Organic Process Research & Development
ARTICLE
Results and Discussion section were cooled to room tempera-
ture, and then water was added to them. The resulting precipitate
was obtained by filtration and washed with water, then purified
by recrystallization from acetone and water to give benzimidazole
1
8 (87%, DMSO/H2O solvent; 86%, DMA/H2O solvent). H
NMR (300 MHz, CDCl3) δ 8.51 (1H, d, J = 1.5 Hz), 7.98 (1H,
dd, J = 9, 1.8 Hz), 7.62 (1H, s), 7.65À7.60 (2H, m), 7.56À7.25
(3H, m), 4.41 (2H, q, J = 7 Hz), 4.36À4.33 (1H, m), 2.40À2.20
(2H, m), 2.00À1.90 (4H, m), 1.42 (3H, t, J = 7.2 Hz), 1.40À1.28
(4H, m); 13C NMR (300 MHz, CDCl3) δ 166.9, 155.3, 143.2,
137.0, 130.5, 129.8, 129.3, 128.6, 124.3, 123.4, 122.3, 112.0, 60.8,
57.1, 31.4, 25.9, 25.3, 14.5; HRMS (FAB) m/z calc’d for
C22H25N2O2 [M]+: 349.1916, found 349.1923.
Figure 7. Change of chord length by crystallization.
Scheme 3. Plausible mechanism of the reductive cyclization
Ethyl 2-Phenyl-1H-benzo[d]imidazole-5-carboxylate (9).
The title compound was isolated from the reaction mixture
(entry 15, Table 2) by flash column chromatography on silica gel
using hexane/ethylacetate (3:2) as the eluent to give 5.8 mg of 9
1
as a white solid. H NMR (300 MHz, CDCl3) δ 8.33 (1H, s),
8.18 (1H, dd, J = 7.8, 1.8 Hz), 7.93 (1H, dd, J = 8.4, 1.5 Hz), 7.54
(1H, d, J = 8.4 Hz), 7.25À7.40 (3H, m), 4.35 (2H, q, J = 7.2 Hz),
1.35 (3H, t, J = 7.1 Hz); 13C NMR (300 MHz, CDCl3) δ 167.2,
154.7, 130.4, 129.2, 128.9, 127.0, 124.6, 124.1, 61.0, 31.6, 22.6,
14.3, 14.2, 14.1; HRMS (FAB) m/z calc’d for C16H15N2O2
[M]+: 267.1133, found 267.1141.
1-Cyclohexyl-2-(furan-3-yl)-1H-benzo[d]imidazole-5-car-
boxylic Acid (1). A 200-mL round-bottomed flask was charged
with ethyl 4-(cyclohexylamino)-3-nitrobenzoate (5 g), DMSO
(25 mL), EtOH (25 mL), 3-furaldehyde (1.81 g), and Na2S2O4
(8.93 g). The mixture was stirred at 90 °C for 2.5 h. The mixture
was quenched with water (100 mL) and extracted with ethyl
acetate (100 mL Â 1, 200 mL Â 1, 50 mL Â 1). The combined
organic layers were washed with water (50 mL Â 3) and
concentrated by rotary evaporation. The crude residue was
dissolved in THF (20 mL) and MeOH (10 mL), and then LiOH
(1.86 g) dissolved in H2O (18.6 mL) was added. The mixture was
stirred at 30 °C for 1 h, cooled to 0 °C, and adjusted to pH 4 with
HCl(aq). The precipitate that formed was obtained by filtration,
washed with H2O (100 mL), and dried at 40 °C under reduced
pressure to obtain the title compound (4.22 g, 80%). 1H NMR
(300 MHz, DMSO-d6) δ 8.28 (1H, d, J = 0.6 Hz), 8.20 (1H, d,
J = 1.8 Hz), 7.94À7.91 (2H, m), 7.83 (1H, dd, J = 8.7, 1.8 Hz), 6.94
(1H, d, J = 2.1 Hz), 4.48À4.39 (1H, m), 2.40À2.20 (2H, m),
2.00À1.80 (4H, m), 1,70À1.60 (1H, m), 1.50À1.30 (3H, m);
13C NMR (300 MHz, DMSO-d6) δ 168.5, 149.1, 145.2, 144.2,
143.7, 137.6, 125.2, 124.0, 121.7, 116.8, 113.6, 112.0, 57.6, 31.5,
26.5, 25.5; HRMS (FAB) m/z calc’d for C22H25N2O2 [M]+:
311.1396, found 311.1394.
