Sulfenamides synthesis

Sulfenamides, R2NSR, prepared from an amine and a sulfenyl halide, are readily cleaved by acid hydrolysis and have been used in syntheses of peptides, penicillins, and nucleosides. They are also cleaved by nucleophiles and by Raney nickel desulfurization." The synthesis and application of sulfenamides have been reviewed. ... 

Mikolajczyk and coworkers have summarized other methods which lead to the desired sulfmate esters These are asymmetric oxidation of sulfenamides, kinetic resolution of racemic sulfmates in transesterification with chiral alcohols, kinetic resolution of racemic sulfinates upon treatment with chiral Grignard reagents, optical resolution via cyclodextrin complexes, and esterification of sulfinyl chlorides with chiral alcohols in the presence of optically active amines. None of these methods is very satisfactory since the esters produced are of low enantiomeric purity. However, the reaction of dialkyl sulfites (33) with t-butylmagnesium chloride in the presence of quinine gave the corresponding methyl, ethyl, n-propyl, isopropyl and n-butyl 2,2-dimethylpropane-l-yl sulfinates (34) of 43 to 73% enantiomeric purity in 50 to 84% yield. This made available sulfinate esters for the synthesis of t-butyl sulfoxides (35). 

Another -activation of amino acids for peptide synthesis is achieved by preparing sulfenamides from sulfenylimidazoles. A sulfenylimidazole is formed in situ from the sulfenyl chloride (prepared from the disulfide and chlorine) and imidazole, which reacts further with an amino acid ester to give a sulfenamide in high yield. Conversion of such sulfenamides with IV-acyl amino acids by means of triphenylphosphine affords dipeptides with racemization of less than 0.5%.[481... 

As it has been shown, there are many ways to assemble the 1,4-(oxa/thia)-2-azole ring. Most of them are performed by inter- or intramolecular cyclization of suitable acyclic precursors. Some of them are found to be suitable for the synthesis of various ring systems, by using readily available, and properly modified reactants. Of particular importance are the following (a) the cyclizations of sulfenamides leading to (oxa/thia)azolium salts (Scheme 33) (b) the cyclization of hydroxamic acids (Scheme 39) (c) the dipolar cycloaddition methodology (Scheme 40) (d) the cyclizations of chlorosulfenyl chlorides (Scheme 46) and (e) the cyclizations of chloromethane sulfonamides (Schemes 47 and 48). Other cyclizations reported are preparative ways used mainly for the synthesis of specific compounds and the scope of these reactions has not been widely studied. 

Their synthesis can also be carried out as a two-phase electrolysis, using ammonium salts 326). Sulfenamides can be produced by oxidizing tetraalkylthiuram disulfides in the presence of amines 321 ... 

Amino-l,2,4-thiadiazoles (16) readily yield monoacylated derivatives of type (129) under the usual conditions whereas both monoacyl and diacyl derivatives (130 and 131, respectively) are easily obtained from the 3-amino isomers (65AHC(5)119, 70CB1805). In a similar manner the 3-amino-l,2,4 thiadiazoles produce mono- and di-sulfenamide derivatives when treated with sulfenyl halides. In general, the reactions of 3-amino- and 5-amino-1,2,4-thiadiazoles with sulfonyl halides under basic conditions produce only low yields of the desired derivatives. Sulfonamides of type (132) are best prepared by ring synthesis methods as illustrated in Scheme 55 (75LA1961). 

Azine approach. Cyclization of sulfenamides by addition of the amino nitrogen to an electrophilic carbon is an important route to isothiazoles. The sulfenamide substituent may be generated in situ from a thiol and chloramine. When the electrophilic carbon is a cyano group, an aminoisothiazole is formed, e.g. as in the synthesis from (140) (73LA1644). 

In a broad program of using chiral oxazolidinones in asymmetric synthesis,100 Evans s group published a paper in 1992 on the synthesis and utilization of fV-sulfinyl oxazolidinones as new sulfinylating agent.87 Two chiral auxiliaries were used in the study oxazolidinones derived from (4R, 5S)-norephedrine 74101 and (45)-phenylalanine 75.102 The corresponding fV-sulfinyl oxazolidinones 77 and 78 were obtained either by sulfmylation of the metallated oxazolidinone or by oxidation of the derived N-sulfenamides (Table 15). 

Amino(dimethylthiocarbamoyl)sulfane may be used for the synthesis of 1,4,2-dithiazines 3 from 2-substituted 4,5-diphenyl-l,3-dithiol-2-ium perchlorates. At room temperature in acetonitrile within a few days, the sulfenamide nitrogen is incorporated into the ring system, the other products being bis(thiocarbamoyl)disulfane and ammonium perchlorate.13... 

A ,2,4-Benzothiadiazines (168) are obtained as minor products, along with open-chain sulfimides (167), by treating iV-arylbenzamidines (166) with A -phenylthiomorpholine (Scheme 25 route a). The yields of benzothiadiazine are improved (43-60%) with 4,4 -thiobismorpholine as the sulfur carrier, and are optimized (30-86%) by using sulfenyl chlorides (Scheme 25 route b) in place of the sulfenamides. Corroborative evidence for the structure of 1,3-diphenyl-1 A, 2,4-benzothiadiazine (170 R = Ph, X = H) was obtained by an alternative synthesis (in 98% yield) involving successive treatment of the amidine (169) with A -chlorosuccinimide and sodium hydroxide <83JCS(P1)49). 

Beckwith [51] and Bowman [34] have developed the use of sulfenamides as precursors for aminyl and amidyl radicals. Bowman [36, 52, 53] and Newcomb [54] have applied the protocols to the synthesis of a range of nitrogen heterocycles. The best examples are given in Table 5. 

Dehydrogenation of sulfenamides. The expedient transformation to sulfen- mines is applicable to the synthesis of an electrophilic glycine synthon appropriate for the elaboration of other amino acids. 

Nitrobenzene and many of its 2-, 3-, and 4-substituted derivatives are converted into nitroaniline derivatives by treatment with sulfenamides in the presence of t-BuOK (eq 90). In this conversion, termed vicarious nucleophilic substitution (VNS), the base presumably promotes both the formation of the nucleophilic sulfenamide anion and the -elimination of the thiocar-bamoyl group from the other examples of t-BuOK-promoted VNS reactions of nitrobenzenes have appeared in recent years. An interesting example of this process involves the synthesis of dithianylated nitrobenzenes which are hydrolyzable to aldehydes (eq 91). The treatment of mixtures of m-nitroaniUne and enoUzable ketones with t-BuOK in DMSO leads to nitroindoles by oxidative nucleophilic substitution of hydrogen (eq 92). The proposed mechanism for this transformation involves attack of the potassium enolate of the ketone on the ring, spontaneous oxidation of the a-adduct, and imine formation and tautomerization. 

Whereas epoxides are readily cleaved by ammonia and amines (6), ring opening of thiiranes is rather sluggish. The situation is ameliorated by adding silver ion (7) to coordinate with the sulfur atom which then renders the ring C-S bond more permanently polarized (and hence less polarizable), i.e., the ring carbon becomes harder and more responsive to hard bases. Precedence for this activation is found in a one-step synthesis of sulfenamides from disulfides (8). 

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