Microwave-assisted synthesis of novel 2,3-disubstituted imidazo[1,2-a]pyridines via one-pot three component reactions

Abstract

An expeditious one-pot, metal-free, three-component reaction of arylglyoxals, cyclic 1,3-dicarbonyls and 2-aminopyridines in the presence of molecular iodine under microwave irradiation is reported. A wide variety of 2,3-disubstituted imidazo[1,2-a]pyridine derivatives can be synthesized in good to very good yields using this methodology. The salient features of this methodology are: metal-free, short reaction time, good yields, use of microwave heating and no harmful by-products.

---

Introduction

Imidazo[1,2-a]pyridines are important molecules for both organic and medicinal chemists due to their wide range of biological and pharmacological activities.¹ Molecules with the imidazo[1,2-a]pyridine moiety exhibit anticancer,² anti-inflammatory,³ antibacterial,⁴ antiprotozonal,⁵ antiviral,⁶ antiulcer,⁷ and antifungal⁸ properties. Some of the commercially available drugs such as, alpidem (I) used as an anxiolytic drug,⁹ zolpidem (II) used in the treatment of insomnia and some brain disorders,¹⁰ zolimidine (III), used for the treatment of peptic ulcers and gastro esophageal reflux disease,¹¹ have a imidazo[1,2-a]pyridine scaffold. Similarly, olprinone (IV) is useful for the treatment of acute heart failure¹² and necopidem (V) and saripidem (VI) are also important sedative and anxiolytic agents¹³ (Fig. 1) having a substituted imidazo[1,2-a]pyridine moiety.

Fig. 1 Representative examples of important substituted imidazo[1,2-a]pyridines.

Considering the widespread applications of substituted imidazo[1,2-a]pyridine moiety there is a continuing interest in developing new and efficient synthetic routes.¹⁴ Some of the useful methods for the synthesis of imidazo[1,2-a]pyridines include reaction of α-halo carbonyl compounds with 2-aminopyridines,¹⁵ condensation between 2-aminopyridines and 2-bromo-1,2-diarylethanone,¹⁶ one-pot condensations of aldehydes, isonitriles, and 2-aminopyridines,¹⁷ three-component reactions of aldehydes, alkynes and 2-aminopyridines using copper catalysis,¹⁸ Suzuki-type cross-coupling between 3-halo-2-arylimidazo[1,2-a]pyridines and arylboronic acid,¹⁹ oxidative couplings through C–H activation,²⁰ and from Morita–Baylis–Hillman acetates of nitroalkenes²¹ etc.

Although these methods are useful still some of these methods have limitations such as use of expensive reagents or commercially less available substrates and α-halo carbonyl compounds which have lachrymatory properties.

Therefore, we realized the need of a new methodology for the rapid synthesis of substituted imidazo[1,2-a]pyridines from the readily available starting materials under green conditions.

Use of microwave heating technology in organic synthesis has gained tremendous popularity due to its ability to reduce reaction times dramatically, usually in minutes.²² In addition to its advantage in terms of reaction time; it saves energy, cost as well as provides clean products in good to excellent yields. Multicomponent reactions (MCRs) in tandem with microwave-assisted chemistry offers lot of advantages in terms of selectivity, chemical yield, purity, enhanced reaction rates and simplicity.²³ Considering the merits of microwave assisted MCRs very recently we have explored this strategy for the synthesis of fused heterocycles.²⁴ In continuation of our work on arylglyoxal-based MCRs^25,26 herein, we report a convenient method to access disubstituted imidazo[1,2-a]pyridine derivatives using three-component reaction of arylglyoxals, cyclic 1,3-dicarbonyls and 2-aminopyridines under microwave irradiation (Scheme 1).

Scheme 1 Synthesis of 2,3-disubstituted imidazo[1,2-a]pyridines by three component reactions.

Result and discussion

Initially, phenylglyoxal monohydrate (1a), 4-hydroxycoumarin (2a) and 2-aminopyridine (3a) were selected for the model reaction to check the feasibility of the proposed reaction. In absence of any catalyst the combination of these substrates in ethanol did not provide our desired three component product 4a both in room as well as reflux temperatures even after 24 hours (Table 1, entries 1–2). Next the same model reaction was tested in the presence of 20 mol% of p-toluene sulphonic acid (PTSA) in ethanol under both room temperature and reflux conditions. Unfortunately, in these cases also the desired three component product was not obtained. Changing solvent from ethanol to toluene in the presence of 20 mol% of PTSA under the reflux conditions provided only 6% of desired product 4a after 24 h. The product 4a was fully characterized by recording IR, ¹H & ¹³C NMR as well as elemental analysis. Encouraged by this positive result we turned our attention to optimize the reaction condition by varying various parameters such as using microwave heating, changing catalyst, solvent etc. Interestingly, the same model reaction in the presence of 20 mol% PTSA in toluene under the influence of microwave heating at 130 °C for 15 minutes provided better yield (38%) than the conventional heating conditions (Table 1, entry 6). Next, the same model reaction was tested in the presence of various metal triflates such as Cu(OTf)₂, Sc(OTf)₃, and Bi(OTf)₃ in ethanol under the influence of microwave irradiation and the yields obtained were moderate to good. To further investigate we also performed the same model reaction using readily available Lewis acids FeCl₃ and CAN following the similar microwave reaction conditions. Results using these Lewis acids were found not encouraging (Table 1, entries 10 and 11). Then we shifted our attention to use molecular iodine as a catalyst in this MCR. Interestingly using the same amount of (20 mol%) iodine and microwave irradiation for 15 minutes the desired three component product was obtained in 72% yield (Table 1, entry 12). Encouraged by this result as well as considering the non metallic, ready availability and benign nature of molecular iodine.²⁷ We focused our optimization using iodine by varying the amount of iodine as well as changing solvents. Finally, the optimized condition was obtained using 30 mol% I₂ at 130 °C in ethanol as solvent (Table 1, entry 13).

Table 1 Optimization of reaction conditions^a

Entry	Solvent	Catalyst (mol%)	Temp. (°C)	Time (min h^−1)	Yield^b (%)
a Reaction conditions: phenylglyoxal monohydrate (1 mmol), 4-hydroxycoumarin (1 mmol), and 2-aminopyridine (1 mmol).b Isolated yield.
1	EtOH	—	RT	24 h	0
2	EtOH	—	Reflux	24 h	0
3	EtOH	PTSA(20)	RT	24 h	0
4	EtOH	PTSA(20)	Reflux	24 h	0
5	Toluene	PTSA(20)	Reflux	24 h	6
6	Toluene	PTSA(20)	130	15 min	38
7	EtOH	Cu(OTf)2(20)	130	15 min	65
8	EtOH	Sc(OTf)3(20)	130	15 min	60
9	EtOH	Bi(OTf)3(20)	130	15 min	69
10	EtOH	FeCl3(20)	130	15 min	45
11	EtOH	CAN(20)	130	15 min	42
12	EtOH	I2(20)	130	15 min	72
13	EtOH	I2(30)	130	15 min	82
14	EtOH	I2(50)	130	15 min	68
15	EtOH	HI(20)	130	15 min	58
16	CH3CN	I2(30)	130	15 min	62
17	THF	I2(30)	130	15 min	Trace
18	DMF	I2(30)	130	15 min	42
19	H2O	I2(30)	130	15 min	51
20	EtOH	I2(30)	100	15 min	74

---

In order to explore the scope of this multicomponent reaction, a wide variety of phenylglyoxal derivatives, cyclic 1,3-dicarbonyl compounds and 2-aminopyridines were reacted under the optimized reaction conditions and the results are summarized in Table 2. Keeping 1a and 2a as fixed substrates 2-amino pyridine derivatives tethered with –Me, –Br, –Cl and –CF₃ groups in different positions were reacted under the optimized reaction conditions and in all these cases the observed yields were good to very good (Table 2, entries 2–5). 2-Aminopyrdines with trifluoromethyl groups or –Cl/–Br provided lesser yields as compared to the unsubstituted 2-aminopyridine or its derivatives having electron donating groups. Lower yields in these cases may be attributed due to the reduced nucleophilicity of the primary amine or of the endocyclic nitrogen of 2-amino pyridines having electron withdrawing groups. Next the variability of arylglyoxal was also checked using its derivatives having –OMe, NO₂ and –F substituents. Similar to phenylglyoxal monohydrate its derivatives having electron donating or withdrawing groups also underwent three component reactions to provide the corresponding 2,3-disubstituted imidazo[1,2-a]pyridines. Finally, we attempted to check the scope and generality of this MCR by replacing 4-hydroxy coumarin with other cyclic 1,3-dicarbonyls such as 4-hydroxy-1-methylquinolin-2(1H)-one, 4-hydroxy-6-methyl-2-pyrone and dimedone. Interestingly in all these cases the corresponding expected three component products were obtained in moderate to good yields. All these products were fully characterized by IR, ¹H NMR, ¹³C NMR and by elemental analysis as well as by recording melting points.

