Anomalous Intramolecular C-H Insertion Reactions of Rhodium Carbenoids: Factors Influencing the Reaction Course and Mechanistic Implications J. Stephen Clark,* ,† Alexander G. Dossetter, † Yung-Sing Wong, † Robert J. Townsend, † William G. Whittingham, ‡ and C. Adam Russell ‡ School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, U.K., and Syngenta, Jealott’s Hill Research Centre, Bracknell, Berkshire RG42 6EY, U.K. j.s.clark@nottingham.ac.uk Received January 16, 2004 The intramolecular insertion of rhodium carbenoids into the R-C-H bonds of allylic ethers to give 3(2H)-furanones has been explored. Cyclopropanation is favored irrespective of the complex used for carbenoid generation or the substitution pattern of the allylic ether, unless a substituent is placed on the tether connecting the ether to the R-diazo ketone. Unusual acetal products resulting from an anomalous C-H insertion process are obtained in addition to the expected 3(2H)-furanones formed by conventional carbenoid C-H insertion. These acetals are the favored C-H insertion products in certain circumstances and particularly in cases where carbenoid generation is effected using an electron-deficient rhodium complex. Experiments with simple deuterium labeled substrates reveal that anomalous C-H insertion products arise by a mechanism that is distinct from that leading to the formation of conventional C-H insertion products. The formation of acetal products and the outcome of reactions performed using deuterium-labeled substrates suggest that a mechanism involving hydride migration to the rhodium center of the carbenoid is operative. Introduction Intramolecular C-H insertion reactions of metal car- benoids, generated from R-diazocarbonyl compounds, have been widely used for the stereoselective construction of substituted cyclopentanones, lactones, and lactams, 1 and the advent of asymmetric variants of these reactions has further extended the scope and general utility of the methodology. 2 The intramolecular insertion of a metal carbenoid into a C-H bond adjacent to an ether oxygen is a particularly favorable reaction, and Adams and co- workers have demonstrated that rhodium carbenoids generated from R-diazo ketones undergo efficient and stereoselective C-H insertion to give 3(2H)-furanones. 3 Taber and co-workers have used the corresponding reaction of R-diazo esters for the stereoselective synthesis of highly functionalized tetrahydrofurans, 4 and Lee has shown that the intramolecular insertion of a carbenoid into a C-H bond adjacent to a trialkylsilyl ether is especially favorable and that this reaction can be utilized to prepare medium-ring cyclic ethers. 5 In the course of studies directed toward the synthesis of the sesquiterpene natural product neoliacinic acid, 6 we prepared the vinyl-substituted 3(2H)-furanone 2 from the R-diazo ketone 1 by generation of a rhodium carbenoid and subsequent intramolecular insertion of this reactive intermediate into the C-H bond of an allyl ether (eq 1). Although the yield for this transformation was reason- able and the furanone 2 was the major product, cyclo- propanation of the alkene to give the pyranone 3 was found to be a significant competing process. 7 To gain a better understanding of the reaction and elucidate those factors controlling the selectivity of the C-H insertion process, we embarked on a study of the rhodium- catalyzed cyclization reactions of some simple R-diazo ketones related to 1. 8 Results and Discussion Four R-diazo ketones (17-20) bearing variously sub- stituted allylic ethers were chosen for our preliminary * To whom correspondence should be addressed. Tel: +44 115 9513542. Fax: +44 115 9513564. † University of Nottingham. ‡ Syngenta. (1) For reviews concerning the C-H insertion reactions of metal carbenoids, see: (a) Taber, D. F. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pattenden, G., Vol. Ed.; Pergamon Press: Oxford, U.K., 1991; Vol. 3, Chapter 4.2, pp 1045-1062. (b) Adams, J.; Spero, D. M. Tetrahedron 1991, 47, 1765. (c) Padwa, A.; Krumpe, K. E. Tetrahedron 1992, 48, 5385. (d) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091. (d) Doyle, M. P. In Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Hegedus, L. S., Vol. Ed.; Pergamon Press: New York, 1995; Vol. 12, Chapter 5.2, pp 421-468. (e) Doyle, M. P.; McKervey, M.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds; Wiley: New York, 1998. (f) Sulikowski, G. A.; Cha, K. L.; Sulikowski, M. M. Tetrahedron: Asymmetry 1998, 9, 3145. (g) Merlic, C. A.; Zechman, A. L. Synthesis 2003, 1137. (2) For an excellent recent review of asymmetric carbenoid C-H insertion reactions, see: Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861. 3886 J. Org. Chem. 2004, 69, 3886-3898 10.1021/jo049900e CCC: $27.50 © 2004 American Chemical Society Published on Web 04/30/2004