One-step synthesis of imidazo[1,2-a]pyridines in water

Abstract

A novel straightforward method for the synthesis of 2,3-disubstituted imidazo[1,2-a]pyridine derivatives in water as a truly safe and cheap reaction medium was developed. Hence, N-alkyl pyridinium and S-alkyl thiouronium salts were reacted in the presence of NaHCO₃ as a mild base in water to produce imidazo[1,2-a]pyridines in moderate to excellent yields.

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Introduction

Imidazopyridine and its derivatives have attracted much attention currently because of their interesting biological activities and broad utilization in the pharmaceutical industry.¹ Among the various derivatives the imidazo[1,2-a]pyridine skeleton is likely to be the most important structure due to its vital role as a key structure in drugs and biologically active compounds with properties such as anti-inflammatory,^2,3 antiviral,^4–6 antiulcer,^7,8 antifungal,⁹ anticancer,¹⁰ and anxiolytic¹¹ properties. There are several drugs available in the market containing the imidazo[1,2-a]pyridine moiety such as zolpidem and alpidem,¹² olprinone,² zolimidine,¹³ and necopidem¹⁴ (Fig. 1).

Fig. 1 Some representative applications of imidazo[1,2-a]pyridine skeleton in drugs.

Various methods have been reported for synthesis of imidazo[1,2-a]pyridine derivatives including the condensation reaction of the a-halocarbonyl compounds with 2-aminopyridines under neutral or weak basic conditions,^15,16 CuI-catalyzed aerobic oxidative synthesis of imidazo[1,2-a]pyridines from acetophenones and 2-aminopyridines,¹⁷ tandem coupling between 2-aminopyridines and nitroolefins,^18,19 one-pot condensation of isocyanide, aldehydes, and 2-aminopyridines,^20–22 three-component reaction of 2-aminopyridines, aldehydes, and alkynes,^23,24 reaction of propargylic alcohols and 2-aminopyridine,²³ reaction of 2-aminopyridine N-oxide and alkynes,²⁵ condensation–cyclization reaction of aryl-2-pyridylmethylamines and aldehydes with sulfur,²⁶ copper-catalyzed aerobic dehydrogenative cyclization of pyridines with ketone oxime esters,²⁷ gold-catalyzed reaction of amino pyridine and alkynes,²⁸ copper-catalyzed oxidative cyclization of halo-alkynes,²⁹ regioselective dicarbonylation of imidazo[1,2-a]pyridines,³⁰ and selective C3-formylation of imidazo[1,2-a]pyridines catalyzed by copper.³¹

Very recently, a copper-catalyzed oxidative coupling reaction of imidazo[1,2-a]pyridines with methyl ketones has been reported for synthesizing of diverse 1,2-dicarbonyl imidazo[1,2-a]pyridine derivatives.³²

Herein, we describe a novel efficient method for the preparation of 2,3-disubstituted imidazo[1,2-a]pyridine derivatives using the reaction of N-alkyl pyridinium and S-alkyl thiouronium salts in the presence of NaHCO₃ as a mild base in water (Scheme 1).

Scheme 1 One-step synthesis of imidazo[1,2-a]pyridines in water.

Results and discussion

Our research continues to focus partly, on the design of novel reactants that enable the synthetic reactions to be performed in a one-step process, in aqueous media, at mild reaction temperatures, and using rather noncorrosive materials accompanying with simple isolation of final product. As part of our ongoing program to develop effective and robust methods for the synthesis of a wide variety of biologically interesting heterocycles, we turn our attention to synthesize imidazo[1,2-a]pyridines from ionic building blocks in water as a cheap and readily available solvent.

Initially, our researches commenced by reaction of pyridinium 1 and thioformamidinium 2 salts in different solvents and temperatures using various bases. The required pyridinium 1 and thioformamidinium 2 salts were readily prepared by the alkylation reaction of their corresponding pyridine and thioamide derivatives with a suitable alkylating agent respectively. In this way, 2-amino-1-(4-nitrobenzyl)pyridinium bromide 1a and 4-((methylthio)(phenyl)methylene) morpholinium iodide 2a were chosen as test substrates and reacted in various solvents and bases to produce 3-(4-nitrophenyl)-2-phenylimidazo[1,2-a]pyridine 3a. The reactions were appropriately monitored by TLC analysis in all cases, and it was observed that the use of highly polar or protic solvents significantly reduced the reaction optimization time and improve the product yield of the reaction (Table 1).