Ethyl 4-(Cyclohexylamino)-3-nitrobenzoate (3). A 1-L
round-bottomed flask was charged with ethyl 4-chloro-3-nitro-
benzoate (50.0 g), NMP (150 mL), cyclohexylamine (64.8 g),
and triethylamine (66.0 g). The mixture was stirred at 90 °C for
1.5 h. The mixture was quenched by water (300 mL) and
extracted by ethyl acetate (500 mL Â 2). The combined organic
layers were washed with water (300 mL), brine (300 mL), and
water (300 mL) and concentrated by rotary evaporation. The
residue was dried under reduced pressure at 40 °C to give 3 (63.3
g, 99%). This compound is already known, and the 1H NMR data
corresponded to the literature data.1d 1H NMR (300 MHz,
CDCl3): 8.86 (1H, d, J = 1.8 Hz), 8.35À8.46 (1H, m), 8.01
(1H, dd, J = 8.7, 1.5 Hz), 6.87 (1H, d, J = 9.3 Hz), 4.35 (2H, q,
J = 7.2 Hz), 3.65À3.50 (1H, m), 2.14À1.29 (10H, m), 1.38 (3H, t,
J = 7.1 Hz)
’ ASSOCIATED CONTENT
Supporting Information. Copies of DSC, 1H NMR, and
S
b
13C NMR. This material is available free of charge via the Internet
’ AUTHOR INFORMATION
Corresponding Author
’ REFERENCES
(1) (a) Beaulieu, P. L.; Gillard, J.; Bykowski, D.; Brochu, C.;
Dansereau, N.; Duceppe, J. S.; Hachꢀe, B.; Jakalian, A.; Lagacꢀe, L.;
LaPlante, S.; McKercher, G.; Moreau, E.; Perreault, S.; Stammers, T.;
Thauvette, L.; Warrington, J.; Kukolj, G. Bioorg. Med. Chem. Lett. 2006,
14, 4987–4993. (b) Beaulieu, P. L.; B€os, M.; Bousquet, Y.; Fazal, G.;
Gauthier, J.; Goulet, S.; LaPlante, S.; Poupart, M. A.; Lefebvre, S.;
McKercher, G.; Pellerin, C.; Austel, V.; Kukolj, G. Bioorg. Med. Chem.
Lett. 2004, 14, 119. (c) Hirashima, S.; Suzuki, T.; Ishida, T.; Noji, S.;
Yata, S.; Ando, I.; Komatsu, M.; Ikeda, S.; Hashimoto, H. J. Med.
Chem. 2006, 49, 4721. (d) Fujishita, T.; Abe, K.; Naito, A.; Makino,
I.; Matsumoto, H.; Onodera, N.; Endo, T.; Iwata, M. WO/2005/
121132A1, 2005.
(2) (a) Yang, D.; Fokas, D.; Li, J.; Yu, L.; Baldino, C. M. Synthesis
2005, 1, 47–56. (b) Surpur, M. P.; Singh, P. R.; Patil, S. B.; Samant, S. D.
Synth. Commun. 2007, 37, 1375–1379.
(3) (a) Barbas, R.; Botija, M.; Camps, H.; Portell, A.; Prohens, R.;
Puigjaner, C. Org. Process. Res. Dev. 2007, 11, 1131–1134. (b) Gustin,
J. L. Org. Process. Res. Dev. 1998, 2, 27–33. (c) Hoogenraad, M.; Linden,
J. B.; Smith, A. A. Org. Process. Res. Dev. 2004, 8, 469–476. (d) Park, K. K.;
Oh, C. H.; Joung, W. K. Tetrahedron Lett. 1993, 34, 7445. (d) Stoessel, F.
J. Loss Prev. Process. Ind. 1993, 6 (2), 79–85.
(4) Urben, P. Bretherick’s Handbook of Reactive Chemical Hazards,
7th ed.; Elsevier: Amsterdam, 2007; pp 1917À1918.
(5) The reactions were monitored by the disappearance of NÀO
antisymmetric vibration peak (1569 cmÀ1) of o-nitroarylamine 3 in
in situ IR analysis and performed using 3 (1 mmol), 6 (1.1 mmol),
Na2S2O4 (3 mmol), and solvent (2.5 mL). The yields of benzimidazole 7
Ethyl 1-Cyclohexyl-2-phenyl-1H-benzo[d]imidazole-
5-carboxylate (7). The reaction mixtures described in the
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dx.doi.org/10.1021/op200251c |Org. Process Res. Dev. 2012, 16, 96–101