Sulfinyl chlorides synthesis

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). 

In 1958 Herbrandson and Cusano (103) prepared menthyl esters of p-iodobenzenesulfinic acid 62. Darwish and McLearen (104) described the synthesis and separation of diastereomeric esters 63 from optically active a-methylbenzyl alchols. Similarly, methane-sulfinyl chloride 64 was found to react with cholesterol to give a... 

It is worth mentioning that the extent of asymmetric induction in the sulfinate synthesis is comparable with that observed in the reaction of sulfinyl chlorides with optically active alcohols. However, in this case, the sulfinate products contain only one chiral center on sulfur the chiral-inducing amine is very easily recovered as the hydrochloride. 

A concerted elimination-cyclization mechansim, involving a sulfenyl halide in a 1,3-butadiene-1-thio system, is the most probable mechanism for the formation of benzo[6 Jthiophenes from cinnamic acids or 4-aryl-2-butanones by treatment with thionyl chloride. The reactions shown in Scheme 5 have been carefully worked out, and the intermediates isolated (75JOC3037). The unique aspect of this synthesis is the reduction of the sulfinyl chloride (a) by thionyl chloride to form the sulfenyl chloride (b). The intermediate (b) was isolated and converted in pyridine to the 3-chlorobenzo[6]thiophene-2-carbonyl chloride in 36% yield (73TL125). The reaction is probably initiated by a sulfenyl ion attack on the aromatic ring, since it is promoted by electron-releasing groups para to the site of ring closure. For example, when X in (36) was N02, a 23% yield of (37), a mixture of 5-and 7-nitro derivatives, was obtained, but when X in (36) was OMe, a 54% yield of (37) was obtained, contaminated with some 3,4-dichloro-5-methoxybenzo[6]thiophene-2-carboxylic acid. 

The corresponding cyclization of the sulfinyl chloride (108) also gives the monoxide, as shown in Scheme 24. In this case the sulfinyl chloride is generated by loss of t-butyl chloride from (107) in what has been shown to be a general synthesis of cyclic sulfinates (76CJC3012). 

Undoubtedly, the most widely used method for the synthesis of o.p. sulfoxides is the nucleophilic addition of metal organic reagent to an electrophilic sulfur with preestablished chirality, and the subsequent displacement of the sulfoxide. The reason is that either a good kinetic resolution of the sulfinyl chloride, generated first, or high separation factor of the intermediate diastereoisomers formed, permits the sulfinylating agent to be obtained in 100% de. 

In order to get better stereochemical control and to circumvent the use of sulfinyl chlorides in the synthesis of sulfinate esters, the reaction of chlorosulfite esters of... 

The method of synthesis described herein is the best procedure for preparing unsymmetrically substituted sulfamides, but it can be applied also to the symmetrically substituted ones. However, it may be a longer procedure for the latter, although the yields obtained will be consistently higher than those obtained by either direct aminolysis of sulfinyl chloride or deamination of sulfamide. The direct aminolysis of sulfuryl chloride does not work well with aromatic amines, for which ring chlorination is a complication. 

I Caution. Some of the substances in this synthesis (e.g., sulfinyl chloride) are volatile and toxic, and must be handled with care in an efficient fume hood. 

The alternate use of sulfinic acids for penem synthesis entails as the key step a reductive acylation to acyldithioazetidinones 147 [93]. When treated with 3 mol equiv. of a thioacid RCOSH, the sulfinyl chlorides derived from 159... 

Additional general methods for the synthesis of 7V-sulfonyl-imines based on the in situ generation of 0-sulfinate derivatives of oximes employing sulfinyl chlorides (phenyl- and methyl-sulfinyl chloride) or sulfonyl cyanides (p-toluenesulfonyl cyanide) and their subsequent rt rearrangement have been detailed. 

This reaction, important in the synthesis of cefaclor and other cephalosporins, has been studied in detail and is discussed in Volume 1, Chapter 2. The postulated mechanism involves formation of a sulfinyl cation (88) which undergoes an ene reaction resulting in the observed product. In an alternate explanation the sulfinyl cation reacts with the double bond to give the episulfoxonium ion (89). A six-electron sigma-tropic rearrangement would then result in the observed exomethylene isomers (Scheme 3) (see Volume 1, Chapter 2). The possible intermediacy of the sulfinyl cation suggested that derivatives other than the sulfinyl chloride could be potential sources of the requisite sulfinyl cation and hence could cyclize to the exomethylenecepham sulfoxide. This has in-... 

