Three-component solvent-free synthesis of highly substituted tetra-hydroimidazo[1,2-a]pyridines

Abstract

An efficient and green method has been developed for the synthesis of tetrahydroimidazo[1,2-a]pyridines by three-component reactions of heterocyclic ketene aminals (HKAs), triethoxymethane and nitroalkenes in one pot in the absence of catalyst and solvent. This protocol has advantages of environmental friendliness, high yields (73–93%), short reaction time and convenient operation.

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Introduction

In recent years worldwide attention has been attracted towards environmental protection, which requires the minimization of waste and avoidance of the use of toxic organic solvents in chemical reactions.¹ Thus, solvent-free and catalyst-free multi-component reactions² (MCRs) are currently of considerable interest. A large number of compounds of a diverse variety can be prepared by one-step reactions with relatively simple starting materials via one-pot MCRs, which are usually synthetically facile, highly atom-economic and highly selective.² These compounds can be perfect candidates for combinatorial, automated syntheses and drug discovery.³

Imidazo[1,2-a]pyridine derivatives are becoming more and more important in medicinal and organic chemistry. They have displayed a broad spectrum of pharmacological and biological activities, such as antitumoral,⁴ antiviral,⁵ antiinflammatory,⁶ antibacterial,⁷ antifungal,⁸ antiulcer,⁹ antiprotozoal¹⁰ and antiretroviral activities.¹¹ So these pyridine derivatives have found their use as glycosidase inhibitors,¹²inhibitors of gastric acid secretion,¹³cyclin-dependent kinase inhibitors,¹⁴calcium channel blockers,¹⁵ agents against herpesviruses¹⁶ and so on.¹⁷ Although various approaches to the preparation of imidazo[1,2-a]pyridine derivatives have been developed by organic or pharmaceutical chemists,^18–20 environmentally benign and highly selective one-pot solvent-free preparation of these highly substituted bicyclic pyridines have rarely been reported.

In our previous paper, we developed a new type of MCR with a convenient and rapid synthetic procedure, and a series of highly substituted bicyclic pyridines containing a ring-junction nitrogen, including imidazo[1,2-a]pyridines, pyrido[1,2-a]pyrimidines, pyrido[1,2-a]diazepines, oxazolo-[3,2-a]pyridines and thiazolo-[3,2-a]pyridines, were synthesized.^18a Nevertheless, this class of compounds are of such significant importance that a lot more effort is still needed to expand the scope and increase the variety of the highly substituted bicyclic pyridines possessing potential bioactivities. Therefore, we herein report the rapid construction of a library of tetrahydroimidazo[1,2-a]pyridine derivatives, which also contain a ring-junction nitrogen, starting with beta-nitrostyrenes. High yields were obtained in a short reaction time.

Results and discussion

In the preceding communication, the design, synthesis and characterization of highly substituted bicyclic pyridines containing a ring-junction nitrogen were described.^18a Using MCRs to synthesize a number of drug-like scaffold compounds in a single step was achieved by simply varying the reaction substrates. In this paper, we aim to utilize the novel synthetic method to afford tetrahydroimidazo[1,2-a]pyridine derivatives 4 in excellent yields by heated HKAs 1, triethoxymethane 2 and nitroalkenes 3 under solvent-free and catalyst-free conditions (Table 1).

Table 1 One-pot three-component synthesis of tetrahydroimidazo[1,2-a]pyridine derivatives 4 under solvent-free and catalyst-free conditions

Entry	1	3	4	Time (min)	Yield (%)^ab
a Isolated yields after silica gel chromatography b Yield of isolated product from reaction on a 2.5 mmol scale.
1				33	82
2				28	83
3				26	85
4				30	85
5				27	89
6				23	91
7				24	93
8				27	78
9				29	81
10				24	82
11				25	83
12				31	86
13				26	89
14				35	92
15				28	75
16				20	78
17				25	79
18				22	80
19				33	84
20				26	86
21				35	90
22				26	73
23				23	75
24				21	84
25				38	74

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In the initial stage, we continued to use the strategy of reacting HKA 1a with triethoxymethane 2 and nitroalkenes3a, instead of active methylene compounds, in one pot under solvent-free and catalyst-free conditions at 110 °C for 33 min. The tetrahydro-imidazo[1,2-a]pyridine 4a was successfully produced in a good yield (82%) (Table 1, entry 1).

To explore the scope of the method, HKAs 1a–e and nitroalkenes 3a–g were used as substrates to react with triethoxymethane 2 (Table 1). The results demonstrated that HKAs with various substituents were all good substrates for the cyclocondensation reaction (Table 1, entries 1–25). The reactions usually took 20–38 min at 110 °C to reach completion and afforded the products with good to excellent yields.