Table 1 Optimization of reaction conditions for synthesis of compound 3a

Entry	Base	Solvent	Time (h)	Yield^a (temperature, °C)
				50	75	90
a Isolated yields.b Under reflux condition.c At room temperature.
1	DBU	CH3CN	12	43	77	70^b
2	Et3N	CH3CN	12	18	31	23^b
3	KOH	CH3CN	12	14	10	<10^b
4	K2CO3	CH3CN	12	29	48	47^b
5	NaHCO3	CH3CN	12	23	44	51^b
6	DBU	DMF	12	41	73	75
7	K2CO3	DMF	12	36	59	71
8	NaHCO3	DMF	12	32	65	73
9	DBU	EtOH	5	28	49	48^b
10	NaHCO3	EtOH	5	35	63	63^b
11	DBU	Water	4	34	69	68
12	NaHCO3	Water–CH3CN, 1 : 1	4	50	86	88
13	NaHCO3	Water	4	53	90	87
14	—	Water	12	—	<10	16
15	NaHCO3	Water	12	26^c

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From Table 1 it is also concluded that, using highly polar aprotic solvents, the reaction course was better proceeded with a non nucleophilic organic base such as DBU (entries 6, 7, and 8), but in protic solvents, NaHCO₃ as a rather weak inorganic base gave the best result (entries 10, 11, 12, and 13). In the case of using a heterogeneous inorganic base in an aprotic solvent or a homogeneous organic base in a protic solvent, the product yield of 3a were moderate (entries 4, 9, and 11). Optimization of the reaction temperature revealed that the best reaction temperature was 75 °C and at higher temperatures, lower yield of 3a was obtained. This is attributed to the fact that, some extent of resinification is occurred in the reaction mixture at higher temperatures. On the other hand, the product yield of 3a was also drastically decreased in the presence of nucleophilic organic or inorganic bases (Table 1, entry 2 and 3). We assume that, it was more likely due to competitive hydrolysis of thioformamidinium salts 2 to the corresponding amides at elevated temperatures, demonstrated by TLC analysis. Fortunately, as we expected, when water was used as the reaction medium, the reaction time and the product yield of 3a was notably improved (Table 1, entry 12). This is ascribed to highly polar and protic character of water and ionic nature of both reactants. We presume that, better solubility of both reactants 1a and 2a in hot water (75 °C) accompanied with the inherent hydrophobicity of the nonionic product 3a caused the reaction not to be reversible and deposit the final product. When, the reaction was conducted in the absence of a base in water, very small amounts of product 3a was produced and this confirms the vital role of presence of a base in the reaction course.

Generality and the efficiency of the method was approved by the successful synthesis of diverse 2,3-disubstituted imidazo[1,2-a]pyridines and the results are shown in Table 2.

Table 2 Straightforward synthesis of 2,3-disubstituted imidazo[1,2-a]pyridines in water^a

a All the reactions were carried out in water at 75 °C for 5 h employing 1.0 equiv. of pyridinium salt 1, 1 equiv. of thioformamidinium salt 2, and 2 equiv. of NaHCO₃. Yields refer to isolated material.

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In one hand, it is clear from Table 2, when R¹ contains a powerful electron withdrawing group such as nitro or fluoro groups, the product yields are increased meaningfully (entries 3a–3i and 3m) which is attributed to higher acidity of the methylene protons in compounds (1a–e). On the other hand, when R² is an aliphatic group such as benzyl (entry 3o) the product yield is diminished. All compounds were characterized by their ¹H, ¹³C NMR, and elemental analysis data. The structure of compound 3c was further approved by single crystal X-ray crystallography (CCDC 1484156,† Fig. 2).

Fig. 2 ORTEP representation of compound 3c. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as small spheres of arbitrary radii.

A tentative mechanism for the formation of imidazo[1,2-a]pyridines 3 can be rationalized as follows: the reaction is triggered by nucleophilic attack of amino function of pyridinium salt 1 on thioformamidinium salt 2 affording intermediate 4 after releasing of a MeSH molecule. Intermediate 4 is then cyclized and aromatized with aid of a base alongside the elimination of a morpholine molecule to produce product 3 (Scheme 2).

