C. T. Brain, S. A. Brunton / Tetrahedron Letters 43 (2002) 1893–1895
1895
produced 9a in 87% yield after purification. The latter
References
procedure was adopted as a standard set of conditions
and was applied to the cyclisations of the remaining
amidines 8b–q (Table 1). The reactions proceeded
smoothly and were all complete after 18 h under reflux
in toluene to give the benzimidazoles 9b–q. Yields were
generally good to excellent.‡
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Some interesting observations can be made from these
results. Most importantly, both electron withdrawing
(8k–m) and electron donating (8g,h,j) groups para to
the amidine bromo substituent were tolerated. Simi-
larly, amidines 8n–o, which contained a methyl group
ortho to the bromo substituent, cyclised successfully. A
range of substituents on the amidine nitrogen was
tolerated and the guanidine 8q also cyclised efficiently
to give the 2(1-pyrrolidinyl) benzimidazole 9q.
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In summary, we have developed a palladium-catalysed
N-arylation reaction which provides a novel synthesis
of benzimidazoles from (o-bromophenyl)amidine pre-
cursors. The route is flexible and allows for the prepa-
ration of highly substituted benzimidazoles including
regioselective N-substitution. Work is currently under-
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stoichiometric quantities of Pd(PPh3)4, see: Boger, D. L.;
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‡ General procedure: To a solution of 8 (0.2 mmol) in toluene (5 ml)
under argon was added K2CO3 (1.6 equiv.), NaOtBu (1.6 equiv.)
and Pd(PPh3)4 (5–10 mol%) sequentially and the resulting mixture
was heated under reflux for 18 h. The reaction mixture was filtered
through Celite and the solvent was removed in vacuo. The crude
residue was purified either by column chromatography or prepara-
tive HPLC to give 9. Data for new compounds. 9e: colourless oil;
1H NMR (400 MHz, CDCl3) 7.67–7.69 (1H, m, ArH), 7.29–7.30
(1H, m, ArH), 7.20–7.23 (2H, m, ArH), 4.27 (2H, t, J 5.5, CH2),
3.68 (2H, t, J 5.5, CH2), 3.26 (3H, s, OCH3), 2.62 (3H, s, CH3); 13C
NMR (100 MHz, DMSO) 152.3, 142.3, 135.2, 121.3, 121.1, 118.1,
110.0, 70.5, 58.4, 43.1, 13.7; m/z (ES+) 191 (M++1, 100%); HRMS
191.1184 (measured), 191.1184 (calculated). 9f: white solid; mp
102–103°C; 1H NMR (400 MHz, CDCl3) 7.74 (1H, dd, J 6.7, 2.0,
ArH), 7.42 (1H, dd, J 6.7, 2.0, ArH), 7.21–7.28 (2H, m, ArH), 4.76
(1H, quint, J 8.9, CH), 2.69 (3H, s, CH3), 2.06–2.23 (6H, brm,
3×CH2), 1.81–1.85 (2H, m, CH2); 13C NMR (100 MHz, DMSO)
151.8, 140.8, 132.4, 121.9, 121.7, 117.9, 111.6, 56.2, 29.6, 24.6, 14.0;
m/z (ES+) 201 (M++1, 100%); HRMS 201.1381 (measured),
201.1382 (calculated). 9n: white solid; mp 115–118°C; 1H NMR
(400 MHz, CDCl3) 7.62 (1H, d, J 8.0, benzimidazole H-4), 7.55–
7.56 (3H, m, ArH), 7.37–7.39 (2H, m, ArH), 7.16 (1H, m, benzimi-
dazole H-5), 6.94 (1H, d, J 7.3 benzimidazole H-6), 2.38 (3H, s,
CH3), 1.92 (3H, s, CH3); 13C NMR (100 MHz, DMSO) 151.8,
142.6, 137.3, 134.5, 129.3, 128.9, 124.3, 121.6, 120.7, 116.5, 17.4,
14.0; m/z (ES+) 223 (M++1, 100%); HRMS 223.1233 (measured),
223.1235 (calculated). 9q: (isolated as a formate salt) white solid;
16. Foloppe, M. P.; Rault, S.; Robba, M. Tetrahedron Lett.
1992, 33, 2803–2804.
17. (a) The reactions worked equally well with the use of 5 or
10 mol% Pd(PPh3)4, however, no cyclisation occurred
with 1 mol% or without any catalyst; (b) Pd(PPh3)4 was
prepared according to the method in: Hegedus, L.
Organometallics in Synthesis; Schlosser, M., Ed.; John
Wiley and Sons, 1994; p. 448.
1
mp 34–36°C; H NMR (400 MHz, CDCl3) 8.46 (1H, s, formate-H),
7.54 (1H, dd, J 6.8, 1.4, ArH), 7.14–7.23 (3H, m, ArH), 3.74–3.80
(7H, m, CH3+2×CH2), 2.06–2.09 (4H, m, 2×CH2); 13C NMR (100
MHz, DMSO) 163.2, 156.4, 141.5, 136.1, 120.8, 119.1, 115.3, 108.1,
49.8, 30.9, 25.2; m/z (ES+) 202 (M++1, 100%); HRMS 202.1342
(measured), 202.1344 (calculated).