Table 2 Synthesis of 2,3-disubstituted imidazo[1,2-a]pyridines^a 4

Entry	Substrate 1	Substrate 2	Substrate 3	Time (min)	Product 4	Yield^b (%)
a Reaction conditions: phenylglyoxal monohydrate or its derivatives (1 mmol), 1,3-dicarbonyls (1 mmol), 2-aminopyridine derivatives (1 mmol) and iodine (0.3 mmol), in ethanol at 130 °C (MW).b Isolated yield.
1				15		82
2				15		84
3				15		72
4				15		83
5				15		65
6				15		81
7				15		71
8				15		83
9				15		76
10				15		74
11				15		68
12				15		71
13				15		67
14				15		69
15				15		62
16				15		58
17				15		76
18				15		72
19				15		68
20				15		72

---

This three component reaction can also be extended to 2-aminopyrimidine. Using similar reaction conditions the combination of phenylglyoxal monohydrate, 2-aminopyrimidine and 4-hydroxycoumarine provided 78% yield whereas using 4-hydroxy-1-methylquinolin-2(1H)-one in place of 4-hydroxycoumarine provided 75% yields as shown in Scheme 2.

Scheme 2 Synthesis of 2,3-disubstituted imidazo[1,2-a]pyrimidines.

On the basis of the above results a plausible reaction mechanism is shown in Scheme 3. It is believed that this reaction goes via Knoevenagel type reaction to form intermediate A. Then the 2-aminopyridine (3) undergoes aza-Michael addition to A affording intermediate B which subsequently undergoes cyclization followed by the loss of water to form desired product 4. Iodine can either act as Lewis acid²⁸ or a source of in situ HI (ref. 29) in organic transformations. To know the actual role of iodine in this three component reaction a few experiments were done.

Scheme 3 Proposed mechanism for the synthesis of 4.

In one of the experiment the model reaction i.e. reaction of 1a, 2a and 3a was tested using 30 mol% HI under the similar reaction conditions, and a moderate yield (55%) of 4a was obtained. To discard the role of in situ HI, we have performed another reaction in the presence of iodine (30 mol%) along with 30 mol% base (NaHCO₃) keeping solvent and heating conditions same. Interestingly, this combination provided 81% of the desired three component product 4a. It is expected that if the reaction is catalyzed by HI in that case presence of equimolar amount of base will nullify the acid and will have drastic effect on the net yield obtained. Since in our case this did not happen thus we believe iodine is acting as a Lewis acid to activate carbonyl CO in all the steps as shown in Scheme 3.

Conclusion

In conclusion, we have developed an iodine mediated one-pot three component reaction for the synthesis of 2,3-disubstituted imidazo[1,2-a]pyridines by using 1,3-binucleophilic nature of 2-aminopyridines. A wide range of cyclic 1,3-dicarbonyls can be tetrhed in the 3-position of imidazo[1,2-a]pyridine moiety in one-pot by this MCRs. Considering the presence of 4-hydroxycoumarin/hydroxypyrone or 4-hydroxy-1-methylquinolin-2(1H)-one moiety linked with imidazo[1,2-a]pyridines or imidazo[1,2-a]pyrimidines it is expected that these hybrid molecules will exhibit promising medicinal activities. From operational point of view, this MCR is easy to perform simply by mixing readily available starting materials under microwave irradiation. All the reactions took place within short times with water as the only benign by-product.

Experimental

General information

All starting materials were purchased either from Sigma Aldrich or Alfa Aesar and used without further purification. NMR spectra were recorded on 400 or 500 MHz for ¹H and 100 or 125 MHz for ¹³C in D₂O or DMSO-d₆, chemical shift values were reported in δ values (ppm) downfield from tetramethylsilane. Infrared (IR) spectra were recorded on a Shimadzu IR Affinity-1, FTIR spectrometer. Elemental analyses were carried out using vario MICRO cube elemental analyzer. Microwave irradiation was carried out with Initiator 2.5 Microwave Synthesizers from Biotage, Uppsala, Sweden. Melting points were recorded by using SRS EZ-Melt automated melting point apparatus by capillary methods and uncorrected.

Typical experimental procedure for the synthesis of 1a. A mixture of phenylglyoxal monohydrate (1a) (1 mmol), 4-hydroxycoumarin (2a) (1 mmol), 2-aminopyridine (3a) (1 mmol) and iodine (0.3 mmol) in 3 mL ethanol was introduced in a 2–5 mL reaction vial, the mixture was irradiated for 15 min, keeping temperature at 130 °C (absorption level: high; fixed hold time and 200 W). The reaction mixture was then cooled to room temperature and the solid was filtered off, and was washed with water–ethanol mixture to get the desired three component product 4a.

Note: due to poor solubility of these compounds in common organic solvents, in most of the cases the resultant products were treated with 1.0 equivalent NaOH in 2 mL H₂O to prepare the corresponding sodium enolate of the products and the solvent was removed under vacuum to record NMR in D₂O.

4-Hydroxy-3-(2-phenylimidazo[1,2-a]pyridin-3-yl)-2H-chromen-2-one (4a). Yield: 82%, white solid, mp. 133–135 °C; IR (KBr): 3400, 3070, 1663, 1597, 1520, 1457, 1407, 1374, 1307, 1267, 1197, 1138, 1109, 1058, 1035, 969, 842, 752, 687, 651 cm⁻¹; ¹H NMR (500 MHz, DMSO-d₆): δ = 8.28 (d, J = 7.0 Hz, 1H, Ar-H), 7.94 (d, J = 8.0 Hz, 2H, Ar-H), 7.88 (d, J = 7.5 Hz, 1H, Ar-H), 7.84 (d, J = 8.0 Hz, 2H, Ar-H), 7.55 (t, J = 8.0 Hz, 1H, Ar-H), 7.49 (t, J = 8.0 Hz, 2H, Ar-H), 7.43–7.38 (m, 2H, Ar-H), 7.27–7.22 (m, 2H, Ar-H); sodium salt of (4a); ¹³C NMR (100 MHz, D₂O-d₂): δ = 177.5, 168.1, 167.5, 153.8, 145.4, 142.1, 134.0, 132.6, 128.7, 127.9, 126.8, 126.6, 124.8, 124.5, 124.0, 120.9, 116.7, 115.9, 115.5, 112.9, 89.7; anal. calcd for C₂₂H₁₄N₂O₃ (354.36): C, 74.57; H, 3.98; N, 7.91; found: C, 74.59; H, 3.95; N, 7.97.

4-Hydroxy-3-(6-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)-2H-chromen-2-one (4b). Yield: 84%, white solid, mp. 257–259 °C; IR (KBr): 3437, 3066, 2620, 1677, 1603, 1534, 1451, 1416, 1373, 1308, 1265, 1203, 1133, 1107, 1057, 967, 898, 852, 810, 759, 690 cm⁻¹; sodium salt of (4b): ¹H NMR (400 MHz, D₂O-d₂): δ = 7.96 (d, J = 7.5, Hz, 1H, Ar-H), 7.83 (d, J = 7.4, Hz, 2H, Ar-H), 7.68 (s, 1H, Ar-H), 7.63 (t, J = 7.6 Hz, 1H, Ar-H), 7.54 (d, J = 9.1 Hz, 1H, Ar-H), 7.40–7.31 (m, 5H, Ar-H), 7.28 (d, J = 9.0 Hz, 1H, Ar-H), 2.25 (s, 3H, CH₃); ¹³C NMR (100 MHz, D₂O-d₂): δ = 177.5, 167.5, 153.7, 144.4, 141.9, 134.2, 132.5, 129.6, 128.7, 127.8, 126.8, 124.5, 124.0, 122.9, 122.4, 120.9, 116.7, 115.7, 114.8, 89.9, 17.2; anal. calcd for C₂₃H₁₆N₂O₃ (368.38): C, 74.99; H, 4.38; N, 7.60; found: C, 74.95; H, 4.40; N, 7.65.

