Attack at Ring Sulfur Atoms

Reactions of this type are rare. Heterocyclic sulfur is usually electron-deficient, which hinders the normal attack of electrophiles, and the normal position for nucleophilic attack is at a ring carbon or hydrogen. However, examples of both types of reactions are known. 

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The sulfonium ylide derived chemistry of penicillins continues to meet the interest of several research groups. It is well known that intermolecular carbenoid attack at the sulfur atom generates a sulfonium ylide which undergoes spontaneous opening of the thiazolidine ring to furnish a l,2-sm>-penicillin 326). Novel examples of this reaction type were found upon Rb2(0Ac)4-catalyzed decomposition of diazomalonic esters in the presence of various penicillins this transformation constituted the opening step of a synthetic sequence directed towards 2-alkoxycarbonyl-cephems 345 a) or modified penicillins 345 b). Similar to its reaction with 4-thio-2-azetidinone... 

Nucleophilic attack at ring sulfurs can proceed at S-l as well as S-2 atoms. The cleavage of the S-S bond in the 1,2,3-dithiazole ring and formation of sulfur heterocycles in the first case, or the formation of compounds with C=S group by the attack on S-2 atom, are the results of these reactions. 

Aromatic sultones, unlike the aliphatic analogues, react with nucleophiles at the electrophilic sulfur atom. As an illustration, naphthalene-1,8-sultone (169) reacts with sodium hydroxide, ammonia or a Grignard reagent to give the products (170)-(172) (Scheme 71). The mechanism of these reactions involves initial nucleophilic attack at the sulfur atom with opening of the sultone ring system (Scheme 71). 

Many reactions, which lead to ring cleavage, often followed by rearrangement and recyclization, are now explained by an initial nucleophilic attack at the sulfur atom rather than at C-3 or C-5. Thus, the reaction of carbanions with a variety of isothiozolium or 1,2-benzisothiazolium salts... 

As was introduced earlier, once the sulfoxide is activated, the resulting sulfonium salt 102 can undergo nucleophilic attack at the sulfur atom This is known as an interrupted Pummerer reaction and is outlined in Scheme 20.24. The nucleophilic substitution on the sulfur atom yields a new sulfonium salt 103. Depending on the structure of R, Nu, and in 103, this can have three a electrophilic positions, which means that a nucleophilic substitution of sulfide will produce the loss of one of the three fragments. Usually, the first nucleophile is present in the same molecule, reacting in an intramolecular way. However, some exanples using interrupted Pummerer reactions in intermolecular processes are described in the literature, and inportantiy, the reaction can be used to activate relatively unreactive positions in heterocyclic rings. 

There are no reports on electrophilic attack at ring carbon or nitrogen. Regarding ring sulfur atom, it has been reported that oxathiazolones (49), act as sulfur sources in their reaction with Mn(CO)s yielding a sulfido cluster of the type [Mn3(CO)9(/i3-S)2] by elimination of PhCN and CO2 <930M1009>. 

Nucleophilic Attack at Ring Atoms 5.16.3.5.1 Oxygen, nitrogen and sulfur nucleophiles... 

The cause for this regioselectivity may be the influence of the sulfoxide (acceptor) which renders its proximal carbon in the epoxide ring more donor like. Furthermore, ring opening at this site would not improve the unfavorable electronic status of the molecule, while attack on the distal carbon atom gives an intermediate in which the unfavorable captodative situation is dissolved on expulsion of phenylsulfenic acid, upon contropolarization at the sulfur atom. 

Electron donation from pyrrole-like nitrogen, or to a lesser extent from analogous sulfur or oxygen atoms, helps electrophilic attack at azole carbon atoms, but as the number of heteroatoms in the ring increases, the tendency toward electrophilic attack at both C and N decreases rapidly. 

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