Atroposelective synthesis of axially chiral imidazo[1,2-a]pyridines via asymmetric multicomponent reaction

Abstract

Imidazo[1,2-a]pyridines are privileged heterocycles with diverse applications in medicinal chemistry; however, the catalytic asymmetric synthesis of these heterocyclic structures remains underexplored. Herein, we present an efficient and modular approach for the atroposelective synthesis of axially chiral imidazo[1,2-a]pyridines via an asymmetric multicomponent reaction. By utilizing a chiral phosphoric acid catalyst, the Groebke-Blackburn-Bienaymé reaction involving various 6-aryl-2-aminopyridines, aldehydes, and isocyanides gave access to a wide range of imidazo[1,2-a]pyridine atropoisomers with high to excellent yields and enantioselectivities. Extensive control experiments underscored the pivotal role of the remote hydrogen bonding donor on the substrates in achieving high stereoselectivity for these reactions. The versatile derivatizations of these atropisomeric products, especially their role as an analog of NOBINs and their facile conversion into unique 6,6-spirocyclic products, further emphasize the merits of this methodology.

An asymmetric multicomponent reaction is developed for the atroposelective synthesis of axially chiral imidazo[1,2-a]pyridines.

INTRODUCTION

Imidazo[1,2-a]pyridines, a class of fused nitrogen-bridged heterocyclic compounds, have garnered considerable research interest because of their diverse biological activities, such as anticancer, antiviral, antimycobacterial, antidiabetic, antimicrobial, and anticonvulsant properties and proton pump inhibitor (1–4). Notably, several marketed drugs contain the imidazo[1,2-a]pyridine core, including zolpidem (for insomnia treatment), zolimidine (for peptic ulcer treatment), saripidem (an anxiolytic agent), and others (Fig. 1A). Consequently, the synthesis of imidazo[1,2-a]pyridines has drawn considerable attention in recent decades, with various effective methods having been disclosed by researchers (5–8). In 1998, Groebke, Blackburn, and Bienaymé (9–11) independently reported the acid-catalyzed three-component reactions involving cyclic H₂N-C=N structures (2-aminoazines or amidines), aldehydes, and isocyanides, yielding a diverse array of imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrazines, and imidazo[1,2-a]pyrimidines (Fig. 1B). Since then, the Groebke-Blackburn-Bienaymé reaction, also known as GBB reaction, has emerged as a powerful method for the efficient synthesis of 3-amino–substituted imidazo[1,2-a]-heterocycles, leading to more than 200 publications and more than 100 patent applications (12, 13).

Fig. 1. Imidazo[1,2-a]pyridine, GBB reaction, and asymmetric GBB reaction for construction of axially chiral imidazo[1,2-a]pyridine.

(A) Imidazo[1,2-a]pyridine-based drugs. (B) GBB reaction. (C) Asymmetric multicomponent reactions (AMCRs) involving isocyanides for the synthesis of chiral products bearing stereogenic centers. (D) This work: Asymmetric GBB reaction for the synthesis of axially chiral imidazo[1,2-a]pyridines.

Asymmetric multicomponent reactions (AMCRs) result in the production of chiral compounds through the simultaneous asymmetric reaction of three or more reagents in a single step, which offers substantial complexity and diversity for a targeted set of scaffolds while minimizing overall synthetic operations (14–17). Isocyanides play a crucial role in AMCRs because of their ability of react simultaneously with nucleophiles and electrophiles at the terminal carbon. Over the past two decades, there have been remarkable advancements in enantioselective multicomponent reactions involving isocyanides, such as the Passerini reaction (18–21), Ugi reaction (22–28), and others (29–32) (Fig. 1C). Notably, all these methods have yielded chiral compounds bearing stereogenic centers.

Axially chiral atropisomers have received considerable attention because of their widespread presence in natural products (33), bioactive molecules (34, 35) and chiral catalysts and ligands (36, 37). Consequently, the catalytic enantioselective synthesis of various axially chiral compounds has been extensively studied, resulting in notable recent advancements (38–46). While various ingenious methods have been disclosed for asymmetric synthesis of axially chiral atropisomers, to our knowledge, their synthesis involving AMCRs has been rarely explored (47, 48). With our continuous interest in the asymmetric synthesis of diverse axially chiral atropisomers (49–53), herein, we report the atroposelective synthesis of axially chiral imidazole[1,2-a]pyridines via AMCRs (Fig. 1D). Specifically, the chiral phosphoric acid–catalyzed (54, 55) GBB reaction between various 6-aryl-2-aminopyridines, aldehydes, and isocyanides yielded a wide range of axially chiral imidazo[1,2-a]pyridines with high to excellent yields and enantioselectivities.

