Catalyst: and solvent-free synthesis of imidazo[1,2-a]pyridines

Abstracts

A highly efficient and facile method has been described for the synthesis of imidazo[1,2-a]pyridines in good to excellent yields by condensation of the α-haloketones (ArCOCHXR², Ar = C6H5, 4-MeOC6H4, 4-ClC6H4, 2,4-Cl2C6H3; X = Br, Cl; R² = H, CH3) with 2-aminopyridines without the use of any additional catalyst and solvent.

imidazo[1,2-a]pyridines; α-haloketones; 2-aminopyridines; catalyst-free; solvent-free

Um método altamente eficiente e simples foi descrito para a síntese de imidazo[1,2-a]piridinas pela condensação de α-halocetonas (ArCOCHXR², Ar = C6H5, 4-MeOC6H4, 4-ClC6H4, 2,4-Cl2C6H3; X = Br, Cl; R² = H, CH3) com 2-aminopiridinas, apresentando rendimentos entre bons a excelentes sem a necessidade de adição de catalisador e solvente.

ARTICLE

Catalyst- and solvent-free synthesis of imidazo[1,2-a]pyridines

Dong-Jian Zhu^I; Jiu-Xi ChenI,^*; Miao-Chang Liu^I; Jin-Chang Ding^I,II; Hua-Yue WuI,^*

^ICollege of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, 325027, China

^IIWenzhou Vocational and Technical College, Wenzhou, 325035, China

ABSTRACT

A highly efficient and facile method has been described for the synthesis of imidazo[1,2-a]pyridines in good to excellent yields by condensation of the α-haloketones (ArCOCHXR², Ar = C₆H₅, 4-MeOC₆H₄, 4-ClC₆H₄, 2,4-Cl₂C₆H₃; X = Br, Cl; R² = H, CH₃) with 2-aminopyridines without the use of any additional catalyst and solvent.

Keywords: imidazo[1,2-a]pyridines, α-haloketones, 2-aminopyridines, catalyst-free, solvent-free

RESUMO

Um método altamente eficiente e simples foi descrito para a síntese de imidazo[1,2-a]piridinas pela condensação de α-halocetonas (ArCOCHXR², Ar = C₆H₅, 4-MeOC₆H₄, 4-ClC₆H₄, 2,4-Cl₂C₆H₃; X = Br, Cl; R² = H, CH₃) com 2-aminopiridinas, apresentando rendimentos entre bons a excelentes sem a necessidade de adição de catalisador e solvente.

Introduction

It has long been known that imidazo[1,2-a]pyridine derivatives exhibit diverse biological activities¹ and were used as antiviral,² antiulcer,³ antibacterial,⁴ antifungal,⁵ antiprotozoal,⁶ antiherpes,⁷ anti-inflammatory.⁸ Recently, Leopoldo et al.⁹ reported synthetic approaches leading to 4-[ω-[4-arylpiperazin-1-yl]alkoxy]phenyl) imidazo[1,2-a] pyridine derivatives (Figure 1, I), which were described as fluorescent high-affinity dopamine D₃ receptor ligands as potential probes for receptor visualization, and the fluorescent moiety compound 2-(4-methoxyphenyl)imidazo[1,2-a]pyridine (Figure 1, II), which is characterized by the 2-phenylimidazo[1,2-a]pyridine moiety, presented an oxygen that can be easily functionalized to afford potential D₃ receptor ligands structurally related to the D₃ receptor ligands.¹⁰ The majority of reported imidazo[1,2-a]pyridines syntheses proceeded from the condensation reaction of the α-bromocarbonyl compounds with 2-aminopyridine derivative under neutral¹¹ or weak basic conditions.¹² A mechanism for the reaction has been proposed,¹³ which includes the nucleophilic substitution of the bromide by the pyridine-nitrogen in the 2-aminopyridine derivative. Imidazo[1,2-a]pyridine derivatives were also synthesized by solid support¹⁴ and using catalyst such as Al₂O₃¹⁵ and TiCl₄.¹⁶ Other methodologies included treating 2-aminopyridines with α-tosyloxyketones,¹⁷ a polymer supported [hydroxy(sulfonyloxy)iodo]benzene with ketones or alcohols,¹⁸ alkynyl(phenyl)iodonium salts,¹⁹α-diazoketones,²⁰ and propargyl bromide.²¹ Although these methods are suitable for certain synthetic conditions sometimes, however, some of these procedures are associated with one or more disadvantages such as hazardous organic solvents, high cost, long reaction time, low yield, use of stoichiometric and even excess amounts of reagents or catalysts, special apparatus and drastic reaction conditions, which leaves scope for further development of new environmentally clean syntheses.

