[4 + 2]-Annulation of MBH-Acetates of Acetylenic Aldehydes with

Jun 23, 2019 - Figure 1. Download Hi-Res ImageDownload to MS-PowerPointCite ...... The Supporting Information is available free of charge on the ACS P...
24 downloads 0 Views 1MB Size
Download PDF
Article Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX

pubs.acs.org/joc

[4 + 2]-Annulation of MBH-Acetates of Acetylenic Aldehydes with Imidazoles/Benzimidazoles To Access Imidazo[1,2‑a]pyridines/ Benzimidazo[1,2‑a]pyridines Chada Raji Reddy* and Amarender Goud Burra Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India

Downloaded via UNIV OF SOUTHERN INDIANA on July 17, 2019 at 10:05:04 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: An unprecedented one-pot successive basemediated allylic amination/cycloisomerization reaction strategy has been developed to construct diversely substituted imidazo[1,2-a]pyridines and benzimidazo[1,2-a]pyridines in good to excellent yield. The advantage of this unique [4 + 2]annulation lies in the employment of readily accessible starting materials, Morita−Baylis−Hillman acetates of acetylenic aldehydes as C4 synthons, and simple imidazoles or benzimidazoles as C2 synthons.

■

INTRODUCTION

Given the significance of imidazo[1,2-a]pyridine skeleton, the development of synthetic methods for their construction has become an emerging theme and witnessed with plethora of strategies using diverse starting materials.9 Usually, majority of these methods employed 2-amino pyridine as N−C−N synthon by reacting with a range of C2 precursors in a [3 + 2] annulation manner (Scheme 1a).10 Alternatively, imidazo[1,2-a]pyridines were also obtained from the [3 + 2] annulation reaction of pyridines as C−N precursor with various C−C−N sources (Scheme 1b).11 In both these cases, five-membered imidazole ring has been constructed on the

Imidazo[1,2-a]pyridines are prevalent in many bioactive natural products, diverse array of pharmaceuticals, and optical/electronic materials.1−3 They display a broad range of biological activities such as anticancer, antibacterial, antiviral, antifungal, antiulcer, anti-inflammatory, and others.4 In addition, they also found to act as histone deacetylase inhibitors, GABA receptor agonists, β-amyloid detectors, and MCH1R antagonists.5 Notably, various drugs such as zolpidem (A), saripidem (B), olprinone (C), soraprazan (D), and others, embedded with imidazo[1,2-a]pyridine framework, are being marketed for the treatment of different diseases (Figure 1).6 Similarly, benzimidazo[1,2-a]pyridine is another important fused-azole motif that exists in a wide range of pharmacologically active molecules, and representative structures (E and F)7 are shown in Figure 1. Further, these compounds exhibit valuable luminescence properties.8

Scheme 1. Strategies for the Synthesis of Imidazo[1,2a]pyridines

Figure 1. Selected biologically active imidazo[1,2-a]pyridines and benzimidazo[1,2-a]pyridines. © XXXX American Chemical Society

Received: April 23, 2019 Published: June 24, 2019 A

DOI: 10.1021/acs.joc.9b01118 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry pyridine ring, which necessitates the substituted pyridines to produce the corresponding diversely substituted imidazo[1,2a]pyridines. On the other hand, methods involving the construction of six-membered pyridine ring on imidazole are limited.12,13 Most of them require the prefunctionalized imidazoles, in particular N-substituted (N-propargyl, N-allyl, N-vinyl, etc.) derivatives (Scheme 1c).12 To the best of our knowledge, procedures for the construction of six-membered pyridine ring on simple imidazole as C−N synthon ([4 + 2]annulation) toward imidazo[1,2-a]pyridines are occasional.13 For instance, in 1963, Roe used thermal condensation of imidazoles with 1,4-diketones to obtain imidazo[1,2-a]pyridines (Scheme 1d).13a Later, in 1987, Davey et al. reported a two-step method from cyclopropyl ketones or 4-halobutytophenones in reaction with imidazoles at 200 °C (Scheme 1e).13b In 2011, Xi and co-workers developed copper-catalyzed coupling of imidazoles with 1,4-dihalo-1,3-dienes at 160 °C for the synthesis of imidazo[1,2-a]pyridines (Scheme 1f).13c Although elegant, these reactions required high temperatures and/or longer reaction times. Hence, the development of novel methods to access imidazo[1,2-a]pyridines having different substitutions on the pyridine part from readily accessible starting materials is undoubtedly a valuable addition to the existing literature methods. In continuation of our interest on enyne-assisted annulations14 and the use of Morita−Baylis−Hillman (MBH) acetates of acetylenic aldehydes as reliable synthetic intermediates,15 we envisaged that these acetates would also be suitable C4 precursors in reactions with simple imidazoles (as C−N synthons) to give the imidazo[1,2-a]pyridine derivatives via base-mediated allylic substitution and subsequent cycloisomerization. This [4 + 2]-annulation approach is anticipated to offer the imidazo[1,2-a]pyridines having substitutions on pyridine ring, and processes for straightforward syntheses of such molecules are rare. Herein, we present the outcome of novel [4 + 2]-annulation to access the diversely substituted imidazo[1,2-a]pyridines.

Table 1. Optimization of Reaction Conditions for the Synthesis of Imidazo[1,2-a]pyridine 4a

■

RESULTS AND DISCUSSION Our study was commenced by treating MBH-acetate 1a (obtained by following the literature procedure)15a,16 with imidazole 2a in the presence of K2CO3 in dimethyl sulfoxide, which provided 3a in 86% yield (entry 1, Table 1). The same reaction was also studied in different solvents such as CH3CN and dimethylformamide (DMF) (entries 2 and 3, Table 1) independently, and we were pleased to find that the reaction in acetonitrile gave 3a in 94% yield. Next, the cycloisomerization was tested under various conditions such as I2/NaHCO3 in dichloroethane (DCE) at 80 °C, iodine monochloride (ICl) at 50 °C, and K2CO3 in DMF at reflux (entries 4−6, Table 1). It was found that the desired imidazo[1,2-a]pyridine 4a was formed in 34% yield in the presence of K2CO3, while there was no cyclized product formed under the other two conditions, wherein the formation of iodo-substituted enynyl imidazole 3a−I was observed (entries 4 and 5, Table 1). The addition of 10 mol % of CuI in the presence of K2CO3 in DMF slightly facilitated the reaction to obtain 4a in 62% yield (entry 7, Table 1). The treatment of 3a with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in CH3CN at 80 °C provided the product 4a in 56% yield (entry 8, Table 1). To our delight, the formation of 4a was observed in 91% yield under 50 mol % of DBU in the presence of CuI (10 mol %) in CH3CN at 80 °C (entry 9, Table 1). Replacement of CuI with other metal

a

Isolated yield. bIsolated yield for the synthesis of 4a in 1 g scale.

catalysts such as Pd(OAc)2 or AgOTf was not effective in improving the yield of the desired product (entries 10 and 11, Table 1). When we tried to carry out the reaction in single operation by adding imidazole and all of the reagents at once, the formation of complex mixture was observed [number of spots were observed on thin-layer chromatography (TLC)]. This may be due to the activation of alkyne in the presence of CuI prior to the allylic substitution, leading to the other competitive reactions along with the allylic substitution. Finally, the reaction of 1a with 2a was carried out in one pot by the sequential addition of K2CO3, and after 10 h, CuI along with DBU in CH3CN, which proceeded efficiently to deliver the imidazo[1,2-a]pyridine 4a in 88% yield (entry 12, Table 1). With the establishment of the optimum one-pot reaction conditions, the substrate scope for the synthesis of 4 was studied (Table 2). First, MBH-acetates, bearing electrondonating aryl group (4-MeO-Ph, 1b) or electron-withdrawing group (4-Cl-Ph, 1c) on alkyne functionality, were allowed to react with imidazole (2a) to obtain the corresponding B

DOI: 10.1021/acs.joc.9b01118 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry Table 2. Synthesized Imidazo[1,2-a]pyridines

Scheme 2. Synthesis of Benzo[4,5]midazo[1,2-a]pyridines

sequential reaction conditions, and we were pleased to afford the corresponding benzo[4,5]imidazo[1,2-a]pyridine 7a in 86% yield via intermediate 6a (isolated and characterized). Moreover, the reaction scope was studied by employing various MBH-acetates 1b−e as annulation partners with 5a to furnish the benzimidazo[1,2-a]pyridines 7b−e in good yield. In addition to 5a, 5-methyl-1H-benzo[d]imidazole (5b) and 6bromo-1H-benzo[d]imidazole (5c) were also found to be compatible C−N synthons in reaction with 1a to give the desired products 7f (71%) and 7g (68%), respectively. Finally, the present annulation reaction also worked well with 5,6dimethyl-1H-benzo[d]imidazole (5d) to provide the desired product 7h in 72% yield under the standard condition. To evaluate the potential synthetic utility of this one-pot protocol, we applied it to the synthesis of pyrido[1,2-e]purine 9 using the Boc-protected purine 8 as N−C building block in reaction with MBH-acetate 1a (Scheme 3). Pleasingly, it was found that the sequential allylic amination/cycloisomerization reactions ensued well to produce the pyrido[1,2-e]purine 9 in 71% yield. The necessity of ester group to facilitate the cycloisomerization was also tested by the treatment of enynyl imidazole 10, prepared from the known enynyl bromide,19 with DBU in the presence of CuI (10 mol %) in CH3CN at 80 °C and observed that the reaction was futile (Scheme 4). This result strongly confirms the vital role of the ester group in providing the desired product. On the basis of the above obtained results and literature precedence,20 a possible mechanism for the described one-pot [4 + 2] annulation is shown in Scheme 5. First, K2CO3mediated allylic substitution of MBH-acetate 1a with imidazole

a

Reaction conditions: MBH-acetate 1 (1 equiv), imidazole 2 (1 equiv), K2CO3 (1 equiv) in CH3CN (6 mL/mmol), then DBU (0.5 equiv), Cul (0.1 equiv). bIsolated yield.

