Abstract
The intramolecular cyclization of 5-hexenyl radicals continues to be an important synthetic method for the construction of five-membered rings. The synthetic utility arises from the high degree of regioselectivity to give predominantly cyclopentyl products in high yield under mild conditions. Recently we reported product cyclization studies on 4-oxa perturbed 5-hexenyl radical. In this paper, we report our results from a computational study (UB3LYP and UCCSD (T)) of the cyclization of a series of 5-hexenyl and 3-and 4-oxa-5-hexenyl radicals. Three highly conserved cyclization tran-sitions states (exo-chair, exo-boat and endo-chair) were located for 10 acyclic radicals. Activation energies were calcu-lated for the three modes of cyclization for each radical. Calculated values for the exo/endo cyclization ratios had a high level of agreement with experiment and predictions were offered for two cases that have not been experimentally tested. The increased percentage of exo-cyclization with 3-and 4-oxa substitution is the result of an increase in the energy dif-ference between the exo-and endo-chair transition states compared to the hydrocarbon systems. The decreased rate of cyclization of the 4-oxa compounds is primarily due to the stabilization of the initial acyclic radical by the vinyl ether linkage. The increase in the rate of cyclization with 3-methyl substitution is due to the increased conformational energy of the starting acyclic radical.
Highlights
Radical cyclizations continue to be extremely useful reactions for the construction of ring systems via single [1,2,3,4,5] and tandem cyclizations [6,7,8,9]
We found that 4-oxa substitution increased the preference for exo cyclization and decreased the rate of cyclization 3.7-fold compared to the related hydrocarbon 5-hexenyl radicals
We located three transition states for cyclization of the 5-hexenyl radicals that were similar to the structures previously reported by Spellmeyer and Houk (UHF-MP2/ STO-3G) [15] for the parent system: exo-chair, exo-boat and endo-chair (Figure 2)
Summary
Radical cyclizations continue to be extremely useful reactions for the construction of ring systems via single [1,2,3,4,5] and tandem cyclizations [6,7,8,9]. The utility of these reactions stems from the relatively mild reaction conditions (low to moderate temperature and neutral pH), which makes the system compatible with multiple functionalities and the predictable regioselectivity of the cyclization. Beckwith established rules to predict the regiochemical outcome for radical cyclizations [10] These systems cyclize under kinetic control to give exo cyclopentyl products. This is in contrast to the intermolecular addition of radicals to alkenes, which in general add endo [11,12]
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