Photocatalytic Dearomative Intermolecular [2 + 2] Cycloaddition of Heterocycles for Building Molecular Complexity

Abstract

Indole and indoline rings are important pharmacophoric scaffolds found in marketed drugs, agrochemicals, and biologically active molecules. The [2 + 2] cycloaddition reaction is a versatile strategy for constructing architecturally interesting, sp 3 -rich cyclobutane-fused scaffolds with potential applications in drug discovery programs. A general platform for visible-light mediated intermolecular [2 + 2] cycloaddition of indoles with alkenes has been realized. A substrate-based screening approach led to the discovery of tertbutyloxycarbonyl (Boc)-protected indole-2-carboxyesters as suitable motifs for the intermolecular [2 + 2] cycloaddition reaction. Significantly, the reaction proceeds in good yield with a wide variety of both activated and unactivated alkenes, including those containing free amines and alcohols, and the transformation exhibits excellent regio-and diastereoselectivity. Moreover, the scope of the indole substrate is very broad, extending to previously unexplored azaindole heterocycles that collectively afford fused cyclobutane containing scaffolds that offer unique properties with functional handles and vectors suitable for further derivatization. DFT computational studies provide insights into the mechanism of this [2 + 2] cycloaddition, which is initiated by a triplet−triplet energy transfer process. The photocatalytic reaction was successfully performed on a 100 g scale to provide the dihydroindole analog.

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

“…[339] Cycloaddition reactions of alkenyl sulfonyl fluorides provide a convenient entry to (partially) saturated (hetero)cyclic adducts bearing the SO 2 F group. In particular, [4 + 2], [340] [3 + 2], [144,341] [2 + 2], [291,342,343] and [2 + 1] [180] cycloadditions were reported. Notable examples with particular relevance to medicinal chemistry include photochemical [2 + 2] cycloaddition providing fused biand tricyclic fused sulfonyl fluorides 69-71 (Scheme 35, A), [342,343] as well as [3 + 2] cycloaddition with azomethine ylide providing pyrrolidines 72 (B).…”

“…In particular, [4 + 2], [340] [3 + 2], [144,341] [2 + 2], [291,342,343] and [2 + 1] [180] cycloadditions were reported. Notable examples with particular relevance to medicinal chemistry include photochemical [2 + 2] cycloaddition providing fused biand tricyclic fused sulfonyl fluorides 69-71 (Scheme 35, A), [342,343] as well as [3 + 2] cycloaddition with azomethine ylide providing pyrrolidines 72 (B). [144] Interesting products were obtained from ESF via its Baylis -Hillman reaction, [344,345] as well as further transformations of adduct 73 thus obtained (Scheme 36).…”

Protonation-Enhanced Reactivity of Triplet State in Dearomative Photocycloaddition of Quinolines to Olefins

“…Dearomatization of arenes is challenging because of the high chemical stability inherent due to aromaticity. Despite this, chemists have developed various dearomative transformations of arenes, which are currently indispensable tools for synthesizing complex molecules. − Photochemical methods are a common approach to induce the loss of aromaticity. − In particular, visible-light photocatalysis has emerged as an efficient and environmentally friendly tool for utilizing energy transfer − and electron transfer, − enabling sustainable reactions, including various dearomative reactions. − …”

Visible-light induced dearomatization reactions

“…Later, the groups of Zhang and Oderinde independently reported the intermolecular dearomative [2+2] cycloaddition reactions of indole derivatives, using Ir-complexes as the photocatalysts via a pathway involving an energy transfer event (Scheme 65). 117,118 Contrast to the dimerization in Zhang's work, indolines were afforded when the reaction was conducted in the presence of DIPEA as an electron sacrificial reagent and hydrogen source. 117 In 2019, the Ko ¨nig group disclosed a Birch-type photoreduction of arenes and heteroarenes by sensitized electron transfer (Scheme 66).…”