# A Convenient Synthesis of C-3-Aryloxymethyl Imidazo[1,2-a]Pyridine Derivatives

Authors: Sridevi Kona; Rama Suresh Ravi; Venkata N. R. Chava; Ramu Sridhar Perali
Journal: Journal of Chemistry
 (2013)

---

## Abstract

Imidazo[1,2-a]pyridine-based tosylhydrazone was prepared and treated with K2CO3 in dioxane at 110°C to generate the corresponding carbene in situ. It was coupled with a variety of aryl alcohols in one pot to obtain a series of imidazo[1,2-a]pyridine derivatives possessing aryl ether moiety at C-3 position.


---

## Body

## 1. Introduction

Imidazopyridines are important class of heterocyclic compounds. Synthesis of imidazo[1,2-a]pyridine derivatives has been the subject of considerable interest because of their wide range of pharmaceutical, biological, and medicinal applications [1–3]. The derivatives of this scaffold show a variety of therapeutic properties such as agonist of benzodiazepine receptor [4], GABAAα2/α3 binding site agonists [5], ligand for detecting β-amyloid [6] and also constitute orally active nonpeptide bradykinin B2 receptor antagonists [7]. These derivatives have been found to possess antibacterial [8], antiviral [9, 10], anti-inflammatory [11], antiulcer [12], antitubercular [13], anticancer [14], antiparasitic [15], and antiprotozoa [16] activities, and so forth Moreover, it is also a core structure of several drugs such as zolimidine (1) (antiulcer), alpidem (2) (anxiolytic), and zolpidem (3) (selective benzodiazepine receptor agonist, for the treatment of insomnia) [17] (Figure 1) which are currently available in the market. As a result, various methods for the preparation of imidazo[1,2-a]pyridine derivatives were developed [18–20]. Gueiffier and coworkers reported that imidazo[1,2-a]pyridine derivatives particularly bearing a thioether side chain at 3-position were found to be very active against human cytomegalovirus (HCMV) and varicella-zoster virus (VZV) [9, 10]. In view of significant importance of 3-substituted imidazo [1,2-a]pyridine derivatives herein we report a convenient preparation of imidazo[1,2-a]pyridine derivatives possessing an aryl ether moiety at C-3 position.Figure 1
Structures of some biologically active imidazo[1,2-a]pyridine derivatives.


