Organic Chemistry Portal
Organic Chemistry Highlights

Friday, December 24, 2004
Vasco D.B. Bonifacio
New University of Lisbon

Sulfoximines, sulfilimines, sulfinimides, sulfonimidates and sulfonimidamides - the chiral sulfur connection

Chiral, nitrogen-containing sulfur(VI) compounds are undergoing a renaissance in the field of organic chemistry. This growing interest is related to their significant potential in asymmetric synthesis, and new synthetic applications are currently being developed.

1. Sulfoximines and sulfilimines

Sulfoximines, referred to by Prof. Barry Trost as "chemical chameleons" for asymmetric synthesis (Synlett, 1992, 27. DOI: 10.1055/s-1992-21253) , constitute a new class of chiral ligands, which have also been studied for their bioactivity as antibiotics, antithrombotics and tumor metastasis inhibitors. Their synthesis and catalytic applications (Chem. Lett. 2004, 33, 482-487. DOI: 10.1246/cl.2004.482) as well the synthetic and spectroscopic investigation of their N-acylated derivatives (Chem. Eur. J. 2004, 10, 2942-2952. DOI: 10.1002/chem.200306016) were recently reviewed by Bolm et al. This group has also published a simple and safe, high-yield, two-step procedure for the synthesis of NH-sulfoximines and -sulfilimines. The procedure calls for a Rh(II)-catalyzed imination using a preformed iminating agent, or sulfonylamides in combination with iodobenzene diacetate and magnesium oxide. Sulfoxides gave 66-88% yields, and sulfides gave 86% yield, without the need for dry solvents and inert atmosphere. The oxidation of chiral sulfoxides occurs with retention of configuration (>99% ee).

Asymmetric iminations using a chiral rhodium catalyst are currently under investigation (Org. Lett. 2004, 6, 1305-1307. DOI: 10.1021/ol049715n).

The Malacria group also developed a iodine (III)-mediated preparation of chiral sulfoximes (ee> 98%) (Synlett 2002, 116-118, DOI: 10.1055/s-2002-19338; Chem. Eur. J. 2004, 10, 906-916. DOI: 10.1002/chem.200305525).

A "green" (non-halogenated solvents, mass-free electrons as reagent), mild electrochemical sulfoxide imination procedure was developed by Yudin and Siu for the synthesis of "free" NH-sulfoximines (46-67% yields), which are valuable synthetic intermediates. (Org. Lett. 2002, 4, 1839-1842. DOI: 10.1021/ol0257530).

The Bolm group developed a sulfoximine N-arylation method using a ligand-free, copper-mediated cross-coupling reaction of sulfoximines with aryl halides in high yields (48-95% yield) under milder and more economical conditions. (Org. Lett. 2004, 6, 3293-3296. DOI: 10.1021/ol048806h) . This method complements the known stereospecific palladium-catalyzed N-arylation (J. Org. Chem. 2000, 65, 169-175. DOI: 10.1021/jo991342u).

a) sulfoximine (1.0 eq.), aryl halide (2.0 eq.), copper salt (1.0 eq.), base (2.5 eq.), degassed DMSO, 90 C, 12h.

2. Sulfinimides

Sharpless has developed a simple and high yield (70-99%) synthetic method to produce sulfinimides from sulfides, by stirring the readily available starting materials in wet acetonitrile. This has abetted a recent growing interest in these compounds due to their biological activity (potential dermal penetration enhancers, Bioorg. Med. Chem. Lett. 1999, 9, 1033-1034. DOI: 10.1016/S0960-894X(99)00131-6; pesticidal derivatives, Rhone-Poulenc Agrochimie, E.P. 839809, 1997). There's also a report of a sulfinimide with a slight antimalarial activity (J. Med. Chem. 1970, 13, 759-760).

