Microwave assisted novel and regioselective functionalization of imidazopyridines with chromene acetals and β-nitrostyrenes

Abstract

A facile synthesis of novel functionalized imidazopyridines has been accomplished through the condensation of imidazopyridines with chromene hemiacetals or β-nitro styrenes with high regioselectivity and excellent yields in the presence of a catalytic amount of PTSA or InCl₃. In this process, the reaction appears to be very general and suitable for direct functionalization of imidazopyridines. In our present method we successfully achieved regioselectivity.

---

Introduction

Imidazo[1,2-a]pyridines¹ (IPs) are found in many natural products and pharmaceuticals which exhibit a wide range of biological activities like antibacterial,² antifungal,³ antiviral,⁴ antitumorous,⁵ and anti-inflammatory⁶ properties. Drug formulations⁷ containing imidazopyridines currently available on the market include alpidem (anxiolytic), zolpidem (hypnotic), and zolimidine (anti-ulcer) (Fig. 1). Owing to their importance in the pharmaceutical and agrochemical fields, the syntheses of these structural units have attracted the attention of chemists. Imidazopyridines are generally synthesized via condensation of 2-aminopyridines with α-haloketones, β-nitro styrenes and aromatic alkynes.⁸ The biological activities of IPs have proved to be greatly dependent on substituents at the C2 and C3 positions. To introduce further diversity at C3 position, various groups reported metal-catalyzed cross-coupling reactions such as Suzuki,⁹ Stille,¹⁰ Heck,¹¹ Sonogashira,¹² Negishitype¹³ type reactions. However, these reactions require a halogenated precursor, which makes the sequence length and increases waste production. IP is known to be an electron-rich aromatic ring¹⁴ that could lead to electrophilic aromatic substitutions at C3. However, the Friedel–Crafts alkylation remains challenging and requires an excess of electrophilic reagent and strong temperature conditions. Many groups synthesized C3-alkylated products via electrophilic formylation and nitration of imidazopyridines followed by multistep conversions to furnish desired product.¹⁵ Recently Chaubet et al.¹⁶ have reported aza-Friedel–Crafts reaction in the presence of thiamine, HCl. Subsequently, Pericherla et al.¹⁷ have reported C3-functionalization of IPs in the presence of Yb(OTf)₃ via aza-Friedel–Crafts reaction. There does not appear to be a large effort for C3-alkylation of imidazo[1,2-a]pyridines, which is probably due to the lack of practical synthetic methodologies to access these compounds.

Fig. 1 Some biologically active molecules of IPs and 4H-chromenes.

In this context a general, flexible and practical approach for C3-functionalization of imidazopyridines is highly desirable.

Chromenes (2H-chromenes and 4H-chromenes) are one of the major classes of naturally occurring compounds.¹⁸ During the past decade many groups have focused on their chemistry because of their utility as biologically active agents¹⁹ such as β-cell KATP channel openers, DNA-dependent protein kinase(DNA-PK), DNA polymerase β inhibitors, anti-tyrpanosomal agents, anti-bacterial, apoptosis inducers, and their utility as key intermediates in the synthesis of numerous natural products and medicinal reagents.²⁰ Microwave-assisted reactions have found wide applications as an efficient way to accelerate many organic reactions. Microwave radiation is an energy source whose applications in organic synthesis are well established.²¹ This approach can produce high yields, modifications in the selectivity, lowering of side products, and easier work-up and purification of products.²² Because of the promising biological activity of imidazopyridine and 4H-chromenes, we have envisioned to construct novel hybrid molecules in single compound. To the best of our knowledge there has never been a report of C3-functionalization of imidazopyridine with chromene acetals and β-nitro styrenes. In continuation of our work²³ on chromene compounds herein we wish to report C3-functionalization of imidazopyridines with β-nitro styrenes and chromene hemiacetals in presence of acid catalyst under microwave irradiation (Scheme 1).

Scheme 1 Synthesis of novel alkyl/4H-chromene substituted imidazopyridines.

Results and discussion

Initially we have chosen 2H-chromene hemiacetal as electrophilic substrate. The model reaction of imidazopyridine (2a) (1 mmol) with chromene hemiacetal (1a) (1 mmol) under MW irradiation at 120 °C in water which did not proceed even after 30 minutes. Further we planned the same reaction in presence of acid catalysts like scandium triflate (Sc(OTf)₃), indium chloride (InCl₃), bismuth chloride (BiCl₃), montmorillonite KSF clay, zinc chloride (ZnCl₂), aluminium chloride (AlCl₃), iodine (I₂), ruthenium chloride (RuCl₃), cyanuric acid, p-toluenesulfonic acid (PTSA) and camphor sulphonic acid (CSA) and summarized the results in Table 1. Among the screened acid catalysts PTSA gave the best results in terms of yield and time. Next, the effect of solvent was studied and tetrahydrofuran was found to be the best for this transformation.

Table 1 Screening of catalysts for the synthesis of new functionalized imidazopyridines^a

S. no	Catalyst	Solvent	Time (min)	Yield^b (%)
a Reaction conditions: 2H-chromene (1a) (1 mmol), imidazopyridine (1 mmol) (2a) and catalyst stirred in appropriate solvent.b Isolated yield of pure product.
1	—	H2O	30	—
2	Sc(OTf)3 (5 mol%)	DMF	10	49
3	InCl3 (5 mol%)	DMF	20	56
4	BiCl3 (5 mol%)	THF	20	28
5	KSF-clay (>100 mol%)	THF	30	10
6	ZnCl2 (10 mol%)	DMF	15	43
7	AlCl3 (10 mol%)	THF	10	52
8	I2 (10 mol%)	THF	25	45
9	RuCl3 (15 mol%)	DMF	20	15
10	Cyanuric acid (15 mol%)	THF	15	29
11	PTSA (10 mol%)	THF	10	85
12	PTSA (10 mol%)	DMF	10	69
13	PTSA (5 mol%)	DCE	10	71
14	CSA (10 mol%)	THF	20	35

---

Having established the optimum conditions, the scope of C3-functionalization was investigated (Table 2). The halogen substituted (Br, Cl) 2H-chromenes proceeded smoothly to furnish the required product (4d, 4g) in good yield. Whereas, the unsubstituted chromene gave moderate yield (4a) of product. Similarly chromene having with electron withdrawing groups like NO₂ or di-halogen substituents reacted slowly in optimized conditions to give the corresponding product (4j) in low yield. During the reaction it was observed that the ester group at C3 position also influences the reaction. For example the reaction of chromenes possessing t-butyl ester group at C3 position went smoothly and furnished the alkylated IP product (4h) in good yield. Whereas, the chromenes with methyl and ethyl esters at C3 position gave the required product in moderate yield (4b). Chromenes with benzoyl and acetyl groups at C3 position gave the product in comparatively low yield. We observed that there is no effect of the substituent at C2 position on the efficiency of the reaction and yield of the product.

