Anti-selective [3+2] (Hetero)annulation of non-conjugated alkenes via directed nucleopalladation

Abstract

2,3-Dihydrobenzofurans and indolines are common substructures in medicines and natural products. Herein, we describe a method that enables direct access to these core structures from non-conjugated alkenyl amides and ortho-iodoanilines/phenols. Under palladium(II) catalysis this [3 + 2] heteroannulation proceeds in an anti-selective fashion and tolerates a wide variety of functional groups. N-Acetyl, -tosyl, and -alkyl substituted ortho-iodoanilines, as well as free -NH₂ variants, are all effective. Preliminary results with carbon-based coupling partners also demonstrate the viability of forming indane core structures using this approach. Experimental and computational studies on reactions with phenols support a mechanism involving turnover-limiting, endergonic directed oxypalladation, followed by intramolecular oxidative addition and reductive elimination.

Fig. 1. Background and project synopsis.

a Larock-type [3 + 2] heteroannulation with alkynes. b Catalytic [3 + 2] heteroannulation with alkenes. c 1,2-difunctionalization via directed nucleopalladation.

Fig. 2. Large-scale reaction, directing group removal and mechanistic studies.

a 50 mmol-scale reaction. b Directing group removal. c Proposed mechanism. d Viability evaluation of an alternative pathway. e Evaluation of the potential reversibility of C(sp³)–O bond formation. f Competition experiments. g Initial rate studies.

Fig. 3. Computational studies.

a Computed energy profiles of the Pd-catalyzed [3 + 2] heteroannulation of 1a and 2aa. Calculations were performed using Gaussian 16 at the M06/SDD-6-311++G(d,p)/SMD(HFIP)//B3LYP-D3/SDD-6-31G(d) level of theory. b DFT calculations on the origin of diastereoselectivity with alkene 1b.