As the increase in environmental consciousness chemical research and industry,²² the challenge for a sustainable environment calls for clean procedures that can avoid using harmful organic solvents, or even better, do not need solvent at all. In continuation of our interest in green chemistry,²³ we herein wish to report the neat reaction of 2-aminopyridine with α-haloketones under catalyst- and solvent-free conditions, affording imidazo[1,2-a]pyridine derivatives in good to excellent yields.

Results and Discussion

To optimize the reaction conditions, initial studies were concentrated on reactions of the α-bromoacetophenone with 2-aminopyridine as a model reaction. After careful screening, to our delight, the reaction occurred for 20 min affording 2-phenylimidazo[1,2-a]pyridine (3a) in 91% yield at 60 ºC in the absence of catalyst and solvent (Table 1, entry 11). It was observed that the mixture was initially in a solid state, and then turned to liquid state during the process of stirring, finally solidified to a light yellow solid mass.

Encouraged by this result, we further carried out comparative reactions to optimize the reaction conditions. The results are summarized in Table 1. When the reaction was carried out at room temperature in the absence of catalyst and solvent, only 65% yield was obtained, even when the reaction time was prolonged to 24 h (Table 1, entry 12). The nonpolar solvents, such as n-hexane, toluene, CCl₄ gave lower yields under similar reaction conditions (Table 1, entries 1-3). The polar aprotic solvents (CH₂Cl₂, THF and CH₃CN) also afforded comparatively lower yields (Table 1, entries 4-6). The polar protic solvents (C₂H₅OH, CH₃OH, PEG-400 and H₂O) still gave comparatively lower conversions (Table 1, entries 7-10). It is remarkable that the reaction carried out at 60 ºC in the absence of catalyst and solvent afforded 3a in excellent yield (91%), which is significantly higher than those obtained for the nonpolar or polar solvents. The structure of 3a was characterized by ¹H NMR, ¹³C NMR, IR and by comparison with authentic samples prepared by literature procedure. The ¹H NMR spectra of 3a shows a characteristic peak at δ 7.87 ppm corresponding to the hydrogen of imidazole ring, whereas in the ¹³C NMR spectrum, the peak appearing of δ 108.1, 145.7 and 145.8 ppm corresponds to C-3, C-2 and C-9, respectively, of the imidazole ring. And in the IR spectrum, the structure of 3a showed C=N stretching peak at 1625 cm^-1.

With the optimized conditions in hand, the reactions of different 2-aminopyridines with various α-haloketones were examined to explore the scope and generality of this present protocol for the synthesis of various imidazo[1,2-a]pyridines (Table 2). As expected, the reaction proceeded smoothly with yields ranging from good to excellent and tolerated various functional groups such as chloro, methyl and methoxy groups.

As shown in Table 2, the α-bromoacetophenone with electron-rich functionality as well as electron-poor functionality undergoes condensation reaction with 2-aminopyridine or substituted 2-aminopyridine equally well to afford the corresponding products in good to excellent yields. Even when employing the hindered α-methylphenacyl bromide and 2-aminopyridine or 2-amino-5-methylpyridine, good yields (Table 2, entries 10-11, 70% and 64%, respectively) were also obtained after slightly prolonging the reaction time to 60 min. Nevertheless, 2-aminopyridine with electron-withdrawing substituted group chloro is less nucleophilic and more slowly than electron-neutral or donating analogues.

Encouraged by our success, we screened a few reactions of the commercially available and deactivated α-chloroketone with 2-aminopyridine or 2-amino-5-methylpyridine. To our delight, when employing α-chloroacetophenone and 2-aminopyridine or 2-amino-5-methylpyridine, excellent yields (Table 2, entries 12-13, 83% and 88%, respectively) were obtained after slightly prolonging the reaction time to 80 min and 40 min, respectively. Furthermore, the para- and ortho-substituted 2,2',4'-trichloroacetophenone with 2-aminopyridine or 2-amino-5-methylpyridine also can afford the corresponding products 3l and 3m in 75% and 65% yields, respectively (Table 2, entries 14-15).

