Progress in Catalytic Asymmetric Reactions with 7-Azaindoline as the Directing Group

Abstract

α-Substituted-7-azaindoline amides and α,β-unsaturated 7-azaindoline amides have emerged as new versatile synthons for various metal-catalyzed and organic-catalyzed asymmetric reactions, which have attracted much attention from chemists. In this review, the progress of research on 7-azaindoline amides in the asymmetric aldol reaction, the Mannich reaction, the conjugate addition, the 1,3-dipole cycloaddition, the Michael/aldol cascade reaction, aminomethylation and the Michael addition-initiated ring-closure reaction is discussed. The α-substituted-7-azaindoline amides, as nucleophiles, are classified according to the type of α-substituted group, whereas the α,β-unsaturated 7-azaindoline amides, as electrophiles, are classified according to the type of reaction.

1. Introduction

Carboxylic acids are widely distributed in nature and are compounds that occur naturally at various stages of the life cycle, such as the living-organism–Krebs cycle, fermentation processes, and geological processes. Carboxylic acids are often present as a functional group in effective medicines, and approximately a quarter of all commercialized pharmaceuticals contain a carboxylic acid group [1,2]. In addition, carboxylic acids play important roles in the food industry, like ascorbic acid, which functions as an antioxidant, propionic acid, which functions as a flavor, and lactic acid, which functions as a preservative [3,4,5,6,7,8]. Accordingly, the synthesis and functionalization of carboxylic acids are of great importance in the development of functional materials, pharmaceuticals, and various other fields [9,10,11,12,13,14]. Because of the resonance of the carboxyl proton between its two oxygen atoms, the carboxyl group usually exhibits a low reactivity, making it uncommon for carboxylic acids to directly participate in reactions [14]. For example, it is difficult for α,β-unsaturated carboxylic acids to undergo the Michael addition, which often readily occurs for α,β-unsaturated carbonyl compounds [15,16,17,18,19,20,21]. Therefore, exploitation of the surrogates of carboxylic acid is, and will continue to be, highly desirable. In this context, considerable efforts have been made by chemists and substantial progress has been made. For instance, esters are important substrates for the following reactions [22,23,24,25,26,27]: (1) Aron et al. [22] reported in 2010 that Ca(OTf)₂-catalyzed α,β-unsaturated esters participate in a [3 + 2] cycloaddition reaction with unprotected amino acid esters and aldehydes, resulting in the formation of polysubstituted pyrrolidines; (2) Shang et al. [23] developed the Michael addition reaction of 1-oxoindane-2-carboxylic acid esters with β-ester enone, catalyzed by an organophosphine containing multiple hydrogen-bond donors. Nevertheless, low substrate activity and selectivity remain issues in the development of carboxylic acid surrogates.

Directing groups have been used to enhance the reactivity and regulate the stereoselectivity of reactions in asymmetric transformations [28]. If the substrate is not suitable for effective interactions with the catalyst or reagent to promote the selective reaction, the appropriate design of a directing group could be feasible. In general, the directing group is expected to satisfy the following requirements: (i) is easy to install in the molecular structure, (ii) ensures efficient control of reaction activity and selectivity, and (iii) is easily removed from the molecular structure. Taking this into account, the introduction of a directing group on the carboxyl group is proposed in order to enhance the reactivity and stereoselectivity of reactions involving carboxylic acids as starting materials.

At present, the main types of directing groups are as follows: 2-oxazolidone (A) [29,30,31,32,33,34,35,36,37,38,39,40], tetrahydropyrrole 2,5-dione (B) [41,42,43], pyrazole or 3,5-dimethylpyrazole (C or D) [44,45,46,47,48,49,50,51,52,53,54,55,56], and 8-aminoquinoline (E) [57,58,59,60,61,62,63,64,65]. They coordinate with metals to form stable five- or six-membered ring complexes that control the stereoselectivity of the reaction through a specific chiral environment (Scheme 1). Despite these seminal works, some challenges remain for the functionalization of carboxylic acids, including the harsh conditions for the removal of the directing group, unsatisfactory stereocontrol, and low activity. Recently, Shibasaki’s group reported a series of asymmetric reactions involving amide substrates with 7-azaindoline as the directing group. The advantages of 7-azaindoline are as follows: (i) it improves the reaction activity and stereoselectivity; (ii) the 7-azaindoline group in the product is easily removed, facilitating the formation of carboxylic acid and carboxylic acid derivatives; (iii) the complexation of 7-azaindoline with metal reagents can prevent over-reduction, -oxidation and dehalogenation. Yuan’s group has also conducted some research using 7-azaindoline amides as substrates.

The 7-azaindoline amides reported in the literature are divided into two categories. One is the α-substituted-7-azaindoline amide, which is a carbonyl compound with weak acidity and usually acts as the nucleophile of an asymmetric direct aldol or Mannich reaction. The other is the α,β-unsaturated 7-azaindoline amide, which is an α,β-unsaturated carbonyl compound with poor electrophilicity and is generally regarded as an electrophile in asymmetric reactions. The preparation method of 7-azaindoline amide is as follows: α-substituted-7-azaindoline amides are synthesized from 7-azaindoline and α-substituted acetyl chloride using 1.2 equivalents of NaHCO₃ in CH₂Cl₂, which have been recognized as efficient substrates. α,β-unsaturated 7-azaindoline amides, which were prepared from 7-azaindoline and cinnamic acids using 1.2 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI·HCl) and 0.5 equivalents of 4-dimethylaminopyridine (DMAP) in CH₂Cl₂, were found to be stable and highly efficient synthons (Scheme 2). In this review, we will summarize the state-of-the-art catalytic asymmetric reactions involving 7-azaindoline amides as nucleophiles and electrophiles, respectively.

2. α-Substituted-7-Azaindoline Amide as a Nucleophile

On the basis of the catalytic asymmetric reactions reported so far, 7-azaindoline amides can be divided into six major types: (1) α-sulfanyl 7-azaindoline amide, (2) fluoroalkyl 7-azaindoline amide, (3) α-azido 7-azaindoline amide, (4) α-alkyl 7-azaindoline amide, (5) α-halo 7-azaindoline amide, and (6) α-oxygen 7-azaindoline amide. These amides are a new class of latent enolates developed by Shibasaki and co-workers, which can react with aldehydes, ketones and imines under the catalysis of synergistic catalysts to obtain corresponding products with high yields and stereoselectivities.

2.1. α-Sulfanyl 7-Azaindoline Amide as an Aldol Donor

The first example of the utilization of 7-azaindoline amide as a nucleophile in the asymmetric aldol reaction was reported by Shibasaki in 2014 [66]. In more detail, the α-sulfanyl 7-azaindoline amide 1 was converted to the corresponding β-hydroxy carbonyl compounds 3 using aliphatic or aromatic aldehydes 2 as aldol acceptors, catalyzed by the AgBF₄/(R,R)-Ph-BPE L1.1 complex with LiOTf and 2-methylthioethanol 4 as additives and Li(OC₆H₄-p-OMe) as a Brønsted base (Scheme 3a). The interaction of α-sulfanyl 7-azaindoline amide 1 with the monomer Ag(I) complex enhanced its acidity, and the proton on the methylene group of α-sulfanyl 7-azaindoline amide 1 is more easily removed by Li(OC₆H₄-p-Me) during the reaction. The NMR and X-ray crystallographic analysis showed that the dimeric silver complex Ag₂(L1.1)₂(OTf)₂ was dominant in THF solution of Ag(I)/L1.1/LiOTf. The ESI-MS analysis revealed that α-sulfanyl 7-azaindoline amide 1 promoted the balance of monomeric and dimeric complexes. When aliphatic aldehydes were used as aldol acceptors, the corresponding aldol products 3 were obtained in good to high yields (72–94% yields) with high levels of stereoselectivities (16:84–6:94 dr, 89–99% ee (syn)). However, when aromatic aldehydes were used as the aldol acceptors, the aldol products 3 were obtained with moderate to good yields (65–92%) and high stereoselectivities (81:19→98:2 dr, 84–99% ee (anti)). Compared with aliphatic aldehydes, aromatic aldehydes reacted with α-sulfanyl 7-azaindoline amide 1 more quickly, but the retro–aldol reaction resulted in a significant decrease in enantioselectivity. Fortunately, 2-methylthioethanol 4, as a fake, can effectively inhibit the occurrence of the retro–aldol reaction. The potential synthetic utility of the methodology in this work was demonstrated by the further conversion of product 3.

The authors proposed a plausible reaction mechanism. The α-sulfanyl 7-azazindoline amide and Ag/L1.1 complex form a seven-membered ring structure through bidentate chelation, which causes the 7-azazindoline group of the amide to tilt, partially breaking the conjugated structure. The carbonyl group of the seven-membered ring structure binds to the hard Lewis acid Li⁺, and the α-H of the amide is easily removed by a Brønsted base to form a Li enolate amide. The absolute configuration of syn-3 and anti-3, obtained by the reaction of aliphatic aldehydes and aromatic aldehydes with the Li enolate amide, consistently shows an R configuration at the α-position. This suggests that the reaction face of the Li enolate amide remains the same, but the transition state is different. The α-sulfanyl 7-azazindoline amide coordinates with the Ag complex to form E-enolate amide, and it forms anti-3 with smaller aromatic aldehydes through a six-membered ring transition state. On the other hand, larger aliphatic aldehydes lead to syn-3 via an open transition state with minimal spatial repulsion (Scheme 3b).

