Substrate and Catalyst Effects in the Enantioselective Copper‐Catalysed C–H Insertion Reactions of α‐Diazo‐β‐oxo Sulfones

Abstract

Excellent enantioselectivities of up to 98 % ee are achieved by employing the copper‐bis(oxazoline)‐NaBARF catalyst system in the C–H insertion reactions of α‐diazo‐β‐oxo sulfones. The influence of variation of the bis(oxazoline) ligand, copper salt, additive and substrate on both the efficiency and the enantioselectivities of these intramolecular C–H insertion reactions has been explored. Optimum enantioselectivities are achieved with phenyl and diphenyl ligands across the substrate series.

Desymmetrization by Asymmetric Copper-Catalyzed Intramolecular C–H Insertion Reactions of α-Diazo-β-oxosulfones

“…Significantly, use of the copper chloride (5 mol %), bis­(oxazoline) (6 mol %), and NaBARF (6 mol %) catalyst system led to faster reaction times and substantially enhanced selectivities, relative to any of the achiral copper catalysts, with up to 98:2 dr and yields of up to 82% for the major thiopyran 29a and enantioselectivities of up to 98% ee with the (4 R )-Ph bis­(oxazoline) ligand L1 (Table , entry 5–9). Interestingly, while the presence of the bis­(oxazoline) ligand had an enormous impact on the outcome, variation of the ligand had little impact on the product ratios, and while the enantioselectivity was ligand sensitive (85–98% ee), this variability was notably less in these transformations than in our earlier studies of insertions into freely rotating alkyl chains . There was no evidence of formation of cis-fused thiopyran products.…”

Exploiting Continuous Processing for Challenging Diazo Transfer and Telescoped Copper-Catalyzed Asymmetric Transformations

“…5-Methyl-5-phenylhexane-2,3-dione (34). 88 The compound was observed in the (10). 14 An aqueous solution of sodium azide (10 mL, 30 mmol, 3.0 M, 3.0 mL min −1 ) was pumped through a micromixer T-piece where it met a dichloromethane solution of triflic anhydride (10 mL, 5 mmol, 0.5 M, 3.0 mL min −1 ); the combined biphasic stream was passed through a reactor coil (4 × 10 mL, rt).…”

“…1−5 In particular, enantioselective rhodiumand copper-catalyzed processes have attracted significant attention, facilitating the efficient formation of new C−C bonds, among other transformations, in a highly diastereoselective and enantioselective fashion, including C−H insertion, 4,5 aromatic addition reaction, 1 and cyclopropanation. 6−8 Within our research team, highly enantioselective coppercatalyzed C−H insertions, employing bis(oxazoline) ligands, have been reported across a range of substrates leading to thiopyran S,S-dioxides (up to 98% ee), 9 sulfolanes (up to 80% ee), 10 cyclopentanones (up to 82% ee), 11 and βand γ-lactams (up to 82% ee), 12 with particular success using sulfonylsubstituted α-diazoketones and α-diazoesters. Extension of this work to copper-mediated desymmetrization proved highly effective, resulting in formation of the desymmetrized thiopyran S,S-dioxide in up to 98% ee.…”

“…Within our research team, highly enantioselective copper-catalyzed C–H insertions, employing bis­(oxazoline) ligands, have been reported across a range of substrates leading to thiopyran S , S -dioxides (up to 98% ee), sulfolanes (up to 80% ee), cyclopentanones (up to 82% ee), and β- and γ-lactams (up to 82% ee), with particular success using sulfonyl-substituted α-diazoketones and α-diazoesters. Extension of this work to copper-mediated desymmetrization proved highly effective, resulting in formation of the desymmetrized thiopyran S , S -dioxide in up to 98% ee …”

Synthesis of non-racemic 4-nitro-2-sulfonylbutan-1-ones via Ni(II)-catalyzed asymmetric Michael reaction of β-ketosulfones

“…Also non-racemic cyclic sulfones can be obtained by the Diels–Alder reaction, catalyzed by chiral Lewis acids or organocatalysts. Rh- and Cu-catalyzed CH-insertion reactions occurring at moderate or high enantioselectivity are also known [13–18]. The studied methods for obtaining acyclic sulfones with stereogenic centers in the side chain are more limited.…”