On the [2+2] Cycloaddition of 2-Aminothiazoles and Dimethyl Acetylenedicarboxylate. Experimental and Computational Evidence of a Thermal Disrotatory Ring Opening of Fused Cyclobutenes

The reaction of 2-(phenylamino)- and 2-(dimethylamino)thiazoles with dimethyl acetylenedicarboxylate
led unexpectedly to dimethyl 6-(phenylamino)- and 6-(dimethylamino)-3,4-pyridinedicarboxylates. Those
compounds reasonably result from a sequence of reactions initiated by a [2 + 2] cycloaddition of the
alkyne to the formal CC of the thiazole ring. These pyridines were obtained in nearly all the cases
assayed as the exclusive reaction products under rather mild conditions and in fair to good yields. In
contrast, the regioisomeric 2-amino-3,4-pyridinedicarboxylates, which would result from a [4 + 2]
cycloaddition followed by sulfur extrusion, were only obtained in one particular case. The two reaction
paths leading alternatively to both regioisomers were investigated computationally. The respective [2 +
2] and [4 + 2] cycloadducts were found to be formed stepwise from a common dipolar intermediate.
Notably, the step following the [2 + 2] cycloaddition (i.e., the ring opening of the fused cyclobutene
intermediate to give an all-cis 1,3-thiazepine) was found to take place in a disrotatory mode. Although
geometric constraints and electronic factors may reduce the energy for the disrotation, the implication of
the fused five-membered ring in the electronic reorganization leading to the 1,3-thiazepine is determinant.
In this sense, this step could be regarded also as a thermally allowed six-electron five-center disrotatory
electrocyclic ring opening. The proposed mechanism was experimentally supported by the isolation of
several intermediates and other experimental facts.