RESULTS

Reaction condition optimizations

We began our study by selecting 6-(2-naphthol)–substituted 2-amino-pyridine 1a as the model substrate (Table 1). Encouragingly, the three-component GBB reaction between 1a, benzaldehyde (2a), and benzylisocyanide (3a), enabled by chiral phosphoric acid (CPA) catalyst A1 (10 mol %), proceeded smoothly to yield the axially chiral imidazole[1,2-a]pyridine 4a in 80% yield with 38% enantiomeric excess (ee) in dichloromethane (DCM) at 20°C, in the presence of 4-Å molecular sieves (4-Å MS) (entry 1). Next, a series of 1,1′-bi-2-naphthol (BINOL)-, H8-BINOL- and 1,1′-spirobiindane-7,7′-diol (SPINOL)-derived CPA catalysts was screened for this reaction (entries 2 to 10), which suggested that the sterically hindered CPA catalyst A8 derived from H8-BINOL gave optimal enantioselectivity (42% ee, entry 8). It was worth noting that a notable background reaction was observed in the absence of CPA catalyst (entry 11). Consequently, to avoid the undesired racemic background reaction, the concentration of this reaction (entry 12) and the amount of 2a and 3a used (entry 13) were reduced, which resulted in remarkable enhancement of the ee values. A range of solvents were examined for this reaction (entries 14 to 18), and we were delighted to find that the corresponding reaction in c-hexane yielded the product 4a in 99% yield with 97% ee (entry 18). The role of 4-Å MS in this reaction was also investigated, revealing notably reduced enantioselectivity in its absence, probably attributable to the formation of H₂O in this reaction (entry 19).

Table 1. Optimizations of reaction conditions.

Entry*	Cat.	Solv.	C of 1a (M)	Yield (%)†	Ee (%)‡
1	A1	DCM	0.2	80	38
2	A2	DCM	0.2	99	11
3	A3	DCM	0.2	88	28
4	A4	DCM	0.2	75	23
5	A5	DCM	0.2	90	35
6	A6	DCM	0.2	99	35
7	A7	DCM	0.2	80	41
8	A8	DCM	0.2	99	42
9	A9	DCM	0.2	99	5
10	A10	DCM	0.2	99	5
11	None	DCM	0.2	41	0
12	A8	DCM	0.05	64	59
§13	A8	DCM	0.05	78	64
§14	A8	CHCl3	0.05	50	83
§15	A8	Toluene	0.05	99	92
§16	A8	Et2O	0.05	99	96
§17	A8	EtOAc	0.05	99	87
§18	A8	c-Hexane	0.05	99	97
§,¶19	A8	c-Hexane	0.05	99	68

*The reactions were performed with 1a (0.05 mmol), 2a (0.2 mmol), 3a (0.15 mmol), and CPA catalysts (0.005 mmol) in solvent (0.25 or 1.0 ml) in the presence of 4-Å MS (30 mg) under N₂ atmosphere at 20°C for 12 hours.

†Isolated yields.

‡The ee values were determined by HPLC analysis using a chiral stationary phase.

§2a (0.1 mmol) and 3a (0.075 mmol) were used.

¶Without 4-Å MS.