Table 2 Scope of substrates for the synthesis of 4H-chromene substituted imidazopyridines^a,b

a 2H-chromene (1 mmol), imidazopyridine (1 mmol) and PTSA (5 mol%) were added in 1 ml of THF and kept under microwave irradiation for 10–20 minutes.b Isolated yield of pure product.

---

We observed that there is no effect of the substituent at C2 position on the efficiency of the reaction and yield of the product. Inspired by these results we intended to apply the reaction of imidazopyridine with other activated alkenes. As a model reaction we performed the reaction of imidazopyridine with β-nitro styrene in presence of PTSA under optimized conditions, but the reaction did not give positive results. Then the same reaction was performed using different acid catalysts like Sc(OTf)₃, InCl₃, BiCl₃, ZnCl₂, FeCl₃. Among the screened catalysts InCl₃ (5 mol%) was turnout as good catalyst for optimum yield in o-xylene (Table 4). It was observed that electronic effect of substituent have considerable influence on the reaction. For example electron donating groups like CH₃, Cl and F possessing styrenes proceeded smoothly and gave the desired product (Table 3, 4n, 4o, 4q) in good yield. Whereas, styrenes with electron withdrawing group like NO₂ went slowly and furnished the C3 alkylated product in low yield. We have performed the reaction of IP with styrene of nitro ethane, produced as mixture of diastereomers (50 : 50) (4x) in equal ratio.

Table 3 Scope of substrates for the synthesis of novel functionalised imidazopyridines^a,b

a Imidazopyridine (1 mmol), β-nitro styrene and InCl₃ (5 mol%) were added in 1 ml of o-xylene and kept under microwave irradiation for 10–20 minutes.b Isolated yield of pure product.

---

Table 4 Screening of catalysts for the synthesis of novel functionalized imidazopyridines^a

Entry	Catalyst	Solvent	Time (min)	Yield^b (%)
a Reaction conditions: β-nitrostyrene (3a) (1 mmol), imidazopyridine (2a) (1 mmol) and catalyst stirred in appropriate solvent.b Isolated yield of pure product.
1	Sc (OTf)3 (5 mol%)	DMF	10	59
2	BiCl3 (5 mol%)	THF	20	38
3	InCl3 (5 mol%)	o-Xylene	20	85
4	InCl3 (10 mol%)	o-Xylene	20	84
5	FeCl3 (5 mol%)	Toluene	20	23
6	ZnCl2 (10 mol%)	DMF	15	14
7	PTSA (5 mol%)	THF	10	5
8	InCl3 (5 mol%)	THF	20	63
9	InCl3 (5 mol%)	Toluene	20	70
10	InCl3 (5 mol%)	CH3CN	20	53
11	InCl3 (5 mol%)	1,4-Dioxane	20	59

---

We have attempted the reaction of imidazopyridines with other Michael acceptors like isatin chalcone, cyclohexenone, benzylideneacetophenone, (E)-methyl 4-oxo-4-phenylbut-2-enoate and (E)-4-phenylbut-3-en-2-one. The results were not satisfactory. The reaction was not proceeded under optimized conditions (Scheme 3, see in ESI†).

Plausible mechanism

Initially chromene acetal in presence of acid catalyst (p-toluenesulfonic acid or InCl₃) forms more stable oxacarbenium cation, which has two reactive sites (C2 & C4). Imidazopyridine selectively attacks at C4 position (which has less steric hindrance) followed by elimination of hydrogen to give novel functionalized imidazopyridines. On the other hand indium metal activates C3 position of imidazopyridine which undergo reaction with β-nitrostyrene to give C3-functionalized imidazopyridines (Scheme 2).

Scheme 2 A plausible mechanism.

Conclusion

We have reported a new strategy for direct regio selective functionalisation imidazopyridines via C–C bond formation with chromene hemiacetals and β-nitrostyrenes in presence of acid catalyst. Operational simplicity, oxidant-free, environmentally benign reaction conditions, and scalability are the attractive features of the present protocol. This work also brings oxocarbenium ions into the realm of viable electrophilic substrates for organic synthesis. We anticipate that this mode of catalysis will find use in related reactions of imidazopyridines with activated alkenes and electrophiles for the synthesis of various functionalized imidazopyridines.

Experimental section

General information

Salicylaldehydes, β-diketones, β-keto esters, amino pyridine, phenacyl bromide, PTSA, InCl_3, nitromethane, nitroethane, aldehydes and all solvents were purchased from Sigma Aldrich and Alpha Aesar company and used without further purification as received. All ¹H and ¹³C NMR spectra were recorded in CDCl₃ on Avance 300 or Avance 500 spectrometers. Chemical shifts (δ) are reported in parts per million (ppm) relative to residual CHCl₃ (¹H: δ 7.26 ppm, ¹³C: δ 77.00 ppm) as an internal reference. Coupling constants (J) are reported in Hertz (Hz). Peak multiplicity is indicated as follows: s—singlet, d—doublet, t—triplet, q—quartet, m—multiplet and dd—doublet of doublet. Melting points were measured on a BUCHI melting point machine. IR spectra were recorded on Thermo Nicolet FT/IR-5700 spectrometer. Mass spectra were recorded using waters mass spectrometer. High resolution mass spectrums (HRMS) were recorded using Applied Bio-Sciences HRMS spectrometer at national center for mass spectroscopy-IICT.

General procedure

Microwave irradiation experiment. All microwave irradiation experiments were carried out in a dedicated CEM-Discover monomode microwave apparatus, operating at a frequency of 2.45 GHz with continuous irradiation power from 0 to 300 W with utilization of the standard absorbance level of 300 W maximum power. A sealed 10 ml glass tube containing 2H-chromene (1a) (1 mmol), imidazopyridine (2a) (1 mmol) and PTSA (5 mol%) in 1 ml of THF kept under microwave irradiation for 10 minutes at 80 °C as mentioned in Table 1. After completion of the reaction (indicated by TLC) removed solvent and the crude product was purified by column chromatography using ethyl acetate/hexane to get pure compounds as white or pale yellow crystals. The isolated compounds were well characterized by IR, ¹H NMR, ¹³C NMR and HRMS.

Characterisation data for the products

Methyl 2-methyl-4-(2-phenylimidazo[1,2-a]pyridin-3-yl)-4H-chromene-3-carboxylate (4a). White solid; Mp 118–120 °C; IR: ν_max 2926, 1706, 1640, 1583, 1486, 1361, 1213, 1062, 757, 697 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.86 (d, J = 5.4 Hz, 3H), 7.61 (d, J = 9.0 Hz, 1H), 7.36–7.52 (m, 3H), 6.93–7.23 (m, 5H), 6.68 (t, J = 6.8 Hz, 1H), 6.07 (s, 1H), 3.29 (s, 3H), 2.41 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 167.0, 160.2, 149.6, 144.6, 144.1, 135.0, 128.7, 128.6, 128.3, 127.7, 124.9, 124.0, 123.2, 122.2, 120.1, 117.7, 116.2, 112.3, 101.4, 51.2, 31.1, 19.1; m/z (ESI); 397 [M + H]⁺.

