Photoinduced copper-catalysed asymmetric amidation via ligand cooperativity

Abstract

The substitution of an alkyl electrophile by a nucleophile is a foundational reaction in organic chemistry that enables the efficient and convergent synthesis of organic molecules. Although there has been substantial recent progress in exploiting transition-metal catalysis to expand the scope of nucleophilic substitution reactions to include carbon nucleophiles^1-4, there has been limited progress in corresponding reactions with nitrogen nucleophiles^5-8. For many substitution reactions, the bond construction itself is not the only challenge, as there is a need to control stereochemistry at the same time. Here we describe a method for the enantioconvergent substitution of unactivated racemic alkyl electrophiles by a ubiquitous nitrogen-containing functional group, an amide. Our method uses a photoinduced catalyst system based on copper, an Earth-abundant metal. This process for asymmetric N-alkylation relies on three distinct ligands-a bisphosphine, a phenoxide and a chiral diamine. The ligands assemble in situ to form two distinct catalysts that act cooperatively: a copper/bisphosphine/phenoxide complex that serves as a photocatalyst, and a chiral copper/diamine complex that catalyses enantioselective C-N bond formation. Our study thus expands enantioselective N-substitution by alkyl electrophiles beyond activated electrophiles (those bearing at least one sp- or sp²-hybridized substituent on the carbon undergoing substitution)^8-13 to include unactivated electrophiles.

Extended Data Fig. 1 |. Continued scope of alkyl bromides serving as electrophilic coupling partners.

Couplings were generally conducted using 0.5 mmol of the amide, and N1* was used as the diamine, unless otherwise noted. All data represent the average of two experiments. The percent yield represents purified product. a: electrophile (1.5 equiv.), Cu(CH₃CN)₄PF₆ (15 mol%), P (5 mol%), N1* (20 mol%), K₃PO₄•H₂O (1.5 equiv.; in place of Cs₂CO₃), 10 °C. Ar¹ = p-(F₃C)C₆H₄, DG = directing group, Bn = benzyl.

Fig. 1.. Chiral secondary amides.

a, Strategies for their synthesis. b, This study. Ar, Ar¹ = aromatic substituents, R = carbon substituent, X = leaving/anionic group, t-Bu = tert-butyl, e.e. = enantiomeric excess, equiv. = equivalent, Et = ethyl, Me = methyl, Ph = phenyl, i-Pr = isopropyl.

Fig. 2.. An array of amides serve as nucleophilic coupling partners.

Couplings were generally conducted using 0.5 mmol of the amide. All data represent the average of two experiments. The percent yield represents purified product. Boc = tert-butoxycarbonyl, i-Bu = isobutyl, n-Bu = n-butyl, d.r. = diastereomer ratio.

Fig. 3.. An array of alkyl bromides serve as electrophilic coupling partners.

Couplings were generally conducted using 0.5 mmol of the amide, and N1* was used as the diamine, unless otherwise noted. All data represent the average of two experiments. The percent yield represents purified product. a: N2* as the diamine, no Cs₂CO₃, 2-Me-THF as solvent. b: N2* as the diamine. c: electrophile (1.5 equiv.), Cu(CH₃CN)₄PF₆ (15 mol%), P (5 mol%), N1* (20 mol%), K₃PO₄•H₂O (1.5 equiv.; in place of Cs₂CO₃), 10 °C. Ar¹ = p-(F₃C)C₆H₄, DG = directing group, Ac = acetyl, Bn = benzyl, TIPS = triisopropylsilyl.

Fig. 4.. Mechanism.

a, Outline of a possible catalytic cycle. b, Redox potentials (vs Fc⁺/Fc). c, Stern–Volmer quenching of [PCu^I(OPh)]* by 2: irradiation at 350 nm, emission at 496 nm. d, EPR studies: X-band spectra (9.4 GHz, 77 K). e, Investigation of an organic radical (R•) as an intermediate: TEMPO trapping and radical-clock experiments. f, Reactions of enantioenriched electrophile. Ar = p-(F₃C)C₆H₄, TEMPO = 2,2,6,6-tetramethyl-1-piperidinyloxy.