imidazo[1,2-a]pyridines 4b and 4c in 68 and 81% yields, respectively (entries 2 and 3, Table 2). The present [4 + 2] annulation was similarly successful when applied to MBHacetates having heteroaryl groups such as 2-thiophenyl (1d) and 3-NBoc-indoloyl (1e) with 2a, to provide the imidazo[1,2a]pyridines 4d and 4e, respectively, in good yield (entries 4 and 5, Table 2). Next, a wide range of imidazoles were also tested to establish the scope of the reaction using MBH-acetate 1a as the reaction partner. Interestingly, the one-pot reaction was feasible with 4-methyl-1H-imidazole (2b), 4-iodo-1Himidazole (2c), imidazole-4-carboxaldehyde (2d), 4-ethynyl1H-imidazole (2e), and 4,5-diphenyl-1H-imidazole (2f) to furnish the corresponding functionalized imidazo[1,2-a]pyridines 4f to 4j in good yield (entries 6−10, Table 2). It is noteworthy to reveal that the products having iodo (4g), aldehyde (4h), and alkyne (4i) functionalities could be more elaborated to a diverse range of their derivatives. However, the reaction of 4-nitro-1H-imidazole (2g) provided the enynylated intermediate 3b (89%), wherein the cycloisomerization was unsuccessful, which might be due to the electron-withdrawing nature of nitro group (entry 11, Table 2). After establishing this one-pot annulation for the synthesis of 4, we extended our study to access benzimidazo[1,2-a]pyridine (Scheme 2),17,18 a key motif present in various bioactive molecules. Thus, the MBH-acetate 1a was treated with 1Hbenzo[d]imidazole (5a) under the above optimized one-pot C

DOI: 10.1021/acs.joc.9b01118 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry Scheme 3. Synthesis of Pyrido[1,2-e]purine 9

and coupling constants J are given in parts per million (ppm) and hertz (Hz), respectively. Chemical shifts are reported relative to residual solvent as an internal standard for 1H and 13C (CDCl3: δ 7.26 ppm for 1H and 77.0 ppm for 13C). Fourier transform infrared spectra were recorded on α (Bruker) infrared spectrometer. High-resolution mass spectra (HRMS) [electrospray ionization (ESI)+] were obtained using either a time-of-flight or a double-focusing spectrometer. Morita−Baylis−Hillman acetates 1a−e were prepared using the literature procedures. Analytical data of all of these compounds were correlated with the corresponding reported data.15,16 General Procedure for the Synthesis of Methyl (E)-2-((1HImidazol-1-yl)methyl)-5-phenylpent-2-en-4-ynoate (3a). To a stirred solution of MBH-acetate 1a (200 mg, 0.77 mmol) and imidazole 2a (53 mg, 0.77 mmol) in 10 mL of acetonitrile was added potassium carbonate (107 mg, 0.77 mmol) at room temperature for 8 h. Then, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (80% EtOAc in petroleum ether) to afford the compound 3a: 192 mg, 94%, yellow solid, mp 115−117 °C, Rf = 0.5 (petroleum ether/EtOAc = 2:8); 1H NMR (400 MHz, CDCl3): δ 7.66 (s, 1H), 7.54−7.51 (m, 2H), 7.46−7.35 (m, 3H), 7.11 (s, 1H), 7.06 (d, J = 1.1 Hz, 1H), 7.03 (s, 1H), 5.05 (s, 2H), 3.80 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 165.5, 137.6, 136.2, 132.0, 130.4, 130.0, 129.1, 128.7, 124.7, 121.4, 119.3, 104.7, 84.5, 52.6, 44.1; IR (KBr): νmax = 2925, 2195, 1714, 1440, 1253, 1107, 761 cm−1; MS (ESI): m/z 267 (M + H)+; HRMS (ESI): m/z calcd for C16H15N2O2 (M + H)+: 267.1134, found: 267.1132. Methyl (E)-2-((2-Iodo-1H-imidazol-1-yl)methyl)-5-phenylpent-2en-4-ynoate (3a−I). Procedure-A (I2/NaHCO3). To a stirred solution of enynylated intermediate (100 mg, 0.37 mmol) in DCE, NaHCO3 (32 mg, 0.37 mmol) was added at 0 °C, followed by the addition of iodine (475 mg, 1.87 mmol), and the solution was stirred at 80 °C for 24 h. After the completion of the reaction (monitored by TLC), the mixture was quenched with Na2S2O3 solution and extracted with CH2Cl2, and the organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (40% EtOAc in petroleum ether) to afford the corresponding product 3a−I, 100 mg, 68%, brown liquid. Procedure B (ICl). To a stirred solution of enynylated intermediate (100 mg, 0.37 mmol) in CH2Cl2, ICl (61 mg, 0.37 mmol) was added dropwise to the reaction mixture at 0 °C followed by stirring the

Scheme 4. Reaction of Enynyl Imidazole 10

2a, through the formation of nitrogen anion at the N − 1 position, leads to enynyl imidazole 3a. Addition of DBU will generate the anion at the second position of imidazole (I) and undergo 6-exo-dig-cyclization, which will be further facilitated by the activation of alkyne with Cu(I) catalyst, to generate the desired imidazo[1,2-a]pyridine 4a via 1,5-hydride shift-based aromatization of intermediate II.

■

CONCLUSIONS In summary, we developed a new strategy for the synthesis of distinctively substituted imidazo[1,2-a]pyridines that relies on the use of simple imidazole as a reaction partner with Morita− Baylis−Hillman acetates of acetylenic aldehydes. The present [4 + 2] annulation approach was further extended using 1Hbenzo[d]imidazoles to access benzo[4,5]imidazo[1,2-a]pyridine derivatives. Having notable features such as readily accessible substrates, mild reaction conditions, handy synthetic procedure, and atom economy, the described one-pot reaction is expected to find wide applications in the efficient construction of pharmacologically valued products.

■

EXPERIMENTAL SECTION

General Methods. Oven-dried glass apparatus were used to perform all of the reactions. All reactions were carried out in a round flask with magnetic stirring under inert atmosphere (nitrogen). Commercially available chemicals and solvents were used as such. Reactions were monitored by silica gel, and thin-layer plates were employed for thin-layer chromatography using UV light and anisaldehyde for visualization. Column chromatography was performed on silica gel (60−120 mesh) using petroleum ether and ethylacetate as eluent. Evaporation of solvents was done under reduced pressure. 1H and 13C NMR spectra were recorded in CDCl3 solvent on 300, 400, and 500 NMR spectrometers. Chemical shifts δ

Scheme 5. Possible Reaction Mechanism

D

DOI: 10.1021/acs.joc.9b01118 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry solution at 50 °C for 24 h. After completion of the reaction (monitored by TLC), the mixture was quenched with Na2S2O3 solution and extracted with CH2Cl2, and the organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (40% EtOAc in petroleum ether) to afford the product 3a−I: 98 mg, 67%, brown liquid. Rf = 0.5 (petroleum ether/EtOAc = 6:4); 1H NMR (400 MHz, CDCl3): δ 7.44 (dd, J = 8.0, 1.6 Hz, 2H), 7.37−7.26 (m, 3H), 7.11 (s, 1H), 7.05 (d, J = 1.4 Hz, 1H), 7.00 (d, J = 1.4 Hz, 1H), 4.96 (s, 2H), 3.72 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ 165.4, 135.1, 132.6, 132.1, 129.9, 128.6, 125.2, 122.8, 121.5, 104.9, 90.8, 84.4, 52.5, 47.3; IR (KBr): νmax = 2926, 2195, 1715, 1443, 1255, 1111, 759 cm−1; MS (ESI): m/z 393 (M + H)+; HRMS (ESI): m/z calcd for C16H14IN2O2 (M + H)+: 393.0094, found: 393.0095. General Procedure for the Preparation of Imidazo[1,2-a]pyridine Derivatives (4a−i). To a stirred solution of MBH-acetate 1a−e (1 mmol) and imidazole 2a−g (1 mmol) in 5 mL of acetonitrile was added potassium carbonate (1 mmol) and stirred at room temperature for 10−13 h. Then, DBU (0.5 mmol) and CuI (0.1 mmol) were added to the reaction mixture at 0 °C and stirring was continued at 80 °C for 4−8 h. After the completion of reaction (monitored by TLC), acetonitrile was evaporated and the crude mixture was purified by column chromatography on silica gel (EtOAc/hexanes) to afford the corresponding imidazo[1,2-a]pyridine products 4a−i. Methyl 8-Benzylimidazo[1,2-a]pyridine-6-carboxylate (4a). Following the general procedure, to a stirred solution of MBH-acetate 1a (100 mg, 0.38 mmol) and imidazole 2a (26 mg, 0.38 mmol) in 5 mL of acetonitrile was added potassium carbonate (53 mg, 0.38 mmol) at room temperature for 10 h. Then, DBU (29 mg, 0.19 mmol) and CuI (7 mg, 0.038 mmol) were added to the reaction mixture at 0 °C and stirring was continued at 80 °C for 4 h. After the completion of reaction (monitored by TLC), acetonitrile was evaporated and the crude mixture was purified by column chromatography on silica gel (20% EtOAc in petroleum ether) to afford the imidazo[1,2-a]pyridine 4a: 91 mg, 88%, white solid, mp 120−122 °C, Rf = 0.5 (petroleum ether/EtOAc = 8:2); 1H NMR (500 MHz, CDCl3): δ 8.80 (d, J = 1.5 Hz, 1H), 7.72 (d, J = 1.3 Hz, 1H), 7.66 (d, J = 1.3 Hz, 1H), 7.43− 7.39 (m, 1H), 7.37 (d, J = 7.4 Hz, 2H), 7.34−7.28 (m, 2H), 7.23 (t, J = 7.3 Hz, 1H), 4.37 (s, 2H), 3.91−3.89 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 165.3, 145.4, 138.3, 133.9, 130.4, 129.3, 128.6, 128.2, 126.6, 123.1, 117.1, 114.1, 52.5, 36.6; IR (KBr): νmax = 2360, 1724, 1441, 1224, 1994, 766, 705 cm−1; MS (ESI): m/z 267 (M + H)+; HRMS (ESI): m/z calcd for C16H15N2O2 (M + H)+: 267.1134, found: 267.1132. Methyl 8-Benzylimidazo[1,2-a]pyridine-6-carboxylate (4a): (1 g Scale). Following the general procedure, to a stirred solution of MBHacetate 1a (1 g, 3.87 mmol) and imidazole 2a (832 mg, 3.87 mmol) in 12 mL of acetonitrile was added potassium carbonate (534 mg, 3.87 mmol) at room temperature for 10 h. Then, DBU (294 mg, 1.93 mmol) and CuI (73 mg, 0.38 mmol) were added to the reaction mixture at 0 °C and stirring was continued at 80 °C for 4 h. After the completion of reaction (monitored by TLC), acetonitrile was evaporated and the crude mixture was purified by column chromatography on silica gel (20% EtOAc in petroleum ether) to afford the product 4a: 1.0 g, 82%. Methyl 8-(4-Methoxybenzyl)imidazo[1,2-a]pyridine-6-carboxylate (4b). Following the general procedure, to a stirred solution of MBH-acetate 1b (100 mg, 0.34 mmol) and imidazole 2a (24 mg, 0.34 mmol) in 5 mL of acetonitrile was added potassium carbonate (48 mg, 0.34 mmol) at room temperature for 10 h. Then, DBU (26 mg, 0.17 mmol) and CuI (7 mg, 0.034 mmol) were added to the reaction mixture at 0 °C and stirring was continued at 80 °C for 5 h. After the completion of reaction (monitored by TLC), acetonitrile was evaporated and the crude mixture was purified by column chromatography on silica gel (20% EtOAc in petroleum ether) to afford the desired product 4b: 70 mg, 68%, white solid, mp 113−115 °C, Rf = 0.6 (petroleum ether/EtOAc = 8:2), 1H NMR (500 MHz, CDCl3): δ 8.81 (d, J = 1.1 Hz, 1H), 7.74 (s, 1H), 7.68 (s, 1H), 7.44