Substrate scope investigation

With the optimal conditions established, we set out to investigate the scope of this method for the asymmetric synthesis of axially chiral imidazole[1,2-a]pyridines (Fig. 2). Initially, a series of para-substituted benzaldehyes was examined with this method, which afforded the desired imidazole[1,2-a]pyridine atropisomers with high yields and enantioselectivities, regardless of their electronic nature (4b to 4 h). The absolute configuration of these products was assigned as (R) by analogy to 4a, whose structure was unambiguously determined by x-ray crystallography. In addition, a series of meta-substituted benzaldehyes (4i to 4l), and even the sterically demanding ortho-substituted benzaldehyes (4 m to 4o) were well tolerated by this method, yielding products with high enantioselectivities. Moreover, 2-naphthaldehyde (4p), 3-furaldehyde (4q), 3-thiophenaldehyde (4r), and cinnamaldehyde (4 s) were found to be amenable to this method, albeit affording products with slightly reduced enantioselectivities. Next, a series of substituted beznylisocyanides was studied under the optimal conditions, which afforded products (4t to 4v) with excellent ee values (up to >99% ee). Moreover, various alkylisocyanides were viable variants (4w to 4y), including the functional group–containing 2-isocyanoacetate (4z), all generating the atropisomeric products with high enantioselectivities. In contrast, the arylisocyanide afforded the product with a reduced ee value (4aa). We also investigated the replacement of the 2-naphthol moiety in substrate 1 with a substituted phenol moiety, which was also viable with this method (4ab to 4ac). Last, the removal of the steric group at the phenol unit and its relocation to the 5-position of the pyridine unit was found to be compatible with this method, leading to the successful synthesis of another type of imidazole[1,2-a]pyridine atropisomers in high yields and excellent enantioselectivities (4ad to 4ag).

Fig. 2. Scope for enantioselective synthesis of axially chiral imidazole[1,2-a]pyridines via asymmetric GBB reaction.

The reactions were performed with 1 (0.1 mmol), 2 (0.2 mmol), and 3 (0.15 mmol) with CPA (R)-A8 (0.01 mmol, 10 mol %) in cyclohexane (2 ml) in the presence of 4-Å MS (60 mg) under N₂ atmosphere at 20°C for 12 hours. Isolated yields were reported. The ee values were determined by HPLC analysis using a chiral stationary phase.

Configurational stability studies

The configurational stabilities of atropisomers are pivotal for their potential applications. Accordingly, as a new type of atropisomeric scaffolds, their configurational stabilities were evaluated by thermal racemization experiments (Fig. 3). A first-order decay of enantiopurity of the axially chiral imidazole[1,2-a]pyridine 4a was observed at 100°C (in toluene), revealing a racemization half-life of 32.9 hours (at 100°C) and a racemization barrier of 31.5 kcal/mol (Fig. 3A). In addition, the other atropisomeric product 4ae was also subjected to thermal racemization study, uncovering a racemization half-life of 23.8 hours (at 100°C in toluene) and a racemization barrier of 31.2 kcal/mol (Fig. 3B). These results underscore the exceptional configurational stabilities of these imidazole[1,2-a]pyridine atropisomers, which could be categorized into class-3 atropisomer according to LaPlante’s atropisomer classification system (with racemization barriers >30 kcal/mol) (35).

Fig. 3. Thermal racemization studies of the products.

(A) Thermal racemization study of 4a. (B) Thermal racemization study of 4ae.

Reaction mechanism investigation

To elucidate the origin of stereoselectivity in this reaction, we performed a set of control experiments (Fig. 4). In comparison to the high enantioselectivity observed for the 6-(2-phenol)–substituted 2-aminopyridine (4ad), its O-Me–substituted counterpart 1ad’ only yielded the product 4ad’ with 26% ee, highlighting the critical role of the OH group in the 2-aminopyridine substrates (Fig. 4A). Moreover, this method was used to examine the 6-(2-aniline)–substituted 2-aminopyridines 5, which would potentially lead to distinct axially chiral imidazole[1,2-a]pyridine products with two amino groups. Encouragingly, the N-Me–substituted 5a afforded the axially chiral product 6a in 76% yield with 84% ee, representing an analogous of the widely studied axially chiral framework of 1,1′-binaphthyl-2,2′-diamine (BINAM) (56, 57) (Fig. 4B). In contrast, the N,N-di-Me–substituted 5b gave the product 6b with only 29% ee, once again emphasizing the importance of the potential hydrogen bonding donor in the substrate (Fig. 4C). Furthermore, a series of sterically and electronically distinct N-substitutions was evaluated on the 2-aminopyridine substrates 5 (Fig. 4D). The N-Bn–substituted 5c delivered the product with a reduced 50% ee, while the N-Bz– and N-Boc–substituted 5d and 5e provided products with 40 and 12% ee, respectively. Notably, the N-Ts–substituted 5f led to the formation of the product in a racemic form. These results collectively suggest that both the steric and electronic effect of the N-substitutions on the substrates 5 play a pivotal role for the high stereoselectivity control of these reactions. On the basis of these experimental results and previous research (12, 26), a plausible reaction mechanism was proposed (Fig. 4E). Initially, the dehydrative condensation between 2-aminopyridine 1 and aldehyde 2 produced the imine INT-A. Upon activation of the imine group by the CPA catalyst through hydrogen bonding, the stereoselective attack by isocyanide 3 led to the formation of INT-B with a stereogenic center. Notably, it was proposed that the remote hydroxy group engaged in hydrogen bonding with the CPA catalyst as well, thereby contributing to a more organized transition state and potentially promoting high stereoselectivity in this step. Subsequently, the cationic intermediate INT-B underwent cyclization in the presence of the chiral phosphate anion, yielding chiral INT-C with established axial chirality. The axial chirality in INT-C was suggested to originate from the preorganization of INT-B in a (R)-conformation by the chiral phosphate, which was the kinetically favorable conformation for the subsequent cyclization step. Moreover, despite the long distance from the generated chiral axis, the chiral stereocenter in INT-B may also influence the formation of the axial chirality in INT-C (58, 59). Last, the imine-enamine tautomerism within INT-C eliminated the chiral stereocenter, ultimately yielding the axially chiral imidazole[1,2-a]pyridines 4.

