Redox-enabled direct stereoconvergent heteroarylation of simple alcohols

The study addresses a central challenge in asymmetric synthesis: converting abundant, racemic feedstock materials (e.g., simple secondary alcohols) into value-added enantiopure compounds efficiently. Classical enantioconvergent approaches often rely on nucleophilic substitutions that generate stabilized ionic intermediates, but these require pre-activation and are not broadly applicable to unfunctionalized feedstock materials. Radical-based, enantioconvergent sp2–sp3 cross-couplings have delivered major advances but typically require prefunctionalized electrophiles (alkyl halides, organotrifluoroborates) and (hetero)aryl halides. The purpose of this work is to develop a mechanistically distinct, redox-enabled and overall redox-neutral enantioconvergent heteroarylation that couples simple racemic secondary alcohols directly with pyrroles, avoiding prefunctionalization. The hypothesis is to remove substrate chirality via catalytic dehydrogenation to a ketone, form a stabilized cationic/iminium intermediate upon pyrrole addition and dehydration, then reset chirality by an enantioselective hydride transfer, all under cooperative catalysis. This approach promises atom- and step-economical access to enantioenriched pyrrole derivatives with minimal waste (only water), addressing sustainability and practicality in asymmetric C–C bond formation.

Prior enantioconvergent sp2–sp3 couplings largely exploit radical pathways. Base-metal catalysis (e.g., Ni, Cu) enables enantioconvergent cross-couplings of racemic alkyl halides/mesylates (Fu and others), and enantioselective reductive couplings of two electrophiles have been realized (Reisman and others). Photoredox/Ni dual catalysis extends to racemic organotrifluoroborates and carboxylic acids with (hetero)aryl halides (Molander, MacMillan). Chiral phosphoric acid (CPA)-enabled Minisci-type enantioselective heteroarene functionalizations have been reported (Phipps; Fu), though using activated MPHI esters instead of simple acids. In contrast, borrowing hydrogen (hydrogen autotransfer) has become a green method to replace alcohols via in situ dehydrogenation–functionalization–hydrogenation, with extensive non-enantioselective variants and emerging enantioselective examples for amination and carbonyl additions (Zhao group; Beller; Donohoe; others). Krische pioneered redox-triggered carbonyl additions for lower-to-higher alcohol conversions via enantioselective transfer hydrogenative C–C bond formation. However, an enantioconvergent heteroarylation of unactivated alcohols using borrowing hydrogen had not been reported. Compared to C–H alkylation of arenes using alkenes (Dong, Pesciaioli, Shi), the current work targets intermolecular coupling of two feedstock substrates without directing groups, introducing a new redox-enabled stereoconvergent manifold.

Catalytic system: Cooperative catalysis by an oxime-derived iridacycle complex (optimal: 4k) and a chiral phosphoric acid (CPA1). The iridium complex promotes alcohol dehydrogenation and hydride delivery; the CPA activates the carbonyl addition/dehydration and imparts enantioselectivity during hydride transfer via ion pairing and H-bonding. Catalyst development: Initial chiral Ir/CPA systems (e.g., 4a/CPA1) gave moderate yield/ee. Diastereomeric combinations indicated enantioselection primarily controlled by CPA. Achiral/tricyclic iridacycles were evaluated: imine-derived 4d gave high yield but low ee. Oxime-derived iridacycles 4e–4h improved enantioselectivity with increasing steric bulk at the oxime substituent; 4k (cyano-substituted, accessible from acetophenone) was optimal, delivering 3aa in 82% yield, 90% ee. Catalysts are air-stable, easily prepared Ir–Cl complexes. General conditions: Typically 2.5 mol% 4k, 5 mol% CPA1, 4 Å molecular sieves, toluene, 100 °C, 20 h, under N2. Variations include temperature adjustments (80–130 °C), higher loadings (up to 5 mol% Ir/10 mol% CPA), and CPA2 for aliphatic substrates. Proposed mechanism (borrowing hydrogen): (1) Ir-catalyzed dehydrogenation of racemic secondary alcohol generates the ketone and an Ir–H species (stereoablation step). (2) CPA-promoted nucleophilic addition of pyrrole to ketone furnishes a tertiary alcohol that rapidly dehydrates to a conjugated iminium/carbocation intermediate paired with chiral phosphate. (3) Enantioselective hydride transfer from Ir–H to the iminium/carbocation resets chirality and affords the enantioenriched pyrrole alkylation product; water is the sole byproduct. Mechanistic experiments: No product forms with CPA alone (rules out simple acid-catalyzed intermolecular SN1). CPA plus 10 mol% acetophenone (a potential redox-chain initiator) without Ir still gave no conversion. Reaction of pyrrole 1a with 2-tetralone (CPA1) provided an alkenyl pyrrole (assigned as dehydration/deprotonation product) that, under Ir/CPA transfer hydrogenation with an alcohol donor, re-entered the catalytic cycle to give the alkylated product (75% yield, 22% ee), paralleling the redox-neutral coupling outcome (65% yield, 32% ee) with the corresponding alcohol under standard conditions. Representative procedure: In a N2-filled glovebox, charge an 8 mL vial with iridium complex 4k (3.1 mg, 0.0050 mmol), CPA1 (7.5 mg, 0.010 mmol), 4 Å MS (20 mg), 2-methylpyrrole 1a (0.200 mmol), 1-phenylethanol 2a (0.400 mmol) and toluene (0.5 mL). Seal, heat to 100 °C for 20 h, then purify by silica gel chromatography to obtain 2-methyl-5-(1-phenylethyl)-1H-pyrrole (3aa).

