Abstract
The regioselectivity in the 1,3-dipolar cycloaddition (1,3-DC) between five-membered cyclic nitrone and methylenecyclopropane (MCP) has been studied through density functional theory (DFT) calculations. The computational study of 1,3-DC with different 1-alkyl- (or 1,1-dialkyl)-substituted alkenes and the comparison with MCP have evidenced that the electrostatic interaction has a central role in the regioselectivity of the reactions. It has been observed that the electronic effect of the substituent (donor or attractor groups) determines the polarization of the alkene double bond and the reaction mechanism, consequently determining the interaction with nitrones and favoring an orientation between this moiety and the dipolarophile.
Highlights
The value of thermal rearrangement of 5-spirocyclopropane isoxazolidines 3 (Brandi-Guarna rearrangement, see Scheme 1)[1,2] for the synthesis of monocyclic and polycyclic heteroScheme 1
Another important synthetic application of 5spirocyclopropane isoxazolidines 3 is the synthesis of β-lactams 5 by thermal fragmentation under acidic conditions.[7−9] Isoxazolidines 3 find their origin in a 1,3-dipolar cycloaddition
A dipolarophile like isobutene (7), which is the alkene with the highest similarity to MCP, reacts with nitrone 6 to give exclusively one adduct, i.e., the 5,5-disubstituted isoxazolidine 8 (Scheme 2),[15] MCP generally affords a mixture of regioisomers, where the 5-spirocyclopropane isoxazolidine is the major, but not the exclusive cycloadduct, as shown in the examples of Scheme 3.16,17
Summary
The value of thermal rearrangement of 5-spirocyclopropane isoxazolidines 3 (Brandi-Guarna rearrangement, see Scheme 1)[1,2] for the synthesis of monocyclic and polycyclic heteroScheme 1. The 1,3-DC reaction mechanism has been computationally investigated with density functional theory (DFT) and post-HF methods: it consists of a concerted, often asynchronous, pericyclic cycloaddition mechanism.[19] To elucidate this possible cyclopropylidene effect on the regioselectivity of the 1,3-DC of MCP with nitrones, DFT calculations have been carried out on the systems summarized in Scheme 5. The kinetic constants of the reactions have been calculated using the Eyring transition state theory.[33−35] The results allowed a comparison of the kinetic parameters for the two different orientations of the alkenes for each reaction in Scheme 5 and to explain the different experimental yields. The kinetic constants have been calculated for the experimental reaction temperature range between 300 and 400 K
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