(s, 1H), 7.29 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.34 (s, 2H), 3.91 (s, 3H), 3.78 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 165.2, 158.4, 145.1, 133.5, 130.8, 130.3, 128.2, 123.2, 117.2, 114.1, 114.1, 55.2, 52.5, 35.7; IR (KBr): νmax = 2190, 1713, 1519, 1254, 1038, 837, 771 cm−1; MS (ESI): m/z 297 (M + H)+; HRMS (ESI): m/z calcd for C17H17N2O3 (M + H)+: 297.1239, found: 297.1239. Methyl 8-(4-Chlorobenzyl)imidazo[1,2-a]pyridine-6-carboxylate (4c). Following the general procedure, to a stirred solution of MBHacetate 1c (100 mg, 0.34 mmol) and imidazole 2a (23 mg, 0.34 mmol) in 5 mL of acetonitrile was added potassium carbonate (47 mg, 0.34 mmol) at room temperature for 11 h. Then, DBU (26 mg, 0.17 mmol) and CuI (7 mg, 0.034 mmol) were added to the reaction mixture at 0 °C and stirring was continued at 80 °C for 5 h. After the completion of reaction (monitored by TLC), acetonitrile was evaporated and the crude mixture was purified by column chromatography on silica gel (20% EtOAc in petroleum ether) to afford the corresponding product 4c: 83 mg, 81%, pale yellow solid, mp 125−127 °C, Rf = 0.5 (petroleum ether/EtOAc = 8:2), 1H NMR (400 MHz, CDCl3): δ 8.82 (d, J = 1.4 Hz, 1H), 7.71 (d, J = 1.2 Hz, 1H), 7.67 (d, J = 1.2 Hz, 1H), 7.43−7.37 (m, 1H), 7.33−7.24 (m, 4H), 4.33 (s, 2H), 3.92 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 165.3, 145.6, 137.1, 134.7, 132.3, 130.4, 129.8, 128.6, 128.4, 122.3, 116.5, 114.1, 52.3, 36.0; IR (KBr): νmax = 3095, 2924, 1720, 1435, 1303, 1220, 761 cm−1; MS (ESI): m/z 301 (M + H)+; HRMS (ESI): m/z calcd for C16H14N2O2Cl (M + H)+: 301.0744, found: 301.0751. Methyl 8-(Thiophen-2-ylmethyl)imidazo[1,2-a]pyridine-6-carboxylate (4d). Following the general procedure, to a stirred solution of MBH-acetate 1d (100 mg, 0.37 mmol) and imidazole 2a (26 mg, 0.37 mmol) in 5 mL of acetonitrile was added potassium carbonate (52 mg, 0.37 mmol) at room temperature for 12 h. Then, DBU (28 mg, 0.19 mmol) and CuI (7 mg, 0.037 mmol) were added to the reaction mixture at 0 °C and stirring was continued at 80 °C for 5 h. After the completion of reaction (monitored by TLC), acetonitrile was evaporated and the crude mixture was purified by column chromatography on silica gel (20% EtOAc in petroleum ether) to afford the product 4d: 74 mg, 72%, pale yellow solid, mp 143−145 °C, Rf = 0.4 (petroleum ether/EtOAc = 8:2); 1H NMR (500 MHz, CDCl3): δ 8.83 (d, J = 1.1 Hz, 1H), 7.73 (d, J = 1.0 Hz, 1H), 7.67 (d, J = 1.0 Hz, 1H), 7.52 (s, 1H), 7.17 (dd, J = 5.1, 1.0 Hz, 1H), 7.04− 6.90 (m, 2H), 4.58 (s, 2H), 3.92 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 165.3, 145.3, 140.5, 134.5, 129.6, 128.4, 126.9, 126.3, 124.3, 122.3, 116.6, 114.1, 52.4, 30.6; IR (KBr): νmax = 3101, 2924, 1719, 1435, 1220, 760, 706 cm−1; MS (ESI): m/z 273 (M + H)+; HRMS (ESI): m/z calcd for C14H13N2O2S (M + H)+: 273.0698, found: 273.0701. Methyl 8-((1-(tert-Butoxycarbonyl)-1H-indol-3-yl)methyl)imidazo[1,2-a]pyridine-6-carboxylate (4e). Following the general procedure, to a stirred solution of MBH-acetate 1e (100 mg, 0.25 mmol) and imidazole 2a (17 mg, 0.25 mmol) in 5 mL of acetonitrile was added potassium carbonate (35 mg, 0.25 mmol) at room temperature for 12 h. Then, DBU (19 mg, 0.12 mmol) and CuI (5 mg, 0.025 mmol) were added to the reaction mixture at 0 °C and stirring was continued at 80 °C for 6 h. After the completion of reaction (monitored by TLC), acetonitrile was evaporated and the crude mixture was purified by column chromatography on silica gel (20% EtOAc in petroleum ether) to afford the corresponding product 4e: 73 mg, 72%, yellow solid, mp 137−139 °C, Rf = 0.4 (petroleum ether/EtOAc = 8:2); 1H NMR (400 MHz, CDCl3): δ 8.83 (d, J = 1.4 Hz, 1H), 7.76 (d, J = 1.2 Hz, 1H), 7.70 (d, J = 1.2 Hz, 1H), 7.53 (s, 1H), 7.45 (d, J = 9.3 Hz, 2H), 7.33−7.26 (m, 2H), 7.17 (t, J = 7.6 Hz, 1H), 4.47 (s, 2H), 3.87 (s, 3H), 1.68 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 165.4, 149.8, 134.6, 130.3, 129.0, 128.3, 124.4, 124.3, 122.5, 122.3, 119.3, 117.3, 116.7, 115.3, 114.1, 112.1, 83.6, 52.4, 29.7, 28.2; IR (KBr): νmax = 2926, 1737, 1450, 1220, 1164, 770 cm−1; MS (ESI): m/z 406 (M + H)+; HRMS (ESI): m/z calcd for C23H24N3O4 (M + H)+: 406.1767, found: 406.1773. Methyl 8-Benzyl-2-methylimidazo[1,2-a]pyridine-6-carboxylate (4f). Following the general procedure, to a stirred solution of MBH-acetate 1a (100 mg, 0.38 mmol) and imidazole 2b (32 mg, 0.38 mmol) in 5 mL of acetonitrile was added potassium carbonate (53 E

DOI: 10.1021/acs.joc.9b01118 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

