct chiral substituted γ-aminobutyric acid (GABA) scaffolds that are prevailing core structures of numerous bioactive natural products and pharmaceutical molecules (Fig. 1b)25,26,27,28,29. Moreover, through simple cyclization, γ-aminobutyric acids can be easily converted into another type of biologically important γ-lactam analogs (Fig. 1b)30,31,32. In spite of its potential benefits, this transformation remains undeveloped and is a significant challenge in organic chemistry, even when employing NH2-protected benzylamine derivatives. The difficulties can be attributed to the following two factors (Fig. 1a). First, deprotonating the α-amino C–H bonds to produce active carbanions for initiating the addition is rather difficult due to the extremely low acidity of α-amino C−H bonds (pKa ~ 42.5)24. Second, owing to the high nucleophilicity of the NH₂ group, the classical N-substitution33,34 usually disrupts the desired α-C alkylation, resulting in the predominant formation of the N-alkylated products 4 and/or 5 (Fig. 1a).

Fig. 1: α C‒H allylic alkylation of benzylamines with MBH adducts.
Fig. 1: α C‒H allylic alkylation of benzylamines with MBH adducts.
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a N-Alkylation vs α-C alkylation (SN2’-SN2’) of NH2-unprotected benzylamines. b Representative bioactive γ-aminobutyric acid derivatives. c This work: chiral pyridoxal catalyzed direct asymmetric α C(sp3)‒H alkylation of NH2-unprotected benzylamines with MBH acetates. Ar, aromatic group; Ph, phenyl; SN2’, bimolecular allylic nucleophilic substitution; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM, dichloromethane; dr, diastereomeric ratio; ee, enantiomeric excess.

Carbonyl catalysis35,36,37,38,39,40 has become an effective strategy for direct α C‒H functionalization of NH2-unprotected primary amines41,42,43,44,45,46,47,48,49,50. With chiral pyridoxals as the carbonyl catalysts, a series of enantioselective transformations of activated primary amines, such as α-amino esters with diverse electrophiles, have been successfully accomplished, affording diverse chiral amino acid derivatives41,42,43. Nevertheless, direct asymmetric α-functionalization of primary amines containing inert α-amino C–H bonds24,44,45, for instance, benzylamines, presents greater difficulties. Till now, for the carbonyl-catalyzed reaction of benzylamines, only the asymmetric addition to aldehydes has been achieved24. Allylic alkylation of benzylamines with MBH acetates is more difficult to achieve, primarily due to the strong interference from the highly nucleophilic amino group and the more complicated functional group compatibility of MBH acetates. Herein, we would like to disclose our success on the direct asymmetric α C−H alkylation of benzylamines 1 with MBH acetates 2, with a switched nucleophilic selectivity from N to α-C of benzylamines 1, enabled by the chiral bifunctional pyridoxal catalysts 641 bearing an amide side chain attached to the C3 position of the naphthyl ring. This reaction produced a wide range of chiral polysubstituted γ-amino acid esters 3 with excellent diastereo- and enantioselectivities (up to >20:1 dr, 99% ee) (Fig. 1c).

Results

Reaction optimization

Our studies commenced with the investigation of the direct asymmetric α C−H alkylation of benzylamine (1a) with MBH acetate 2a (Fig. 2, Supplementary Table S1). To our delight, with pyridoxal (S,S)-6a as the catalyst and DBU as the base, the reaction proceeded smoothly for 24 h as anticipated to afford chiral γ-amino acid ester 3a in a 58% yield with >20:1 diastereomeric ratio (dr) and 99% ee for the major diastereomer accompanied by the formation of some N-alkylated by-products (Fig. 2, Supplementary Table S1, entry 1). The pyridoxal catalyst is crucial for this reaction, as no desired α-C allylic alkylation but only N-alkylation can be observed in its absence (Supplementary Table S1, entries 2 and 3), demonstrating that the pyridoxal catalyst is capable of switching the nucleophilic selectivity of benzylamine 1a from N to α-C without protecting the NH₂ group. Extending the reaction time to 72 h can effectively improve the yield of the reaction to 71% while maintaining the excellent diastereo- and enantioselectivities ( > 20:1 dr, 99% ee) (Fig. 2, Supplementary Table S1, entry 4). The diastereomeric pyridoxal (R,S)-6a was less effective for the reaction, resulting in the product 3a with decreased yield and stereoselectivity (Fig. 2). Among the pyridoxals 6a-e examined, compound (S,S)-6a displayed the best performance regarding activity, diastereo-, and enantioselectivities (Fig. 2). Pyridoxals (R,S)-7 and (S,S)-7 possessing a lateral amide chain at the C2 position of the naphthyl ring were completely ineffective for the reaction (Fig. 2), indicating the side chain is important for the activity of the pyridoxal catalyst. Reaction condition investigations exhibited that DBU was the base of choice (Supplementary Table S1, entry 1 vs 12-16) and dichloromethane was the optimal solvent (Supplementary Table S1, entry 1 vs 17-20).

