C−H Coupling Reactions Directed by Sulfoxides: Teaching an Old Functional Group New Tricks

Abstract

Sulfoxides are classical functional groups for directing the stoichiometric metalation and functionalization of C-H bonds. In recent times, sulfoxides have been given a new lease on life owing to the development of modern synthetic methods that have arisen because of their unique reactivity. They have recently been used in catalytic C-H activation proceeding via coordination of an internal sulfoxide to a metal or through the action of an external sulfoxide ligand. Furthermore, sulfoxides are able to capture nucleophiles and electrophiles to give sulfonium salts, which subsequently enable the formation of C-C bonds at the expense of C-H bonds. This Review summarizes a renaissance period in the application of sulfoxides arising from their versatility in directing C-H functionalization.

Regioselective synthesis of C3 alkylated and arylated benzothiophenes

“…Recently, we34353637383940 and others41424344454647484950515253545556 reported the metal-free, sulfoxide directed57 C–H functionalization of a variety of molecular scaffolds, which was enabled by an interrupted Pummerer reaction28. Spurred on by these recent achievements, we considered the use of benzothiophene S -oxides 1 for the synthesis of important C3-functionalized benzothiophenes, as the corresponding sulfonium salts I and II , formed after reaction with the coupling partners, lack aromaticity about the five-membered ring and should therefore undergo facile C–C bond formation via [3,3]-sigmatropic rearrangement58, thus delivering unexplored reactivity not accessible in benzothiophenes.…”

Palladium‐Catalyzed Enantioselective C−H Olefination of Diaryl Sulfoxides through Parallel Kinetic Resolution and Desymmetrization

“…Notably, ortho substituents,including fluoro,chloro,methyl, ethyl, isopropyl, [22] and methoxy groups,onthe benzene rings of substrates improved the enantioselectivity of this asymmetric transformation to excellent levels (97-99 % ee;entries [4][5][6][7][8][10][11][12][13][14], presumably due to the higher steric hindrance of ortho-substituted groups. Notably, ortho substituents,including fluoro,chloro,methyl, ethyl, isopropyl, [22] and methoxy groups,onthe benzene rings of substrates improved the enantioselectivity of this asymmetric transformation to excellent levels (97-99 % ee;entries [4][5][6][7][8][10][11][12][13][14], presumably due to the higher steric hindrance of ortho-substituted groups.…”

“…Notably, ortho substituents,including fluoro,chloro,methyl, ethyl, isopropyl, [22] and methoxy groups,onthe benzene rings of substrates improved the enantioselectivity of this asymmetric transformation to excellent levels (97-99 % ee;entries [4][5][6][7][8][10][11][12][13][14], presumably due to the higher steric hindrance of ortho-substituted groups. To our delight, when the reaction was carried out at 100 8 8Cwith aslightly changed ratio of 4/3b (2:1), olefination occurred at both of the aryl groups and therefore furnished products 5 and 6.N ot surprisingly,s ulfoxides 4 with ortho substituents on the benzene rings were olefinated with excellent ee values and in good yields ( Table 3, entries [1][2][3][4][5][6][8][9]. Thea bsolute configuration of product 2b was confirmed to be methyl (S,E)-3-(5-methyl-2-(ptolylsulfinyl)phenyl)acrylate by comparison with the known compound through ar eported method (for details,s ee the Supporting Information).…”

“…[1] In particular, the catalytic enantioselective activation of inert C À Hb onds offers ah ighly atom-and step-economic approach towards the facile synthesis of optically active molecules and intermediates. However,P d II -catalyzed asymmetric C(sp 2 ) À Hf unctionalization through parallel kinetic resolution (PKR, Scheme 1), in which both enantiomers of the starting material can be transformed into different enantiomerically enriched products in one pot, has never been reported and remains as ab ig challenge.H erein, we report the first example of Pd II -catalyzed enantioselective CÀ Ho lefination using non-chiral or racemic sulfoxide as directing groups, [6] through which av ariety of chiral diaryl sulfoxides were obtained with high enantioselectivity through desymmetrization or parallel kinetic resolution (PKR). However,P d II -catalyzed asymmetric C(sp 2 ) À Hf unctionalization through parallel kinetic resolution (PKR, Scheme 1), in which both enantiomers of the starting material can be transformed into different enantiomerically enriched products in one pot, has never been reported and remains as ab ig challenge.H erein, we report the first example of Pd II -catalyzed enantioselective CÀ Ho lefination using non-chiral or racemic sulfoxide as directing groups, [6] through which av ariety of chiral diaryl sulfoxides were obtained with high enantioselectivity through desymmetrization or parallel kinetic resolution (PKR).…”

“…As shown in Table 2, aw ide range of diaryl sulfoxides bearing electron-donating groups,s uch as methyl, ethyl, isopropyl, and methoxy groups,o rw eaklu electronwithdrawing groups,s uch as fluoro and chloro substituents, afforded the corresponding products with excellent ee (71-99 %, entries [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Enantioselective CÀHo lefination of symmetric diaryl sulfoxides 1 was first carried out.…”