2.2. Fluoroalkyl 7-Azaindoline Amides as Mannich Donors or Aldol Donors

Based on the application of α-sulfanyl 7-azaindoline amide in the catalytic asymmetric aldol reaction (Scheme 3), Shibasaki’s group reported the first example of an asymmetric Mannich reaction of α-CF₃ 7-azaindoline acetamide 5 with N-Boc imine 6 using the [Cu(CH₃CN)₄]PF₆/L1.2/Barton’s base as a cooperative catalyst in 2014 (Scheme 4a) [67]. The α-CF₃ enolate was catalytically generated without undesirable fluoride elimination, and the synthesis of various N-Boc-protected β-amino acid derivatives 7 was achieved in good to high yields (77–96%) with high stereoselectivities (2.8:1→20:1 dr, and 74–99% ee). The reaction exhibits a broad substrate scope, accommodating both aromatic and heteroaromatic imines in the catalytic system. In particular, the aliphatic imines with low activity were able to participate effectively in the reaction, resulting in good results for the corresponding products.

A coordination mode for the α-CF₃ 7-azaindoline amide 5 and the Cu(I) complex was also brought forward, as shown in Scheme 4b. The defluorination of α-CF₃ 7-azaindoline amide 5 was effectively avoided through the complexation of the pyridinyl nitrogen with the chiral Cu(I) complex. The authors also found that α-CF₃ 7-azaindoline amide 5 preferred E-conformation in the solution using Nuclear Overhauser Effect (NOE) analysis.

Benefiting from the investigation of the acid/base binary catalytic system, which used Barton’s base as a Brønsted base and [Cu(CH₃CN)₄]PF₆ as a soft Lewis acid, Shibasaki’s group developed an exceptionally efficient method for synthesizing enantioenriched α-fluorinated and α-fluoroalkylated β-amino acid derivatives through the direct catalytic asymmetric Mannich reaction of other fluorinated amides 5a–d with imine 6 (Scheme 5, Scheme 6, Scheme 7, Scheme 8, Scheme 9, Scheme 10 and Scheme 11). This method was developed in response to the high demand for fluorinated chiral compounds [68].

The α-F-α-CF₃ carbonyl compounds correspond to perfluorinated analogues of propionic acid units and are common structural units of many bioactive compounds. The α-F-α-CF₃ 7-azazindoline acetamide is very useful for constructing chiral centers containing both CF₃ and F substitutions, which are difficult to obtain via the asymmetric fluorination or trifluoromethylation [69,70,71,72,73]. In this work, the authors constructed a family of β-amino acid derivatives 9 through the direct catalytic asymmetric Mannich reaction between racemic α-F-α-CF₃ 7-azaindoline acetamide 5a and imines 6 (Scheme 5). The β-amino acid derivatives 9 bearing both CF₃ and F substituents at the stereogenic carbon center were obtained in an up to 95% yield, >20:1 dr, and 99% ee under the catalysis of [Cu(CH₃CN)₄]PF₆/L1.2/Barton’s base. Compared to the optimization conditions determined above, the concentration of 5a in this system was slightly increased from 0.3 M in Scheme 3 to 0.5 M in Scheme 5, which also compensated for the weaker nucleophilicity. The further conversion of product 9f to other compounds with an unchanged chiral configuration also demonstrates the potential synthetic utility of the methodology. Notably, Product 9f also can be converted into (2R,3S)-3,4,4,4-tetrafluorovaline hydrochloride product 12a in 34% yield via a series of transformations [74] (Scheme 6).

More importantly, some products can be converted into biologically active substances in a few steps [75]; for example, the β-amino acid derivative 9c can be converted into the fluorinated analogue 17a of calcium channel blocker 17 via several steps (Scheme 7). Moreover, the racemic α-F-α-CF₃ 7-azazindoline amide 5a could also be used as a nucleophile to react with a para-chloro-substituted imine to synthesize the fluorinated analogue 19a of propyl carboxypeptidase inhibitor 19 (Scheme 8). The results of the preliminary research are an important foundation for the future development of bioactive substances with an α-F-α-CF₃ tetra-substituted stereogenic center.

To extend the range of β-amino acid derivatives containing fluorinated groups on the α-carbon, the authors also developed an asymmetric catalytic system using a less sterically hindered ligand, (R)-xyl-Segphos L1.3, in combination with [Cu(CH₃CN)₄]PF₆ for the asymmetric Mannich reaction of α-C₂F₅ 7-azaindoline acetamide 5b with amine 6. This method generated enantiomerically enriched α-C₂F₅-β-amino acid derivatives 20 containing adjacent tertiary stereocenters in good yields and high enantioselectivities (Scheme 9). The electronic properties of phenyl substituents in imines have little effect on the reactivity and enantioselectivity of Mannich reactions. Finally, it was also found that aliphatic imines with low reactivity were suitable for the catalytic system.

The authors also described the asymmetric Mannich reaction of α-CF₂CF₂Br 7-azaindoline acetamide 5c as a nucleophile with imines to synthesize a variety of α-CF₂CF₂Br β-amino acid derivatives 21 through the catalysis of [Cu(CH₃CN)₄]PF₆/L1.3 complex. They used plenty of imines (6 equiv) to ensure the formation of target products from the enolate, even if faster defluorination occurred during the reaction (Scheme 10). In addition, Shibasaki and co-workers also explored the catalytic asymmetric synthesis of α-monofluorinated β-amino acid derivatives 22 using a α-F 7-azaindoline acetamide 5d as a nucleophile that reacted with imines (Scheme 11). In this work, N-Cbz imine reacted with α-monofluorinated amide in the presence of the [Cu(CH₃CN)₄]PF₆/(R,R-p)-Cy-Taniaphos L1.4 catalyst to provide chiral β-amino acid derivatives 22 bearing an α-F stereogenic center in high enantioselectivities. Although soft Lewis basic functional groups likely interfered with the catalysis, both the -SMe substituted imine and 3-thiophenimine reacted smoothly with 5d in the accepted results (Scheme 11, 22d and 22f).

Because of the inherent chirality of α-F-α-CF₃ 7-azaindoline amide 5a, a plausible pathway for the Mannich reaction between 5a and an imine was proposed, as shown in Scheme 12. Firstly, both the (R)-amide 5a and (S)-amide 5a were combined with the chiral complex Cu(I)/(R)-L1.2 (paths a, b), resulting in the formation of the 5a/Cu(I)/(R)-L1.2 complex. This complex underwent rapid reprotonation, leading to the formation of enolate E-23. Reversible enolization occurred through paths c and e. Finally, the desired adduct 9a was generated through the irreversible Mannich reaction of enolate E-23 (path d). In addition, the authors advanced the following conclusions: (i) in the presence of Barton’s base, the acidity of α-F-α-CF₃ 7-azaindoline amide 5a is sufficient for deprotonation, and the rate of deprotonation significantly accelerated in the presence of the Cu(I) complex; (ii) the Cu(I) complex plays a crucial role in bringing together α-F-α-CF₃ 7-azaindoline amide 5a and imine 6 to facilitate the formation of C-C bonds, but it does not directly accelerate deprotonation.

Inspired by the fact that α-CF₃ 7-azaindoline acetamide was a highly efficient nucleophile for constructing chiral α-CF₃ β-amino acid derivatives, Shibasaki and co-workers developed another class of β-hydroxyl compounds 25 bearing an α-CF₃ stereogenic center, which were synthesized by arylglyoxal hydrates 24 and α-CF₃ 7-azaindoline amide 5 via the direct catalytic asymmetric aldol reaction (Scheme 13) [76]. The catalyst was a combination of a soft Lewis acid Cu(I)/L1.5 and a hard Brønsted base DBU, which was essential to achieve high stereoselectivity in the products.

To understand the key role of the 7-azaindoline group of amides in the success of this reaction, the authors also calculated the pKa values of a series of acetamides 26–29 with similar structure in DMSO using the density functional theory (DFT) method (Scheme 14a). The results showed that amides 26–28 have a higher acidity than their aliphatic counterparts 29. Despite their having a much higher acidity than acetamide 26–29, the α-CF₃ amides 30–32 with different structures failed to produce the corresponding aldol product in the reaction using arylglyoxal hydrates as electrophiles (Scheme 14b). The results of these control experiments suggested that the 7-azaindoline moiety increased the acidity of the α-protons in the amides and facilitated enolization without causing undesired defluorination during the reaction.

Continuing their efforts, in 2017, Shibasaki and co-workers proposed a strategy for the asymmetric α-allylation of α-CF₃ 7-azaindoline amide 5 with allylic carbonates 33 under Cu/Pd synergistic catalysis (Scheme 15) [77]. In the Cu(I)/Pd(0) synergistic catalyst system, Cu(I)/DBU catalyzed the enolization of α-CF₃ 7-azaindoline amide, while Pd(0) activated the allyl carbonate. In the Cu(I)/Pd(0) synergistic catalyst system, Cu(I)/DBU catalyzed the enolization of α-CF₃ 7-azaindoline amide, while Pd(0) activated the allyl carbonate. The method showed good tolerance to the substituents of the substrate, and the reaction between allyl carbonates with various substituents and α-CF₃ 7-azaindoline amide produced products 34 with at least one tertiary stereocenter in a high yield and with high enantioselectivity. It is worth noting that in the Cu(I)/Pd(0) synergistic catalyst system, 1,3-dissubstituted carbonate 33f successfully reacted with α-CF₃ 7-azaindoline amide to produce 34f containing two successive tertiary stereocenters with good results (70% yield, 99% ee, and 85:15 dr).

