A Diastereoselective Sakurai-Metathesis Route to Dihydrobenzofurans

Significance

A short diastereoselective synthesis of cis- or trans-2,3-dihydrobenzofuran using a combined Sakurai-Grubbs metathesis route is described. Using readily available vinylsilane derivatives of phenols, the metathesis step leads to 2,3-dihydrobenzo[f]oxasilepin derivatives which, under typical Sakurai conditions, provide the dihydro­benzofuran products. The diastereoselectivity in the Sakurai process was found to be highly dependent on the electronic nature of the aldehyde. Thus, electron-poor aldehydes lead to cis products, whereas electron-rich aldehydes lead to the formation of the trans isomers. The stereo­chemistry was assigned by NMR studies and by X-ray crystal structure analysis on representative derivatives. A mechanistic proposal for the Sakurai reaction is given.

Comment

2,3-Dihydrobenzofuran is a core structure for numerous biologically active natural products (e.g., pterocarpans: R. Maurya, P. P. Yadav Nat. Prod. Rep. 2005, 22, 400-424) and synthetic drugs used in treatment of pulmonary hypertension and atherosclerotic peripheral arterial disease (S. Ohata et al. Clin. Exp. Pharmacol. Physiol. 2006, 33, 381-387). Previous syntheses of 2,3-dihydrobenzofurans are based, for example, on Lewis acid promoted reactions (K. M. Rupprecht et al. J. Org. Chem. 1991, 56, 6180-6188), anionic cyclizations (F. F. Kneisel et al. Tetrahedron Lett. 2002, 43, 4875-4879) or palladium-catalyzed couplings (R. V. Rozhkov, R. C. Larock J. Org. Chem. 2003, 68, 6314-6320). The herein presented method shows an application of allylsilanes in the synthesis of heterocylic compounds (T. K. Sarkar, Sk. A. Haque, A. Basak Angew. Chem. Int. Ed. 2004, 43, 1417-1419).