One-pot, three component tandem reaction of 2-aminopyridines, acetophenones and aldehydes: synthesis of 3-aroylimidazo[1,2-a]pyridines

Abstract

A facile synthesis of 3-aroylimidazo[1,2-a]pyridine derivatives has been achieved through the one-pot, three-component tandem reaction of acetophenones, arylaldehydes and 2-aminopyridines in the presence of a catalytic amount of copper(II) chloride and air as the sole oxidant. The developed one-pot method is atom-economical and utilizes readily available precursors to offer highly functionalized N-fused imidazoles in moderate to good yields (26–82%). The presented tandem process is expected to proceed via crossed aldol condensation, Michael addition, copper catalyzed oxidative cyclization and subsequent aromatization.

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Introduction

Construction of bioactive fused heterocycles by exploiting transition metal catalyzed coupling reactions is a highly challenging and attractive task in organic synthesis.¹ Multicomponent reactions (MCRs) together with tandem sequences have been recognized as a powerful tool in modern organic chemistry for the synthesis of fused heterocycles with diverse substitutions.² The basic concepts of disconnections are generally overruled for the synthesis of molecules following the combination of MCRs and tandem processes. Several innovative strategies have been witnessed in last decade where coupling reactions have been amalgamated with MCRs/tandem reactions.³

In recent years, synthesis of imidazo[1,2-a]pyridines have gained great interest because of their significance in medicinal chemistry, material science and organometallics.⁴ Several drugs such as alpidem, zolpidem, zolimidine, saripidem, and necopidem (Fig. 1) contain imidazo[1,2-a]pyridine skeleton as a core with slight variations in substitutions. In addition, several novel molecules with imidazo[1,2-a]pyridine as a key structure have been synthesized and studied for their activity against various biological targets.⁵ Among them, 3-aroylimidazo[1,2-a]pyridines are the interesting structures with anticancer activities (Fig. 1).⁶ It has been reported that direct C-3 aroylation of imidazo[1,2-a]pyridine nucleus is unsuccessful and desired 3-aroylimidazo[1,2-a]pyridines were obtained in four-steps from 2-aminopyridine.^6a Aroyl functionality has also been reported to be highly responsible for the elevated biological applications of various other heterocycles.⁷ In this context, direct methods toward the synthesis of 3-aroylimidazo[1,2-a]pyridines is highly desirable.

Fig. 1 Bio-active molecules containing imidazo[1,2-a]pyridine skeleton.

2-Aminopyridine is the most common precursor for the syntheses of imidazo[1,2-a]pyridines. Recently, some interesting results have been obtained when 2-aminopyridine was reacted with carbonyl compounds in the presence of copper catalysts (Scheme 1).⁸ Several groups including ours have independently shown that 2-arylimidazo[1,2-a]pyridines are obtained by the reaction of 2-aminopyridine with methyl ketones in presence of catalytic amount of copper via imine formation followed by intramolecular oxidative cyclization (Scheme 1)⁹ and Su group reported that 2-alkenylimidazo[1,2-a]pyridines were obtained when 2-aminopyridine was reacted with methyl vinyl ketones in the presence of copper (Scheme 1).¹⁰

Scheme 1 Reaction of 2-aminopyridines with various carbonyl partners in the presence of copper.

Very recently, Hajra and our group¹¹ independently reported the copper catalyzed oxidative cyclization of chalcones and 2-aminopyridines for the synthesis of 3-aroylimidazo[1,2-a]pyridines. However, to the best of our knowledge there is no report available for the synthesis of 3-aroylimidazo[1,2-a]pyridines via one-pot, three-component tandem approach. With our continuous interest in synthesis and functionalizations of imidazo[1,2-a]pyridines,^9b,12 herein we wish to report an efficient synthesis of 3-aroylimidazo[1,2-a]pyridines via one-pot three-component copper catalyzed tandem reaction of acetophenones, arylaldehydes and 2-aminopyridines with air as a sole oxidant (Scheme 1).