In summary, we have described a simple, highly efficient, and facile procedure for the synthesis of imidazo[1,2-a]pyridine derivatives from the readily available starting materials. To the best of our knowledge, this is the first report catalyst-free synthesis of imidazo[1,2-a]pyridines in the absence of solvent under mild conditions. The procedure offers simple experimental procedure, short reaction time, catalyst-free, solvent free, low cost, efficient yield and mild reaction conditions, which makes this method a useful and attractive strategy in view of economic and environmental advantages. Currently, studies on the extension of this protocol are ongoing in our laboratory.

Experimental

All reagents were commercial available and used without any purification. Melting points were recorded on Digital Melting Point Apparatus WRS-1B and are uncorrected. IR spectra were recorded on a Bruker-EQUINOX55 spectrometer. Mass spectra (EI, 70 ev) were measured with SHIMADZU GCMS-QP2010 Plus. ¹H NMR and ¹³C NMR spectra were recorded on a Brucker AC 300 instrument using CDCl₃ as the solvent with tetramethylsilane (TMS) as an internal standard at room temperature. Chemical shifts were given in d relative to TMS, the coupling constants J are given in Hz. Elemental analysis was determined on a Carlo-Erba 1108 instrument. All reactions were conducted using standard Schlenk techniques. Column chromatography was performed using EM Silica gel 60 (300-400 mesh).

General procedure for the preparation of pyrazoles

A mixture of α-haloketone 2 (1.0 mmol), 2-aminopyridine or substituted 2-aminopyridine 1 (1.0 mmol) was stirred at 60 ºC under vigorous magnetic stirring for the specified time as mentioned in Table 2. The progress of the reaction was monitored by TLC. After completion of the reaction, the product was washed with dehydrated alcohol or ethyl acetate (3 × 10 mL). The combined organic solvent was removed under vacuum to obtain the crude solid product. The crude product was further purified by silica gel column chromatography using ethyl acetate-petroleum ether (1:3) as eluent to afford the pure product 3.

The spectral and analytical data of all compounds are given below.

2-Phenylimidazo[1,2-a]pyridine (3a)

White solid, mp 136-137 ºC (lit. 131-133 ºC);²⁰¹H NMR (300 MHz, CDCl₃) δ (ppm) 8.12 (dd, J 1.04, 1.03, 1H), 7.98-7.96 (m, 2H), 7.88 (s, 1H), 7.64 (d, J 9.14, 1H), 7.45 (t, J 7.22, 2H), 7.35 (d, J 7.33, 1H), 7.20-7.17 (m, 1H), 6.79 (d, J 6.78, 1H); ¹³C NMR (75 MHz, CDCl₃) δ (ppm) 145.8, 145.7, 133.8, 128.7, 127.9, 126.0, 125.6, 124.6, 117.5, 112.4, 108.1. IR (KBr) ν_max/cm^-1: 2925, 2857, 1738, 1625, 1511, 1460, 1383, 1269, 1201, 1122, 1081, 1040, 744, 688, 458. MS (ESI): m/z (%) 195 ([M+H]⁺, 100).

6-Methyl-2-phenylimidazo[1,2-a]pyridine (3b)

White solid, mp 171-173 ºC (lit. 172-174 ºC);²⁴¹H NMR (300 MHz, CDCl₃) δ (ppm) 7.95 (d, J 7.05, 2H), 7.83 (s, 1H), 7.73 (s, 1H), 7.53 (d, J 9.09, 1H), 7.44 (t, J 6.63, 2H), 7.33 (d, J 6.44, 1H), 7.00 (d, J 8.82, 1H), 2.29 (s, 3H, CH₃); ¹³C NMR (75 MHz, CDCl₃) δ (ppm) 145.4, 144.7, 133.9, 128.7, 127.84, 127.78, 125.9, 123.3, 122.0, 116.7, 107.9, 18.0; IR (KBr) ν_max/cm^-1: 2921, 1628, 1525, 1471, 1418, 1342, 1259, 1206, 1159, 1079, 846, 805, 768, 715, 685, 571, 506.

