LETTER
Synthesis of 1-Methylbenzimidazoles
65
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range of aliphatic and aromatic including heteroaromatic
carbonitriles was investigated. After optimization of reac-
tion time and temperature for every single substrate yields
in the range of 50–93% can be obtained. Importantly, this
method is fully compatible with acid-labile ethoxyethyl-
protected cyanohydrins. The p-bromophenyl-substituted
product can be further converted in cross-couplings such
as Suzuki, Sonogashira, Heck, and Buchwald–Hartwig
reactions.
(16) Sims, H. J.; Parseghian, H. B.; de Benneville, P. L. J. Org.
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Acknowledgment
(17) Schlosser, M.; Brich, Z. Helv. Chim. Acta 1978, 61, 1903.
(18) (a) Wilfred, C. D.; Taylor, R. J. K. Synlett 2004, 1628.
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Williams, A. F.; Bernardinelli, G. Helv. Chim. Acta 2006,
89, 841. (c) Algül, Ö.; Özcelik, B.; Abbasoglu, U.; Gümüs,
F. Turk. J. Chem. 2005, 29, 607.
(19) Chang, C.-S.; Lin, Y.-T.; Shih, S.-R.; Lee, C.-C.; Lee, Y.-C.;
Tai, C.-L.; Tseng, S.-N.; Chern, J.-H. J. Med. Chem. 2005,
48, 3522.
This work was generously supported by the Fonds der Chemischen
Industrie. Ligands cataCXium FSulf and FBu were a generous gift
from Evonik Degussa GmbH, Hanau, Germany.
References and Notes
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(23) 1-Methyl-2-phenyl-1H-benzimidazole (3h)
Diamine 1 (6.1 g, 50 mmol), NaH (2.0 g, 60% dispersion in
mineral oil, 50 mmol) and abs. mesitylene (10 mL) were
successively added to nitrile 2h (5.2 g, 50 mmol). The
mixture was heated to reflux for 16 h (inner temp ca. 170 °C,
oil bath 210 °C). After cooling to ambient temperature, the
mixture was filtered through SiO2 (1 cm), the residue
washed with CH2Cl2 (5 mL), and the combined filtrates
evaporated. The residue was chromatographed (SiO2,
hexane–EtOAc, 1:1; Rf = 0.34) to give the title compound 3a
(6.2 g, 30 mmol, 60%) as a light yellow solid, mp 91 °C
(lit.18b 92–93 °C). 13C{1H} NMR (125 MHz, CDCl3):
d = 31.57 (CH3), 109.54 (CH), 119.76 (CH), 122.33 (CH),
122.67 (CH), 128.58 (2 CH), 129.35 (2 CH), 129.63 (CH),
130.16 (C), 136.51 (C), 142.91 (C), 153.70 (C) ppm. All
other data were in accordance with the literature.18b
(24) cataCXium FSulf = dicyclohexyl{2-sulfo-9-[3-(4-sulfo-
phenyl)propyl]-9-fluorenyl}phosphonium hydrogensulfate;
for use in Suzuki reactions, see: (a) Fleckenstein, C. A.;
Plenio, H. Green Chem. 2007, 9, 1287. (b) Fleckenstein,
C. A.; Plenio, H. Chem. Eur. J. 2007, 13, 2701.
(25) 2-(Biphenyl-4-yl)-1-methyl-1H-benzimidazole (4)
A mixture of bromophenyl compound 3i (91 mg, 0.32 mmol,
1.0 equiv), PhB(OH)2 (42 mg, 0.35 mmol, 1.1 equiv),
Na2PdCl4 (1.2 mg, 4.2 mmol, 1.3 mol%), cataCXium Fsulf
(3.3 mg, 4.5 mmol, 1.5 mol%), and K2CO3 (131 mg, 945
mmol, 3 equiv) was placed in a Schlenk tube and twice
evacuated and flushed with N2. Degassed H2O (0.5 mL) and
BuOH (0.5 mL) were added, and the resulting mixture was
stirred for 16 h at 100 °C. Subsequently, the organic layer
was separated and the aqueous layer extracted with CH2Cl2
(5 mL). The combined organic layers were dried (MgSO4),
and after filtration, the solvent was evaporated and the
residue chromatographed (SiO2, hexane–EtOAc = 1:1,
Rf = 0.48) to give the title compound 4 (82 mg, 0.29 mmol,
92%) as a yellow solid, mp 164 °C. 1H NMR (500 MHz,
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2008, 1467.
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2001, 57, 8145. (c) Renouard, T.; Fallahpour, R.-A.;
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Lever, A. B. P.; Grätzel, M. Inorg. Chem. 2002, 41, 367.
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2260.
(11) 2-Cyclohexyl-1-methyl-1H-benzimidazole (3a)
Diamine 1 (244 mg, 2.00 mmol), NaH (80.0 mg, 60%
dispersion in mineral oil, 2.00 mmol), and abs. toluene (1.0
mL) were successively added to nitrile 2a (218 mg, 2.00
mmol). The mixture was stirred for 3 h at 120 °C in a tightly
closed reaction vial, then completely transferred on top of a
column (SiO2), and chromatographed (hexane–EtOAc, 1:1;
Rf = 0.32) to give the title compound 3a (384 mg, 1.79
mmol, 90%) as a light brown solid, mp 102 °C (lit.13a
104 °C). 1H NMR (500 MHz, CDCl3): d = 1.30–1.48 (m,
3 H), 1.74–2.03 (m, 7 H), 2.84 (tt, J = 3.5, 11.6 Hz, 1 H),
3.74 (s, 3 H), 7.20–7.31 (m, 3 H), 7.72–7.77 (m, 1 H) ppm.
13C{1H} NMR (125 MHz, CDCl3): d = 25.82 (CH2), 26.32
(2 CH2), 29.52 (CH3), 31.46 (2 CH2), 36.33 (CH), 108.80
(CH), 119.27 (CH), 121.66 (CH), 121.87 (CH), 135.64 (C),
142.55 (C), 159.00 (C) ppm. IR (ATR): n = 3173 (w), 3052
(w), 2929 (s), 2851 (m), 1730 (m), 1615 (m), 1506 (m), 1441
(s), 1278 (m), 1239 (m), 842 (m), 736 (s) cm–1. MS (EI, 70
eV): m/z (%) = 214 (14) [M+], 159 (100). HRMS (CI,
isobutane): m/z calcd for C14H19N2: 215.1548; found:
215.1548 [M + H+]. Anal. Calcd for C14H18N2 (214.31): C,
78.46; H, 8.47; N, 13.07. Found: C, 78.40; H, 8.55; N, 13.05.
Synlett 2009, No. 1, 63–66 © Thieme Stuttgart · New York