Fig. 2: Catalyst screening.
Fig. 2: Catalyst screening.
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Reaction conditions: 1a (0.20 mmol), 2a (0.10 mmol), catalyst 6 (0.01 mmol, 10 mol%), and DBU (0.20 mmol) in DCM (0.5 mL) at -20 oC for 72 h. Isolated yields were based on 2a. The dr values were determined by 1H NMR analysis of the crude reaction mixtures. The ee values were determined by chiral HPLC analysis. iPr: isopropyl; tBu: tert-butyl; Ph: phenyl; Bn: benzyl; Ac, acetyl; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM, dichloromethane. aThe reaction time was 24 h.

Substrate scope

Under the optimal reaction conditions, substrate scope on benzylamines was investigated (Fig. 3). A variety of benzylamines 1 bearing different electron-donating and/or electron-withdrawing substituents at the ortho-, meta-, or/and para-positions of the benzene ring all smoothly underwent the direct asymmetric α C‒H allylic alkylation with MBH acetate 2a, producing the corresponding products 3b-m in good yields (60-77%) with excellent diastereo- and enantioselectivities ( > 20:1 dr and 96-99% ee) (Fig. 3a). The absolute configuration of the major diastereomer of product 3m was determined as (3S,4 R) by X-ray analysis (Fig. 3a). Delightfully, the reaction is not sensitive to the steric hindrance. The ortho-substituted benzylamine, such as o-tolylmethanamine (as for 3j), still displayed good reactivity with high stereoselectivity ( > 20:1 dr, 98% ee). Naphthyl substituted methanamines (as for 3n and 3o) as well as heteroarylmethanamines such as thiophen-3-ylmethanamine (as for 3p), pyridin-3-ylmethanamine (as for 3q), and (4-methoxypyridin-2-yl)methanamine (as for 3r) were also applicable for the reaction. The other reaction partner MBH acetates were also examined. Phenyl (as for 3s), substituted phenyl (as for 3t–ad) and heteroaromatic (as for 3ae–ah) MBH acetates with different electronic properties and substitution patterns on the benzene ring were proven to be effective substrates for the α-C allylic substitution, as they all exhibited good reactivities and led to the formation of products 3s–ah with uniformly high diastereomeric ratios ( > 20:1 dr) and high enantiopurities (94-98% ee) (Fig. 3b). The electronic property of the substituted phenyl groups seems to have little impact on the diastereo- and enantioselectivity. Alkenyl- and alkynyl-substituted MBH acetates are also reactive for the transformation, producing chiral γ-amino acid esters 3ai and 3aj with excellent diastereoselectivity (Fig. 3b). The relatively low ee value observed for 3aj is likely due to the linear geometry of the alkyne group, which lacks sufficient steric hindrance for effective enantiocontrol. Alkyl-substituted MBH acetates, such as tert-butyl 3-acetoxy-2-methylene-5-phenylpentanoate, are completely ineffective for the α-C allylic alkylation. Notably, when utilizing substrates containing a biologically active chiral moiety derived from D-glucose (as for 3ak), testosterone51 (as for 3al), or estrone (as for 3am), the reaction proceeded fluently to afford products 3ak-am in good yields with excellent diastereocontrol (Fig. 3c).

Fig. 3: Substrate scope.
Fig. 3: Substrate scope.
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a Investigation on benzylamines. b Investigation on MBH acetates. c Investigation on chiral substrates. Reaction conditions: 1 (0.40 mmol), 2 (0.20 mmol), (S,S)-6a (0.02 mmol, 10 mol%) and DBU (0.40 mmol) in DCM (1.0 mL) at −20 °C for 72 h. The isolated yields were based on 2. The dr values were determined by 1H NMR analysis of crude reaction mixtures. The ee values were determined by chiral HPLC analysis. The absolute configuration for 3m was determined as (3S,4R) by X-ray analysis, and those for 3a-3l, 3n-3am were tentatively assigned by analog. DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM, dichloromethane.

