Calcium-Catalyzed Formal [5 + 2] Cycloadditions of Alkylidene β-Ketoesters with Olefins: Chemodivergent Synthesis of Highly Functionalized Cyclohepta[b]indole Derivatives

Abstract

The calcium-catalyzed, formal [5 + 2] cycloaddition of indolyl alkylidene β-ketoesters with mono- and disubstituted aryl olefins to form cyclohepta­[b]­indole derivatives has been established. Unanticipated chemodivergence with phenyl vinyl sulfide/ether revealed a double [5 + 2] cycloaddition cascade providing ethano-bridged cyclohepta­[b]­indoles. Overall, the method’s highlights include: (1) use of a green, calcium-based catalyst (2.5 mol % loading); (2) reaction times under 1 h; (3) mild reaction conditions; (4) substrate-derived chemodivergence; (5) functional group tolerance; and (6) examples of derivatization.

Ready access to 7,8-dihydroindolo[2,3-d][1]benzazepine-6(5H)-one scaffold and analogues via early-stage Fischer ring-closure reaction

“…As an alternative approach to obtain indole-2-acetic acid with a protecting group at the indole nitrogen the application of conditions documented for Arndt-Eistert synthesis [31] was prompted from benzyl-protected indole-2-carboxylic acid 20 (Scheme 4) [32]. While the acid chloride of unsubstituted indole-2-carboxylic acid was reported to be highly unstable [33], we did not experience that issue with the benzyl-protected compound.…”

Lewis Acid-Catalyzed 2,3-Dihydrofuran Acetal Ring-Opening Benzannulations toward Functionalized 1-Hydroxycarbazoles

“…B. Synthesis of Indolyl-α-diazo-β-ketoesters 1 . General Procedure: Using the following modified literature procedure [ 55 ]: To a dry flask charged with a stir bar and the corresponding indole carboxylic acid (1.0 equiv. ), dry CH 2 Cl 2 was added to make a 0.5 M solution, followed by addition of catalytic DMF (a few drops).…”

An Update on Cyclohepta[b]indoles

“…Intriguingly, the racemic bicyclo[3.2.2]nonane‐derived cyclohepta[ b ]indole 79 was obtained by two consecutive non‐concerted (5+2) cycloadditions of 76 with phenyl vinyl thioether 77 (Figure 26). [36] The core carbon structure of the bicyclo[3.2.2]nonane‐derived cyclohepta[ b ]indole 79 resembles the core carbon structure of astolarsine 20 (Figure 5).…”

“…In 2019, France et al reported the synthesis of racemic tetrahydrocyclohepta[b]indoles 78 by intermolecular (5 + 2) cycloaddition (Figure 25). [36] The catalytically active species is formed in situ from calcium triflimide and tetrabutylammonium hexafluorophosphate. Notably, triflimide (HNTf 2 ) catalyzed the formation of 78 b in 64 % yield.…”