The Addition of Sulfur Nucleophiles

What products would be formed from the preceding reaction if the carboxylic acid group were not protected  

Show how each of the following compounds could be prepared from the given starting material. In each case, you will need to use a protecting group. 

Aldehydes and ketones react with thiols (the sulfur analogues of alcohols Section 11.11) to form thioacetals. The mechanism for the addition of a thiol is the same as the mechanism for the addition of an alcohol (Section 17.12). 

Thioacetal formation is useful in organic synthesis because a thioacetal is desulfurized when it reacts with H2 and Raney nickel. Desulfurization replaces the C—S bonds with C—H bonds. 

thioacetal formation followed by desulfurization provides a way to convert a carbonyl group into a methylene group. 

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The addition of sulfur nucleophiles to aldehydes and ketones may be exemplified by the formation of hydrogensulfite (bisulfite) adducts (3.12). These are sulfonates that are water soluble. However, their stcric bulk means that whereas they are formed from aldehydes and methyl ketones, more highly substituted ketones are reluctant to form these derivatives. 

The addition of sulfur nucleophiles to alkynes is a less developed transformation. However, Yamamoto described the attack of the sulfur atom of aryl thioethers to afford benzothiophenes (equation 31). More recently, it has been showed that propargylic thioethers or thioacetals undergo migration to give carbenes that cyclize in hydroarylation processes and thiocarbamates that evolve by propargylic rearrangement. Thiosilanes can perform as both sulfur nucleophiles and silicon electrophiles in intramolecular reactions to afford benzothiophenes (equation 32). ... 

The addition of sulfur nucleophiles to (x,P-unsaturated sulfoxides is known, although the stereochemical outcome of such additions has not been studied extensively [12,72,94],... 

The addition of sulfur nucleophiles to activated alkenes is a popular and valuable approach to the synthesis of sulfur-carbon(sp ) bonds. Due to the importance of the products, a vast array of catalysts and conditions have been developed to promote this reaction. One of the most direct approaches to these thia-Michael additions entailed simply stirring a thiol with the activated alkene in water (Scheme 5.4) [4]. This remarkably straightforward approach was also fast, and outstanding yields of a range of sulfides were obtained in less than 15 min. It should be noted that water was critical for the success of this reaction. Removing the water and performing the reaction under neat conditions was less successful. 

The action of sulfur nucleophiles like sodium bisulfite and thiophenols causes even pteridines that are unreactive towards water or alcohols to undergo covalent addition reactions. Thus, pteridin-7-one smoothly adds the named S-nucleophiles in a 1 1 ratio to C-6 (65JCS6930). Similarly, pteridin-4-one (73) yields adducts (74) in a 2 1 ratio at C-6 and C-7 exclusively (equation 14), as do 4-aminopteridine and lumazine with sodium bisulfite. Xanthopterin forms a 7,8-adduct and 7,8-dihydropterin can easily be converted to sodium 5,6,7,8-tetrahydropterin-6-sulfonate (66JCS(C)285), which leads to pterin-6-sulfonic acid on oxidation (59HCA1854). 

In this chapter the addition of carbon nucleophiles to simple a,j8-unsaturated sulfoxides, a-sulfinyl-a,/ -unsaturated ketones and a-sulfmyl-a,/ -unsaturated lactones will be discussed separately, in most cases the asymmetric induction arises from the chirality at sulfur. 

Interesting examples of the addition of N-nucleophiles to nitrile oxides are syntheses of chelated Z-amidoxime, N-[2-(dimethylaminomethyl)phenyl]mesitylene-carboamidoxime (118), and pyranosyl amidoximes (119) from the respective nitrile oxides and amines. Aromatic aldoximes undergo unusual reactions with chloramine-T (4 equiv, in refluxing MeOH). N-(p-toly 1 )-N-(p-tosy 1 )benzamides are formed via addition of 2 equiv of chloramine-T to the intermediate nitrile oxide followed by elimination of sulfur dioxide (120). 