Synthetic utility

To demonstrate the practical utility of the protocol, the reaction was carried out on a gram-scale. Chiral γ-amino acid ester 3h (1.051 g) was obtained in a comparable yield with the same diastereo- and enantioselectivies (Fig. 4a). The synthetic utility of the product was further investigated. Chiral γ-amino acid esters 3 can be facilely transformed into different derivatives with potential bioactivities (Fig. 4b). Deprotection of the tert-butyl moiety of the major diastereomer (3S,4R)-3h by means of HCl produced chiral γ-aminobutyric acid 8h in 95% yield while maintaining the same enantiopurity. As illustrated in Fig. 4b, cyclic α-methylene-γ-lactam 9a and 9h were successfully obtained in satisfactory yields with high enantiopurities via sequential deprotection and condensation. Notably, α-methylene-γ-lactam derivatives have been discovered to exhibit anti-inflammatory, phytotoxic, cytotoxic, and antimicrobial bioactivities30,31,32. Additionally, under Pd-catalyzed hydrogenation conditions, the reduction of 3h proceeded smoothly to afford a pair of chromatographically separable diastereomers (2R,3R,4R)-10h (46% yield) and (2S,3R,4R)-10h’ (32% yield) without any loss of enantiopurity, as depicted in Fig. 4b. Furthermore, compound 10h’ can be converted into cyclic γ-lactam 11h’ as presented in Fig. 4b. The absolute configuration of compounds 11h’ as well as 9a were confirmed by X-ray analysis (see Supplementary Information).

Fig. 4: Synthetic applications.
Fig. 4: Synthetic applications.
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a Gram-scale reaction. b Synthetic transformations. Ac, acetyl; EDCl, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; HOBT, 1-hydroxybenzotriazole; DIPEA, N, N-Diisopropylethylamine; EA, ethyl acetate; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM, dichloromethane.

Mechanistic studies

The reaction was proposed to proceed through a carbonyl catalysis mechanistic pathway, in which the chiral pyridoxal catalyst served as a pivotal factor (Fig. 5a)35,36,37,38,39. The condensation between chiral pyridoxal catalyst 6a and arylmethanamine 1 results in the formation of imine 12, which activates the benzylic C–H bonds and remarkably increases the C–H acidity for further deprotonation to generate delocalized carbanion 1352,53. Computational pKa analysis reveals the benzylic C–H of imine 12 is more acidic than the phenolic O–H and N–H of the pyridoxal scaffold, thermodynamically favoring the formation of the carbanion via selective C–H deprotonation (see Supplementary Information for details). The carbanion 13 undergoes an asymmetric addition reaction to quaternary ammonium salt intermediate 14, which is generated via the nucleophilic addition of DBU to MBH acetate 2. The addition is accompanied by the expulsion of DBU, leading to the formation of species 16. Hydrolysis of compound 16 leads to the liberation of the SN2’-SN2’ α-C alkylation product 3 and the regeneration of the pyridoxal catalyst 6a, completing the catalytic cycle.

Fig. 5: Mechanistic studies.
Fig. 5: Mechanistic studies.
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a Proposed reaction mechanism. b Kinetic isotope effect studies. c Computationally-optimized transition state. d Comparison of catalysts. DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM, dichloromethane.

Kinetic isotope effect (KIE) studies were conducted with equimolar amounts of benzylamine 1a and α-deuterated counterpart 1a-d (Fig. 5b). The reaction led to the formation of compound 3a and the deuterated 3a-d, with a ratio of 7.69:1. The distinct kinetic isotope effect strongly suggests that the deprotonation of imine 12 to afford the active carbanion intermediate 13 is the rate-determining step for the entire reaction pathway.

