We carried out a theoretical study of the radical [3 + 2] cycloaddition reaction of NCO + RCCH (R = H, CH3, F, Cl, CN), which produced a five-membered ring heterocyclic oxazole. An asynchronous two-bond formation mechanism was found, which led to a certain regioselectivity in the products when the substituted alkyne was used as a reactant. The preferable reactive sites of RCCH in various substituents are calculated by employing the Fukui functions and HSAB theory, and the results are in good agreement (except R = F) with the calculated energy barriers of the transition states in the potential energy surfaces. The N atom of NCO attacks the unsubstituted carbon atom of RCCH first, followed by the ring closure of the 0 atom with the other carbon atom to form the substituted oxazole. The order of the calculated first transition barriers (uts1) in the substituted alkynes (RCCH) is R = H > F > CN > Cl > CH3, and that for the second transition barriers (uts2), R = H > CH3 > CN > Cl > F. The reason for the decreased transition barriers of the substituted alkynes is analyzed.