291 (M + H)+; HRMS (ESI): m/z calcd for C18H15N2O2 (M + H)+: 291.1134, found: 291.1137. Methyl 8-Benzyl-2,3-diphenylimidazo[1,2-a]pyridine-6-carboxylate (4j). Following the general procedure, to a stirred solution of MBH-acetate 1a (100 mg, 0.38 mmol) and imidazole 2f (85 mg, 0.38 mmol) in 5 mL of acetonitrile was added potassium carbonate (53 mg, 0.38 mmol) at room temperature for 10 h. Then, DBU (29 mg, 0.19 mmol) and CuI (7 mg, 0.038 mmol) were added to the reaction mixture at 0 °C and stirring was continued at 80 °C for 4 h. After the completion of reaction (monitored by TLC), acetonitrile was evaporated and the crude mixture was purified by column chromatography on silica gel (20% EtOAc in petroleum ether) to afford the corresponding product 4j: 121 mg, 75%, white solid, mp 201−203 °C, Rf = 0.5 (petroleum ether/EtOAc = 8:2); 1H NMR (500 MHz, CDCl3): δ 8.55 (d, J = 1.5 Hz, 1H), 7.75−7.68 (m, 2H), 7.59−7.48 (m, 5H), 7.48−7.42 (m, 3H), 7.39−7.23 (m, 6H), 4.46 (s, 2H), 3.84 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 165.7, 145.2, 143.6, 139.0, 133.8, 130.7, 130.4, 129.7, 129.5, 129.3, 129.2, 128.5, 128.3, 128.2, 127.8, 126.5, 125.7, 122.5, 122.2, 116.3, 52.3, 36.7; IR (KBr): νmax = 1724, 1441, 1226, 770, 704 cm−1; MS (ESI): m/z 419 (M + H)+; HRMS (ESI): m/z calcd for C28H23N2O2 (M + H)+: 419.1760, found: 419.1765. Methyl (E)-2-((4-Nitro-1H-imidazol-1-yl)methyl)-5-phenylpent-2en-4-ynoate (3b). To a stirred solution of MBH-acetate 1a (100 mg, 0.38 mmol) and imidazole 2g (44 mg, 0.38 mmol) in 10 mL of acetonitrile was added potassium carbonate (53 mg, 0.38 mmol) at room temperature for 13 h. Then, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (80% EtOAc in petroleum ether) to afford the compound 3b: 107 mg, 89%, yellow solid, mp 152−154 °C, Rf = 0.5 (petroleum ether/EtOAc = 8:2); 1H NMR (400 MHz, CDCl3): 7.89 (d, J = 1.5 Hz, 1H), 7.60 (d, J = 1.5 Hz, 1H), 7.56−7.50 (m, 2H), 7.49−7.37 (m, 3H), 7.20 (s, 1H), 5.10 (s, 2H), 3.84 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 165.1, 148.0, 136.5, 134.3, 132.0, 130.4, 128.8, 126.2, 120.9, 119.6, 106.2, 83.9, 52.9, 45.4; IR (KBr): νmax = 2947, 2195, 1714, 1496, 1258, 1111, 769, 689 cm−1; MS (ESI): m/z 312 (M + H)+; HRMS (ESI): m/z calcd for C16H14N3O4 (M + H)+: 312.0984, found: 312.0982. General Procedure for the Preparation of Benzimidazo[1,2a]pyridine Derivatives (7a−g). To a stirred solution of MBH-acetate 1a−e (1 mmol) and benzimidazole 5a and 5b (1 mmol) in 5 mL of acetonitrile was added potassium carbonate (1 mmol) and stirred at room temperature for 10−13 h. Then, DBU (0.5 mmol) and CuI (0.1 mmol) were added to the reaction mixture at 0 °C and stirring was continued at 80 °C for 4−8 h. After the completion of reaction (monitored by TLC), acetonitrile was evaporated and the crude mixture was purified by column chromatography on silica gel (EtOAc/hexanes) to afford the corresponding benzimidazo[1,2a]pyridine products 7a−g. Methyl (E)-2-((1H-Benzo[d]imidazol-1-yl)methyl)-5-phenylpent2-en-4-ynoate (6a). To a stirred solution of MBH-acetate 1a (200 mg, 0.77 mmol) and benzimidazole 5a (92 mg, 0.77 mmol) in 10 mL of acetonitrile was added potassium carbonate (107 mg, 0.77 mmol) at room temperature for 10 h. Then, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (80% EtOAc in petroleum ether) to afford the compound 6a: 225 mg, 92%, yellow solid, mp 154−156 °C, Rf = 0.5 (petroleum ether/EtOAc = 3:7); 1H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H), 7.83−7.74 (m, 1H), 7.74−7.63 (m, 1H), 7.55 (dt, J = 13.8, 5.7 Hz, 2H), 7.50−7.36 (m, 3H), 7.29−7.24 (m, 2H), 7.17 (s, 1H), 5.30 (s, 2H), 3.76 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 165.5, 144.1, 143.5, 135.3, 133.8, 132.0, 130.1, 128.7, 124.5, 123.0, 122.1, 121.5, 120.3, 110.2, 105.3, 84.7, 52.5, 42.8; IR (KBr): νmax = 2953, 2196, 1716, 1493, 1255, 769, 690 cm−1; MS (ESI): m/z 317 (M + H)+; HRMS (ESI): m/z calcd for C20H17N2O2 (M + H)+: 317.1290, found: 317.1296. Methyl 4-Benzylbenzo[4,5]imidazo[1,2-a]pyridine-2-carboxylate (7a). Following the general procedure, to a stirred solution of MBHacetate 1a (100 mg, 0.38 mmol) and benzimidazole 5a (45 mg, 0.38 mmol) in 5 mL of acetonitrile was added potassium carbonate (53

mg, 0.38 mmol) at room temperature for 10 h. Then, DBU (29 mg, 0.19 mmol) and CuI (7 mg, 0.038 mmol) were added to the reaction mixture at 0 °C and stirring was continued at 80 °C for 4 h. After the completion of reaction (monitored by TLC), acetonitrile was evaporated and the crude mixture was purified by column chromatography on silica gel (20% EtOAc in petroleum ether) to afford the product 4f: 85 mg, 78%, white solid, mp 162−164 °C, Rf = 0.6 (petroleum ether/EtOAc = 8:2); 1H NMR (500 MHz, CDCl3): δ 8.69 (s, 1H), 7.41 (s, 1H), 7.38−7.28 (m, 5H), 7.24 (dd, J = 11.5, 4.2 Hz, 1H), 4.35 (s, 2H), 3.87 (s, 3H), 2.50 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 165.7, 145.6, 144.9, 138.7, 129.5, 129.4, 128.5, 127.5, 126.5, 121.9, 115.8, 111.1, 52.2, 36.3, 14.5; IR (KBr): νmax = 2925, 2360, 1722, 1443, 1292, 756, 698 cm−1; MS (ESI): m/z 281 (M + H)+; HRMS (ESI): m/z calcd for C17H17N2O2 (M + H)+: 281.1290, found: 281.1291. Methyl 8-Benzyl-2-iodoimidazo[1,2-a]pyridine-6-carboxylate (4g). Following the general procedure, to a stirred solution of MBH-acetate 1a (100 mg, 0.38 mmol) and imidazole 2c (75 mg, 0.38 mmol) in 5 mL of acetonitrile was added potassium carbonate (53 mg, 0.38 mmol) at room temperature for 10 h. Then, DBU (29 mg, 0.19 mmol) and CuI (7 mg, 0.038 mmol) were added to the reaction mixture at 0 °C and stirring was continued at 80 °C for 4 h. After the completion of reaction (monitored by TLC), acetonitrile was evaporated and the crude mixture was purified by column chromatography on silica gel (20% EtOAc in petroleum ether) to afford the corresponding product 4g: 127 mg, 84%, yellow solid, mp 162−164 °C, Rf = 0.6 (petroleum ether/EtOAc = 8:2); 1H NMR (400 MHz, CDCl3): δ 8.70 (d, J = 1.4 Hz, 1H), 7.75 (s, 1H), 7.43− 7.28 (m, 5H), 7.26 (q, J = 2.4 Hz, 1H), 4.35 (s, 2H), 3.89 (s, 3H); 13 C{1H} NMR (125 MHz, CDCl3): δ 165.1, 147.3, 138.2, 129.9, 129.4, 128.6, 126.7, 126.5, 122.7, 119.3, 116.9, 92.5, 52.5, 36.2; IR (KBr): νmax = 2925, 2360, 1722, 1443, 1292, 756, 698 cm−1; MS (ESI): m/z 393 (M + H)+; HRMS (ESI): m/z calcd for C16H14IN2O2 (M + H)+: 393.0112, found: 393.0107. Methyl 8-Benzyl-2-formylimidazo[1,2-a]pyridine-6-carboxylate (4h). Following the general procedure, to a stirred solution of MBH-acetate 1a (100 mg, 0.38 mmol) and imidazole 2d (37 mg, 0.38 mmol) in 5 mL of acetonitrile was added potassium carbonate (53 mg, 0.38 mmol) at room temperature for 10 h. Then, DBU (29 mg, 0.19 mmol) and CuI (7 mg, 0.038 mmol) were added to the reaction mixture at 0 °C and stirring was continued at 80 °C for 4 h. After the completion of reaction (monitored by TLC), acetonitrile was evaporated and the crude mixture was purified by column chromatography on silica gel (20% EtOAc in petroleum ether) to afford the product 4h: 92 mg, 81%, pale yellow solid, mp 146−148 °C, Rf = 0.4 (petroleum ether/EtOAc = 8:2); 1H NMR (300 MHz, CDCl3): δ 10.02 (d, J = 1.6 Hz, 1H), 10.00 (s, 1H), 8.39 (s, 1H), 7.84 (s, 1H), 7.39−7.28 (m, 4H), 7.26−7.22 (m, 1H), 4.43 (s, 2H), 3.96 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 178.1, 164.8, 149.7, 147.5, 138.0, 130.9, 130.1, 129.1, 128.7, 128.3, 126.8, 126.0, 119.5, 52.7, 36.5; IR (KBr): νmax = 2925, 1727, 1659, 1277, 1164, 758, 701 cm−1; MS (ESI): m/z 295 (M + H)+; HRMS (ESI): m/z calcd for C17H15N2O3 (M + H)+: 295.1083, found: 295.1085. Methyl 8-Benzyl-2-ethynylimidazo[1,2-a]pyridine-6-carboxylate (4i). Following the general procedure, to a stirred solution of MBHacetate 1a (100 mg, 0.38 mmol) and imidazole 2e (36 mg, 0.38 mmol) in 5 mL of acetonitrile was added potassium carbonate (53 mg, 0.38 mmol) at room temperature for 10 h. Then, DBU (29 mg, 0.19 mmol) and CuI (7 mg, 0.038 mmol) were added to the reaction mixture at 0 °C and stirring was continued at 80 °C for 4 h. After the completion of reaction (monitored by TLC), acetonitrile was evaporated and the crude mixture was purified by column chromatography on silica gel (20% EtOAc in petroleum ether) to afford the imidazopyridine 4i: 78 mg, 69%, pale yellow solid, mp 128−130 °C, Rf = 0.5 (petroleum ether/EtOAc = 8:2); 1H NMR (300 MHz, CDCl3): δ 8.85 (s, 1H), 7.88 (s, 1H), 7.47 (s, 1H), 7.30− 7.17 (m, 5H), 4.31 (s, 2H), 3.87 (s, 3H), 3.79 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 165.2, 146.0, 139.8, 138.4, 130.9, 129.1, 128.6, 127.3, 126.7, 123.9, 117.5, 109.6, 88.4, 70.8, 52.5, 36.5; IR (KBr): νmax = 3283, 2921, 2364, 1726, 1224, 995, 771, 702 cm−1; MS (ESI): m/z F

DOI: 10.1021/acs.joc.9b01118 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