Ethyl 2-methyl-4-(2-phenylimidazo[1,2-a]pyridin-3-yl)-4H-chromene-3-carboxylate (4b). White solid; Mp 124–126 °C; IR: ν_max 2931, 1705, 1647, 1580, 1474, 1359, 1211, 1056, 759, 699 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.78–7.99 (m, 3H), 7.41–7.49 (m, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.38 (t, J = 7.3 Hz, 1H), 7.10–7.21 (m, 2H), 6.99–7.06 (m, 2H), 6.98–6.93 (m, 1H), 6.71 (t, J = 6.6 Hz, 1H), 6.08 (s, 1H), 3.88–3.95 (m, 1H), 3.78–3.70 (m, 1H), 2.37 (s, 3H), 0.77 (t, J = 7.1 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 166.6, 159.7, 149.5, 144.5, 143.9, 134.9, 128.7, 128.6, 128.5, 128.3, 127.7, 124.8, 124.0, 123.3, 122.4, 120.3, 117.7, 116.2, 112.3, 101.8, 60.2, 31.0, 19.1, 13.6; m/z (ESI); 411 [M + H]⁺. HRMS calcd for C₂₆H₂₃O₃N₂: 411.17032, found: 411.17029.

Ethyl 6-chloro-2-methyl-4-(2-phenylimidazo[1,2-a]pyridin-3-yl)-4H-chromene-3-carboxylate (4c). White solid; Mp 131–133 °C; IR: ν_max 3038, 2969, 2924, 1707, 1633, 1470, 1362, 1302, 1231, 1144, 1065, 809, 704 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 7.87–7.97 (m, 1H), 7.69–7.80 (m, 2H), 7.63 (d, J = 9.0 Hz, 1H), 7.38.7.59 (m, 3H), 7.13–7.25 (m, 2H), 6.95–7.02 (m, 2H), 6.80 (t, J = 6.3 Hz, 1H), 5.99 (s, 1H), 3.31 (s, 3H), 2.37 (s, 3H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 165.9, 159.2, 147.4, 143.8, 143.6, 143.5, 134.0, 128.7, 128.1, 127.9, 127.6, 127.2, 127.1, 123.7, 122.4, 121.2, 117.1, 116.9, 112.0, 100.5, 50.6, 30.2, 18.4; m/z (ESI); 431 [M + H]⁺. HRMS calcd for C₂₆H₂₀O₃N₂Cl: 431.15070, found: 431.1501.

Ethyl 6-chloro-2-methyl-4-(2-phenylimidazo[1,2-a]pyridin-3-yl)-4H-chromene-3-carboxylate (4d). White solid; Mp 134–136 °C; IR: ν_max 3032, 2956, 2922, 1704, 1637, 1469, 1352, 1314, 1225, 1143, 1066, 808, 701 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 7.90–7.90 (m, 1H), 7.70–7.80 (m, 2H), 7.64 (d, J = 8.8 Hz, 1H), 7.35.7.49 (m, 3H), 7.11–7.21 (m, 2H), 6.98 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 6.75 (t, J = 6.6 Hz, 1H), 6.00 (s, 1H), 3.87–3.96 (m, 1H), 3.70–3.80 (m, 1H), 2.34 (s, 3H), 0.78 (t, J = 7.1 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ δ 165.7, 158.9, 147.5, 143.9, 143.6, 134.1, 128.9, 128.3, 128.1, 127.8, 127.4, 127.3, 123.8, 122.6, 121.7, 117.3, 117.2, 112.1, 101.0, 59.8, 30.4, 18.5, 13.1; m/z (ESI); 445 [M + H]⁺.

tert-Butyl 6-chloro-2-methyl-4-(2-phenylimidazo[1,2-a]pyridin-3-yl)-4H-chromene-3-carboxylate (4e). White solid; Mp 196–198 °C; IR: ν_max 3040, 2975, 2928, 1710, 1643, 1482, 1361, 1309, 1229, 1159, 1060, 813, 696 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 8.08 (d, J = 6.8 Hz, 1H), 7.62–7.75 (m, 3H), 7.32–7.47 (m, 3H), 7.11–7.23 (m, 2H), 6.92–6.99 (m, 2H), 6.78 (t, J = 6.8 Hz, 1H), 5.90 (s, 1H), 2.17 (s, 3H), 1.01 (s, 9H); ¹³C NMR (75 MHz, CDCl₃): δ 165.7, 156.7, 148.1, 144.5, 144.3, 134.5, 129.3, 128.7, 128.3, 127.8, 127.7, 124.2, 123.2, 122.4, 117.8, 112.4, 103.4, 81.0, 31.2, 27.5, 18.5; m/z (ESI); 473 [M + H]⁺. HRMS calcd for C₂₈H₂₆O₃N₂Cl: 473.16265, found: 431.16259.

Methyl 6-bromo-2-methyl-4-(2-phenylimidazo[1,2-a]pyridin-3-yl)-4H-chromene-3-carboxylate (4f). White solid; Mp 130–132 °C; IR: ν_max 3028, 1716, 1652, 1477, 1432, 1219, 1072, 741, 694 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.72–7.90 (m, 3H), 7.64 (d, J = 9.1 Hz, 1H), 7.37–7.53 (m, 3H), 7.25–7.32 (m, 1H), 7.13–7.22 (m, 2H), 6.90 (d, J = 8.7 Hz, 1H), 6.73 (t, J = 6.8 Hz, 1H), 6.00 (s, 1H), 3.28 (s, 3H), 2.38 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 166.6, 159.8, 146.6, 144.6, 144.4, 134.7, 131.7, 131.1, 128.6, 128.3, 127.8, 124.2, 123.0, 122.3, 121.7, 117.9, 117.8, 117.2, 112.5, 101.3, 51.3, 30.9, 19.0; m/z (ESI); 475 [M + H]⁺. HRMS calcd for C₂₅H₂₀O₃N₂Br: 475.06518, found: 475.06480.