• Established a redox-enabled, overall redox-neutral enantioconvergent heteroarylation of racemic secondary alcohols with pyrroles using cooperative Ir/CPA catalysis; water is the only byproduct and no prefunctionalization of substrates is required.
• Oxime-derived iridacycle 4k with CPA1 is optimal; catalysts are air-stable and easily prepared.
• Scope in alcohols: Broad, including aryl–alkyl benzylic alcohols and unactivated alkyl–alkyl secondary alcohols. Electron-donating/withdrawing substituents (including cyano and nitro) are tolerated. Selected outcomes: 3aa 82% yield, 90% ee; 3ap (from 1-(2-naphthyl)ethanol) 75% yield, 96% ee; vinyl-substituted alcohol gave 3aj 56% yield, 85% ee (some over-reduction). Aliphatic alcohols furnished products in 50–90% yields and 72–88% ee under slightly modified conditions (CPA2, 90 °C, increased catalyst loading).
• Complex/drug-derived alcohols: Nabumetone- and Pentoxifylline-derived alcohols converted to 3aA (81%, 80% ee) and 3aB (85%, 86% ee).
• Scope in pyrroles: Mono-, di-, and tri-alkyl substituted pyrroles and 2-arylpyrroles performed well. Examples: 3bp 91%, 93% ee; 3cp 93%, 83% ee; 3fp 70%, 93% ee (at 130 °C, higher loadings); 3gp–3ip high yields and ees. 2,5-Dialkylations (pyrroles lacking ortho-substituents) provided major anti products with high enantioselectivity via Horeau amplification: 3jp 50%, 90% ee; 3kp 57%, 95% ee.
• Overall performance: 38 examples reported, up to 93% yield and 96% ee.
• Mechanistic evidence supports a borrowing hydrogen pathway: Ir is essential (no product with CPA alone or with acetophenone additive), and an isolated alkenyl pyrrole (off-cycle dehydration product) can re-enter the catalytic cycle under Ir/CPA transfer hydrogenation to give the same alkylated product (75% yield, 22% ee), consistent with the redox-neutral coupling outcome (65% yield, 32% ee) for the corresponding alcohol.

The findings demonstrate that a redox-enabled, borrowing hydrogen strategy can achieve enantioconvergent C–C bond formation between two unactivated feedstock partners: racemic secondary alcohols and simple pyrroles. By removing chirality through Ir-catalyzed dehydrogenation to ketones and reinstating it via CPA-controlled enantioselective hydride transfer to a stabilized iminium/carbocation, the method circumvents the need for prefunctionalized electrophiles and avoids the limitations of classical SN1 or radical-based cross-coupling routes. The cooperative Ir/CPA catalysis delivers high yields and enantioselectivities across diverse alcohol and pyrrole substrates, including challenging unactivated aliphatic alcohols and drug-derived scaffolds. Mechanistic experiments corroborate the proposed sequence and the necessity of both catalysts, while the ability of an alkenyl pyrrole to re-enter the cycle supports equilibrium with a key cationic intermediate. This approach advances sustainable asymmetric synthesis by being atom- and step-economical, redox-neutral, and generating only water as waste, and it complements established radical coupling strategies by offering distinct substrate classes and functional group tolerance (e.g., nitro, cyano).

A direct, enantioconvergent heteroarylation of unactivated racemic secondary alcohols with pyrroles has been developed via cooperative catalysis by oxime-derived iridacycles and chiral phosphoric acids. The borrowing hydrogen mechanism enables stereoablation through alcohol dehydrogenation and stereocontrol during hydride delivery to a catalytically generated iminium/carbocation, affording substituted pyrroles in high yields and enantioselectivities (up to 93% yield, 96% ee) across a broad scope, including aliphatic alcohols and drug-derived substrates. The catalysts are air-stable and accessible, and the overall process is redox-neutral with water as the only byproduct. Future work will extend this redox-enabled enantioconvergent coupling to other heteroarenes and alcohol classes.

• Some substrates require elevated temperatures (up to 130 °C) and/or increased catalyst loadings to achieve high conversion (e.g., ester-substituted pyrroles).
• Certain substrates show moderate yields (e.g., 3aq low yield) or partial side reactions (e.g., over-reduction observed with a vinyl substituent).
• Enantioselectivity can decrease when substituent size differences are minimal (e.g., 3aC 32% ee under standard conditions).