Sulfinamides synthesis

Hogeveen and co-workers <82JOC1909 83JOC4275> also reported the synthesis of tricyclic sulfinamides by the reaction of cyclobutadiene aluminum halide o complexes (65 or 66) with 53 at low temperature. Treatment of 65 or 66 with 53 at -60 °C resulted in the formation of 67 or 68 in 52% and 55% yields, respectively (Scheme 18). 

Menthyl p-toluenesulfinate 45, a key compound in the stereospecific synthesis of sulfoxides, was also found to be a very convenient starting material for chiral sulfinamides. Montanari... 

A different approach to the stereospecific synthesis of sulfinamides described by Johnson (117,118) is based on the conversion of suitable chiral tetracoordinate sulfur compounds into sulfinamides. It was shown (117) that optically active methyl phenyl sulfoximide undergoes a clean and stereospecific reduction to the corresponding sulfinamide by means of aluminum amalgam. On the other hand,... 

In addition to sulfimides, the nitrogen analogs of sulfinates and sulfinamides are chiral and have been obtained as optically active compounds. For instance, the synthesis of diastereomeric menthyl p-toluenesulfinimidoates 90 mentioned above was effected by Cram and his collaborators (18,137) on two ways. The first comprised the reaction of racemic A -tosyl-p-tolueneiminosulfinyl chloride 92 with menthol, followed by separation of the diastereomers of 90, whereas in the second method the reaction of the ester (->45 with chloramine T was utilized. 

Of great importance was the discovery by Johnson et al. (185) of the stereospecific synthesis of optically active sulfonimidoyl chlorides, which are key substrates for making new types of sulfonimidoyl compounds. The method involves chlorination of readily available chiral sulfinamides with chlorine or A/-chlorobenzotriazole. Scheme 12 summarizes the synthesis of (-)-(/ )-A/-methylphenylsulfonimidoyl chloride 163 from (+HS>N-methyl benzenesulfinamide 164 and its reactions with sodium phenoxide and dimethylamine. 

Finally, chlorination of chiral sulfinamides (185,186) which may be classified as electrophilic reaction at a tricoordinate sulfur, proceeds with retention at sulfur, yielding chiral sulfonimidoyl chlorides. This reaction is exemplified by the synthesis of sulfonimidoyl... 

A very convenient asymmetric synthesis of cyclopropane or epoxide systems developed by Johnson (184) is based on the use of chiral sulfur ylides as the agents that induce optical activity. Generally, this method consists of the asymmetric addition of a chiral sulfur ylide to the C=C or C=0 bond and subsequent cyclization of the addition product to form a chiral cyclopropane or epoxide system together with chiral sulfinamide. A wide range of chiral... 

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. 

A considerable amount of work on the synthesis and crystal structure of peptides containing a p-aminoethane sulfonamide moiety, i.e. taurine (Tau), has been described by Calcagni et aj [7,ii5-ii7] an(j Diaz et alJ118] and a p-aminoethane sulfinamide (hypotaurine) moiety by Moree et alJ111,112,119,120 ... 

Introducing the Tau residue into a peptide according to the first approach demands protection of the amino group, usually in the form of a Z-derivative and turning the sulfonic acid into sulfonyl chloride. Synthesis of (j-su Ifonamidopeptides via an iterative process, both in solution and in the solid phase, has been described.11201 Chiral methylene sulfinamide peptides can be synthesized both in solution and in the solid phase using the sulfonyl chlorides derived from enantiomerically pure 2-substituted taurines under mild coupling conditions (DMAP catalysis and excess methyl trimethylsilyl dimethylketene acetal as a proton trap).11261... 

The presence of the additional p-carbon atom in Tau analogues offers the opportunity to study the influence of functionalization at this p-position as compared to functionalization at the a-position. Naturally occurring a-amino acids can be used as starting materials for the synthesis of homochiral P-substituted methylene sulfinamide and sulfonamide transition-state isosteres incorporated in peptides.11201... 

In a further approach to the synthesis of methylene sulfonamides the S—N bond is first generated as a sulfinamide followed by oxidation to the sulfonamide by RuCVNalC as illustrated in Scheme 27)111,112 ... 

Nitro- or 2,4-dinitrobenzenesulfonamides of primary or secondary amines can be hydrolyzed under mildly basic conditions, and are increasingly being used for amine protection (see Section 10.1.10.7 [123,139,140]). /V-(2-Nitrobenzenesulfonyl)amino acids can be used as an alternative to TV-Fmoc amino acids for the solid-phase synthesis of peptides [141]. Deprotection is achieved by treatment of the polystyrene-bound sulfonamide with a solution of PhSH (0.5 mol/L) and K2C03 (2 mol/L) in DMF for 10 min at room temperature [141], conditions that do not lead to cleavage of esters (e.g. of the Wang linker) or to racemization. The condensation of polystyrene-bound sulfinamides H2N-SO-Pol with aldehydes yields /V-sulfinylimines, which add... 

A recoverable cyclic sulfinamide has been proposed as a source of chiral sulfoxides for asymmetric synthesis [395]. 

The propensity of N-sulfinylanilines to cycloadd, which has already been used to prepare five- and six-membered heterocyclic sulfinamides, has now been applied to the synthesis of 2,1,3-benzothiadiazines, but with... 

A similar synthesis of enantiopure (l )-sulfinamides 123 from indane-derived toluenesulfonyl 1,2,3-oxathiazolidine-2-oxide 121 has been developed. This method includes chemoselective ring opening with inversion of configuration at the sulfur atom, using Grignard reagent at the first step and lithium amide in liquid ammonia in the second step (Scheme 17) <2002JA7880>. Intermediate stable and crystalline sulfinate esters 122 were isolated in >95% yield in diastereopure form. 

Moree, W. J., Vand der Marel, G. A., and Liskamp R. M. J. (1995) Synthesis of peptidosulfinamides and peptidosulfonamides peptidomimetics containing the sulfinamide or sulfonamide transition-state isostere../. Org. Chem. 60, 5157-5169. 

The ortholithiation of benzenesulfinamides 256 is of use in the regioselective synthesis of m ta-substituted compounds 257 the sulfinamide group is used to set up two ortho... 

Table 13. Synthesis of Ephedrine Sulfinamides 72 from Oxathiazolidine 70...

Table 14. Synthesis of Sulfoxides 73 from Sulfinamides 72 (Scheme 21)...

Moreover, N-sulfinyl oxazolidinones have been shown to be good intermediates for the synthesis of chiral sulfinate esters and sulfinamides with excellent ee. In all cases, the absolute configuration of the sulfoxide obtained is in agreement with the fact that nucleophilic displacement occurs with inversion of configuration at the sulfur center in the starting /V-sulfinyl oxazolidinone. 

Table 17. Synthesis of Optically Active Alkyl (or Aryl) p-Tolyl Sulfoxides 83 from Sulfinamide 82 and Organometallic RM (Scheme 25)...

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

A more convenient synthesis of the diastereomerically pure cyclic sulfonimidates 6 and 7 has been developed. The diastereomeric sulfinamides 10 and 11 are more... 

The [2,3] sigmatropic rearrangement of sulfenate esters 3, prepared in situ on treatment of 4-morpholinesulfenyl chloride with allylic alcohols, allows easy synthesis of diastereomeric allylic sulfinamides 4 (configurations were not established)104. 

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