6-Chloro-2-phenylimidazo[1,2-a]pyridine (3c)

White solid, mp 204-206 ºC (lit. 204-207 ºC);²⁵¹H NMR (300 MHz, CDCl₃) δ (ppm) 8.15 (s, 1H), 7.94 (d, J 7.25, 2H), 7.82 (s, 1H), 7.57 (d, J 9.12, 1H), 7.51-7.38 (m, 2H), 7.34 (d, J 7.19, 1H), 7.14 (d, J 9.41, 1H); ¹³C NMR (75 MHz, CDCl₃) δ (ppm) 146.9, 144.1, 133.3, 128.8, 128.3, 126.1, 126.0, 123.4, 120.5, 117.9, 108.5; IR (KBr) ν_max/cm^-1: 2976, 2925, 1635, 1512, 1473, 1425, 1387, 1332, 1241, 1206, 1133, 1074, 938, 809, 772, 719, 506.

2-(4-Methoxyphenyl)imidazo[1,2-a]pyridine (3d)

White solid, mp 135-136 ºC (lit. 133-134 ºC);¹⁷¹H NMR (300 MHz, CDCl₃) δ (ppm) 8.09 (d, J 6.77, 1H), 7.89 (dd, J 1.95, 1.94, 2H), 7.77 (s, 1H), 7.61 (d, J 9.08, 1H), 7.17-7.15 (m, 1H), 6.97 (dd, J 1.97, 1.94, 2H), 6.76 (dd, J 0.82, 0.81, 1H), 3.85 (s, 3H, OCH₃); ¹³C NMR (75 MHz, CDCl₃) δ (ppm) 159.6, 145.64, 145.57, 127.3, 126.4, 125.4, 124.5, 117.2, 114.1, 112.3, 107.2, 55.3; IR (KBr) ν_max/cm^-1: 2961, 2838, 1612, 1548, 1482, 1371, 1285, 1244, 1175, 1110, 1077, 1030, 924, 838, 743, 631, 536, 446.

2-(4-Methoxyphenyl)-6-methylimidazo[1,2-a]pyridine (3e)

White solid, mp 179-181 ºC; ¹H NMR (300 MHz, CDCl₃) δ (ppm) 7.88 (d, J 2.26, 2H), 7.86 (d, J 2.11, 1H), 7.68 (s, 1H), 7.51 (d, J 9.48, 1H), 7.01 (d, J 1.57, 2H), 6.96 (dd, J 2.10, 2.06, 1H), 3.85 (s, 3H, OCH₃), 2.31 (s, 3H, CH₃); ¹³C NMR (75 MHz, CDCl₃) δ (ppm) 159.5, 145.3, 144.6, 127.7, 127.2, 126.6, 123.3, 121.9, 116.5, 114.1, 107.0, 55.3, 18.1; IR (KBr) ν_max/cm^-1: 2926, 1612, 1546, 1483, 1413, 1341, 1301, 1246, 1174, 1103, 1023, 839, 794, 744, 710, 591, 528; MS (ESI): m/z (%), 239 ([M+H]⁺, 100); Anal. calc. for C₁₅H₁₄N₂O: C, 75.61; H, 5.92; N, 11.76. Found: C, 75.63; H, 5.90; N, 11.78.

6-Chloro-2-(4-methoxyphenyl)imidazo[1,2-a]pyridine (3f)

White solid, mp 234-236 ºC (lit. 227-228 ºC);²⁶¹H NMR (300 MHz, CDCl₃) δ (ppm) 8.16-8.15 (m, 1H), 7.88 (dd, J 2.05, 2.04, 2H), 7.75 (s, 1H), 7.56 (d, J 9.54, 1H), 7.13 (dd, J 1.99, 1.96, 1H), 6.99 (dd, J 2.00, 2.01, 2H), 3.87 (s, 3H, OCH₃); ¹³C NMR (75 MHz, CDCl₃) δ (ppm) 160.1, 147.1, 144.2, 127.6, 126.3, 126.0, 123.4, 120.5, 117.8, 114.4, 107.8, 55.5. IR (KBr) ν_max/cm^-1: 2995, 1610, 1551, 1487, 1371, 1305, 1250, 1176, 1108, 1070, 1030, 933, 841, 803, 742, 705, 575, 524; MS (ESI): m/z (%), 259 ([M+H]⁺, 100).