A plausible pathway for the reaction of α-CF₃ 7-azaindoline amide 5 and racemic carbonate 35 has been tentatively proposed, as shown in Scheme 16. They presumed that the Cu(I)/Pd(0) catalyst acted in a synergistic manner. The α-CF₃ 7-azaindoline amide 5 reacted with diastereomers 35a and 35a′ to provide products 36 and 36a′, respectively, suggesting that a double inversion mechanism probably occurred in the α-allylation, in which the DBU in the Cu(I) catalytic system acted as a base to promote the removal of a hydrogen proton from the α-carbon atom of the α-CF₃ 7-azaindoline amide 5, and then the formed Cu(I) enolate acted as a soft nucleophile to attack the back of the π-allyl-Pd(II) intermediate. The stereochemical selectivity of the reaction is highly dependent on the chiral environment of the Cu(I) complex. The two catalysts Cu(I)/L1.6 and Pd(0)/L1.7 with phosphine ligands played the different roles in the α-allylation, as indicated by ¹H, ³¹P, and ¹⁹F NMR analyses.

In their continuing program of the catalytic enolization chemistry of the α-CF₃ 7-azaindoline amide, Shibasaki and colleagues developed the asymmetric 1,6-conjugate addition between α-CF₃ 7-azaindoline amide 5 and p-quinone methides (p-QM) 37 catalyzed using mesitylcopper/L1.3 as a cooperative catalyst (Scheme 17) [78]. The addition products 38, containing two successive tertiary stereocenters, achieved good results (up to 98% yield, 20:1 dr, and 98% ee).

Moreover, a plausible pathway for the reaction of α-CF₃ 7-azaindoline amide with p-QMs was proposed. As shown in Scheme 18, the mesitylcopper/L1.3 is combined with α-CF₃ 7-azaindoline amide 5 to form the Cu-enolate complex I, which is stabilized by binding interactions and decorated with the biaryl-type ligand. Then, the enolate oxygen anion of α-CF₃ 7-azaindoline amide undergoes the 1,6-conjugate addition to p-quinone methides, affording the intermediate II, which acts as a soft Lewis acid/Brønsted base synergistic catalyst in the following catalytic cycle. Finally, the catalyst is released for the next cycle through the deprotonation of α-carbon of α-CF₃ 7-azaindoline amide to provide the adduct 38, in which the Cu(I)-aryl oxide moiety in the intermediate II served as the Brønsted base.

As part of their ongoing research on asymmetric reactions with α-CF₃ 7-azaindoline amide 5 as the nucleophile under a soft Lewis acid/Brønsted base catalysis, Shibasaki’s group developed another asymmetric Mannich reaction of α-CF₃ 7-azaindoline amide 5 with isatin imines 39 catalyzed by a Cu(I)/Ph-BPE ligand L1.1/Barton’s base complex, providing simple and convenient access to the Mannich adduct 40, which contained two contiguous stereogenic centers, in 66–99 yields with 86:14→20:1 dr and 92–99% ee (Scheme 19) [79]. The substrate range was found to be quite broad. The potential application of this method was also demonstrated by the gram-scale reaction (1.46 g).

To demonstrate the synthetic utility of the products, the conversions of Mannich adducts to other products are shown in Scheme 20. In the presence of DIBALH, the Mannich adduct 40a was subjected to a triple-bond formation process to provide a multisubstituted tricyclic product 41 in 46% yield with 94:6 dr. This process included two reductions and one cyclization. Specifically, an aluminum alkoxide was formed via reduction of the oxindole moiety, the 7-azaindoline group was reduced to a masked aldehyde rather than an overreduced product, and the cyclization between aluminum alcohol and aldehyde resulted in product 41.

2.3. α-Azido 7-Azaindoline Amide as a Nucleophile

Enantio-enriched β-hydroxy-α-amino acid derivatives, which are functionalized α-amino acids and are commonly found in both natural products and biologically active molecules, can be used to synthesize numerous important chiral compounds. The β-hydroxy-α-azido amide compounds can be regarded as β-hydroxy-α-amino acid derivatives.

In 2015, Shibasaki’s group reported the asymmetric aldol reaction of α-azido 7-azaindoline amide 42 with aldehydes 2, catalyzed by the mesitylcopper/ligand complex, which produced a series of β-hydroxy-α-amino acid derivatives bearing two adjacent tertiary stereocenters (Scheme 21) [80]. More specifically speaking, the anti-adducts 43 were obtained with 86–99% ee using mesitylcopper/L1.1 catalyst, and the syn-adducts 43 were obtained with 93–99% ee using mesitylcopper/L1.8 catalyst through the asymmetric aldol reaction of α-azido 7-azaindoline amide 42 with ortho-substituted aromatic aldehydes 2. The authors also demonstrated that success in the mesitylcopper/L1.1 catalytic asymmetric aldol reaction of α-azido 7-azaindoline amide 42 with ortho-nonsubstituted aromatic aldehydes 2 provided an effective method for the construction of syn-β-hydroxy-α-azido amides 46 (Scheme 22, Formula (1)). Unfortunately, the current catalytic systems were not applicable to other aldehydes, such as aliphatic aldehydes and α,β-unsaturated aldehydes, due to their lower reactivity. Notably, the anti-adducts 48 bearing a propargyl unit were also generated via the asymmetric aldol reaction between α-azido 7-azaindoline amide 42 and ynals 47 using mesitylcopper/L1.1 catalyst (Scheme 22, Formula (2)).

From the experimental results, the following conclusions can be drawn: (i) The aldol reaction involving ortho-substituted aromatic aldehydes and ynals is carried out in a trans-selective manner using mesitylcopper/L1.1 as the catalyst; (ii) The configuration of the stereocenter at the α-position of the adducts was switched via adjustments of the chiral ligand [L1.1: 2S, L1.8: 2R], regardless of the type of aldehyde used. In addition, both the reactions of ortho-nonsubstituted aromatic aldehydes catalyzed by mesitylcopper/L1.8 and ortho-substituted aromatic aldehydes catalyzed by mesitylcopper/L1.1 or mesitylcopper/L1.8 prefer syn-adducts through the six-membered transition state. However, the reaction of ortho-substituted aromatic aldehydes catalyzed by mesitylcopper/L1.1 forms anti-adducts 43 through an open transition state, likely due to the large steric effect.

To further explore the important role of α-azido 7-azaindoline amide in the synthesis of α-amino acid derivatives by direct enolization chemistry, Shibasaki’s group developed an asymmetric Mannich reaction of α-azido 7-azaindoline acetamide 42 and N-thiophosphinoyl imines 6 with Cu(CH₃CN)₄]PF₆/(R)-xyl-Segphos L1.3/Barton’s base as a catalyst, affording Mannich adducts 49 containing both 7-azaindoline amide moiety and N-thiophosphinoyl amide fragment. Product 49 was easily hydrolyzed in acidic conditions, providing anti-β-amino-α-azido acid derivatives 50 with 84–98% ee (Scheme 23) [81]. This catalytic system was quite general for aromatic aldehydes with different substituents. The o-Cl-substituted imine gave the product 50a with a slightly lower ee value (89%) than the other cases of Cl-substitution positions. Compared to the case of the o-Cl substituted imine, an improved ee value (96%) for the adducts 50d was obtained by the reaction of the o-F-substituted imine as Mannich receptors, indicating that the decrease in the steric hindrance of imines positively influenced the enantioselectivity of the reaction. Moreover, other anti-β-amino-α-azido acids 50 derived from the reaction of α-azido 7-azaindoline acetamide and aliphatic imines could be obtained in 33–62% yields and 92–96% ee using increased catalyst loadings.

The results of NMR spectroscopy (¹H and ¹⁵N) showed that (E)-42 was converted to (Z)-42 after coordinating with Cu(I)/rac-Binap, and the azide group of α-azido 7-azaindoline amide did not coordinate with the Cu(I) complex (Scheme 24a). In addition, structurally similar α-azido amides 42b–e failed to react with N-thiophosphinoyl imines 6 in the (Cu(CH₃CN)₄]PF₆/L1.3/Barton’s base catalysis because the bidentate coordination of 7-azaindoline amide and Cu(I) was not possible in these cases. The results showed that the 7-azazindoline group in α-azido 7-azaindoline amide plays a key role in activating the substrate and controlling the stereoselectivity of the reaction (Scheme 24b).

To further study the utility values of α-N₃ 7-azaindoline amide in the synthesis of a crucial class of chiral building blocks, Shibasaki and co-workers subsequently explored the asymmetric aldol reaction between α-N₃ 7-azaindoline amide 42 and α-trifluoromethyl ynones 51 using Cu(OTf)₂/(R,R)-BHAL1.9/Barton’s base as catalysts and MS13X as an additive, providing trifluoromethyl substituted propargylic tertiary alcohols 52 in 82–96% yields and 17:83–8:92 dr and 83–96% ee (Scheme 25) [82]. Triisopropylsilyl (TIPS)-substituted trifluoromethyl ynones reacted smoothly with α-N₃ 7-azaindoline amide 42 to provide syn-52a in 94% ee. The substrates of trifluoromethyl ketones with alkyl (cyclo-C₆H₁₃) on the alkynyl group were tolerated. However, a slightly lower ee value (52b vs. 52c) was observed in the case of cyclo-C₆H₁₃ ynones than in the case of n-C₆H₁₃ ynones. It was also found that other α-fluorinated ketones were appropriate for this aldol reaction with high efficiency. The substrate 53d, which carries a CF₂CF₃ group in the α-position of ynone, reacted with α-N₃ 7-azaindoline amide to provide the adduct 54d in 89% ee, but in low yield (only 19%), even when the catalyst loading was increased to 20 mol% (Scheme 26).

