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

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.

Direct α-Imination of N-Acyl Pyrazoles with Nitrosoarenes.

Unprecedented α-imino N-acyl pyrazoles were efficiently and selectively prepared through the 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD)-catalyzed reaction of nitrosoarenes with N-acyl pyrazoles via an N-nitroso aldol reaction/dehydration sequence. The α-imino acyl pyrazoles were demonstrated to be new versatile intermediates for practical one-pot syntheses of α-imino amides, dipeptide precursors, esters, and ß-amino alcohols. The synthetic method competes with known protocols in terms of ready availability of the reagents and catalyst, mild and catalytic reaction conditions, gram-scale applicability, and scope of the α-imino acid derivatives achievable.

Catalytic enantioselective one-pot approach to cis- and trans-2,3-diaryl substituted 1,5-benzothiazepines.

The first enantioselective catalytic approach to cis- and trans-2,3-diaryl substituted 1,5-benzothiazepines has been conveniently developed in a one-pot fashion, starting from α,ß-unsaturated acyl pyrazoles and 2-aminothiophenol. The organocatalytic two-step sulfa-Michael/lactamization sequence is promoted by a readily available bifunctional thiourea and p-toluenesulfonic acid, respectively. The protocol enables access to both N-unprotected cis- and trans-diastereoisomers in moderate to satisfactory overall yields (up to 84%) and good to excellent ee values (up to 99%). Mechanistic investigations helped to shed light on the regio- and stereoselective outcome of the process.

Catalytic Enantioselective Synthesis of Protecting-Group-Free 1,5-Benzothiazepines.

A one-pot enantioselective route to N-unprotected 2,3-dihydro-1,5-benzothiazepinones, by an organocatalyzed sulfa-Michael reaction of readily available α,ß-unsaturated N-acyl pyrazoles with 2-aminothiophenols followed by silica-gel-catalyzed lactamization, has been developed. The method proceeds under mild conditions at room temperature and it requires only 1 mol % catalyst loading, to give 2-aryl/alkyl-substituted 1,5-benzothiazepines in generally good to excellent yields and enantioselectivities. The process, used for a short synthesis of antidepressant drug (R)-(-)-thiazesim, represents the first method to access enantioenriched unprotected 1,5-benzothiazepines, which are useful for rapid derivatization in drug discovery.

Stereoselective amine-thiourea-catalysed sulfa-Michael/nitroaldol cascade approach to 3,4,5-substituted tetrahydrothiophenes bearing a quaternary stereocenter.

An investigation on the stereoselective cascade sulfa-Michael/aldol reaction of nitroalkenes and commercially available 1,4-dithiane-2,5-diol to 3,4,5-substituted tetrahydrothiophenes, bearing a quaternary stereocenter, is presented. A secondary amine thiourea derived from (R,R)-1,2-diphenylethylamine was found to be the most effective catalyst when using trans-ß-methyl-ß-nitrostyrenes affording the heterocyclic products in good yields and moderate stereoselectivities.