Catalytic Enantioselective Access to Dihydroquinoxalinones via Formal α-Halo Acyl Halide Synthon in One Pot

Abstract

An enantioselective one-pot catalytic strategy to dihydroquinoxalinones, featuring novel 1-phenylsulfonyl-1-cyano enantioenriched epoxides as masked α-halo acyl halide synthons, followed by a domino ring-opening cyclization (DROC), is documented. A popular quinine-derived urea served as the catalyst in two out of the three steps performed in the same solvent using commercially available aldehydes, (phenylsulfonyl)acetonitrile, cumyl hydroperoxide and 1,2-phenylendiamines. Medicinally relevant 3-aryl/alkyl-substituted heterocycles are isolated in generally good to high overall yield and high enantioselectivity (up to 99 % ee). A rare example of excellent reusability of an organocatalyst at higher scale, subjected to oxidative conditions, is demonstrated. Mechanistically, labile α-ketosulfone has been detected as the intermediate involved in the DROC process. Theoretical calculations on the key epoxidation step rationalize the observed stereocontrol, highlighting the important role played by the sulfone group.

Keywords: asymmetric catalysis; domino ring-opening cyclization; epoxidation; heterocycles; one-pot reactions.

Scheme 1

Comparison of the state‐of‐the‐art and this work.

Scheme 2

a) One‐pot Knoevenagel/asymmetric epoxidation catalysed by eQNU. b) DROC of racemic epoxide.

Scheme 3

One‐pot asymmetric sequence to 3‐alkyl‐substituted dihydroquinoxalinones from a) aliphatic alkenes and from b) aldehyde and (phenylsulfonyl)acetonitrile.

Scheme 4

a) 1 mmol scale‐up one‐pot synthesis of dihydroquinoxalinone 3 l with recyclability of eQNU. b) Reduction of compounds 3 to tetrahydroquinoxalines.

Figure 1

Full reaction pathway for the asymmetric epoxidation of alkene 1 a to epoxide 2 a with TBHP. Free energies are relative to reagents, in kcal mol⁻¹ at the IEF‐PCM B3LYP‐GD3(BJ)/6–311+G(2d,p)//B3LYP/6‐31G(d) level of theory. Structures in blue boxes are the two TSs for the formation of the (S,S) stereoisomer.