Alkylation of Sulfides Sulfonium Salts

The—N=C=S unit in sulforaphane is the isothiocyanate group. Isothiocyanates are among the ingredients responsible for the flavor of wasabi. 

Sulfur is more nucleophilic than oxygen (Section 8.5), and sulfides react with alkyl halides much faster than do ethers. The products of these reactions are called sulfonium salts. 

CH3(CH2)ioCH2SCH3 + CH3I Dodecyl methyl sulfide Methyl iodide 

What other combination of aikyi haiide and suifide wiii yieid the same suifonium sail shown in the preceding exampie Predict which combination wiii yieid the suifonium sait at the faster rate. 

A naturally occurring sulfonium salt, S-adenosylmethionine (SAM), is a key substance in certain biological processes. It is formed by a nucleophilic substitution in which the sulfur atom of methionine attacks the primary carbon of adenosine triphosphate, displacing the triphosphate leaving group. 

PROBLEM 16.18 What other combination of alkyl halide and sulfide will yield the same sulfonium salt shown in the preceding example Predict which combination will yield the sulfonium salt at the faster rate. 

The S in S-adenosylmethionine indicates that the adenosyl group is bonded to sulfur. It does A of stand for the Cahn-Ingold-Prelog stereochemical descriptor. 

Epinephrine is also known as adrenaiine and is a hormone with profound physiological effects designed to prepare the body for fight or flight.  

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The first attempt at a catalytic asymmetric sulfur ylide epoxidation was by Fur-ukawa s group [5]. The catalytic cycle was formed by initial alkylation of a sulfide (14), followed by deprotonation of the sulfonium salt 15 to form an ylide 16 and... 

Thia-[2,3]-Wittig sigmatropic rearrangement of lithiated carbanions 47, obtained by deprotonation of the S-allylic sulfides 46, affords the thiols 48 or their alkylated derivatives 49. The corresponding sulfonium ylides 51, prepared by deprotonation of the sulfonium salts 50 also undergoes a [2,3]-sigmatropic shift leading to the same sulfides 49 [36,38] (Scheme 13). As far as stereochemistry is concerned, with crotyl (R R =H,R =Me) and cinnamyl (R, R =H,R =Ph) derivatives, it has been shown that the diastereoselectivity depends on the nature of the R substituent and on the use of a carbanion or an ylide as intermediate. 

Sulfonium salts are available by alkylation of sulfides. They have been known for a long time, and their syntheses and general reactivity have been reviewed [194-199]. 

Figure 10.2 illustrates selected examples of these epoxide products. Aromatic and heteroaromatic aldehydes proved to be excellent substrates, regardless of steric or electronic effects, with the exception of pyridine carboxaldehydes. Yields of aliphatic and a,/ -unsaturated aldehydes were more varied, though the enantio-selectivities were always excellent. The scope of tosylhydrazone salts that could be reacted with benzaldehyde was also tested (Fig. 10.3) [29]. Electron-rich aromatic tosylhydrazones gave epoxides in excellent selectivity and good yield, except for the mesitaldehyde-derived hydrazone. Heteroaromatic, electron-poor aromatic and a,/ -unsaturated-derived hydrazones gave more varied results, and some substrates were not compatible with the catalytic conditions described. The use of stoichiometric amounts of preformed sulfonium salt derived from 4 has been shown to be suitable for a wider range of substrates, including those that are incompatible with the catalytic cycle, and the sulfide can be recovered quantitatively afterwards [31]. Overall, the demonstrated scope of this in situ protocol is wider than that of the alkylation/deprotonation protocol, and the extensive substrate...

Destlylation. Anhydrous cesium fluoride desilylates trimethylsilylmethyl-sulfonium, trimethylsilylmethylammonium, and trimethylsilylmethylphosphonium salts at room temperature to produce ylides, which undergo various useful transformations. Use of potassium fluoride-18-crown-6 or a tetraalkylammonium fluoride gives products in low yield in these reactions. The trimethylsilylmethyl-onium salts are prepared by alkylation of sulfides, amines, imines, and phosphines with (trifluoromethanesulfonylmethyl)trimethylsilane (1). 