According to the results of the control experiment, the mechanism of the asymmetric aldol reaction between an α-N₃ 7-azaindoline amide and α-trifluoromethyl ynones was explored (Scheme 27). In the current catalytic system, consisting of Cu(OTf)₂/(R,R)-BHA L1.9/Barton’s base, equivalent amounts of Cu(OTf)₂ and the ligand L1.9 form a 7-membered chelate complex 55. When the α-N₃ 7-azaindoline amide was added to the complex 55 solution, a precipitate complex 59 with a 1:2 Cu/amide but no ligand was formed. The Barton’s base is usually used for the deprotonation and enolization of α-N₃ 7-azaindoline amide, but the excessive amount of Barton’s base led to the deprotonation of the ligand L1.9. Thus, the undesired species (56 and 57) were also formed in the presence of excess Barton’s base in the solution of complex 55. In particular, the formation of 57 is irreversible. An unstable complex 58 and a slightly cloudy solution 60 were also obtained when the α-N₃ 7-azaindoline amide 42 was added to the solution of complex 55 and 56, respectively. The hydroxamic acids (L1.9) deprotonated in the presence of Barton’s base and became more strongly bound ligands. The solution 60 was converted into insoluble substances 61 using another equivalent of Barton’s base. Therefore, a higher loading of Barton’s base was not good for the catalytic system because the insoluble materials (57, 61) were formed. The additive MS13X has a suitable pore structure to reserve α-N₃ 7-azaindoline amide and Barton’s base, so that the pathways used to form the 57, 59, and 61 were suppressed. The authors presumed that the Cu(II)/L1.9 complex should play a bifunctional role. As shown in 62, the Cu(II) moiety in the complex served as a Lewis acid to activate α-N₃ 7-azaindoline amide 42 via intermolecular bonding, affording the compound of Cu(II)/L1.9/amide. Simultaneously, the proton-deficient moiety of Cu(II)/L1.9 served as a Brønsted base to remove the α-proton of α-N₃ 7-azaindoline amide in Cu(II)/L1.9/amide. In other words, the proton-deficient Cu(II)/L1.9 complex promoted the enolization of α-N₃ 7-azaindoline amide 42. The high stereoselectivity of the aldol reaction likely benefited from non-bonding interactions (such as hydrogen bonding or ion–dipole interactions) between the fluorine atoms in the ynones 51 and the acidic protons in the ligand, as illustrated in complex 64.

In 2018, Shibasaki and co-workers developed an highly effective asymmetric 1,6-conjugate addition of α-N₃ 7-azaindoline amide 42 to p-quinone methides (p-QMs) 37 [78]. As shown in Scheme 28, the adduct 65 was synthesized in 83% yield, 10:1 (anti/syn) dr and 90% ee using the mesitylcopper/chiral ligand L1.3 complex as a catalyst at −40 °C. This is a part of the research on the asymmetric 1,6-conjugate addition of α-substituted amides (CF₃, N₃, Me, and OBn) to p-QMs.

2.4. α-Alkyl Substituted 7-Azaindoline Amide as a Nucleophile

In 2016, Shibasaki’s group reported the direct asymmetric Mannich reaction of α-alkyl 7-azaindoline amide 66 with N-Boc imines 6 using a Lewis acid/Brønsted base cooperative catalyst (Scheme 29) [83]. Interestingly, two different configurations of β-amino acid derivatives (anti-67 and syn-67) were obtained with good results via modulation of the type of ligand. Specifically, the catalyst consisting of [Cu(CH₃CN)₄]PF₆/L1.10/Barton’s base was applied to the Mannich reaction between α-alkyl 7-azaindoline amide and imines at −10 °C, providing anti-67 with two tertiary stereocenters with 90–98% ee. Adduct 67 was converted into an α-methyl-β-amino acid via treatment with 6 M HCl in MeOH at 80 °C. They also developed the [Cu(CH₃CN)₄]PF₆/L1.11/Barton’s base for the asymmetric synthesis of β-amino acid derivatives through the reaction between amide and electron-deficient imines, providing the syn-67 with 83–95% ee.

Shibasaki and coworkers further extended this catalytic system to 7-azaindoline acetamide 68 and found that the [Cu(CH₃CN)₄]PF₆/L1.11 complex was effective with DME as a solvent. The reaction between 7-azaindoline acetamide 68 and 1.5 equivalents of N-Boc imine 6 proceeded smoothly, affording the Mannich adducts 69 bearing a chiral β-aminoacetate unit with 81–92% ee but only 42–55% yields (Scheme 30) [83]. This extended catalytic system was helpful to develop the application of acetamides via enolization in the asymmetric Mannich reaction, because products 69 tend to participate in enolization.

The authors also investigated the coordination of propionamides with the Cu(I)/L1.8 through NMR research, which showed that 7-azaindoline propionamide binds to the Cu(I)/L1.8 via bidentate coordination, with the conformation changing from E to Z. In contrast, amides 66a-b, structurally similar to 7-azaindoline amide 66, failed to form a bidentate coordination with the Cu(I) complex. The NMR results revealed that 50% of 66a formed the Z-66a/Cu(I)/L1.8 complex, whereas 66b scarcely afforded the corresponding Z-66b/Cu(I)/L1.8 complex. The difference in reactivity mainly depended on the coordination capacity of the amide with the Cu(I)/L1.8 complex (Scheme 31).

To further expand the scope of α-alkyl 7-azaindoline propionamide in direct catalytic asymmetric addition reactions, Shibasaki and co-workers explored the performance of α-alkyl 7-azaindoline propionamide 66 in the asymmetric aldol reaction [84]. The reaction in which the ynals 47 and aromatic aldehydes 2 were used as electrophiles proceeded smoothly and provided the aldol adducts with good results. The reaction, in which the ynals 47 and aromatic aldehydes 2 were used as electrophiles, proceeded smoothly and provided the aldol adducts with good results. As shown in Scheme 32, the reaction of α-methyl 7-azaindoline amide 66 and ynals 47 was catalyzed by mesitylcopper/L1.10 with ArOH 45 as the proton source, affording the anti-70 containing the propargylic alcohol unit with 90–97% ee. The desired adducts 70 were efficiently obtained regardless of the electronic properties and the positions of the substituents on the phenyl ring, probably because the phenyl of the ynals was far away from the reaction site. The aromatic aldehydes 2 were also employed as nucleophiles, providing a series of β-hydroxy propionate derivatives syn-71 with 81–93% ee under the catalysis of the mesitylcopper/L1.12 complex (Scheme 33).

A plausible catalytic cycle process for the reaction of α-methyl 7-azaindoline amide and aldehydes was put forward, as shown in Scheme 34. Firstly, E-configuration α-methyl 7-azaindoline amide 66 was combined with the mesitylcopper/ligand to form Z-configuration amide/Cu(I)/enolate 72 via bidentate coordination, which controlled the chiral environment in the aldol reaction. Then, an aldol addition occurred between the aldehydes (2 or 47) and complex 72 to form Cu(I) aldolate 73. Finally, the Cu(I) aldolate 73, acting as a Brønsted base, deprotonated α-methyl 7-azaindoline amide 66 to provide the desired product.

In the work by Shibasaki’s research group in 2018, a series of α-substituted 7-azaindoline amides (CF₃, N₃, Me, and OBn) were employed as donors to react with p-QMs 37 for the asymmetric synthesis of the desired adducts bearing a diarylmethane unit [78]. The α-methyl 7-azaindoline amide 66 also participated in the 1,6-conjugate addition catalyzed by the mesitylcopper/L1.3 complex, affording the product 74 with 87% ee (Scheme 35).

Motivated by the successful application of the mesitylcopper/L1.10 complex as a catalyst in the asymmetric addition of α-methyl 7-azaindoline amide 66 to aromatic aldehydes 2 and ynals 47 (Scheme 32 and Scheme 33), Shibasaki et al. applied the same complex to the asymmetric aldol reaction of α-vinyl 7-azaindoline acetamide 75 with both aliphatic and aromatic aldehydes [85]. When phloroglucinol 77 was used as an additive, α-vinyl 7-azaindoline acetamide 75 as a nucleophile reacted with aliphatic aldehydes 2 to give adducts syn-76 bearing contiguous tertiary stereocenters with 98→99% ee (Scheme 36). The mesitylcopper/L1.10 complex was also suitable for aromatic aldehydes by switching the additive 77 to 78, affording the desired products anti-76 with 95–98% ee (Scheme 36). From the above results, we reached the conclusion that the α-vinyl 7-azaindoline acetamide 75 reacted with aromatic aldehydes in an anti-selective manner using (R)-trimethoxy-Biphep L1.10 as a chiral ligand, while, complementarily, the α-Me 7-azaindoline acetamide reacted with aromatic aldehydes in a syn-selective manner by employing (S,S)-Ph-BPE L1.12 as a chiral ligand. The catalytic system also proved to be almost unbiased for the ynal, affording adduct 76f with good results.

