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

Carlos H Escalante; Eder I Martínez-Mora; Carlos Espinoza-Hicks; Alejandro A Camacho-Dávila; Fernando R Ramos-Morales; Francisco Delgado; Joaquín Tamariz

doi:10.3762/bjoc.16.113

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

Beilstein J Org Chem. 2020 Jun 17:16:1320-1334. doi: 10.3762/bjoc.16.113. eCollection 2020.

Authors

Carlos H Escalante¹, Eder I Martínez-Mora^{1

2}, Carlos Espinoza-Hicks³, Alejandro A Camacho-Dávila³, Fernando R Ramos-Morales⁴, Francisco Delgado¹, Joaquín Tamariz¹

Affiliations

¹ Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala S/N, 11340 Mexico City, Mexico.
² Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad Autónoma de Coahuila, Blvd. Venustiano Carranza e Ing. J. Cárdenas S/N, 25280 Saltillo, Coah., Mexico.
³ Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad Autónoma de Chihuahua, Circuito Universitario S/N, 31125 Chihuahua, Chih., Mexico.
⁴ Unidad de Servicios de Apoyo en Resolución Analítica, Universidad Veracruzana, Luis Castelazo Ayala S/N, 91190 Xalapa, Ver., Mexico.

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.

Grants and funding

J.T. acknowledges SIP/IPN (Grants 20140858, 20150917, 20160791, 20170902, 20180198, 20195228 and 20200227) and Consejo Nacional de Ciencia y Tecnología (CONACYT, Mexico) (Grants 178319, A1-S-17131 and 300520) for financial support. C.E.-H. and A.A.C.-D. are grateful to CONACYT for a grant to purchase the NMR instrument (INFR-2014-01-226114). E.I.M.-M. greatly appreciate the support given by the SEP through the NPTC program (UACOAH-PTC-498). C.H.E. and E.I.M.-M. are beholden to CONACYT for awarding them graduate scholarships, and also thank SIP/IPN (BEIFI) and the Ludwig K. Hellweg Foundation for scholarship complements. F.D. and J.T. are fellows of the EDI-IPN and COFAA-IPN programs.