Results and discussion

In our initial study, acetophenone (1a), benzaldehyde (2a) and 2-aminopyridine (3a) were chosen as model substrates for the screening of reaction conditions. Based on literature survey, several competing reactions could be expected with the present set of substrates and other parameters which includes 1,3-diphenyl-3-(pyridin-2-ylamino)propan-1-one (5a),¹¹ 2-phenylimidazo[1,2-a]pyridine (6a),^9b chalcone (7a), 2,4-diphenyl-1,8-naphthyridine (8a)¹³ (Scheme 2). With these concerns in mind, 1a (1.0 mmol) was treated with 2a (1.0 mmol) and 3a (1.0 mmol) in presence of CuCl₂·2H₂O in toluene for 12 h at reflux. As envisaged, moderate yields of expected product, phenyl(2-phenylimidazo[1,2-a]pyridin-3-yl)methanone (4a) was obtained along with other by-products such as 6a and 7a in minor quantities (entry 1, Table 1). However, Michael adduct (5a) and naphthyridine (8a) were not detected in the reaction mass. The structure of 4a was characterized by spectral data (IR, MS, and NMR). In the IR spectrum of 4a, a strong peak appeared at 1597 cm⁻¹ for C=O stretching. In the ¹H NMR spectrum of 4a, a doublet appeared at δ 9.60 ppm for highly deshielded C₅–H along with other protons at their respective positions. The ketonic carbon of 4a appeared at δ 187.34 along with all other expected carbons in the ¹³C NMR spectrum. The peak at 299.1162 for [M + H]⁺ ion in the HRMS mass spectrum of 4a further confirmed its structure.

Scheme 2 Competing reactions with selected set of precursors.

Table 1 Optimization of reaction conditions^a

Entry	Catalyst	Base	Solvent	Temp. (°C)	Yield^b (%)
a Reagents and conditions: 1a (1.0 mmol), 2a (1.2 mmol), 3a (1.2 mmol), catalyst (20 mol%), base (2.0 mmol), solvent (4 mL), 12 h, air.b Isolated yields.c No base was present in the reaction and 1a, 2a, and 3a were used 1 mmol each.d Starting materials were recovered.e 4a not detected.
1	CuCl2·2H2O	—^c	Toluene	120	35
2	CuCl2·2H2O	K2CO3	Toluene	120	38
3	CuCl2·2H2O	K2CO3	DMF	120	45
4	CuCl2·2H2O	K2CO3	DMF	150	81
5	CuCl2·2H2O	K2CO3	Water	Reflux	55
6	CuCl2·2H2O	K2CO3	DMA	150	72
7	CuCl2·2H2O	K2CO3	DMSO	150	63
8	CuCl2·2H2O	K2CO3	1,4-Dioxane	Reflux	—^d^,^e
9	CuCl2·2H2O	K2CO3	EtOH	Reflux	—^d^,^e
10	CuCl2·2H2O	Cs2CO3	DMF	150	52
11	CuCl2·2H2O	NaHCO3	DMF	150	—^d^,^e
12	CuCl2·2H2O	KOH	DMF	150	46
13	CuCl2·2H2O	K3PO4	DMF	150	64
14	Cu(OAc)2·H2O	K2CO3	DMF	150	38
15	Cu(OTf)2	K2CO3	DMF	150	66
16	CuBr	K2CO3	DMF	150	—^d^,^e
17	CuI	K2CO3	DMF	150	48

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To enhance the yields of tandem product, we turned our focus on minimization of unwanted products by varying the molar ratios of precursors. It was observed that the formation of by-product 6a could be reduced if rate of reaction between 1a and 2a to give 7a is faster than the rate of reaction between 1a and 3a. We succeeded in eliminating formation of 6a in the reaction by keeping 1a as a limiting agent with other substrates (2a and 3a) in 1.2 equivalents. Addition of K₂CO₃ to the reaction keeping other parameters same resulted in slight improvement in the yield of 4a (entry 2, Table 1). A smooth enhancement in yield of 4a was observed with DMF as solvent (entry 3, Table 1). With the encouraging result in hand, we next increased the reaction temperature to 150 °C keeping other parameters constant. Gratifyingly, excellent yield of 4a was observed at 150 °C (entry 4, Table 1). Among other solvents, good yields of 4a were obtained in polar solvents like DMA and DMSO (entries 6–7, Table 1) while moderate yields of 4a was obtained in water (entry 5, Table 1). Desired product 4a was not obtained when 1,4-dioxane and ethanol were used as solvents (entries 8–9, Table 1). Simultaneously, various bases were screened for the model reaction and the use of K₂CO₃ gave the optimum result for the tandem process among other bases like Cs₂CO₃, KOH and K₃PO₄ which also offered good yields of tandem products (entries 10 and 12–13, Table 1). However, no product was noticed in case of NaHCO₃ (entry 11, Table 1). Attempts were failed to replace the copper catalyst to facilitate higher yields of tandem products (entries 14–17, Table 1).