Besides simple alkyl-substituted sulfoxides, (a-chloroalkyl)sulfoxides have been used as reagents for diastereoselective addition reactions. Thus, a synthesis of enantiomerically pure 2-hydroxy carboxylates is based on the addition of (-)-l-[(l-chlorobutyl)sulfinyl]-4-methyl-benzene (10) to aldehydes433. The sulfoxide, optically pure with respect to the sulfoxide chirality but a mixture of diastereomers with respect to the a-sulfinyl carbon, can be readily deprotonated at — 55 °C. Subsequent addition to aldehydes afforded a mixture of the diastereomers 11A and 11B. Although the diastereoselectivity of the addition reaction is very low, the diastereomers are easily separated by flash chromatography. Thermal elimination of the sulfinyl group in refluxing xylene cleanly afforded the vinyl chlorides 12 A/12B in high chemical yield as a mixture of E- and Z-isomers. After ozonolysis in ethanol, followed by reductive workup, enantiomerically pure ethyl a-hydroxycarboxylates were obtained. 

The synthesis of enantiomerically pure propargylic alcohols is possible using the same methodology 43b. Thus, addition of (—)-[(l-chloro-2-phenylethyl)sulfinyl]-4-methylbenzene (14) to propan-al led to a mixture of the diastereomers 15A/15B (d.r. 44 56) which are easily separated by column chromatography. After thermal elimination of the sulfinyl group the vinyl chlorides 16A/16B were obtained as a mixture of E- and Z-oleftns. Elimination of hydrogen chloride was carried out with three equivalents of butyllithium, leading to enantiomerically pure 1 -phenyl-1-pentyn-3-ol. 

Usually, N-sulfinyl compounds (59) behave as thionyl transfer reagents, similar to, but milder than, thionyl chloride. For example, o-diamines with A-sulfinylbenzeneamine (59 R = Ph) afford fused 1,2,5-thiadiazoles, as in Scheme 8a.77 The advantage of using Af-sulfinyl compounds, rather than thionyl chloride itself, is that concomitant chlorinations and oxidations are avoided. This is of particular importance in the synthesis of 2,1-benzisothia-zoles (Section V,B,6). Singerman s reagent, N-sulfinylmethanesulfonamide (60) is especially valuable 78 it was used very successfully in the synthesis of a series of benzobis(isothiazoles).79... 

More recently, an interesting reaction was discovered which provides the means for the synthesis of a wide variety of methylcarbamate derivatives containing the N-sulfinyl [N-S(O)] moiety (34). In attempting to prepare isopropoxy-N-methyliminoyl chloride by the reaction between Isopropyl methylcarbamate and thionyl chloride, an unexpected product, isopropyl ll-chloro-sulfinyl-N-methylcarbamate was obtained according to the equation below. The same product also was obtained when the... 

The acid-catalyzed reaction of enol silyl ethers of cyclic ketones with optically active methyl 4-methylphenylsulfinate has been reported as a very efficient method for the synthesis of chiral a-sulfinyl cycloalkanones 212. Boron trifluoride-diethyl ether, titanium tetrachloride and tin(IV) chloride may all be used as catalysts, however, the reproducibility of this procedure has recently been questioned71. 

A simple synthesis of 1,3,5-trichloro-l A4,2,4.6-thiatriazine (1) is by treatment of sodium or tetraalkylammonium dicyanamide with thionyl chloride.910 Originally, this reaction was described in 1970 and the product was thought to be jV -chloro-A/-(chlorosulfanyl)-/V-cyano-carboximidic chloride.60 The reaction is carried out with a great excess of thionyl chloride in the presence of a catalytic amount of dimethylformamide. The first reaction step consists of the formation of the thionyl chloride-dimethylformamide complex and reaction with the dicyanamide anion. The second step is a further sulfinylation with elimination of sulfur dioxide.32... 

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