2-(4-Chlorophenyl)imidazo[1,2-a]pyridine (3g)

White solid, mp 207-209 ºC (lit. 201 ºC);¹⁸¹H NMR (300 MHz, CDCl₃) δ (ppm) 8.09 (d, J 6.78, 1H), 7.87 (d, J 8.52, 2H), 7.82 (s, 1H), 7.61 (d, J 9.15, 1H), 7.39 (d, J 8.52, 2H), 7.17 (t, J 7.17, 1H), 6.77 (t, J 6.60, 1H); ¹³C NMR (75 MHz, CDCl₃) δ (ppm) 145.7, 144.6, 133.6, 132.3, 128.9, 127.2, 125.6, 124.9, 117.5, 112.6, 108.2; IR (KBr) ν_max/cm^-1: 2917, 1632, 1471, 1369, 1250, 1202, 1089, 1009, 933, 830, 742, 598, 510.

2-(4-Chlorophenyl)-6-methylimidazo[1,2-a]pyridine (3h)

White solid, mp 239-240 ºC (lit. 240-242 ºC);¹⁵¹H NMR (300 MHz, CDCl₃) δ (ppm) 7.89 (d, J 2.83, 2H), 7.88 (s, 1H), 7.75 (s, 1H), 7.54 (t, J 6.05, 1H), 7.39 (d, J 8.53, 2H), 7.05 (d, J 9.34, 1H), 2.33 (s, 3H, CH₃); ¹³C NMR (75 MHz, CDCl₃) δ (ppm) 144.8, 144.4, 133.5, 132.5, 128.9, 128.1, 127.1, 123.3, 122.3, 116.8, 107.9, 18.1; IR (KBr) ν_max/cm^-1: 2921, 1635, 1540, 1465, 1409, 1257, 1206, 1090, 1010, 944, 835, 803, 734, 511.

6-Chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine (3i)

White solid, mp 205-207 ºC (lit. 209 ºC);²⁷¹H NMR (300 MHz, CDCl₃) δ (ppm) 8.14-8.13 (m, 1H), 7.85 (dd, J 1.99, 1.97, 2H), 7.77 (s, 1H), 7.55 (d, J 9.57, 1H), 7.42-7.39 (m, 2H), 7.14 (dd, J 1.98, 1.97, 1H); ¹³C NMR (75 MHz, CDCl₃) δ (ppm) 145.9, 144.3, 134.3, 132.0, 129.2, 127.5, 126.6, 123.6, 121.0, 118.1, 108.7; IR (KBr) ν_max/cm^-1: 3130, 1653, 1525, 1470, 1419, 1336, 1260, 1202, 1071, 1009, 935, 833, 799, 734, 511; MS (ESI): m/z (%), 263 ([M+H]⁺, 100), 265 ([M+2+H]⁺, 70), 267 ([M+4+H]⁺, 15).

3-Methyl-2-phenylimidazo[1,2-a]pyridine (3j)

Pale yellow solid, mp 159-161 ºC (lit. 153-154 ºC);¹⁷¹H NMR (300 MHz, CDCl₃) δ (ppm) 7.88 (d, J 6.87, 1H), 7.82-7.78 (m, 2H), 7.64 (d, J 9.06, 1H), 7.49-7.44 (m, 2H), 7.36 (d, J 7.38, 1H), 7.17-7.16 (m, 1H), 6.84 (d, J 6.75, 1H), 2.63 (s, 3H, CH₃); ¹³C NMR (75 MHz, CDCl₃) δ (ppm) 144.3, 142.4, 134.9, 128.5, 128.3, 127.3, 123.5, 122.8, 117.4, 115.9, 112.0, 9.6; IR (KBr) ν_max/cm^-1: 3027, 1629, 1494, 1443, 1393, 1351, 1243, 1143, 1072, 909, 751, 697, 583, 505; MS (ESI): m/z (%), 209 ([M+H]⁺, 100).