3-(6-Bromo-2-phenylimidazo[1,2-a]pyridin-3-yl)-4-hydroxy-2H-chromen-2-one (4c). Yield: 72%, light yellow solid, mp. 273–275 °C; IR (KBr): 3381, 1670, 1646, 1600, 1528, 1496, 1456, 1415, 1368, 1323, 1214, 1107, 1082, 1044, 967, 899, 841, 798, 759, 694 cm⁻¹; ¹H NMR (500 MHz, DMSO-d₆): δ = 8.61 (s, 1H, Ar-H), 7.92 (d, J = 7.5 Hz, 1H, Ar-H), 7.81 (d, J = 7.5 Hz, 2H, Ar-H), 7.77–7.74 (m, 2H, Ar-H), 7.65 (t, J = 7.5 Hz, 1H, Ar-H), 7.44–7.32 (m, 5H, Ar-H); sodium salt of (4c); ¹³C NMR (100 MHz, D₂O-d₂): δ = 177.5, 167.3, 153.8, 143.8, 142.9, 133.7, 132.6, 129.4, 128.8, 128.1, 126.9, 125.0, 124.5, 124.0, 120.9, 116.7, 116.5, 116.4, 107.0, 89.3; anal. calcd for C₂₂H₁₃BrN₂O₃ (433.25): C, 60.99; H, 3.02; N, 6.47; found: C, 60.96; H, 3.05; N, 6.49.

3-(8-Bromo-6-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)-4-hydroxy-2H-chromen-2-one (4d). Yield: 83%, white solid, mp. 274–276 °C; IR (KBr): 3410, 3063, 1717, 1612, 1534, 1451, 1391, 1289, 1234, 1104, 1077, 959, 847, 745, 726, 578 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 8.15 (s, 1H, Ar-H), 7.96 (d, J = 5.6 Hz, 1H, Ar-H), 7.81 (d, J = 5.2 Hz, 2H, Ar-H), 7.73–7.68 (m, 2H, Ar-H), 7.49–7.20 (m, 5H, Ar-H), 2.28 (s, 3H, CH₃); sodium salt of (4d); ¹³C NMR (125 MHz, D₂O-d₂): δ = 177.5, 167.3, 166.4, 153.7, 143.1, 142.2, 133.8, 132.6, 131.6, 128.7, 128.0, 127.2, 124.5, 124.0, 123.3, 122.2, 120.9, 117.9, 116.7, 108.3, 89.9, 17.0; anal. calcd for C₂₃H₁₅BrN₂O₃ (447.28): C, 61.76; H, 3.38; N, 6.26; found: C, 61.74; H, 3.36; N, 6.29.

3-(8-Chloro-2-phenyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)-4-hydroxy-2H-chromen-2-one (4e). Yield: 65%, pale yellow solid, mp. 219–221 °C; IR (KBr): 3465, 1672, 1640, 1596, 1530, 1455, 1367, 1343, 1298, 1218, 1165, 1135, 1092, 1069, 1030, 966, 892, 844, 761, 689, 667 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 8.99 (s, 1H, Ar-H), 7.96 (d, J = 8.0 Hz, 1H, Ar-H), 7.91 (s, 1H, Ar-H), 7.83 (d, J = 7.2 Hz, 2H, Ar-H), 7.78–7.74 (m, 1H, Ar-H), 7.52–7.48 (m, 1H, Ar-H), 7.44–7.38 (m, 3H, Ar-H), 7.34–7.31 (m, 1H, Ar-H); sodium salt of (4e); ¹³C NMR (100 MHz, D₂O-d₂): δ = 177.9, 168.6, 167.6, 154.2, 151.4, 148.3, 143.9, 134.2, 133.9, 133.1, 129.2, 128.8, 127.6, 124.9, 124.5, 121.2, 117.2, 115.5, 109.6, 89.1; anal. calcd for C₂₃H₁₂ClF₃N₂O₃ (456.80): C, 60.47; H, 2.65; N, 6.13; found: C, 60.45; H, 2.64; N, 6.17.

4-Hydroxy-3-(2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)-2H-chromen-2-one (4f). Yield: 81%, yellow solid, mp. 246–248 °C; IR (KBr): 3450, 3079, 2838, 2545, 1669, 1601, 1516, 1457, 1424, 1395, 1372, 1312, 1254, 1180, 1141, 1104, 1028, 954, 897, 835, 756 cm⁻¹; sodium salt of (4f) ¹H NMR (500 MHz, D₂O-d₂): δ = 7.90–7.80 (m, 1H, Ar-H), 7.75–7.60 (m, 3H, Ar-H), 7.58–7.40 (m, 2H, Ar-H), 7.30–7.20 (m, 3H, Ar-H), 6.85–6.70 (m, 3H, Ar-H), 3.16 (s, 3H, OMe); ¹³C NMR (100 MHz, D₂O-d₂): δ = 177.5, 167.5, 158.5, 153.8, 145.3, 142.0, 132.6, 128.3, 127.2, 126.4, 124.7, 124.5, 124.0, 121.1, 116.7, 115.4, 114.2, 112.8, 89.6, 55.3; anal. calcd for C₂₃H₁₆N₂O₄ (384.38): C, 71.87; H, 4.20; N, 7.29; found: C, 71.88; H, 4.22; N, 7.32.

3-(8-Bromo-2-(4-methoxyphenyl)-6-methylimidazo[1,2-a]pyridin-3-yl)-4-hydroxy-2H-chromen-2-one (4g). Yield: 71%, pale yellow solid, mp. 261–263 °C; IR (KBr): 3438, 3069, 2571, 1677, 1603, 1529, 1451, 1377, 1271, 1179, 1156, 1105, 1031, 957, 897, 842, 759, 690 cm⁻¹; sodium salt of (4g) ¹H NMR (500 MHz, D₂O-d₂): δ = 7.94 (s, 1H, Ar-H), 7.90 (d, J = 7.2 Hz, 1H, Ar-H), 7.72 (d, J = 8.8 Hz, 2H, Ar-H), 7.50–7.45 (m, 2H, Ar-H), 7.33–7.22 (m, 2H, Ar-H), 6.84 (d, J = 8.8 Hz, 2H, Ar-H), 3.67 (s, 3H, OCH₃), 2.11 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆): δ = 177.1, 166.8, 158.7, 153.9, 143.6, 143.0, 132.5, 128.9, 128.6, 127.1, 124.9, 124.8, 124.0, 121.4, 116.7, 116.5, 115.8, 114.2, 106.8, 88.8, 55.3, 29.8; anal. calcd for C₂₄H₁₇BrN₂O₄ (477.31): C, 60.39; H, 3.59; N, 5.87; found: C, 60.37; H, 3.61; N, 5.85.

4-Hydroxy-3-(2-(4-nitrophenyl)imidazo[1,2-a]pyridin-3-yl)-2H-chromen-2-one (4h). Yield: 83%, dark red solid, mp. 297–299 °C; IR (KBr): 3438, 3106, 1672, 1654, 1603, 1525, 1423, 1350, 1289, 1202, 1114, 1054, 962, 870, 764, 713, 690, 653 cm⁻¹; sodium salt of (4h) ¹H NMR (400 MHz, D₂O-d₂): δ = 8.18 (d, J = 8.0 Hz, 2H, Ar-H), 8.10 (d, J = 8.4 Hz, 2H, Ar-H), 8.01 (d, J = 8.0 Hz, 1H, Ar-H), 7.91 (d, J = 6.8 Hz, 1H, Ar-H), 7.70 (d, J = 9.6 Hz, 1H, Ar-H), 7.64 (t, J = 7.6 Hz, 1H, Ar-H), 7.45 (t, J = 7.6 Hz, 1H, Ar-H), 7.41–7.35 (m, 2H, Ar-H), 7.0 (t, J = 6.8 Hz, 1H, Ar-H); ¹³C NMR (100 MHz, D₂O-d₂): δ = 177.3, 166.8, 163.9, 154.4, 146.8, 145.6, 142.3, 140.2, 132.5, 127.8, 126.8, 125.2, 125.1, 123.9, 123.8, 121.6, 116.8, 116.2, 113.9, 88.5; anal. calcd for C₂₂H₁₃N₃O₅ (399.36): C, 66.17; H, 3.28; N, 10.52; found: C, 66.19; H, 3.25; N, 10.57.