Ethyl 6-bromo-2-methyl-4-(2-phenylimidazo[1,2-a]pyridin-3-yl)-4H-chromene-3-carboxylate (4g). White solid; Mp 138–140 °C; IR: ν_max 3031, 1712, 1648, 1466, 1424, 1208, 1075, 743, 699 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.91–7.99 (m, 1H), 7.72–7.80 (m, 2H), 7.64 (dt, J₁ = 9.0 Hz, J₂ = 1.0 Hz, 1H), 7.42–7.49 (m, 2H), 7.36–7.42 (m, 1H), 7.27–7.30 (m, 1H), 7.12–7.21 (m, 2H), 6.89 (d, J = 8.7 Hz, 1H), 6.76 (t, J = 6.8 Hz, 1H), 6.01 (s, 1H), 3.86–3.96 (m, 1H), 3.69–3.78 (m, 1H), 0.77 (t, J = 7.1 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 166.2, 159.4, 148.6, 144.5, 144.2, 134.7, 131.7, 131.0, 128.6, 128.4, 127.8, 124.2, 123.1, 122.6, 118.0, 117.9, 117.0, 112.5, 101.8, 60.4, 30.9, 19.0, 13.6; m/z (ESI); 489 [M + H]⁺. HRMS calcd for C₂₆H₂₂O₃N₂Br: 489.08083, found: 489.08083.

Tert-butyl 6-bromo-2-methyl-4-(2-phenylimidazo[1,2-a]pyridin-3-yl)-4H-chromene-3-carboxylate (4h). White solid; Mp 201–203 °C; IR: ν_max 3043, 1715, 1646, 1479, 1435, 1223, 1069, 747, 700 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 8.08 (d, J = 6.0 Hz, 1H), 7.62–7.75 (m, 3H), 7.28–7.49 (m, 4H), 7.20 (t, J = 8.3 Hz, 1H), 7.11 (s, 1H), 6.90 (d, J = 8.7 Hz, 1H), 6.79 (t, J = 8.7 Hz, 1H), 5.90 (s, 1H), 2.16 (s, 3H), 1.00 (s, 9H); ¹³C NMR (75 MHz, CDCl₃): δ 165.7, 156.7, 148.7, 144.5, 144.4, 134.5, 131.7, 130.7, 128.7, 127.9, 124.3, 123.3, 122.9, 118.2, 117.8, 116.8, 112.4, 103.6, 81.1, 31.1, 27.6, 18.6; m/z (ESI); 517 [M + H]⁺.

1-(6-Bromo-2-methyl-4-(2-phenylimidazo[1,2-a]pyridin-3-yl)-4H-chromen-3-yl)ethanone (4i). White solid; Mp 146–148 °C; IR: ν_max 3035, 1719, 1657, 1482, 1445, 1223, 1068, 749, 698 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.93 (d, J = 6.4 Hz, 1H), 7.70–7.77 (m, 2H), 7.65 (d, J = 9.1 Hz, 1H), 7.46–7.51 (m, 2H), 7.42 (t, J = 7.3 Hz, 1H), 7.33 (dd, J₁ = 6.6 Hz, J₂ = 1.4 Hz, 1H), 7.24–7.26 (m, 1H), 7.17–7.22 (m, 1H), 6.93 (d, J = 8.7 Hz, 1H), 6.75 (t, J = 6.6 Hz, 1H), 5.99 (s, 1H), 2.21 (s, 3H), 1.79 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 198.9, 156.1, 148.8, 144.9, 144.4, 134.3, 131.9, 130.8, 128.7, 128.6, 128.3, 124.8, 123.1, 122.4, 118.2, 117.9, 117.1, 112.8, 110.9, 31.2, 29.4, 19.2; m/z (ESI); 459 [M + H]⁺. HRMS calcd for C₂₅H₂₀O₂N₂Br: 459.07027, found: 475.07063.

Ethyl 2-methyl-6-nitro-4-(2-phenylimidazo[1,2-a]pyridin-3-yl)-4H-chromene-3-carboxylate (4j). White solid; Mp 153–155 °C; IR: ν_max 3027, 2934, 1705, 1637, 1585, 1472, 1366, 1224, 1068, 762, 692 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 8.11–8.21 (m, 1H), 8.06 (dd, J₁ = 9.1 Hz, J₂ = 2.45 Hz, 1H), 7.87 (d, J = 2.1 Hz, 1H), 7.48–7.70 (m, 3H), 7.34–7.47 (m, 3H), 7.25 (t, J = 8.1 Hz, 1H), 7.10 (d, J = 9.1 Hz, 1H), 6.88 (t, J = 6.8 Hz, 1H), 6.01 (s, 1H), 3.77–4.01 (m, 2H), 2.33 (s, 3H), 0.82 (t, J = 7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 165.3, 158.2, 153.1, 144.4, 143.9, 143.6, 133.9, 128.3, 127.8, 127.5, 124.1, 123.8, 122.5, 121.7, 117.3, 116.8, 112.4, 102.2, 60.1, 30.3, 18.4, 13.2; m/z (ESI); 456 [M + H]⁺.

Tert-butyl 6,8-dichloro-2-methyl-4-(2-phenylimidazo[1,2-a]pyridin-3-yl)-4H-chromene-3-carboxylate (4k). White solid; Mp 184–186 °C; IR: ν_max 3035, 2954, 2928, 1709, 1645, 1453, 1367, 1306, 1211, 1135, 1058, 803, 703 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 8.11 (d, J = 6.0 Hz, 1H), 7.94 (d, J = 1.5 Hz, 1H), 7.67 (d, J = 9.1 Hz, 1H), 7.51–7.60 (m, 2H), 7.33–7.46 (m, 3H), 7.15–7.26 (m, 2H), 6.85 (t, J = 6.8 Hz, 1H), 5.82 (s, 1H), 2.19 (s, 3H), 1.02 (s, 9H); ¹³C NMR (75 MHz, CDCl₃): δ 165.7, 156.9, 148.9, 145.9, 144.8, 144.5, 136.8, 134.3, 128.7, 128.3, 128.0, 124.4, 124.0, 123.2, 117.9, 112.7, 104.5, 87.6, 85.8, 81.3, 31.4, 27.6, 18.5; m/z (ESI); 507 [M + H]⁺.

(6-Bromo-2-phenyl-4-(2-phenylimidazo[1,2-a]pyridin-3-yl)-4H-chromen-3-yl) (phenyl)methanone (4l). White solid; Mp 176–180 °C; IR: ν_max 3057, 1665, 1637, 1475, 1312, 1227, 1179, 970, 751, 698 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 8.22 (d, J = 7.0 Hz, 1H), 7.53–7.63 (m, 3H), 7.30–7.46 (m, 9H), 7.12–7.23 (m, 5H), 7.12–7.22 (m, 3H), 6.95–7.05 (m, 1H), 6.23 (s, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 195.4, 153.3, 149.5, 145.3, 144.9, 136.6, 133.9, 133.0, 132.6, 131.9, 130.9, 129.9, 128.8, 128.7, 128.5, 128.3, 128.1, 128.0, 127.9, 125.9, 125.5, 124.6, 123.3, 122.1, 119.6, 118.4, 117.9, 117.5, 117.1, 112.5, 112.3, 110.3, 108.1, 33.4; m/z (ESI); 583 [M + H]⁺. HRMS calcd for C₃₅H₂₄O₂N₂Br: 583.09952, found: 583.10188.