To elucidate the origin of chirality, computational investigations have been conducted. Figure 5c depicts the optimized transition state (15) for the step involving the asymmetric addition of carbanion 13 to intermediate 14. While benzylamine 1 is bound by the catalyst via the formation of the imine with the pyridoxal moiety, the MBH acetate-derived intermediate 14 is activated by the side chain of the pyridoxal catalyst. This activation occurs via a hydrogen-bonding interaction54,55,56 between the NH group of the side chain and the carbonyl group of intermediate 14. To minimize steric repulsion, intermediate 14 adopts an orientation wherein both the bulky R group and the DBU moiety are directed away from the biaryl backbone of the pyridoxal catalyst. The carbanion originating from arylmethanamines approaches 14 from above to afford chiral γ-amino acid esters 3 with (3S,4R)-configuration from chiral pyridoxal (S,S)-6a.

The postulated transition state is supported by control experiments on the comparison of catalysts (Fig. 5d). Methylation of the amide N–H group on the lateral side chain of pyridoxal 6a resulted in a significant decline in activity and enantioselectivity. As shown in Fig. 5d, the reaction with catalyst 6f afforded a 10% yield, a diastereomeric ratio (dr) of >20:1, and an enantiomeric excess (ee) of 53%, in contrast to the 34% yield, >20:1 dr, and 92% ee obtained with catalyst 6e. The result implies that the amide N–H group likely participates in the catalytic process via hydrogen bonding, as proposed in transition state 15. The cooperative bifunctional activation accounts for the excellent performance of pyridoxals 6 bearing a C3 amide side chain in the reaction. This was further confirmed by the fact that pyridoxals 7, having a C2 amide side chain, are completely inactive for the reaction (Fig. 2). It is supposed that the side chain is too close to the aldehyde moiety to guarantee effective bifunctional activation during the catalysis.

Discussion

In summary, we have successfully developed a direct asymmetric α C−H allylic alkylation of benzylamines 1 with MBH acetates 2 by utilizing bifunctional chiral pyridoxal (S,S)-6a as the catalyst. This reaction furnishes diverse chiral γ-amino acid esters 3, which are of biological significance, in 40–77% yields with excellent diastereo- ( > 20:1 dr) and enantioselectivities (79–99% ee). This work exemplifies a remarkable illustration of organocatalyzed inert C–H bond functionalization under mild conditions, offering high stereocontrol without directing or protecting group manipulations. Moreover, it also highlights the distinctive exceptional capabilities of vitamin B657,58 based organocatalysts59,60,61 in organic synthesis.

Methods

General procedure for asymmetric α C(sp 3)‒H allylic alkylation of benzylamines with MBH acetates (Fig. 3)

To a 4 mL vial equipped with a magnetic stirrer bar were successively added chiral pyridoxal (S,S)-6a (0.0046 g, 0.010 mmol), DBU (0.0304 g, 0.20 mmol), DCM (0.3 mL) and benzylamine 1 (0.20 mmol). The mixture was stirred at −20 °C for 5 min, and a solution of MBH acetate 2 (0.10 mmol) in DCM (0.2 mL) was added in portions over 1 h. After the reaction mixture was stirred at −20 °C for 72 h, it was allowed to warm up to room temperature and concentrated via rotary evaporator to remove most of the solvent. Then it was dried under vacuum and submitted to 1H NMR analysis to determine the dr values. The product 3 was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 3:1). The dr values of products 3a-ak were determined by 1H NMR analysis of the crude reaction mixtures. The enantiomeric excesses (ee’s) of products 3a-ak were determined by chiral HPLC analysis.

Procedure for synthesis of γ-amino acid ester 3 h in gram-scale (Fig. 3a)

To a 25 mL flask equipped with a magnetic stirrer bar were successively added chiral pyridoxal (S,S)-6a (0.144 g, 0.312 mmol), DBU (0.950 g, 6.250 mmol), DCM (9.35 mL) and arylmethanamine 1h (1.094 g, 6.250 mmol). The mixture was stirred at −20 °C for 5 min, and a solution of MBH acetate 2a (1.100 g, 3.130 mmol) in DCM (6.25 mL) was added in portions over 1 h. After the reaction mixture was stirred at −20 °C for 72 h, it was allowed to warm up to room temperature and concentrated via rotary evaporator to remove most of the solvent. Then it was dried under vacuum and submitted to 1H NMR analysis to determine the dr values. The crude reaction mixture was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 3:1) to afford compound (S,R)-3h (1.051 g, 72% yield, >20:1 dr, 96% ee) as a white solid.