3-(6-Bromo-2-(4-nitrophenyl)imidazo[1,2-a]pyridin-3-yl)-4-hydroxy-2H-chromen-2-one (4i). Yield: 76%, reddish solid, mp. 315–319 °C; IR (KBr): 3427, 3090, 3060, 1681, 1654, 1603, 1520, 1455, 1423, 1349, 1271, 1183, 1160, 1109, 1040, 957, 897, 865, 759, 690 cm⁻¹; sodium salt of (4i) ¹H NMR (500 MHz, D₂O-d₂): δ = 8.10 (dd, J = 9.0, 2.0 Hz, 2H, Ar-H), 8.05 (s, 1H, Ar-H), 7.95 (dd, J = 8.5, 1.5 Hz, 2H, Ar-H), 7.90 (dd, J = 7.5, 1.5 Hz, 1H, Ar-H), 7.58 (dt, J = 9.0, 1.5 Hz, 1H, Ar-H), 7.51 (d, J = 9.5 Hz, 1H, Ar-H), 7.42–7.40 (m, 1H, Ar-H), 7.31 (t, J = 7.5 Hz, 2H, Ar-H); ¹³C NMR (125 MHz, D₂O-d₂): δ = 177.2, 166.8, 153.7, 146.4, 143.9, 140.7, 140.6, 132.6, 129.9, 127.4, 125.3, 124.5, 124.0, 123.9, 120.9, 118.6, 116.7, 116.6, 107.4, 88.8; anal. calcd for C₂₂H₁₂BrN₃O₅ (478.25): C, 55.25; H, 2.53; N, 8.79; found: C, 55.28; H, 2.54; N, 8.82.

3-(2-(4-Fluorophenyl)imidazo[1,2-a]pyridin-3-yl)-4-hydroxy-2H-chromen-2-one (4j). Yield: 74%, orange solid, mp. 220–222 °C; IR (KBr): 3438, 3087, 1677, 1605, 1523, 1460, 1423, 1400, 1280, 1239, 1197, 1165, 1165, 1059, 960, 905, 850, 754 cm⁻¹; sodium salt of (4j) ¹H NMR (500 MHz, D₂O-d₂): δ = 7.94 (d, J = 7.0 Hz, 1H, Ar-H), 7.82 (d, J = 6.0 Hz, 3H, Ar-H), 7.63 (d, J = 9.0 Hz, 1H, Ar-H), 7.60 (d, J = 8.0 Hz, 1H, Ar-H), 7.41–7.33 (m, 3H, Ar-H), 7.10 (t, J = 8.0 Hz, 2H, Ar-H), 6.92 (t, J = 6.5 Hz, 1H, Ar-H); ¹³C NMR (125 MHz, D₂O-d₂): δ = 177.5, 167.4, 163.2, 161.3, 153.8, 145.4, 141.5, 132.6, 130.3, 128.8, 126.6, 124.8, 124.5, 124.1, 121.0, 116.7, 115.6, 115.4, 112.9, 89.5; anal. calcd for C₂₂H₁₃FN₂O₃ (372.35): C, 70.96; H, 3.52; N, 7.52; found: C, 70.99; H, 3.54; N, 7.55.

3-(6-Bromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)-4-hydroxy-2H-chromen-2-one (4k). Yield: 68%, yellow solid, mp. 149–151 °C; IR (KBr): 3428, 3079, 2375, 1676, 1596, 1533, 1503, 1456, 1423, 1375, 1353, 1266, 1231, 1157, 1107, 1039, 955, 897, 846, 764 cm⁻¹; sodium salt of (4k) ¹H NMR (400 MHz, D₂O-d₂): δ = 8.12–8.0 (m, 2H, Ar-H), 7.98–7.88 (m, 2H, Ar-H), 7.65 (d, J = 9.1 Hz, 2H, Ar-H), 7.47 (d, J = 8.8 Hz, 1H, Ar-H), 7.40 (d, J = 6.4 Hz, 2H, Ar-H), 7.13 (d, J = 6.8 Hz, 2H, Ar-H); ¹³C NMR (100 MHz, D₂O-d₂): δ = 167.1, 163.3, 161.3, 153.7, 143.7, 142.3, 132.5, 129.9, 129.3, 128.8, 125.1, 124.5, 123.9, 120.9, 116.7, 116.3, 115.5, 115.4, 107.0, 89.1; anal. calcd for C₂₂H₁₂BrFN₂O₃ (451.24): C, 58.56; H, 2.68; N, 6.21; found: C, 58.58; H, 2.66; N, 6.25.

3-(6-Bromo-2-phenylimidazo[1,2-a]pyridin-3-yl)-4-hydroxy-1-methylquinolin-2(1H)-one (4l). Yield: 71%, white solid, mp. 300–302 °C; IR (KBr): 3460, 3084, 1700, 1650, 1627, 1539, 1496, 1458, 1442, 1417, 1365, 1312, 1198, 1088, 1064, 958, 872, 810, 752, 710, 689 cm⁻¹; sodium salt of (4l) ¹H NMR (400 MHz, D₂O-d₂): δ = 8.07 (dd, J = 7.9, 1.4 Hz, 1H, Ar-H), 7.94 (d, J = 1.2 Hz, 1H, Ar-H), 7.88 (dd, J = 8.6, 1.4 Hz, 2H, Ar-H), 7.53 (d, J = 9.5 Hz, 1H, Ar-H), 7.46 (t, J = 7.5 Hz, 1H, Ar-H), 7.39–7.31 (m, 3H, Ar-H), 7.28–7.21 (m, 3H, Ar-H), 3.44 (s, 3H, NMe); ¹³C NMR (100 MHz, D₂O-d₂): δ = 173.9, 164.9, 143.6, 142.6, 140.1, 134.0, 131.2, 128.9, 128.6, 127.8, 126.9, 124.8, 121.9, 121.6, 118.7, 116.3, 114.7, 106.8, 96.1, 29.2; anal. calcd for C₂₃H₁₆BrN₃O₂ (446.30): C, 61.90; H, 3.61; N, 9.42; found: C, 61.92; H, 3.63; N, 9.46.

3-(8-Bromo-6-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)-4-hydroxy-1-methylquinolin-2(1H)-one (4m). Yield: 67%, white solid, mp. 237–239 °C; IR (KBr): 3075, 3028, 2366, 1662, 1635, 1590, 1535, 1506, 1456, 1378, 1310, 1262, 1165, 1091, 1041, 899, 851, 762, 709 cm⁻¹; sodium salt of (4m) ¹H NMR (500 MHz, D₂O-d₂): δ = 8.00 (d, J = 7.5 Hz, 1H, Ar-H), 7.69 (d, J = 7.5 Hz, 2H, Ar-H), 7.47–7.43 (m, 2H, Ar-H), 7.42 (s, 1H, Ar-H), 7.30–7.23 (m, 3H, Ar-H), 7.22–7.16 (m, 2H, Ar-H), 3.35 (s, 3H, NMe), 2.07 (s, 3H, CH₃); ¹³C NMR (125 MHz, D₂O-d₂): δ = 173.8, 165.1, 142.7, 142.0, 140.1, 134.1, 131.4, 128.6, 127.8, 127.1, 124.8, 123.1, 122.1, 121.9, 121.7, 119.9, 114.9, 108.2, 96.9, 29.3, 16.9; anal. calcd for C₂₄H₁₈BrN₃O₂ (460.32): C, 62.62; H, 3.94; N, 9.13; found: C, 62.65; H, 3.96; N, 9.15.