## 2. Experimental Section

### 2.1. General

All the chemicals used were purchased from Aldrich Chemical Co and were used without further purification. Freshly distilled solvents were used. For TLC, aluminum plates coated with silica gel containing F254 indicator were used, and the spots were visualized by UV light and/or by exposing to iodine. Column chromatography was performed on silica gel 100–200 mesh, using EtOAc and hexanes mixture as eluent. The1H and 13C spectra were recorded using 5 mm tubes on a Bruker 400 MHz NMR spectrometer field strengths: 400 and 100 MHz, resp. in CDCl3 solution (unless specified otherwise) with shifts referenced to SiMe4 (1H, 13C: δ=0), respectively. All J values were in Hz. IR spectra were recorded on a JASCO FT/IR 5300 spectrometer. Elemental (C, H, N) analysis was done using Perkin-Elmer 240C CHN FLASH EA analyzer. Melting points were determined by using a SUPERFIT hot-stage melting point apparatus and are uncorrected.4-Methyl-N′-{(2-phenylimidazo[1,2-a]pyridine-3-yl)methylene}benzenesulfonohydrazide(8). To a rapidly stirred suspension of toluenesulfonyl hydrazide (4.6 g, 24.7 mmol) in methanol (10 mL) a solution of aldehyde 7 (5 g, 22.5 mmol) in methanol (20 mL) portion wise for a period of 15 minutes was added. A mildly exothermic reaction occurred and the solution became transparent. Within 15–20 min the tosylhydrazone began to precipitate. After stirring for 1 h the mixture was filtered, and the filter cake was washed with small quantity of methanol. The obtained product 8 was dried and used in the next step without further purification. Yield: 7.65 g (98%; colorless solid); Mp 102–104C°; IR (νmax, cm−1): 3379, 2762, 1605, 1345, 1166, 947, 739; 1H NMR (400 MHz, CDCl3): δH 2.42 (s, 3H, CH3), 7.02–7.06 (m, 1H, Ar-H), 7.32–7.54 (m, 8H, Ar-H), 7.76, (d, 3J(H-H) = 8.8 Hz, 1H, Ar-H), 7.90, (d, 3J(H-H) = 8.0 Hz, 2H, Ar-H), 8.16 (s, 1H, Ar-H), 9.34 (d, 3J(H-H) = 6.8 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 21.6, 114.1, 114.9, 117.2, 127.7, 127.9, 128.7(6), 128.7(4), 128.9, 129.2, 129.8, 132.7, 135.3, 140.3, 144.4, 146.8, 151.1; LC/MS: m/z 391 [M + H]+; Anal. Calcd. for C21H18N4O2S: C, 64.60; H, 4.65; N, 14.35. Found: C, 64.69; H, 4.60; N, 14.45.General Procedure for the Synthesis Ether Derivatives: 2-Phenyl-3-(P-tolyloxymethyl)imidazo[1,2-a]pyridine
(10a)
. An oven-dried 10 mL round bottom flask was charged with tosylhydrazone 8 (391 mg, 1.0 mmol), p-cresol (216 mg, 2.0 mmol), and K2CO3 (483 mg, 3.5 equiv). The flask was evacuated for 5 min and filled with N2. To this dioxane (4 mL) was added and contents were stirred at 110C° for 12 h under nitrogen. After completion of the reaction (monitored by TLC), the mixture was cooled to room temperature and the solvent was evaporated by rotary evaporator to obtain the crude reaction mixture. To this, saturated solution of NaOH (5 mL) and dichloromethane (15 mL) were added subsequently and the layers were separated. The aqueous phase was extracted with dichloromethane (2×5 mL). The combined organic layers were washed with NaOH solution (2×5 mL), brine (3×5mL) and then dried over anhydrous Na2SO4. The crude product was purified by column chromatography (hexane:EtOAc 6 : 4) to afford 10a. Yield 0.20 g (64%; colorless solid); Mp 116–118°C; IR (νmax, cm−1): 3015, 1507, 1358, 1225, 1034, 976, 739; 1H NMR (400 MHz, CDCl3): δH 2.32 (s, 3H, CH3), 5.40 (s, 2H, CH2), 6.86–6.92 (m, 3H, Ar-H), 7.12–7.49 (m, 6H, Ar-H), 7.70 (d, 3J(H-H) = 9.2 Hz, 1H, Ar-H), 7.77 (s, 1H, Ar-H), 7.79 (d, 3J(H-H) = 1.2 Hz, 1H, Ar-H), 8.16 (d, 3J(H-H) = 6.8 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 20.5, 60.1, 112.7, 114.8, 115.5, 117.7, 124.2, 125.3, 128.2, 128.7, 130.1, 131.0, 133.9, 145.5, 146.2, 156.0; LC/MS: m/z 315 [M + H]+; Anal. Calcd. For C21H18N2O: C, 80.23; H, 5.77; N, 8.91. Found: C, 80.32; H, 5.81; N, 8.79.2-Phenyl-3-(o-tolyloxymethyl)imidazo[1,2-a]pyridine
(10b)
