Nitriles thioamides

Imidothioates in the neutral or ionic form are the most generally applied educts for the preparation of dithiocarboxylic esters. They are themselves prepared from nitriles, thioamides or isothiocyanates, and react with hydrogen sulfide under appropriate conditions to yield the dithioesters (Scheme 7) 6,14,26,27,29,141 Interesting examples (62)-<73) were described in the recent literature. 

Nitriles. Thioamides and amides e room temperature and high temperatures, r... 

Aromatic thioamides can be prepared as described in the literature by different ways, either by S -> O exchange between the corresponding benzamides and phosphorus pentasulfide in pyridine solution in the presence of triethylamine (65, 646) as strong base, or by action of H2S on the appropriate nitrile with pyridine and triethylamine solvents using the method of Fairfull et al. (34, 374, 503). In this reaction, thioacetamide in acidic medium can also be used as a H2S generator with dimethylform-amide as the solvent (485). 

In catalytic hydrogenation, a compound is reduced with molecular hydrogen in the presence of a catalyst. This reaction has found appHcations in many areas of chemistry including the preparation of amines. Nitro, nitroso, hydroxylamino, azoxy, azo, and hydrazo compounds can all be reduced to amines by catalytic hydrogenation under the right conditions. Nitriles, amides, thioamides, and oximes can also be hydrogenated to give amines (1). Some examples of these reactions foUow ... 

Hydrogen sulfide reacts with nitriles in the presence of a basic catalyst forming thioamides. A commercial example is its addition to cyanamide with the formation of thiourea [62-56-6]. ... 

Several examples exist for the conversion of 5-aminothiazoles into the corresponding thiazolopyrimidines. Shaw and Butler report the formation of aminothiazole thiocarboxyamide 27 from the thioamide 26 and carbon disulphide using Cook and Heilbron s procedure. Methylation of 27 gave carboxythioimidate 28 which then reacted with sodium hydroxide to give amino-nitrile 29, and with formic acid and acetic anhydride to give the thiazolopyrimidine 30. 

Simple isothiazole-4-carboxylic acids have been made from the corresponding nitriles, which are available in turn from the halogeno derivatives, or directly by the olefin route.5-Aminoiso-thiazole-4-esters and -nitriles are readily obtained by the thioamide route. The 4-acids behave normally and form acid chlorides, esters, amides, and hydrazides. In contrast to the 5-series... 

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

Tiazofurine (142) is an antimetabolite with antineoplastic activity. It preferentially affects leukemic lymphocytes over normal cells due to selective activation by formation of its adenine dinucleotide by transformed cells. Of the syntheses available, one starts by conversion of iniidate 138 to methyl 2,5-anhydroallonothioate (139). Next, condensation with ethyl 2-amino-2-cyanoac-etate leads to the thioamide which undergoes thiol addition to the nitrile function to produce the amminothiazolecarboxyester system of 140 directly. Sodium nitrite in aqueous hypophosphorus acid eliminates the superfluous amino group via the diazonium transformation to give 141. This synthesis of tiazofurine (142) concludes by ester amide exchange in methanolic ammonia [48]. 

H) 2-(n)-Propyl-lsonicotinic Thioamide The 11 grams of nitrile just obtained, dissolved... 

Transformation of the Nitrile Groups of PAN into Amino Groups Thioamidation... 

The reaction of PAN with hydrogen sulfide was for the first time achieved in DMF solution at 50-70 °C. It has been shown that under these conditions the nitrile groups are partially converted into thioamide groups and polymers corresponding to copolymers of AN with acrylthioamide are formed54 ... 

This reaction has recently been applied with success5 s for the modification of poly-(a-chloroacrylonitrile). As reported by the authors, the level of conversion of the nitrile groups into thioamide groups reaches 90%. 

This makes it possible to assume that by thioamidation of PAN under mild conditions, modified polymers are obtained composed of macromolecules with alternating nitrile and thioamide groups56. ... 

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. 

Fig. 4. Dependence of the conversion level on the time of thioamidation of PAN and low-molecular nitriles at 20 °C in DMFA. (1) PAN (2) 1,35-pentanetricarbonitrile. (3) glutaro-dinitrile. (4) acetonitrile...

This, naturally, results in an increased electrophilicity of the nitrile group and also creates favourable conditions for the nucleophilic attack of the mercapto anion and an easy addition of hydrogen sulfide in accordance with the above scheme. The activation energy of the thioamidation of the model compounds is much higher (for glutarodinitrile — 11,8 [49,4] and for trinitrile - 7,97 kcal/mol [33,4 kJ/mol]) than in PAN (6,18 kcal/mol [25,9 kJ/mol]). 

Fig. 5. Effect of the nature of adjacent functional groups in copolymers on the rate of conversion of the nitrile groups into thioamide groups. (1) PAN (2) AN-VDC (3) AN-AA (4) AN-MA (5) AN-VC (6) AN-ST...