3-(6-Bromo-2-phenylimidazo[1,2-a]pyridin-3-yl)-4-hydroxy-6-methyl-2H-pyran-2-one (4n). Yield: 69%, white solid, mp. 249–251 °C; IR (KBr): 3066, 2999, 2748, 1709, 1658, 1601, 1555, 1516, 1488, 1449, 1414, 1362, 1305, 1257, 1215, 1177, 1075, 1025, 1005, 987, 892, 827, 788, 754, 716, 690, 528, 513 cm⁻¹; sodium salt of (4n) ¹H NMR (400 MHz, D₂O-d₂): δ = 8.08 (s, 1H, Ar-H), 7.83 (d, J = 7.5 Hz, 2H, Ar-H), 7.54 (d, J = 9.4 Hz, 1H, Ar-H), 7.48–7.47 (m, 3H, Ar-H), 7.45–7.40 (m, 1H, Ar-H), 5.99 (s, 1H, CH), 1.94 (s, 3H, CH₃); ¹³C NMR (100 MHz, D₂O-d₂): δ = 181.6, 168.5, 162.9, 143.8, 142.8, 133.6, 129.4, 128.8, 128.1, 126.8, 125.0, 116.3, 116.0, 107.3, 107.0, 88.9, 18.8; anal. calcd for C₁₉H₁₃BrN₂O₃ (397.22): C, 57.45; H, 3.30; N, 7.05; found: C, 57.47; H, 3.32; N, 7.09.

3-(8-Bromo-6-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)-4-hydroxy-6-methyl-2H-pyran-2-one (4o). Yield: 62%, white solid, mp. 257–259 °C; IR (KBr): 3070, 1689, 1643, 1505, 1451, 1411, 1345, 1263, 1162, 1041, 991, 915, 840, 809, 774, 690, 581 cm⁻¹; sodium salt of (4o) ¹H NMR (400 MHz, D₂O-d₂): δ = 7.69 (dd, J = 8.5, 1.4 Hz, 2H, Ar-H), 7.56 (s, 1H, Ar-H), 7.45 (s, 1H, Ar-H), 7.34 (t, J = 7.7 Hz, 2H, Ar-H), 7.29–7.23 (m, 1H, Ar-H), 5.85 (s, 1H, CH), 2.13 (s, 3H, CH₃), 1.81 (s, 3H, CH₃); ¹³C NMR (100 MHz, D₂O-d₂): δ = 181.6, 168.6, 167.9, 162.9, 142.9, 142.2, 133.7, 131.7, 128.7, 128.1, 127.1, 123.4, 122.1, 117.4, 108.3, 107.4, 89.5, 18.9, 17.0; anal. calcd for C₂₀H₁₅BrN₂O₃ (411.25): C, 58.41; H, 3.68; N, 6.81; found: C, 58.43; H, 3.67; N, 6.84.

3-(8-Chloro-2-phenyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)-4-hydroxy-6-methyl-2H-pyran-2-one (4p). Yield: 58%, pale yellow solid, mp. 249–251 °C; IR (KBr): 3429, 3015, 2903, 2840, 1706, 1675, 1653, 1609, 1569, 1520, 1496, 1459, 1417, 1340, 1304, 1257, 1173, 1153, 1093, 1029, 983, 899, 832, 760, 672, 538 cm⁻¹; sodium salt of (4p) ¹H NMR (400 MHz, D₂O-d₂): δ = 8.30 (s, 1H, Ar-H), 7.86 (dd, J = 7.0, 1.5 Hz, 2H, Ar-H), 7.78 (s, 1H, Ar-H), 7.52–7.40 (m, 3H, Ar-H), 5.99 (s, 1H, CH), 2.28 (s, 3H, CH₃); ¹³C NMR (100 MHz, D₂O-d₂): δ = 181.6, 168.4, 163.2, 144.6, 142.5, 133.0, 128.8, 128.5, 127.2, 123.2, 122.1, 120.9, 119.2, 116.9, 116.5, 107.3, 88.5, 18.9; anal. calcd for C₂₀H₁₂ClF₃N₂O₃ (420.77): C, 57.09; H, 2.87; N, 6.66; found: C, 57.11; H, 2.85; N, 6.69.

2-(6-Bromo-2-phenylimidazo[1,2-a]pyridin-3-yl)-3-hydroxy-5,5-dimethylcyclohex-2-enone (4q). Yield: 76%, yellow solid, mp. 226–228 °C; IR (KBr): 3530, 3381, 3100, 2962, 2869, 1662, 1592, 1549, 1516, 1408, 1352, 1267, 1173, 1144, 1129, 1089, 1041, 923, 806, 772, 741 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 8.06 (s, 1H, Ar-H), 7.76 (dd, J = 8.4, 1.2 Hz, 2H, Ar-H), 7.59 (d, J = 9.6, Hz, 1H, Ar-H), 7.39–7.35 (m, 3H, Ar-H), 7.29 (t, J = 7.6 Hz, 1H, Ar-H), 2.68 (d, J = 16.8 Hz, 2H, Ar-H), 2.36 (d, J = 16.8 Hz, 2H, Ar-H), 1.15 (s, 6H, CH₃); sodium salt of (4q); ¹³C NMR (100 MHz, D₂O-d₂): δ = 196.9, 181.9, 144.0, 142.9, 134.4, 129.4, 129.1, 128.3, 127.6, 125.2, 118.9, 116.7, 107.2, 102.1, 49.7, 31.8, 28.9, 27.7, 23.7; anal. calcd for C₂₁H₁₉BrN₂O₂ (411.29): C, 61.33; H, 4.66; N, 6.81; found: C, 61.35; H, 4.67; N, 6.85.

2-(8-Bromo-6-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)-3-hydroxy-5,5-dimethylcyclohex-2-enone (4r). Yield: 72%, pale yellow solid, mp. 230–232 °C; IR (KBr): 3423, 3071, 2945, 2866, 1667, 1608, 1538, 1492, 1399, 1298, 1234, 1186, 1145, 1088, 1028, 894, 818, 717, 629 cm⁻¹; sodium salt of (4r) ¹H NMR (400 MHz, D₂O-d₂): δ = 7.68–7.65 (m, 2H, Ar-H), 7.46–7.45 (m, 2H, Ar-H), 7.39–7.35 (dt, J = 7.8, 1.2 Hz, 2H, Ar-H), 7.29 (t, J = 7.36, 1H, Ar-H), 2.37 (d, J = 16.6 Hz, 2H, Ar-H), 2.25 (d, J = 16.8 Hz, 2H, Ar-H), 2.18 (s, 3H, CH₃), 1.10 (s, 3H, CH₃), 1.05 (s, 3H, CH₃); ¹³C NMR (100 MHz, D₂O-d₂): δ = 196.6, 168.0, 142.8, 142.1, 134.1, 131.3, 128.6, 127.9, 127.4, 123.1, 121.9, 119.6, 108.3, 102.3, 49.3, 31.4, 28.4, 27.3, 17.1; anal. calcd for C₂₂H₂₁BrN₂O₂ (425.32): C, 62.13; H, 4.98; N, 6.59; found: C, 62.15; H, 4.99; N, 6.62.

2-(8-Chloro-2-phenyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)-3-hydroxy-5,5-dimethylcyclohex-2-enone (4s). Yield: 68%, white solid, mp. 235–237 °C; IR (KBr): 3280, 3070, 2960, 2562, 1661, 1624, 1576, 1545, 1490, 1416, 1317, 1212, 1179, 1142, 1102, 1075, 1031, 893, 855, 775, 694 cm⁻¹; sodium salt of (4s) ¹H NMR (400 MHz, D₂O-d₂): δ = 8.04 (s, 1H, Ar-H), 7.74 (d, J = 7.5 Hz, 2H, Ar-H), 7.69 (s, 1H, Ar-H), 7.45 (t, J = 7.5 Hz, 2H, Ar-H), 7.40–7.38 (m, 1H, Ar-H), 2.47 (d, J = 16.5 Hz, 2H, Ar-H), 2.30 (d, J = 16.8 Hz, 2H, Ar-H), 1.15 (s, 3H, CH₃), 1.11 (s, 3H, CH₃); ¹³C NMR (100 MHz, D₂O-d₂): δ = 196.7, 163.9, 144.55, 142.3, 133.4, 128.7, 128.4, 127.6, 124.2, 122.9, 122.1, 121.3, 120.5, 116.4, 116.2, 115.9, 115.6, 101.2, 49.2, 31.4, 28.5, 27.1; anal. calcd for C₂₂H₁₈ClF₃N₂O₂ (434.84): C, 60.77; H, 4.17; N, 6.44; found: C, 60.79; H, 4.19; N, 6.48.