. Yield: 0.24 g (76%; colorless solid); Mp 110–112C°; IR (νmax, cm−1): 2924, 1458, 1233, 1192, 1117, 997, 750; 1H NMR (400 MHz, CDCl3): δH 2.21 (s, 3H, CH3), 5.44 (s, 2H, CH2), 6.87–6.84 (m, 3H, Ar-H), 7.19–7.32 (m, 3H, Ar-H), 7.41–7.50 (m, 3H, Ar-H), 7.71–7.79 (m, 3H, Ar-H), 8.18 (d, 3J(H-H) = 6.8 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 16.3, 60.0, 111.5, 112.6, 115.7, 117.7, 121.3, 124.1, 125.3, 126.9, 127.4, 128.2, 128.7, 131.0, 133.9, 145.6, 156.2. LC/MS: m/z 315 [M + H]+; Anal. Calcd. For C21H18N2O: C, 80.23; H, 5.77; N, 8.91. Found: C, 80.12; H, 5.72; N, 8.97.3-((4-tert-Butylphenoxy)methyl)-2-phenylimidazo[1,2-a]pyridine
(10c)
. Yield: 0.31 g (87%; colorless solid); Mp 134–136C°; IR (νmax, cm−1): 2948, 1607, 1507, 1233, 1181, 999, 737; 1H NMR (400 MHz, CDCl3): δH 1.33, (s, 9H, (CH3)3), 5.41, (s, 2H, CH2), 6.87, (t, 3J(H-H) = 6.8 Hz, 1H, Ar-H), 6.98, (d, 3J(H-H) = 8.8 Hz, 2H, Ar-H), 7.28–7.49, (m, 6H, Ar-H), 7.70, (d, 3J(H-H) = 9.2 Hz, 1H, Ar-H), 7.79, (d,3J(H-H) = 7.6 Hz, 2H, Ar-H), 8.15, (d, 3J(H-H)= 6.8 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 31.5, 34.1, 59.9, 112.6, 114.4, 115.5, 117.6, 124.1, 125.3, 126.4, 128.2, 128.7, 133.9, 144.4, 145.5, 146.2, 155.9; LC/MS: m/z 357 [M + H]+; Anal. Calcd. For. C24H24N2O: C, 80.87; H, 6.79; N, 7.86. Found: C, 80.77; H, 6.75; N, 7.80.3-((4-Methoyphenoxy)methyl)-2-phenylimidazo[1,2-a]pyridine
(10d)
. Yield 0.29 g (88%; colorless solid); Mp 116–118C°; IR (νmax, cm−1): 3011, 1507, 1358, 1225, 1034, 976, 738; 1H NMR (400 MHz, CDCl3): δH 3.79 (s, 3H, OCH3), 5.38 (s, 2H, CH2), 6.84–6.95 (m, 5H, Ar-H), 7.29–7.49 (m, 4H, Ar-H), 7.71 (d, 3J(H-H) = 8.8 Hz, 1H, Ar-H), 7.77 (d, 3J(H-H) = 7.2 Hz, 2H, Ar-H), 8.17 (d, 3J(H-H) = 6.8 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 55.8, 60.8, 112.7, 114.8, 115.7, 116.2, 117.7, 124.2, 125.3, 128.2, 128.7, 134.0, 145.6, 146.3, 152.2, 154.6; LC/MS: m/z 331 [M + H]+; Anal. Calcd. For C21H18N2O2: C, 76.34; H, 5.49; N, 8.48. Found: C, 76.43; H, 5.48; N, 8.45.3-((4-Chlorophenoxy)methyl)-2-phenylimidazo[1,2-a]pyridine
(10e)
. Yield: 0.28 g (84%; colorless solid); Mp 134–136C°; IR (νmax, cm−1): 3044, 2922, 1491, 1356, 1231, 984, 817, 735; 1H NMR (400 MHz, CDCl3): δH 5.41 (s, 2H, CH2), 6.90 (s, 1H, Ar-H), 6.92 (s, 2H, Ar-H), 7.27–7.76 (m, 9H, Ar-H), 8.15 (d, 3J(H-H)= 5.6 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 60.3, 112.9, 115.0, 116.3, 117.8, 124.1, 125.5, 126.6, 128.4, 128.7, 128.8, 129.6, 133.8, 145.6, 146.5, 156.7; LC/MS: m/z 335 [M + H]+; Anal. Calcd. For C20H15ClN2O: C, 71.75; H, 4.52; N, 8.37. Found: C, 71.65; H, 4.58; N, 8.31.3-((4-Nitrophenoxy)methyl)-2-phenylimidazo[1,2-a]pyridine
(10f)
. Yield 0.25 g (73%;  yellow colored solid); Mp 132–134C°; IR (νmax, cm−1): 2924, 1505, 1318, 1146, 1086, 754, 700. 1H NMR (400 MHz, CDCl3): δH 4.85 (s, 2H, CH2), 6.89 (t, 3J(H-H) = 6.8 Hz, 1H, Ar-H), 7.04–7.17 (m, 3H, Ar-H), 7.29–7.36 (m, 7H, Ar-H), 7.66 (d, 3J(H-H) = 9.2 Hz, 1H, Ar-H), 8.41 (d, 3J(H-H) = 6.8 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 52.4, 108.2, 112.8, 117.1, 124.8, 126.0, 127.9, 128.0(9),128.0(0), 128.1, 129.6, 132.6, 134.0, 145.1, 145.6, 146.9; LC/MS: m/z 346 [M + H]+; Anal. Calcd. For C20H15N3O3: C, 69.56; H, 4.38; N, 12.17. Found: C, 69.45; H, 4.31; N, 12.25.3-((2,4-Dimethylphenoxy)methyl)-2-phenylimidazo[1,2-a]pyridine
(10g)
. Yield 0.26 g (79%; colorless solid); Mp 110–112C°; IR (νmax, cm−1): 2921, 1505, 1356, 1215, 1129, 984, 741; 1H NMR (400 MHz, CDCl3): δH 2.18 (s, 3H, CH3), 2.30 (s, 3H, CH3), 5.40 (s, 2H, CH2), 6.83–6.98 (m, 3H, Ar-H), 7.02 (s, 1H, Ar-H), 7.28–7.50 (m, 4H, Ar-H), 7.72 (d, 3J(H-H) = 8.8 Hz, 1H, Ar-H), 7.79 (d, 3J(H-H) = 7.6 Hz, 2H, Ar-H), 8.16 (d, 3J(H-H) = 6.8 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 16.2, 20.4, 60.1, 111.6, 112.5, 115.9, 117.6, 124.0, 125.2, 127.0, 127.1, 128.1, 128.7, 130.5, 131.8, 133.9, 145.4, 146.1, 154.1; LC/MS: m/z 329 [M + H]+; Anal. Calcd. for C22H20N2O: C, 80.46; H, 6.14; N, 8.53. Found: C, 80.35, H, 6.18, N, 8.45.3-((3,5-Dimethylphenoxy)methyl)-2-phenylimidazo[1,2-a]pyridine
(10h)