The 7-azaindoline moiety of adducts 76 was easily converted, which helped to synthesize the key intermediate of blumiolide C 83 and kainic acid 86. Treatment of the adduct 76c with TBSOTf, followed by Myers’ reduction of the 7-azaindoline group of 76c, afforded the primary alcohol 79 with 97% yield. The unsaturated valerolactone 80 was smoothly obtained by esterification with acryloyl chloride followed by ring-closing metathesis with the second-generation Grubbs catalyst. The key intermediate 82 for blumiolide C 83 was received with 96% yield via the conjugate addition of 81 and 4-iodo-2-methylbut-1-ene (Scheme 37a). The reaction of acetaldehyde 2a with α-vinyl 7-azazoline acetamide 75 was catalyzed by mesitylcopper/ent-L1.10/phloroglucinol, resulting in the formation of syn-84, which is the enantiomer of 76b. The adduct 84 was silicified and reduced to produce intermediate 85, which was essential for the final synthesis of the kainic acid 86 (Scheme 37b). The importance lies in that the kainic acid 86 is a type of natural marine product and has biological applications because of the biological activities such as neuroexcitatory, insecticidal, and anthelmintic properties.

In their continuing study of catalytic enolization chemistry, the direct catalytic asymmetric aldol reaction of 7-azaindolinyl thioamides 87 with aliphatic aldehydes 2 in the presence of the [Cu(CH₃CN)₄]PF₆/(S,S)-Ph-BPE L1.12/LiOPh was disclosed by Shibasaki and co-workers in 2020 (Scheme 38) [86]. In this reaction, a variety of aldol products 88 bearing two consecutive stereocenters were successfully obtained with moderate to good yields (44–78%), with 9:1→20:1 dr and 88–98% ee (syn). In this catalytic system, the scope of aldehydes as substrates has been greatly expanded. When 7-azaindolinyl thioamides 87 were reacted with 3-phenylpropanal, no self-aldol product was formed and syn-88a was obtained with 95% ee. Notably, (-)-citronellal reacted with thioamides 87 to provide the target products 88e-f with a similar diastereoselectivity, regardless of whether (S,S)-Ph-BPE L1.12 or (R,R)-Ph-BPE L1.1 was used, indicating that the chiral environment of the Z-enolate determined the diastereoselectivity of the aldol reaction.

According to the NMR spectroscopy results, the proton (H_f) of the enolate and the protons (H_e) of the pyrroline moiety were identified by remarkable NOE signals, suggesting that the reaction of mesitylcopper with (E)-α-alkyl 7-azaindolinyl thioamide 87 provided the corresponding Z-configured thioamide enolate. The 7-azaindoline group had sufficient capacity to prevent rotation from the C(py)-N(amide) bond and stabilize the thioamide enolate via Cu(I)/ligand coordination (Scheme 39).

2.5. α-Halo Substituted 7-Azaindoline Amide as Nucleophiles

In view of the wide application of the enolate chemistry of α-substituted 7-azaindoline amides, Shibasaki et al. were encouraged to investigate the reaction of α-halo (α-F, -Cl, -Br, -I) 7-azaindoline amides as potential enolates with imines. They achieved a direct catalytic asymmetric Mannich reaction between α-Cl 7-azaindoline amide 89 and N-carbamoyl imines 6 without undesirable dehalogenation, using [Cu(CH₃CN)₄]PF₆/(S,S)-Ph-BPE L1.11/Barton’s base as a synergistic catalyst (Scheme 40 and Scheme 41) [87]. The use of 5 mol% loading of the catalyst smoothly promoted the Mannich reaction at −60 °C, affording adducts containing halogen atoms on the stereogenic carbon in high yields with moderate to good stereoselectivities. In their unremitting efforts, the authors extended the range of α-Cl substituted adducts 90 via Mannich addition with monosubstituted N-Boc aromatic imines under the synergistic catalysis. Specifically, the syn-90 were obtained with 85–99% ee by using a variety of monosubstituted imines without o-substituents, whereas the anti-90 was received with 94–97% ee when the o-monosubstituted imines were reacted with the α-Cl 7-azaindoline amide 89. In the series of adducts 90, the α-chiral carbons of the syn-90 and the anti-90 were consistent in S-configuration, whereas the β-chiral carbons were inconsistent in configuration, indicating that the presence of imine ortho-substituents altered the selectivity of the prochiral face.

The authors further investigated the substituent effect to obtain an in-depth understanding of the reason for the change in diastereoselectivity. They explored the asymmetric Mannich reaction of α-Cl 7-azaindoline amide 89 and disubstituted N-Boc imines 6 catalyzed by the [Cu(CH₃CN)₄]PF₆/(S,S)-Ph-BPE L1.11/Barton’s base. The adducts were obtained in 72–97% yields with 5:95–76:24 (syn/anti) dr and 84–98% ee using a variety of disubstituted imines with at least one o-substituent (Scheme 41). Compared to the anti-90f, the m′-Cl or o′-Cl substituted dichloro adducts anti-90i–j were obtained with a comparable stereoselectivity, but p′-Cl substituted dichloro adduct 90k had a significantly reduced anti-selectivity. The anti-selectivity of the disubstituted imines was significantly influenced by the steric factor of the p′-substituents, which was suggested by the variation in selectivity from 15:85 (syn/anti) in the case of the p′-F substituted imine (6l) to 33:67 in the case of the p′-Br substituted imine (6m). In comparison, the o-F substituent (6e) had a lesser influence on the anti-diastereoselectivity (syn/anti = 19/81) compared to the o-Cl case (6f) (syn/anti = 7/93). Interestingly, the preferential syn-selectivity was more dependent on the anchoring effect in the cases of the p′-Cl substituted imine (6o) and p′-Br substituted imine (6p) than in the case of the o-F substituent. The preferential syn-selectivity of the p′-substituent was similar for the imines 6q-r with o-Br-p′-Cl and o-NO₂-p′-Cl, respectively (anti-90g vs. anti-90q, anti-90c vs. anti-90r). Ortho-substituted imines tend to synthesize syn-90, whereas non-ortho-substituted imines easily produce anti-90, as the presence of ortho-substituents alters the face selection of aromatic imines.

Based on the experimental results, the authors proposed a reasonable explanation for the divergent diastereoselectivity (Scheme 42). Consistent with previous studies of various α-substituted 7-azaindoline amides, the α-Cl 7-azaindoline amide 89 exhibited an E-configuration in solution, and the configuration of 89 changed from an E-configuration to Z-configuration when the 89/Cu(I) complex was afforded via 89, which was coordinated with the Cu(I) complex. The corresponding enolate was obtained via deprotonation of the 89/Cu(I) complex with Barton’s base, and subsequently underwent the asymmetric Mannich reaction with imine 6. In case (i), under the catalysis of the Cu(I) complex, α-Cl 7-azaindoline amide 89 preferentially attacked the Re-face of m- or p-substituted imines 6-(i) via a transition-state model I with the minimum steric hindrance and dipole moment, affording products 90b and 90d in a syn-selective manner. In the case (ii), imine 6-(ii) tended to form an s-trans configuration rather than an s-cis configuration, due to the repulsion between the nitrogen atom and the ortho substituent of the imine. The Si-face of imine in s-trans configuration was more likely to be attacked to form a C–C bond via the transition-state model IV, providing the anti-configuration adducts anti-90i–j. The low anti-selectivity of the products 90h was obtained via the reaction of the o-Ome-substituted imine with α-Cl 7-azaindoline amide 89. This was attributed to the fact that both the nitrogen atom and the o-OMe group of the imine formed hydrogen bonds with the proton, which facilitated the attack on the Re face of the imine with s-cis configuration, thus providing the major product with syn-configuration via the transition-state model III′. In the case (iii), the major isomer with an anti-configuration was obtained by attacking the Si-face of the p′-substituted o-Cl imines 6k–m, owing to the small repulsion of the p′-substituent steric hindrance via the transition-state model VI. Imines with larger substituents at the p′ position, such as o-F-p′-Cl- or o-F-p′-Br-substituted imines 6o–p, were conducive to form syn-90o–p via the transition-state model V, whereas the o-F-p′-F-substituted imine 6n was conducive to forming anti-product 90n via the transition-state model IV. In the reaction between the o-substituted p′-Cl imines 6q–r and α-Cl 7-azaindoline amide 89, the anti-products 6q–r were more easily formed by attacking the Si-face of imines via the transition-state model VI.

Aliphatic imines were also used as electrophiles to the asymmetric Mannich reaction with α-Cl 7-azaindoline amide 89, providing the Mannich products 91 with 85–90% yield, 79:21–83:17 (syn/anti) dr, and 85–90% ee (syn), by switching the chiral ligand from L1.11 to L1.12 of the current Cu(I)/Barton’s base catalytic system (Scheme 43).

The Cu(I)/L1.11/Barton’s base catalyst was used in the Mannich reaction between α-Br 7-azaindoline amide 92 and imines 6, which provided adducts 93 in good yields with excellent enantioselectivities. The diastereoselectivity of products 93 showed a similar trend to that of products 90 (Scheme 44). The α-I 7-azaindoline amide 94 was used as a competent latent enolate to react with aromatic imines 6 for the asymmetric synthesis of α-I β-amino acid derivatives 95 (Scheme 45 Formula (3)). The diastereoselectivity trend observed in Scheme 42 was also shown for α-I 7-azaindoline amide 94. The authors previously reported the transformation between α-F 7-azaindoline amide 5d and N-Cbz imines 6b catalyzed by the [Cu(CH₃CN)₄]PF₆/L1.4/Barton’s base, in which Mannich adducts 22 were received in 51–79% yield with 15:85–9:91 (syn/anti) dr and 90–93% ee (Scheme 45 Formula (4)). In the specific case of α-F 7-azaindoline amide 5d, the reaction proceeded via the E-enolate, which benefited from the smaller steric factor and smaller dipole moment in the fluorine-substituted case. However, in the cases of α-Cl 7-azaindoline amide 91, α-Br 7-azaindoline amide 92, and α-I 7-azaindoline amide 94, the reaction occurred via the Z-enolate, meaning that the observed absolute configuration at the α-position was opposite to that of α-F 7-azaindoline amide 5d. The E-enolization intermediate of the α-F 7-azaindoline amide 5d case reacted with imines 6, bearing m- or p- substituents, following the transition state model VII, to provide products 22 with high anti-selectivity.

