Facile and simple synthesis of novel 1-Methyl-2-(2-substituted-oxazol-4-yl) -1H-benzimidazole derivatives

Article abstract of DOI:10.1080/00397910902985465

Novel 1-methyl-2-(2-substituted-oxazol-4-yl)-1H-benzimidazole derivatives were obtained in good yields and purity by treating corresponding 2-benzimidazolyl esters with acetamide in the presence of BF₃- etherate, a Lewis acid.

Full text of DOI:10.1080/00397910902985465

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Facile and Simple Synthesis of Novel 1-
Methyl-2-(2-substituted-oxazol-4-yl)-1H-
benzimidazole Derivatives
E. Vishnu Vardhan Reddy a , P. Bhanu Prakash a , Sandip Khobare a ,
J. Ramanatham b & N. Devanna c
a Custom Pharmaceutical Services, Dr. Reddy's Laboratories Limited ,
Miyapur, Hyderabad, India
b Pfizer Pharmaceuticals India Pvt. Ltd. , Navi Mumbai, India
c Department of Chemistry , JNT University , Ananthapur,
Andhrapredesh, India
Published online: 06 Jan 2010.
To cite this article: E. Vishnu Vardhan Reddy , P. Bhanu Prakash , Sandip Khobare , J. Ramanatham
& N. Devanna (2010) Facile and Simple Synthesis of Novel 1-Methyl-2-(2-substituted-oxazol-4-
yl)-1H-benzimidazole Derivatives, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:3, 414-422, DOI: 10.1080/00397910902985465
To link to this article: http://dx.doi.org/10.1080/00397910902985465
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Synthetic Communications1, 40: 414–422, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902985465
FACILE AND SIMPLE SYNTHESIS OF NOVEL 1-METHYL-
2-(2-SUBSTITUTED-OXAZOL-4-YL)-1H-BENZIMIDAZOLE
DERIVATIVES
E. Vishnu Vardhan Reddy,1 P. Bhanu Prakash,1
Sandip Khobare,1 J. Ramanatham,2 and N. Devanna3
1Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Limited, Miyapur,
Hyderabad, India
2Pfizer Pharmaceuticals India Pvt. Ltd., Navi Mumbai, India
3Department of Chemistry, JNT University, Ananthapur, Andhrapredesh, India
Novel 1-methyl-2-(2-substituted-oxazol-4-yl)-1H-benzimidazole derivatives were obtained
in good yields and purity by treating corresponding 2-benzimidazolyl esters with acetamide
in the presence of BF3-etherate, a Lewis acid.
Keywords: Acetamide; 2-benzimidazolyl ester; Lewis acid; oxazole
INTRODUCTION
Benzimidazoles are an important class of heterocyclic compounds with a wide
spectrum of biological activity[1] and behave as antihypertensive, antiviral, antifungal,
antitumor, and anthelmintic agents in veterinary medicine.[2] The oxazole heterocycle
is a fundamental ring system found in natural products, pharmaceuticals, agrochem-
icals, peptidomimetics, and polymers.[3] Naturally occurring oxazoles are usually
found with a 2,4-substitution pattern,[4] a consequence of their biosynthetic assembly
from serine residues, although 2,5-substituted oxazole natural products are known.[5]
Synthesis and study of biological activities of compounds having both benzi-
miadazole and oxazole moieties have attracted our attention because both these
moieties exhibit considerable biological activity independently, and when present
together they may have synergistic affects leading to more potent molecules.
RESULTS AND DISCUSSION
Condensation of o-phenylenediamine (1) with lactic acid under the Philips
condition[6] gave the known 2-(a-hydroxyethyl)benzimidazole (2). Compound 2 on
oxidation with acid dichromate yielded the required 2-acetyl benzimidazole (3).[7]
Received January 23, 2009.
Address correspondence to E. Vishnu Vardhan Reddy, Process Research and Development,
Dr. Reddy’s Laboratories Ltd., TDC-106 Bollaram Road, JPN Nagar, Miyapur, Hyderabad, 500049,
India. E-mail: evishnureddy@rediffmail.com
414

