Hydrogen‐Bond‐Enabled Dynamic Kinetic Resolution of Axially Chiral Amides Mediated by a Chiral Counterion

Abstract Non‐biaryl atropisomers are valuable in medicine, materials, and catalysis, but their enantioselective synthesis remains a challenge. Herein, a counterion‐mediated O‐alkylation method for the generation of atropisomeric amides with an er up to 99:1 is outlined. This dynamic kinetic resolution is enabled by the observation that the rate of racemization of atropisomeric naphthamides is significantly increased by the presence of an intramolecular O−H⋅⋅⋅NCO hydrogen bond. Upon O‐alkylation of the H‐bond donor, the barrier to rotation is significantly increased. Quantum calculations demonstrate that the intramolecular H‐bond reduces the rotational barrier about the aryl–amide bond, stabilizing the planar transition state for racemization by approximately 40 kJ mol−1, thereby facilitating the observed dynamic kinetic resolution.


S1
Supporting Information

General Information
Reactions requiring moisture-sensitive reagents were carried out in flame-dried glassware, under an atmosphere of argon (balloon pressure). Dry dichloromethane and tetrahydrofuran were purified by filtration through activated alumina columns employing the method of Grubbs et al. [1] Tetrahyrofuran was further dried using activated 3 Å molecular sieves in accordance with procedures suggested by Williams et al. [2] Water was purified by an Elix® UV-10 system. Reagents were used directly as supplied by major chemical suppliers. Petrol refers to the fraction of petroleum ether which boils in the range 40-60 °C. Brine refers to a saturated aqueous solution of sodium chloride.
Infrared spectra were prepared as a neat film and were recorded using a Bruker Tensor 27 FTIR spectrometer using an ATR module.
HRMS was carried out using Bruker MicroTDF and Micromass GCT spectrometers under electrospray ionization (ESI) or ammonia chemical ionization (CI)/electron ionization (EI) conditions respectively.
Melting points were determined using a Reichert melting point apparatus and are uncorrected.
Optical rotations were recorded on a Schmidt-Haensch Unipol L2000 polarimeter and values are quoted [° mL g −1 dm S6

Rotational Barrier Determination
Barriers to rotation of benzylated naphthols were measured in m-xylene (10 mg/mL) and heated to the temperature stated by an oil bath. Samples were removed periodically and diluted with 50% isopropanol in hexane at room temperature. Barriers of naphthols were measured in solvent stated (concentration unknown) at room temperature (298 K) and samples were directly injected into HPLC.

2-(2-Bromo-6-iodophenyl)-N,N-diisopropylacetamide, S2
Acid S1 (2.00 g, 5.87 mmol) was dissolved in anhydrous dichloromethane. Oxalyl chloride (960 μL, 11.7 mmol) and DMF (0.1 mL) were added and the reaction was stirred at room temperature for 1 h until no more bubbles were produced. The solution was concentrated in vacuo and redissolved in anhydrous dichloromethane with diisopropylamine (2.47 mL, 17.6 mmol) and stirred at room temperature for 2 h. The solution was diluted with dichloromethane and washed with water and brine. The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude mixture, which was purified by column chromatography, eluting with 5-10% ethyl acetate in petrol, to yield title compound S2 as a white solid (2.07 g, 83%).

Enantioselective O-Alkylation
The enantioselective O-alkylation was carried out according to the general schemes below.

Scheme S13
Asymmetric reaction conditions according to General Procedure L Scheme S14 Racemic reaction conditions according to General Procedure K

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