N-sulfinimine

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],... 

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]. 

Table 18. Synthesis of Optically Active (5)-N-Sulfinimines 85 from Sulfinamide 82...

Scheme 13.4 Aza MBH reactions of N sulfinimines with methyl acrylate.

Subsequently, enantiopure N sulfinimines were also adopted by Shi and Xu in the... 

In expanding the number Michael/aldol domino processes, chiral N-sulfinimines 27 could be subjected to a magnesium thiolate in the presence of an acrylate 26 to undergo an asymmetric thio-Michael/nucleophilic addition reaction (Scheme 7.4)... 

Similarly, the conjugated addition of thiolate derivatives to a,p-unsaturated ester 63a in the presence of chiral N-sulfinimines 64 afforded a-phenylthiomethyl-p-... 

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],... 

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)]-)... 

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. 

With LiHMDS sulfinyl chloride 37 gave N,N-bis(trimethylsilyl) sulfinamide 38 in situ. Subsequent addition of an aldehyde and CsF affords sulfinimines 39 in good yield.32 This one-pot procedure is suitable for the preparation of both alkylidene and arylidene sulfinamides. 

Bravo et al. treated (Ss)-(+)-p-toluenesulfinamide (63), prepared by hydrolysis of 44,23 with triphenylphosphine in the presence of DEAD to give the N-sulfinyl iminophosphorane 64 in 92% yield.45 The Staudinger, aza-Wittig reaction of 64 with methyl or ethyl trifluoropyruvate afforded the unstable sulfinimine 65. Attempts to purify the imino sulfinimines by flash chromatography resulted in hydrolysis. 

Sulfoximides, N- or a-halo, rearrange to sulfinimines on treatment with base.49-51 Thus, N-halosulfoximides 71 or a-halosulfoximides 72 react with 1,5-diazabicy-clo-[5.4.0]-undec-5-ene (DBU) or KjCOj to afford sulfinimines 74 in good to excellent yield. The formation of 74 is suggested to occur via rearrangement of an intermediate thiazirine S-oxide 73. 

A variety of heterocyclic sulfinimines 85 have been prepared by a [4+2] cycloaddition of alkenes 83 with N-sulfinylurethanes (84, R = Me, Et).53-59 The reaction was found to proceed with the retention of the configuration of the alkene. Alkynes 86 react with 84 in a similar manner.60,61... 

V-Sulfinylamino)azines 89 cycloadd as heterodienes with 4-epoxy-1,4-dihydro-naphthalenes (88, R = H, Me) in refluxing benzene to give trans and cis-exo adducts 90 which differ in their configuration at sulfur.62 With alkenes 91 (N-sulfiny-lamino)azine 92 affords 94 which results from rearomatization of the initially formed sulfinimine cycloadduct 93.62 64... 

Himbert reported that ynamine 95 reacts with aiylsulfonylazides 96 to give 2-oxo-3-siloxy N-sulfinyl-3-butenamides 98 in fair to good yields.65,66 The reaction was thought to involve initial formation of diazo compound 97 which gives on elimination of N2 and migration of one of the sulfonyl oxygens, the sulfinimine. 

Etiolates. Asymmetric addition of enolates to enantiopure sulfinimines is an important method for the preparation of P-amino esters.21,84,85 For example, treatment of (Ss)-sulfinimine 47 with the sodium enolate of methyl acetate in ether afforded P-amino ester 149 in 84-85% yield and in >98% de.86,87 After removal of the N-sulfinyl group, P-amino esters 150 were obtained in >90% yield.84 The P-amino esters were further elaborated into the Taxol C-13 side chain 151a,21 its fluoro analogue 151b,85 (+)-2-phenylpiperidine (152a), and (+)-dihydropinidine (152b).87... 

Dienolates. Garcia Ruano and co-workers reported that N-2-methoxynaphthyl sulfinimine (Ss)-163 reacts with the lithium dienolate of 3-butenoic methyl ester (164) to afford a-ethylidene-P-sulfinylamino ester 165 as a single isomer in 82% yield.90 In the presence of ZnBr2, a-vinyl-P-sulfinylamino esters 166 were obtained in 90% as a diastereomeric mixture in a ratio of 30 70. Both (Ss,2S,3R)-166/(Ss,2/ ,3/ )-166 can be converted to the same a-ethylidene-P-amino ester 168 via deprotection of the N-sulfinyl group and subsequent base promoted epimeriza-tion of the a-chiral center.90... 

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