FACILE SYNTHESIS OF OXAZOLYL BENZIMIDAZOLES
415
Scheme 1. Synthesis of oxazole.
The resulting 3 was subjected to N-methylation with dimethylsulfate in acetonitrile,
potassium carbonate, and triethylbenzylammonium chloride (as a phase-transfer
catalyst), giving the corresponding N-methylated compound (4),[8] which on bromin-
ation in acetic acid gave 5[9] and its dibromoderivative. Compound 5 was converted
into its ester (7) on reacting with carboxylic acid (6) in acetone medium.
Initially, we attempted to convert the ester (7) into an oxazole under Corn-
forth’s condition,[10] which yielded a major by-product and, based on the litera-
ture,[11] was presumed to be 9 (Scheme 1).
Attempts to convert the compound 5 directly to 8 using amide derivatives[12]
did not yield the required product. However, 7, on reacting with acetamide in the
presence of BF3-Et2O, led to the isolation of the corresponding oxazoles (8) in good
yield and quality. Using this new protocol, different oxazoles were synthesized as
shown in Table 1. (Scheme 2).
Based on the literature information, the mechanism proposed for the conver-
sion of the ester to the corresponding oxazoles is shown in Scheme 3.
In summary, a facile synthetic process for 1-methyl-2-(2-substituted-oxazol-
4-yl)-1H-benzimidazole derivatives was developed, and a plausible mechanism is
proposed for the conversion of ester to the corresponding oxazole.
EXPERIMENTAL
1H NMR spectra were recorded in CDCl3 and dimethyl sulfoxide (DMSO-d6)
on a Mercury Plus Varian 400-MHz spectrometer. Proton chemical shifts (d) are
relative to tetramethylsilane (TMS, d 0.00) as internal standard and are expressed
in parts per million (ppm). Spin multiplicities are given as s (singlet), d (doublet), t
(triplet), and m (multiplet). Coupling constants (J) are given in hertz. Melting points
were determined using a scientific capillary melting-point apparatus and are uncor-
rected. Mass spectra were obtained on an HP-5989A mass spectrometer. Thin-layer
chromatography (TLC) was performed on silica-gel plates (SRL 230–400 mesh). All
the solvents used are commercially available and were distilled before use.
General Procedure for Synthesis of Ester 7a–g
A mixture of 5 (1.0 mol), 6 (1.0 mol), triethylamine (1.5 mol), and acetone
(10 ml) were stirred at 25–30ꢀC for 30–60 min. After completion of reaction, as
monitored by thin-layer chromatography (TLC), triethylamine hydrobromide salt
was filtered, and the mother liquor was distilled off under vacuum. The residue
was stirred with water and filtered and, on recrystallization from methanol the wet
cake afforded the corresponding ester. Please see Table 2 for details.

416

417

418
E. V. V. REDDY ET AL.
Scheme 2. R¼Methyl, pheny, 4-cyano phenyl, etc. Reagent and conditions: (i) 4 N HCl, lactic acid, 100ꢀC,
3 h; (ii) K2Cr2O7, H2SO4, rt, 2 h; (iii) K2CO3, dimethyl sulfate, TEBAC, CH3CN, rt, 3 h; (iv) Br2, acetic
acid, 100ꢀC, (v) TEA, acetone, rt; and (vi) acetamide, BF3-etherate, ethylacetate, reflux, 48 h.
General Procedure for Synthesis of Oxazole Derivatives 8a–g
To a mixture of 7 (1.0 mol) and acetamide (5.0 mol) in ethyl acetate (10 mol),
47% BF3-Et2O (10 mmol) dropwise was added. The resulting mixture was refluxed
for 48 h. After completion of the reaction, as monitored by TLC, the solution was
quenched with water, and the resulting solid was filtered, washed with water, and
dried. Please see Table 1 for details.
Spectral Data
2-Iodo-benzoic acid 2-(1-methyl-1H-benzimidazol-2-yl)-2-oxo-ethyl
ester (7a). Solid, mp 128–129ꢀC; IR (KBr, cmꢁ1): 3664, 3061, 2948, 2551, 1931,
1744, 1702, 1613, 1582, 1562, 1488, 1463, 1428, 1407, 1362, 1346, 1282, 1269,
1247, 1200, 1124, 1105, 1026, 1014, 1002, 965, 898; 1H NMR (400 MHz, DMSO-d6):
dH 8.09 (dd, J ¼ 7.8 Hz, 1H), 7.96 (dd, J ¼ 7.8 Hz, 1H), 7.88 (dd, J ¼ 8.0 Hz, 1H), 7.78
(dd, J ¼ 8.3 Hz, 1H), 7.60 (dt, J ¼ 7.5 Hz, 1H), 7.57–7–59 (m, 1H), 7.33–7.53 (m, 2H),
5.84 (s, 2H), 4.11 (s, 3H); 13C NMR (200 MHz, DMSO-d6): ppm, d 186.6, 165.4,
143.5, 141.0, 136.4, 134.1, 133.4, 130.8, 128.3, 125.9, 123.7, 121.1, 111.66, 94.8,
67.2, 31.8; ESI-MS (m=z): 421.1 (M þ 1), 231.0.
2-[2-(2-Iodo-phenyl)-oxazol-4-yl]-1-methyl-1H-benzimidazole (8a). Solid,
mp 243–245ꢀC; IR (KBr, cmꢁ1): 3674, 3486, 3102, 3039, 2884, 1956, 1751, 1628,
Scheme 3. Proposed mechanism.

