Pd/Cu-Catalyzed Oxidative C-H Alkenylation of Imidazo[1,2-a]pyridines

Abstract

A novel direct and regioselective Pd/Cu-catalyzed intermolecular oxidative coupling of imidazo[1,2-a]pyridines with alkenes was successfully developed. The scope and limitations of the reaction were further studied by using various alkenes. This method provides a 'green' route to 3-alkenylimidazo[1,2-a]pyridine derivatives in high yields.The ability to form C-C bonds is an indispensable tool in synthetic organic chemistry, and the development of powerful catalytic methods has opened new routes to complex molecule synthesis. Usually, heteroaryl-aryl bonds are formed by the coupling of two functionalized heteroaromatic carbons, but that is not always necessary. It is sometimes possible to directly arylate an aromatic ring by replacing a C-H bond with a C-C bond. In the past three decades, the development of transition-metal-catalyzed C-H activation reactions has received considerable attention. 1 A wide range of metal catalysts, including Ru, Rh, Pt, and Pd catalysts, have been exploited with varying levels of success.Considering the remarkable progress made in the development of palladium-catalyzed C-C bond-forming reactions of various heterocycles, 2,3 we turned our attention to intermolecular C-H alkenylation via oxidative Pd/Cu-catalyzed reactions. In the recent years a limited number of methods for regioselective couplings of heteroaromatic systems using oxidative palladium-catalyzed reactions of arenes and olefins have been described; 4 however, in some cases, these procedures have shown moderate regioselectivity. 4Our group has a long-standing interest in imidazo[1,2-a]pyridine derivatives. 5 We have reported a regioselective palladium-catalyzed (hetero)arylation 6 at C-3 of imidazo[1,2-a]pyridines and the first examples of one-pot, twostep Suzuki cross-coupling/direct arylation and one-pot, three-step cyclization/Suzuki cross-coupling/regioselective arylation. 7 Herein, we describe recent advances in the direct and regioselective alkenylation of imidazo[1,2-a]pyridines by oxidative Pd/Cu-catalyzed C-H bond activation (Scheme 1). As far as we know, this is the first example of intermolecular oxidative C-3 alkenylation of bicyclic heterocycles with a bridgehead nitrogen atom.To the best of our knowledge, few approaches, including palladium cross-coupling, are known for preparing 3-alkenylimidazo[1,2-a]pyridines 3 from imidazo[1,2-a]pyridines 1 (Scheme 1): pathway A, involving halogenation of imidazo[1,2-a]pyridines 1 5a,8-10 followed by Heck,5a,8,11 Stille, 12 or Suzuki 13 cross-coupling; pathway B, involving bromination of alkene followed by the 'inverse' Heck reaction. 14 Although these sequences were successful, an additional step for the activation of imidazo[1,2-a]pyridines and alkenes is required and expensive reagents are used (alkenylboronic acids for Suzuki and alkenylstannanes for Stille couplings). Compared to these methods, the oxidative alkenylation reaction is obviously advantageous in terms of starting material price and byproduct (i.e., brominated alkene) formation.