3,6-Dimethyl-2-phenylimidazo[1,2-a]pyridine (3k)

Pale yellow solid, mp 114-116 ºC; ¹H NMR (300 MHz, CDCl₃) δ (ppm) 7.82-7.79 (m, 2H), 7.66 (s, 1H), 7.54 (d, J 9.16, 1H), 7.46 (t, J 7.36, 2H), 7.34 (t, J 7.49, 1H), 7.02 (d, J 9.17, 1H), 2.61 (s, 3H, CH₃), 2.36 (s, 3H, CH₃); ¹³C NMR (75 MHz, CDCl₃) δ (ppm) 143.5, 142.3, 135.1, 128.5, 128.2, 127.2, 126.6, 121.5, 120.6, 116.8, 115.6, 18.4, 9.7; IR (KBr) ν_max/cm^-1: 2920, 1634, 1496, 1447, 1388, 1332, 1261, 1188, 1127, 1043, 777, 699, 581, 507; MS (ESI): m/z (%), 223 ([M+H]⁺, 100); Anal. calc. for C₁₅H₁₄N₂: C, 81.05; H, 6.35; N, 12.60. Found: C, 81.08; H, 6.34; N, 12.58.

2-(2,4-Dichlorophenyl)imidazo[1,2-a]pyridine (3l)

Pale yellow solid, mp 181-182 ºC; ¹H NMR (300 MHz, CDCl₃) δ (ppm) 8.28-8.26 (m, 2H), 8.14 (d, J 6.77, 1H), 7.62 (d, J 9.11, 1H), 7.49-7.48 (m, 1H), 7.36 (dd, J 2.01, 1.99, 1H), 7.23-7.18 (m, 1H), 6.81 (t, J 6.76, 1H); ¹³C NMR (75 MHz, CDCl₃) δ (ppm) 144.5, 140.8, 133.6, 132.1, 131.7, 130.9, 130.0, 127.4, 125.8, 125.1, 117.6, 112.6, 112.4; IR (KBr) ν_max/cm^-1: 3042, 1632, 1544, 1461, 1367, 1242, 1105, 1043, 931, 826, 749, 704, 623, 555; MS (ESI): m/z (%), 263 ([M+H]⁺, 100), 265 ([M+2+H]⁺, 70), 267 ([M+4+H]⁺, 15); Anal. calc. for C₁₅H₁₂Cl₂N₂: C, 61.87; H, 4.15; N, 9.62. Found: C, 61.88; H, 4.17; N, 9.59.

2-(2,4-Dichlorophenyl)-6-methylimidazo[1,2-a]pyridine (3m)

Pale yellow solid, mp 134-135 ºC; ¹H NMR (300 MHz, CDCl₃) δ (ppm) 8.25 (d, J 8.55, 1H), 8.17 (s, 1H), 7.91 (s, 1H), 7.51 (d, J 9.33, 1H), 7.46 (d, J 2.13, 1H), 7.34 (dd, J 2.16, 2.07, 1H), 7.04 (dd, J 1.47, 1.50, 1H); ¹³C NMR (75 MHz, CDCl₃) δ (ppm) 143.6, 140.5, 133.4, 132.0, 131.6, 131.1, 130.0, 128.3, 127.3, 123.4, 122.2, 116.8, 112.2, 18.1; IR (KBr) ν_max/cm^-1: 2960, 1641, 1540, 1458, 1419, 1380, 1342, 1256, 1201, 1142, 1096, 1039, 938, 853, 793, 743, 700, 563, 461; MS (ESI): m/z (%), 277 ([M+H]⁺, 100), 279 ([M+2+H]⁺, 70), 281 ([M+4+H]⁺, 15); Anal. calc. for C₁₄H₁₀Cl₂N₂: C, 60.67; H, 3.64; N, 10.11. Found: C, 60.69; H, 3.65; N, 10.09.

Acknowledgments

We are grateful to the National Key Technology R&D Program (No. 2007BAI34B00) and the Natural Science Foundation of Zhengjiang Province (No. Y4080107) for financial support.

Supplementary Information

Supplementary data are available free of charge at http://jbcs.sbq.org.br, as PDF file.

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Received: November 10, 2008

Web Release Date: February 20, 2009

Supplementary Information

Figure S1 - click to extend

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Publication Dates

• Publication in this collection
  25 May 2009
• Date of issue
  2009

History

• Received
  10 Nov 2008
• Accepted
  20 Feb 2009