EtOAc = 8:2); 1H NMR (300 MHz, CDCl3): δ 9.15 (s, 1H), 7.99 (dd, J = 15.6, 8.2 Hz, 2H), 7.72 (s, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.20 (d, J = 5.1 Hz, 1H), 7.06 (d, J = 2.7 Hz, 1H), 6.98 (dd, J = 4.9, 3.6 Hz, 1H), 4.66 (s, 2H), 3.96 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 165.1, 148.0, 144.6, 140.0, 129.6, 129.3, 127.9, 127.0, 126.6, 126.6, 126.4, 124.5, 122.2, 120.3, 114.4, 110.8, 52.4, 30.8; IR (KBr): νmax = 2924, 2360, 1724, 1459, 1257, 1079, 754 cm−1; MS (ESI): m/z 323 (M + H)+; HRMS (ESI): m/z calcd for C18H15N2O2S (M + H)+: 323.0860, found: 323.0854. Methyl 4-((1-(tert-Butoxycarbonyl)-1H-indol-3-yl)methyl)benzo[4,5]imidazo[1,2-a]pyridine-2-carboxylate (7e). Following the general procedure, to a stirred solution of MBH-acetate 1e (100 mg, 0.25 mmol) and benzimidazole 5a (30 mg, 0.25 mmol) in 5 mL of acetonitrile was added potassium carbonate (35 mg, 0.25 mmol) at room temperature for 12 h. Then, DBU (19 mg, 0.12 mmol) and CuI (5 mg, 0.025 mmol) were added to the reaction mixture at 0 °C and stirring was continued at 80 °C for 7 h. After the completion of reaction (monitored by TLC), acetonitrile was evaporated and the crude mixture was purified by column chromatography on silica gel (20% EtOAc in petroleum ether) to afford the corresponding product 7e: 83 mg, 73%, pale yellow solid, mp 184−186 °C, Rf = 0.5 (petroleum ether/EtOAc = 8:2); 1H NMR (400 MHz, CDCl3): δ 9.08 (d, J = 1.4 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.54 (dd, J = 9.5, 5.0 Hz, 3H), 7.40 (t, J = 7.5 Hz, 2H), 7.27−7.20 (m, 1H), 7.14−7.05 (m, 1H), 4.49 (s, 2H), 3.84 (s, 3H), 1.61 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3): δ 165.3, 149.8, 148.6, 135.7, 130.3, 129.5, 129.0, 127.8, 126.7, 126.3, 124.6, 124.5, 122.6, 122.2, 120.4, 119.3, 117.0, 115.3, 114.5, 110.9, 83.6, 52.4, 28.2, 26.1; IR (KBr): νmax = 2928, 1725, 1450, 1371, 1223, 1159, 768 cm−1; MS (ESI): m/z 456 (M + H)+; HRMS (ESI): m/z calcd for C27H26N3O4 (M + H)+: 456.1923, found: 456.1922. Methyl 4-Benzyl-7-methylbenzo[4,5]imidazo[1,2-a]pyridine-2carboxylate (7f). Following the general procedure, to a stirred solution of MBH-acetate 1a (100 mg, 0.38 mmol) and benzimidazole 5b (51 mg, 0.38 mmol) in 5 mL of acetonitrile was added potassium carbonate (53 mg, 0.38 mmol) at room temperature for 11 h. Then, DBU (29 mg, 0.19 mmol) and CuI (7 mg, 0.038 mmol) were added to the reaction mixture at 0 °C and stirring was continued at 80 °C for 8 h. After the completion of reaction (monitored by TLC), acetonitrile was evaporated and the crude mixture was purified by column chromatography on silica gel (20% EtOAc in petroleum ether) to afford the desired product 7f: 91 mg, 71%, white solid, mp 146−148 °C, Rf = 0.6 (petroleum ether/EtOAc = 8:2); 1H NMR (400 MHz, CDCl3): δ 9.02 (d, J = 4.1, 1H), 7.79 (dd, J = 28.1, 8.4 Hz, 1H), 7.71 (d, J = 19.6 Hz, 1H), 7.48 (dd, J = 11.7, 1.3 Hz, 1H), 7.33 (d, J = 7.6 Hz, 2H), 7.30−7.22 (m, 2H), 7.19 (m, 2H), 4.38 (s, 2H), 3.86 (s, 3H), 2.52 (d, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 165.4, 138.3, 132.5, 130.5, 130.3, 129.4, 128.7, 128.4, 127.7, 126.7, 123.9, 119.9, 114.3, 110.6, 110.4, 52.4, 36.7, 22.0; IR (KBr): νmax = 2923, 1719, 1625, 1440, 1224, 997, 767 cm−1; MS (ESI): m/z 331 (M + H)+; HRMS (ESI): m/z calcd for C21H19N2O2 (M + H)+: 331.1447, found: 331.1452. Methyl 4-Benzyl-8-bromobenzo[4,5]imidazo[1,2-a]pyridine-2carboxylate (7g). Following the general procedure, to a stirred solution of MBH-acetate 1a (100 mg, 0.38 mmol) and benzimidazole 5c (76 mg, 0.38 mmol) in 5 mL of acetonitrile was added potassium carbonate (53 mg, 0.38 mmol) at room temperature for 11 h. Then, DBU (29 mg, 0.19 mmol) and CuI (7 mg, 0.038 mmol) were added to the reaction mixture at 0 °C and stirring was continued at 80 °C for 9 h. After the completion of reaction (monitored by TLC), acetonitrile was evaporated and the crude mixture was purified by column chromatography on silica gel (20% EtOAc in petroleum ether) to afford the product 7g: 99 mg, 68%, white solid, mp 156− 158 °C, Rf = 0.5 (petroleum ether/EtOAc = 8:2); 1H NMR (400 MHz, CDCl3): δ 8.98 (d, J = 11.5 Hz, 1H), 8.05 (d, J = 15.1 Hz, 1H), 7.76 (dd, J = 27.2, 8.7 Hz, 1H), 7.56 (dd, J = 17.5, 8.0 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.33 (d, J = 7.9 Hz, 2H), 7.26 (m, 2H), 7.22− 7.14 (m, 1H), 4.36 (s, 2H), 3.87 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 165.1, 146.2, 143.8, 138.1, 129.8, 129.3, 128.6, 127.5, 126.7, 125.1, 123.2, 121.7, 119.7, 114.9, 114.0, 111.9, 52.5, 36.7; IR

mg, 0.38 mmol) at room temperature for 10 h. Then, DBU (29 mg, 0.19 mmol) and CuI (7 mg, 0.038 mmol) were added to the reaction mixture at 0 °C and stirring was continued at 80 °C for 5 h. After the completion of reaction (monitored by TLC), acetonitrile was evaporated and the crude mixture was purified by column chromatography on silica gel (20% EtOAc in petroleum ether) to afford the corresponding product 7a: 105 mg, 86%, white solid, mp 173−175 °C, Rf = 0.6 (petroleum ether/EtOAc = 8:2); 1H NMR (500 MHz, CDCl3): δ 9.13 (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.62−7.54 (m, 2H), 7.48−7.38 (m, 3H), 7.34 (dd, J = 10.3, 4.8 Hz, 2H), 7.29−7.22 (m, 1H), 4.46 (s, 2H), 3.94 (s, 3H); 13 C{1H} NMR (75 MHz, CDCl3): δ 165.3, 148.6, 144.8, 138.3, 130.5, 129.4, 128.6, 127.7, 126.7, 126.5, 126.4, 122.1, 120.3, 114.4, 110.8, 52.4, 36.7; IR (KBr): νmax = 2925, 1721, 1444, 1251, 998, 757, 701 cm−1; MS (ESI): m/z 317 (M + H)+; HRMS (ESI): m/z calcd for C20H17N2O2 (M + H)+: 317.1285, found: 317.1304. Methyl 4-(4-Methoxybenzyl)benzo[4,5]imidazo[1,2-a]pyridine-2carboxylate (7b). Following the general procedure, to a stirred solution of MBH-acetate 1b (100 mg, 0.35 mmol) and benzimidazole 5a (41 mg, 0.35 mmol) in 5 mL of acetonitrile was added potassium carbonate (48 mg, 0.35 mmol) at room temperature for 12 h. Then, DBU (26 mg, 0.17 mmol) and CuI (7 mg, 0.038 mmol) were added to the reaction mixture at 0 °C and stirring was continued at 80 °C for 6 h. After the completion of reaction (monitored by TLC), acetonitrile was evaporated and the crude mixture was purified by column chromatography on silica gel (20% EtOAc in petroleum ether) to afford the product 7b: 79 mg, 66%, white solid, mp 165− 167 °C, Rf = 0.5 (petroleum ether/EtOAc = 8:2); 1H NMR (400 MHz, CDCl3): δ 9.14 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.67−7.55 (m, 2H), 7.45 (dd, J = 11.4, 4.0 Hz, 1H), 7.33 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 4.43 (s, 2H), 3.95 (s, 3H), 3.80 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 165.0, 158.5, 147.6, 130.8, 130.5, 129.8, 129.0, 127.6, 127.2, 122.7, 119.8, 115.4, 114.2, 111.0, 55.3, 52.6, 35.9; IR (KBr): νmax = 2923, 1723, 1458, 1251, 1032, 769 cm−1; MS (ESI): m/z 347 (M + H)+; HRMS (ESI): m/z calcd for C21H19N2O3 (M + H)+: 347.1396, found: 347.1400. Methyl 4-(4-Chlorobenzyl)benzo[4,5]imidazo[1,2-a]pyridine-2carboxylate (7c). Following the general procedure, to a stirred solution of MBH-acetate 1c (100 mg, 0.34 mmol) and benzimidazole 5a (40 mg, 0.34 mmol) in 5 mL of acetonitrile was added potassium carbonate (48 mg, 0.34 mmol) at room temperature for 11 h. Then, DBU (26 mg, 0.17 mmol) and CuI (7 mg, 0.038 mmol) were added to the reaction mixture at 0 °C and stirring was continued at 80 °C for 5 h. After the completion of reaction (monitored by TLC), acetonitrile was evaporated and the crude mixture was purified by column chromatography on silica gel (20% EtOAc in petroleum ether) to afford the corresponding product 7c: 96 mg, 80%, white solid, mp 145−147 °C, Rf = 0.5 (petroleum ether/EtOAc = 8:2); 1H NMR (400 MHz, CDCl3): δ 9.09 (d, J = 1.6 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.57−7.50 (m, 2H), 7.40−7.37 (m, 1H), 7.30−7.25 (m, 2H), 7.25−7.20 (m, 2H), 4.36 (s, 2H), 3.89 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 165.3, 148.5, 144.8, 136.8, 132.5, 131.5, 130.7, 129.9, 129.4, 128.8, 128.0, 126.7, 126.5, 122.3, 120.4, 114.4, 110.9, 52.5, 36.2; IR (KBr): νmax = 2925, 1719, 1629, 1438, 1219, 994, 768 cm−1; MS (ESI): m/z 351 (M + H)+; HRMS (ESI): m/z calcd for C20H16N2O2Cl (M + H)+: 351.0900, found: 351.0903. Methyl 4-(Thiophen-2-ylmethyl)benzo[4,5]imidazo[1,2-a]pyridine-2-carboxylate (7d). Following the general procedure, to a stirred solution of MBH-acetate 1d (100 mg, 0.38 mmol) and benzimidazole 5a (45 mg, 0.38 mmol) in 5 mL of acetonitrile was added potassium carbonate (52 mg, 0.38 mmol) at room temperature for 12 h. Then, DBU (29 mg, 0.19 mmol) and CuI (7 mg, 0.038 mmol) were added to the reaction mixture at 0 °C and stirring was continued at 80 °C for 6 h. After the completion of reaction (monitored by TLC), acetonitrile was evaporated and the crude mixture was purified by column chromatography on silica gel (20% EtOAc in petroleum ether) to afford the corresponding product 7d: 85 mg, 70%, white solid, mp 157−159 °C, Rf = 0.5 (petroleum ether/ G