Scheme 2 A plausible mechanism for the formation of compound 3.

Serendipitously, it was found that when compound 1a alone is treated with DBU in acetonitrile for 20 h at reflux temperature, 2,3-bis(4-nitrophenyl)imidazo[1,2-a]pyridine 3p is produced as a sole product in moderate yield (48%). Although the reason for production of such compound is not unveiled for us so far, but a rather reasonable mechanism for the formation of this compound was proposed and shown in Scheme 3.

Scheme 3 A probable mechanism for the conversion of aminopyridinium salt 1a to imidazo[1,2-a]pyridine 3p.

It is assumed that, the reaction is started with nucleophilic attack of imino group of intermediate 5 produced by deprotonation of compound 1a in the presence of DBU, on another 1a molecule to produce intermediates 6. This intermediate is then tautomerized to 7 and after cyclization in the presence of DBU transforms to intermediate 8. It seems that intermediate 8 is then air oxidized to produce imidazo[1,2-a]pyridine 3p. Unfortunately, all attempts to isolate intermediates 6 and 7 were not successful.

Experimental

General remarks

All reagents, unless otherwise stated, were used as received from commercial suppliers. CH₃CN was distilled from P₂O₅. Thin layer chromatography (TLC) was performed on UV-active aluminum-backed plates of silica gel (TLC Silica gel 60 F₂₅₄). ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were recorded on Bruker Avance 400 spectrometer referenced to residual solvent protons and signals are reported in ppm (δ). Low-resolution mass spectra (LRMS) were recorded on a Bell and Howell 21-490 spectrometer. LECO CHNS-932 Elemental Analyzer was used to obtain CHN data. X-ray crystallographic data was obtained using a Bruker AXS Kappa APEX II single crystal X-ray diffraction instrument.

Synthetic procedure for the preparation of 3-(4-nitrophenyl)-2-phenylimidazo[1,2-a]pyridine 3a in acetonitrile

In a 25 mL round bottom flask, 2-amino-1-(4-nitrobenzyl)pyridinium bromide 1a (1 mmol, 310 mg) and 4-((methylthio)(phenyl)methylene)morpholinium iodide 2a (1 mmol, 349 mg) were dissolved in CH₃CN (5 mL) and DBU (2 mmol, 0.3 mL) was added dropwise during 5 min at room temperature. The reaction mixture was stirred vigorously and the reaction temperature raised to 75 °C and heated at this temperature overnight (12 h). After stripping off the half of solvent under reduced pressure, water (1 mL) was added and set it aside to crystallize. The crude crystals were recrystallized from EtOH to obtain pure compound 3a as deep yellow crystals (243 mg, 77%).

General procedure for the preparation of imidazo[1,2-a]pyridines 3a–3o in water

In a 25 mL round bottom flask, pyridinium salt 1 (1 mmol) and 4-((methylthio)(aryl)methylene) morpholinium iodide 2 (1 mmol) were suspended in water (5 mL) and heated to 75 °C with vigorous stirring. Then NaHCO₃ (2 mmol, 168 mg) was added to the reaction mixture at once and heating was continued at the same temperature for 4 h. After completion of the reaction (TLC), the reaction mixture was cooled to room temperature and the precipitated crude product was filtered and washed with water (10 mL) followed by cold MeOH (0 °C, 5 mL). Finally, the crude crystals were recrystallized from EtOH to obtain pure compounds 3a–3o as deep yellow to yellowish orange crystals.

Unusual reaction of 2-amino-1-(4-nitrobenzyl)pyridinium bromide 1a with DBU in CH₃CN

In a 25 mL round bottom flask, pyridinium salt 1 (1 mmol) and DBU (2 mmol, 304 mg) were dissolved in CH₃CN and the reaction mixture was heated under reflux condition for 20 h. After evaporation of half of solvent, the final deep yellow product was precipitated on cooling to room temperature. The crude solid was filtered and recrystallized from EtOH to obtain compound 3p as yellow-orange needles in moderate yield (173 mg, 48%).

