Unusual Regioselectivity of the Dipolar Cycloaddition Reactions of Nitrile Oxides and Tertiary Cinnamides and Crotonamides¹

Abstract

Benzonitrile oxides undergo 1,3-dipolar cycloaddition reactions with methyl cinnamate to produce the 5-phenyl and 4-phenyl regioisomers in approximately an 80:20 ratio. However, use of N,N-diethylcinnamide as the dipolarophile unexpectedly resulted in the formation of the 5-phenyl and 4-phenyl regioisomers in a 23:77 ratio. Studies have shown that this phenomena occurs only for tertiary cinnamides. In addition, it has been demonstrated that the phenyl group of tertiary cinnamides is not essential for the reversal of regioselectivity since crotonamides produce the same results and trends as the cinnamides. However, since acrylates and acrylamides both produce the 5-carbonyl regioisomers, it can be concluded that the beta-substituent is playing a key role for the unexpected results by possibly increasing steric interactions between the dipole and dipolarophile in the transition state. Transition state energies were calculated for the regioisomeric cycloadduct pairs derived from several crotonamides as well as methyl crotonate. These calculations indicate that steric factors are indeed responsible for the reversal of regioselectivity.

Concomitant Addition and Acetalization of α,β‐Unsaturated Aldehydes with Diols.

“…They are useful in olefin cross methathesis, 2,3 as dienophiles, [4][5][6] as dipolarophiles, 7,8 and in C-C bond formation by umpolung addition. [9][10][11] They are also important in polymer research.…”

Synthesis of Spiroisoxazoline[5,31]chroman-41-one

“…12,13 In the case of nitrile oxides, the fact that the C atom is more sensitive to steric requirements than the O atom is known in the literature. A plausible explanation for the observed mode of cycloaddition is that a steric effect overweighs the electronic effect.…”

“…,13 Since there is not much difference in the atomic coefficients of the dipolarophile (1a-e) in its LUMO, the carbon terminal of the 1,3-dipole approaches the less substituted carbon of the dipolarophile from the least hindered side to give the observed regioisomer (3a-j).To conclude, efficient synthesis of spiroisoxazoline[5.3 1 ]-chroman-4 1 -one has been demonstrated by the regioselective cycloaddition reaction of 3-arylidene-4-chromanone with nitrile oxide and the regiochemistry of the cycloaddition is independent of the electronic nature of the substituent on the arylidene ring of the dipolarophile.…”

The 2:1 cycloadducts from [3 + 2] 1,3-dipolar cycloaddition of nitrile oxide and vinylacetic acid. Synthesis and liquid crystal behaviour

“…The oxadiazole oxide can be formed by the addition of one equivalent of arylnitrile oxide 4a, which was formed in situ, followed by the subsequent addition of one equivalent of oxime 3a [27]. Furthermore, we failed to prepare the corresponding 3,5-disubstituted isoxazolines 9 from the cycloaddition of the aryloxime 3a and the aryl ester derived from vinylacetic acid 5 due to the base-induced isomerisation of vinylacetic acid to crotonic acid that was observed in the esterification step [28][29][30].…”