. Yield: 0.31 g (95%; colorless solid); Mp: 126-128C°; IR (νmax, cm−1): 2919, 1593, 1502, 1404, 1294, 1154, 736; 1H NMR (400 MHz, CDCl3): δH 2.29 (s, 6H, (CH3)2), 5.43 (s, 2H, CH2), 6.63 (s, 2H, Ar-H). 6.68 (s, 1H, Ar-H), 6.91 (t, 3J(H-H) = 6.8 Hz, 1H, Ar-H), 7.31–7.52 (m, 3H, Ar-H), 7.73 (d, 3J(H-H) = 8.8 Hz, 1H, Ar-H), 7.79–7.81 (m, 3H, Ar-H), 8.19 (d, 3J(H-H) = 6.8 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 21.4, 59.6, 112.6, 112.7, 115.6, 117.6, 123.3, 124.2, 125.4, 128.2, 128.8(7), 128.8(1), 133.9, 139.5, 145.5, 146.1, 158.1; LC/MS: m/z 329 [M + 1]+; Anal. Calcd. for C22H20N2O: C, 80.46; H, 6.14; N, 8.53. Found: C, 80.32; H, 6.19; N, 8.45.3-((2,6-Dimethylphenoxy)methyl)-2-phenylimidazo[1,2-a]pyridine
(10i)
. Yield 0.21 g (64%; colorless solid); Mp 118–120C°; IR (νmax, cm−1): 2924, 1503, 1358, 1190, 1090, 955, 764; 1H NMR (400 MHz, CDCl3): δH 2.09 (s, 6H, (CH3)2), 5.31 (s, 2H, CH2), 6.85–7.00 (m, 4H, Ar-H), 7.27–7.39 (m, 4H, Ar-H), 7.58 (d, 3J(H-H) = 7.2 Hz, 2H, Ar-H), 7.69 (d, 3J(H-H) = 8.8 Hz, 1H, Ar-H), 8.14 (d, 3J(H-H) = 6.4 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 16.5, 63.4, 112.5, 117.2, 117.6, 124.1, 124.4, 125.2, 128.0, 128.5, 128.7, 129.1, 131.1, 133.8, 145.3, 146.2, 155.6; LC/MS: m/z 329 [M + H]+; Anal. Calcd. for C22H20N2O: C, 80.46; H, 6.14; N, 8.53. Found: C, 80.35; H, 6.22; N, 8.61.3-((2-tert-Butyl-4-methylphenoxy)methyl)-2-phenyl-imidazo[1,2-a]pyridine
(10j)
. Yield 0.30 g (81%; colorless solid); Mp 144–146C°; IR (νmax, cm−1): 2957, 1499, 1362, 1219, 1094, 1004, 731; 1H NMR (400 MHz, CDCl3): δH 1.32 (s, 9H, (CH3)3), 2.35 (s, 3H, CH3), 5.38 (s, 2H, CH2), 6.87 (t, 3J(H-H) = 6.8 Hz, 1H, Ar-H), 6.94 (d, 3J(H-H) = 8.4 Hz, 1H, Ar-H), 7.04 (d, 3J(H-H) = 8.0 Hz, 1H, Ar-H), 7.19 (s, 1H, Ar-H), 7.27–7.48 (m, 4 H, Ar-H), 7.74 (d, 3J(H-H) = 8.8 Hz, 1H, Ar-H), 7.82 (d, 3J(H-H) = 7.6 Hz, 2H, Ar-H), 8.12 (d, 3J(H-H)= 6.8 Hz, 1 H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 20.8, 29.8, 34.7, 59.4, 111.5, 112.6, 115.7, 117.7, 123.8, 125.3, 127.2, 127.9, 128.1, 128.6, 128.7, 130.0, 133.8, 138.1, 145.5, 146.1, 155.0; LC/MS: m/z 371 [M + H]+; Anal. Calcd. for C25H26N2O: C, 81.05; H, 7.07; N, 7.56. Found: C, 81.13; H, 7.12; N, 7.48.3-((2,4-Di-tert-butylphenoxy)methyl)-2-phenylimidazo [1,2-a]pyridine
(10k)
. Yield 0.34 g (84%; colorless solid); Mp 164–166C°; IR (νmax, cm−1): 2961, 1495, 1360, 1229, 1092, 993, 737; 1H NMR (400 MHz, CDCl3): δH 1.33 (s, 9H, (CH3)3), 1.35 (s, 9H, (CH3)3), 5.39 (s, 2H, CH2), 6.87 (t, 3J(H-H) = 6.8 Hz, 1H, Ar-H), 6.97 (d, 3J(H-H) = 8.4 Hz, 1H, Ar-H), 7.23–7.47 (m, 6H, Ar-H), 7.74 (d, 3J(H-H)= 8.8 Hz, 1H, Ar-H), 7.81 (d, 3J(H-H) = 7.2 Hz, 2H, Ar-H), 8.11 (d, 3J(H-H)= 6.8 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 29.9, 31.6, 34.4, 35.1, 59.4, 111.0, 112.6, 115.8, 117.8, 123.4, 123.9, 124.4, 125.3, 128.2, 128.7, 128.8, 133.9, 137.7, 143.4, 145.6, 146.3, 154.9; LC/MS: m/z 413 [M + H]+; Anal. Calcd. For C28H32N2O: C, 81.51; H, 7.82; N, 6.79. Found: C, 81.46; H, 7.88; N, 6.71.3-(Mesityloxymethyl)-2-phenylimidazo[1,2-a]pyridine
(10l)
. Yield 0.26 g (76%; colorless solid); Mp 126–128C°; IR (νmax, cm−1): 2917, 1482, 1358, 1198, 1142, 961, 747; 1H NMR (400 MHz, CDCl3): δH 2.07 (s, 6H, (CH3)2), 2.26 (s, 3H, CH3), 5.28 (s, 2H, CH2), 6.81 (s, 2H, Ar-H), 6.85–6.89 (m, 1H, Ar-H), 7.26–7.31 (m, 1H, Ar-H), 7.37–7.42 (m, 3H, Ar-H), 7.58–7.61 (m, 2H, Ar-H), 7.70 (d, 3J(H-H)= 8.8 Hz, 1H, Ar-H), 8.18 (d,3J(H-H) = 6.8 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 16.4, 20.7, 63.5, 112.6, 117.4, 117.6, 124.2, 125.3, 128.0, 128.5, 128.8, 129.7, 130.7, 133.7, 133.9, 145.3, 146.2, 153.3; LC/MS: m/z 343 [M + H]+; Anal. Calcd. for C23H22N2O: C, 80.67; H, 6.48; N, 8.18. Found: C, 80.59; H, 6.41; N, 8.25.2-Phenyl-3-((pyridine-4-yloxy)methyl)imidazo[1,2-a]pyridine
(10m)
. Yield 0.19 g (63%; colorless solid); Mp 102-103C°; IR (νmax, cm−1): 2923, 1505, 1302, 1142, 1084, 669, 546; 1H NMR (400 MHz, CDCl3): δH 4.87 (s, 2H, CH2), 6.95–7.74 (m, 12H, Ar-H), 8.47 (d, 3J(H-H) = 6.8 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 52.6, 108.4, 113.1, 117.3, 125.0, 126.3, 128.1, 128.2, 128.3, 128.8, 128.9, 129.8, 134.1, 145.3, 145.7; LC/MS: m/z 302 [M + H]+; Anal. Calcd. For C19H15N3O: C, 75.73; H, 5.02; N, 13.94. Found: C, 75.63; H, 5.10; N, 13.85.