FACILE SYNTHESIS OF OXAZOLYL BENZIMIDAZOLES
419
Table 2. Preparation of ester upon reaction with carboxylic acid in acetone medium
Yield Time
(%)
Entry
Acid (6)
Ester (7)
(h) Mp (ꢀC)
a
72
0.5 128–129
b
75
68
0.5 155–156
c
0.5 193–194
d
89
0.5 132–133
e
f
72
75
89
0.5
88–90
0.5 117–119
g
0.5 153–154
1610, 1578, 1560, 1491, 1476, 1466, 1420, 1334, 1312, 1279, 1259, 1246, 1225, 1162,
1143, 1090, 1061, 1029, 1002, 984, 880; 1H NMR (400 MHz, DMSO-d6): dH
8.16–8.22 (m, 2H), 7.82–7.91 (m, 2H), 7.65–7.74 (m, 2H), 7.50–7.55 (m, 2H),
7.42–7.46 (m, 1H), 3.90 (s, 3H); 13C NMR (200 MHz, DMSO-d6): ppm, d 165.1,
152.6, 143.5, 141.5, 134.5, 133.27, 131.9, 130.9, 128.5, 125.4, 124.9, 118.7, 114.2,
111.7,96.1, 31.4.

420
E. V. V. REDDY ET AL.
3-Phenyl-acrylic acid 2-(1-methyl-1H-benzimidazol-2-yl)-2-oxo-ethyl
ester (7b). Solid, mp 155–156ꢀC; IR (KBr, cmꢁ1): 3790, 3574, 3031, 1791, 1718,
1704, 1631, 1575, 1484, 1464, 1448, 1407, 1348, 1331, 1314, 1281, 1244, 1206,
1164, 1119, 1011, 983, 942, 896; 1H NMR (400 MHz, DMSO-d6): dH 7.87 (d,
J ¼ 8.31 Hz, 1H), 7.75–7.79 (m, 4H), 7.40–7.50 (m, 5H), 6.81 (d, J ¼ 16.1 Hz, 1H),
5.7 (s, 2H), 4.10 (s, 3H); 13C NMR (200 MHz, CDCl3): ppm, d 187.0, 165.6,
145.5, 143.5, 141.0, 136.4, 133.8, 130.6, 128.9, 128.4, 125.9, 123.7, 121.1, 117.1,
111.6, 66.5, 31.76; ESI-MS (m=z): 321.2 (M þ 1), 131.1.
1-Methyl-2-(2-styryl-oxazol-4-yl)-1H-benzimidazole (8b). Solid, mp 217–
218ꢀC; IR (KBr, cmꢁ1): 3650, 3036, 2925, 2854, 1836, 1742, 1629, 1556, 1476,
1
1448, 1335, 1306, 1260, 1242, 1162, 1117, 1071, 1031, 1004, 959, 870; H NMR
(400 MHz, DMSO-d6), dH 7.99 (d, J ¼ 15.9 Hz, 1H), 7.70–7.88 (m, 5H), 7.47–7.69
(m, 5H), 7.02 (d, J ¼ 16.1 Hz, 1H), 3.93 (s, 3H).
2-(1-Methyl-1H-benzimidazol-2-yl)-2-oxoethyl 4-cyanobenzoate (7c).
Solid, mp 193–194ꢀC; IR (KBr, cmꢁ1): 3637, 3381, 2951, 2231, 1945, 1792, 1732,
1698, 1607, 1579, 1487, 1463, 1409, 1358, 1307, 1278, 1250, 1196, 1118, 1036,
1016, 1003, 969, 751; 1H NMR (400 MHz, DMSO-d6); dH 8.19–8.22 (m, 2H),
