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.

Keywords: 2-formylpyrrole; endo-Diels–Alder stereocontrol; intramolecular Heck arylation reaction; non-covalent interactions; pyrroloindoles; pyrroloisoindoles.

Figure 1

Fused aza-hetero polycyclic frames and natural pyrrolizine- and isoindole-containing alkaloids.

Scheme 1

Synthetic approaches for the preparation of pyrrolo-fused aza-hetero polycyclic frames.

Scheme 2

Preparation of 1,2-substituted pyrroles 8a–f and 8i,j.

Scheme 3

Diels–Alder cycloadditions of pyrroles 8a–j and 16a–b with maleimides 7b–c.

Figure 2

Structures of 9m (a) and 10m (b) as determined by single-crystal X-ray diffraction crystallography (ellipsoids at the 30% probability level).

Scheme 4

Pd(0)-catalyzed intramolecular Heck cross-coupling reaction of 2-vinylpyrroles 8c,d and 8g.

Scheme 5

Synthesis of 2-vinylpyrroles 8k,l and their Pd(0)-catalyzed intramolecular Heck cross-coupling to pyrrolo[2,1-a]isoindoles 18d,e.

Scheme 6

Diastereoselective Diels–Alder reaction of pyrrolo[2,1-a]isoindole 18a with 7c.

Scheme 7

Synthetic approach to the fused aza-heterocyclic pentacycle 12.

Figure 3

M06-2X/6-31+G(d,p) Optimized geometry for each of the SCs (a and d), TSs (b and e) and ADs (c and f) of the Diels–Alder reactions of diene 8g and dienophile 7c, for the endo (a–c) and the exo (d–f) approaches, respectively.

Figure 4

M06-2X/6-31+G(d,p) Optimized geometry for each of the TSs of the Diels–Alder reactions of dienes 8b, 8c, 8g, 8j and 18a with dienophiles 7b,c for the endo approach, showing the π···π, C–H···π, C–H···OC and C–H···Br stacking interactions and their distances (Å).

Figure 5

M06-2X/6-31+G(d,p) Optimized geometry of the endo SCs (a) and TSs (b) for the Diels–Alder reaction of diene 8c and dienophile 7b, the endo TSs (c) of the reaction of 8j and 7c, the endo approach of the SC (d) and TS (e) for the cycloaddition of 16a and 7c, and the endo TS (f) for the cycloaddition of 18a and 7c.