On the importance of an acid additive in the synthesis of pyrido[1,2-a]benzimidazoles by direct copper-catalyzed amination

Masters, Kye-Simeon, Rauws, Tom R.M., Yadav, Ashok K., Herrebout, Wouter A., Van der Veken, Benjamin, & Maes, Bert U.W. (2011) On the importance of an acid additive in the synthesis of pyrido[1,2-a]benzimidazoles by direct copper-catalyzed amination. Chemistry, 17(23), pp. 6315-6320.

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Pyrido[1,2-a]benzimidazoles1, 2a are interesting compounds both from the viewpoint of medicinal chemistry2–7 (solubility,7 DNA intercalation3) and materials chemistry8 (fluorescence). Of note among the former is the antibiotic drug Rifaximin,5 which contains this heteroaromatic core. The classical synthetic approach for the assembly of pyrido[1,2-a]benzimidazoles is by [3+3] cyclocondensation of benzimidazoles containing a methylene group at C2 with appropriate bielectrophiles.2a However, these procedures are often low-yielding, involve indirect/lengthy sequences, and/or provide access to a limited range of products, primarily providing derivatives with substituents located on the pyridine ring (A ring, Scheme 1).2–4 Theoretically, a good alternative synthetic method for the synthesis of pyrido[1,2-a]benzimidazoles with substituents in the benzene ring (C ring) should be accessible by intramolecular transition-metal-catalyzed CN bond formation in N-(2-chloroaryl)pyridin-2-amines, based on chemistry recently developed in our research group.9 These substrates themselves are easily available through SNAr or selective Pd-catalyzed amination10 of 2-chloropyridine with 2-chloroanilines.11 If a synthetic procedure that eliminated the need for preactivation of the 2-position of the 2-chloroarylamino entity could be developed, this would be even more powerful, as anilines are more readily commercially available than 2-chloroanilines. Therefore the synthesis of pyrido[1,2-a]benzimidazoles (4) by a transition-metal-catalyzed intramolecular CH amination approach from N-arylpyridin-2-amines (3) was explored (Scheme 1).

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ID Code: 69930
Item Type: Journal Article
Refereed: Yes
Keywords: catalysis, C-H activation, C-H amination, C-H functionalization, copper
DOI: 10.1002/chem.201100574
ISSN: 0947-6539
Divisions: Current > QUT Faculties and Divisions > Science & Engineering Faculty
Copyright Owner: Copyright 2011 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim
Deposited On: 09 Apr 2014 03:08
Last Modified: 15 May 2014 06:46

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