Preparation thioamides from amides

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.2 The preparation of thioamides from amides and P4S,0 is improved by use of an ultrasonic laboratory cleaner. Lower temperatures and shorter reaction times can be used P4S10 is not required in large excess. Yields by use of ultrasound are 80-95%. 

Ionic liquids have been used both in solution and under homogeneous conditions. For example, Ley [37] described the preparation of thioamides from amides. Although the reaction under classical conditions occurs in excellent yield, the reaction time can be shortened by using MW irradiation (Scheme 5.4). The reaction was performed in toluene and, because this is not an optimum solvent for absorption and dissipation of MW energy, a small amount of polar solvent was added to the reaction mixture to ensure efficient heat distribution. 

Preparation of thioamides from amides was also shown to proceed faster and more efficiently under ultrasonic conditions (Scheme 88). Yields of between 77 and 97 % were obtained within 1-2 h [193]. In contrast, the standard reaction involves use of a large excess of reagent as a result of the insolubility of P4S q> results obtained using Lawesson s reagent tend to be unpredictable. 

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). 

Table 13.21) or from amides by treatment with Lawesson s reagent. Thioamides can also be prepared on cross-linked polystyrene by the addition of H2S to nitriles (Entry 5, Table 13.21), by thiocarbamoylation of resin-bound organolithium compounds (Entry 6), or by the acylation of amines with reactive thio acid derivatives (Entry 7, Table 13.21). 

Tetrakis(dimethylamino)titanium is a useful reagent for preparing amidines from secondary amides. From A X-thionyldiimidazole and secondary amides of boA aromatic and aliphatic carboxylic acids amidines (313 Scheme 50) are formed under mild conditions in moderate to good yields. N-Tosyl-amidines (314) can be obtained by reacting secondary thioamides (aliphatic and aromatic) with tosyl azide. Thiobenzamides have been condensed with anilines to afford amidines (315). Thioamides can be converted to amidines, e.g. (316), by treatment with ammonia in the presence of mercury acetate. ... 

Spending thioamides in the best yields. Thiolysis of iminium salts derived from amides and oxalyl chloride or phosphoric trichlorides with ammonium tetra-thiomolybdate 40 occurs below room temperature within 2 h (Eq. 10) [32]. It is advantageous that the by-products are easily separated, although H2S is needed in order to prepare 40. 

Thioamides and Related Compounds. Thioamides are the most stable thiocarbonyl compounds and have been prepared, for a century, from amides and P4S10 under rather drastic conditions. However, even for this purpose LR has turned out to be a superior reagent. High yields are obtained for all types of thioamides and -lactams including the elusive unsubstituted acrylo-thioamide (eq 18) and thioformamides or thioamides bearing sensitive substituents such as NO2, Z-NH, or OH (eq 19). ... 

The dimer of p-methoxyphenylthionophosphine (169) has been found to be a very useful reagent for the conversion of amides into thioamides ° as well as for preparing thionesters from esters and dithioesters from thioesters. The usual... 

Imidoyl chlorides are useful starting materials for the preparation of seleno-amides and for labile thioamides, e.g. (107), prepared from the amide (108),... 

Thioamides and Related Compounds. Thioamides are the most stable thiocarbonyl compounds and have been prepared, for a century, from amides and P4S10 under ratber drastic conditions. However, even for this purpose LR has turned out to be a superior... 

Trifluoromethyl groups can be converted to carboxyl groups under mild conditions by photohydrolysis Phosphonitrile chloride has been recommended as carboxyl activator, particularly for the preparation of amides and hydrazides The preparation of amides from inactive esters can be facilitated by the use of bifunctional catalysts such as 2-hydroxypyridine The preparation of imidate hydrochlorides, including N-subst. ones, from amides and thioamides with chloroformate has been investigated. ... 

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)... 

Direct reduction of a peptide bond with diborane 59 or a thioamide bond with several reductive procedures 60 is an alternative route for the production of a reduced peptide bond in a peptide. In some cases the reductive amination does not give satisfactory results. As described earlier, preparation of Boc-Pher )[CH2N]Pro-OH by reductive amination yields two diastereomers (Scheme ll). 57 In this case treatment of Boc-Phe-Pro-OBzl by diborane yielded the reduced pseudodipeptide Boc-Pher )[CH2N]Pro-OBzl without epimerization (Scheme 12). However, in some cases diborane is not entirely selective for the amide bond and can reduce ester functions when they are present. Another procedure is to prepare endothiopeptides directly from protected dipeptides 61-66 followed by their selective reduction. 60 ... 

Other routes to 1,3-oxazines employ condensation reactions between /3-chloroketones and nitriles or between chloroalkyl amides and alkynes <69LA(723)ill) (Scheme 62). Thiazines are available through similar condensations between thioamides, aldehydes and acetylenes (74G849), and AH- 1,3-benzoxazines may be prepared from 2-hydroxybenzyl alcohols and nitriles in the presence of either perchloric or sulfuric acids (Schemes 63 and 64) (68MIP22700). 

L-Prolinethioamides (39, R = alkyl including chiral alkyl), prepared from proline and amines, are effective in acetone-benzaldehyde reactions.110 Mechanistic studies focused in particular on suppression of non-enantioselective side-reactions, and also on the role of the side-chain of the catalyst acting as hydrogen bond donor, especially as the thioamides (with their more acidic N—H protons) are more catalytic than their amide analogues. 

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. 

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