2.6. α-Oxygen-Substituted 7-Azaindoline Amide as Nucleophiles

Encouraged by the successful developments of the Mannich reaction with α-substituted (α-thio-, fluoroalkyl-, nitrogen-, alkyl-, halo-) 7-azaindoline amide, Shibasaki and co-workers explored a direct catalytic asymmetric reaction between α-oxygen-substituted 7-azaindoline amide 96 and imines 6 catalyzed by the [Cu(CH₃CN)₄]PF₆/L1.11/Barton’s base (Scheme 46) [88]. In this process, a series of α-hydroxy-β-amino carboxylic acid derivatives 97 were obtained with good yields (up to 97%) and moderate to high stereoselectivities (3.3:1→20:1 (syn/anti)), with excellent enantioselectivities (up to 99% ee). The m′- or p′-substituted o-halogen imines were partially tolerated and the configuration of 97e–f was influenced by the m′- or p′-substituent. More importantly, α-OBn 7-azaindoline amide 96a reacted with N-Boc imine 6a and N-Bz imine 6a′ to construct the side chains of Taxol and Taxotere, respectively (Scheme 47).

The results of control experiments showed that α-oxygen-substituted amides 96a–c reacted with imines, whereas amides 96d–f, which had a similar structure to 96a, did not react with imines, indicating that the 7-azazindoline group was the optimal structure to improve the reaction activity and stereoselectivity (Scheme 48).

In 2018, Shibasaki’s group also reported a transformation between α-OBn 7-azaindoline amide 96a and p-QMs 37, catalyzed by the mesitylcopper/L1.3 complex via the asymmetric 1,6-conjugate addition, providing the corresponding adduct 98 with 81% yield with 8.5:1 (anti/syn) dr and 90% ee (Scheme 49) [78].

In their ongoing project to simplify the synthesis of a variety of fluorinated compounds, Shibasaki and co-workers developed a direct catalytic asymmetric aldol reaction of α-oxygen-substituted 7-azaindoline amide 96 with α-fluorinated ketones 99. All the involved α-alkoxy substituents, α-OBn, -OPh, -OMe, -OPMB, -Oallyl, -OMOM, OBOM amides, were tolerated to afford 1,2-dihydroxycarboxylic acid derivatives 100 in a highly stereoselective manner (Scheme 50) [89]. The diastereoselectivity switched smoothly, depending on the type of the chiral ligands, which was attributed to the reaction occurring through an open transition state. The syn-selectivity of adduct 100a was not affected by α-OBn 7-azaindoline amide 96a in the gram reaction with the mesitylcopper/L1.10 complex as a catalyst. Other α-alkoxy substituted amides, such as α-OPh and α-OMe amides, were also suitable for this catalytic system, and the corresponding products 100b–c were obtained with syn-selectivity. The α-alkoxy substituted 7-azaindoline amides 96a–c reacted with α-fluorinated ketones 99 to produce the desired products anti-100g-i by switching the ligand L1.10 to L1.12 of the current catalytic system. The structure of the ketones influenced the activity and diastereoselectivity, probably due to the open transition state. The o-substituted aryl ketones did not react with α-alkoxy substituted 7-azaindoline amides, while the p- or m-substituted ketones readily and smoothly reacted with α-OBn 7-azaindoline amide 96a. The major isomers of products 100d–f with syn-configuration were obtained using ligand 1.10, and products 100j–l with the anti-configuration were obtained using the ligand 1.12. Other fluoroalkyl-substituted ketones 99p–r were also explored. Notably, difluoromethyl ketone reacted with α-OBn 7-azaindoline amide 96a povided the major isomers of product 100m with syn-configuration instead of anti-configuration, using mesitylcopper/L1.10 complex as a catalyst, probably because the the CF₂H group has a hydrogen bonding capability, which influenced the reaction face attacked by Cu(I) enolate intermediate 101 (Scheme 51).

Similar to the previously reported α-substituted amides, the (E)-α-OBn 7-azaindoline amide 96a was coordinated with the Cu(I) complex to obtain the (Z)-α-OBn 7-azaindoline amide/Cu(I) complex (Scheme 52a). A possible aldol process proposed by the authors, Cu(I) enolate complex 101, was formed by irreversible deprotonation, and then the stereoselective aldol reaction was carried out with the α-fluorinated ketone 99 as the electrophile, affording the Cu(I) aldolate intermediate 102. Intermediate 102 acted as a soft Lewis acid/Brønsted base cooperative catalyst to promote the deprotonation of α-OBn 7-azaindoline amide 96a and the subsequent catalytic cycle process (Scheme 52b).

3. α,β-Unsaturated 7-Azaindoline Amides Act as Electrophiles

Conjugate addition is beneficial for electron-deficient alkenes and the nucleophiles to form larger molecular scaffolds. In general, the reaction efficiency is largely determined by the electrophilicity of the electron-deficient alkenes, and relevant substrates include α,β-unsaturated ketones, unsaturated aldehydes and nitroolefins, which have been widely reported. α,β-unsaturated carboxylic acids are relatively less explored due to their weak electrophilicity, although the products added to these compounds are of high synthetic value. In recent years, the catalytic asymmetric reaction using α,β-unsaturated 7-azindolinolamide as an electrophile has become a very interesting topic and was studied by Shibasaki, Yuan and Wu’s group.

The α-substituted 7-azindoline amides summarized above are easily enolized via complexation with metal complexes, and this activation pattern also applies to the electrophilic activation of α,β-unsaturated 7-azindoline amides. X-ray crystallographic analysis shows that α,β-unsaturated 7-azindoline amides tend to be in the E-conformation, their conversion to the Z-conformation is achieved by adding Cu(I) complexes, and the β-carbon electrophilicity of α,β-unsaturated 7-azindoline amides in the Z-conformation is increased.

3.1. α,β-Unsaturated 7-Azaindoline Amides as Electrophiles in Vinylogous Conjugate Addition

In 2016, Shibasaki and co-workers first reported an asymmetric conjugate addition reaction of α,β-unsaturated 7-azaindoline amides 103 with γ-butyrolactones 104 using the [Cu(CH₃CN)₄]PF₆/L1.8 as a cooperative catalyst, providing the desired conjugate adducts 105 in 88→99% yield with 13:1→20:1 (anti/syn)) dr and 91–98% ee. When the [Cu(CH₃CN)₄]PF₆/(R)-DTBM-Segphos L1.13 was used, the reaction of β-CF₃-substituted and β-C₂F₅-substituted 7-azaindoline amides with γ-butyrolactones produced the desired products 105g-h with high yield and excellent stereoselectivities using iPr₂O as the solvent (Scheme 53) [90]. The authors also explored the asymmetric vinylogous conjugate addition of α,β-unsaturated γ-butyrolactones 106 and α,β-unsaturated 7-azaindoline amides 103 catalyzed by the Cu(I)/L1.13 complex, which provided access to desired products 107, bearing continuous trisubstituted stereogenic centers with high yield and excellent stereoselectivities (Scheme 54).

As shown in Scheme 55a, the α,β-unsaturated 7-azaindoline amide 103 with an E-configuration were converted to the Z-configuration after coordination with the Cu(I)/L1.8 complex, as observed in the NMR study. This coordination resulted in an increase in the electrophilicity of the β-carbon of the α,β-unsaturated 7-azaindoline amide 103. Using the Cu(I)/L1.8 complex as a catalyst, a series of amides 108–111, which have a similar structure to 7-azindolinamide, were not suitable for the catalytic system and did not react with γ-butyrolactones. Moreover, esters 112–113 failed in this reaction system (Scheme 55b). These results indicated that 7-azazindoline was the best directing group in terms of reactivity and stereoselectivity.

3.2. α,β-Unsaturated 7-Azaindoline Amides as Electrophiles in 1,3-Dipolar Cycloaddition

To further illustrate the important role of the 7-azazindoline group of α,β-unsaturated amides 103 in controlling the stereoselectivity of the reaction, in 2017, Shibasaki and co-workers subsequently examined the catalytic asymmetric synthesis of isoxazolidines 115 via the asymmetric exo-selective 1,3-dipolar cycloaddition of β-alkyl α,β-unsaturated amides 103a′ and aromatic nitrones 114 under In(III) complex catalysis (Scheme 56) [91]. The use of 5 mol% or 10 mol% of In(OTf)₃/bishydroxamic acid complex promoted a smooth reaction at room temperature to afford highly substituted isoxazolidines 115 in 67–95% yields with 3:1→20:1 (exo/endo) dr and 79–99% ee (exo). The catalytic system has a wide range of substrate universality. The o-Br-substituted aromatic nitrone 114d also reacted with 103a′ for the asymmetric synthesis of isoxazolidines 115a′d, where 10 mol% of the In(OTf)₃/L1.14 catalyst was required due to the steric hindrance factor of 114d. The authors expanded the range of β-alkyl α,β-unsaturated amides with aliphatic nitrones using the In(III) complex catalyst (Scheme 57).

