Primary thioamides

The reactions of the benzenesulfonyl ester of mandelonitrile (177) provide another illustration of the masked bielectrophile approach. On reaction with a primary thioamide the 4-aminothiazole (178) was obtained and this is a convenient route to these derivatives. With a thiourea, the thiazoline (179) was the initial product, and this on treatment with water gave the thiazolidin-4-one (180) (61JOC2715). 

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. 

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... 

Chlorination of amide or lactam using oxalyl chloride gives the chloro-iminium salts in situ. They react with tetrathiomolybdate to afford the corresponding thioamides and thiolactams in short-time and at low temperature in high yields. This method affords high yields of secondary or tertiary thioamides on the other hand it gives low yield of primary thioamide (17% yield) (Scheme 12).3 3... 

Thiazine derivatives have been obtained by reactions of primary thioamides with a,p-unsaturated ketones (Scheme 26).53... 

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... 

Primary thioamides undergo photochemical hydrogen sulphide extrusion in the absence of oxygen (equation 118)173. 

Chieli, E., Aliboni, F., Saviozzi, M. Malvaldi, G. (1987) Induction of micronucleated erythrocytes by primary thioamides and their metabolites in the mouse. Mutat. Res., 192, 141-143... 

Replacement of the a-halo ketone by a cyano analogue can lead to amino derivatives. The benzenesulfonyl ester of mandelonitrile (168) with a primary thioamide, RCSNH2 gives the 4-aminothiazole (169). 

Nucleophilic bis-O-demethylation of dimethoxybenzenes in one flask is often difficult. It can, however, be achieved by use of sodium TMS thiolate in l,3-dimethyl-2-imidazolidinone (DMEU) at high temperature in a sealed tube101. The same reagent system converts nitriles into primary thioamides at or slightly above room temperature in varying yields102. 

Aryl nitriles with (Me3Si)2S in the presence of MeONa/l,3-dimethyl-2-imidazolidinone results in the conversion to primary thioamides, while amides and lactams yields the thio derivative using (Me3Si)2S and an oxophilic promoter such as POCI3, triphosgene or oxalyl chloride. Thus the intermediate [CIRC=NR R"]+C1 reacts with the silthiane to give the thioamide (equation 24)44. 

Dehydrosulfuration.1 Primary thioamides arc converted into nitriles by reaction with 1 (or di-n-butyltin oxide) in refluxing benzene (75-98% yield). 

New routes have been designed by Katritzky and co-workers using ben-zotriazole derivatives. Alkylation of primary thioamides has been achieved on the nitrogen atom using an aldehyde as a source of the alkyl group [42]. A variety of thioamides is accessible by a one pot reaction of a Grignard reagent with carbon disulfide (in THF), followed by treatment with benzo-triazole triflate and aminolysis of the activated thiocarbonyl intermediate [43, 44]. 

The most widely used method for the synthesis of thiazoles (see Chapter 4.19) is of this type and involves the reaction of a-halo compounds (Y = halogen in Scheme 2) with a reactive component containing an N—C(=S)— structural entity. Reaction of the a-bromoketone (65) with the primary thioamide (66) in hot benzene gave the intermediate hydroxy compound (67), which could be isolated in certain instances but in most cases underwent dehydration to form the thiazole (68). The diversity in the substituents capable of being introduced into the resultant thiazole by this procedure is illustrated in Chapter 4.19. Especially noteworthy in this respect is the reaction of the bromopyruvaldehyde oxime (69) with thiourea in methanol at room temperature. Neutralization with sodium carbonate resulted in the isolation of the 2-aminothiazole-4-carbaIdehyde oxime (70) in 39% yield (73JOC806). 

Dithiocarboxylates, R CSSR give a faster reaction with amines than G-alkyl thiocarboxylates (2 cf. Section 2.4.2. ). As shown in equation (8), this pronounced reactivity may lead to an undesired in situ reaction with the liberated ammonia to give a primary thioamide, when the ester is generated by thiolysis of a thioimidate. ... 

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... 

If the substrate molecule contains further nucleophilic centers, these can be attacked flrst. With powerful alkylating reagents both functions are alkylated, - e.g. in (108) and (109 Scheme 11). Tertiary alkyl halides, e.g. trityl chloride, under basic conditions can alkylate primary thioamides at the nitrogen of the thioamide group. From thio-DMF and 2,4-dinitrochlorobenzene the corresponding 5-aryl-methyleneiminium compound was prepared. ... 

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). 

A variety of thioamides possessing either mono- or di-alkyl substitution on the nitrogen can undergo the Eschenmoser coupling reaction. Primary thioamides are not acceptable substrates because of their ready conversion to nitriles under the condensation conditions. Although alkylation proceeds more readily on secondary rather than tertiary thioamides, use of the latter allows subsequent sulfur extrusion to... 

A microwave-assisted Willgerodt-Kindler reaction was developed to synthesize a-aryl thioacetamides 16 from aromatic ketones, morpholine, and elemental sulfur (Eq. 3) [13]. The reaction is carried out without solvents and completes within 4 min. The reaction can also be used for aldehydes. The reaction temperature and times are dependent on the substituents in the aldehydes and amines [13,14]. The use of secondary cyclic amines gives the corresponding thioamides in good to high yields. In the primary amine reaction, higher reaction temperatures are necessary. Primary thioamides are formed by... 

The rhodium-catalyzed reaction of primary thioamide 50 with a-diazomonoketone 51 in the presence of triphenylphosphine gives thiazo-line 53 (14JOC7405).The reaction pathway may involve thioether intermediate 52 where the imine nitrogen could attack the carbonyl carbon to give 53. 

Iron pentacarbonyl in boiling dibutyl ether converts primary thioamides to nitriles [47] in moderately good yields, for example, m-toluonitrile (66%), ben-zonitrile (64%). Reduction of a carboxamide by sodium borohydride requires fairly drastic conditions [48] but if the amide is first converted into the imino-ether by means of Meerwein s reagent and this is then treated with the reducing agent in ethanol at 60°, a good yield of the nitrile is obtained replacing the borohydride by sodium ethoxide raises the yield appreciably [49], for example, benzonitrile (95%), pentanenitrile (90%), 2,2-dimethylpropanenitrile (86%), diphenylacetonitrile (100%). 

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... 

Keywords Primary thioamides, 1,2-dichloroethane, DDQ, room temperature, oxidative cycli-zation, 1,2,4-thiadiazoles... 

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