Compound 3a. Yellow solid (284 mg, 90%); ¹H NMR (400 MHz, CDCl₃) δ: 8.31 (d, ³J_HH = 8.8 Hz, 2H), 8.03 (d, ³J_HH = 7.0 Hz, 1H), 7.68 (d, ³J_HH = 9.1 Hz, 1H), 7.61 (d, ³J_HH = 8.8 Hz, 2H), 7.51–7.53 (m, 2H), 7.22–7.29 (m, 4H), 6.8 (dt, ³J_HH = 6.8 Hz, ⁴J_HH = 1.1 Hz, 1H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ: 147.4, 145.7, 144.5, 136.7, 133.4, 131.1, 128.6, 128.5, 128.2, 127.1, 1125.6, 124.8, 122.8, 118.1, 113.2 ppm; anal. calcd for C₁₉H₁₃N₃O₂: C, 72.37; H, 4.16; N, 13.33 found: C, 72.35; H, 4.14; N, 13.30.

Compound 3b. Yellow solid (290 mg, 88%); ¹H NMR (400 MHz, CDCl₃) δ: 8.29 (d, ³J_HH = 8.8 Hz, 2H), 8.01 (d, ³J_HH = 6.9 Hz, 1H), 7.65 (d, ³J_HH = 9.1 Hz, 1H), 7.59 (d, ³J_HH = 8.8 Hz, 2H), 7.40 (d, ³J_HH = 8.1 Hz, 2H), 7.21 (m, 1H), 7.06 (d, ³J_HH = 8.1 Hz, 2H), 6.76 (dt, ³J_HH = 6.8 Hz, ⁴J_HH = 1.1 Hz, 1H), 2.28 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ: 147.4, 145.7, 144.7, 138.1, 136.9, 131.0, 130.6, 129.3, 128.4, 125.5, 124.7, 122.7, 118.5, 118.0, 113.1, 21.3 ppm; anal. calcd for C₂₀H₁₅N₃O₂: C, 72.94; H, 4.59; N, 12.76 found: C, 72.90; H, 4.61; N, 12.71.

Compound 3c. Yellow solid (266 mg, 77%); ¹H NMR (400 MHz, CDCl₃) δ: 8.47 (d, ³J_HH = 8.5 Hz, 2H), 8.10 (d, ³J_HH = 6.7 Hz, 1H), 7.72 (d, ³J_HH = 9 Hz, 1H), 7.77 (d, ³J_HH = 8.5 Hz, 2H), 7.62 (d, ³J_HH = 8.5 Hz, 2H), 7.29 (t, ³J_HH = 7.5 Hz, 1H), 6.85–6.89 (m, 3H), 3.83 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ: 159.7, 147.3, 145.7, 144.5, 137.0, 131.0, 129.8, 125.9, 125.5, 124.7, 122.7, 118.1, 117.9, 114.0, 113.0, 55.3 ppm; anal. calcd for C₂₀H₁₅N₃O₃: C, 69.56; H, 4.38; N, 12.17 found: C, 69.59; H, 4.37; N, 12.13.

Compound 3d. Yellow solid (276 mg, 79%); ¹H NMR (400 MHz, CDCl₃) δ: 8.40 (d, ³J_HH = 8.8 Hz, 2H), 8.09 (d, ³J_HH = 8.1 Hz, 1H), 7.74 (d, ³J_HH = 9.0 Hz, 1H), 7.67 (d, ³J_HH = 8.8 Hz, 2H), 7.54 (d, ³J_HH = 8.6 Hz, 2H), 7.29–7.35 (m, 3H), 6.88 (dt, ³J_HH = 6.8 Hz, ⁴J_HH = 1.1 Hz, 1H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ: 147.6, 145.7, 143.3, 136.4, 134.2, 132.0, 131.1, 129.7, 128.8, 125.9, 124.9, 122.8, 118.9, 118.1, 113.3 ppm; anal. calcd for C₁₉H₁₂ClN₃O₂: C, 65.24; H, 3.46; Cl, 10.14; N, 12.01 found: C, 65.20; H, 3.47; Cl, 10.16; N, 12.04.

