Conjugate sulfur 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). 

Intramolecular conjugate addition occurs in the /3-sulfonylstyrenes (196) (72BCJ1893) and (197) (74JMC549) to give 1,2,4-thiadiazines. In the case of (197), subsequent elimination of HBr gave the fully unsaturated system. Similar intramolecular conjugate addition of oxygen and sulfur nucleophiles to sulfonylstyrenes and sulfonylalkynes also occurs. 

Most fused benzene rings are stable toward nucleophilic attack but exceptions are known for highly electron-deficient benzazoles having o-quinonoid structures. Thus, sulfur nucleophiles attack 27/-benzimidazole-2-spirocyclohexane 556 via an initial Michael-type 1,4-conjugate addition, followed by a prototropic shift in the adduct 557. When the nucleophile is electron withdrawing (e.g., phenylsulfonyl), 1,3-dihydro products 558 are isolated. If the nucleophile is electron donating, the adducts are oxidized in situ to 559. 

Reaction (a) proceeds by a straightfoi W ard conjugate addition ot a sulfur nucleophile. One stereogenic centre is formed from two achiral reagents and the product must therefore be racemic. 

This looks complicated but it s just a question of working through each reaction. The stereochemistry needs some thought. The first reaction is a conjugate addition of a sulfur nucleophile to a very electrophilic alkene. The base used, piperidine, is an ordinary secondary amine but that is basic enough (pKaH about 11) to produce reasonable amounts of anion from the thiol pfCa also about 10). There is no stereochemistry in this step. 

In the second step, thiophenol gives the conjugate addition, rather than the direct addition product to either carbonyl group. Sulfur nucleophiles are soft, and this is typical behaviour for thiols. 

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). 

For a recent review covering the catalytic asymmetric conjugate addition of sulfur nucleophiles see D. Enders, K. Liitgen and A. A. Narine, Synthesis, 2007, 959. 

Conjugated dienes and activated olefins like indene undergo intermolecular gold-catalyzed additions of sulfur nucleophiles. Aliphatic and aromatic thiols, as well as thioacids, afforded the hydrothiolation products with good yield in the... 

In 2005, J0rgensen et al. extended the conjugate addition of sulfur nucleophiles to a,P-unsaturated aldehydes under iminium catalysis with trimethylsilyl ether 56 (10 mol%) as catalyst [385]. Very high enantioselectivities (89-97% ee) were reported for the addition of aliphatic thiols to different aromatic and aliphatic enals at low temperatures (-24°C) where the employment of an acid cocatalyst (PhCOjH, 10 mol%) was mandatory in order to improve the reaction rate. This methodology has been incorporated into domino reactions by the same group and others to successfully prepare optically active sulfur-containing heterocyclic compounds [385, 386],... 

Recently an expansion of the electrophile scope of the conjugate addition of sulfur nucleophiles has been reported by different groups. As depicted in Fig. 2.29 for selected examples, Cinchona-denwed catalysts 203 and 205 promote highly enantioselective additions to nitrooleflns [387] and a,p-unsaturated V-acylated oxazolidin-2-ones [388] through non-covalent catalysis. Especially interesting results the Michael reaction to P-substituted nitroacrylates catalyzed by chiral thio-... 

Few examples have been reported for the organocatalytic asymmetric conjugate addition of sulfur nucleophiles other than thiols. The reaction of thiocarboxylic acids to cyclohex-2-enones [390] and a,p-nnsatnrated esters [391] was initially studied by Wynberg et al. employing Cinchona alkaloid catalysts with limited success in terms of selectivity (up to 54% ee). Slightly better enantioselectivities have been recently obtained by Wang et al. in the 1,4-addition of thioacetic acid to P-nitrostyrenes (up to 78% ee) [392] and trani-chalcones (up to 65% ee) [393], using Takemoto s thiourea 142 as catalyst (2-10 mol%). 

The organocatalyzed conjugate addition of sulfur nucleophiles to electron-poor alkenes is probably the most frequently used process for the asymmetric formation of C—S bond [2b, 5]. Analogously, the employment of selenium nucleophiles may, in principle, be used for the formation of C—Se bonds. Because previous reviews were already reported on this topic, more recent reports are especially highlighted in this chapter. 

Sulfur nucleophiles - conjugate addition + reduction REFERENCES... 

Using the achiral lithium amide derived from Af-trimethylsilylbenzylamine, an enantioselective conjugate addition followed by alkylation has been realized by Tomioka and coworkers by using the chiral additive 1,2-diphenyl-1,2-dimethoxyethane [149]. Various enantioselective conjugate additions of nitrogen, oxygen, and sulfur nucleophiles under in situ protonation of the intermediate enolate, without trapping with other electrophiles have been described [144]. 

Marigo et al. developed a multicomponent domino-conjugated nucleophilic thiol addition-electrophilic amination reaction that gave access to 1,2-aminothiol derivatives with >99% ee in a one-pot process using 128 as a catalyst (Scheme 1.72) [ 114]. The soft sulfur nucleophile 168 first reacted with the iminium ion intermediate, followed by addition of the enamine intermediate to the azodicarboxylates 169. In situ reduction and cyclization resulted in the formation of highly functionalized oxazolid-inones 170 in nearly enantiopure form. 

Catalytic asymmetric conjugate additions of heteroatoms such as nitrogen or sulfur nucleophiles provide access to important / -substituted carbonyl deri-vates, and a number of successful strategies have been devised (38, 39, 41). Tomioka developed enantioselective additions of thiophenols to ,/i-unsatu-rated esters (Equation 42) [164]. This reaction proceeds in the presence of the presumed lithium complex 220, which was suggested as the catalytically active species. As a control experiment, the chiral amino diether itself is not a catalyst for the addition of thiophenol 219 to 218. A variety of trans enoates were shown to undergo addition to give the products with high levels of induction, as illustrated by the formation of thioether 221 (99 % yield, 97 % ee). 

Alkylation of 2-methylaminothiazole (204) with ROH in 85% sulfuric acid gives 2-methylimino-3-alkyl-4-thiazoIine (54). 2-Amino-4-rnethyl-thiazoie alkylated with an excess of isopropanol, however, gives 95% of 2-isopropylamino-4-methyl-5-isopropylthiazole (56). The same result is obtained with cyclohexanol (242). These results and those reported in Sections III.l.C and IV.l.E offer interesting new synthetic possibilities in thiazole chemistry. The reactive species in these alkylations is the conjugate acid of 2-aminothiazole. and the diversity of the products obtained suggests that three nucleophilic centers may be operative in this species. 

It resembles tetracyanoethylene in that it adds reagents such as hydrogen (31), sulfurous acid (31), and tetrahydrofuran (32) to the ends of the conjugated system of carbon atoms suffers displacement of one or two cyano groups by nucleophilic reagents such as amines (33) or sodiomalononittile (34) forms TT-complexes with aromatic compounds (35) and takes an electron from iodide ion, copper, or tertiary amines to form an anion radical (35,36). The anion radical has been isolated as salts of the formula (TCNQ) where is a metal or ammonium cation, and n = 1, 1.5, or 2. Some of these salts have... 

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