Fig. 4. Experimental studies and the proposed reaction mechanism.

(A) Control experiment of the O-substitution. (B) Results for substrate bearing NHMe group. (C) Control experiment of the NMe₂ group. (D) Control experiments of the N-substitutions. (E) Proposed reaction mechanism.

Derivatizations of chiral products

To showcase the practicability of this method, we conducted a large-scale asymmetric reaction. Gram-scale preparation of the axially chiral imidazole[1,2-a]pyridine 4a was achieved through the asymmetric three-component GBB reaction involving 1a (3.0 mmol), benzaldehyde 2a, and benzylisocyanide 3a, resulting in 4a in 82% yield with >99% ee, using only 1 mol % of CPA catalyst (R)-A8 (Fig. 5A). Notably, no column chromatography purification was necessary, and simple trituration with DCM afforded the enantiopure product. Furthermore, we explored the derivatizations of the chiral product. Oxidation of 4a using MnO₂ produced imine 7a, which displayed high configurational stability as well, with racemization barrier of 32.4 kcal/mol (Fig. 5B) The acidic hydrolysis of 7a yielded the axially chiral biaryl amino alcohol 8a, serving as an analog of the versatile chiral scaffold 2-amino 2′-hydroxy-1,1′-binaphthyl (NOBIN) (60, 61). Consequently, the condensation between 8a and salicylic acid afforded the chiral Schiff-base type tridentate ligand 9a (62, 63). In addition, the coupling between 8a and 2-picolinic acid yielded the axially chiral picolinamide-type ligand 10a in 60% yield with >99% ee (64). Moreover, the direct coupling of 4a with SOCl₂ yielded the eight-membered cyclic sulfuramidite 11a in 95% yield with 8.3:1 dr and 98% ee, in which the axial chirality was well preserved, and effectively modulated the newly generated S(IV)-stereogenic center (Fig. 5C). Intriguingly, treatment of 4a with Pd/C and oxygen resulted in the formation of the chiral 6,6-spirocyclic product 12a with a quantitative yield and complete axial-to-central chirality conversion, which represent a type of highly appealing structure within the field of medicinal chemistry (Fig. 5D) (65, 66). This transformation likely proceeded through sequential dehydrogenative imine formation, followed by a Mannich reaction-type intramolecular dearomatization of 2-naphthol (67) and subsequent imine regeneration through another dehydrogenation process. Moreover, the catalytic hydrogenation of 12a selectively reduced the enone olefine, affording 13a in 95% yield. The application of the axially chiral imidazole[1,2-a]pyridine scaffold in developing chiral organocatalysts was also explored. Following selective O-methylation with MeI, a two-step process was used to remove the N-benzyl group, yielding the axially chiral amine, which was subsequently coupled with CSCl₂ and (R,R)-N¹,N¹-dimethylcyclohexane-1,2-diamine to give the chiral thiourea-tertiary amine 14a (Fig. 5E). This catalyst was then utilized in the enantioselective electrophilic amination of β-ketoester 15 with di-tert-butyl azodicarboxylate (68), which afforded the amination product 16 in 99% yield with 88% ee without optimization (Fig. 5F). Noteworthy, the chiral thiourea-tertiary amine catalyst 17, having only point chirality, led to the synthesis of 16 with 48% ee, underscoring the vital role of the axially chiral midazole[1,2-a]pyridine scaffold in 14a.