## 2.1. General

All the chemicals used were purchased from Aldrich Chemical Co and were used without further purification. Freshly distilled solvents were used. For TLC, aluminum plates coated with silica gel containing F254 indicator were used, and the spots were visualized by UV light and/or by exposing to iodine. Column chromatography was performed on silica gel 100–200 mesh, using EtOAc and hexanes mixture as eluent. The1H and 13C spectra were recorded using 5 mm tubes on a Bruker 400 MHz NMR spectrometer field strengths: 400 and 100 MHz, resp. in CDCl3 solution (unless specified otherwise) with shifts referenced to SiMe4 (1H, 13C: δ=0), respectively. All J values were in Hz. IR spectra were recorded on a JASCO FT/IR 5300 spectrometer. Elemental (C, H, N) analysis was done using Perkin-Elmer 240C CHN FLASH EA analyzer. Melting points were determined by using a SUPERFIT hot-stage melting point apparatus and are uncorrected.4-Methyl-N′-{(2-phenylimidazo[1,2-a]pyridine-3-yl)methylene}benzenesulfonohydrazide(8). To a rapidly stirred suspension of toluenesulfonyl hydrazide (4.6 g, 24.7 mmol) in methanol (10 mL) a solution of aldehyde 7 (5 g, 22.5 mmol) in methanol (20 mL) portion wise for a period of 15 minutes was added. A mildly exothermic reaction occurred and the solution became transparent. Within 15–20 min the tosylhydrazone began to precipitate. After stirring for 1 h the mixture was filtered, and the filter cake was washed with small quantity of methanol. The obtained product 8 was dried and used in the next step without further purification. Yield: 7.65 g (98%; colorless solid); Mp 102–104C°; IR (νmax, cm−1): 3379, 2762, 1605, 1345, 1166, 947, 739; 1H NMR (400 MHz, CDCl3): δH 2.42 (s, 3H, CH3), 7.02–7.06 (m, 1H, Ar-H), 7.32–7.54 (m, 8H, Ar-H), 7.76, (d, 3J(H-H) = 8.8 Hz, 1H, Ar-H), 7.90, (d, 3J(H-H) = 8.0 Hz, 2H, Ar-H), 8.16 (s, 1H, Ar-H), 9.34 (d, 3J(H-H) = 6.8 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 21.6, 114.1, 114.9, 117.2, 127.7, 127.9, 128.7(6), 128.7(4), 128.9, 129.2, 129.8, 132.7, 135.3, 140.3, 144.4, 146.8, 151.1; LC/MS: m/z 391 [M + H]+; Anal. Calcd. for C21H18N4O2S: C, 64.60; H, 4.65; N, 14.35. Found: C, 64.69; H, 4.60; N, 14.45.General Procedure for the Synthesis Ether Derivatives: 2-Phenyl-3-(P-tolyloxymethyl)imidazo[1,2-a]pyridine
(10a)
. An oven-dried 10 mL round bottom flask was charged with tosylhydrazone 8 (391 mg, 1.0 mmol), p-cresol (216 mg, 2.0 mmol), and K2CO3 (483 mg, 3.5 equiv). The flask was evacuated for 5 min and filled with N2. To this dioxane (4 mL) was added and contents were stirred at 110C° for 12 h under nitrogen. After completion of the reaction (monitored by TLC), the mixture was cooled to room temperature and the solvent was evaporated by rotary evaporator to obtain the crude reaction mixture. To this, saturated solution of NaOH (5 mL) and dichloromethane (15 mL) were added subsequently and the layers were separated. The aqueous phase was extracted with dichloromethane (2×5 mL). The combined organic layers were washed with NaOH solution (2×5 mL), brine (3×5mL) and then dried over anhydrous Na2SO4. The crude product was purified by column chromatography (hexane:EtOAc 6 : 4) to afford 10a. Yield 0.20 g (64%; colorless solid); Mp 116–118°C; IR (νmax, cm−1): 3015, 1507, 1358, 1225, 1034, 976, 739; 1H NMR (400 MHz, CDCl3): δH 2.32 (s, 3H, CH3), 5.40 (s, 2H, CH2), 6.86–6.92 (m, 3H, Ar-H), 7.12–7.49 (m, 6H, Ar-H), 7.70 (d, 3J(H-H) = 9.2 Hz, 1H, Ar-H), 7.77 (s, 1H, Ar-H), 7.79 (d, 3J(H-H) = 1.2 Hz, 1H, Ar-H), 8.16 (d, 3J(H-H) = 6.8 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 20.5, 60.1, 112.7, 114.8, 115.5, 117.7, 124.2, 125.3, 128.2, 128.7, 130.1, 131.0, 133.9, 145.5, 146.2, 156.0; LC/MS: m/z 315 [M + H]+; Anal. Calcd. For C21H18N2O: C, 80.23; H, 5.77; N, 8.91. Found: C, 80.32; H, 5.81; N, 8.79.2-Phenyl-3-(o-tolyloxymethyl)imidazo[1,2-a]pyridine
(10b)