8.06–8.08 (m, 2H), 7.87–7.89 (m, 1H), 7.76–7.79 (m,1H), 7.39–7.53 (m, 2H), 5.89
(s, 2H), 4.1 (s, 3H); ESI-MS (m=z): 320.1 (M þ 1).
4-(4-(1-Methyl-1H-benzimidazol-2-yl)oxazol-2-yl)benzonitrile (8c). Solid,
mp 306–309ꢀC; IR (KBr, cmꢁ1): 3673, 3491, 3109, 2813, 2231, 1949, 1859, 1754,
1603, 1621, 1560, 1490, 1474, 1421, 1409, 1274, 1255, 1231, 1180, 1163, 1136,
1
1055, 1025, 984; H NMR (400 MHz, DMSO-d6): dH 8.35 (dd, J ¼ 6.8 Hz, 2H),
8.14 (dd, J ¼ 6.6 Hz, 2H), 7.82–7.87 (m, 2H), 7.70–7.73 (m, 1H), 7.50–7.54 (m,
2H), 3.88 (s, 3H).
3-Trifluoromethyl-benzoic acid 2-(1-methyl-1H-benzimidazol-2-yl)-2-
oxo-ethyl ester (7d). Solid, mp 132–133ꢀC; IR (KBr, cmꢁ1): 3635, 3072, 2939,
1935, 1836, 1738, 1706, 1616, 1593, 1585, 1541, 1488, 1460, 1434, 1407, 1358,
1
1340, 1333, 1291, 1252, 1200, 1173, 1155, 1116, 1093, 1070, 1040, 999, 919; H
NMR (400 MHz, DMSO-d6): dH 8.36 (d, J ¼ 7.8 Hz 1H), 8.30 (s, 1H), 8.13 (d,
J ¼ 7.8 Hz, 1H), 7.88 (dd, J ¼ 8.3 Hz, 2H), 7.78 (d, J ¼ 8.3 Hz, 1H), 7.41–7.53 (m,
2H), 5.90 (s, 2H), 4.10 (s, 3H); ESI-MS (m=z): 363.1(M þ 1).
1-Methyl-2-[2-(3-trifluoromethyl-phenyl)-oxazol-4-yl]-1H-benzimidazole
(8d). Solid, mp 132–133ꢀC; IR (KBr, cmꢁ1): 3679, 3093, 1915, 1831, 1755, 1625,
1562, 1490, 1476, 1467, 1449, 1420, 1336, 1286, 1226, 1165, 1133, 1087, 1071,
1030, 1014, 1002, 988; 1H NMR (400 MHz, DMSO-d6): dH 8.50 (d, J ¼ 7.8 Hz,
1H), 8.45 (s, 1H), 8.20 (d, J ¼ 7.8 Hz, 1H), 7.80–7.95 (m, 3H), 7.70–7.73 (m, 1H),
7.50–7.54 (m, 2H), 3.89 (s, 3H); 13C NMR (200 MHz, DMSO-d6): ppm, d 164.0,
152.9, 134.0, 133.2, 130.9, 130.6, 130.1, 129.5, 128.8, 128.4, 127.9, 126.4, 125.3,
124.8, 118.5, 114.1, 117.7, 31.3.
Succinic acid methyl ester 2-(1-methyl-1H-benzimidazol-2-yl)-2-oxo-
ethyl ester (7e). Solid, mp 88–90ꢀC; 1H NMR (400 MHz, DMSO-d6): dH
7.85–7.87 (m, 1H), 7.40–7.46 (m, 2H), 7.26–7.39 (m, 1H), 5.66 (s, 2H), 4.13 (s,
3H), 3.72 (s, 3H), 2.86 (t, J ¼ 6.9 MHz, 2H), 2.71–2.75 (t, J ¼ 6.7 Hz, 2H); 13C