Fig. 5. Large-scale asymmetric synthesis and derivatizations of the chiral products.

(A) Large-scale preparation of 4a. (B) Derivatizations of 4a into NOBIN analogs. (C) Conversion of 4a into eight-membered cyclic sulfuramidite. (D) Transformation of 4a into 6,6-spirocyclic product. (E) Synthesis of chiral bifunctional organocatalyst 14a from 4a. (F) Application of 14a in the enantioselective electrophilic amination reaction.

DISCUSSION

In conclusion, we have developed a highly modular and efficient approach for the atroposelective synthesis of axially chiral imidazo[1,2-a]pyridines through AMCRs. By using a chiral phosphoric acid catalyst, the GBB reaction between various 6-aryl-2-aminopyridines, aldehydes, and isocyanides yielded a wide array of imidazo[1,2-a]pyridine atropoisomers with excellent yields and enantioselectivities. Detailed control experiments indicate that the presence of a remote hydrogen bonding donor on the substrates play a vital role in achieving high stereoselectivity in these reactions. The diverse derivatizations of these atropisomeric products, including serving as an analog of NOBIN and readily converting into distinctive 6,6-spirocyclic products, underscore the significance of this method.

MATERIALS AND METHODS

Unless otherwise noted, all commercial reagents were used without further purification. DCM, toluene, ether, tetrahydrofuran (THF) were purified by passage through an activated alumina column under argon. Thin-layer chromatography (TLC) analysis of reaction mixtures was performed using Huanghai silica gel HSGF254 TLC plates and visualized under ultraviolet or by staining with ceric ammonium molybdate or potassium permanganate. Flash column chromatography was carried out on Huanghai Silica Gel HHGJ-300, 300 to 400 mesh. Nuclear magnetic resonance (NMR) spectra were recorded using a Bruker Avance III HD spectrometer (FT, 500 MHz for ¹H, 126 MHz for ¹³C, 471 MHz for ¹⁹F, or 400 MHz for ¹H, 101 MHz for ¹³C, 376 MHz for ¹⁹F). ¹H and ¹³C chemical shifts are reported in parts per million downfield of tetramethylsilane and referenced to residual solvent peak [CDCl₃, δH = 7.26 and δC = 77.16; (CD₃)₂O, δH = 2.05 and δC = 29.84; (CD₃)₂SO, δH = 2.50 and δC = 39.52]. Multiplicities are reported using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad resonance. Mass spectral data were obtained from the Agilent Technologies 6230 time-of-flight liquid chromatography–mass spectrometry spectrometer in electrospray ionization (ESI⁺) mode. X-ray structure analyses were performed using a Bruker D8 Venture X-ray single crystal diffractometer. Optical rotations were measured with an Autopol V Plus/VI digital polarimeter. Enantiomeric excesses were determined on an Agilent 1260 Chiral HPLC using IA, IB, IB N-5, IC, ID, and IG columns. The racemic products were synthesized by using diphenyl phosphate as a catalyst.

General procedure for enantioselective synthesis of axially chiral imidazole[1,2-a]pyridines

To solution of 1 (0.1 mmol, 1.0 equiv.), CPA (R)-A8 (0.01 mmol, 10 mol %) and 4-Å MS (60 mg) in dry c-hexane (2 ml) were added 2 (0.2 mmol, 2.0 equiv.) and 3 (0.15 mmol, 1.5 equiv.) sequentially at 20°C. After stirring at this temperature for 12 hours, the reaction mixture was directly purified by column chromatography (300- to 400-mesh silica gel, petroleum ether/THF = 1:1) to afford the products 4 as a yellow or reddish solid.

Supplementary Materials

This PDF file includes:

Supplementary Text

Tables S1 to S4

Figs. S1 to S8

References