Redox-enabled direct stereoconvergent heteroarylation of simple alcohols

Abstract

The direct transformation of racemic feedstock materials to valuable enantiopure compounds is of significant importance for sustainable chemical synthesis. Toward this goal, the radical mechanism has proven uniquely effective in stereoconvergent carbon-carbon bond forming reactions. Here we report a mechanistically distinct redox-enabled strategy for an efficient enantioconvergent coupling of pyrroles with simple racemic secondary alcohols. In such processes, chirality is removed from the substrate via dehydrogenation and reinstalled in the catalytic reduction of a key stabilized cationic intermediate. This strategy provides significant advantage of utilizing simple pyrroles to react with feedstock alcohols without the need for leaving group incorporation. This overall redox-neutral transformation is also highly economical with no additional reagent nor waste generation other than water. In our studies, oxime-derived iridacycle complexes are introduced, which cooperate with a chiral phosphoric acid to enable heteroarylation of alcohols, accessing a wide range of valuable substituted pyrroles in high yield and enantioselectivity.

Fig. 1. Redox- vs. radical-based enantioconvergent (hetero)arylation.

a General mechanism of radical-based enantioconvergent (hetero)arylation. b Different strategies achieved for enantioconvergent (hetero)arylation using the radical mechanism. c The working hypothesis of redox-enabled enantioconvergent heteroarylation of feedstock secondary alcohols. d This work: enantioconvergent reaction of feedstock secondary alcohols with pyrroles catalyzed by oxime-derived iridacycle and chiral phosphoric acid (CPA) catalysts.

Fig. 2. Catalyst development for enantioconvergent heteroarylation of alcohols with pyrroles.

Reaction conditions. 1a (0.20 mmol), 2a (0.40 mmol), 4 (0.005 mmol), CPA1 (0.01 mmol) and 4 Å MS (20 mg) in toluene (0.5 mL) at 100 °C under N₂ for 20 h.

Fig. 3. Scope of alcohols for enantioconvergent heteroarylation using pyrrole 1a^a.

^aReaction conditions: 1a (0.20 mmol), 2a (0.40 mmol), 4 (0.005 mmol), CPA1 (0.01 mmol) and 4 Å MS (20 mg) in toluene (0.5 mL) at 100 °C under N₂ for 20 h, unless otherwise noted. See supplementary information for details. ^bReaction performed at 130 °C. ^cReaction performed with 3 equiv. of alcohol. ^dReaction performed with CPA2 instead of CPA1. ^eReaction performed at 90 °C. ^fReaction performed with 4 mol% 4k and 8 mol% CPA.

Fig. 4. Scope of pyrroles for enantioconvergent heteroarylation using alcohol 2p^a.

a Scope of pyrroles for enantioconvergent heteroarylation of 2p. b 2,5-Dialkylation of pyrroles. ^aReaction conditions: 1a (0.20 mmol), 2a (0.40 mmol), 4 (0.005 mmol), CPA1 (0.01 mmol) and 4 Å MS (20 mg) in toluene (0.5 mL) at 100 °C under N₂ for 20 h, unless otherwise noted. See supplementary information for details. ^bReaction performed at 80 °C. ^cReaction performed at 130 °C. ^dReaction performed with 5 mol% 4k and 10 mol% CPA1. ^eReaction performed with 4 mol% 4k and 8 mol% CPA. ^fReaction performed at 90 °C.

Fig. 5. Mechanistic aspects of enantioconvergent heteroarylation of alcohols.

a Confirmation of the role of iridium catalyst for enantioconvergent heteroarylation of alcohols. b Isolation and investigation of 9 as an off-cycle isomer of the key carbocation intermediate for enantioconvergent heteroarylation of alcohols. c Proposed catalytic pathway for enantioconvergent heteroarylation of alcohols with pyrroles.