With the optimized conditions in hand (entry 4, Table 1), substrate scope for cascade process was evaluated and the results are summarized in Table 2. In early experiments, diversely substituted 2-aminopyridines were tested which offered moderate to good yields of 3-aroylimidazo[1,2-a]pyridines (entries 2–4 and 15, Table 2). It is worth to mention that highly sensitive bromo substitution, towards transition metal catalyzed transformations was well tolerated under the optimized conditions and afforded good yields of tandem product (entry 15, Table 2). Aryl aldehydes substituted with electron-withdrawing groups such as 4-Cl, 2-F and 4-NO₂ offered high yields of tandem products (entries 7–8 and 10–16, Table 2). On the other hand, reactions involving aryl aldehydes with electron rich substituents produced 2-arylimidazo[1,2-a]pyridines instead of tandem product (entry 17, Table 2). This may be due to the fact that under these reaction conditions, reaction of acetophenones and 2-aminopyridines is faster as compared to the tandem reaction to give corresponding 2-arylimidazo[1,2-a]pyridines.⁹ To our delight, heterocyclic ketones and aldehydes such as 2-acetylthiophene and thiophene-2-carbaldehyde reacted smoothly under the optimized conditions to give the corresponding tandem products in moderate yields (entries 6 and 9, Table 2).

Table 2 Substrate scope for one-pot, three-component tandem reaction for the synthesis of 3-aroylimidazo[1,2-a]pyridines^a

Entry	Ar^1	Ar^2	R	Product (4)	Yield^b (%)
a Reagents and conditions: 1a (1.0 mmol), 2a (1.2 mmol), 3a (1.2 mmol), CuCl2·2H2O (20 mol%), K2CO3 (2.0 mmol), DMF (4 mL), 150 °C, 12 h, air.b Isolated yields.c 4q was not formed.d 2-(p-Tolyl)imidazo[1,2-a]pyridine was isolated in 56% yield.
1	C6H5	C6H5	H		81
2	C6H5	C6H5	3-Me		62
3	C6H5	C6H5	4-Me		26
4	C6H5	C6H5	5-Me		63
5	3,4-(OMe)2C6H3	C6H5	H		47
6	2-Thienyl	C6H5	H		36
7	C6H5	4-ClC6H4	H		52
8	C6H5	4-NO2C6H4	H		76
9	C6H5	2-Thienyl	H		46
10	C6H5	4-ClC6H4	5-Me		82
11	4-ClC6H4	4-ClC6H4	H		63
12	4-ClC6H4	4-ClC6H4	5-Me		75
13	4-ClC6H4	2-FC6H4	H		45
14	4-ClC6H4	2-FC6H4	4-Me		42
15	4-ClC6H4	2-FC6H4	5-Br		51
16	4-OMeC6H4	4-NO2C6H4	H		44
17	4-MeC6H4	4-MeC6H4	H		—^c^,^d