Compound 3e. Yellow solid (254 mg, 71%); ¹H NMR (400 MHz, CDCl₃) δ: 8.4 (d, ³J_HH = 8.7 Hz, 2H), 8.10 (d, ³J_HH = 6.9 Hz, 1H), 7.74 (d, ³J_HH = 9.1 Hz, 1H), 7.70 (d, ³J_HH = 8.2 Hz, 2H), 7.52 (d, ³J_HH = 8.2 Hz, 2H), 7.30 (t, ³J_HH = 6.8 Hz, 1H), 7.20 (d, ³J_HH = 8.2 Hz, 2H), 6.86 (t, ³J_HH = 6.8 Hz, 1H), 2.87–2.98 (m, 1H), 1.27 (d, ³J_HH = 6.9 Hz, 6H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ: 149.0, 147.4, 145.7, 144.6, 137.0, 131.1, 130.9, 128.4, 126.7, 125.5, 124.8, 122.7, 118.0, 113.0, 33.9, 23.9 ppm; anal. calcd for C₂₂H₁₉N₃O₂: C, 73.93; H, 5.36; N, 11.76 found: C, 73.95; H, 5.35; N, 11.79.

Compound 3f. Yellow solid (305 mg, 78%); ¹H NMR (400 MHz, CDCl₃) δ: 8.42 (d, ³J_HH = 8.8 Hz, 2H), 8.11 (d, ³J_HH = 6.9 Hz, 1H), 7.58–7.78 (m, 9H), 7.46 (t, ³J_HH = 7.6 Hz, 2H), 7.38 (d, ³J_HH = 7.3 Hz, 1H), 7.30–7.35 (m, 1H), 6.88 (dt, ³J_HH = 6.4 Hz, ⁴J_HH = 0.9 Hz, 1H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ: 147.6, 145.7, 143.3, 136.4, 134.2, 132.0, 131.1, 129.7, 128.8, 125.9, 124.9, 122.8, 118.9, 118.1, 113.3 ppm; anal. calcd for C₂₅H₁₇N₃O₂: C, 76.71; H, 4.38; N, 10.74 found: C, 76.73; H, 4.36; N, 10.77.

Compound 3g. Yellow solid (290 mg, 81%); ¹H NMR (400 MHz, CDCl₃) δ: 8.34 (d, ³J_HH = 8.6 Hz, 2H), 8.08 (d, ³J_HH = 6.9 Hz, 1H), 7.66–7.69 (m, 3H), 7.47 (d, ³J_HH = 8.8 Hz, 2H), 7.22–7.26 (m, 1H), 6.80 (t, ³J_HH = 6.8 Hz, 1H), 6.66 (d, ³J_HH = 8.8 Hz, 2H), 3.01 (s, 6H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ: 150.3, 147.1, 145.7, 145.2, 137.4, 131.0, 129.4, 125.2, 124.6, 122.5, 121.0, 117.6, 117.4, 112.7, 112.1, 40.3 ppm; anal. calcd for C₂₁H₁₈N₄O₂: C, 70.38; H, 5.06; N, 15.63 found: C, 70.41; H, 5.05; N, 15.61.

Compound 3h. Yellow solid (296 mg, 79%); ¹H NMR (400 MHz, CDCl₃) δ: 8.39 (d, ³J_HH = 8.8 Hz, 2H), 8.09 (d, ³J_HH = 6.9 Hz, 1H), 7.74 (d, ³J_HH = 9, 1H), 7.70 (d, ³J_HH = 8.8 Hz, 2H), 7.30–7.32 (m, 2H), 7.00 (dd, ³J_HH = 8.7 Hz, ⁴J_HH = 2 Hz, 1H), 6.86 (dt, ³J_HH = 5.8 Hz, ⁴J_HH = 1.1 Hz, 1H), 6.79 (d, ³J_HH = 8.4 Hz, 1H), 3.90 (s, 3H), 3.84 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ: 149.1, 147.3, 145.7, 144.5, 137.0, 131.2, 126.2, 125.6, 124.7, 122.7, 121.1, 117.9, 113.1, 11.5, 11.0, 55.9, 55.8 ppm; anal. calcd for C₂₁H₁₇N₃O₄: C, 67.19; H, 4.56; N, 11.19 found: C, 67.22; H, 4.54; N, 11.16.