2-(6-Bromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)-3-hydroxy-5,5-dimethylcyclohex-2-enone (4t). Yield: 72%, pale yellow solid, mp. 193–195 °C; IR (KBr): 3401, 3106, 2977, 1658, 1608, 1580, 1515, 1488, 1465, 1428, 1363, 1243, 1179, 1091, 1045, 856, 810, 699 cm⁻¹; sodium salt of (4t) ¹H NMR (400 MHz, D₂O-d₂): δ = 7.92 (s, 1H, Ar-H), 7.79 (d, J = 7.0 Hz, 1H, Ar-H), 7.77 (d, J = 7.5 Hz, 1H, Ar-H), 7.53 (d, J = 11.5 Hz, 1H, Ar-H), 7.46 (d, J = 11.0 Hz, 1H, Ar-H), 7.21 (t, J = 11.0 Hz, 2H, Ar-H), 2.48 (d, J = 21.0 Hz, 2H, CH₂), 2.37 (d, J = 21.0 Hz, 2H, CH₂), 1.22 (s, 3H, CH₃), 1.18 (s, 3H, CH₃); ¹³C NMR (100 MHz, D₂O-d₂): δ = 196.5, 163.5, 143.6, 142.1, 129.1, 129.0, 128.9, 124.9, 118.2, 116.4, 115.5, 115.3, 106.8, 101.5, 49.3, 31.4, 29.6, 28.5, 27.3; anal. calcd for C₂₁H₁₈BrFN₂O₂ (429.28): C, 58.75; H, 4.23; N, 6.53; found: C, 58.77; H, 4.25; N, 6.56.

4-Hydroxy-3-(2-phenylimidazo[1,2-a]pyrimidin-3-yl)-2H-chromen-2-one (4u). Yield: 78%, white solid, mp. 220–222 °C; IR (KBr): 3435, 1675, 1642, 1598, 1545, 1449, 1418, 1361, 1317, 1264, 1215, 1106, 1063, 1027, 965, 899, 865, 760, 716, 681 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ = 8.81 (bs, 1H, Ar-H), 8.72 (d, J = 6.8 Hz, 1H, Ar-H), 7.92 (d, J = 8.0 Hz, 1H, Ar-H), 7.86 (d, J = 7.6 Hz, 2H, Ar-H), 7.64 (d, J = 8.0 Hz, 1H, Ar-H), 7.44 (t, J = 7.6 Hz, 2H, Ar-H), 7.38 (d, J = 7.6 Hz, 2H, Ar-H), 7.33 (t, J = 8.0 Hz, 2H, Ar-H); sodium salt of (4u); ¹³C NMR (100 MHz, D₂O-d₂): δ = 177.9, 168.5, 154.3, 145.4, 143.1, 133.7, 133.0, 129.2, 127.8, 125.0, 124.5, 123.8, 122.7, 122.1, 121.2, 120.2, 117.2, 89.2; anal. calcd for C₂₁H₁₃N₃O₃ (355.35): C, 70.98; H, 3.69; N, 11.83; found: C, 70.95; H, 3.72; N, 11.85.

4-Hydroxy-1-methyl-3-(2-phenylimidazo[1,2-a]pyrimidin-3-yl)quinolin-2(1H)-one (4v). Yield: 75%, yellow solid, mp. 247–249 °C; IR (KBr): 3428, 3070, 2888, 1640, 1616, 1533, 1498, 1417, 1381, 1320, 1251, 1161, 1114, 1084, 959, 878, 808, 768, 716 cm⁻¹; sodium salt of (4v) ¹H NMR (400 MHz, D₂O-d₂): δ = 8.58 (dd, J = 4.3, 1.8 Hz, 1H, Ar-H), 8.22 (dd, J = 6.8, 1.8 Hz, 1H, Ar-H), 8.11 (dd, J = 7.9, 1.2 Hz, 1H, Ar-H), 7.84 (dd, J = 8.1, 1.5 Hz, 2H, Ar-H), 7.70 (dt, J = 8.5, 1.4 Hz, 1H, Ar-H), 7.56 (d, J = 8.5 Hz, 1H, Ar-H), 7.40–7.33 (m, 4H, Ar-H), 7.07 (dd, J = 6.7, 4.3 Hz, 1H, Ar-H), 3.60 (s, 3H, NMe); ¹³C NMR (100 MHz, D₂O-d₂): δ = 173.9, 168.4, 165.1, 150.8, 147.8, 143.2, 140.2, 133.8, 133.6, 131.5, 128.7, 128.2, 127.2, 124.8, 121.9, 117.2, 115.0, 109.1, 95.6, 29.3; anal. calcd for C₂₂H₁₆N₄O₂ (368.39): C, 71.73; H, 4.38; N, 15.21; found: C, 71.75; H, 4.37; N, 15.25.

Acknowledgements

L.H.C gratefully acknowledges financial support from the Department of Science and Technology India, with Sanction no. SR/FT/CS-042/2009 for carrying out this work. S.K and M.N.K are grateful to CSIR for their research fellowships (SRF). Authors are also grateful to IIT Madras, and SAIF, Panjab University for providing analytical facilities for characterization of compounds.