DOI: 10.1021/acs.joc.9b01118 J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

■

(KBr): νmax = 1725, 1446, 1284, 1225, 770, 703 cm−1; MS (ESI): m/z 395 (M + H)+; HRMS (ESI): m/z calcd for C20H16BrN2O2 (M + H)+: 395.0395, found: 395.0400. Methyl 4-Benzyl-7,8-dimethylbenzo[4,5]imidazo[1,2-a]pyridine2-carboxylate (7h). Following the general procedure, to a stirred solution of MBH-acetate 1a (100 mg, 0.38 mmol) and benzimidazole 5cd (56 mg, 0.38 mmol) in 5 mL of acetonitrile was added potassium carbonate (53 mg, 0.38 mmol) at room temperature for 12 h. Then, DBU (29 mg, 0.19 mmol) and CuI (7 mg, 0.038 mmol) were added to the reaction mixture at 0 °C and stirring was continued at 80 °C for 9 h. After the completion of reaction (monitored by TLC), acetonitrile was evaporated and the crude mixture was purified by column chromatography on silica gel (20% EtOAc in petroleum ether) to afford the product 7h: 96 mg, 72%, white solid, mp 186− 188 °C, Rf = 0.5 (petroleum ether/EtOAc = 8:2); 1H NMR (400 MHz, CDCl3): δ 9.04 (s, 1H), 7.76 (s, 1H), 7.69 (s, 1H), 7.51 (s, 1H), 7.45−7.37 (m, 2H), 7.37−7.29 (m, 2H), 7.26−7.21 (m, 1H), 4.43 (s, 2H), 3.92 (s, 3H), 2.47 (d, J = 5.2 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 165.5, 148.3, 143.7, 138.5, 136.0, 131.7, 130.2, 129.4, 128.6, 127.9, 127.6, 126.6, 125.5, 120.2, 113.8, 110.8, 52.3, 36.7, 20.8, 20.7; IR (KBr): νmax = 2945, 2918, 1715, 1429, 1226, 997, 763, 702 cm−1; MS (ESI): m/z 345 (M + H)+; HRMS (ESI): m/z calcd for C22H21N2O2 (M + H)+: 345.1598, found: 345.1593. Pyrido[1,2-e]purine (9). Following the general procedure, to a stirred solution of MBH-acetate 1a (100 mg, 0.38 mmol) and N-Boc Adenine 8 (130 mg, 0.38 mmol) in 5 mL of acetonitrile was added potassium carbonate (53 mg, 0.38 mmol) at room temperature for 10 h. Then, DBU (29 mg, 0.19 mmol) and CuI (7 mg, 0.038 mmol) were added to the reaction mixture at 0 °C and stirring was continued at 80 °C for 5 h. After the completion of reaction (monitored by TLC), acetonitrile was evaporated and the crude mixture was purified by column chromatography on silica gel (20% EtOAc in petroleum ether) to afford the corresponding product 9: 146 mg, 71%, yellow solid, mp 178−180 °C, Rf = 0.5 (petroleum ether/EtOAc = 9:1); 1H NMR (400 MHz, CDCl3): δ 8.96 (s, 1H), 8.20 (s, 1H), 7.35−7.22 (m, 6H), 5.25 (s, 2H), 3.72 (s, 3H), 1.32 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3): δ 164.8, 152.6, 149.9, 148.3, 144.3, 133.9, 132.8, 132.1, 130.1, 128.5, 126.2, 124.0, 121.5, 120.9, 84.4, 52.8, 44.7, 27.8; IR (KBr): νmax = 2980, 1717, 1596, 1446, 1249, 1109, 850, 764 cm−1; MS (ESI): m/z 534 (M + H)+; HRMS (ESI): m/z calcd for C28H32N5O6 (M + H)+: 534.2353, found: 534.2347. (Z)-1-(3-Methyl-5-phenylpent-2-en-4-yn-1-yl)-1H-imidazole (10). To a stirred solution of 60% NaH (33 mg, 0.85 mmol) in 5 mL of tetrahydrofuran at 0 °C were added (Z)-(5-bromo-3-methylpent-3en-1-yn-1-yl)benzene 1f (100 mg, 0.42 mmol) and imidazole 2a (29 mg, 0.42 mmol) at 0 °C for 2 h. After the completion of reaction (monitored by TLC), it was quenched with saturated NH4Cl solution and extracted with ethylacetate (3 × 10 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20% EtOAc in petroleum ether) to afford the corresponding product 10: 80 mg, 85%, pale yellow liquid, Rf = 0.5 (petroleum ether/EtOAc = 9:1); 1H NMR (500 MHz, CDCl3): δ 7.54 (s, 1H), 7.51−7.42 (m, 2H), 7.39−7.31 (m, 3H), 7.07 (s, 1H), 6.97 (s, 1H), 5.84 (td, J = 7.1, 1.5 Hz, 1H), 4.81 (dd, J = 7.1, 0.9 Hz, 2H), 2.02 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 136.9, 131.5, 130.2, 129.5, 128.7, 128.4, 123.8, 122.5, 118.8, 95.3, 86.7, 46.6, 23.1; IR (KBr): νmax = 3107, 2925, 1676, 1499, 1227, 1074, 759, 690 cm−1; MS (ESI): m/z 223 (M + H)+; HRMS (ESI): m/z calcd for C15H15N2 (M + H)+: 223.1235, found: 223.1234.

■

Article

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Chada Raji Reddy: 0000-0003-1491-7381 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS A.G.B. acknowledges the Council of Scientific and Industrial Research (CSIR), New Delhi, for research fellowship. C.R.R. is grateful to Science and Engineering Research Board (SERB), Department of Science and Technology, New Delhi, for funding this project (EMR/2016/006253). CSIR-IICT Communication No. IICT/Pubs./2019/154.

■

REFERENCES

(1) For selected references, see: (a) Enguehard-Gueiffier, C.; Gueiffier, A. Recent Progress in the Pharmacology of Imidazo[1,2a]pyridines. Mini-Rev. Med. Chem. 2007, 7, 888−899. (b) Kang, S.; Kim, R. Y.; Seo, M. J.; Lee, S.; Kim, Y. M.; Seo, M.; Seo, J. J.; Ko, Y.; Choi, I.; Jang, J.; Nam, J.; Park, S.; Kang, H.; Kim, H. J.; Kim, J.; Ahn, S.; Pethe, K.; Nam, K.; No, Z.; Kim, J. Lead Optimization of a Novel Series of Imidazo[1,2-a]pyridines Amides Leading to a Clinical Candidate (Q203) as Multi and Extensively-Drug Resistant Antituberculosis Agent. J. Med. Chem. 2014, 57, 5293−5349. (2) (a) Wan, J.; Zheng, C. J.; Fung, M. K.; Liu, X. K.; Lee, C. S.; Zhang, X. H. Multifunctional electron-transporting indolizine derivatives for highly efficient blue fluorescence, orange phosphorescence host and two-color based white OLEDs. J. Mater. Chem. 2012, 22, 4502−4510. (3) (a) Douhal, A.; Guerri, F. A.; Acufia, U. Photoinduced Intramolecular Proton Transfer and Charge Redistribution in Imidazopyridines. J. Phys. Chem.A 1995, 99, 76−80. (4) For representative references, see: Anticancer: (a) Kamal, A.; Reddy, J. S.; Ramaiah, M. J.; Dastagiri, D.; Bharathi, E. V.; Sagar, M. V. P.; Pushpavalli, S. N. C. V. L.; Ray, P.; Bhadra, M. P. Design, Synthesis and biological evaluation of imidazopyridine/pyrimidinechalcone derivatives as potential anticancer agents. Med. Chem. Commun. 2010, 1, 355−360. Antibacterial (b) Rival, Y.; Grassy, G.; Michel, G. Synthesis and antibacterial activity of some imidazo[1,2a]pyrimidine derivatives. Chem. Pharm. Bull. 1992, 40, 1170−1176. Antifungal (c) Rival, Y.; Grassy, G.; Taudou, A.; Ecalle, R. Antifungal activity in vitro of some imidazo[1,2-a]pyrimidine derivatives. Eur. J. Med. Chem. 1991, 26, 13−18. (d) Lusi, A.; Fisher, M. H. Imidazo[1,2a]pyrimidine anthelmintic and antifungal agents. J. Med. Chem. 1972, 15, 982−985. (e) Lhassani, M.; Chavignon, O.; Chezal, J.-M.; Teulade, J.-C.; Chapat, J.-P.; Snoeck, R.; Andrei, G.; Balzarini, J.; Clercq, E. D.; Gueiffier, A. Synthesis and antiviral activity of imidazo[1,2-a]pyridines. Eur. J. Med. Chem. 1999, 34, 271−274. Antiviral: (f) Hamdouchi, C.; Blas, J. D.; Prado, M. D.; Gruber, J.; Heinz, B. A.; Vance, L. 2-Amino-3-substituted-6-[(E)-1-phenyl-2-(Nmethylcarbomoyl)vinyl]imidazo[1,2-a]pyridines as a Novel class of inhibitors of human rhinovirus: Stereospecific and antiviral activity. J. Med. Chem. 1999, 42, 50−59. Antiulcer: (g) Doweyko, A. M.; Kaminski, J. J. Antiulcer agents. analysis of the in vitro biochemical and in vivo gastric antisecretory activity of substituted imidazo[1,2a]pyridines and related analogues using comparative molecular field analysis and hypothetical active site lattice methodologies. J. Med. Chem. 1997, 40, 427−436. (5) (a) Mackwitz, M. K. W.; Hamacher, A.; Osko, J. D.; Held, J.; Scholer, A.; Christianson, D. W.; Kassack, M. U.; Hansen, F. K. Multicomponent Synthesis and Binding Mode of Imidazo[1,2a]pyridine-Capped Selective HDAC6 Inhibitors. Org. Lett. 2018, 20, 3255−3258. (b) Goodacre, S. C.; Street, L. J.; Hallett, D. J.; Crawforth, J. M.; Kelly, S.; Owens, A. P.; Blackaby, W. P.; Lewis, R.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b01118. 1