NMR analysis shows that an intramolecular hydrogen bond is formed between the nitrogen atom of the pyridinyl group and the α-hydrogen atom. This finding confirms that amide 103a′ contains an E-configuration in the solution. After coordinating the amide 103a′ with In(III)/L1.14, NOE analysis showed that the amide 103a′ was converted to a Z-configuration (Scheme 58a). Subsequently, a 1,3-dipole cycloaddition reaction occurred between Z-amide 103a′ and nitrones 114. A series of similarly structured amides 103f′–i′ and methyl esters 103j′ were investigated to illustrate the important role of 7-azazindoline in reactivity and stereoselectivity (Scheme 58b). It was found that none of these amides reacted with nitrone 114a in the current catalytic system. Indolinamides 103f′ and 5-azazindolinamides 103g′ did not react with nitrone, suggesting that the presence of a nitrogen atom at the 7-position is essential for the reaction to proceed and that the substrates and In(III) complexes most likely interact via bidentate coordination. The importance of the five-membered pyrrole scaffold in 7-azazindoline was further demonstrated by the failure of amide 103h′ in the reaction.

Inspired by the fact that α,β-unsaturated 7-azaindoline amides were highly efficient electrophiles in the construction of isoxazolidines, and based on the important role of the 7-azindoline group of the amides in controlling the stereoselectivity of the reaction, Yuan’s group developed a highly enantio- and diastereoselective 1,3-dipolar cycloaddition between α,β-unsaturated 7-azaindoline amides 103 and azomethine ylides 116 catalyzed by the AgOAc/quinine-derived aminophosphine complex (Dixon’s catalyst) in 2019 (Scheme 59) [92]. In this reaction, highly substituted pyrrolidine derivatives 117 bearing four contiguous stereogenic centers were obtained in 29–99% yields with >20:1 dr and 82–99% ee using aromatic, heteroaromatic and aliphatic α,β-unsaturated 7-azaindoline amides as electrophiles. It was noteworthy that α,β-unsaturated 7-azaindoline amides 103 with electron-donating groups exhibited much higher ee values than those with electron-withdrawing groups in the 1,3-dipolar cycloaddition. The reaction of α-methyl azomethine ylide 117b proceeded with a dramatic decrease in yield (30%), which was attributed to the greater steric hindrance at the R⁴ position in the azomethine ylides 116b.

Yuan’s group also investigated the role of the 7-azazindoline moiety in α,β-unsaturated amides. A series of amides of similar structure reacted with azomethine ylides 116a under the present catalytic conditions, as follows: Indolinylamide 108 was suitable for the reaction and provided the target product with 75% yield, with >20:1 dr and 67% ee. The reaction of 6-azazindoline amide 118 and 7-azaindole amide 119 with 116a produced the corresponding products, with 37% ee and 27% ee, respectively. However, other amides, such as 109, 110 and 120, failed following 1,3-dipolar cycloaddition (Scheme 60a). The results of these control experiments showed that 7-azazindoline was the optimal structure for controlling the stereoselectivity of the reaction. According to the results of the control experiments presented above, the possible reaction transition state for the 1,3-dipolar cycloaddition reaction of α,β-unsaturated 7-azazindoline amides 103 and azomethine ylides 116 was proposed (Scheme 60b). First, AgOAc coordinates with the aminophosphine ligand L1.16, which is derived from quinine, to form the complex. The AgOAc/L1.16 complex activated amide 103 by coordinating Ag⁺ with the pyridinyl nitrogen atoms and carbonyl oxygen atoms of the 7-azindolinyl moiety in the amide. The methylene group of the azomethine ylide 116 is deprotonated by the tertiary amine in the AgOAc/L1.16 complex to form an anion. The 116 was activated through hydrogen bonding, which was then followed by a 1,3-dipolar cycloaddition reaction with the activated amide. This reaction resulted in the formation of enantioenriched pyrrolidine derivatives 117.

To demonstrate the synthetic utility of highly substituted pyrrolidine derivatives, transformations of the pyrrolidines 117aa were also investigated (Scheme 61). The treatment of 117aa with m-chloroperoxybenzoic acid did not cause a decrease in stereoselectivity for the N-hydroxyl pyrrolidine 121. Notably, the desired carboxylic ester derivative 123 was smoothly obtained with 74% yield with >20:1 dr and 95% ee by first removing 7-azindoline from product 122 under acidic conditions, followed by esterification.

In 2020, Shibasaki and colleagues investigated the asymmetric 1,3-dipolar cycloaddition of α,β-unsaturated 7-azaindoline amides 103 and azomethine imines 124 using the In(OTf)₃/bishydroxamic acid L1.9 complex as a catalyst, affording bicyclic compounds 125 with 54–90% yield in all cases >20:1 dr and 30–48% ee (Scheme 62) [93]. The p-OTBS-substituted α,β-unsaturated 7-azaindoline amides provided the corresponding product 125ia with 48% ee, which is higher than that of the amides substituted with electron-withdrawing groups. In the current catalytic system, structurally similar amides 108–111 did not react with azomethine imine 124, indicating that the 7-azazindoline moiety of amide 103 is crucial for activating the amides and enhancing the stereoselectivity of the target products (Scheme 63).

3.3. α,β-Unsaturated 7-Azaindoline Amides Act as Electrophiles in Michael/Aldol Cascade Reaction

The first example of the organocatalyzed asymmetric Michael/aldol cascade reaction with α,β-unsaturated 7-azaindoline amides as electrophilic partners was reported by Yuan’s group in 2019, as shown in Scheme 64 [94]. The process was catalyzed by only 1 mol% of cinchonidine-derived bifunctional squaramide 127, in which α,β-unsaturated 7-azaindoline amides 103 underwent an enantioselective Michael/aldol reaction with the 2-mercaptobenzaldehyde 126. The product thiochromenes 128, bearing three contiguous stereogenic centers, were afforded with 88–99% yield, >20:1 dr and ≥99% ee. Both α,β-unsaturated 7-azaindoline amides substituted with electron-donating groups and electron-withdrawing groups were able to effectively participate in the reaction, demonstrating the broad substrate universality of this reaction. A cyclohexyl-substituted substrate was investigated and the target product 128ha was produced with a high yield and stereoselectivity at −20 °C using 5 mol% catalyst loadings. Notably, a methyl substituent on the C5 position of the phenyl group of 2-mercaptobenzaldehyde 126b was also compatible with the current catalytic system. The desired product, 128ab, was successfully obtained using a 5 mol% catalyst 127.

The potential application value of this methodology was confirmed by the gram reaction and diversity transformation experiments (Scheme 65). To investigate the important role of the 7-azazindoline group of α,β-unsaturated amides in terms of their reactivity and stereoselectivity, a series of amides with similar structure were reacted with 2-mercaptobenzaldehyde (Scheme 66). The failure of amides 109, 112 and 118 to react with 2-mercaptobenzaldehyde indicated that the position of the nitrogen atom in the pyridine ring of 7-azazindoline was crucial to the bidentate’s coordination with the organocatalyst. N-methyl-(2-pyridyl) amide 110 and 1,2,3,4-tetrahydro-1,8-naphthyridinylamide 120 did not react with 2-mercaptobenzaldehyde, demonstrating that the rigid skeleton of the pyrrole ring of 7-azindoline was also important to the reaction. The α,β-unsaturated 7-azaindoline amide 119 was well-tolerated and provided a corresponding product with acceptable results. These control experiments showed that the 7-azazindoline group in amides is the most effective directing group.

Based on previous reports in the literature [95,96,97,98] and the results of the control experiments, a plausible pathway for the Michael/aldol cascade reaction of α,β-unsaturated 7-azazindoline amide and 2-mercaptobenzaldehyde was proposed, as shown in Scheme 67. As presumed, the tertiary amine-squaramide 127 should act in a bifunctional manner. Firstly, the tertiary amine moiety in catalyst 127, which acts as a base, deprotonated the mercapto group of 2-mercaptobenzaldehyde. At the same time, the squaramide moiety of catalyst 127 activates the α,β-unsaturated 7-azazindoline amides 103 through double hydrogen bonds. Secondly, the anion of 2-mercaptobenzaldehyde attacks the β-position of α,β-unsaturated 7-azazindoline amides from the Re face via the sulf-Michael addition reaction (TS-A). Thirdly, the carbanion of the α,β-unsaturated 7-azazindoline amides approaches the aldehyde group of 2-mercaptobenzaldehyde from the Re face via an intramolecular aldol reaction (TS-B). Finally, the oxygen anion intermediate was protonated to provide the target product 128 (TS-C), and the catalyst 127 was released for the subsequent catalytic cycle.

