Sulfinimine

The Darzens condensation reaction has been used with a wide variety of enolate equivalents that have been covered elsewhere. A recent application of this important reaction was appljed toward the asymmetric synthesis of aziridine phosphonates by Davis and coworkers.In this application, a THF solution of sulfinimine 34 (0.37 mmol, >98% ee) and iodophosphonate 35 (0.74 mmol) was treated with LiHMDS (0.74 mmol) at -78 °C to give aziridine 36 in 75% yield. Treatment of 36 with MeMgBr removed the sulfinyl group to provide aziridine 37 in 72% yield. 

More recently, Davis and co-workers developed a new method for the asymmetric syntheses of aziridine-2-carboxylates through the use of an aza-Darzens-type reaction between sulfinimines (N-sulfinyl imines) and a-haloenolates [62-66]. The reaction is highly efficient, affording cis- N-sulfmylaziridine-2-carboxylic esters in high yield and diastereoselectivity. This method has been used to prepare a variety of aziridines with diverse ring and nitrogen substituents. As an example, treatment of sulfinimine (Ss)-55 (Scheme 3.18) with the lithium enolate of tert-butyl bromoacetate gave aziridine 56 in 82% isolated yield [66],... 

An aza-Darzens reaction, involving the addition of chloromethylphosphonate anions to enantiopure N-sulfinimines, has also been developed by Davis and others for the asymmetric synthesis of aziridine-2-phosphonates [81-84], As an example, treatment of the lithium anion generated from dimethyl chloromethylphos-phonate (93 Scheme 3.30) with N-sulfmimine (Ss)-92 gave the a-chloro-P-amino phosphonate 94, which could be isolated in 51% yield. Cyclization of 94 with n-BuLi gave cis-N-sulfmylaziridine-2-phosphonate 95 in 82% yield [81],... 

Within the biooxidation of disulfides, chiral thiosulfinates become available. Tert-Butyl tert-butanethiosulfinate represents a particularly valuable chiral auxiliary for the preparation of several chiral sulfoxides and sulfinimines, which can be subsequently transformed into branched amine compounds, P-aminoacids, and chiral aziridines. This product is accessible readily by mediated biooxidation of tert-butyl... 

The furazan ring can be constructed by the one-pot reaction of iV-(5,5-dimethyl-3-oxocyclohexenyl)-.S,.S-diphenyl-sulfilimine 272 with isopentyl nitrite <2006SC2087> and also by a one-pot procedure from sulfinimines 273, without isolation of the nitroso intermediates, in refluxing toluene (Scheme 71) <2002T10073>. 

The preparation of chiral isoquinoline derivatives continued to be investigated. Sulfanamide 59 was prepared by addition of a lateral lithiated o-toluonitrile with the corresponding sulfinimine. Treatment of 59 with MeLi followed by acidification afforded cyclic imine 60. Reduction of imine 60 with liAlHi/MejAl afforded the trans-1,3 derivative, and... 

Chiral sulfinimines 236 are very useful intermediates for the preparation of enantiomer-ically pure primary amines 237 (equation 158) . This reaction has been applied to the synthesis of a-amino acids . For sulfinimines obtained from simple ketones, lithium reagents are preferable for the addition , while for cyclic ketones organomagnesium compounds gave the best results. Addition of alkyl and aryl Grignard compounds to sulfinimines, derived from 3- and 4-substituted cyclohexanones, proceeds with excellent diastereoselectivity, depending on the stereochemistry of the ring substituents rather than the sulfinyl group . 