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Next, we performed some control experiments to understand the synthetic sequence and plausible mechanism of the reported protocol (Scheme 3). In the absence of copper catalyst, no product formation was observed (eqn (1), Scheme 3) which confirmed the crucial role of copper catalyst for the successful formation of 4a. When the model reaction was performed under nitrogen atmosphere, only catalytic amount of product was formed which confirms the necessity of aerobic conditions for the current transformation (eqn (2), Scheme 3). Reaction performed in the presence of radical scavenger, (2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO), produced both tandem product 4a and 6a in 46% and 24% isolated yields, respectively (eqn (3), Scheme 3). It was concluded that both 4a and 6a are formed via a non-radical pathway as reported earlier for 6a.⁹ Two synthetic routes could be possible to attain the tandem product 4 from corresponding substrates (a) via chalcone intermediate and (b) via imine intermediate. However, formation of imine was not observed from the reaction of 2a with 3a in the absence of 1a under these conditions (eqn (5), Scheme 3). This excludes the possibility of imine as intermediate in this tandem process. In other experiment 1a and 2a were reacted under the same standard reaction condition to result chalcone (7a) which confirm the given reaction path (eqn (6), Scheme 3). Thus, it is believed that the probable pathway for this transformation is via chalcone intermediate which is formed through the crossed aldol condensation between 1a and 2a. This was further supported by the fact that reaction of pre-synthesized chalcone 7a with 3a under similar conditions afforded good yield of tandem product 4a (eqn (4), Scheme 3). It is important to mention that the yield of 4a was higher from tandem reaction than that of step-wise approach under these conditions.

Scheme 3 Control experiments.

Based on literature reports^3a,11a and findings from the control experiments, the mechanism of the tandem process for the synthesis of 3-aroylimidazo[1,2-a]pyridines is proposed as shown in Scheme 4. It is believed that initially chalcone (7) is generated by the crossed aldol condensation of 1 and 2 which then undergoes Michael addition with 3 to afford intermediate 5. Interaction of 5 with copper salt through pyridinium nitrogen and enolic carbon simultaneously affords intermediate 9.^11a Oxidation of copper(II) to copper(III)^9a,14 gives intermediate 10, which on reductive elimination may result in the formation dihydro imidazopyridine 11. Rapid aromatization of intermediate 11 under aerobic conditions affords the desired product 4. Oxidation of Cu(I) to Cu(II) in the presence of air completes the catalytic cycle.¹⁵ Reaction of 2-aminopyridine (3) with methylketones (1) in presence of copper results in the formation of 2-arylimidazo[1,2-a]pyridines (6).⁹

Scheme 4 Plausible mechanism for the synthesis of 3-aroylimdazo[1,2-a]pyridines.

Experimental section

General

Melting points were determined in open capillary tubes on a EZ-Melt Automated melting point apparatus and are uncorrected. Reactions were monitored by using thin layer chromatography (TLC) on 0.2 mm silica gel F₂₅₄ plates (Merck). The chemical structures of final products were determined by their NMR spectra (¹H and ¹³C NMR). Chemical shifts are reported in parts per million (ppm) using deuterated solvent peak or tetramethylsilane as an internal standard. The HRMS data were recorded on a mass spectrometer with electrospray ionization and TOF mass analyzer. IR spectra were recorded on a FTIR spectrophotometer and the ν_max is expressed in cm⁻¹. All chemicals were obtained from the commercial suppliers and used without further purification.

General procedure for synthesis of 4a

An oven-dried 10 mL RB flask was charged with acetophenone (120 mg, 1.0 mmol), benzaldehyde (122 mg, 1.2 mmol), 2-aminopyridine (113 mg, 1.2 mmol), K₂CO₃ (276 mg, 2.0 mmol), CuCl₂·2H₂O (34 mg, 20 mol%) and DMF (4 mL). The resulting solution was stirred at 150 °C for 12 h. On completion of the reaction, the reaction mass was allowed to cool to ambient temperature and then diluted with water (10 mL). The mixture was extracted with EtOAc (2 × 10 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and evaporated to dryness. The crude residue so obtained was purified by column chromatography (EtOAc–hexane) to afford 4a in 81% (241 mg) yield.