3-(2-Nitro-1-phenylethyl)-2-phenylimidazo[1,2-a]pyridine (4m). Semi solid; IR: ν_max 3056, 2932, 2848, 1551, 1530, 1434, 1347, 745, 725 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.72 (d, J = 7.0 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.59–7.63 (m, 2H), 7.39–7.46 (m, 3H), 7.27–7.36 (m, 3H), 7.16–7.22 (m, 2H), 6.72 (dt, J₁ = 5.9 Hz, J₂ = 0.9 Hz, 1H), 5.61 (t, J = 7.6 Hz, 1H), 5.07 (dd, J₁ = 7.6, Hz, J₂ = 5.6 Hz, 1H), 4.95 (dd, J₁ = 7.6 Hz, J₂ = 5.6 Hz 1H); ¹³C NMR (75 MHz, CDCl₃): δ 145.3, 145.1, 135.9, 129.4, 129.1, 128.5, 128.4, 128.1, 126.8, 124.8, 123.3, 117.9, 116.6, 112.8, 76.4, 39.1; m/z (ESI); 344 [M + H]⁺. HRMS calcd for C₂₁H₁₈O₂N₃: 344.13935, found: 344.13955.

3-(1-(4-Chlorophenyl)-2-nitroethyl)-2-phenylimidazo[1,2-a]pyridine (4n). Semi solid; IR: ν_max 3051, 2933, 2847, 1556, 1509, 1434, 1348, 731, 707 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.66–7.71 (m, 2H), 7.55–7.59 (m, 2H), 7.31–7.34 (m, 2H), 7.22–7.26 (m, 1H), 7.11–7.16 (m, 2H), 6.78 (t, J = 7.5 Hz, 1H), 5.57 (t, J = 7.6 Hz, 1H), 5.03 (dd, J₁ = 7.6, Hz, J₂ = 5.3 Hz, 1H), 4.93 (dd, J₁ = 7.3 Hz, J₂ = 5.9 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 145.4, 145.2, 134.6, 134.2, 134.0, 129.7, 129.1, 128.7, 128.3, 125.1, 123.1, 118.1, 116.2, 113.1, 76.5, 38.8; m/z (ESI); 378 [M + H]⁺. HRMS calcd for C₂₁H₁₇O₂N₃Cl: 378.10038, found: 378.10067.

3-(1-(4-Fluorophenyl)-2-nitroethyl)-2-phenylimidazo[1,2-a]pyridine (4o). Semi solid; IR: ν_max 3045, 2928, 2844, 1561, 1524, 1439, 1346, 739, 713 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.67–7.72 (m, 2H), 7.57–7.61 (m, 2H), 7.41–7.49 (m, 3H), 7.22–7.26 (m, 1H), 7.16–7.20 (m, 2H), 7.02–7.08 (m, 2H), 6.78 (dt, J₁ = 5.6 Hz, J₂ = 1.2 Hz, 1H), 5.57 (t, J = 7.6 Hz, 1H), 5.03 (dd, J₁ = 8.1, Hz, J₂ = 5.0 Hz, 1H), 4.94 (dd, J₁ = 7.2 Hz, J₂ = 6.1 Hz 1H); ¹³C NMR (75 MHz, CDCl₃): δ 145.4, 145.2, 134.2, 131.9, 131.8, 129.2, 128.7, 128.6, 124.9, 123.1, 118.2, 116.6, 116.4, 112.9, 76.7, 38.7; m/z (ESI); 362 [M + H]⁺. HRMS calcd for C₂₁H₁₇O₂N₃F: 362.12993, found: 362.13026.

3-(2-Nitro-1-(4-nitrophenyl)ethyl)-2-phenylimidazo[1,2-a]pyridine (4p). Semi solid; IR: ν_max 3042, 2924, 2853, 1555, 1523, 1442, 1351, 732, 703 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 8.11–8.16 (m, 1H), 8.07–8.10 (m, 1H), 7.79 (d, J = 7.0 Hz, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.48–7.55 (m, 4H), 7.40–7.47 (m, 3H), 7.24–7.30 (m, 1H), 6.83 (t, J = 6.9 Hz, 1H), 5.67 (t, J = 7.6 Hz, 1H), 5.13 (dd, J₁ = 8.2, Hz, J₂ = 5.3 Hz, 1H), 5.02 (dd, J₁ = 7.2 Hz, J₂ = 6.4 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 148.7, 145.8, 145.2, 138.3, 133.8, 133.2, 130.4, 129.1, 128.7, 128.6, 125.2, 123.2, 122.7, 121.8, 118.2, 115.5, 113.4, 75.9, 38.8; m/z (ESI); 389 [M + H]⁺. HRMS calcd for C₂₁H₁₇O₄N₄: 389.12443, found: 389.12451.

3-(2-Nitro-1-(p-tolyl)ethyl)-2-phenylimidazo[1,2-a]pyridine (4q). Semi solid; IR: ν_max 3038, 2931, 2865, 1558, 1517, 1438, 1360, 741, 709 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.72 (d, J = 7.0 Hz, 1H), 7.68 (d, J = 9.0 Hz, 1H), 7.60–7.64 (m, 1H), 7.39–7.47 (m, 3H), 7.18–7.24 (m, 2H), 7.11–7.18 (m, 2H), 7.07–7.11 (m, 2H), 6.74 (t, J = 6.9 Hz, 1H), 5.57 (t, J = 7.6 Hz, 1H), 5.04 (dd, J₁ = 7.6 Hz, J₂ = 5.5 Hz, 1H), 4.94 (dd, J₁ = 7.63 Hz, J₂ = 5.65 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 145.3, 145.1, 137.9, 134.3, 132.9, 130.1, 129.2, 128.5, 128.4, 126.7, 124.7, 123.3, 118.0, 116.7, 112.7, 76.7, 38.9, 20.9; m/z (ESI); 358 [M + H]⁺.

3-(1-(Naphthalen-2-yl)-2-nitroethyl)-2-phenylimidazo[1,2-a]pyridine (4r). Semi solid; IR: ν_max 3043, 2955, 2923, 2854, 1634, 1550, 1502, 1371, 1236, 923, 780, 730 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.97–8.04 (m, 1H), 7.89–7.94 (m, 1H), 7.81–7.84 (m, 1H), 7.74–7.78 (m, 1H), 7.60–7.69 (m, 3H), 7.51–7.56 (m, 2H), 7.35–7.48 (m, 5H), 7.11–7.22 (m, 1H), 6.70 (dt, J₁ = 5.8 Hz, J₂ = 1.1 Hz, 1H), 6.19–6.25 (m, 1H), 5.19 (dd, J₁ = 9.1 Hz, J₂ = 5.13 Hz, 1H), 5.07 (dd, J₁ = 6.1 Hz, J₂ = 8.1 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 145.5, 145.1, 134.6, 134.3, 130.9, 130.7, 129.5, 129.4, 128.6, 128.5, 127.4, 126.3, 125.3, 125.1, 124.7, 123.2, 121.9, 118.0, 116.3, 112.9, 74.8, 37.1; m/z (ESI); 394 [M + H]⁺. HRMS calcd for C₂₅H₂₀O₂N₃: 394.15500, found: 394.15495.

