Synthesis of Quinoline Silyloxymethylsulfones as Intermediates to Sulfonyl Derivatives

Abstract

Heterocyclic sulfones, sulfonamides, and sulfonyl fluorides constitute an important structural motif in medicinal chemistry. Methods to make six-membered heteroaromatic sulfonyl compounds, however, remain challenging, and most efforts rely on commercial sulfonyl chlorides. We report herein the reaction of sodium tert-butyldimethyl silyloxymethylsulfinate with quinoline N-oxides to selectively furnish C2-substituted sulfones. The silyloxymethylsulfinate can be deprotected to then form sulfonyl fluorides, sulfonamides, and sulfones. This transformation is scalable and has broad applicability to a wide array of quinoline and isoquinoline functionality.

Synthesis of Quinoline-2-thiones by Selective Deoxygenative C–H/C–S Functionalization of Quinoline N-Oxides with Thiourea

“…Initially, the reaction between the quinoline- N -oxides 1 preactivated by triflic anhydride and thiourea lead to isothiuronium triflates 3 (Scheme A). Based on the previous reports, , we speculate that the mechanism of the formation of salts 3 involves the initial activation of the N -oxide with triflic anhydride for a nucleophilic attack, the addition of a nucleophile to the quinolinium moiety, and subsequent aromatization. Although intermediate salts 3 did not need to be isolated to obtain the desired products 2 in good yields and high purities, they could be easily obtained after aqueous workup of the reaction mixture by omitting the basic hydrolysis step, as exemplified by 3a and 3b ( Scheme A ).…”

“…In recent years, many important for research and industrial application protocols for the synthesis of functionalized pyridines and quinolines using N -oxide chemistry have been developed . Among others, there have been a few reports on the synthesis of heterocyclic sulfides and sulfones from N -oxides using sulfur-based nucleophiles . In the continuation of our studies on the deoxygenative C–H-functionalization of heterocyclic N -oxides, herein we report for the first time on the reaction of readily available quinoline- N -oxides with thiourea to deliver important quinoline-2-thiones in a regioselective manner.…”

Recent Progress in Functionalization of the Pyridine Ring through C−S Bond Formation under Transition Metal Catalyst Free Conditions

“…[52] One more approach to hexavalent sulfur derivatives uses of silyloxymethylsulfones 76 as universal reagents in the synthesis of sulfonyl fluorides 77, sulfonamides, sulfonate esters, and sulfones (Scheme 33). [53] Silyloxymethylsulfones 76 can be regioselectively prepared from sodium tert-butyldimethylsilyloxymethylsulfinate 78 quinoline N-oxides activated with TsCl. The reaction displayed a wide functional group tolerance.…”

“…Sulfonylation with silyloxymethylsulfones. [53] Scheme 34. Proposed mechanisms of sulfonylation with silyloxymethylsulfones.…”

Ts2O Promoted Deoxygenative C–H Dithiocarbonation of Quinoline N-Oxides with Potassium O-Alkyl Xanthates

“…Over the past few years, a great many methodologies for the preparation of 2-substituted quinolines have been established via deoxygenative C2–H functionalization of quinoline N -oxides with various nucleophiles in the presence of electrophilic activating agents . These nucleophiles mainly include alcohols, amines, phenols, thiols, 1,3-dicarbonyl compounds, arylsulfonyl derivatives, and AgSCF 3 . However, to the best of our knowledge, the C–H functionalization of quinoline N -oxides using potassium O -alkyl xanthates as a nucleophile to construct S -quinolyl xanthates has never been reported yet.…”