Thiols reaction with nitriles

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 ... 

In addic solution nitriles undergo an addition reaction with thiols forming iminothioesters ... 

The addition of Grignard reagents to aldehydes, ketones, and esters is the basis for the synthesis of a wide variety of alcohols, and several examples are given in Scheme 7.3. Primary alcohols can be made from formaldehyde (Entry 1) or, with addition of two carbons, from ethylene oxide (Entry 2). Secondary alcohols are obtained from aldehydes (Entries 3 to 6) or formate esters (Entry 7). Tertiary alcohols can be made from esters (Entries 8 and 9) or ketones (Entry 10). Lactones give diols (Entry 11). Aldehydes can be prepared from trialkyl orthoformate esters (Entries 12 and 13). Ketones can be made from nitriles (Entries 14 and 15), pyridine-2-thiol esters (Entry 16), N-methoxy-A-methyl carboxamides (Entries 17 and 18), or anhydrides (Entry 19). Carboxylic acids are available by reaction with C02 (Entries 20 to 22). Amines can be prepared from imines (Entry 23). Two-step procedures that involve formation and dehydration of alcohols provide routes to certain alkenes (Entries 24 and 25). 

The base-catalyzed joint reaction of nitroalkenes with thiophenol in the presence of aldehydes gives y-phenylthio-P-nitro alcohols in one pot (Eq. 4.5).8 The joint reaction of nitroalkenes with thiols and a,p-unsaturated nitriles (or esters) has also been achieved. (Eq. 4.6).9 P-Nitro sulfides thus prepared show unique reactivity toward nucleophiles or tin radicals. The nitro... 

S-Nucleophiles are very reactive in 1,3-addition reactions with nitrile oxides. A series of a-glucosinolates 27 (R = CR1=NOH R1 =Ph, CH2PI1, CH2CH2PI1, ( )-CH=CHPh, 3-indolylmethyl) was prepared by addition reactions of thiol 27 (R = H) with nitrile oxides (123). The indolyl-substituted glucosinolate was then converted to a-glucobrassicin 28. 

Sealants obtained by curing polysulfide liquid polymers with aryl bis(nitrile oxides) possess stmctural feature of thiohydroximic acid ester. These materials exhibit poor thermal stability when heated at 60°C they soften within days and liquefy in 3 weeks. Products obtained with excess nitrile oxide degrade faster than those produced with equimolar amounts of reagents. Spectroscopic studies demonstrate that, after an initial rapid addition between nitrile oxide and thiol, a second slower reaction occurs which consumes additional nitrile oxide. Thiohydroximic acid derivatives have been shown to react with nitrile oxides at ambient temperature to form 1,2,4-oxadiazole 4-oxides and alkyl thiol. In the case of a polysulfide sealant, the rupture of a C-S bond to form the thiol involves cleavage of the polymer backbone. Continuation of the process leads to degradation of the sealant. These observations have been supported by thermal analysis studies on the poly sulfide sealants and model polymers (511). 

By contrast, softer nucleophiles, such as thiols (111), evidently do react with SENAs at the a-C atom (307) (see Scheme 3.94). This interpretation is confirmed by a substantial difference in the configuration of thiohydroxamate 112a isolated in the reaction with silyl nitronate (a) and analogous product 112b (b) prepared from authentic nitrile oxide. 

Substituted thioindigoid dyes are usually obtained via the appropriate benzenethiol in a Heumann-type synthesis. The final cyclisation of the phenylthioglycolic acid derivative can often be achieved in concentrated sulphuric acid or by using chlorosulphonic acid. Several routes make use of the Herz reaction (Scheme 6.22), in which a substituted aniline is converted into the corresponding o-aminothiophenol by reaction with sulphur monochloride followed by hydrolysis of the intermediate dithiazolium salt [47]. After reaction between the thiol and chloroacetic acid, the amino group is converted into a nitrile group by a Sandmeyer reaction. Hydrolysis of the nitrile leads to the formation of the required thioindoxyl derivative. 