. Yield: 0.24 g (76%; colorless solid); Mp 110–112C°; IR (νmax, cm−1): 2924, 1458, 1233, 1192, 1117, 997, 750; 1H NMR (400 MHz, CDCl3): δH 2.21 (s, 3H, CH3), 5.44 (s, 2H, CH2), 6.87–6.84 (m, 3H, Ar-H), 7.19–7.32 (m, 3H, Ar-H), 7.41–7.50 (m, 3H, Ar-H), 7.71–7.79 (m, 3H, Ar-H), 8.18 (d, 3J(H-H) = 6.8 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 16.3, 60.0, 111.5, 112.6, 115.7, 117.7, 121.3, 124.1, 125.3, 126.9, 127.4, 128.2, 128.7, 131.0, 133.9, 145.6, 156.2. LC/MS: m/z 315 [M + H]+; Anal. Calcd. For C21H18N2O: C, 80.23; H, 5.77; N, 8.91. Found: C, 80.12; H, 5.72; N, 8.97.3-((4-tert-Butylphenoxy)methyl)-2-phenylimidazo[1,2-a]pyridine
(10c)
. Yield: 0.31 g (87%; colorless solid); Mp 134–136C°; IR (νmax, cm−1): 2948, 1607, 1507, 1233, 1181, 999, 737; 1H NMR (400 MHz, CDCl3): δH 1.33, (s, 9H, (CH3)3), 5.41, (s, 2H, CH2), 6.87, (t, 3J(H-H) = 6.8 Hz, 1H, Ar-H), 6.98, (d, 3J(H-H) = 8.8 Hz, 2H, Ar-H), 7.28–7.49, (m, 6H, Ar-H), 7.70, (d, 3J(H-H) = 9.2 Hz, 1H, Ar-H), 7.79, (d,3J(H-H) = 7.6 Hz, 2H, Ar-H), 8.15, (d, 3J(H-H)= 6.8 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 31.5, 34.1, 59.9, 112.6, 114.4, 115.5, 117.6, 124.1, 125.3, 126.4, 128.2, 128.7, 133.9, 144.4, 145.5, 146.2, 155.9; LC/MS: m/z 357 [M + H]+; Anal. Calcd. For. C24H24N2O: C, 80.87; H, 6.79; N, 7.86. Found: C, 80.77; H, 6.75; N, 7.80.3-((4-Methoyphenoxy)methyl)-2-phenylimidazo[1,2-a]pyridine
(10d)
. Yield 0.29 g (88%; colorless solid); Mp 116–118C°; IR (νmax, cm−1): 3011, 1507, 1358, 1225, 1034, 976, 738; 1H NMR (400 MHz, CDCl3): δH 3.79 (s, 3H, OCH3), 5.38 (s, 2H, CH2), 6.84–6.95 (m, 5H, Ar-H), 7.29–7.49 (m, 4H, Ar-H), 7.71 (d, 3J(H-H) = 8.8 Hz, 1H, Ar-H), 7.77 (d, 3J(H-H) = 7.2 Hz, 2H, Ar-H), 8.17 (d, 3J(H-H) = 6.8 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 55.8, 60.8, 112.7, 114.8, 115.7, 116.2, 117.7, 124.2, 125.3, 128.2, 128.7, 134.0, 145.6, 146.3, 152.2, 154.6; LC/MS: m/z 331 [M + H]+; Anal. Calcd. For C21H18N2O2: C, 76.34; H, 5.49; N, 8.48. Found: C, 76.43; H, 5.48; N, 8.45.3-((4-Chlorophenoxy)methyl)-2-phenylimidazo[1,2-a]pyridine
(10e)
. Yield: 0.28 g (84%; colorless solid); Mp 134–136C°; IR (νmax, cm−1): 3044, 2922, 1491, 1356, 1231, 984, 817, 735; 1H NMR (400 MHz, CDCl3): δH 5.41 (s, 2H, CH2), 6.90 (s, 1H, Ar-H), 6.92 (s, 2H, Ar-H), 7.27–7.76 (m, 9H, Ar-H), 8.15 (d, 3J(H-H)= 5.6 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 60.3, 112.9, 115.0, 116.3, 117.8, 124.1, 125.5, 126.6, 128.4, 128.7, 128.8, 129.6, 133.8, 145.6, 146.5, 156.7; LC/MS: m/z 335 [M + H]+; Anal. Calcd. For C20H15ClN2O: C, 71.75; H, 4.52; N, 8.37. Found: C, 71.65; H, 4.58; N, 8.31.3-((4-Nitrophenoxy)methyl)-2-phenylimidazo[1,2-a]pyridine
(10f)
. Yield 0.25 g (73%;  yellow colored solid); Mp 132–134C°; IR (νmax, cm−1): 2924, 1505, 1318, 1146, 1086, 754, 700. 1H NMR (400 MHz, CDCl3): δH 4.85 (s, 2H, CH2), 6.89 (t, 3J(H-H) = 6.8 Hz, 1H, Ar-H), 7.04–7.17 (m, 3H, Ar-H), 7.29–7.36 (m, 7H, Ar-H), 7.66 (d, 3J(H-H) = 9.2 Hz, 1H, Ar-H), 8.41 (d, 3J(H-H) = 6.8 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 52.4, 108.2, 112.8, 117.1, 124.8, 126.0, 127.9, 128.0(9),128.0(0), 128.1, 129.6, 132.6, 134.0, 145.1, 145.6, 146.9; LC/MS: m/z 346 [M + H]+; Anal. Calcd. For C20H15N3O3: C, 69.56; H, 4.38; N, 12.17. Found: C, 69.45; H, 4.31; N, 12.25.3-((2,4-Dimethylphenoxy)methyl)-2-phenylimidazo[1,2-a]pyridine
(10g)
. Yield 0.26 g (79%; colorless solid); Mp 110–112C°; IR (νmax, cm−1): 2921, 1505, 1356, 1215, 1129, 984, 741; 1H NMR (400 MHz, CDCl3): δH 2.18 (s, 3H, CH3), 2.30 (s, 3H, CH3), 5.40 (s, 2H, CH2), 6.83–6.98 (m, 3H, Ar-H), 7.02 (s, 1H, Ar-H), 7.28–7.50 (m, 4H, Ar-H), 7.72 (d, 3J(H-H) = 8.8 Hz, 1H, Ar-H), 7.79 (d, 3J(H-H) = 7.6 Hz, 2H, Ar-H), 8.16 (d, 3J(H-H) = 6.8 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 16.2, 20.4, 60.1, 111.6, 112.5, 115.9, 117.6, 124.0, 125.2, 127.0, 127.1, 128.1, 128.7, 130.5, 131.8, 133.9, 145.4, 146.1, 154.1; LC/MS: m/z 329 [M + H]+; Anal. Calcd. for C22H20N2O: C, 80.46; H, 6.14; N, 8.53. Found: C, 80.35, H, 6.18, N, 8.45.3-((3,5-Dimethylphenoxy)methyl)-2-phenylimidazo[1,2-a]pyridine
(10h)