Epoxides are generally very susceptible to attack by sulfur nucleophiles, in accordance with the recognized nucleophilicity of these reagents.1 The direction of ring fission is governed by the same electronic and stereochemical principles as those operating in other related reactions, e.p. the additions of hydroxylic nucleophiles discussed in section IV.4.A. 

The /J-sultones 3 are readily formed by the addition of sulfur trioxide to polyfluorinated al-kenes.45,46 They are the building blocks of DuPont s Nation membranes.52 Possible mechanisms for the rearrangement have been proposed,45,46,53,54 which all involve initial attack of the nucleophile at the sulfur atom with ring opening at the S-O bond. 

The addition of heteroatomic nucleophiles, e.g. oxygen, nitrogen, sulfur, halogen, phosphorus, etc., to activated alkenes is covered in this section. 

Formation of three-membered-ring systems can also be the result of a nucleophilic addition leading to a zwitterionic intermediate, followed by loss of nitrogen. In these cases, the reactions are related to the addition of sulfur or phosphorus ylides to Michael acceptors. ... 

Many other examples of the addition of electrogenerated nucleophiles from sulfur on activated olefins are available [154]. However, such reactions are rarely specific and regioselective. 

Addition of sulfur nucleophiles such as phenylthiolate to diethyl l-(ethoxycarbonyl)vinylphos-phonate has been used in the synthesis of P-acetoxy- and p-hydroxy-a-methylene-y-butyrolac-tones Similarly, addition of isopropylthiolate to diethyl l-(ethoxycarbonyl)vinylphosphonate represents a key step in the synthesis of a-methylidenebutyrolactones such as confertin (Scheme arteannuin B, - - rhopaloic acid and hippospongic acid A Addition... 

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. 

In the base-promoted addition the elemental sulfur reacts with amines to yield polysidfide anions [63, 64], that can behave as nucleophiles. The methylene group of appropriate oc, / imsaturated nitrile 9 is being deprotonated first and then sulfur addition takes place (Scheme 8). The most suitable base for the activation with sulfur and the subsequent sulfur addition morpholine has been proved [59]. The morpholine exhibits the best solubility of sulfur from the entire organic base used in Gewald reaction. Additionally, by mixing the morpholine with sulfur at 150 °C the morpholine polysufide (MPS) is formed, which structure is presumed to contain from 2-5 sulfur atoms within two morpholine molecules [57, 65]. MPS acts then in two ways - as a base needed in each reaction step, and also as a S-nucleophile in the addition of sulfur step to the o yff-imsaturated substrate 9 to create reactive ylidene sulfur adduct 10 (Scheme 8). 

The addition of thiols to electron-deficient alkenes is a very important process in C—S bond formation. The position of an electron-withdrawing group on alkenes primarily dictates the approach of sulfur nucleophiles, leading to the... 

The chemical production of aminophenols via the reduction of nitrobenzene occurs in two stages. Nitrobenzene [98-95-3] is first selectively reduced with hydrogen in the presence of Raney copper to phenylhydroxylamine in an organic solvent such as 2-propanol (37). With the addition of dilute sulfuric acid, nucleophilic attack by water on the aromatic ring of /V-phenylhydroxylamine [100-65-2] takes place to form 2- and 4-aminophenol. The by-product, 4,4 -diaminodiphenyl ether [13174-32-8] presumably arises in a similar manner from attack on the ring by a molecule of 4-aminophenol (38,39). Aniline [62-53-3] is produced via further reduction (40,41). 

The importance of steric effects in determining the oxidation state of the product can be illustrated by a thioether linkage, eg (57). If a methyl group is forced to be adjacent to the sulfur bond, the planarity required for efficient electron donation by unshared electrons is prevented and oxidation is not observed (48). Similar chemistry is observed in the addition of organic nitrogen and oxygen nucleophiles as well as inorganic anions. 

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