A -Silylmethyl-amidines and -thioamides (42) (X=NR or S) undergo alkylation at X with, for example methyl triflate, and then fluorodesilylation to give the azomethine ylides 43 (identical with 38 for the thioamides) (25,26). Cycloaddition followed by elimination of an amine or thiol, respectively, again leads to formal nitrile ylide adducts. These species again showed the opposite regioselectivity in reaction with aldehydes to that of true nitrile ylides. The thioamides were generally thought to be better for use in synthesis than the amidines and this route leads to better yields and less substituent dependence than the water-induced desilylation discussed above. 

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. 

Reaction of Nitriles with Thiols via Imidothioic Acid Ester Hydrochlorides (Pinner Reaction)... 

A modification of the Pinner reaction using liquid HF has been used to improve the yields of the dithioester products. The N-protected amino acid and peptide nitriles 6 dissolve in liquid HF at temperatures below 0°C and react with thiols to form the imidothioic acid ester hydrofluorides 7 that further react with H2S in pyridine at 0°C to form the dithioesters 8 (Scheme 2)J71 Several isotopic dithioesters have been synthesized by this method with improved yield (Table 2). The use of liquid HF at low temperature helps to dissolve the amino acid nitriles that are not very soluble under Pinner conditions (HCl-saturated CH2C12). 

Morton, M, J. A. Cala and J. Piirma The branching reaction. I. Chain transfer of styrene with thiol, alcohol and nitrile. J. Am. Chem. Soc. 78, 5394 (1956). 

Another approach to the construction of a thiophene ring based on functionalized pyrimidines involves thiolation of the methyl group in uz c-methylpyrimidinecarbo-nitriles 139 with elemental sulfur followed by cyclization of the intermediate thiols 140 to give thienopyrimidines 141. The reactions were carried out with pyrimidinethiones (1990LA1215) and pyrimidinediones (1990MI5, 1991MI3). 

Chemically, CS is a moderately reactive electrophile due to the presence of two electron-withdrawing nitrile groups attached to the olefinic bond. The site of reaction with nucleophiles is the olefinic carbon adjacent to the aromatic ring. Reactions are SN2-like, i.e. CS reacts with nucleophiles directly in a bimolecular fashion. CS reacts quite rapidly with water when in solution (half-life 14 min, 25°C, pH 7.4) to give 2-chlorobenzaldehyde and malonitrile. Reactions are much faster with thiols and amines. CS reacts rapidly with glutathione and plasma protein, although the reaction products have not been characterized (Cucinell et al., 1971). 

This reaction was initially reported by Granacher in 1922. It is the preparation of thionic acid by the treatment of Aldol Condensation product from an aldehyde and rhodanine with a base (e.g., NaOH). Therefore, this reaction is known as the Granacher synthesis or Granacher reaction." The prepared thionic acid in this reaction can be further converted into a variety of derivatives under different conditions. For example, it can be transformed into a-thiol acid under a basic sodium amalgam reduction, whereas aliphatic acid is formed under an acidic zinc amalgam reduction. In addition, when the thionic acid is treated with ammonia, a-keto acid is generated, and the thionic acid can be converted into af-carboxyl oxime in reaction with hydroxylamine, from which either cy-amino acid or aliphatic nitrile forms via the treatment of sodium amalgam reduction or acetic anhydride, respectively. 

Because of the huge importance of pyridine derivatives, a considerable amoimt of effort has been directed to the development of multicomponent routes for their synthesis, including reactions performed in water. For instance, a one-pot four-component condensation of aldehydes, malononitrile and thiophenols in the presence of boric acid as catalyst in aqueous medium afforded high yields of 2-amino-3,5-dicaibonitrile-6-thiopyridines 46 [29], either by conventional heating or under ultrasound-aided conditions (Scheme 1.21). This reaction can also be performed in an aqneons snspension of basic almnina [30] or in water with microporous mo-lecnlar sieves as catalysts [31]. Mechanistically, this transformation involves an initial Knoevenagel condensation of the aldehyde with a molecule of malononitrile, followed by the Michael addition of the second molecule of malononitrile, reaction of one of the nitrile groups with the thiol, cyclization and a final air oxidation step. 

---