H and 13C NMR spectra of all synthesized compounds (PDF) H

DOI: 10.1021/acs.joc.9b01118 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry T.; Stanley, J.; Smith, A. J.; Ferris, P.; Sohal, B.; Cook, S. M.; Pike, A.; Brown, N.; Wafford, K. A.; Marshall, G.; Castro, J. L.; Atack, J. R. Imidazo[1,2-a]pyridines as Functionally Selective and Orally Bioavailable GABAAα2/α3 Binding Site Agonists for the Treatment of Anxiety Disorders. J. Med. Chem. 2006, 49, 35−38. (c) Zhuang, Z.P.; Kung, M.-P.; Wilson, A.; Lee, C.-W.; Plossel, K.; Hou, C.; Holtzman, D. M.; Kung, H. F. Structure-Activity Relationship of Imidazo[1,2-a]pyridines as Ligands for Detecting β-Amyloid Plaques in the Brain. J. Med. Chem. 2003, 46, 237−243. (d) Hervieu, G. Melanin-concentrating hormone functions in the nervous system: food intake and stress. Exp. Opin. Ther. Targets 2003, 7, 495−511. (e) Kishino, H.; Moriya, M.; Sakurba, S.; Sakamoto, T.; Takahashi, H.; Suzuki, T.; Moriya, R.; Ito, M.; Iwaasa, H.; Takenaga, N.; Ishihara, A.; Kanatani, A.; Sato, N.; Fukami, T. Discovery of Imidazo[1,2a]pyridines as Potent MCH1R Antagonists. Bioorg. Med. Chem. Lett. 2009, 19, 4589−4593. (6) For representative references, see: Zolpidem: (a) Monti, J. M.; Spence, W.; Pandi-Perumal, S. R.; Langer, S. Z.; Hardeland, R. Pharmacotherapy of Insomnia: Focus on Zolpidem Extended Release. Clin. Med.: Ther. 2009, 1, 123−140. (b) George, P.; Rossy, G.; Depoortere, H.; Allen, J.; Wick, A. Zolpidem: a new hypnotic with the imidazo[1,2-a]pyridine structure. Actual. Chim. Ther. 1991, 18, 215− 239. (c) Hanson, S. M.; Morlock, E. V.; Satyshur, K. A.; Czajkowski, C. Structural Requirements for Eszopiclone and Zolpidem Binding to the γ-Aminobutyric Acid Type-A (GABAA) Receptor Are Different. J. Med. Chem. 2008, 51, 7243−7252. Saripedem: (d) Chioua, M.; Soriano, E.; Infantes, L.; Jimeno, M. L.; Contelles, J. M.; Samadi, A. Silver-Catalyzed Cyclization of N-(Prop-2-yn-1-yl)pyridine-2-amines. Eur. J. Org. Chem. 2013, 35−39. Olprinone: (e) Mizushige, K.; Ueda, T.; Yukiiri, K.; Suzuki, H. Olprinone: A Phosphodiesterase III Inhibitor with Positive Inotropic and Vasodilator Effects. Cardiovasc. Drug Rev. 2002, 20, 163−174. Soraprazan: (f) Senn-Bilfinger, J.; Ferguson, J. R.; Holmes, M. A.; Lumbard, K. W.; Huber, R.; Zech, K.; Hummel, R.-P.; Zimmermann, P. J. Glucuronide conjugates of soraprazan (BY359), a new potassium-competitive acid blocker (PCAB) for the treatment of acid-related diseases. Tetrahedron Lett. 2006, 47, 3321−3323. (7) (a) Bansal, Y.; Silakari, O. The therapeutic journey of benzimidazoles: A review. Bioorg. Med. Chem. 2012, 20, 6208− 6236. (b) RameshBabu, V. N. S.; NarahariBabu, A.; Anand, V.; Hanumanthu, P. A Facile Synthesis of Pyrido[1,2-a]benzimidazoles. Synth. Commun. 1998, 28, 4439−4443. (8) For selected papers, see: (a) Chalmers, B. A.; Saha, S.; Nguyen, T.; McMurtrie, J.; Sigurdsson, S. T.; et al. TMIO-Pyrlmid Hybrids are Profluorescent, Site-Directed Spin Labels for Nucleic Acids. Org. Lett. 2014, 16, 5528−5531. (b) Gong, W.; Gao, P.; Li, G.; Mehdi, H.; Ning, G.; Yu, J. Construction of fluorescence-tunable pyrido-fused benzimidazoles via direct intramolecular C-H amination under transition-metal-free conditions. RSC Adv. 2014, 4, 51268−51271. (c) Yan, L.; Zhao, D.; Lan, J.; Cheng, Y.; Guo, Q.; Li, X.; Wu, N.; You, J. Palladium-catalyzed tandem N-H/C-H arylation: regioselective synthesis of N-heterocycle-fused phenanthridines as versatile blue-emitting luminophores. Org. Biomol. Chem. 2013, 11, 7966− 7977. (d) Chen, X.; Yang, H.; Ge, Y.; Feng, L.; Jia, J.; Wang, J. Synthesis, X-ray crystal structure and optical properties of novel 2aryl-3-ethoxy-carbonyl-4-phenylpyrido[1,2-a]benzimidazoles. Luminescence 2012, 27, 382−389. (e) Li, G.; Gong, W.-T.; Ye, J.-W.; Lin, Y.; Ning, G.-L. Unprecedented intramolecular cyclization of pyridinium to pyrido[1,2-a]benzimidazole: a novel chemodosimeter for fluoride ions. Tetrahedron Lett. 2011, 52, 1313−1316. (f) Yang, H.; Ge, Y.-Q.; Jia, J.; Wang, J.-W. Synthesis and optical properties of novel pyrido[1,2-a]benzimidazole-containing 1,3,4-oxadiazole derivatives. J. Lumin. 2011, 131, 749−755. (9) Selected review articles on the synthesis of imidazo[1,2-a] pyridines, see: (a) Bagdi, A. K.; Santra, S.; Monir, K.; Hajra, A. Synthesis of Imidazo[1,2-a]pyridines: A Decade Update. Chem. Commun. 2015, 51, 1555−1575. (b) Pericherla, K.; Kaswan, P.; Pandey, K.; Kumar, A. Recent Development in the Synthesis of Imidazo[1,2-a]pyridines. Synthesis 2015, 47, 887−912.