Compound 3i. Yellow solid (324 mg, 82%); ¹H NMR (400 MHz, CDCl₃) δ: 8.33 (d, ³J_HH = 8.8 Hz, 2H), 8.04 (d, ³J_HH = 6.9 Hz, 1H), 7.67 (d, ³J_HH = 8.8 Hz, 3H), 7.23–7.27 (m, 1H), 6.81 (dt, ³J_HH = 6.9 Hz, ⁴J_HH = 1.1 Hz, 1H), 6.77 (s, 2H), 3.82 (s, 3H), 3.81 (s, 6H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ: 153.2, 147.3, 145.5, 144.1, 136.8, 131.3, 130.6, 128.8, 125.8, 124.5, 122.8, 117.8, 113.2, 105.6, 104.3, 56.2, 55.9; anal. calcd for C₂₂H₁₉N₃O₅: C, 65.18; H, 4.72; N, 10.37 found: C, 65.15; H, 4.71; N, 10.39.

Compound 3j. Yellow solid (257 mg, 67%); ¹H NMR (400 MHz, CDCl₃) δ: 7.86 (d, ³J_HH = 8.6 Hz, 1H), 7.60 (d, ³J_HH = 8.4 Hz, 3H), 7.50 (d, ³J_HH = 8.6 Hz, 2H), 7.25 (d, ³J_HH = 8.4 Hz, 2H), 7.14–7.21 (m, 3H), 6.70 (dt, ³J_HH = 6.8 Hz, ⁴J_HH = 1.1 Hz, 1H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ: 145.0, 141.6, 138.0, 133.0, 132.2, 131.7, 129.4, 128.7, 125.4, 123.1, 117.6, 112.9, 108.1, 105.7, 101.7 ppm; anal. calcd for C₁₉H₁₂BrClN₂: C, 59.48; H, 3.15; Br, 20.83; Cl, 9.24; N, 7.30 found: C, 59.45; H, 3.16; Br, 20.87; Cl, 9.26; N, 7.33.

Compound 3k. Yellow solid (236 mg, 65%); ¹H NMR (400 MHz, CDCl₃) δ: 7.96 (d, ³J_HH = 6.9 Hz, 1H), 7.67–7.71 (m, 3H), 7.55 (d, ³J_HH = 8.1 Hz, 2H), 7.36 (d, ³J_HH = 8.4 Hz, 2H), 7.21–7.25 (m, 1H), 7.14 (d, ³J_HH = 8.1 Hz, 2H), 6.78 (dt, ³J_HH = 6.8 Hz, ⁴J_HH = 1.0 Hz, 1H), 2.36 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ: 137.5, 132.8, 132.3, 131.7, 129.1, 129.0, 128.0, 124.8, 123.0, 117.6, 112.4, 21.3 ppm; anal. calcd for C₂₀H₁₅BrN₂: C, 66.13; H, 4.16; Br, 22.00; N, 7.71 found: C, 66.11; H, 4.14; Br, 22.05; N, 7.74.

Compound 3l. Yellow solid (256 mg, 70%); ¹H NMR (400 MHz, CDCl₃) δ: 8.02 (dd, ³J_HH = 4.9 Hz, ⁴J_HH = 0.9 Hz, 2H), 7.35–7.39 (m, 1H), 6.98 (d, ³J_HH = 1.9 Hz, 2H), 6.96 (d, ³J_HH = 1.9 Hz, 1H), 6.94 (d, ³J_HH = 1.9 Hz, 1H), 6.86 (d, ³J_HH = 8.3 Hz, 2H), 6.57–6.60 (m, 1H), 6.45 (d, ³J_HH = 8.3 Hz, 1H), 3.87 (s, 3H), 3.63 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ: 170.3, 158.5, 150.4, 149.0, 148.0, 137.7, 127.5, 120.4, 120.7, 119.8, 113.8, 110.9, 110.5, 109.2, 108.6, 66.9, 55.9 ppm; anal. calcd for C₂₁H₁₇ClN₂O₂: C, 69.14; H, 4.70; Cl, 9.72; N, 7.68 found: C, 69.11; H, 4.69; Cl, 9.70; N, 7.69.

Compound 3m. Yellow solid (247 mg, 71%); ¹H NMR (400 MHz, CDCl₃) δ: 8.04 (dd, ³J_HH = 8.0 Hz, ⁴J_HH = 1.0 Hz, 2H), 7.31–7.36 (m, 1H), 7.24–7.27 (m, 2H), 7.19 (s, 1H), 6.92–6.97 (m, 2H), 6.29 (d, ³J_HH = 8.4 Hz, 2H), 4.42 (s, 3H), 4.40 (s, 3H) ppm; 163.3, 158.5, 148.2, 137.4, 135.0, 129.0, 128.9, 124.3, 115.5, 115.3, 113.3, 106.9, 45.6 ppm; anal. calcd for C₂₁H₁₇FN₂O₂: C, 72.40; H, 4.92; F, 5.45; N, 8.04 found: C, 72.42; H, 4.90; F, 5.42; N, 8.08.

