Nitriles thioamide synthesis

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). ... 

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]. 

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. 

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 ... 

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

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. 

N-Thioacylamidines (78), the starting materials required in this synthesis, are most readily accessible by the condensation of nitriles (75) and thioamides (76) in ethereal solution in the presence of hydrogen chloride. This reaction, first performed by Matsui101 and correctly... 

More stable than many other thiocarbonyl compounds, thioamides have been known and used for a long time. Reliable methods of synthesis [119] were introduced as early as 1815 by Gay-Lussac for the reaction of nitriles with hydrogen sulfide and 1878 by Hoffman for the thionation of amides by means of tetraphosphorus decasulfide. 

Addition of HaS to nitriles (73) represents an important method for the synthesis of primary thioamides (74 equation 33). The reaction is carried out under base or acid catalysis. The base-catalyzed process is particularly useful in the preparation of aromatic thioamides, i.e. for R = aryl, hetaryl in (73) triethylamine in molar proportion or pyridine, which at the same time also serves as solvent, are employed most commonly. The approach tolerates the presence of various other functionalities such as an amide, hydrazone, enamine, a-oxo, a-acetoxy ° or a-amino group. Moreover, the reaction has been applied to the synthesis of thioasparagine as such or incorporated into a dipeptide, as shown... 

The most widely used synthesis of thioamides (86) involves thionation of the corresponding amides by heating with phosphorus pentasulfide in xylene (Hofmann, 1878) (Scheme 45). In the preparation of primary thioamides (87) by this procedure, care must be taken to avoid the decomposition of the product into the nitrile and hydrogen sulfide—the reverse of the earliest preparative route to thioamides (Gay Lussac, 1815) (Scheme 46). 

Many other functional groups are reduced by Sml. For example, sulfonyl halides are converted to disulfides. The reduction of nitro compounds by this reagent enables synthesis of 1,2-diamines based on a reaction sequence initiated by nitronate addition to aldimines, and in the presence of nitriles it furnishes amidines, and that of isothiocyanates in the presence of conjugated esters, the half thioamide derivatives of succinic esters. 

A general synthesis of thioamides from nitriles which utilizes thioacetamide as the source of hydrogen sulfide under acidic conditions is reported by Taylor and Zoltewicz.1 The thioamides are formed in good yield and high purity and the method is equally applicable to aliphatic nitriles and to aromatic nitriles containing either electronreleasing, electron-withdrawing, or potentially reducible substituents. One equivalent of the nitrile is heated on a steam bath for 15-30 min. with 2 eq. of thioacetamide in s s... 

In a general annulation method, 4-aminonicotinonitriles are treated with ethyl orthoformate to give the corresponding (ethoxymethylene)amino compounds. The nitrile group is then converted with sodium hydrogen sulfide into a thioamide function which cyclizes to yield the 2-sulfanylpyrimidine moiety. An application of this method is the synthesis of 6-benzyl-5,6,7,8-tetrahydropyrido[4,3-t/]pyrimidine-2-thiol (3) from l-benzyl-4-[(ethoxymethylene)amino]-l,2,5,6-tetrahydropyridine-3-carbonitrile (2).491 492... 

A popular reaction type in recent years has been the conversion of alcohols into other compounds by use of an organophosphorus compound in the presence of a source of a nucleophile [reaction (8)]. PhsP plus diethyl azodicarboxylate has been a particularly popular form of organophosphorus reagent, and the product is formed with inversion of configuration. In 1977 there appeared a number of variations on this general theme, for the synthesis of halides, thiocyanates, thio-ethers, azides, and esters from alcohols.Similar systems have been used to convert amides and thioamides into nitriles. ... 

Synthesis.—The addition of H2S to nitriles to give primary thioamides is conveniently performed in the presence of a phase-transfer catalyst in dilute aqueous NajS and a liquid organic phase. Other examples of this reaction employ... 

The dehydration of amides is one of the most important methods for the preparation of nitriles, and many reagents are known to effect this transformation. Two new reagents have now been reported " which significantly add to the available methodology. In one, amides (and thioamides) undergo conversion into the corresponding nitriles when treated with cyanuric chloride in DMF solution at room temperature (Scheme 22). In the other, " the preformed Vilsmeier reagent (16) and pyridine in DMF also effect the dehydration within minutes at 0°C this method is especially useful for the synthesis of a ,/3-unsaturated nitriles (Scheme 23). 

Hydrogen sulfide and aliphatic and aromatic thiols react readily with [ C]nitriles to give [ C]thioamides in yields of 45-70%. Upon treatment with a-halocarbonyl compounds they form [ C]thiazoles (Hantzsch thiazole synthesis). This was exploited for the synthesis of 2-(4-chlorophenyl)[2- C]thiazol-4-acetic acid f89. X = COOH) (Figure 7.23) and the 2-(2-phthalimidoethyl)-[2- C]tliiazole derivative 91 °. which were obtained when the corresponding thioamides M and 90 were treated with 1,3-dichloroacetone and bromo-acetaldehyde diethylacetal, respectively. As illustrated by the third example in Figure 7.23,... 

Some of the most common nucleophiles through which a new CC bond can be formed are carbanions from hydrocarbons, nitriles, ketones, esters, N,N-dialkyl acetamides and thioamides, and mono- and dianions from 3-dicarbonyl compounds. The synthesis of indoles, isocarbostyrils, isoquinolines, benza-zepines, binaphthyls, etc. and an important number of natural products has been achieved by ring closure reactions of carbanions with suitable substrates through the Sgj.jl mechanism. Several reviews have been published in relation to aromatic Sgj,l reactions and to the synthetic applications of the process. - ... 

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