FACILE SYNTHESIS OF OXAZOLYL BENZIMIDAZOLES
421
NMR (200 MHz, CDCl3): ppm d 186.8, 172.4, 171.7, 143.3, 141.6, 136.5, 126.3,
124.0, 121.8, 110.4, 66.8, 51.82, 31.8, 28.8, 28.7; ESI-MS (m=z): 305.0 (M þ 1).
3-[4-(1-Methyl-1H-benzimidazol-2-yl)-oxazol-2-yl]-propionic acid methyl
ester (8e). Solid, mp 148–150ꢀC; 1H NMR (400 MHz, DMSO-d6); dH 7.71 (s, 1H),
7.51–7.57 (m, 2H), 7.16–7.23 (m, 2H), 4.12 (s, 3H), 3.6, (s, 3H), 2.99 (t, J ¼ 7.22 Hz,
2H), 2.49–2.50 (t, J ¼ 6.9 Hz, 2H).
2-(1-Methyl-1H-benzimidazol-2-yl)-2-oxoethyl acetate (7f). Solid, mp
117–119ꢀC; IR (KBr, cmꢁ1): 3664, 3053, 3020, 2940, 2854, 1905, 1755, 1704, 1611,
1580, 1488, 1463, 1407, 1336, 1291, 1227, 1193, 995, 975; 1H NMR (400 MHz,
DMSO-d6): dH 7.85–7.88 (m, 1H), 7.36–7.48 (m, 3H), 5.6 (s, 2H), 4.13 (s, 3H), 2.25
(s, 3H); 13C NMR (200 MHz, CDCl3): ppm d 187.2, 170.2, 143.4, 141.7, 136.6,
126.3, 124.0, 121.9, 110.5, 66.0, 31.9, 20.4; ESI-MS (m=z): 233.1 (M þ 1), 211.1.
2-Methyl-4-(1-methyl-1H-benzimidazol-2-yl)oxazole
(8f). Solid,
mp
217–218ꢀC; IR (KBr, cmꢁ1): 3632, 3079, 3051, 2881, 2508, 2240, 1975, 1975, 1856,
1782, 1708, 1628, 1611, 1557, 1492, 1476, 1417, 1372, 1334, 1316, 1270, 1245, 1203,
1
1195, 1119, 1033; H NMR (400 MHz, CDCl3): dH 7.83–7.86 (m, 1H), 7.50–7.69
(m, 2H), 7.48–7.49 (m, 2H), 3.92 (s, 3H), 2.39 (s, 3H); 13C NMR (200 MHz, CDCl3):
ppm d 170.0, 152.3, 133.2, 130.9, 125.2, 124.7, 118.3, 114.1, 111.7, 31.3, 20.3.
2-(1-Methyl-1H-benzimidazol-2-yl)-2-oxoethyl benzoate (7g). 1H NMR
(400 MHz, CDCl3): dH 8.06–809 (m, 2H), 7.88 (dd, J ¼ 8.05 Hz, 1H), 7.78 (d,
J ¼ 8.29 Hz, 1H), 7.71–7.75 (m, 1H), 7.58–7.62 (m, 2H), 7.49–7.53 (m, 1H),
7.39–7.43 (m, 1H). ESI-MS (m=z): 295 (M þ 1).
ACKNOWLEDGMENTS
The authors thank Dr. Reddy’s Laboratories Ltd. for supporting this work.
The authors also thank Mr. Abhijit Mukherjee and Dr. Vilas Dahanukar for their
constant help and encouragement. The cooperation extended by all colleagues of
the analytical division is gratefully acknowledged.
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