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.

One‐Pot Catalytic Synthesis of Optically Active Drug (S)‐Clopidogrel

“…Next, we embarked on the optimization of the DROE step. In our previous work, [12,13] the bis‐nucleophile used, embedded in the same reagent, was readily set up to capture the α‐keto sulfone intermediate I intramolecularly, after epoxide ring‐opening in the DROC step (Table 2). Conversely, in the DROE step, after the selective ring‐opening of the epoxide by the secondary amine, the following displacement of the phenylsulfinic acid from the α‐keto sulfone intermediate I would occur by amine or methanol, giving rise to a mixture of ester and amide products.…”

“…The DROE step was preliminarily investigated using racemic epoxide 5 a in the presence of the structurally similar piperidine, but cheaper than 4,5,6,7‐tetrahydrothieno[3,2‐c]pyridine and triethylamine under previously reported conditions at room temperature (Table 2). [12] To the epoxide solution in toluene, at the optimal concentration (C=0.02 M) of the epoxidation step, methanol (400 equiv), piperidine and Et 3 N as an acid scavenger were added in a one portion and stirred for 18 hours (entry 1). Although the conversion of the epoxide was good after an acceptable time, a mixture of ester 6 and amide 7 in a 60/40 ratio was observed.…”

“…All starting materials were purchased from Merck‐Sigma Aldrich, or TCI and used as received. Alkenes 3 are known compounds, they were prepared according to the literature [12,18] . 2‐(Naphthalene‐2‐ylsulfonyl)acetonitrile and 2‐(naphthalene‐1‐ylsulfonyl)acetonitrile are known compound, they were prepared according to the literature [19] .…”

“…Over the last years, we have been interested in the asymmetric organocatalytic preparation of building blocks and heterocyclic compounds using readily available promoters [11] . More recently, we disclosed a one‐pot enantioselective route to medicinally relevant dihydroquinoxalin‐2‐ones, [12] piperazin‐2‐ones and morpholin‐3‐ones, [13] using commercially available reagents, a popular quinine derived urea as the organocatalyst using a single solvent (Scheme 1d). The Knoevenagel condensation and the asymmetric epoxidation were catalysed by the quinine‐derived urea to give highly enantioenriched 1‐phenylsulfonyl‐1‐cyano epoxides, which act as α‐halo acyl halide synthons in the domino ring‐opening cyclization step (DROC).…”