The addition–elimination mechanism in the nucleophilic heteroaromatic substitution of 3-(4′,4′-dimethyl-4′,5′-dihydro-oxazol-2′-yl)pyridine. Solvent effect on the regiochemistry of the addition reaction

Abstract

The nucleophilic heteroaromatic substitution of 3-(4′,4′-dimethyl-4′,5′-dihydro-oxazol-2′-yl)pyridine (3) with organolithium compounds has been studied. The reaction of (3) with butyl-lithium gave a mixture of the corresponding 2,3-, 3,4-, and 2,5-disubstituted pyridines; however, the predominant product was the 3,4-isomer (5c). With s-butyl-lithium, the 2,3- and 3,4-disubstituted pyridines were obtained; again, the 3,4-disubstituted derivative (5d) was the major isomer. With methyl-lithium or phenyl-lithium, the 3,4-isomer was also the predominant product. With t-butyl-lithium, the 3,4-compound was not isolated; instead only starting compound (3) was recovered. The substitution reactions proceed via an addition–elimination mechanism.

The regiochemistry of the nucleophilic substitution of (3) with butyl-lithium was found to be solvent dependent. Thus, when solutions of (3) in ether or tetrahydro furan were treated with butyl-lithium, (5c) was the major product. When tetramethylethylenediamine was the solvent, the predominant product was 2-butyl-5-(4′,4′-dimethyl-4′,5′-dihydro-oxazol-2′-yl)pyridine(8).