Thioamides from ketones

Carboxylic acid thioamides from ketones and enamines Modified Willgerodt-Kindler reaction... 

Miscellaneous Reactions of LR. Under particular conditions, certain carbonyl compounds and other substrates react with LR to form thiophosphonates or heterocycles, which fact throws some hght on the mechanism of thionation reactions with LR. Carbinols undergo nucleophilic substitution with LR to form the corresponding thiols. The redox properties of LR can be utilized to prepare dithiolactones from dialdehydes (eq 22), a-0X0 thioamides from nitro ketones (eq 23), or sulfides from sulfoxides. ... 

Thioamides can be obtained in 40—60% yield by the reaction of Grignard reagents with triphenylphosphine thiocyanate. In a continuation of earlier work, Yoshida s group has found that a large range of enolates (e.g. those from ketones, esters, amides, acetoacetates) add in a conjugative manner to a,jS-unsaturated thioamides the derivatives thus obtained can easily be converted into esters and amides (cf. 3, 253). 

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)... 

Thiazole and its derivatives are conventionally prepared from lachrymatory, a-halo-ketones and thioureas (or thioamides) by Hantzsch procedure [146]. In a marked improvement, Varma et al. have synthesized the title compounds by the simple reaction of in situ-generated a-tosyloxyketones, from arylmethyl ketones and [hydroxy(tosyl-oxy)iodo]benzene (HTIB), with thioamides in the presence of K 10 clay using micro-wave irradiation (Scheme 6.43) the process is solvent-free in both the steps [147]. 

Secondary amides have the advantage over tertiary amides that they are relatively easy to remove. It is quite difficult to stop the addition products from aldehydes, ketones, amides, epoxides and nitriles cyclizing directly to give a variety of lactone derivatives (by attack of OH on the secondary amide) or lactam derivatives (by attack of the secondary amide on the new electrophihc centre). Thioamides behave similarly . 

Conventional preparations of thiazoles and 2-aroylbenzo[fc]-furans require the use of lachrymatory a-haloketones and thioureas (or thioamides). To avoid this problem, Varma et al. have synthesized various hetero cycles via solvent-free reactions of thioamides, ethylenethioureas and salicylalde-hydes with a-tosyloxyketones that are generated in situ from arylmethyl ketones and [hydroxy(tosyloxy)iodo]benzene (HTIB) under microwave conditions (Scheme 15) [70]. 

Retrosynthetic disconnection of the nitrogen-carbon bond in thiazole 3.26 leads formally to enol 3.27 which is equivalent to ketone 3.28. This can be derived from haloketone 3.29 and thioamide 3.30. 

Carbanions from hydrocarbons, nitriles, ketones, esters, TV./V-dialkyl acetamides and thioamides, and mono and dianions from (3-dicarbonyl compounds are some of the most common nucleophiles through which a new C-C bond can be formed. This C-C bond formation is also achieved by reaction with aromatic alkoxides. Among the nitrogen nucleophiles known to react are amide ions to form anilines however, the anions from aromatic amines, pyrroles, diazoles and triazoles, react with aromatic substrates to afford C-arylation. 

So the only remaining question is when thioamides combine with a-haloketones, which atom (N or S) attacks the ketone, and which atom (N or S) attacks the alkyl halide Carbonyl groups are hard electrophiles—their reactions are mainly under charge control and so they react best with basic nucleophiles (Chapter 12). Alkyl halides are soft electrophiles—their reactions are mainly under frontier orbital control and they react best with large uncharged nucleophiles from the lower rows of the periodic table. The ketone reacts with nitrogen and the alkyl halide with sulfur. 

Vinylogous thioamides 33 (NR2 = dimethylamino or morpholino) react with benzyl chloride to give thiophenes42, while thienyl ketones are produced from a-bromo ketones43 (equation 22). 

Q or Br designates the corresponding a-chloro or a-bromo-aldehyde or ketone PjS5 designates thioamides formed in situ from amides. 

The analysis in the chapter (p. 1200 reproduced below) shows that we need the thioamide of renzoic acid (thiobenzamide available from Aldrich) and an a-bromoketone. We need these rarticular starting materials because the soft sulfur atom will displace the bromide in a frontier-orbital-controlled Sn2 reaction whilst the hard amino group will attack the ketone in a charge-controlled nucleophilic attack on a carbonyl group. 

Thiazoles have been readily obtained from thioamides and a-tosyloxy-ketones, catalyzed by montmorillonite K-10 clay under MW irradiation, in excellent yields. These compounds are very difficult to synthesize under conventional heating conditions (Scheme 8.25). ... 

The synthesis of thiazoles 43 adds an element of regioselectivity as the thioamide has soft (S orbital controlled) andhard (N charge controlled) nucleophilic sites anditis essential to differentiate equally clearly between the two electrophilic centres on the carbonyl part of the molecule. We need to know that a thioamide will react with an a-haloketone 48 X = Cl, Br so that the hard nitrogen atom attacks the ketone and the soft sulfur atom attacks the saturated carbon atom. Thus the simple non-steroidal anti-inflammatory drug Fentiazac 50 is made from thiobenzamide 51 and the simple bromoketone 52, made in turn by bromination of the ketoacid. The synthesis is just that.3... 

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