3-(1-(2-Bromophenyl)-2-nitroethyl)-2-phenylimidazo[1,2-a]pyridine (4s). Semi solid; IR: ν_max 3034, 2915, 2858, 1553, 1521, 1427, 1336, 730, 715 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.87 (d, J = 7.0 Hz, 1H), 7.67 (d, J = 9.0 Hz, 1H), 7.61–7.65 (m, 1H), 7.43–7.47 (m, 2H), 7.35–7.42 (m, 3H), 7.22–7.26 (m, 1H), 7.13–7.19 (m, 2H), 7.08–7.12 (m, 1H), 6.82–6.87 (m, 1H), 5.71 (dd, J₁ = 5.8 Hz, J₂ = 3.8 Hz, 1H), 4.97 (dd, J₁ = 9.6 Hz, J₂ = 4.9 Hz, 1H), 4.84 (dd, J₁ = 8.7 Hz, J₂ = 5.8 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 145.4, 144.7, 134.8, 134.6, 133.8, 129.8, 129.5, 128.9, 128.5, 128.3, 128.1, 124.9, 124.3, 122.9, 117.8, 115.9, 113.0, 74.2, 39.8; m/z (ESI); 422 [M + H]⁺.

3-(1-(2-Fluorophenyl)-2-nitroethyl)-2-phenylimidazo[1,2-a]pyridine (3t). Semi solid; IR: ν_max 3040, 2927, 2859, 1546, 1511, 1423, 1369, 747, 717 cm⁻¹; ¹H NMR (300 MHz, CDCl₃ + DMSO): δ 7.76–7.86 (m, 1H), 7.55–7.71 (m, 5H), 7.39–7.54 (m, 3H), 7.23–7.37 (m, 3H), 7.06 (dt, J₁ = 5.8 Hz, J₂ = 0.9 Hz, 1H), 5.93 (t, J = 7.9 Hz, 1H), 5.24–5.41 (m, 2H); ¹³C NMR (75 MHz, CDCl₃ + DMSO): δ 161.2, 157.9, 144.2, 143.9, 133.5, 129.2, 129.1, 128.3, 127.4, 124.0, 123.8, 122.8, 122.2, 122.0, 116.7, 115.4, 115.1, 114.9, 112.0, 73.9, 32.9; m/z (ESI); 362 [M + H]⁺.

3-(2-Nitro-1-(thiophen-2-yl)ethyl)-2-phenylimidazo[1,2-a]pyridine (4u). Semi solid; IR: ν_max 3049, 2931, 2858, 1540, 1509, 1424, 1355, 747, 715 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.80 (d, J = 6.9 Hz, 1H), 7.68 (d, J = 9.0 Hz, 1H), 7.63–7.66 (m, 2H), 7.39–7.48 (m, 3H), 7.20–7.26 (m, 2H), 6.96–7.00 (m, 1H), 6.88–6.91 (m, 1H), 6.75–6.80 (m, 1H), 5.81 (t, J = 7.6 Hz, 1H), 5.11 (dd, J₁ = 7.6 Hz, J₂ = 5.5 Hz, 1H), 4.94 (dd, J₁ = 7.5 Hz, J₂ = 5.6 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 145.3, 139.6, 133.8, 129.0, 128.6, 128.5, 127.4, 125.8, 125.1, 124.9, 123.4, 118.0, 116.2, 112.8, 76.3, 35.6; m/z (ESI); 350 [M + H]⁺.

3-(1-(4-Methoxyphenyl)-2-nitroethyl)-2-phenylimidazo[1,2-a]pyridine (4v). Semi solid; IR: ν_max 3031, 2924, 2853, 1552, 1505, 1431, 1367, 744, 712 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.72 (d, J = 7.0 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.60–7.64 (m, 2H), 7.38–7.46 (m, 3H), 7.17–7.22 (m, 1H), 7.10 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 6.72 (t, J = 6.9 Hz, 1H), 5.54 (t, J = 7.6 Hz, 1H), 5.02 (dd, J₁ = 8.1 Hz, J₂ = 5.0 Hz, 1H), 4.92 (dd, J₁ = 7.5 Hz, J₂ = 5.6 Hz, 1H), 3.76 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 159.2, 145.1, 145.0, 134.2, 129.1, 128.5, 128.4, 127.9, 127.7, 124.7, 123.3, 117.9, 116.8, 114.7, 112.7, 76.7, 55.2, 38.6; m/z (ESI); 374 [M + H]⁺.

3-(1-(Benzo[d][1,3]dioxol-5-yl)-2-nitroethyl)-2-phenylimidazo[1,2-a]pyridine (4w). Semi solid; IR: ν_max 3029, 2933, 2857, 1552, 1522, 1440, 1353, 745, 706 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 7.75 (d, J = 6.9 Hz, 1H), 7.67 (d, J = 9.0 Hz, 1H), 7.59–7.63 (m, 2H), 7.39–7.48 (m, 3H), 7.19–7.24 (m, 1H), 6.73–6.77 (m, 2H), 6.66–6.69 (m, 1H), 6.64 (d, J = 1.7 Hz, 1H), 5.92 (s, 2H), 5.48 (t, J = 7.6 Hz, 1H), 4.98 (dd, J₁ = 7.9 Hz, J₂ = 5.2 Hz, 1H), 4.89 (dd, J₁ = 7.3 Hz, J₂ = 5.8 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 148.7, 147.4, 145.0, 134.2, 129.6, 129.2, 128.5, 124.8, 123.3, 119.9, 117.9, 116.6, 112.8, 108.8, 107.4, 101.4, 76.7, 39.1; m/z (ESI); 388 [M + H]⁺.

