Thioamides, oxidation

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. 

It has been tentatively suggested that one mechanism underlies the Willgerodt reaction and the Kindler modification of it. A labile intermediate is first formed which has a carbon—carbon bond in the side chain. The scheme is indicated below it postulates a series of steps involving the addition of ammonia or amine (R = H or alkyl), elimination of water, re addition and eUmination of ammonia or amine until the unsaturation appears at the end of the chain then an irreversible oxidation between sulphur and the nitrogen compound may occur to produce a thioamide. 

As foretold in the introduction, ring formation via attack on a double bond in the endo-trig mode is not well exemplified. The palladium(II) catalyzed oxidative cyclization of o-aminostyrenes to indoles has been described (78JA5800). The treatment of o-methyl-selenocinnamates with bromine in pyridine gives excellent yields of benzoselenophene-2-carboxylates (Scheme 10a) (77BSF157). The base promoted conversion of dienoic thioamides to 2-aminothiophenes is another synthetically useful example of this type (Scheme 10b) (73RTC1331). 

When, aiming at its cardiotonic activity (stimulant), the 2,5-dioxo-l,2,5,6,7,8-hexahydro-3-cyano-6-bromoquinoline is made to react with different thioamides, the appropriate 6-substituted 8,9-dihydro- (R = cyanomethyl-, 2-oxopyrrolidinyl-methyl-, 2-oxohexahydroazepinomethyl-, and thioxopyrrolidinylmethyl-) (94KFZ43) or (R = H, Me, NH2, NH/S ) (86JAP(K)1, 89H1517) thiazolo[4,5-/Iquinolines 37 or oxidized products (89H1517) are produced. 

In the oxidative Eschenmoser sulfide contraction (Scheme 11), thioamide 59 is oxidized by benzoyl peroxide to give either a symmetrical disulfide or the O-benzoate of the thiolactam-S-oxide. In any event, the once-nucleophilic thioamide sulfur atom is now forced to adopt the role of electrophile a reactivity umpolung has, in effect, been achieved.13 The nucleophilic enamide 65 attacks the sulfur atom leading to the formation of sulfur-bridged intermediate 66. The action of a phosphine or a phosphite thiophile on the putative episulfide then gives vinylogous amidine 67. 

The reaction of alcohols with CO was catalyzed by Pd compounds, iodides and/or bromides, and amides (or thioamides). Thus, MeOH was carbonylated in the presence of Pd acetate, NiCl2, tV-methylpyrrolidone, Mel, and Lil to give HOAc. AcOH is prepared by the reaction of MeOH with CO in the presence of a catalyst system comprising a Pd compound, an ionic Br or I compound other than HBr or HI, a sulfone or sulfoxide, and, in some cases, a Ni compound and a phosphine oxide or a phosphinic acid.60 Palladium(II) salts catalyze the carbonylation of methyl iodide in methanol to methyl acetate in the presence of an excess of iodide, even without amine or phosphine co-ligands platinum(II) salts are less effective.61 A novel Pd11 complex (13) is a highly efficient catalyst for the carbonylation of organic alcohols and alkenes to carboxylic acids/esters.62... 

Electrophilic substitution of the ring hydrogen atom in 1,3,4-oxadiazoles is uncommon. In contrast, several reactions of electrophiles with C-linked substituents of 1,3,4-oxadiazole have been reported. 2,5-Diaryl-l,3,4-oxadiazoles are bromi-nated and nitrated on aryl substituents. Oxidation of 2,5-ditolyl-l,3,4-oxadiazole afforded the corresponding dialdehydes or dicarboxylic acids. 2-Methyl-5-phenyl-l,3,4-oxadiazole treated with butyllithium and then with isoamyl nitrite yielded the oxime of 5-phenyl-l,3,4-oxadiazol-2-carbaldehyde. 2-Chloromethyl-5-phenyl-l,3,4-oxadiazole under the action of sulfur and methyl iodide followed by amines affords the respective thioamides. 2-Chloromethyl-5-methyl-l,3,4-oxadia-zole and triethyl phosphite gave a product, which underwent a Wittig reation with aromatic aldehydes to form alkenes. Alkyl l,3,4-oxadiazole-2-carboxylates undergo typical reactions with ammonia, amines, and hydrazines to afford amides or hydrazides. It has been shown that 5-amino-l,3,4-oxadiazole-2-carboxylic acids and their esters decarboxylate. 

The coupling of thioamides with a variety of oxidizing agents is a widely utilized method for the synthesis of 3,5-diaryl-l,2,4-thiadiazoles (see Section 5.08.9.2). This method is not suitable for alkyl derivatives. 3,5-Dialkyl derivatives can be more effectively prepared from a suitably substituted thioacylamidine (see Equation 22), and this method allows a range of unsymmetrical derivatives to be prepared. 

FA Kuliev. Organic Sulfides, Disulfides and Thioamides as Inhibitors of Oxidation, Doct. Sci. (Chem.) Thesis Dissertation, Petrochem. Inst., Ufa, 1986 (in Russian). 

The answer is d. (Hardman, pp 1398-MOO.) Methimazole is classified as a thioamide and is used in the treatment of hyperthyroidism It prevents the organification of F by blocking the oxidation of F to active I and also inhibits coupling of iodotyrosines. Excessive treatment with this drug may induce hypothyroidism. Some other adverse reactions reported for... 

Formation of the Nitrogen-Sulfur Bond 3.6.1 Oxidation of Thioamides... 

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