Phosphorus thioamides

The O-S exchange method in presence of a-halogenated carbonyl compound is a very good one for thiazole compounds. The thioamide is prepared in situ by the action of amide upon phosphorus pentasulphide with solvent. The a-halogenated aldehyde reacts directly. But the O-Se exchange cannot be performed with a-halogenated carbonyl compounds because of the apparition of phosphoric acid. (Scheme 3), The C-Se bond is very sensitive to add pH. 

When chloroacetaldehyde is condensed with higher thioamides prepared from amides and phosphorus pentasulfide according to Schwarz s method (222), 2-substituted thiazoles are obtained (4, 10,"22, 175). 

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). 

Thiazolium salts with alkyl (103, 722), arylalkyl (116), aryl (305), or heteroaryl (96) substituents on the nitrogen have been also prepared by this procedure. As in the thiazole series, N-substituted thioamides can be formed directly in the reaction mixture from phosphorus pentasulfide and N-substituted amides (127). These methods are important in the synthesis of thiamine 102 (vitamin Bj) (Scheme 45). 

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)... 

Next the product is acylated with bromoacetyl chloride and the glycine equivalent is constructed in place by a Gabriel amine synthesis (phthalamide anion followed by hydrazine) subsequent to which cyclization to benzodiazepine occurs. The synthesis of the tranquilizer quazepam (88) is finished by thioamide conversion with phosphorus pentasulfide. ... 

Ivonin synthesized dihydrodipyrrolophosphorins by reaction of dipyrrolylpropane 424 with phosphorus tribromide <1999CHE1383>. The initial P-bromo product is unstable, so can be converted to the phosphite 425 or a thioamide (Equation 115). The corresponding diphosphorins can also be synthesized from the pyrrolyl-bisdibromophosphine 426. The P,P -dibromo product 428 is stable and can be isolated (Equation 116) <2000CHE498>. 

The ultrasonic preparation of thioamides from amides and phosphorus pentasulfide by Raucher(51) and of dichlorocarbene from chloroform and potassium hydroxide by Regen(52) are some of the more recent examples of nonmetallie applications. We were surprised to find that ultrasound greatly accelerates the reduction of haloaroma-tics by lithium aluminum hydride, permitting the reaction to be... 

Thioamides and their use in the preparation of the heterocyclic compounds are widely reported in the literature. Also they attract considerable interests in peptide chemistry. Molecular and crystal structures of some thioamide derivatives have been confirmed by X-ray diffraction data.8 10 Lawesson s reagent or phosphorus pentasulfide (P4S10) is actively used for the synthesis of thio-carbonyl compounds. Their preparation methods, reactions, applications in the synthesis of heterocycles and biological effects are mainly described in this section. 

The method described for the preparation of N-methyl-2-pyrrolidinethione is very similar to that of Peak and Stansfield 2 for the preparation of 4-thioacetylmorpholine. N-Methyl-2-pyrrolidinethione has also been prepared by the reaction of 2-chloro-N-methyl-A1-pyrrolinium chloride with hydrogen sulfide [yield 83% b.p. 144-145° (15 mm.)]3 and by heating N-methyl-2-pyrrolidinone with 2 equivalents of phosphorus pentasulfide in xylene [yield not reported b.p. 125-132° (10 mm.)].4 General procedures for the preparation of N,N-disubstituted thioamides have been reviewed.5, 6... 

On treatment with phosphorus pentasulfide, 4-amino-5-thio-477-[l,2,4]triazoles 86 are converted into 6-aryl-3-(2-aminophenyl)[l,2,4]triazolo[3,4-4][l,3,4]thiadiazoles 3. This transformation is presumed to involve three steps first, the transformation of the amide into the thioamide second, transfer of the thioaroyl group from the phenylamino side chain to the iV-amino group of the triazole ring and, finally, cyclodehydrosulfurization leading to 3 (Equation 21) <1989LA1055>. 

