Three-Carbon Dowd-Beckwith Ring Expansion Reaction versus Intramolecular 1,5-Hydrogen Transfer Reaction: A Theoretical Study Diego Ardura and Toma ´s L. Sordo* Departamento de Quı ´mica Fı ´sica y Analı ´tica, Universidad de Oviedo, C/Julia ´ n Claverı ´a, 8, Oviedo 33006, Spain tsordo@uniovi.es Received July 26, 2005 The evolution of the primary radicals formed by addition of AIBN/HSnBu 3 to methyl 1-(3-iodopropyl)- 5-oxocyclopentanecarboxylate, methyl (1R*,2R*)-1-(3-iodopropyl)-2-methyl-5-oxocyclopentanecar- boxylate, and methyl (1R*,2S*)-1-(3-iodopropyl)-2-methyl-5-oxocyclopentanecarboxylate in benzene has been theoretically investigated by ROMP2/6-311++G(2d,2p)//UB3LYP/6-31G(d,p) calculations taking into account the effect of solvent through a PCM-UAHF model. According to the theoretical results, for methyl 1-(3-iodopropyl)-5-oxocyclopentanecarboxylate and methyl (1R*,2S*)-1-(3- iodopropyl)-2-methyl-5-oxocyclopentanecarboxylate the major product is the cyclooctane derivative from the three-carbon ring expansion, whereas for methyl (1R*,2R*)-1-(3-iodopropyl)-2-methyl-5- oxocyclopentanecarboxylate the major product is that corresponding to the 1,5-H transposition in agreement with the experimental findings. This different behavior is a consequence of several factors determining the relative energy barriers. The methyl substituent destabilizes the ring expansion process for methyl (1R*,2R*)-1-(3-iodopropyl)-2-methyl-5-oxocyclopentanecarboxylate because of steric repulsion but favors it in the case of the -trans-substituted substrate because it makes possible the evolution of the system along more favorable conformations. The methyl group also favors the 1,5-H transposition rendering the transposed product a tertiary radical. The second stage of the ring expansion process is stabilized by resonance. Introduction An attractive way to approach the synthesis of medium and large rings is to take advantage of existing cyclic structures through ring expansion reactions. 1 One of these synthetic strategies is the so-called Dowd-Beck- with free radical ring expansion which uses -keto esters as starting materials. 2-4 The efficiency of this method has been experimentally proved for both one- and three- carbon ring expansions (see Scheme 1). However, in the case of the three-carbon expansion processes experimen- tal work has identified a competing 1,5-hydrogen transfer which can become dominant for some substrates. For methyl 1-(3-iodopropyl)-2-oxocyclopentanecarboxy- late (5 in Scheme 2) the ring expansion product 6 accounts for 77% of the products. In addition, 15% of the directly reduced product 8 and 8% of reduction product 7 with deuterium incorporated  to the carbonyl are formed, showing that 1,5-H transfer is occurring. For the -trans-substituted precursor methyl (1R*,2R*)-1-(3- iodopropyl)-2-methyl-5-oxocyclopentanecarboxylate, 9, ring expansion (10), 1,5-hydrogen transfer (11), and direct reduction (12) products are formed in 8%, 86%, and 6% yields, respectively. In contrast, reaction of the -cis- * Corresponding author. Phone: +34 98 5 103 125. Fax: +34 98 5 103 125. (1) Hesse, M. Ring Enlargement in Organic Chemistry; VCH: Weinheim, Germany, 1991. (2) (a) Dowd, P.; Choi, S.-C. J. Am. Chem. Soc. 1987, 109, 6548- 6549. (b) Dowd, P.; Choi, S.-C. J. Am. Chem. Soc. 1987, 109, 3493- 3494. (c) Dowd, P.; Zhang, W. Chem. Rev. 1993, 93, 2091. (3) Beckwith, A. L. J.; O’Shea, D. M.; Wetswood, S. W. J. Am. Chem. Soc. 1988, 110, 2565-2572. (4) Wang, C.; Gu, X.; Yu, M. S.; Curran, D. P. Tetrahedron 1988, 54, 5442. 10.1021/jo051551g CCC: $30.25 © 2005 American Chemical Society J. Org. Chem. 2005, 70, 9417-9423 9417 Published on Web 10/07/2005