Compound 3n. Yellow solid (205 mg, 68%); ¹H NMR (400 MHz, CDCl₃) δ: 7.88 (d, ³J_HH = 6.9 Hz, 1H), 7.60 (d, ³J_HH = 9 Hz, 1H), 7.53 (d, ³J_HH = 8.9 Hz, 2H), 7.38–7.48 (m, 5H), 7.10–7.14 (m, 1H), 6.76 (d, ³J_HH = 8.9 Hz, 2H), 6.65 (dt, ³J_HH = 8 Hz, ⁴J_HH = 1.0 Hz, 1H), 3.73 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ: 159.1, 142.3, 130.8, 130.0, 129.6, 129.3, 128.8, 126.7, 124.6, 123.2, 117.3, 113.7, 112.2, 55.2 ppm; anal. calcd for C₂₀H₁₆N₂O: C, 79.98; H, 5.37; N, 9.33 found: C, 79.95; H, 5.36; N, 9.36.

Compound 3o. Yellow solid (214 mg, 65%); ¹H NMR (400 MHz, CDCl₃) δ: 8.38 (d, ³J_HH = 8.8 Hz, 2H), 8.14 (d, ³J_HH = 6.9 Hz, 1H), 7.69 (d, ³J_HH = 9.1 Hz, 1H), 7.63 (d, ³J_HH = 8.8 Hz, 2H), 7.18–7.30 (m, 5H), 6.85 (dt, ³J_HH = 6.8 Hz, ⁴J_HH = 1.1 Hz, 1H), 4.21 (s, 2H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ: 147.1, 145.6, 145.3, 139.5, 136.1, 129.8, 128.6, 128.5, 126.4, 125.3, 124.6, 123.0, 120.0, 118.0, 113.0, 34.3 ppm; anal. calcd for C₂₀H₁₅N₃O₂: C, 72.94; H, 4.59; N, 12.76 found: C, 72.96; H, 4.60; N, 12.78.

Compound 3p. Yellow-orange solid (173 mg, 48%); ¹H NMR (400 MHz, CDCl₃) δ: 8.36 (d, ³J_HH = 8.8 Hz, 2H), 8.10 (d, ³J_HH = 9.0 Hz, 2H), 7.95 (d, ³J_HH = 6.9 Hz, 1H), 7.70 (d, ³J_HH = 9.0 Hz, 2H), 7.67 (d, ³J_HH = 10.4 Hz, 1H), 7.60 (d, ³J_HH = 8.8 Hz, 2H), 7.27 (ddd, ³J_HH = 8.0 Hz, ⁴J_HH = 6.8 Hz, ⁵J_HH = 1.2 Hz, 1H), 6.82 (dt, ³J_HH = 6.8 Hz, ⁴J_HH = 1.2 Hz, 1H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ: 147.5, 146.5, 145.0, 140.3, 132.0, 128.6, 126.8, 124.8, 124.3, 123.9, 120.6, 117.3, 113.8 ppm; anal. calcd for C₁₉H₁₂N₄O₄: C, 63.33; H, 3.36; N, 15.55 found: C, 63.30; H, 3.35; N, 15.58.

Conclusions

In conclusion, a robust and versatile method for synthesis of imidazo[1,2-a]pyridine derivatives in water was developed. The presented method is the first example of synthesis of imidazo[1,2-a]pyridines that benefits from the reaction of two different salts in water as a safe and cheap reaction medium. The synthetic procedure is very simple and scalable and the final product is isolated via filtration and purified with crystallization from a suitable solvent. Additionally, an unusual result in the reaction of 2-amino-1-(4-nitrobenzyl)pyridinium 1a with DBU as a base in CH₃CN as a solvent was discovered. Further studies on the mechanistic clarification, scope, and synthetic utility of this finding are underway in our laboratory.

Acknowledgements

We are grateful to the University of Isfahan research council for partial support of this work.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1484156. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra17065j

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