In the Sepracor synthesis of chiral cetirizine di hydrochloride (4), the linear side-chain as bromide 51 was assembled via rhodium octanoate-mediated ether formation from 2-bromoethanol and ethyl diazoacetate (Scheme 8). Condensation of 4-chlorobenzaldehyde with chiral auxiliary (/f)-f-butyl sulfinamide (52) in the presence of Lewis acid, tetraethoxytitanium led to (/f)-sulfinimine 53. Addition of phenyl magnesium bromide to 53 gave nse to a 91 9 mixture of two diastereomers where the major diasteromer 54 was isolated in greater than 65% yield. Mild hydrolysis conditions were applied to remove the chiral auxiliary by exposing 54 to 2 N HCl in methanol to provide (S)-amine 55. Bisalkylation of (S)-amine 55 with dichlonde 56 was followed by subsequent hydrolysis to remove the tosyl amine protecting group to afford (S)-43. Alkylation of (5)-piperizine 43 with bromide 51 produced (S)-cetirizine ethyl ester, which was then hydrolyzed to deliver (S)-cetirizine dihydrochloride, (5)-4. 

SULFINIMINES (THIOOXIMINE S-OXIDES) ASYMMETRIC SYNTHESIS OF METHYL (R)-(+)- 3-PHENYLALANATE FROM (S)-(+)-N-(BENZYLIDENE)-p-TOLUENESULFIN AMIDE (Benzenepropanoic acid, p-amino-, (R)-, methyl ester from Benzenesulfinamide, 4-methyl-N-(phenylmethylene)- [S-(E)]-)... 

Many other asymmetric syntheses of amine derivatives using enantiopure sulfinimines have been reported.28-33... 

SULFINIMINES (THIOOXIMINE S-OXIDES) ASYMMETRIC SYNTHESIS OF METHYL (R)-(+)-p-PHENYLALANATE FROM (S)-(+)-N-(BENZYLIDENE)-p-TOLUENESULFIN AMIDE. 

Addition of phosphates to chiral sulfinimines derived from aromatic aldehydes has been used to prepare a-amino phosphonate esters asymmetrically.35 The sulfinimines employed, p- Me Ph S (= O) N=C H A r. have sufficiently bulky substituents to prevent inversion, as shown by 1H-NMR over a wide range of temperatures. 

The addition of Grignard reagents to chiral trifluoromethyl r-butyl sulfinimine-ethanol adducts has afforded protected trifluoromethylamines in high yields with good ... 

Asymmetric aza Morita-Baylis-Hillman reactions of N-sulfonylimines or N-sulfinimines with Michael accepters in the presence a Lewis base catalyst to give the corresponding chiral a-methylene-/ -amino compounds have been described [27]. 

Diastereoselective Mannich-type reactions between ketene silyl acetals and chiral sulfinimines using simple metal-free Lewis bases such as tetraalkylammonium car-boxylates have been reported. The sulfinimine can even be generated in situ (from aldehyde and a chiral sulfonamide), using cesium carbonate, followed by addition of ketene silyl acetal at -78 °C, and as little as 1 mol% of catalyst.32... 

Strecker-type reaction of TMS cyanide with chiral sulfinimines gives diastereoselective cyanations at the imine carbon, at —78 °C in DMF, using simple metal-free Lewis base catalysts such as tetraalkylammonium carboxylates.73... 

Unusual -branched Baylis-Hillman adducts have been prepared by Li and coworkers by a novel Et2AlCl promoted domino Michael-aldol reaction of propynoates 50 with organo-cuprates and chiral p-toluenesulfinimines 52 (Scheme 10) [42], These condensations proceeded with very good diastereoselectivity to give allylic amines 53. The selectivity can be explained through the chairlike transition state 54. The anion intermediate approaches the sulfinimine from the sterically less hindered side of the lone pair of electrons. The nucleo-... 

A recently reported novel asymmetric aziridination route involves the action of methylene transfer reagents on chiral sulfinimines 97, whereby the selectivity is conferred by the asymmetric sulfinyl center. The stereochemical outcome of this reaction is dependent upon the methylene transfer reagent. Thus, dimethyloxosulfonium methylide provided predominantly isomer 98, whereas the use of dimethylsulfonium methylide led to the formation of 99 as the major product [95TL295]. 

Diastereoselectivity in functionalized piperidine synthesis has also been reported using chiral sulfinimines (Scheme 18) <2003OL3855>. It was postulated that the observed selectivity arose from an intermediate alkoxy aluminium species shielding one face of the imine during reduction. 

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