References and notes

1. (a) A. Gueiffier, A. M. Lhassani, A. Elhakmaoui, R. Snoeck, G. Andrei, O. Chavignon, J. C. Teulade, A. Kerbal, E. K. Essassi, J. C. Debouzy, M. Witvrouw, Y. Blache, J. Balzarini, E. De Clercq and J. P. Chapat, J. Med. Chem., 1996, 39, 2856; (b) K. S. Gudmundsson, J. C. Drach and L. B. Townsend, J. Org. Chem., 1997, 62, 3453; (c) Y. Abe, H. Kayakiri, S. Satoh, T. Inoue, Y. Sawada, K. Imai, N. Inamura, M. Asano, C. Hatori, A. Katayama, T. Oku and H. Tanaka, J. Med. Chem., 1998, 41, 564; (d) C. Hamdouchi, J. Blas, M. Prado, J. Gruber, B. A. Heinz and L. Vance, J. Med. Chem., 1999, 42, 50; (e) G. Trapani, M. Franco, A. Latrofa, L. Ricciardi, A. Carotti, M. Serra, E. Sanna, G. Biggio and G. Liso, J. Med. Chem., 1999, 42, 3934; (f) J. Zhu, Eur. J. Org. Chem., 2003, 2003, 1133; (g) K. C. Rupert, J. R. Henry, J. H. Dodd, S. A. Wadsworth, D. E. Cavender, G. C. Olini, B. Fahmy and J. Siekierka, Bioorg. Med. Chem. Lett., 2003, 13, 347; (h) A. Domling, Chem. Rev., 2006, 106, 17; (i) D. Bonne, M. Dekhane and J. P. Zhu, Angew. Chem., 2007, 119, 2537; (j) H. L. Wei, Z. Y. Yan, Y. L. Niu, G. Q. Li and Y. M. Liang, J. Org. Chem., 2007, 72, 8600; (k) F. Couty and G. Evano, in Comprehensive Heterocyclic Chemistry III, ed. A. R. Katritzky, C. A. Ramsden, E. F. V. Scriven and R. J. K. Taylor, Elsevier, Oxford, 2008, vol. 11, p. 409; (l) B. Jiang, T. Rajale, W. Wever, S. J. Tu and G. G. Li, Chem.–Asian J., 2010, 5, 2318; (m) D. Hong, Y. X. Zhu, Y. Li, X. F. Lin, P. Lu and Y. G. Wang, Org. Lett., 2011, 13, 4668; (n) S. Husinec, R. Markovic, M. Petkovic, V. Nasufovic and V. Savic, Org. Lett., 2011, 13, 2286; (o) O. N. Burchak, L. Mugherli, M. Ostuni, J. J. Lacapere and M. Y. Balakirev, J. Am. Chem. Soc., 2011, 133, 10058; (p) B. Chattopadhyay and V. Gevorgyan, Angew. Chem., 2012, 124, 886; (q) C. Enguehard-Gueiffier and A. Gueiffier, Mini-Rev. Med. Chem., 2007, 7, 888.
2. (a) P. V. Kumar and V. R. Rao, Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem., 2005, 41B, 2120; (b) O. Kim, Y. Jeong, H. Lee, S.-S. Hong and S. Hong, J. Med. Chem., 2011, 54, 2455; (c) A. Kamal, J. S. Reddy, M. J. Ramaiah, D. Dastagiri, E. V. Bharathi, M. V. P. Sagar, S. N. C. V. L. Pushpavalli, P. Ray and M. Pal-Bhadra, Med. Chem. Commun., 2010, 1, 355.
3. (a) C. Hamdouchi, J. de Blas, M. del Prado, J. Gruber, B. A. Heinz and L. Vance, J. Med. Chem., 1999, 42, 50; (b) K. C. Rupert, J. R. Henry, J. H. Dodd, S. A. Wadsworth, D. E. Cavender, G. C. Olini, B. Fahmy and J. Siekierka, Bioorg. Med. Chem. Lett., 2003, 13, 347.
4. (a) Y. Rival, G. Grassy and G. Michel, Chem. Pharm. Bull., 1992, 40, 1170; (b) M. Hammad, A. Mequid, M. E. Ananni and N. Shafik, Egypt. J. Chem., 1987, 29, 5401.
5. (a) T. Biftu, D. Feng, M. Fisher, G. B. Liang, X. Qian, A. Scribner, R. Dennis, S. Lee, P. A. Liberator, C. Brown, A. Gurnett, P. S. Leavitt, D. Thompson, J. Mathew, A. Misura, S. Samaras, T. Tamas, J. F. Sina, K. A. McNulty, C. G. McKnight, D. M. Schmatz and M. Wyvratt, Bioorg. Med. Chem. Lett., 2006, 16, 2479; (b) M. A. Ismail, R. K. Arafa, T. Wenzler, R. Brun, F. A. Tanious, W. D. Wilson and D. W. Boykin, Bioorg. Med. Chem., 2008, 16, 681; (c) A. Scribner, R. Dennis, S. Lee, G. Ouvry, D. Perrey, M. Fisher, M. Wyvratt, P. Leavitt, P. Liberator, A. Gurnett, C. Brown, J. Mathew, D. Thompson, D. Schmatz and T. Biftu, Eur. J. Med. Chem., 2008, 43, 1123.
6. (a) A. Gueiffier, M. Lhassani, A. Elhakmaoui, R. Snoeck, G. Andrei, O. Chaxignon, J. C. Teulade, A. Kerbal, E. M. Essassi, J. C. Debouzy, M. Witvrouw, Y. Blache, J. Balzarini, E. De Clercq and J. P. Chapat, J. Med. Chem., 1996, 39, 2856; (b) A. Gueiffier, S. Mavel, M. Lhassani, A. Elhakmaoui, R. Snoeck, G. Andrei, O. Chavignon, J. C. Teulade, M. Witvrouw, J. Balzarini, E. De Clercq and J. P. Chapat, J. Med. Chem., 1998, 41, 5108; (c) G. Puerstinger, J. Paeshuyse, E. Declercq and J. Neyts, Bioorg. Med. Chem. Lett., 2007, 17, 390; (d) J. B. Veron, H. Allouchi, C. Enguehard Gueiffier, R. Snoeck, G. A. E. De Clercq and A. Gueiffier, Bioorg. Med. Chem., 2008, 16, 9536.
7. Y. Katsura, S. Nishino, Y. Inoue, M. Tomoi and H. Takasugi, Chem. Pharm. Bull., 1992, 40, 371.
8. Y. Rival, G. Grassy, A. Taudou and R. Ecalle, Eur. J. Med. Chem., 1991, 26, 13.
9. (a) B. Musch, P. L. Morselli and P. Priore, Pharmacol., Biochem. Behav., 1988, 4, 803; (b) S. Z. Langer, S. Arbilla, J. Benavides and B. Scatton, Adv. Biochem. Psychopharmacol., 1990, 46, 61; (c) P. G. George, G. Rossey, M. Sevrin, S. Arbilla, H. Depoortere and A. E. L. E. R. S. Wick, Monograph Ser., 1993, 8, 49.
10. (a) J. M. Monti, S. D. Warren, S. R. Pandi-Perumal, S. Z. Langer and R. Hardeland, Clin. Med.: Ther., 2009, 1, 123; (b) B. Du, A. Shan, Y. Zhang, X. Zhong, D. Chen and K. Cai, Am. J. Med. Sci., 2014, 3, 172.
11. L. Almirante, L. Polo, A. Mugnaini, E. Provinciali, P. Rugarli, A. Biancotti, A. Gamba and W. Murmann, J. Med. Chem., 1965, 8, 305.
12. (a) Y. Uemura, S. Tanaka, S. Ida and T. Yuzuriha, J. Pharm. Pharmacol., 1993, 45, 1077; (b) K. Mizushige, T. Ueda, K. Yukiiri and H. Suzuki, Cardiovasc. Drug Rev., 2002, 20, 163.
13. R. J. Boerner and H. J. Moller, Psychopharmakotherap, 1997, 4, 145.
14. (a) K. S. Gudmundsson and B. A. Johns, Org. Lett., 2003, 5, 1369; (b) H. Cao, H. Zhan, Y. Lin, X. Lin, Z. Du and H. Jiang, Org. Lett., 2012, 14, 1688; (c) J. Zeng, Y. J. Tan, M. L. Leow and X.-W. Liu, Org. Lett., 2012, 14, 4386; (d) A. V. Gulevich, V. Helan, D. J. Wink and V. Gevorgyan, Org. Lett., 2013, 15, 956; (e) O. A. Attanasi, L. Bianchi, L. A. Campisi, L. D. Crescentini, G. Favi and F. Mantellini, Org. Lett., 2013, 15, 3646; (f) H. Huang, X. Ji, X. Tang, M. Zhang, X. Li and H. Jiang, Org. Lett., 2013, 15, 6254; (g) C. Ravi, D. C. Mohan and S. Adimurthy, Org. Lett., 2014, 16, 2978; (h) N. Devi, R. K. Rawal and V. Singh, Tetrahedron, 2015, 71, 183; (i) A. K. Bagdi, S. Santra, K. Monir and A. Hajra, Chem. Commun., 2015, 51, 1555.
15. (a) W. L. Mosby, in Heterocyclic Systems with Bridgehead Nitrogen Atoms, ed. W. L. Mosby, Wiley, New York, 1961, Part I; p. 460 and Part II; p. 802; (b) W. L. Blewitt, in Special Topics in Heterocyclic Chemistry, ed. A. Weissberger and E. C. Taylor, Wiley, New York, 1977, p. 117; (c) C. Sablayrolles, G. H. Cros, J. C. Milhavet, E. Rechenq, J.-P. Chapat, M. Boucard, J. J. Serrano and J. H. McNeill, J. Med. Chem., 1984, 27, 206; (d) W. A. Spitzer, F. Victor, D. G. Pollock and J. S. Hayers, J. Med. Chem., 1988, 31, 1590.