3.4. α,β-Unsaturated 7-Azaindoline Amides Act as Electrophiles in Aminomethylation

Based on the successful example of the Cu-catalyzed 7-azazindoline amide involved in the highly stereoselective construction of a C-C bond via asymmetric reaction and the lack of research on 7-azazindoline as a directing group in the field of photocatalysis, Shibasaki and coworkers developed an enantioselective aminomethylation of α,β-unsaturated 7-aza-6-MeO-indoline amides 135 with α-silylamines 133 using the Cu(I)/L1.3 complex and Ir(III) photocatalyst as a synergistic catalyst, producing the γ-aminobutyric acid derivatives 136 with 66–97% yield with 88→99% ee (Scheme 68) [99]. After the initial optimization of the reaction conditions, it was found that the target product 134a was obtained with 89% ee (Scheme 69). The influence of substituents on the 7-azaindoline group in the reaction was then investigated, showing that the activity and enantioselectivity of the reaction were significantly increased when 7-aza-6-methoxy-indoline was used as the directing group. Therefore, 7-aza-6-methoxy-indoline amide was chosen as the electrophile for the aminomethylation with α-silylamines. The α,β-unsaturated 7-aza-6-MeO-indoline amides 135 with different substituents, independent of the electron-donating or electron-withdrawing groups on the benzene ring, were successfully reacted with α-silylamines 133 to provide products 136ba–ca with high yields and high enantioselectivities. The α-Me substituted amide 135d was also tolerated in this reaction, generating the desired product 136da with a 66% yield with 81:19 dr, and the major isomer with only 34% ee.

A plausible pathway for the aminomethylation of α,β-unsaturated 7-aza-6-MeO-indoline amides and α-silylamines was proposed, as shown in Scheme 70. The β-methyl α,β-unsaturated 7-aza-6-MeO-indoline amide 135e bound to the Cu complex to form complex 137, which prevented the [2 + 2] photocycloaddition of 7-aza-6-MeO-indoline amide 135e. The Ir(III) photocatalyst in the ground state was excited to the excited state, and the photoexcited Ir(III)* complex oxidized α-silylamine 133a to produce α-amino radical 138 and TMS cations under the condition of blue light irradiation. The 7-aza-6-MeO-indoline amide 135e in complex 137 was electrophilic enough to couple with the α-amino radical 138, and the resulting α-amino radical 139 exhibited good stereoselectivity. Enolate amide 140 was obtained by the single-electron transfer of Ir(II) complex to α-amino radical 139. Meanwhile, the photoexcited Ir(III)* complex returned to the ground state, completing the photocatalytic cycle. Enolate amide 140 is protonated, releasing the γ-amino amide 136aa. When ethanol-d₄ was used instead of regular ethanol, the deuterium-labeled products 136aa-d accounted for 85% of the total yield. This finding further supports the hypothesis that ethanol acts as a source of protons.

The potential synthetic utility of this method was demonstrated by further transformation of the product (Scheme 71). The treatment of 136aa with hydrochloric acid provided methyl ester 141 and carboxylic acid 142, depending on the concentration of hydrochloric acid used. Both 141 and 142 are important derivatives of γ-aminobutyric acid, a key structural unit that exists in several drugs used to treat diseases of the central nervous system. Treating 136aa with an organolithium reagent in tetrahydrofuran at −78 °C, methyl ketone 143 was obtained without over-alkylated product. Lactam 144 was obtained by the simple treatment of product 136ad with potassium tert-butanol. In addition, the 6-methoxy-7-azazindoline was successfully removed, with a recovery of more than 95%.

3.5. α,β-Unsaturated 7-Azaindoline Amides Act as Electrophiles in Michael Addition-Initiated Ring-Closure Reaction

As part of Shibasaki’s group, ongoing research focuses on asymmetric reactions using α,β-unsaturated 7-azaindoline amide as the electrophile under metal catalysis. They developed a highly stereoselective synthesis of 1,2,3-substituted cyclopropanes 147 through the Michael addition-initiated ring-closure reaction of α,β-unsaturated 7-azaindoline amides 145 and sulfur ylides 146 catalyzed by chiral Cu(I) complexes (Scheme 72) [100]. In this process, the use of the 2 mol% [Cu(CH₃CN)₄]PF₆/L1.17 complex smoothly promoted the Michael addition at room temperature to afford CF₃-functionalized trisubstituted cyclopropanes 147 in 84–98% yields with >94:6→99:1 dr and 58–97% ee. This method was applicable to sulfur ylides with various substituents.

A possible reaction pathway was proposed, as shown in Scheme 73. The Z-configuration complex 148 was obtained by the coordination of β-CF₃ α,β-unsaturated 7-azaindoline amide 145 and Cu(I)/L* complex, which increased the electrophilicity of amide 145 and facilitated attack by nucleophile 146a. The major Cu-enolate intermediate 149 was obtained by the formation of C-C bonds at the β-position via an irreversible pathway, and then Cu-enolate intermediate 149 underwent intramolecular S_N2 reaction to provide major diastereomer 147a. Minor Cu-enolate intermediate 150 provided minor diastereomer 147a′. The Newman projection shows that major diastereomer 147a is formed via stable intermediate 149. This is because the -CF₃ and the sterically bulkier -COPh group were in the anti-periplanar conformation, and the dihedral angle between the Cu-enolate and the -SMe₂ group was 180°. In contrast, the Cu-enolate, -COPh, and -CF₃ in intermediate 150 were crowded and underwent a strong torsional interaction. The minor diastereomer 147a′ was probably formed by a high-energy transition state.

The β-alkyl α,β-unsaturated 7-azaindoline amide was also explored under the current catalytic system, and the corresponding products 147aa′–147ah′ were easily obtained with good yields and stereoselectivities (Scheme 74). Compared to β-alkyl α,β-unsaturated 7-azaindoline amides, β-aryl α,β-unsaturated 7-azaindoline amides showed lower activity, which required further screening of chiral ligands in the catalytic system. Finally, the authors found a suitable ligand L1.18 for β-aryl α,β-unsaturated 7-azaindoline amides, although the corresponding product 147a was only 76% ee. Compared with the catalysis of the Cu/L1.17 complex, the performance of the Cu/L1.18 complex was better in the reaction between β-aryl α,β-unsaturated 7-azaindoline amides with different substituents and sulfur ylides, in which the products 147aa–147ma were afforded, with excellent dr values and uniformly increased ee values (Scheme 75).

To showcase the practicality of 1,2,3-substituted cyclopropanes, the authors conducted further investigations into various transformations of cyclopropanes. It is worth noting that the 7-azindoline group of the cyclopropane derivative 147a was removed under acidic conditions, and the product ester 151 was afforded with an unchanged dr value. In the presence of the Lewis acid FeCl₃, the ketone carbonyl of ester 151 underwent a Schmidt rearrangement reaction with TMSN₃, and the desired product, 152, showed high regioselectivity (Scheme 76). Product 152 was an important precursor in pharmaceutical chemistry because of its similar structure to the β-aminocyclopropane carboxylic acids (β-ACCs), a special synthon of polypeptide ligands with high affinity for neuropeptide Y1 receptors.

In 2023, Wu’s group [101] explored an asymmetric 1,4-hydroboration of α,β-unsaturated 7-azaindoline amides 103 and B₂pin₂ 153 using a Cu(I)/L1.19 complex as the catalyst. Treatment of alkyl borate esters 154 with NaBO₃·4H₂O gave the expected products β-hydroxy amides 155 in moderate to good yields with moderate enantioselectivities (up to 96% yield and 84% ee) (Scheme 77). The possible mechanism of the 1,4-hydroboration reaction was proposed, as shown in Scheme 78. First, copper salts interact with chiral ligands L1.19 and NaOAc to form the L*CuOR complex 156, and then react with B₂pin₂ to provide the active L*Cu-Bpin complex 157. The α,β-unsaturated 7-azaindoline amide 103 is then activated by binding to the hydrogen bond donors of complex 157. The Si face of complex 157 attacks α,β-unsaturated 7-azaindoline amide 103, resulting in the formation of intermediate 158. In the presence of the proton source MeOH, the intermediate 158 is converted into target product 154, releasing the species L*CuOMe into the next catalytic cycle.

4. Summary and Outlook

As discussed in this review, great progress has been made in metal-catalyzed and organo-catalyzed asymmetric reactions in recent years, using 7-azazindoline amides as universal reagents. The use of various α-substituted-7-azaindoline amides and α,β-unsaturated 7-azaindoline amides as synthons has greatly expanded the range of substrates for enolization chemistry. This has allowed for the development of new transformations to obtain compounds that are difficult to synthesize through other reactions. In this research area, it is observed that metal catalysts and organic catalysts can be utilized for the catalytic conversion of such reactions as the asymmetric aldol reaction, Mannich reaction, conjugate addition, 1,3-dipole cycloaddition, Michael/aldol cascade reaction, aminomethylation, and Michael addition-initiated ring-closure reaction. However, there relatively few reactions are catalyzed by organocatalysts. One case of the Michael/aldol cascade reaction is reported by Yuan’s group. Therefore, the asymmetric reaction of 7-azaindoline amide, catalyzed by the organocatalyst, has great research potential due to its application in the field of pharmaceutical science. The organocatalysis strategy is currently one of the most thriving research areas in contemporary organic synthesis [102,103,104,105,106]. Moreover, the number of asymmetric reactions with α-substituted 7-azaindoline amides and α,β-unsaturated 7-azaindoline amides as synthons is still limited, as well as the unabundant types and quantities of 7-azaindoline amides. In other words, developing other types of 7-azaindoline amides and applying them to novel asymmetric reactions will be an interesting but challenging research direction. Further study is needed to investigate the coordination mode between 7-azaindoline amides and metal or organic catalysts, which are possibly verified through theoretical calculations. In general, the relevant examples described in this review highlight the unique utility and potential applications of 7-azaindoline amide as a synthetic precursor for the construction of structurally diverse chiral carboxylic acid compounds through a variety of novel reactions. It is believed that more breakthrough findings on 7-azaindoline amides will be reported in the future.