Conversion of an amide a thioamide enhances the reactivity of that function since it favors the enol form and provides a better leaving group for addition-elimination reactions (mercaptide vs. hydroxide). Thioamides obtained by treatment of diazepi-none such as (15-1) or (16-1) with phosphorus pentasulhde provide starting materials for further modihcation of the benzodiazepine nucleus. (More recently developed reagents such as Lawesson s Reagent or hw(tricyclohexyltin) sulhde provide more convenient methods for that transformation.) Thus, reaction of the thioamide (15-2) with (9-allylhydroxylamine leads directly to the amidine, probably via an addition-elimination sequence of the thioenol tautomer of (15-2). There is thus obtained the antianxiety agent uldazapam (15-3) [17]. 

Thioamide formation benzodiazepinone, 505 heteiodiazepinone, 621 phosphorus pentasulf ide, 323, 600 Thioazole formation, nitrile addition, 301 Thiocarbamate formation, 588 phenol, 95 rearrangement, 517 Thioenol ether formation, 185, 517 addition-elimination, 554 Thioester formation, mixed anhydride, 184 Thioether formation, 241, 300, 413, 416 alkylation, 586, 588 aromatic displacement, 416 Thiohydantoin formation, 293 Thiol interchange, benzothiazole formation, 422... 

The reaction of phosphorus ylides with elemental sulfur gave thioaldehydes, which were trapped in situ by treatment with secondary amines to afford the corresponding thioamides (equation 17)237. 

The thioamides themselves are conveniently prepared from the corresponding amides by treatment with phosphorus (V) sulphide (see the Paal—Knorr synthesis of thiophenes, Chapter 2, for this type of conversion). A variation of the Hantzsch reaction utilises thioureas, where R3 in 3.30 is a nitrogen and not a carbon substituent. For instance, thiourea itself is used in the preparation of 2-aminothiazoles such as 3.32. 

Thiazole itself can be obtained by condensing chloroacetaldehyde and thioformamide (Scheme 159). The reaction is explosive and proceeds in low yield because of the instability of the thioformamide under acid conditions. Higher thioamides are more stable and react under milder conditions with chloroacetaldehyde, affording 2-substituted thiazoles in moderate yields. It is possible, and often preferable, to prepare the thioamide in situ in dioxane solution by the action of phosphorus pentasulfide on the corresponding amide and in the presence of solid MgC03 (Scheme 160). With arylthioamides, except for some nitrothiobenzamides, yields are usually higher and the cyclization is carried out over several hours in boiling absolute alcohol. Chloroacetaldehyde can be replaced in these reaction by derivatives such as 1,2-dichloro- or dibromo-ethyl methyl or ethyl ether, 1,2-dichloro- or dibromo-ethyl acetate, 2-chloro- or dibromo-ethyl acetate, and 2-chloro or bromo-diethyl-acetal. 

Thioamides are usually made by reaction of ordinary amides with P2S5 or Lawesson s reagent. Since C=S is so much less stable than C=0, there is a clear case to call in phosphorus to remove the oxygen. The situation is rather like that in the Wittig reaction C=C is less stable than C=0, so phosphorus is called in to remove the oxygen because of the even greater stability of the P-0 bond. 

Other variations include formamide (57JA6421), sodium dithioformate or phosphorus oxychloride-DMF (69RTC1263), a thioamide (78MI41000) and acetylacetone (77JHC813). Reduction of 2,6-dibenzamido-3-(2-butoxypyrid-5-ylazo)pyridine with iron and hydrochloric acid resulted in ring closure to 5-benzamido-2-phenylimidazo[4,5-f>]pyridine (60AC(R)125). 

Two related syntheses of this period must be noted. The malonamide derivative 63, when heated with ammoniacal cupric sulfate (1(X) C, 3 h), yielded 95% of 4-amino-2-phenyl-l,2,3-triazole-5-carboxamide, which was converted to 8-phenyl-8-azapurin-6-one in 67% yield by refluxing with triethyl orthoformate and acetic anhydride (4 h). Alternatively, the triazole amide was changed to the thioamide with phosphorus pentasulfide (79% conversion). This thioamide produced 8-phenyl-8-azapurine-6-thione when... 

Phosphorus pentasulfide is a valuable reagent for conversion of carbonyl into thiocarbonyl groups for instance, amides are converted to thioamides, ketones to thioketones (see Chapter 8, p. 137), carboxylic acids to thioacids, and alcohols are converted to the corresponding phosphorodithioic acids (18) (Scheme 16). 

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