Month 2014
Thermal Synthesis of 3-Bromothieno[3,2-c]pyridin-4-(5H)-one: A Telescoped
Procedure with Tributylamine
Figure 1. 1H NMR spectra (400MHz; 7.2–5.8ppm) from solutions isocyanate E-5 in d4-dichlorobenzene after heating with (A and B) and without (C and D)
tributylamine. Solvent peaks (S) are labeled (7.20 and 6.94 ppm).
(M + 1), 232 (M + 1); 1H NMR (400 MHz, DMSO-d6) d 6.83
(d, 1H, J = 7 Hz), 7.24 (d, 1H, J = 7 Hz), 7.63 (br s, 1H), 11.46
(br s, 1H) [5].
with tributylamine in p-cymene avoids both isolation of
azide 4 and charging of tributyl amine prior to the high
temperature stage. The modified procedure affords the title
compound in good yield (71%) and purity (>98% by
LCMS). Spectral data of 1 were in agreement with
literature values [5].
REFERENCES AND NOTES
[1] Ford, J.; Madge, D. J.; Payne, H. J.; Knight, J. D. PCT Interna-
tional Patent Application WO 2007/066127 A2, 2007, Chem Abstr 2007,
147, 72734.
EXPERIMENTAL
[2] Abbott, L.; Betschmann, P.; Burchat, A.; Calderwood, D. J.;
Davis, H.; Hrnciar, P.; Hirst, G. C.; Li, B.; Morytko, M.; Mullen, K.;
Yang, B. Bioorg Med Chem Lett 2007, 17, 1167.
[3] Miyazaki, Y.; Nakano, M.; Sato, H.; Truesdale, A. T.; Stuart,
J. D.; Nartey, E. N.; Hightower, K. E.; Kane-Carson, L. Bioorg Med
Chem Lett 2007, 17, 250.
[4] Heyman, H. R.; Frey, R. R.; Bousquet, P. F.; Cunha, G. A.;
Moskey, M. D.; Ahmed, A. A.; Soni, N. B.; Marcotte, P. A.; Pease, L.
J.; Glaser, K. B.; Yates, M.; Bouska, J. J.; Albert, D. H.; Black-Schaefer,
C. L.; Dandliker, P. J.; Stewart, K. D.; Rafferty, P.; Davidsen, S. K.;
Michaelides, M. R.; Curtin, M. L. Bioorg Med Chem Lett 2007,
17, 1246.
[5] Engstrom, K. M.; Baize, A. L.; Franczyk, T. S.; Kallemeyn,
J. M.; Mulhern, M. M.; Rickert, R. C.; Wagaw, S. J Org Chem 2009,
74, 3849.
[6] Eloy, F.; Deryckere, A. Helv Chim Acta 1970, 53, 645.
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[8] Gentile, G.; Bernasconi, G.; Pozzan, A.; Merlo, G.;
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2011, 21, 4823.
3-Bromo-thieno[3,2-c]pyridin-4-(5H)-one (1).
Diphenyl
phosphorylazide (390 g, 1.42 mol) was added drop wise to a
stirred solution of (2E)-3-(4-bromo-2-thienyl)-2-propenoic acid
(300 g, 1.29 mol) and tributylamine (286g, 1.54 mol) in p-cymene
(2.2 L) at RT, and the reaction mixture was stirred overnight.
The reaction mixture was basified with 1N NaOH. The phases
were separated, and the organic layer was washed with 1N
NaOH (2 ꢁ 2L) to remove the diphenylphosphoric acid by-
product. The organic phase was washed with brine, dried over
MgSO4, and filtered. The p-cymene filtrate containing 4 and
tributylamine was split into two equal volumes and used in
separate batches without further purification. This solution
(0.64 mol of 4) was added by pump over 3h (flow rate 8 mL/min)
to stirred p-cymene (2 L) at 165ꢀC internal temperature. Following
the addition, the reaction mixture was maintained at 170ꢀC for an
additional 2.5h and then allowed to cool to ambient temperature
overnight. The slurry was diluted with heptane (700 mL), cooled
to ꢂ10ꢀC, and the product (1) was collected by filtration as a light
beige solid (105g, 71% yield): LCMS purity >98%; m/z 230
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet