Alkyl thioamides, condensation with

Thioamides and thioureas (326 R2 = alkyl, NR2) condense with dimethyl acetylenedicar-boxylate (330), yielding a 2-substituted 5-methoxycarbonylmethylene-A 1thiazolin-4-one (331 Scheme 216). 

An important classical synthesis of 1,2,4-triazoles is the Pellizzari reaction in which an acylhydrazide is condensed with an amide (or thioamide) at high temperature. Variations exist in which the amide component is first activated towards nucleophilic attack as a S-alkyl thioamide salt. Employing this type of approach, S-methyl isothioamide... 

Although many phenylacetamides were successfully alkylated with 2-bromo-pyridine, the corresponding thioamides were not. The pyrrolidone XI-14was employed as the active methylene compound in a condensation with 2-bromopyridines. ° Treatment of quaternary salts of halo- or alkoxy-pyridines... 

Alkylation and Arylation. The 5-methylation of thioamides by diazomethane is catalysed by silica gel. 5-Phenyl derivatives of thiobenzanilides are obtained in high yield by radical arylation with nitrosoacetanilide or phenylazotriphenyl-methane. Thiols are made from alkyl (or cycloalkyl, or aralkyl) halides by their reaction with dimethylthioformamide and treatment of the imidium ester with methanol other methods of hydrolysis lead to side-reactions, giving impure products. Mono- and bi-protic thiocarboxamides condense with ethyl bromo-cyanoacetate and one equivalent of NaOEt with spontaneous separation of sulphur and the formation of ff-amino-cr-cyano-acrylates, as shown in reaction (5). The... 

Acyl hydrazides are useful precursors for the synthesis of 1,2,4-triazoles. Reaction of acyl hydrazides 149 with imidoylbenzotriazoles 148 in the presence of catalytic amounts of acetic acid under microwave irradiation afforded 3,4,5-trisubstituted triazoles 150 <06JOC9051>. Treatment of A-substituted acetamides with oxalyl chloride generated imidoyl chlorides, which reacted readily with aryl hydrazides to give 3-aryl-5-methyl-4-substituted[ 1,2,4]triazoles <06SC2217>. 5-Methyl triazoles could be further functionalized through a-lithiation and subsequent reaction with electrophiles. ( )-A -(Ethoxymethylene)hydrazinecarboxylic acid methyl ester 152 was applied to the one-pot synthesis of 4-substituted-2,4-dihydro-3//-1,2,4-triazolin-3-ones 153 from readily available primary alkyl and aryl amines 151 <06TL6743>. An efficient synthesis of substituted 1,2,4-triazoles involved condensation of benzoylhydrazides with thioamides under microwave irradiation <06JCR293>. 

One of the most valuable methods for the preparation of A2-thiazolines is of this class. The reaction of 2-haloalkylamines (334) with thioamides, metal thiocyanates or carbon disulfide give 2-alkyl- or -aryl- (335), 2-amino- (336), and 2-mercapto- (337) A2-thiazolines, respectively (Scheme 218) (17CB804). A method derived from the last procedure leads to a convenient synthesis of 2-phenyl-A2-thiazolines (340) under very mild conditions and consists of the condensation between a-aminothiols (338) and thiobenzoylmercaptoacetic acid (339 Scheme 219) (74TL1863) (this method could be better classified under Type E, Section 4.19.3.2.5). 

Condensation of thioamides with a-bromoketoesters under mild conditions gives 4-hydroxy-2-thiazolines which are easily dehydrated to afford thiazoles <86JHC577,86S992,88JHC289>. 2-Amino-4-arylsulfonylimino-2-thiazolines (320) can be prepared by reacting thiourea (or thiourea hydrochloride) with A-alkyl- or A, iV-dialkyl-iV -p-toluensulfonyl-a-chloroacetamidines (Equation (57)) <88JHC1849>. 

The mitomycins are a class of antitumor antibiotics that has been the target of numerous synthetic efforts. The Eschenmoser reaction was a key coupling step in the synthesis of a mitomycin intermediate, apomitomycin (153). Thiopyrrolidinone (149) was alkylated with the aryl bromoacetate (150), and the intermediate a-thioiminium salt was heated with DBU (Scheme 32). The desired condensation product (151) was obtained in excellent yield, although epimerization about the pyrrolidine ring had occurred to produce a 1 1 mixture of the cis and trans substituted diastereomers. Note that, in contrast to a-alkyl-substituted electrophiles, which require conversion to triflates for complete thioamide alkylation, the more reactive benzylic bromide in (150) gave efficient alkylation. The key intermediate (151) was cy-clized in the presence of sodium hydride and copper(I) bromide to yield a single product (152) in nearly quantitative yield. Epimerization to the more stable trans isomer occurred under the cyclization conditions. This intermediate was readily converted to the final product (153). 

The synthesis of the antibiotic anisomycin (160) provides another example of the efficient alkylation of a thioamide with an a-bromoarylacetate. Thiolactam (154) was alkylated with a-bromo ester (155) followed by sulfide contraction to generate the vinylogous carbamate (156) in good yield (Scheme 33). In contrast, initial attempts to condense the imidate of the dimethoxylactam (161) with various aryl components (162) met with failure that was attributed to the steric hindrance created by the alkoxy groups (Scheme 34). The vinylogous carbamate (156) was converted to the acid, which decarboxylated to the enamine (157). Reduction yielded a 70 30 mixture of pyrrolidines (158) and (159) and the latter was converted to anisomycin. 

Alkyl- and 4-aryl-4/7-l,3,5-thiadiazines (224) are readily accessible by a one-pot BFs-etherate-catalyzed condensation of an aldehyde, a carbonitrile and a thioamide <758266,81JAP(K)5657779>. The reaction is also successful with dialkyl ketones but not with diaryl ketones <77S476>. A mechanistic rationale involving initial addition of the thioamide to the aldehyde (or ketone) followed by 1,4-polar cycloaddition of the derived cation (223) to the nitrile is proposed (Scheme 37) <75S266>. 

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