Phenyl(2-phenylimidazo[1,2-a]pyridin-3-yl)methanone (4a). Yield 81%; colorless solid; mp 124–127 °C; ¹H NMR (300 MHz, CDCl₃) δ 9.60 (d, J = 7.0 Hz, 1H), 7.86 (d, J = 8.9 Hz, 1H), 7.64–7.49 (m, 3H), 7.37 (dd, J = 7.8, 1.4 Hz, 2H), 7.35–7.30 (m, 1H), 7.22–7.08 (m, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 187.3, 155.0, 147.4, 138.7, 134.0, 131.7, 130.2, 129.5, 129.2, 128.3, 128.2, 127.7, 120.0, 117.5, 114.6; IR (KBr): 3070, 1597, 1388, 1326, 1218 cm⁻¹; HRMS (ESI) calcd for C₂₀H₁₅N₂O 299.1179 found 299.1162 [M + H]⁺.

(8-Methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)(phenyl)methanone (4b). Yield 62%; colorless solid; mp 140–143 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.43 (d, J = 4.9 Hz, 1H), 7.51 (d, J = 6.5 Hz, 2H), 7.38–7.32 (m, 3H), 7.30–7.22 (m, 1H), 7.15–7.06 (m, 5H), 7.04–6.98 (m, 1H), 2.75 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 187.5, 154.6, 147.7, 138.9, 134.4, 131.7, 130.4, 129.6, 128.2, 127.8, 127.8, 127.6, 126.1, 120.6, 114.7, 17.2; IR (KBr): 3063, 1606, 1466, 1388, 1250, 910, 702 cm⁻¹; HRMS (ESI) calcd for C₂₁H₁₇N₂O 313.1335 found 313.1352 [M + H]⁺.

(7-Methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)(phenyl)methanone (4c). Yield 26%; off-white solid; mp 137–140 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.52 (d, J = 3.0 Hz, 1H), 7.63 (s, 1H), 7.56 (d, J = 6.2 Hz, 2H), 7.41–7.28 (m, 3H), 7.20–7.11 (m, 5H), 7.01 (d, J = 0.9 Hz, 1H), 2.59 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 187.1, 155.4, 147.9, 140.9, 138.8, 134.2, 131.6, 130.2, 129.1, 128.2, 127.7, 127.7, 127.5, 117.1, 116.1, 21.6; IR (KBr): 3060, 1605, 1466, 1396, 918, 694 cm⁻¹; HRMS (ESI) calcd for C₂₁H₁₇N₂O 313.1335 found 313.1321 [M + H]⁺.

(6-Methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)(phenyl)methanone (4d). Yield 63%; colorless solid; mp 156–158 °C ¹H NMR (400 MHz, CDCl₃) δ 9.38 (s, 1H), 7.71 (d, J = 8.9 Hz, 1H), 7.51 (d, J = 7.2 Hz, 2H), 7.38 (d, J = 8.9 Hz, 1H), 7.31 (d, J = 6.7 Hz, 2H), 7.29–7.22 (m, 1H), 7.14–7.04 (m, 5H), 2.45 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 187.4, 154.9, 146.5, 138.8, 134.2, 132.2, 131.7, 130.2, 129.6, 128.2, 127.8, 127.8, 126.2, 124.6, 119.9, 116.7, 18.6; IR (KBr): 3063, 1605, 1466, 1389, 903, 733 cm⁻¹; HRMS (ESI) calcd for C₂₁H₁₇N₂O 313.1335 found 313.1348 [M + H]⁺.

(3,4-Dimethoxyphenyl)(2-phenylimidazo[1,2-a]pyridin-3-yl)methanone (4e). Yield 47%; gummy mass; ¹H NMR (400 MHz, CDCl₃) δ 9.29 (d, J = 7.0 Hz, 1H), 7.72 (d, J = 8.9 Hz, 1H), 7.44–7.39 (m, 1H), 7.34 (dd, J = 7.5, 1.7 Hz, 2H), 7.19 (dd, J = 8.4, 1.8 Hz, 1H), 7.11–7.06 (m, 3H), 7.05 (d, J = 1.8 Hz, 1H), 6.98 (t, J = 6.9 Hz, 1H), 6.52 (d, J = 8.4 Hz, 1H), 3.74 (s, 3H), 3.58 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 186.0, 153.4, 152.5, 148.3, 147.3, 134.2, 131.1, 130.1, 128.7, 128.4, 128.0, 127.9, 124.5, 119.9, 117.4, 114.3, 112.4, 110.0, 56.0, 55.7; IR (KBr): 3073, 2947, 1605, 1466, 1389, 1227, 913, 733 cm⁻¹; HRMS (ESI) calcd for C₂₂H₁₉N₂O₃ 359.1390 found 359.1385 [M + H]⁺.

