Thioamides reactivity

In the oxidative Eschenmoser sulfide contraction (Scheme 11), thioamide 59 is oxidized by benzoyl peroxide to give either a symmetrical disulfide or the O-benzoate of the thiolactam-S-oxide. In any event, the once-nucleophilic thioamide sulfur atom is now forced to adopt the role of electrophile a reactivity umpolung has, in effect, been achieved.13 The nucleophilic enamide 65 attacks the sulfur atom leading to the formation of sulfur-bridged intermediate 66. The action of a phosphine or a phosphite thiophile on the putative episulfide then gives vinylogous amidine 67. 

In thioamidation the nitrile groups of PAN have a much higher reactivity than those of the corresponding model compounds. This fact is explained by the specific character of the polymeric nature of PAN and by the mutual influence of adjacent groups. As it is seen from the data presented in Fig. 4, the highest reaction rate and conversion level, as compared with low-molecular nitriles, is observed in the thioamidation of PAN. 

Beside thioamides, dithioesters are the most stable and accessible thiocarbonyl compounds. Their specific reactivity, in particular towards nucleophiUc reagents and their apphcations to the formation of carbon-carbon bonds, have already been reviewed [8]. However, as shown below, the presence of a phosphonate function alpha or beta to the thiocarbonyl group in phosphonodithioformates and phosphonodithioacetates makes these difunctional compounds very versatile building blocks. Moreover, for the phosphonodithioacetates, the substitution of the methylenic hydrogen atoms by fluorine increases again their potential as intermediates for the synthesis of modified natural and bioactive phosphorylated structures. 

Most reactive metabolites produced by CYP metabolic activation are electrophilic in nature, which means that they can react easily with the nucleophiles present in the protein side chains. Several functional groups are recurrent structural features in M Bis. These groups have been reviewed by Fontana et al. [26] and can be summarized as follows terminal (co or co — 1) acetylenes, olefins, furans and thiophenes, epoxides, dichloro- and trichloroethylenes, secondary amines, benzodioxoles (methylenediox-yphenyl, MDP), conjugated structures, hydrazines, isothiocyanates, thioamides, dithiocarbamates and, in general, Michael acceptors (Scheme 11.1). 

Sandmeyer s valuable isatin synthesis involves the removal of sulphur from diphenylthiourea (I) (p. 169) with basic lead carbonate. Hydrogen cyanide is combined with the reactive diphenylcarbodiimide (II) so obtained, and the nitrile (III) produced is converted by means of hydrogen sulphide into tbe thioamide (IV). Concentrated sulphuric acid brings about ring closure and the product is the a-anil of isatin (V). Then, by hydrolysis with dilute sulphuric acid, aniline is removed ... 

Benzenecarhodithioesters and carbo-thio-S-esters were shown to yield diphenylacetylene by the cathodic reduction in aprotic media. Thus, the formation of diphenylacetylene involves [202] two molecules of a substrate. The cathodic reactivity of thioamides involving a similar alkylation of the C=S group in the presence of primary alkyl halides was reviewed [199-201]. 

Thioamide enolates are also interesting substrates for the stereoselective aldol-type reactions. The aldol stereochemistry is very sensitive to the conditions of preparation of magnesium thioamide enolates and it generally gives different results depending on the procedure used. Illustrations of some aspects of the reactivity are provided in the examples presented below. 

Conversion of an amide a thioamide enhances the reactivity of that function since it favors the enol form and provides a better leaving group for addition-elimination reactions (mercaptide vs. hydroxide). Thioamides obtained by treatment of diazepi-none such as (15-1) or (16-1) with phosphorus pentasulhde provide starting materials for further modihcation of the benzodiazepine nucleus. (More recently developed reagents such as Lawesson s Reagent or hw(tricyclohexyltin) sulhde provide more convenient methods for that transformation.) Thus, reaction of the thioamide (15-2) with (9-allylhydroxylamine leads directly to the amidine, probably via an addition-elimination sequence of the thioenol tautomer of (15-2). There is thus obtained the antianxiety agent uldazapam (15-3) [17]. 

In a systematic study of the chemistry of A-sulfinylamines (R—N=SO), Kresze and his co-workers33 demonstrated the outstanding reactivity of the closely related A-sulfinylsulfonamides (RS02N=S0). Their initial sulfinylating action [e.g. on alcohols and amines, Eqs. (1) and (2)] may be followed by immediate further reaction. Thus, amides yield nitriles [Eq. (3)], while both aromatic and aliphatic thioamides are converted into 3,5-disubstituted 1,2,4-thia-diazoles [Eq. (4)] in satisfactory yields. 

Side-chain amides (Asn, Gin) are reactive towards thionylating reagents, but in their absence appropriately protected peptides can be converted into thioamide peptides. Examples of short, singly thionylated peptides are given in Table 1. 

Table 13.21) or from amides by treatment with Lawesson s reagent. Thioamides can also be prepared on cross-linked polystyrene by the addition of H2S to nitriles (Entry 5, Table 13.21), by thiocarbamoylation of resin-bound organolithium compounds (Entry 6), or by the acylation of amines with reactive thio acid derivatives (Entry 7, Table 13.21). 

Alkynes continue to be used as a reactive functionality in quinoline synthesis. The readily available thiocarba-mates, thioamides, and thioureas allow intramolecular cyclization of pendant alkynes to give modest to good yields of the quinolines (Equation 118) <20030L1765>. An intermolecular reaction involving a zinc-mediated alkynylation-cyclization provides an efficient route to 4-trifluoromethyl-substituted quinolines (Equation 119) <2002JOC9449>. 

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