A practical oxone® - Mediated, high-throughput, solution-phase synthesis of benzimidazoles from 1,2-phenylenediamines and aldehydes and its application to preparative scale synthesis

Synthesis

Volumn , Issue 11, 2003, Pages 1683-1692

  Beaulieu, Pierre L ^a   Haché, Bruno ^a   Von Moos, Elisabeth ^a  

^a BOEHRINGER INGELHEIM CANADA LTD   (Canada)

Author keywords

Aldehydes; Amines; Benzimidazoles; Combinatorial chemistry; Heterocycles; Oxone

Indexed keywords

ADDITION REACTIONS; ALDEHYDES; MIXTURES; PRECIPITATION (CHEMICAL); SOLUTIONS; SYNTHESIS (CHEMICAL); THERMAL EFFECTS;

SOLUTION-PHASE SYNTHESIS;

NITROGEN COMPOUNDS;

1,2 PHENYLENEDIAMINE; ACID; ALDEHYDE; AMINE; BENZIMIDAZOLE DERIVATIVE; HETEROCYCLIC COMPOUND; N,N DIMETHYLFORMAMIDE; OXIDIZING AGENT; SODIUM PEROXIDE; UNCLASSIFIED DRUG;

ARTICLE; CARBON NUCLEAR MAGNETIC RESONANCE; COMBINATORIAL CHEMISTRY; DRUG SYNTHESIS; MASS SPECTROMETRY; OXIDATION; PROTON NUCLEAR MAGNETIC RESONANCE; REVERSED PHASE HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; ROOM TEMPERATURE; SAFETY;

EID: 0043240483     PISSN: 00397881     EISSN: None     Source Type: Journal    
DOI: 10.1055/s-2003-40888     Document Type: Article

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40. (b) For other uses of oxone® in organic synthesis, see for example: Lee, K.-J.; You, H.-W. Synlett 2001, 105; and references cited therein.
41. (c) After submission of this manuscript, Borhan et al. reported on the use of oxone® for the oxidation of aldehydes to carboxylic acids: Travis, B. R.; Sivakumar, M.; Hollist, G. O.; Borhan, B. Org. Lett. 2003, 5, 1031; it appears that formation of benzimidazoles under the present reaction conditions is faster than oxidation of the aldehyde substrate to the corresponding carboxylic acid. It is possible however that this latter pathway can become competitive for less reactive substrates and account for some of the lower yields.
42. For an alternative reduction of nitro groups with stannous chloride, see for example: Bellamy, F. D.; Ou, K. Tetrahedron Lett. 1984, 25, 839.
43. The formation of an intermediate formate ester from the starting aldehyde through a Baeyer-Villiger oxidation is inferred from detection of the corresponding alcohol. Precedent for this kind of process can be found in the literature, but usually involves organic peracids as oxidant. See for example: (a) Yeager, G. W.; Schissel, D. N. Synthesis 1991, 63. (b) Krow, G. R. Org. React. 1993, 43, 251. (c) Occurrence of an oxone®-promoted Baeyer-Villiger process has been proposed in the literature: Wu, X.-Y.; She, X.; Shi, Y. J. Am. Chem. Soc. 2002, 124, 8792; see also earlier reference (Ref. 14c).
44. The formation of an intermediate formate ester from the starting aldehyde through a Baeyer-Villiger oxidation is inferred from detection of the corresponding alcohol. Precedent for this kind of process can be found in the literature, but usually involves organic peracids as oxidant. See for example: (a) Yeager, G. W.; Schissel, D. N. Synthesis 1991, 63. (b) Krow, G. R. Org. React. 1993, 43, 251. (c) Occurrence of an oxone®-promoted Baeyer-Villiger process has been proposed in the literature: Wu, X.-Y.; She, X.; Shi, Y. J. Am. Chem. Soc. 2002, 124, 8792; see also earlier reference (Ref. 14c).
45. The formation of an intermediate formate ester from the starting aldehyde through a Baeyer-Villiger oxidation is inferred from detection of the corresponding alcohol. Precedent for this kind of process can be found in the literature, but usually involves organic peracids as oxidant. See for example: (a) Yeager, G. W.; Schissel, D. N. Synthesis 1991, 63. (b) Krow, G. R. Org. React. 1993, 43, 251. (c) Occurrence of an oxone®-promoted Baeyer-Villiger process has been proposed in the literature: Wu, X.-Y.; She, X.; Shi, Y. J. Am. Chem. Soc. 2002, 124, 8792; see also earlier reference (Ref. 14c).
46. DMF alone or its dimethyl acetal can also promote conversion of 1,2-phenylenediamines to 2H-benzimidazoles, but this usually requires elevated temperatures and is not suspected to occur under the present oxone®-promoted reaction conditions: Mataka, S.; Shimojyo, Y.; Hashimoto, I.; Tashiro, M. Liebigs Ann. 1995, 10, 1823.
47. The ratio of 14 to 15 did not vary significantly upon prolonged reaction times indicating that under the reaction conditions, equilibration of the diamine 15 to benzamidine 3 and eventually to product 14 did not occur.
48. It is very likely that the quenched reaction mixtures still retain some oxidizing potential and should be disposed of appropriately to avoid hazardous decompositions. It has been reported for example that oxone® will lose active oxygen slowly under alkaline conditions, see: (a) Kennedy, R. J.; Stock, A. M. J. Org. Chem. 1960, 25, 1901. (b) Ball, D. L.; Edwards, J. O. J. Am. Chem. Soc. 1956, 78, 1125.
49. It is very likely that the quenched reaction mixtures still retain some oxidizing potential and should be disposed of appropriately to avoid hazardous decompositions. It has been reported for example that oxone® will lose active oxygen slowly under alkaline conditions, see: (a) Kennedy, R. J.; Stock, A. M. J. Org. Chem. 1960, 25, 1901. (b) Ball, D. L.; Edwards, J. O. J. Am. Chem. Soc. 1956, 78, 1125.
50. (a) Chang, J.; Zhao, K.; Pan, S. Tetrahedron Lett. 2002, 43, 951; and references cited therein.
51. (b) Hari, A.; Karan, C.; Rodrigues, W. C.; Miller, B. L. J. Org. Chem. 2001, 66, 991.