Highly selective Diels–Alder and Heck arylation reactions in a divergent synthesis of isoindolo- and pyrrolo-fused polycyclic indoles from 2-formylpyrrole

Abstract

A highly regio-, chemo- and stereoselective divergent synthesis of isoindolo- and pyrrolo-fused polycyclic indoles is herein described, starting from 2-formylpyrrole and employing Diels–Alder and Heck arylation reactions. 3-(N-Benzyl-2-pyrrolyl)acrylates and 4-(pyrrol-2-yl)butenones underwent a highly endo-Diels–Alder cycloaddition with maleimides to furnish octahydropyrrolo[3,4-e]indoles, which served as precursors in the regioselective synthesis of aza-polycyclic skeletons via an intramolecular Heck arylation reaction. Through the latter reaction, the 3-(N-benzyl-2-pyrrolyl)acrylates give rise to 3-(pyrrolo[2,1-a]isoindol-3-yl)acrylates. A further oxidative aromatization of the polycyclic intermediates provides the corresponding polycyclic pyrrolo-isoindoles and isoindolo-pyrrolo-indoles. A theoretical study on the stereoselective Diels–Alder reactions, carried out by calculating the endo/exo transition states, revealed the assistance of non-covalent interactions in governing the endo stereocontrol.

Pericyclic Cascade Reactions Affording Thienyl- and Benzo[b]thienyl-Fused Architectures: A Synthetic and Density Functional Theory Analysis of Asynchronous Diels–Alder Reactions of Thioarylmaleimides

“…This design is not free of problems. Vinyl furans, indoles, and pyrroles are known to undergo [4+2] cycloaddition with various dienophiles. − Although fewer examples of vinylthiophene-based cycloadditions exist, presumably due to their aromatic stabilization energy being greater than those of pyrrole and furan, , the addition of dienophiles such as maleic anhydride, N -phenylmaleimide, and dimethylacetylenedicarboxylate (DMAD) to 2-vinyl thiophenes and benzo­[ b ]­thiophenes is possible. − Spontaneous isomerization of the ensuing Diels–Alder (D–A) adducts is commonly observed for cycloadditions involving vinylheteroaryls. − This result is significant because isomerization leads to rearomatization of the heteroaryl motif (Figure ). Via the exploitation of the regio- and stereoselectivity of the D–A reaction, followed by isomerization and further oxidation, this reaction could be an invaluable approach to a new brand of thienyl maleimide-fused architectures with increased chemical complexity.…”

Regioselective Mercury(I)/Palladium(II)-Catalyzed Single-Step Approach for the Synthesis of Imines and 2-Substituted Indoles

“…Our group has an ongoing interest in designing and carrying out the novel synthesis of heterocycles [ 69 , 70 , 71 ], and in particular of aza-heterocycles and indoles [ 72 , 73 , 74 , 75 ]. Accordingly, the aim of the present study was to assess the feasibility of preparing indoles in a one-pot process, involving the regioselective Hg(I)-catalyzed hydroamination of terminal alkynes to produce imines as intermediates, and their subsequent Pd(II)-catalyzed cross-coupling oxidative cyclization to afford the corresponding C-2-substituted indoles ( Scheme 1 c).…”

“…The latter regenerates the Hg(II) catalyst by protonolysis to give the enamine, which is converted into the desired imine 5a (Scheme 1a) [53,54]. Our group has an ongoing interest in designing and carrying out the novel synthesis of heterocycles [69][70][71], and in particular of aza-heterocycles and indoles [72][73][74][75]. Accordingly, the aim of the present study was to assess the feasibility of preparing indoles in a one-pot process, involving the regioselective Hg(I)-catalyzed hydroamination of terminal alkynes to produce imines as intermediates, and their subsequent Pd(II)-catalyzed crosscoupling oxidative cyclization to afford the corresponding C-2-substituted indoles In contrast, indoles have been elaborated by diverse protocols [55], such as the wellknown Fischer [56,57], Julia [58], Bartoli [59], and Gassman [60] procedures, each of which include a sigmatropic rearrangement at a high temperature.…”