Thiolysis nitriles

Peptide thioesters (Section 15.1.10) are generally prepared by coupling protected amino acids or peptides with thiols and are used for enzymatic hydrolysis. Peptide dithioesters, used to study the structures of endothiopeptides (Section 15.1.11), may be prepared by the reaction of peptide nitriles with thiols followed by thiolysis (Pinner reaction). Peptide vinyl sulfones (Section 15.1.12), inhibitors of various cysteine proteases, are prepared from N-protected C-terminal aldehydes with sulfonylphosphonates. Peptide nitriles (Section 15.1.13) prepared by dehydration of peptide amides, acylation of a-amino nitriles, or the reaction of Mannich adducts with alkali cyanides, are relatively weak inhibitors of serine proteases. 

The most common method for synthesizing peptide dithioesters is based on the Pinner reaction. N-Protected peptide nitriles react with thiols in the presence of HQ to give imi-dothioic acid ester hydrochlorides that are treated with H2S (Section 15.1.11.1). 1 61 A modification of this procedure is made by dissolving the nitriles in liquid HF and reacting with thiols to form imidothioic acid ester hydrofluorides, followed by thiolysis with H2S (Section 15.1.11.1.1). 7 The second approach is to synthesize the thiopiperidide derivative using Lawesson s reagent, followed by S-methylation with iodomethane and thiolysis with H2S (Section 15.1.11.2). 4 A modification of the Lawesson s procedure via a thioamide is also used to prepare amino acid dithioesters (Section 15.1.11.2.1). 8 ... 

The most common source of imidates is nitriles (c/. Volume 6, Chapter 2.7) and, as these can be directly transformed into thioamides (c/. Section 2.4.3.4), this one-step approach is usually preferred. Moreover, depending on the reaction conditions and the substitution pattern, thiolysis of imidates may give thioesters rather than thioamides (c/. Volume 6, Chapter 2.5). However, some high-yield applications of imidates in thioamide synthesis have been reported and are detailed in equations (27) ° and (28). ... 

The thiolysis of nitrile groups can also be applied to cyanamides giving thioureas. - ... 

In the acid-catalyzed thiolysis of nitriles (73) HaS is commonly replaced by appropriate precursors or equivalents. Thus, thioacids, RCOSH, have been used together with HC1 or SnCU. Thioacetamide (77) is a very convenient source of HaS as shown in equation (36), an equilibrium is established which is shifted to the right, if the liberated MeCN is removed by distillation. Alternative sources of HaS are di-thiophosphoric, HSP(=S) (OR)a with R = Et or Pr, " or phosphinodithioic acid derivatives, HSPPha(= S). ° The last mentioned approach allows the elegant synthesis of a-hydroxythioamides (78) in Scheme 11. ... 

Reactions of the nitrile group(s) In general, these reactions start with a nucleophilic attack at the C atom of the nitrile group. Thus 10 reacted with its anion in basic media to yield the dimerization product 2-amino-1,1,3-tricyanopropene . Thiolysis with H2S gave cyanothioacetamide. Acidic alcoholysis in an neutral solvent produced dialkyl propanediimidate dihydrohalides Metal-catalyzed reactions of 10 with methyl acetoacetate and other j5-dicarbonyls have been reported. ... 

Reactions of phthalazinecarbonitriles already covered include conversion of Reissert nitriles into extracyclic hydroxyphthalazines (Section 11.2.1), hydrolysis to phthalazinecarboxylic acids (Section 14.1.1), controlled hydrolysis to phthalazine-carboxamides (Section 14.4.1), and thiolysis to phthalazinecarbothioamides (Section 14.4.1). A variety of other reactions are illustrated in the following examples. 

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