Regio- and Stereoselectivity of Captodative Olefins in 1,3-Dipolar Cycloadditions. A DFT/HSAB Theory Rationale for the Observed Regiochemistry of Nitrones

Abstract

Captodative olefins 1-acetylvinyl carboxylates proved to be highly regioselective dipolarophiles in 1,3-dipolar cycloadditon to propionitrile oxide, arylphenylnitrile imines, diazoalkanes, and nitrones to yield the corresponding 5-substituted heterocycles. The addition of the latter was also stereoselective, being slightly susceptible to steric demand of the carboxylate substituent in the olefin. All atempts to cleave the isoxazolidine N-O bond under reductive conditions failed, providing diverse products with side-group reduction. FMO theory was unsuccessful to explain the regioselectivity observed with nitrones, since the opposite orientation was predicted. The recently formulated DFT/HSAB theoretical model was able to rationalize this regioselectivity, identifying the nucleophilic and electrophilic atoms involved in the process via calculation of interaction energies, suggesting the specific direction of the electronic process at each of the reaction sites.

Conceptual, Qualitative, and Quantitative Theories of 1,3‐Dipolar and Diels–Alder Cycloadditions Used in Synthesis

“…[28] They showed that regioselectivity is controlled because the electron-donating groups in the captodative olefins increase the interaction between the nitrone carbon atom and the b-C1 carbon of the a,b-unsaturated ketone. This subtle stereoelectronic effect was reflected in the electrophilic attack values of the nitrone carbon atom and the C1 atom of the captodative olefins.…”

A DFT study of 1,3-dipolar cycloaddition reactions of 5-membered cyclic nitrones with α,β-unsaturated lactones and with cyclic vinyl ethers: Part 1

“…[17][18][19][20][21][22][23][24][25][26][27][28][29][30] Ten years ago, Tanaka et al 17 examined the 1,3-DC of 3,4-dihydroisoquinoline N-oxide to methyl 2-butenoate. The authors proposed a concerted mechanism with a nonsymmetric transition state in which the C-O bond is formed to a greater degree than the C-C one.…”

Investigation into the Regiochemistry of 1,3‐Dipolar Cycloaddition of C,N‐Diphenyl Nitrone with Some Vinyl Sulfoximines as Dipolarophile: Theoretical Studies

“…In these cases, analysis of the most electrophilic center of the electrophile and the most nucleophilic center of the nucleophile accounts for the regioselectivity in these polar processes. 23 To put in evidence the preferential cyclization mode and consequently the major cycloadducts of 1,3-dipolar cycloaddition reactions under investigation, we will consider two-center Table 1 Energies of reactives, transition states and cycloadducts 3, 4, 5 and 6, E (a.u. ), relative activation energies ∆E a (kJ•mol -1 ) and relative energies between products and reactives, ∆E r (kJ•mol…”