Thioamide derivatives

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. 

Several reports are available on the biological activities of thioamide derivatives. The thioamide derivatives have shown significant activities, such as antituberculosis drug, anti-influenza virus activity, antitumor activity, anthelmintic activity, opioid receptor binding property, etc.94 101... 

A large number of thioamide derivatives have been obtained by Mirek and associates by allowing substituted indolizines to react with an aryl171,172 or aroyl173 isothiocyanate in a refluxing inert solvent. If a diisocyanate or a carbodiimide is used, products such as 109 and 110 are formed.17 ... 

The intramolecular cyclization toward tetrahydroisoquinolines can lead to some interesting chemistry. The reaction of isothiocyanatocarbonyls with aromatic ethyl amines gives the fused systems under mild conditions (Seheme 47) <2003CHE277>. Reaction of thioamide derivatives with bromoacetyl chloride upon cyclization leads to A -acetaltetrahydroisoquinoline derivatives, which can be treated with Raney nickel to produce 38... 

Thiopyrrolopyrimidines (135) are available directly from thioamide derivatives (134) upon heating with substituted amines (Equation (46)) <84S703>. 

The synthesis of enantiopure thiazolines has been reported. The mixture of enantiomerically pure diastereoisomeric amido selenides 64, obtained from the reaction of camphorselenyl sulfate with trans alkenes, when treated with Lawesson s reagent affords a mixture of two thioamide derivatives 65a and 65b. The two diastereoisomeric thioamide selenides were easily separated by chromatography, each was then treated with phenyl selenyl chloride which caused deselenylation to occur in a stereospecific manner furnishing the thiazolines 66a and 66b in an enantiopure form <02TA429>. 

A very fast reaction occurs between dialkylzinc compounds and the more acidic amide and thioamide derivatives of the... 

Crystal structures of two thioamide derivatives of thiazole, A -methylthioamide 8, and A -phenylthioamide 20 thiazoles were determined by X-ray diffraction. The data are shown in Table 5 compared with the unsubstitued compound, determined by MW <1971JST(8)225>, and also with the mean values taken from Cambridge Structural Database (CSD) for monosubstituted derivatives <1999JST(479)21>. 

The oxidation of some sulfur-containing compounds, such as thioke-tones and thioamides (derivatives of ketones and acids, respectively), has been mentioned in earlier sections. 

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 facile and efficient synthetic route to densely substituted thiophenes based on base induced cyclization reaction between thioamides derived from morpholine and a-haloketones has been reported. Thus, the thioamides 4 were subjected to treatment with the haloketones 5 (R = H, Ar, Me) under basic conditions to provide the tetrasubstituted thiophenes 6. Likewise, the reaction was also demonstrated to give good yields of thiophenes when the haloketones were replaced with 2-bromo-3-oxobutyric acid derivatives or propargyl bromide <04T6085>. 

Thus, a variety of thioamides derived from 2-aminobenzimidazole are oxidized by bromine to 2-substituted l,2,4-thiadiazolo[2,3-a]benzimida-zoles (258).198... 

The POClj-mediated reaction of acetamides with DMF followed by treatment with HCIO4 forms the iminium salts 102 (Eq. 37) [68]. The reaction of 102 with sodium selenide gives the p-amino-a,p-unsaturated selenoamides 103 as thermally stable compounds, although the yields of 103 are lower than those of thioamides derived by a similar reaction. 

Cyclodehydration of the thioamide-derived structures was induced by treatment with an acetic anhydride and phosphoric acid mixture, hi the case of the mixture of 90 and 91, N-glucopyranosyl tetrahydrothioxopyridine 92 was obtained upon acidic treatment [123]. Under the same conditions, compound 93 evolved to N-glucopyranosyl thioxopyrroline 94. 

For example, Dimroth treated thioamides, derived from isothiocyanates and malonates, with phosphorus pentachloride, and he obtained the corresponding imidoyl chlorides (III), which can be dehydro-chlorinated to produce the ketenimines IV. 

