Cycloadditions of 4-Alkenyl-2-aminothiazoles with Nitroalkenes in the Formal Synthesis of Pramipexole: An Experimental and Computational Study

4-Alkenyl-2-dialkylaminothiazoles act as in-out dienes in [4 + 2] cycloaddition reactions with nitroalkenes, furnishing 2-amino-6-nitro-4,5,6,7-tetrahydrobenzothiazoles in moderate to good yields, accompanied by a subsequent 1,3-<i>H</i> migration. These transformations proceed with exquisite site-, regio-, and diastereoselectivity. This strategy is further enriched by revealing a novel route for pramipexole synthesis. The examination of the potential energy surfaces associated with the four possible reaction pathways for the Diels-Alder cycloaddition (relative approach of the diene-dienophile and <i>endo</i>/<i>exo</i> approach of the nitro group) not only aligns with experimental observations but also unveils key mechanistic insights. Specifically, computational analyses uncover the favored pathway yielding 6-nitro-4,5,6,7-tetrahydrobenzothiazoles, with some instances proceeding through a two-step mechanism involving a tandem sequence of chemical processes, and the influence of various factors such as dienophile structure and the approach mode of the nitro group. Additionally, the stabilization of the <i>exo</i>-transition states, particularly facilitated by phenyl substitution in the dienophile, is highlighted. Asynchronicity, dipole moment, and other parameters indicative of polar character further characterize these Diels-Alder reactions. Conceptual DFT calculations underscore the pivotal role of the 1,3-thiazole ring in enhancing dienic activation and dictating regioselectivity, emphasizing interactions between the C5 of the thiazole nucleus and the Cβ atom of the nitroalkenes.