These copolymers undergo side reactions which are mainly reducible to reactions in which chloride atoms take part. When copolymers of AN and vinylidene chloride are treated with aqueous solutions of ammonium sulfide at 90 °C, nitrile groups have been shown to be almost fully converted into thioamide groups, and practically no hydrolysis of the formed thioamide groups is taking place in this case. At the same time, it was found that in the course of this treatment dehydrochlorination is taking place almost quantitatively ... 

When PAN-T samples are heated by a gradual increase of temperature, the mercapto groups of the tautomeric form of the thioamide groups, enter into an intramolecular reaction with the nitrile groups in accordance with the following scheme ... 

Bei der Reduktion von Aldehyden und Ketonen werden neben den Alkoholen auch Di- und Polysulfane er-halten (s. S. 276), mit aromatischen Nitrilen im UberschuB5, mit Oxiranen (S. 422) und mit Thiiranen (S. 449) werden Thioamide, Dihydroxy-disulfane oder Polysulfane gebildet. Mit Thiolen entstehen Borsaure-trithioester, die mit Aldehyden und Ketonen Thioacetale ergeben6. Prim. Nitro-alkane Iiefern Nitrile, sek. Ketone und Oxime (S. 472), Nitro-aromaten die entspreehenden Amine (S. 478). Oxime konnen selektiv zu Hydroxylaminen Oder weiter zu Aminen reduziert werden (S. 375). 

Bagley and coworkers have described the preparation of primary thioamides by treatment of nitriles with ammonium sulfide in methanol solution (Scheme 6.139) [276], While the reactions with electron-deficient aromatic nitriles proceeded at room temperature, other aromatic and aliphatic nitriles required microwave heating at 80-130 °C for 15-30 min to furnish the thioamides in moderate to high yields. This protocol avoids the use of hydrogen sulfide gas under high pressure, proceeds in the absence of base, and usually provides thioamides without the need for chromatographic purification. 

The oxidation of thioamides 63 with a wide variety of oxidizing agents is a well-employed method for the synthesis of 3,5-disubstituted-l,2,4-thiadiazoles 64 <1982AHC285>. However, this method is limited mainly to arylthioamides. The most common oxidizing agents tend to be halogens, hydrogen peroxide, dimethyl sulfoxide (DMSO), and nitrous acid. Yields from these reactions are variable and depend on the thioamide, oxidant, and conditions used (Equation 19). By-products such as nitriles and isothiocyanates are usually formed. 

Conversion of nitrile using thionating reagent gives the corresponding primary thioamides (Scheme 8). 

Treatment of nitriles with gaseous hydrogen sulfide in the presence of anion exchange resin (Dowex 1X8, SH from) at room temperature affords the corresponding primary thioamides.27 Treatment of nitriles with 70% sodium hydrosulfide hydrate and magnesium chloride hexahydrate in DMF or methanol affords primary thioamides in high yields.28 Primary thioamides have been... 

Thioamides have been transformed into the corresponding nitriles. Treatment of primary thioamides by tellurium tetrachloride or selenium tetrachloride in combination with triethylamine affords nitriles.66 Treatment of primary amides and thioamides with l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) gives nitriles.67 Reactions of thioamides with metal carboxylates in organic solvents enables the selective preparation of nitriles, imides or amides depending on the substitution pattern of the starting material (Scheme 33).68... 

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 ... 

Thioamides 176 react photochemically with 2,3-dimethyl-2-butene in the absence of oxygen to give ketones (equation 116)172. In the absence of oxygen, the photoproducts of 176 include nitriles, 1,2,4-thiadiazole and isothiazoline (equation 117). 

The classical reaction of hydrogen sulphide with nitriles in basic media is catalysed by the addition of, for example, Aliquat or tetra-n-butylammonium bromide [4], The reaction proceeds most rapidly with dilute aqueous solutions of sodium sulphide under l -2 atmospheres of hydrogen sulphide to produce thioamides in good yields (>70%). 

The nitrile (0.14-0.15 mol) in PhH (20 ml) is added to Na2S.9H20 (0.54 g, 2.5 mmol) and Aliquat (l.O g, 2.5 mmol) in H20 (20 ml). The reaction vessel is flushed with H,S and then maintained under a pressure of ca. 2 atmos. while the reaction mixture is stirred at 70 °C. The mixture is then cooled to room temperature and the precipitated thioamide is collected, washed with H20, and recrystallized. 

Selected examples of the synthesis of thioamides from nitriles ... 

Amides [41,44], thioamides [41 ] and amidines [45] are converted into nitriles by the reaction with dichlorocarbenes generated by Makosza s procedure (Table 7.16). Under similar conditions, monosubstituted and A.A-disubstituted ureas are converted into cyanamides (Table 7.17) JV,(V -disubstituted ureas produce carbodi-imides in low yield [41,46,47]. /V-Carbamoyl derivatives of dibenzo[/ /]diazepines and the related 10, l l-oxirane derivatives are converted into the corresponding... 

Thioamides are converted into 5-benzyl salts under basic catalysed conditions. The unstable salts spontaneously eliminate benzylthiol to yield nitriles (>80%) [47] the benzylthiol is benzylated during the reaction and is isolated as dibenzyl sulphide. 

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