Kinetic and thermodynamic stereocontrol in the atroposelective formation of sulfoxides by oxidation of 2-sulfanyl-1-naphthamides

Abstract

Atropisomeric aromatic amides bearing 2-sulfanyl groups are oxidised by m-CPBA to the corresponding sulfoxides apparently with very high diastereoselectivity. NMR studies and oxidations of chiral benzamides however indicate that the kinetic selectivity of the oxidation is in fact relatively poor, and that the final diastereoisomeric ratio (typically >99:1) is under thermodynamic control, with relatively unhindered Ar-CO rotation readily converting the less stable to the more stable product diastereoisomer. Molecular mechanics indicates that the thermodynamic diastereoselectivity results principally from electrostatic repulsion between the C=O and S-O dipoles.

Enantioselective Synthesis of an Atropisomeric Diaryl Ether

“…The versatility of sulfoxide chemistry,12 along with the powerful dipole associated with the SO bond,13 prompted us to choose a sulfinyl group as a means of achieving conformational control. Sulfinyl groups have previously performed well in controlling functional group orientation in aromatic amides10, 13, 14 and ureas 15. We chose to make the required ethers by the route shown in Scheme .…”

Conformational preference in aromatic amides bearing chiral ortho substituents: its origin and application to relayed stereocontrol

“…Naphthamides bearing 2-sulfinyl substituents are not atropisomeric because of the poor barrier to rotation offered by second row substituents, 7 but they exhibit extremely high levels of conformational control: for 5p we found that one Ar-CO conformer is populated to a degree of >99.5% at ambient temperature. 24 We made enantiomerically enriched sulfoxide 28 by ortholithiation of N,N-diisopropylnaphthamide 9 and reaction with (1R,2S,5R,S S )-(−)-menthyl p-toluenesulfinate 29 (Scheme 10). 9,50,51 ¶ The variable temperature NMR spectrum of 28 showed a single clean set of peaks at temperatures down to −50 • C in CDCl 3 , and from this we deduce that 28, like 5p, exhibits a strong preference for the same single Ar-CO conformer, which we rationalise by proposing (on the basis of modelling studies 24 ) that Scheme 10 Synthesis of 2-sulfinyl benzamide 28.…”

Conformational arm-wrestling: battles for stereochemical control in benzamides bearing matched and mismatched chiral 2- and 6-substituents

“…Of all of the groups we have shown to exert an influence over the amide's orientation, a 2-sulfinyl group has been the most powerful. 1,2, 19 We therefore made three compounds (24, 25 and 26) in which we pitted the sulfinyl group against three other groups of slightly lower rank 1 in terms of conformational control: a 1-(trimethylsilyl)ethyl group, 20 an ephedrine-derived oxazolidine and a diamine-derived imidazolidine. Low temperature NMR experiments had shown that despite the high thermodynamic selectivity for a single amide conformer, the kinetic selectivity in the oxidation of an amido sulfide to an amido sulfoxide is low.…”

“…Low temperature NMR experiments had shown that despite the high thermodynamic selectivity for a single amide conformer, the kinetic selectivity in the oxidation of an amido sulfide to an amido sulfoxide is low. 19 We reasoned therefore that the oxidations of the corresponding sulfides to sulfoxides should proceed with poor stereoselectivity, and give a mixture of two diastereoisomers, one matched and one mismatched with regard to control over the amide Scheme 14 Matched and mismatched sulfinylsilanes.…”