Phenyl(2-(thiophen-2-yl)imidazo[1,2-a]pyridin-3-yl)methanone (4f). Yield 36%; pale yellow solid; mp 122–124 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.17 (d, J = 7.0 Hz, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.45 (dd, J = 6.6, 2.9 Hz, 2H), 7.43–7.36 (m, 2H), 7.18–7.12 (m, 3H), 7.02 (dd, J = 3.7, 0.7 Hz, 1H), 6.98–6.92 (m, 1H), 6.63–6.55 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 178.8, 153.2, 147.2, 143.6, 134.5, 134.2, 133.1, 130.0, 128.8, 128.5, 128.1, 127.8, 127.4, 119.8, 117.5, 114.3; IR (KBr): 3078, 2947, 1589, 1466, 1389, 1227, 795, 756, 733 cm⁻¹; HRMS (ESI) calcd for C₁₈H₁₃N₂OS 305.0743 found 305.0749 [M + H]⁺.

(2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl)(phenyl)methanone (4g). Yield 52%; off-white solid; mp 132–134 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.55 (dt, J = 7.0, 1.1 Hz, 1H), 7.82 (d, J = 9.0, 1H), 7.59–7.54 (m, 1H), 7.54–7.52 (m, 1H), 7.51 (d, J = 1.3 Hz, 1H), 7.38–7.32 (m, 1H), 7.28 (t, J = 1.5 Hz, 1H), 7.27–7.25 (m, 1H), 7.18–7.12 (m, 3H), 7.10–7.08 (m, 1H), 7.07–7.05 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 187.2, 153.5, 147.4, 138.5, 134.5, 132.5, 132.0, 131.4, 129.4, 129.4, 128.3, 182.0, 120.1, 117.5, 114.8; IR (KBr): 3070, 1605, 1489, 1466, 1389, 1327, 1227, 933, 748 cm⁻¹; HRMS (ESI) calcd for C₂₀H₁₄ClN₂O 333.0789 found 333.0795 [M + H]⁺.

(2-(4-Nitrophenyl)imidazo[1,2-a]pyridin-3-yl)(phenyl)methanone (4h). Yield 76%; pale yellow solid; mp 241–243 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 9.42 (d, J = 6.9 Hz, 1H), 7.98–7.89 (m, 3H), 7.78–7.69 (m, 1H), 7.57 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 7.2 Hz, 2H), 7.41–7.28 (m, 2H), 7.19–7.16 (m, 2H); ¹³C NMR (101 MHz, DMSO-d₆) δ 186.7, 151.7, 147.2, 147.1, 141.2, 138.9, 132.5, 131.6, 130.7, 130.6, 129.9, 128.4, 128.4, 123.0, 117.9, 116.1; IR (KBr): 3078, 1605, 1512, 1466, 1389, 1250, 1227, 856, 748 cm⁻¹; HRMS (ESI) calcd for C₂₀H₁₄N₃O₃ 344.1030 found 344.1025 [M + H]⁺.

(2-Phenylimidazo[1,2-a]pyridin-3-yl)(thiophen-2-yl)methanone (4i). Yield 46%; off-white solid; mp 118–120 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.30 (d, J = 7.0 Hz, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.62–7.57 (m, 2H), 7.46–7.40 (m, 1H), 7.37–7.28 (m, 1H), 7.21–7.19 (m, 1H), 7.18–7.16 (s, 1H), 7.17–7.15 (m, 1H), 6.98 (td, J = 6.9, 1.2 Hz, 1H), 6.63–6.58 (m, 1H), 6.56–6.54 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 187.1, 147.5, 147.2, 138.6, 135.8, 132.3, 130.1, 129.5, 129.3, 128.2, 128.0, 127.7, 127.2, 117.3, 114.6, 100.0; IR (KBr): 3078, 2947, 1603, 1466, 1389, 1227, 748, 756 cm⁻¹; HRMS (ESI) calcd for C₁₈H₁₃N₂OS 305.0743 found 305.0746 [M + H]⁺.