3-(1-(4-Methoxyphenyl)-2-nitropropyl)-2-phenylimidazo[1,2-a]pyridine (4x). Semi solid; IR: ν_max 3034, 2931, 2865, 1558, 1517, 1438, 1360, 741, 709 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 8.09 (d, J = 7.0 Hz, 1H), 7.85 (d, J = 7.0 Hz, 1H), 7.72–7.76 (m, 2H), 7.67 (d, J = 7.6 Hz, 1H), 7.56–7.62 (m, 3H), 7.41–7.54 (m, 6H), 7.16–7.23 (m, 4H), 7.09 (d, J = 8.7 Hz, 2H), 6.78–6.85 (m, 5H), 6.73–6.78 (m, 1H), 5.49–5.60 (m, 2H), 5.37 (d, J = 11.1 Hz, 1H), 5.04 (d, J = 10.8 Hz, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 1.55 (d, J = 6.6 Hz, 3H), 1.32 (d, J = 6.7 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 159.1, 159.0, 145.4, 145.1, 144.9, 144.7, 134.9, 134.3, 129.7, 129.2, 129.0, 128.7, 128.5, 128.3, 128.1, 127.7, 124.7, 124.5, 123.4, 123.2, 118.2, 118.1, 117.9, 117.4, 114.6, 114.4, 112.9, 112.5, 84.2, 83.5, 55.2, 55.1, 45.4, 44.1, 19.5, 19.4; m/z (ESI); 388 [M + H]⁺.

Acknowledgements

The authors thank CSIR, New Delhi, for financial support as part of XII. Five Year Plan Program under the title ORIGIN (CSC-0108) and Dr A. Kamal, outstanding scientist and Head of MCP Division, for his support and encouragement. L. C. R. and N. S. K. thank CSIR for the award of a fellowship.