Our motivation for investigating thioamide derivatives, which potentially can form N-H... S interactions, arises from the presence of the -N(H)-C(=S)- residue, and derivatives thereof, in several dmgs [20], see Scheme 6.2 for chemical structures of these species. Thus, the antithyroid drugs 6-n-propyl-thiouracil (I) and l-methyl-3//-imidazole-2-thione (II, Methimazole , also marketed as Tapazole ) feature the -N(H)-C(=S)- functional group [21]. Hyperthyroidism may be treated with 3-methyl-2-thioxo-4-imidazoline-l-carboxylate (III, Carbimazole ) which is metabolised in vivo to the active form, known as Methimazole [22]. Anti-tubercular agents containing the thioamide residue and which inhibit mycolic acid synthesis include 2-ethyl-thioisonicotinamide (IV, Ethionamide ) and its -propyl derivative (Prothionamide ) [23-25]. 

On the other hand, replacement of the morpholino moiety (ring C) by a 3-methyl-l,2,4-oxadiazol-5-yl g oup produces active compounds (2013EJMC533). Compounds 78a—d (F yne 27) show lower activity compared to linezolid against standard S. aureus, but a direct comparison could not be performed because the test were performed on racemic mixtures. Nevertheless, as a racemate, thioamide derivatives 78c,d showed major activity against MRSA strains, with MIC values twofold lower than those of reference drug. Moreover, a safety profile similar to HnezoHd was evidenced by means of cytotoxicity data on PK15, HaCat, and HepG2 cell lines. 

Perlmutter and coworkers reported an improved reaction of amides 45 with solid-supported P2S5 reagent in tetrahydrofuran (TH F) at 60 °C under microwave irradiation to generate 11 new thioamide derivatives 46 in 76-92% yields (Scheme 12.17). Compared to that with conventional heating, the reaction time is significantly reduced by microwave irradiation. Besides the shortened reaction periods, this thionation method also allowed more convenient workup procedure [38]. 

A proposal for the mechanism of the Fukuyama indole synthesis is proposed as shown below. Treatment of the isonitriles 1 with tributyltin hydride and a catalytic amount of AIBN, affords a-stannoimidoyl radical 2, followed by cyclization, to give radical 16. It was found that the substrates bearing radical-stabilizing groups at the P-position gave indoles 3 in excellent yield after tautomerization, and acidic workup. Similarly, when thioamide derivatives such as 2-alkenylthioanilide 18 are subjected to radical-initiating conditions, radical 5 or imidoyl radical species are formed, which then undergo radical cyclization to furnish 2,3-disubstiuted indoles 6. 

The Hantzsch synthesis has been used to generate pyrroles, thiazoles and dihydropyridine derivatives. Pyrroles (3) are generated from the reaction of P-ketoesters with ammonia, ammonia derivatives or primary amines, and a-haloketones (path A). Thiazoles (5) are generated from the reaction between a-haloketones and thiourea or thioamide derivatives (path B). Dihydropyridines (7) are generated from the reaction of aldehydes with p-ketoesters and ammonia or ammonia derivatives, or enamines derived from the reaction of ketones or P-ketoesters with amines (path C). Dihydropyridines can be readily converted to the corresponding pyridine derivatives and so this reaction is often termed the Hantzsch pyridine synthesis. 

The thionation of amides with phosphorus pentasulphide constitutes a traditional synthetic route to thioamides, which have been found to be especially useful for the synthesis of heterocyclic thiones containing the thiolactam grouping.However, thioformylhydroxylamine and some thioamides derived from 2-furanoic acid and anthranilic acid have also been obtained by this reaction. In the latter case, the reaction was performed in pyridine, and the authors were able to isolate the intermediate... 

It has been suggested that H2 may bind to the Ni as a dihydrogen complex, which easily lose protons (Section 3.5), and so could account for the isotope exchange seen in nation 16.45. Dihydrogen complexes do indeed catalyze the reaction in Eq. 16.45. Some Ni(II) complexes are now known that electro-catalytically release H2 from protic solvents and so can be considered functional models of H2ase. Complex 16,24 requires acidic (pH 4) solutions to protonate the reduced form, but a thioamide derivative related to 16.17 is active at pH7. ... 

The a//-homocalixarene pe of host not only allowed the modification of ring size (10 to 80 ring members, cf. Fig. 4) but also the modification of functional groups. Their demethylation led to a series of oligophenols [11] which, aside from exhibiting endoacidic cavities, could be transformed into oxapropionic ester, acid, amide [12], and thioamide derivates. These now bear ligand-arms which provide many coordination sites (Fig. 6). 

NHj, NEtj, or pyridine as the basic catalyst.Nitriles are also converted into thioamide derivatives in the presence of the Lewis acids SnCl4 and AsFj, using AcSH" and Et4N as sources of SH". Nitriles react with 00-dialkyl... 

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