(2-(4-Chlorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl)(phenyl)methanone (4j). Yield 82%; off-white solid; mp 148–150 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.35 (s, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.50 (d, J = 7.2 Hz, 2H), 7.39 (dd, J = 9.1, 1.5 Hz, 1H), 7.33 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.14 (t, J = 7.7 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 2.45 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 187.1, 153.4, 146.4, 138.7, 134.3, 132.7, 132.3, 131.9, 131.3, 129.6, 127.9, 126.1, 124.8, 119.9, 116.7, 18.5; IR (KBr): 3089, 2947, 1612, 1458, 1389, 1227, 1088, 795, 733 cm⁻¹; HRMS (ESI) calcd for C₂₁H₁₆ClN₂O 347.0946 found 347.0956 [M + H]⁺.

(4-Chlorophenyl)(2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methanone (4k). Yield 63%; off-white solid; mp 192–194 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.51 (dt, J = 7.0, 1.1 Hz, 1H), 7.81–7.79 (m, 1H), 7.61–7.53 (m, 1H), 7.49–7.43 (m, 2H), 7.30–7.24 (m, 2H), 7.17–7.09 (m, 5H); ¹³C NMR (101 MHz, CDCl₃) δ 185.7, 153.6, 147.5, 138.5, 136.9, 134.9, 132.4, 131.4, 130.9, 129.6, 128.2, 128.2, 119.9, 117.6, 115.0; IR (KBr): 3086, 1612, 1496, 1404, 1335, 1227, 795, 756 cm⁻¹; HRMS (ESI) calcd for C₂₀H₁₃Cl₂N₂O 367.0399 found 367.0387 [M + H]⁺.

(4-Chlorophenyl)(2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl)methanone (4l). Yield 75%; off-white solid; mp 154–156 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.32 (d, J = 1.8, Hz, 1H), 7.71 (dd, J = 9.1, 0.5 Hz, 1H), 7.48–7.45 (m, 1H), 7.45–7.39 (m, 2H), 7.28–7.23 (m, 2H), 7.15–7.10 (m, 4H), 2.46 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 185.6, 153.5, 146.5, 138.3, 137.2, 134.7, 132.6, 132.5, 131.3, 130.9, 128.2, 128.1, 126.1, 125.0, 119.7, 116.8, 18.5; IR (KBr): 3063, 2955, 1605, 1466, 1381, 1335, 1242, 957, 764 cm⁻¹; HRMS (ESI) calcd for C₂₁H₁₅Cl₂N₂O 381.0556 found 381.0551 [M + H]⁺.

(4-Chlorophenyl)(2-(2-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methanone (4m). Yield 45%; off-white solid; mp 144–146 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.58 (d, J = 6.6 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.64–7.53 (m, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 5.4 Hz, 1H), 7.21–7.05 (m, 4H), 6.74 (t, J = 9.0 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 185.75, 159.11 (d, J = 248.7 Hz), 148.4, 147.7, 137.8, 136.9, 131.2 (d, J = 2.4 Hz), 130.9, 130.9 (d, J = 8.3 Hz), 129.3, 128.2, 127.7, 124.2 (d, J = 3.5 Hz), 122.8, 122.7, 120.9, 117.6, 115.2 (d, J = 22.0 Hz), 115.0; IR (KBr): 3055, 2924, 1612, 1481, 1389, 1227, 1080, 764 cm⁻¹; HRMS calcd for C₂₀H₁₃ClFN₂O 351.0695 found 351.0698 [M + H]⁺.

