Synthesis of 3-Benzylcoumarins Using Suzuki Coupling Reaction

Abstract

Coumarins are a structural scaffold in the numerous natural product 1 and one of well known oxygen containing heterocycles showing a variety of biological activities. 2 In addition, they have found in the technological applications 3 and used as intermediate for the synthesis of important molecules. 4 Because of their diverse applications, a variety of classical routes 5 to coumarins such as Pechmann, Knoevenagel, Perkin, Reformatsky and Wittig condensation reactions have been reported. However, these methods have their own problems such as harsh reaction conditions, multistep synthesis or low chemical yield. To overcome the problems associated with these classical methods, many strategies for the convenient and versatile synthesis of coumarin derivatives by direct ring formations 6 and by metal catalyzed coupling reactions of coumarin derivatives 7,8 have recently been developed. Among coumarin derivatives, 3-alkylcoumarins including benzylcoumarins are important building block and showed important biological activities. 9 As an example, Warfarin, a 3benzylcoumarin derivative, is the most widely used oral anticoagulant. 10 New, convenient, and versatile syntheses of 3-alkylcoumarins has been developed. 9 Wadia et al. reported the synthesis of 3-benzylcoumarins from the reaction of a complex of the amides and POCl3 with substituted salicylaldehydes. 9 Brase and his colleagues synthesized successfully the 3-benzylcoumarins from the salicylaldehydes and cinnamyl aldehydes using nucleophilic carbenes in ionic liquid in one-step. 9 Recently, 3-allylcoumarin was prepared by decarboxylative allylation of allyl ester of 3-carboxylcoumarin using palladium catalyst under mild condition. 9 But those methods have several drawbacks such as limited number of substrates, and harsh reaction condition. Palladium catalyzed cross coupling reactions have emerged as a powerful method for the carbon-carbon bond formation. Among them, Suzuki coupling is the most widely used method, because organoboronic acids are generally non-toxic and thermally, air-, and moisture-stable. The palladium catalyzed benzyl halides and allyl halide coupling with organoboronic acids are also well established 11 and the reaction has been known to proceed through η 3 -complex. 12 Here, we report the efficient cross coupling reaction of 3-(chloromethyl)coumarins prepared from salicylaldehydes 13 with arylboronic acid to give the corresponding 3-benzylcoumarins in excellent yields (Scheme 1). The reaction of 3-(chloromethyl)coumarin 1a and phenylboronic acid as a model was first examined using palladium acetate and Na2CO3 as a base in methanol.