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.
Highlights
2,3-Dihydrobenzofurans and indolines are common substructures in medicines and natural products
Later in 1995 and 2005, the Larock group reported analogous methods for benzo[b]furan and indene synthesis[6,7]. Such reactions are generally believed to proceed via oxidative addition, migratory insertion of the resultant arylpalladium(II) species, and C(sp2)–N/O/C reductive elimination
While palladium-catalyzed alkyne annulation reactions are well developed and widely deployed in preparative chemistry, employment of alkenes in analogous processes is comparatively rare and limited to activated substrates like styrenes8–10, 1,3dienes[11], norbornenes[12], and enol ethers/esters[13,14,15,16,17] (Fig. 1b). Extension of this mode of reactivity to unactivated alkenes has proven to be challenging for several interrelated reasons: (1) competitive β-hydride elimination following migratory insertion; (2) inherently challenging C(sp3)–N/O/C reductive elimination[18]; and (3) competitive alkene isomerization pathways[19]
Summary
2,3-Dihydrobenzofurans and indolines are common substructures in medicines and natural products. After brief optimization (see Supplementary Information for details), we identified effective conditions using Pd(OAc)[2] (5 mol%) as the catalyst, K2CO3 (1.0 equiv) as the base, and HFIP (1.0 M) as the solvent, at 80 °C, under an air atmosphere, allowing for isolation of desired product 3aa in 96% yield. Reaction conditions: 1a (0.1 mmol), 2 (1.2 equiv), Pd(OAc)[2] (5 mol%), K2CO3 (1.0 equiv), HFIP (1.0 M for ortho -iodophenols and Ts-protected ortho -iodoanilines, 0.5 M for non-protected ortho-iodoanilines), air, 80°C, 24 h.
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