. Yield: 0.31 g (95%; colorless solid); Mp: 126-128C°; IR (νmax, cm−1): 2919, 1593, 1502, 1404, 1294, 1154, 736; 1H NMR (400 MHz, CDCl3): δH 2.29 (s, 6H, (CH3)2), 5.43 (s, 2H, CH2), 6.63 (s, 2H, Ar-H). 6.68 (s, 1H, Ar-H), 6.91 (t, 3J(H-H) = 6.8 Hz, 1H, Ar-H), 7.31–7.52 (m, 3H, Ar-H), 7.73 (d, 3J(H-H) = 8.8 Hz, 1H, Ar-H), 7.79–7.81 (m, 3H, Ar-H), 8.19 (d, 3J(H-H) = 6.8 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 21.4, 59.6, 112.6, 112.7, 115.6, 117.6, 123.3, 124.2, 125.4, 128.2, 128.8(7), 128.8(1), 133.9, 139.5, 145.5, 146.1, 158.1; LC/MS: m/z 329 [M + 1]+; Anal. Calcd. for C22H20N2O: C, 80.46; H, 6.14; N, 8.53. Found: C, 80.32; H, 6.19; N, 8.45.3-((2,6-Dimethylphenoxy)methyl)-2-phenylimidazo[1,2-a]pyridine
(10i)
. Yield 0.21 g (64%; colorless solid); Mp 118–120C°; IR (νmax, cm−1): 2924, 1503, 1358, 1190, 1090, 955, 764; 1H NMR (400 MHz, CDCl3): δH 2.09 (s, 6H, (CH3)2), 5.31 (s, 2H, CH2), 6.85–7.00 (m, 4H, Ar-H), 7.27–7.39 (m, 4H, Ar-H), 7.58 (d, 3J(H-H) = 7.2 Hz, 2H, Ar-H), 7.69 (d, 3J(H-H) = 8.8 Hz, 1H, Ar-H), 8.14 (d, 3J(H-H) = 6.4 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 16.5, 63.4, 112.5, 117.2, 117.6, 124.1, 124.4, 125.2, 128.0, 128.5, 128.7, 129.1, 131.1, 133.8, 145.3, 146.2, 155.6; LC/MS: m/z 329 [M + H]+; Anal. Calcd. for C22H20N2O: C, 80.46; H, 6.14; N, 8.53. Found: C, 80.35; H, 6.22; N, 8.61.3-((2-tert-Butyl-4-methylphenoxy)methyl)-2-phenyl-imidazo[1,2-a]pyridine
(10j)
. Yield 0.30 g (81%; colorless solid); Mp 144–146C°; IR (νmax, cm−1): 2957, 1499, 1362, 1219, 1094, 1004, 731; 1H NMR (400 MHz, CDCl3): δH 1.32 (s, 9H, (CH3)3), 2.35 (s, 3H, CH3), 5.38 (s, 2H, CH2), 6.87 (t, 3J(H-H) = 6.8 Hz, 1H, Ar-H), 6.94 (d, 3J(H-H) = 8.4 Hz, 1H, Ar-H), 7.04 (d, 3J(H-H) = 8.0 Hz, 1H, Ar-H), 7.19 (s, 1H, Ar-H), 7.27–7.48 (m, 4 H, Ar-H), 7.74 (d, 3J(H-H) = 8.8 Hz, 1H, Ar-H), 7.82 (d, 3J(H-H) = 7.6 Hz, 2H, Ar-H), 8.12 (d, 3J(H-H)= 6.8 Hz, 1 H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 20.8, 29.8, 34.7, 59.4, 111.5, 112.6, 115.7, 117.7, 123.8, 125.3, 127.2, 127.9, 128.1, 128.6, 128.7, 130.0, 133.8, 138.1, 145.5, 146.1, 155.0; LC/MS: m/z 371 [M + H]+; Anal. Calcd. for C25H26N2O: C, 81.05; H, 7.07; N, 7.56. Found: C, 81.13; H, 7.12; N, 7.48.3-((2,4-Di-tert-butylphenoxy)methyl)-2-phenylimidazo [1,2-a]pyridine
(10k)
. Yield 0.34 g (84%; colorless solid); Mp 164–166C°; IR (νmax, cm−1): 2961, 1495, 1360, 1229, 1092, 993, 737; 1H NMR (400 MHz, CDCl3): δH 1.33 (s, 9H, (CH3)3), 1.35 (s, 9H, (CH3)3), 5.39 (s, 2H, CH2), 6.87 (t, 3J(H-H) = 6.8 Hz, 1H, Ar-H), 6.97 (d, 3J(H-H) = 8.4 Hz, 1H, Ar-H), 7.23–7.47 (m, 6H, Ar-H), 7.74 (d, 3J(H-H)= 8.8 Hz, 1H, Ar-H), 7.81 (d, 3J(H-H) = 7.2 Hz, 2H, Ar-H), 8.11 (d, 3J(H-H)= 6.8 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 29.9, 31.6, 34.4, 35.1, 59.4, 111.0, 112.6, 115.8, 117.8, 123.4, 123.9, 124.4, 125.3, 128.2, 128.7, 128.8, 133.9, 137.7, 143.4, 145.6, 146.3, 154.9; LC/MS: m/z 413 [M + H]+; Anal. Calcd. For C28H32N2O: C, 81.51; H, 7.82; N, 6.79. Found: C, 81.46; H, 7.88; N, 6.71.3-(Mesityloxymethyl)-2-phenylimidazo[1,2-a]pyridine
(10l)
. Yield 0.26 g (76%; colorless solid); Mp 126–128C°; IR (νmax, cm−1): 2917, 1482, 1358, 1198, 1142, 961, 747; 1H NMR (400 MHz, CDCl3): δH 2.07 (s, 6H, (CH3)2), 2.26 (s, 3H, CH3), 5.28 (s, 2H, CH2), 6.81 (s, 2H, Ar-H), 6.85–6.89 (m, 1H, Ar-H), 7.26–7.31 (m, 1H, Ar-H), 7.37–7.42 (m, 3H, Ar-H), 7.58–7.61 (m, 2H, Ar-H), 7.70 (d, 3J(H-H)= 8.8 Hz, 1H, Ar-H), 8.18 (d,3J(H-H) = 6.8 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 16.4, 20.7, 63.5, 112.6, 117.4, 117.6, 124.2, 125.3, 128.0, 128.5, 128.8, 129.7, 130.7, 133.7, 133.9, 145.3, 146.2, 153.3; LC/MS: m/z 343 [M + H]+; Anal. Calcd. for C23H22N2O: C, 80.67; H, 6.48; N, 8.18. Found: C, 80.59; H, 6.41; N, 8.25.2-Phenyl-3-((pyridine-4-yloxy)methyl)imidazo[1,2-a]pyridine
(10m)
. Yield 0.19 g (63%; colorless solid); Mp 102-103C°; IR (νmax, cm−1): 2923, 1505, 1302, 1142, 1084, 669, 546; 1H NMR (400 MHz, CDCl3): δH 4.87 (s, 2H, CH2), 6.95–7.74 (m, 12H, Ar-H), 8.47 (d, 3J(H-H) = 6.8 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 52.6, 108.4, 113.1, 117.3, 125.0, 126.3, 128.1, 128.2, 128.3, 128.8, 128.9, 129.8, 134.1, 145.3, 145.7; LC/MS: m/z 302 [M + H]+; Anal. Calcd. For C19H15N3O: C, 75.73; H, 5.02; N, 13.94. Found: C, 75.63; H, 5.10; N, 13.85.