When chiral six-membered cyclic sulfides are treated under these conditions, a 9:1 anti-diastereoselectivity is observed in the sulfinimide products (J. Org. Chem. 2001, 66, 594-596. DOI: 10.1021/jo0012039).

a) sulfide (1.0 eq.), chloramine-T trihydrate (1.2 eq.), MeCN, 16 h, rt. Chloramine T= TsN-Cl Na+

The Carreira group also developed a synthesis of chiral sulfinimides (up to 92% ee) from sulfides using optically active nitridomanganese(V) complexes as electrophilic amination reagents (Helv. Chim. Acta, 2002, 3773-3784. DOI: 10.1002/1522-2675(200211)85:11%3c3773::AID-HLCA3773%3e3.0.CO;2-O).

a) MnN (1.0 eq.), anhydride (5.0 eq.), CH2Cl2, -78 to 23 C.

3. Sulfonimidates

The sulfonimidates are a very interesting class of chiral molecules with applications in material science. Polyorganooxothiazenes are thermally stable and solvent resistant sulfur(VI)-nitrogen backbone polymers obtained from the thermally induced condensation of sulfonimidates (J. Am. Chem. Soc. 1993, 115, 2604-2612; U.S. Patent 5233019, 1993). These compounds are also known to exhibit human carbonic anhydrase II inhibitory activity (Carbonic Anhydrase, Proc. Int. Workshop; VCH, Weinheim, 1991, 50-64). The Malacria group reported their one-pot synthetic procedure (60-95% yield) starting from sulfinamides (Org. Lett. 2002, 4, 4093-4095. DOI: 10.1021/ol026837b) . The asymmetric version of this reaction was recently reported to occur with retention of configuration (Chem. Eur. J. 2004, 10, 906-916. DOI: 10.1002/chem.200305525) .

4. Sulfonimidamides

The sulfonimidamide is a relatively unknown functional group, although it was first reported four decades ago (Zh. Obshch. Khim. 1962, 32, 1208). Aryl sulfonimidamide derivatives have received the most attention to date, while unsubstituted alkyl derivatives have more recently been postulated to mimic the tetrahedral intermediates in protease and amidase reactions based on their geometry and electronics (Bioorg. Med. Chem. Lett. 1999, 9, 1527-1532. DOI: 10.1016/S0960-894X(99)00241-3) . Sulfonimidamides are also known to be bioactive analogs of oncolytic sulfonylureas (J. Med. Chem. 1997, 40, 1018-1025. DOI: 10.1021/jm960673l) . The Malacria group has reported their use as the first chiral nitrene precursors in copper (II)-mediated multi-component reactions. Applications include the synthesis of sulfimides (53-63% yield), sulfoximines (54-80% yield) and aziridines (43-78% yield); the lower yield in the latter case is for electron-poor olefins due to the electrophilic character of the nitrene, with a moderate level of diastereoselection (50%). No sulfonimidamide enantiomers have been reported; the diastereoselection is explained on the basis of both steric and electronic effects (Org. Lett. 2004, 6, 3573-3575. DOI: 10.1021/ol0485520) .

a) sulfonimidamide (1.0 eq.), alkene, sulfoxide (chiral or racemic) or sulfide (1.0 eq.), Cu(OTf)2 (10 mol %, 5 lots with one portion every 15 min), PhI=O (1.1 eq.), MS 3, MeCN, 1h, rt.

In the first report of an in situ chiral iminoiodane generation, the Dodd group has also recently demonstrated that sulfonimidamide enantiomers obtained by resolution with (S)- or (R)-α-methylbenzylamine can be used as highly efficient nitrene precursors in copper (I)-catalyzed diastereoselective aziridinations (35-96% yield, up to 60% de) (Org. Lett. 2004, 6, 4503-4505. DOI: 10.1021/ol048167a) .

a) (+)- or (-)-N-(p-toluenesulfonyl)-p-toluenesulfonimidamide (1.2 eq.), alkene (1.0 eq.), Cu(MeCN)4PF6 (10 mol%), PhI=O (1.2 eq.), MS 4, MeCN, 24h, -18 C.

V. D. B. Bonifacio, Org. Chem. Highlights 2004, December 24