The generation of sulfonium yhdes relies mostly on three strategies (Scheme 78). The classic variant uses sulfide alkylation to the sulfonium salts 316 which can be deprotonated to dehver the desired yhdes 317 [180,181]. A related method involves silane 320 as the alkylating agent to allow for regioselective ylide generation via fluoride ion induced desilylation [182]. Finally, the action of carbenes 319 or metal-bound carbenoids offers a direct means for ylide generation [183,184]. 

A class of compounds which have drawn some interest are the sulfonium salt complexes 416, prepared by alkylation of sulfide derivatives (415) (Table IV). These coordinated ylides have found use as stable, stereospecific cyclopropanating reagents yielding compounds of the class 417. 

Sulfur ylides are primarily synthesized by deprotonation of a sulfonium salt, which in turn is usually prepared by alkylation of a sulfide. Branched chain sulfonium salts are not generally preparable by simple sulHde displacement, although some can be made by other routes. While ylide solutions are most commonly prepared and used immediately, frozen stock solutions of the more stable (2) can be stored for several months in DMSO at -20 C. ... 

Several examples of the alkylation of sulfur ylides are known. " " This reaction is particularly useful for the synthesis of j-alkyl diphenylsulfonium salts which cannot otherwise be prepared from diphenyl sulfide, 5-alkyl iodides and silver tetrafluoroborate, since the latter reaction usually leads to a mixture of regioisomeric sulfonium salts. Diphenylsulfonium methanide on reaction with [ C]methyl iodide allows the synthesis of [ C]isopropyl diphenyl sulfonium salt which has been used for the synthesis of [ C]-2,3-epoxysqualene (Scheme 130, entry a). This reaction unfortunately is not general... 

Alkylation of sulfides. In a study of the possible role of sulfonium ylides in the coupling of allyl units to give squalene and related terpenes, Baldwin el al. examined the alkylation of the sulfide (1). The only product was the symmetrical salt (2). 

Sulfonium and ammonium salts are prepared readily by alkylation of sulfides or amines. For example, allylation of the amine 318 gave the intermediate ammonium salt 319 (3.205). Deprotonation to the ylide with sodium hydride was followed by [2,3]-sigmatropic rearrangement at room temperature to give the peni-cilhn derivative 320. In a synthesis of y-cyclocitral, the sulfonium salt 321 was prepared by alkylation of 1,3-dithiane and was converted to the ylide 322 and hence the rearranged product 323 (3.206). 

The catalysts in Scheme 20.5 can be roughly divided into two classes non-C2-symmetric (1-6,12-13) and C2-symmetric (7-11) sulfides. In the initial alkylation step generating the sulfonium salts, a C2-symmetric sulfide can avoid the lone pair selectivity issue, as in this case the two lone pairs at the sulfur atom are identical. In contrast, the alkylation at the two diastereotopic lone pairs of the S atom in non-C2-symmetric sulfides would lead to the formation of two diastereoisomers of the sulfoniums. (Figure 20.1). This lone pair-selectivity can be reflected in the influence of the diastereomeric purity of preformed sulfonium salts on the enan-tioselectivity [7]. Several chiral sulfides (1-3 and 13) lacking Ci symmetry possess a similar camphor framework. 

Electrophilic attack on the sulfur atom of thiiranes by alkyl halides does not give thiiranium salts but rather products derived from attack of the halide ion on the intermediate cyclic salt (B-81MI50602). Treatment of a s-2,3-dimethylthiirane with methyl iodide yields cis-2-butene by two possible mechanisms (Scheme 31). A stereoselective isomerization of alkenes is accomplished by conversion to a thiirane of opposite stereochemistry followed by desulfurization by methyl iodide (75TL2709). Treatment of thiiranes with alkyl chlorides and bromides gives 2-chloro- or 2-bromo-ethyl sulfides (Scheme 32). Intramolecular alkylation of the sulfur atom of a thiirane may occur if the geometry is favorable the intermediate sulfonium ions are unstable to nucleophilic attack and rearrangement may occur (Scheme 33). 

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