## 3. Results and Discussion

Towards the synthesis of 3-substituted imidazo[1,2-a]pyridine derivatives, we were attracted by recent reports on the use of tosylhydrazones in C–C and C–O bond formation under metal-free reaction conditions [21–24].2-Phenyl-imidazo[1,2-a]pyridine 6 was synthesized by refluxing 2-aminopyridine 4 and bromoacetophenone 5 in ethanol for 4 h. Vilsmeier-Haack formylation of 6 provided aldehyde 7 [9, 10] in excellent yield. Treatment of 7 with tosylhydrazide lead to the required hydrozone precursor 8 which was used for etherification reaction (Scheme 1).Scheme 1
Synthesis of imidazo[1,2-a]pyridine-derived tosylhydrazone precursor.We first examined the reaction of tosyl hydrazone8with p-cresol 9a in the presence of K2CO3 as a base in dioxane solvent at 110C°. We were pleased to find that the reaction proceeded smoothly to afford the corresponding ether, 10a in 95% yield. The scope of the reaction was further carried out using various monosubstituted phenols (Table 1 entries 1–5). Irrespective of the electronic and steric factors of the substituents all the reactions provided the corresponding ethers (10b-10f) in excellent yield (73–88%). Similarly, the disubstituted phenols (Table 1 entries 6–10) and the trisubstituted phenol (entry 11) also provided the corresponding imidazo[1,2-a]pyridine derivatives bearing an ether side chain at 3-position (10g-10l). Interestingly, reaction of tosylhydrazone 8 with 4-hydroxypyridine also afforded the corresponding ether derivative 10 m in 63% yield.Table 1
Scope of the synthesis of C-3-aryl ether substituted 2-phenyl imidazo[1,2-a]pyridines 10a–10m. aReaction conditions: Tosylhydrazone 8 (1.0 mmol), phenol (2.0 mmol), K2CO3(3.5 mmol) dioxane (4.0 mL), 110°C, 12 h. byield refers to pure and isolated.
Serial no.
Ether
Yield (%)
Serial no.
Ether
Yield (%)
1
76
7
95
2
87
8
64
3
88
9
81
4
84
10
84
5
73
11
76
6
79
12
63


## 4. Conclusion

In conclusion, we have demonstrated a convenient method for the synthesis of C-3 aryl ether derivatives of imidazo[1,2-a]pyridine via insertion reaction of in situ generated diazocompound with various phenols. This method is fairly general and provides access for the synthesis of aryl ether imidazo[1,2-a]pyridine compounds. The bioactivity assays of these derivatives against HCV and VZV are under progress.



---

*Source: 296792-2012-10-21.xml*