(10) Synthesis of imidazo[1,2-a]pyridines from 2-aminopyridines, for recent representative papers, see: (a) Ghosh, P.; Ganguly, B.; Kar, B.; Dwivedi, S.; Das, S. Green procedure for highly efficient, rapid synthesis of imidazo[1,2-a]pyridine and its late stage functionalization. Synth. Commun. 2018, 48, 1076−1084. (b) Mackwitz, M. K. W.; Hamacher, A.; Osko, J. D.; Held, J.; Scholer, A.; Christianson, D. W.; Kassack, M. U.; Hansen, F. K. Multicomponent Synthesis and Binding Mode of Imidazo[1,2-a]pyridine-Capped Selective HDAC6 Inhibitors. Org. Lett. 2018, 20, 3255−3258. (c) Tan, J.; Ni, P.; Huang, H.; Deng, G.-J. Metal- and base-free synthesis of imidazo[1,2-a]pyridines through elemental sulfur-initiated oxidative annulation of 2-aminopyridines and aldehydes. Org. Biomol. Chem. 2018, 16, 4227−4230. (d) Balalaie, S.; Derakhshan-Panah, F. D.; Zolfigol, M. A.; Rominger, F. A Convenient Method for the Synthesis of Imidazo[1,2-a]pyridines with a New Approach. Synlett 2018, 29, 89−593. (e) Roslan, I. I.; Ng, K.-H.; Wu, J.-E.; Chuah, G.-K.; Jaenicke, S. Synthesis of Disubstituted 3-Phenylimidazo[1,2-a]pyridines via a 2-Aminopyridine/CBrCl3 αBromination Shuttle. J. Org. Chem. 2016, 81, 9167−9174. (f) Lee, S. K.; Park, J. K. Room-Temperature Transition-Metal-Free One-Pot Synthesis of 3-Aryl Imidazo[1,2-a]pyridines via Iodo-hemiaminal Intermediate. J. Org. Chem. 2015, 80, 3723−3729. (11) Synthesis of imidazo[1,2-a]pyridines from pyridine, for selected references, see (a) Ren, Z.-H.; Zhao, M.-N.; Yi, Y.; Wang, Y.-Y.; Guan, Z.-H. Copper-Catalyzed Aerobic Oxidative Cyclization of Ketoxime Acetates with Pyridines for the Synthesis of Imidazo[1,2-a]pyridines. Synthesis 2016, 48, 1920−1926. (b) Donthiri, R. R.; Pappula, V.; Reddy, N. N. K.; Bairagi, D.; Adimurthy, S. Copper-Catalyzed C−H Functionalization of Pyridines and Isoquinolines with Vinyl Azides: Synthesis of Imidazo Heterocycles. J. Org. Chem. 2014, 79, 11277− 11284. (c) Attanasi, O. A.; Bianchi, L.; Campisi, L. A.; Crescentini, L. D.; Favi, G.; Mantellini, F. A Novel Solvent-Free Approach to Imidazole Containing Nitrogen-Bridgehead Heterocycles. Org. Lett. 2013, 15, 3646−3649. (d) Huang, H.; Ji, X.; Tang, X.; Zhang, M.; Li, X.; Jiang, H. Conversion of Pyridine to Imidazo[1,2-a]pyridines by Copper-Catalyzed Aerobic Dehydrogenative Cyclization with Oxime Esters. Org. Lett. 2013, 15, 6254−6257. (e) Yu, J.; Jin, Y.; Zhang, H.; Yang, X.; Fu, H. Copper-Catalyzed Aerobic Oxidative C-H Functionalization of Substituted Pyridines: Synthesis of Imidazopyridine Derivatives. Chem. − Eur. J. 2013, 19, 16804−16808. (12) Synthesis of imidazo[1,2-a]pyridines from prefunctionalized imidazoles, see: N-propargyl imidazoles. (a) Galons, H.; Bergerat, I.; Farnoux, C. C.; Miocque, M. Synthesis of imidazo[1,2-a]pyridines from 1-(2-Alkynyl)-2-aminomethylimidazoles. Synthesis 1982, 1103− 1105. (b) Dai, W.; Peterson, J. L.; Wang, K. K. Synthesis of IndenoFused Derivatives of Quinolizinium Salts, Imidazo[1,2-a]pyridine, Pyrido[1,2-a]indole, and 4H-Quinolizin-4-one via Benzannulated Enyne-Allenes. J. Org. Chem. 2005, 70, 6647−6652. N-allyl imidazoles: (c) Basso, D.; Broggini, G.; Passarella, D.; Pilati, T.; Terraneo, A.; Zecchi, G. Synthetic approach to imidazo[1,2a]pyridines derivatives by the intramolecular nitrone cycloaddition methodology. Tetrahedron 2002, 58, 4445−4450. N-vinyl imidazoles: (d) Dong, L.; Huang, J.-R.; Qu, C.-H.; Zhang, Q.-R.; Zhang, W.; Han, B.; Peng, C. Rhodium(III)-catalyzed vinylic sp 2 C-H bond functionalization: efficient synthesis of pyrido[1,2-α]benzimidazoles and imidazo[1,2-α]pyridines. Org. Biomol. Chem. 2013, 11, 6142− 6149. (13) Synthesis of imidazo[1,2-a]pyridines form simple imidazole, see: (a) Roe, A. M. The thermal condensation of imidazoles with carbonyl compounds. J. Chem. Soc. 1963, 410, 2195−2200. (b) Davey, D. D. Synthesis of Novel 8-Arylimidazo-[1,2-a]pyridines and 8-Arylimidazo[1,5-a]pyridines. J. Org. Chem. 1987, 52, 1863− 1867. (c) Liao, Q.; Zhang, L.; Li, S.; Xi, C. Domino N-H/C-H Bond Activation: Copper-Catalyzed Synthesis of Nitrogen-Bridgehead Heterocycles Using Azoles and 1,4-Dihalo-1,3-dienes. Org. Lett. 2011, 13, 228−231. (14) (a) Reddy, C. R.; Valleti, R. R.; Dilipkumar, U. One-Pot Sequential Propargylation/Cycloisomerization: A Facile [4+2]Benzannulation Approach to Carbazoles. Chem. − Eur. J. 2016, 22, 2501−2506. (b) Reddy, C. R.; Dilipkumar, U.; Shravya, R. Atom and I

DOI: 10.1021/acs.joc.9b01118 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry Pot-Economical Consecutive Multi-Step Reaction Approach to Polycyclic Aromatic Hydrocarbons (PAHs). Chem. Commun. 2017, 53, 1904−1907. (c) Reddy, C. R.; Mallesh, K. Rh(III)-Catalyzed Cascade Annulations To Access Isoindolo[2,1-b]isoquinolin-5(7H)ones via C-H Activation: Synthesis of Rosettacin. Org. Lett. 2018, 20, 150−153. (15) For selected references on MBH- acetates as reliable intermediates, see: (a) Reddy, C. R.; Reddy, M. D.; Srikanth, B.; Prasad, K. R. Morita-Baylis-Hillman acetate of acetylenic aldehydes: versatile synthons for substituted pyrroles via a metal-free tandem reaction. Org. Biomol. Chem. 2011, 9, 6027−6033. (b) Reddy, C. R.; Valleti, R. R.; Reddy, M. D. Thioannulation Approach to Substituted Thiophenes from Morita-Baylis-Hillman Acetates of Acetylenic Aldehydes. J. Org. Chem. 2013, 78, 6495−6502. (c) Reddy, C. R.; Dilipkumar, U.; Reddy, M. D. Novel [4+2]-Benzannulation To Access Substituted Benzenes and Polycyclic Aromatic and Benzene-Fused Heteroaromatic Compounds. Org. Lett. 2014, 16, 3792−3795. (d) Reddy, C. R.; Kumaraswamy, P.; Singarapu, K. K. Sequential Allylic Substitution/Pauson-Khand Reaction: A Strategy to Bicyclic Fused Cyclopentenones from MBH-Acetates of Acetylenic Aldehydes. J. Org. Chem. 2014, 79, 7880−7888. (e) Reddy, C. R.; Panda, S. A.; Reddy, M. D. Aza-Annulation of Enynyl Azides: A New Approach to Substituted Pyridines. Org. Lett. 2015, 17, 896−899. (f) Reddy, C. R.; Ranjan, R.; Prajapati, S. K.; Warudikar, K. One-Pot Consecutive Sulfonamidation/ipso-Cyclization Strategy for the Construction of Azaspirocyclohexa-dienones. J. Org. Chem. 2017, 82, 6932−6939. (16) Park, S. P.; Ahn, S.-H.; Lee, K.-J. 3,5-Disubstituted 6Hpyrrolo[1,2-c]Triazoles from Morita-Baylis-Hillman Adducts of Propargyl Aldehydes. Tetrahedron 2010, 66, 3490−3498. (17) Review article for the synthesis of benzimidazole[1,2-a] pyridines, see: Khajuria, R.; Rasheed, S.-K.; Khajuria, C.; Kapoor, K. K.; Das, P. Recent Development in the Synthesis of Pyrido[1,2a]benzimidazoles. Synthesis 2018, 50, 2131−2149. (18) Literature methods for the synthesis of benzimidazole[1,2-a] pyridines, see: (a) Wu, Z.; Haung, Q.; Zhou, X.; Yu, L.; Li, Z.; Wu, D. Synthesis of Pyrido[1,2-a]benzimidazoles through a Copper-Catalyzed Cascade C-N Coupling Process. Eur. J. Org. Chem. 2011, 5242− 5245. (b) Liang, D.; He, Y.; Liu, L.; Zhu, Q. A Metal-Free Tandem Demethylenation/C(sp2)-H Cycoamination Process of N-Benzyl-2aminopyridines via C-C and C-N Bond Cleavage. Org. Lett. 2013, 15, 3476−3479. (c) Rao, D. N.; Rasheed, S.; Vishwakarma, R. A.; Das, P. Hypervalent iodine (III) catalyzed oxidative C-N bond formation in water: synthesis of benzimidazole-fused heterocycles. RSC Adv. 2014, 4, 25600−25604. (d) Rasheed, S.; Rao, D. N.; Das, P. CopperCatalyzed Inter and Intramolecular C-N Bond Formation: Synthesis of Benzimidazole-Fused Heterocycles. J. Org. Chem. 2015, 80, 9321− 9327. (e) Xie, Y.; Wu, J.; Che, X.; Chen, Y.; Huang, H.; Deng, G.-J. Efficient pyrido[1,2-a]benzimidazole formation from 2-aminopyridines and cyclohexanones under metal-free conditions. Green Chem. 2016, 18, 667−671. (19) Odedra, A.; Wu, C.-J.; Madhushaw, R. J.; Wang, S.-L.; Liu, R.-S. A new Co2(CO)8-mediated tandem [5+1]/[2+2+1]-cycloaddition reaction: A one-pot synthesis of tricyclic δ-lactones from cis-epoxy ene-ynes. J. Am. Chem. Soc. 2003, 125, 9610−9611. (20) (a) Li, J.; Wang, X.; Zhang, Y. Remarkable rate acceleration of water-promoted nucleophilic substitution of Baylis-Hillman acetate: a facile and highly efficient synthesis of N-substituted imidazoles. Tetrahedron Lett. 2005, 46, 5233−5237. (b) Rodrigues, M. T., Jr.; Santos, M. S.; Santos, H.; Coelho, F. 1, 1′-Carbonyldiimidazole mediates the synthesis of N-substituted imidazole derivatives from Morita-Baylis-Hillman adducts. Tetrahedron Lett. 2014, 55, 180−183. (c) Ö zenç, A. K.; Celik, I.; Kokten, S. Stereoselective and regioselective synthesis of N-substituted methyl 2-((azolyl)methyl)3-arylacrylates from Baylis-Hillman acetates. Turk. J. Chem. 2017, 41, 323−334.

J

DOI: 10.1021/acs.joc.9b01118 J. Org. Chem. XXXX, XXX, XXX−XXX