Synthesis of Exo-Methylenecyclopentane Derivatives via Radical Cyclization Starting from the Baylis-Hillman Adducts

Abstract

Substituted cyclopentanes have been synthesized in a variety of ways including radical cyclizations of dienes or enynes and rhodium or palladium-catalyzed cyclization of enynes. These compounds also have been used as useful synthetic intermediates and act as an important backbone of some biologically important compounds. Recently, the synthesis of exo-methylenetetrahydrofurans was carried out via the n-Bu3SnH-mediated radical cyclization as the key step starting from the Baylis-Hillman adduct by us and Shanmugam’s group. Meanwhile we presumed that we could synthesize the corresponding carbon analog by applying similar strategy as shown in Scheme 1. The reaction of the Baylis-Hillman acetate and active methylene compounds in the presence of K2CO3 afforded the starting material 1a-f in good yields as reported. Propargylation of 1a-f under the influence of NaH/DMF/ propargyl bromide conditions gave 2a-f in 81-95% yields. With these compounds 2a-f in our hand, we examined the radical cyclization. Tributyltinhydride-mediated radical cyclization of 2a-f in benzene in the presence of AIBN produced cyclopentane derivatives 3a-f selectively via the 5exo-trig mode after hydrodestannylation. We could not observe the corresponding cyclohexane analogs, which could be formed via the 6-endo-trig mode, as in our previous paper. The results are summarized in Table 1. It is interesting to note that we isolated only one stereoisomer in entries 5 and 6. But, we did not determine the stereochemistry. As a next trial, we examined the synthesis of exo-methylene cyclohexane derivatives by using 4 as starting material. The compound 4 was synthesized by using the DABCO salt concept (Scheme 2), which was already established in our group and used extensively for the regioselective introduction of nucleophile at the secondary position of the BaylisHillman adduct. However, the radical cyclization of 4 showed the formation of many intractable mixtures of products during the radical cyclization step. When we subjected 3a under the Friedel-Crafts reaction conditions (Scheme 3), double bond isomerization occurred in high yield in short time to give 5 (rt, 1 h, 86%) instead of the generally expected Friedel-Crafts reaction. The use of AlCl3 instead of sulfuric acid showed no reaction. In summary, we disclosed the facile synthesis of highly substituted cyclopentane derivatives from the modified Baylis-Hillman adducts by radical cyclization protocol.