Regio- and stereochemistry in the intramolecular [4 + 2] and intermolecular [3 + 2] cycloaddition reactions in the synthesis of epoxypyrrolo[3,4-g]indazoles: a density functional theory study

Both intramolecular [4 + 2] and intermolecular [3 + 2] cycloaddition reactions for the synthesis of 1,3-dioxoepoxyisoindole and epoxypyrrolo[3,4-g]indazoles, respectively, experimentally explored by Alizadeh and co-workers, were studied theoretically at the M06-2X/6-311G(d,p) computational level in both gaseous and solution (acetonitrile, benzene and DMSO) phases. In the first stage, it was studied the intramolecular [4 + 2] cycloaddition reaction generating potentially two diastereomeric adducts and it was confirmed the formation of experimentally reported product, 1,3-dioxoepoxyisoindole DEI-1 by the local reactivity indices as well as potential energy surface analysis. In the second stage, the [3 + 2] cycloaddition reaction of DEI-1 with three nitrilimines including NI–H, NI-C and NI–N, which generates potentially four possible regio- and stereoisomeric adducts was studied. The local reactivity indices described satisfactorily the experimentally observed regioselectivities. The results of potential energy surface analysis indicated that among the four possible products, only two exo regioisomeric adducts (namely, epoxypyrrolo[3,4-g]indazoles, CA-x1 and CA-x2) can be formed. In fact, for the reaction of DEI-1 with NI–H, NI-C and NI–H, the ratio of CA-x1:CA-x2 was estimated to be 57:43, 86:14 and 39:61, respectively, which is in satisfactory agreement with the experimental outcomes. The structural variations during the reactions were also studied and the results indicated that the transition states are not completely synchronous.