Sulfur-based soft nucleophiles

However, formation of this bond through the conjugate addition of a soft sulfur nucleophile to a,P-unsaturated aldehydes is efficiently catalysed using iminium ion catalysis [116], Using diarylprolinol silyl ether 55 the addition of a series of sulfur based nucleophiles to a variety of a,P-unsaturated aldehydes was shown to be effective (73-87% yield 89-97% ee). The products were isolated as their p-hydroxy sulfide derivatives 73 after in situ reduction of the products (Scheme 33). 

It is appropriate at this point to summarize the tendency of various nucleophiles to add to the carbonyl group. In general, the strong bases (organometallics, hydrides, negative ions) are most effective among the neutral nucleophiles, the soft ones, for example the sulfur bases, tend to be more effective in addition than the hard ones, for example the oxygen bases. 

The asymmetric conjugate addition of sulfur-based nucleophiles to Michael acceptors has been achieved using enantiomerically pure metal-based catalysts and organocatalysts. Sulfur nucleophiles are soft, and preferentially react by conjugate addition with a, p-unsaturated carbonyl compounds. Only catalytic amounts of the lithium thiolate (11.65) are required, since addition to the enone (11.66) generates the enolate (11.67). The enolate is then able to deprotonate thiol (11.68), regenerating thiolate (11.65) with formation of the product (11.69). 

Sulfoxonium salts react with hard bases at sulfur and with soft nucleophiles at the oxygen end. Although the acid-catalyzed oxidation of isonitriles to isocyanates (139) has been formulated as involving an a addition of H and DMSO at the carbon atom of the isonitrile, the alternative mechanism shown below appears more viable in the HSAB context. 

The relative reactivities of nucleophiles toward sulfur differ a great deal depending on whether the sulfur is di-, tri-, or tetracoordinated, This is to be expected from the theory of hard and soft acids and bases. As the oxidation state... 

The regioselectivity of the cleavage of cyclic sulfites depends on the nature of the nucleophile, and this dependence can be interpreted in terms of the hard and soft acid and base principle <2000T7051>. For instance, in reactions with PhONa, PhSNa, NaN3, NaCN, BnNH2, and Pr NI I2, the Sn2 attack occurs exclusively at the less sterically hindered carbon atom. In contrast, the harder, less polarizable nucleophiles BnNHNa, PhNHNa, BnONa, and BnSNa attack at both the carbon and the sulfur atoms, sometimes with a predominance at the latter <2000T7051>. 

Taking into account the fact that the solvation of ambident anions in the activated complex may differ considerably from that of the free anion, another explanation for the solvent effect on orientation, based on the concept of hard and soft acids and bases (HSAB) [275] (see also Section 3.3.2), seems preferable [366]. In ambident anions, the less electronegative and more polarizable donor atom is usually the softer base, whereas the more electronegative atom is a hard Lewis base. Thus, in enolate ions, the oxygen atom is hard and the carbon atom is soft, in the thiocyanate ion the nitrogen atom is hard and the sulfur atom is soft, etc. The mode of reaction can be predicted from the hardness or softness of the electrophile. In protic solvents, the two nucleophilic sites in the ambident anion must interact with two electrophiles, the protic solvent and the substrate RX, of which the protic solvent is a hard and RX a soft acid. Therefore, in protic solvents it is to be expected that the softer of the two nucleophilic atoms (C versus O, N versus O, S versus N) should react with the softer acid RX. 

Thiolate ions react with a-(alkylthio)carbonyl compounds to afford disulfides and the corresponding reduced ketone (equation 26). The reaction apparently involves direct nucleophilic attack by thiolate on the sulfur atom of the alkylthio group. Other soft bases, such as cyanide ion, thiourea and tertiary phosphines, also effect this conversion. Raney nickel of course readily desulfurizes a-alkylthiocarbonyl compounds. The reaction is quite selective for example, the ester, ketone and alkenic moieties of (43) are unaffected by the Raney nickel treatment (equation 27). Raney nickel reduction of (44) is reported to proceed with retention of configuration in ethanol and with inversion in acetone. Telluride salts also desulfurize a-alkylthio ketones. ... 

Nucleophiles with two sites that could react with electrophiles are called ambident nucleophiles. The Hard and Soft Acids and Bases (HSAB) principle applies because a hard electrophile reacts at the harder nucleophilic site and a soft electrophile at the softer nucleophilic site. For instance, the sulfenate ion 70 is an ambident nucleophile, because it reacts (a) with methyl fluorosulfonate, a hard electrophile, at the oxygen atom, where most of the negative charge is concentrated, to give the sulfenate ester 71 and (b) with methyl iodide, a soft electrophile, to give the sulfoxide 72. Sulfur atom is the softer of the two nucleophilic sites available in the sulfenate ion and, furthermore, it is rendered more nucleophilic by the a-effect arising from the adjacent oxygen atom. 

Recently Aliev et al. 70) have discussed the formation of alkenes in the polymerization of thiiranes and the degradation of the corresponding polymers. A modified mechanism was proposed, assuming that the thiiranium sulfur atom is subject to nucleophilic attack by soft bases 71 72) ... 

The common method involves deprotonation of a thiocarbonyl compound and reaction of the intermediate enethiolate with an allyl halide (Scheme 9.8). This actually relies on two noticeable features of the sulfur series. (1) The proton located a to a thiocarbonyl group is much more acidic, by 7-10 pKa units, than the one of a carbonyl moiety [39, 41]. This may be related to the strong ability of the sulfur atom (polarizability) to stabilize the negative charge of the enethiolate. Presently, the preferred conditions involve LDA as a base for optimum deprotonation [42-45]. (2) The resulting anionic species are soft ambident nucleophiles. The... 

This mechanism takes advantage of the known enhanced susceptibility of methyl sulfonium salts to nucleophilic attack in non-polar media (1, 23). In addition, it allows for the methylation of a soft base, the sulfur atom of methionine, by SAM in a more polar surrounding. Soft bases are known to react readily with methylsulfonium salts in aqueous media (19). The proposed mechanism for histamine methylation is shown in Fig. 2. 

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