16. (a) H. S. Patel, J. A. Linn, D. H. Drewry, D. A. Hillesheim, W. J. Zuercher and W. J. Hoekstra, Tetrahedron Lett., 2003, 44, 4077; (b) L. Yin, F. Erdmann and J. Liebscher, J. Heterocycl. Chem., 2005, 42, 1369; (c) 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; (d) C. Enguehard-Gueiffier, S. Musiu, N. Henry, J. B. Veron, S. Mavel, J. Neyts, P. Leyssen, J. Paeshuyse and A. Gueiffier, Eur. J. Med. Chem., 2013, 64, 448; (e) Y. Wang, B. Frett and H.-Y. Li, Org. Lett., 2014, 16, 3016.
17. (a) K. Groebke, L. Weber and F. Mehlin, Synlett, 1998, 1998, 661; (b) H. Bienayme and K. Bouzid, Angew. Chem., Int. Ed., 1998, 37, 2234; (c) C. Blackburn, Tetrahedron Lett., 1998, 39, 5469; (d) C. Blackburn, B. Guan, P. Fleming, K. Shiosaki and S. Tsai, Tetrahedron Lett., 1998, 39, 3635; (e) G. S. Mandair, M. Light, A. Russell, M. Hursthouse and M. Bradley, Tetrahedron Lett., 2002, 43, 4267; (f) R. S. Varma and D. Kumar, Tetrahedron Lett., 1999, 40, 7665; (g) S. M. Ireland, H. Tye and M. Whittaker, Tetrahedron Lett., 2003, 44, 4369; (h) A. Shaabani, E. Soleimani and A. Maleki, Tetrahedron Lett., 2006, 47, 3031; (i) A. T. Khan, R. S. Basha and M. Lal, Tetrahedron Lett., 2012, 53, 2211.
18. N. Chernyak and V. Gevorgyan, Angew. Chem., Int. Ed., 2010, 49, 2743.
19. V. Gembus, J.-F. Bonfanti, O. Querolle, P. Jubault, V. Levacher and C. Hoarau, Org. Lett., 2012, 14, 6012.
20. (a) L. Ma, X. Wang, W. Yu and B. Han, Chem. Commun., 2011, 47, 11333; (b) M. R. Collins, Q. Huang, M. A. Ornelas and S. A. Scales, Tetrahedron Lett., 2010, 51, 3528; (c) A. K. Bagdi, M. Rahman, S. Santra, A. Majee and A. Hajra, Adv. Synth. Catal., 2013, 355, 1741; (d) D. C. Mohan, R. R. Donthiri, S. N. Rao and S. Adimurthy, Adv. Synth. Catal., 2013, 355, 2217; (e) K. Pericherla, P. Kaswan, P. Khedar, B. I. Khungar, K. Parang and A. Kumar, RSC Adv., 2013, 3, 18923; (f) Z.-J. Cai, S.-Y. Wang and S.-J. Ji, Adv. Synth. Catal., 2013, 355, 2686; (g) Y. Zhang, Z. Chen, W. Wu, Y. Zhang and W. Su, J. Org. Chem., 2013, 78, 12494.
21. D. K. Nair, S. M. Mobin and I. N. N. Namboothiri, Org. Lett., 2012, 14, 4580.
22. (a) A. Lew, P. O. Krutzik, M. E. Hart and A. R. Chamberlin, J. Comb. Chem., 2002, 4, 95; (b) G. Minetto, L. F. Raveglia and M. Taddei, Org. Lett., 2004, 6, 389; (c) W. S. Bremner and M. G. Organ, J. Comb. Chem., 2007, 9, 14; (d) B. Jiang, L.-J. Cao, S.-J. Tu, W.-R. Zheng and H.-Z. Yu, J. Comb. Chem., 2009, 11, 612; (e) L. Wen, C. Ji, Y. Li and M. Li, J. Comb. Chem., 2009, 11, 799; (f) B. Jiang, F. Shi and S.-J. Tu, Curr. Org. Chem., 2010, 14, 357; (g) B. Jiang, Q.-Y. Li, S.-J. Tu and G. Li, Org. Lett., 2012, 14, 5210; (h) B. Jiang, X. Wang, H.-W. Xu, M.-S. Tu, S.-J. Tu and G. Li, Org. Lett., 2013, 15, 1540; (i) W. Fan, Q. Ye, H.-W. Xu, B. Jiang, S.-L. Wang and S.-J. Tu, Org. Lett., 2013, 15, 2258; (j) K. Pericherla, A. Jha, B. Khungar and A. Kumar, Org. Lett., 2013, 15, 4304; (k) C. Val, A. Crespo, V. Yaziji, A. Coelho, J. Azuaje, A. E. Maatougui, C. Carbajales and E. Sotelo, ACS Comb. Sci., 2013, 15, 370; (l) L.-P. Fu, Q.-Q. Shi, Y. Shi, B. Jiang and S.-J. Tu, ACS Comb. Sci., 2013, 15, 135.
23. (a) R. Gedey, F. Smith, K. Westaway, H. Ali, L. Baldisera, L. Laberge and J. Roussel, Tetrahedron Lett., 1986, 27, 279; (b) G. Majetich and R. J. Hicks, Journal of Microwave Power and Electromagnetic Energy, 1995, 30, 27; (c) G. Majetich and R. Hicks, Radiat. Phys. Chem., 1995, 45, 567; (d) S. Caddick, Tetrahedron, 1995, 51, 10403; (e) V. Sridar, Curr. Sci., 1998, 74, 446; (f) A. Fini and A. Breccia, Pure Appl. Chem., 1999, 71, 573; (g) M. Larhed and A. Hallberg, Drug Discovery Today, 2001, 6, 406; (h) P. Lidström, J. Tierney, B. Wathey and J. Westman, Tetrahedron, 2001, 57, 9225; (i) D. A. Jones, T. P. Lelyveld, S. D. Mavrofidis, S. W. Kingman and N. J. Miles, Resour., Conserv. Recycl., 2002, 34, 75; (j) V. Santagada, E. Perissutti and G. Caliendo, Curr. Med. Chem., 2002, 9, 1251; (k) J. Lu, B. Yang and Y. Bai, Synth. Commun., 2002, 32, 3703; (l) N. Kuhnert, Angew. Chem., Int. Ed., 2002, 41, 1863; (m) A. D. L. Hoz, A. Díaz-Ortiz and A. Moreno, Curr. Org. Chem., 2004, 8, 903; (n) C. O. Kappe, Angew. Chem., Int. Ed., 2004, 43, 6250; (o) A. D. L. Hoz, A. Diaz-Ortiz and A. Moreno, Chem. Soc. Rev., 2005, 34, 164; (p) C. O. Kappe and D. Dallinger, Nat. Rev. Drug Discovery, 2006, 5, 51; (q) S.-J. Tu, X.-D. Cao, W.-J. Hao, X.-H. Zhang, S. Yan, S.-S. Wu, Z.-G. Han and F. Shi, Org. Biomol. Chem., 2009, 7, 557; (r) M. A. Surati, S. Jauhari and K. R. Desai, Arch. Appl. Sci. Res., 2012, 4, 645.
24. M. N. Khan, S. Pal, S. Karamthulla and L. H. Choudhury, New J. Chem., 2014, 38, 4722.
25. S. Karamthulla, S. Pal, M. N. Khan and L. H. Choudhury, Synlett, 2014, 25, 1926.
26. S. Karamthulla, S. Pal, M. N. Khan and L. H. Choudhury, RSC Adv., 2014, 4, 37889.
27. (a) B. K. Banik, M. S. Manhas and A. K. Bose, J. Org. Chem., 1994, 59, 4714; (b) B. K. Banik, S. Samajdar and I. Banik, J. Org. Chem., 2004, 69, 213; (c) M. Jereb, D. Vrazic and M. Zupan, Tetrahedron, 2011, 67, 1355; (d) P. T. Parvatkar, P. S. Parameswaran and S. G. Tilve, Chem.–Eur. J., 2012, 18, 5460; (e) G. R. Reddy, T. R. Reddy, S. C. Joseph, K. S. Reddy and M. Pal, RSC Adv., 2012, 2, 3387; (f) G. Ramachandran, N. S. Karthikeyan, P. Giridharan and K. I. Sathiyanarayanan, Org. Biomol. Chem., 2012, 10, 5343; (g) Z. Fei, Y. Zhu, M.-C. Liu, F.-C. Jia and A.-X. Wu, Tetrahedron Lett., 2013, 54, 1222; (h) S. Pal, M. N. Khan, S. Karamthulla and L. H. Choudhury, RSC Adv., 2013, 3, 15705.
28. (a) M. Srivastava, P. Rai, J. Singh and J. Singh, New J. Chem., 2014, 38, 302; (b) K. B. Puttaraju and K. Shivashankar, RSC Adv., 2013, 3, 20883; (c) M. Kidwai, P. Mothsra, V. Bansal, R. K. Somvanshi, A. S. Ethayathulla, S. Dey and T. P. Singh, J. Mol. Catal. A: Chem., 2007, 265, 177; (d) L.-Y. Zeng and C. Cai, J. Comb. Chem., 2010, 12, 35; (e) A. Sagar, S. Vidyacharan and D. S. Sharada, RSC Adv., 2014, 4, 37047; (f) A. T. Khan, M. M. Khan and K. K. R. Bannuru, Tetrahedron, 2010, 66, 7762; (g) F.-L. Yang and S.-K. Tian, Angew. Chem., Int. Ed., 2013, 52, 4929; (h) M. Sharma and P. J. Bhuyan, RSC Adv., 2014, 4, 15709; (i) M. Sathishkumar and K. I. Sathiyanarayanan, RSC Adv., 2014, 4, 8808.
29. (a) J. L. Wahlstrom and R. C. Ronald, J. Org. Chem., 1998, 63, 6021; (b) F. Yang, Y.-F. Qiu, K.-G. Ji, Y.-N. Niu, S. Ali and Y.-M. Liang, J. Org. Chem., 2012, 77, 9029; (c) J. S. Yadav, M. Satyanarayana, S. Raghavendra and E. Balanarsaiah, Tetrahedron Lett., 2005, 46, 8745.

---

Footnote

† Electronic supplementary information (ESI) available: ¹H NMR and ¹³C NMR spectra for all reactions products are available. See DOI: 10.1039/c4ra16298f

---