Notes and references

1. D. P. Becker, D. L. Flynn, A. E. Moormann, R. Nosal, C. I. Villamil, R. Loeffler, G. W. Gullikson, C. Moummi and D. C. Yang, J. Med. Chem., 2006, 49, 1125; R. Abou-Jneid, S. Ghoulami, M. T. Martin, E. T. H. Dau, N. Travert and A. Al-Mourabit, Org. Lett., 2004, 6, 3933.
2. Y. Rival, G. Grassy and G. Michel, Chem. Pharm. Bull., 1992, 40, 1170.
3. Y. Rival, G. Grassy, A. Taudou and R. Ecalle, Eur. J. Med. Chem., 1991, 26, 13.
4. (a) C. Hamdouchi, J. de Blas, M. del Prado, J. Gruber, B. A. Heinz and L. Vance, J. Med. Chem., 1999, 42, 50; (b) M. Lhassani, O. Chavignon, J. M. Chezal, J. C. Teulade, J. P. Chapat, R. Snoeck, G. Andrei, J. Balzarini, E. D. Clercq and A. Gueiffier, Eur. J. Med. Chem., 1999, 34, 271; (c) J. B. Veron, H. Allouchi, C. Enguehard-Gueiffier, R. Snoeck, G. Andrei, E. De Clercq and A. Gueiffier, Bioorg. Med. Chem., 2008, 16, 9536.
5. (a) M. Andaloussi, E. Moreau, N. Masurier, J. Lacroix, R. C. Gaudreault, J. M. Chezal, A. El Laghdach, D. Canitrot, E. Debiton, J. C. Teulade and O. Chavignon, Eur. J. Med. Chem., 2008, 43, 2505; (b) T. Cupido, P. G. Rack, A. J. Firestone, J. M. Hyman, K. Han, S. Sinha, C. A. Ocasio and J. K. Chen, Angew. Chem., Int. Ed., 2009, 48, 2321.
6. K. C. Rupert, J. R. Henry, J. H. Dodd, S. A. Wadsworth, D. E. Cavender, G. C. Olini, B. Fahmy and J. J. Siekierka, Bioorg. Med. Chem. Lett., 2003, 13, 347.
7. S. M. Hanson, E. V. Morlock, K. A. Satyshur and C. Czajkowski, J. Med. Chem., 2008, 51, 7243.
8. (a) S. Santra, S. Mitra, A. K. Bagdi, A. Majee and A. Hajra, Tetrahedron Lett., 2014, 55, 5151; (b) H. Yan, Y. Wang, C. Pan, H. Zhang, S. Yang, X. Ren, J. Li and G. Huang, Eur. J. Org. Chem., 2014, 13, 2754; (c) U. Makoto, N. Takahiro and T. Hideo, J. Org. Chem., 2013, 68, 6424; (d) H. Chuan, H. Jing, X. Huan, M. Yiping, L. Huiying, H. Juanjuan and L. Aiwen, Chem. Commun., 2012, 48, 11073; (e) H. Huawen, J. Xiaochen, T. Xiaodong, Z. Min, L. Xianwei and J. Huanfeng, Org. Lett., 2013, 15, 6254.
9. (a) J. G. Kettle, S. Brown, C. Crafter, B. R. Davies, P. Dudley, G. Fairley, P. Faulder, S. Fillery, H. Greenwood, J. Hawkins, M. James, K. Johnson, C. D. Lane, M. Pass, J. H. Pink, H. Plant and S. C. Cosulich, J. Med. Chem., 2012, 55, 1261; (b) S. El KAzzouli, S. Berteina-Raboin, A. Mouaddib and G. Guillaumet, Lett. Org. Chem., 2012, 9, 118; (c) F. Bischoff, D. Berthelot, M. De Cleyn, G. MacDonald, G. Minne, D. Oehlrich, S. Pieters, M. Surkyn, A. A. Trabanco, G. Tresadern, S. Van Brandt, I. Velter, M. Zaja, H. Borghys, C. Masungi, M. Mercken and H. J. M. Gijsen, J. Med. Chem., 2012, 55, 9089.
10. (a) A. M. Palmer, B. Grobbel, C. Jecke, C. Brehm, P. J. Zimmermann, W. Buhr, M. P. Feth, W. A. Simon and W. Kromer, J. Med. Chem., 2007, 50, 6240; (b) G. M. Buckley, R. Rosbeary, J. L. Fraser, L. Gowers, C. R. Groom, A. P. Higueruelo, L. A. James, K. Jenkins, S. R. Mack, T. Morgan, D. Parry, W. R. Pitt, O. Rausch, M. D. Richard and S. Verity, Bioorg. Med. Chem. Lett., 2008, 18, 3656.
11. (a) C. Enguehard-Gueiffier, C. Croix, M. Hervet, J.-Y. Kazock, A. Gueiffier and M. Abarbri, Helv. Chim. Acta, 2007, 90, 2349; (b) Z. Bahlaouan, M. Abarbri, A. Duchene, J. Thibonnet, N. Henry, C. Enguehard-Gueiffier and A. Gueiffier, Org. Biomol. Chem., 2011, 9, 1212; (c) S. El Kazzouli, A. G. du Bellay, S. Berteina-Raboin, P. Delagrange, D.-H. Caignard and G. Guillaumet, Eur. J. Med. Chem., 2011, 46, 4252.
12. A. El Akkaoui, I. Bassoude, J. Koubachi, S. Berteina-Raboin, A. Mouaddib and G. Guillaumet, Tetrahedron, 2011, 67, 7128.
13. (a) Y. Pan, C. P. Holmes and D. Tumelty, J. Org. Chem., 2005, 70, 4897; (b) M. Alam, R. E. Beevers, T. Ceska, R. J. Davenport, K. M. Dickson, M. G. Mara, H. A. F. Lewis, L. A. James, M. W. Jones, N. Kinsella, C. Lowe, J. W. G. Meissner, A.-L. Nicolas, B. G. Perry, D. J. Phillips, W. R. Pitt, A. Platt, A. J. Ratcliffe, A. Sharpe and L. J. Tait, Bioorg. Med. Chem. Lett., 2007, 17, 3463; (c) Z. Lu, G. R. Ott, R. Anand, R.-Q. Liu, M. B. Covington, K. Vaddi, M. Qian, R. C. Newton, D. D. Christ, J. Trzaskos and J. J.-W. Duan, Bioorg. Med. Chem. Lett., 2008, 18, 1958.
14. (a) N. Masurier, R. Aruta, V. Gaumet, S. Denoyelle, E. Moreau, V. Lisowski, J. Martinez and L. T. Maillard, J. Org. Chem., 2012, 77, 3679; (b) N. Masurier, E. Moreau, C. Lartigue, V. Gaumet, J. M. Chezal, A. Heitz, J. C. Teulade and O. Chavignon, J. Org. Chem., 2008, 73, 5989; (c) W. W. Paudler and H. J. Blewitt, J. Org. Chem., 1965, 30, 4081; (d) W. W. Paudler and H. L. Blewitt, Tetrahedron, 1965, 21, 353.
15. (a) W. Jing, Z. Cai-Jun, F. Man-Keung, L. Xiao-Ke, L. Chun-Sing and Z. Xiao-Hong, J. Mater. Chem., 2012, 22, 4502; (b) K. Poonam, P. Kasiviswanadharaju and K. Anil, Synlett, 2012, 23, 2609; (c) E. Oehler, E. Zbiral and M. El-Badawi, Tetrahedron Lett., 1983, 24, 5599; (d) H. Wang, Y. Wang, D. Liang, L. Liu, J. Zhang and Q. Zhu, Angew. Chem., Int. Ed., 2009, 50, 5678; (e) B. Marc-Antoine, M. Sophie, T. Alain and M. Pascal, Tetrahedron Lett., 2013, 54, 5378; (f) Y. Ru-Long, Y. Hao, M. Chao, R. Zhi-Yong, G. Xi-Ai, H. Guo-Sheng and L. Yong-Min, J. Org. Chem., 2012, 77, 2024.
16. G. Chaubet, L. T. Maillard, J. Martinez and N. Masurier, Tetrahedron, 2011, 67, 4897.
17. K. Pericherla, B. Khungar and A. Kumar, Tetrahedron Lett., 2012, 53, 1253.
18. (a) M. Curini, G. Cravotto, F. Epifano and G. Giannone, Curr. Med. Chem., 2006, 13, 199; (b) R. D. H. Murray, J. Mendez, R. A. Brown, The Natural Coumarins, Wiley: New York, 1982; (c) K. C. Fylaktakidou, D. J. Hadjipavlou-Litina, K. E. Litinas and D. N. Nicolaides, Curr. Pharm. Des., 2004, 10, 3813; (d) J. R. S. Hoult and M. Paya, Gen. Pharmacol., 1996, 27, 713; (e) E. Melliou, P. Magiatis, S. Mitaku, A. L. Skaltsounis, E. Chinou and I. Chinou, J. Nat. Prod., 2005, 68, 78.
19. G. A. Iacobucci and J. G. Sweeny, Tetrahedron, 1983, 39, 3005; K. M. Meepagala, W. Osbrink, C. Burandt, A. Lax and S. O. Duke, Pest Manage. Sci., 2011, 67, 1446; M. Khoshneviszadeh, N. Edraki, R. Miri, A. Foroumadi and B. Hemmateenejad, Chem. Biol. Drug Des., 2012, 79, 442.
20. (a) E. J. Corey and L. I. Wu, J. Am. Chem. Soc., 1993, 115, 9327; (b) D. Salni, M. V. Sargent, B. W. Skelton, I. Soediro, M. Sutisna, A. H. White and E. Yulinah, Aust. J. Chem., 2002, 55, 229; (c) F. Shaheen, M. Ahmad, S. N. Khan, S. S. Hussain, S. Anjum, B. Tashkhodjaev, K. Turgunov, M. N. Sultankhodzhaev, M. I. Choudhary and A. Rahman, Eur. J. Org. Chem., 2006, 71, 2371; (d) J. L. Wang, D. X. Liu, Z. J. Zhang, S. M. Shan, X. B. Han, S. M. Srinivasula, C. M. Croce, E. S. Alnemri and Z. W. Huang, Proc. Natl. Acad. Sci. U. S. A., 2000, 97, 7124.
21. (a) Microwaves in Organic Synthesis, ed. A. de la Hoz and A. Loupy, WILEY-VCH, Weinheim, 3rd edn, 2012; (b) B. L. Hayes, Microwave Synthesis: Chemistry at the Speed of Light, CEM Publishing, NC, 2002; (c) P. Lidstöm and J. P. Tierney, Microwave-Assisted Organic Synthesis, Blackwell Scientific, Oxford U.K., 2005; (d) C. O. Kappe, A. Stadler and D. Dallinger, Microwaves in Organic and Medicinal Chemistry, Wiley-VCH, Weinheim, 2nd edn, 2012; (e) C. O. Kappe, D. Dallinger and S. S. Murphree, Practical Microwave Synthesis for Organic Chemists-Strategies, Instruments, and ProtocolsWiley-VCH, Weinheim, 2009; (f) C. O. Kappe, Chem. Soc. Rev., 2008, 37, 1127; (g) A. Díaz-Ortiz, A. de la Hoz and A. Moreno, Curr. Org. Chem., 2004, 8, 903.
22. A. Díaz-Ortiz, A. de la Hoz, J. R. Carrillo and M. A. Herrero, in Microwaves in Organic Synthesis, ed. A. de la Hoz and A. Loupy, Wiley-VCH, Weinheim, 3rd edn, 2012, vol. 5, p. 209.
23. (a) L. C. Rao, N. S. Kumar, N. J. Babu and H. M. Meshram, Tetrahedron Lett., 2014, 55, 5342; (b) L. C. Rao, N. S. Kumar, V. Dileepkumar, U. S. N. Murthy and H. M. Meshram, RSC Adv., 2015, 5, 28958; (c) L. C. Rao, H. M. Meshram, N. S. Kumar, N. N. Rao and N. J. Babu, Tetrahedron Lett., 2014, 55, 1127; (d) L. C. Rao, N. S. Kumar and H. M. Meshram, Helv. Chim. Acta, 2015, 98, 978; (e) L. C. Rao, N. S. Kumar, N. J. Babu and H. M. Meshram, New J. Chem., 2015 10.1039/c5nj01377a.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra14674g

---