The structure of HKAs 1 and nitroalkene 3 had an influence on the yield. It was observed that the electron-rich group on the aromatic ring of nitroalkene 3 can contribute to the yield of the reaction. Specifically, under the experimental conditions, the order of the contribution to the yield was 3g > 3f > 3e > 3d > 3c >3b > 3a (Table 1, entries 1–7, 8–14, 15–21 and 22–24). It was also demonstrated that different substituents of HKA 1 contribute to the yield when the same nitroalkene 3 was used. The electron-deficient group on the aromatic ring of HKA 1 can also contribute to the yield of the reaction (Table 1, entries 1, 8, 15, 22; 2, 9, 16, 23; 3, 10, 17; 4, 11, 18; 5, 12, 19, 24, 25; 6, 13, 20 and 7, 14, 21). Under the experimental conditions, the order of contribution to the yield was 1a > 1b > 1c > 1d > 1e.

To verify the structure of the bicyclic pyridine product, 4f was selected as a representative compound and was characterized by X-ray crystallography as shown in Fig. 1 (CCDC 818211†).²¹

Fig. 1 ORTEP diagram of 4f; ellipsoids are drawn at the 30% probability level.

A proposed mechanism for the three-component reaction is depicted in Scheme 1. HKAs 1 reacted with triethoxymethane 2 to form intermediate 5, which was different from what we have previously described.^18a Then, 5 reacted with nitroalkenes 3 possibly via an Aza–Michael type reaction mechanism to afford 6. Finally, EtOH was removed from compound 6 to give the final product 4.

Scheme 1 Proposed mechanism for the three-component reaction.

Conclusions

To summarize, compared with our previous report, we have expanded the scope of a one-pot three-component, solvent-free and catalyst-free reaction to synthesize another type of highly functional bicyclic pyridine containing a ring-junction nitrogen. These pyridines are substituted by nitro, aryl and hetero-aryl. Using HKAs, triethoxymethane and nitroalkenes as building blocks, a novel library of highly substituted tetrahydroimidazo-[1,2-a]pyridine derivatives was constructed. It demonstrated that this facile and environmentally friendly process has great potential to be applied to parallel synthesis in drug discovery.

Experimental

General Procedure

HKA derivative 1 (2.5 mmol), triethoxy-methane 2 (3 mmol) and nitroalkene derivatives 3 (3 mmol) were charged into a 25 mL round-bottom flask and the mixture was heated to 110 °C. The resulting solution was stirred for 20–38 min until the HKA derivative 1 was completely consumed. The mixture was diluted with EtOAc (50 mL × 2) and quenched with water (50 mL). The organic layer was dried by Na₂SO₄, concentrated, and purified by flash column chromatography (Petro/AcOEt = 1/1) to afford product 4 with 73–93% yield. The products were further identified by FTIR, NMR and HRMS, being in good agreement with the assigned structures (ESI†).

(4-Chlorophenyl)(5-(furan-2-yl)-1,2,3,5-tetrahydro-6-nitro-imidazo[1,2-a]pyridin-8-yl)methanone (4a)

Yellow solid; Mp 257–258 °C; IR (KBr): 3288, 2900, 1594, 1408, 1292, 1228, 1163, 1075, 769 cm⁻¹; ¹H NMR (500 MHz, DMSO-d₆): δ = 3.18–3.23 (m, 1H, NCH₂), 3.75–3.80 (m, 3H, NCH₂CH₂N), 6.02 (s, 1H, NCH), 6.48 (s, 1H, ArH), 6.54 (s, 1H, ArH), 7.55 (d, J = 8.1 Hz, 2H, ArH), 7.60 (d, J = 8.1 Hz, 2H, ArH), 7.67 (s, 1H, ArH), 7.99 (s, 1H, CH=), 9.37 (br, 1H, NH); ¹³C NMR (125 MHz, DMSO-d₆): δ = 43.7, 45.9, 51.6, 91.4, 109.7, 111.1, 123.1, 128.9, 130.2, 135.6, 137.3, 138.4, 143.8, 150.2, 159.4, 188.3; HRMS (TOF ES⁺): m/z calcd for C₁₈H₁₅ClN₃O₄ [(M+H)⁺], 372.0746; found, 372.0753.

Acknowledgements

We gratefully acknowledge the financial support from the Natural Science Foundation of China (grant numbers 30860342 and 20762013) and the Natural Science Foundation of Yunnan Province (2009CC017, 2008CD063).

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Footnotes

† Electronic supplementary information (ESI) available: Supplementary information. CCDC reference number 818211. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c1ra00242b

‡ These authors contributed equally to this paper.

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