(4-Chlorophenyl)(2-(2-fluorophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methanone (4n). Yield 42%; off-white solid; mp 147–149 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.45 (d, J = 7.1 Hz, 1H), 7.59 (s, 1H), 7.49 (td, J = 7.4, 1.7 Hz, 1H), 7.45–7.40 (m, 2H), 7.26–7.19 (m, 1H), 7.12–7.04 (m, 3H), 7.00–6.96 (m, 1H), 6.75–6.65 (m, 1H), 2.54 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 185.6, 159.2 (d, J = 248.7 Hz), 148.8, 148.2, 141.1, 137.6, 137.0, 131.2 (d, J = 2.5 Hz), 130.8 (d, J = 8.3 Hz), 130.5, 127.6, 127.5, 124.1 (d, J = 3.5 Hz), 123.0, 122.8, 120.6, 117.5, 116.2, 115.2 (d, J = 22.0 Hz), 21.6; IR (KBr): 3055, 2965, 1612, 1481, 1227, 1076, 764 cm⁻¹; HRMS calcd for C₂₁H₁₅ClFN₂O 365.0851 found 365.0835 [M + H]⁺.

(6-Bromo-2-(2-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)(4-chlorophenyl)-methanone (4o). Yield 51%; off-white solid; mp 173–175 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.71 (s, 1H), 7.73 (d, J = 9.3 Hz, 1H), 7.63 (d, J = 9.4 Hz, 1H), 7.53 (t, J = 6.9 Hz, 1H), 7.45 (d, J = 7.4 Hz, 2H), 7.24 (d, J = 5.4 Hz, 1H), 7.15–7.05 (m, 3H), 6.71 (t, J = 9.1 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 185.7, 159.1 (d, J = 249.1 Hz), 148.3, 146.1, 138.2, 136.4, 136.4, 132.7, 131.2 (d, J = 6.4 Hz), 131.1, 130.4, 128.3, 127.8, 124.3 (d, J = 3.5 Hz), 122.3 (d, J = 14.0 Hz), 120.9, 118.1, 115.3 (d, J = 22.0 Hz), 109.9; IR (KBr): 3101, 3055, 2924, 1612, 1481, 1389, 1227, 1080, 764 cm⁻¹; HRMS calcd for C₂₀H₁₂BrClFN₂O 428.9800 found 428.9822 [M + H]⁺.

(4-Methoxyphenyl)(2-(4-nitrophenyl)imidazo[1,2-a]pyridin-3-yl)methanone (4p). Yield 44%; pale yellow solid; mp 199–201 °C ¹H NMR (400 MHz, CDCl₃) δ 9.38 (s, 1H), 8.07 (d, J = 6.9 Hz, 2H), 7.87 (d, J = 8.7 Hz, 1H), 7.67–7.57 (m, 5H), 7.18–7.16 (m, 1H), 6.70 (d, J = 6.8 Hz, 2H), 3.80 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 185.6, 163.4, 150.3, 147.2, 147.2, 140.7, 132.0, 130.9, 130.8, 129.2, 127.9, 123.0, 120.6, 117.7, 114.9, 113.5, 55.5; IR (KBr): 3109, 3070, 2222, 1612, 1512, 1478, 1342, 1026, 756 cm⁻¹; HRMS calcd for C₂₁H₁₆N₃O₄ 374.1135 found 374.1123 [M + H]⁺.

Conclusions

In summary, we have developed a straightforward method for the synthesis of 3-aroylimidazo[1,2-a]pyridines through one-pot, three-component tandem reaction. This protocol makes the use of simple and readily available precursors like acetophenones, aldehydes and 2-aminopyridines to deliver highly functionalized bio-active imidazo[1,2-a]pyridines in single step. Atom and step-economy, use of economically attractive and readily available precursors, simple isolation procedures, moderate to good yields of tandem products, air as a sole oxidant, and good functional group tolerance are the salient features of the method.

Acknowledgements

Authors sincerely acknowledge Council of Scientific and Industrial Research (CSIR), New Delhi [02(0115)/13/EMR-II] and Department of Science and Technology, New Delhi [DST-FIST, CSI-174/2008] for the financial support. PK and HKS are thankful to CSIR, New Delhi for junior research fellowship. KP is thankful to UGC, New Delhi for senior research fellowship.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Characterization data for 6a, copies of ¹H NMR and ¹³C NMR spectra for compounds 4a–p and 6a are available. See DOI: 10.1039/c4ra13056a

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