Conjugation, thioamides

In both cases this process is accompanied with the formation of conjugated —C=N— bonds, which is indicative of the participation of the thioamide groups in the cyclization reaction. 

Thioamides react under mild conditions with conjugated azoalkenes (32) to give thiazolines (33) that exhibit hydrazono hydrazino tautomerism. X-ray diffraction studies on (33) showed the compound existed as the hydrazono tautomer <95S1397>. 

The preparation and reactions of V-thiocarbonyl carbohydrate derivatives, such as sugar isothiocyanates, thioamides, thioureas, thiocarbamates and their conjugates have been the subject of valuable comprehensive as well as specialized accounts, which should be consulted for details.198... 

Most reactive metabolites produced by CYP metabolic activation are electrophilic in nature, which means that they can react easily with the nucleophiles present in the protein side chains. Several functional groups are recurrent structural features in M Bis. These groups have been reviewed by Fontana et al. [26] and can be summarized as follows terminal (co or co — 1) acetylenes, olefins, furans and thiophenes, epoxides, dichloro- and trichloroethylenes, secondary amines, benzodioxoles (methylenediox-yphenyl, MDP), conjugated structures, hydrazines, isothiocyanates, thioamides, dithiocarbamates and, in general, Michael acceptors (Scheme 11.1). 

The torsional barrier of the amino group in thioamides is generally ca. 2 kcal/ mol higher than in the corresponding amides (26), and this trend is also found in the enamino thioketones (17,23 Table 2). The increased conjugative interaction in the thioamides is reflected in the Ct—C2 barriers, and the larger size of sulfur compared to oxygen affects the EIZ population ratio. 

Sakamoto et al. reported the X-ray crystallographic data and the solid-state photoreaction of eight Ar,AT-disubstituted a,p-unsaturated thioamides 23a-h, which involves hydrogen abstraction by the alkenyl carbon atom conjugated with thiocarbonyls (Fig. 9) [44-46]. 

If thioamide enolates are prepared by conjugate addition of Grignard reagents to a,/3-unsaturated thioamides of secondary amines, the reaction of these enolates with aldehydes affords anti aldols. These results are rationalized by the formation of a boat-like, chelate transition state" Representative examples are provided in equation 112 and Table 16. 

In thioamide vinylogues (96) the conjugation was proved in a qualitative sense from the enhanced values of dipole moments223. The derivatives of furane (97) were investigated by several experimental methods224 while the conformation on C—N followed mainly from IR spectra, dipole moments served to determine conformation of the furan ring on the Car—C bond but the result was not convincing (due also to some misprints). 

The predominant formation of five-membered carbocydes or heterocycles 122 (Scheme 50) via a sequential conjugate addition-carbene insertion pathway is generally observed in the reactions of the appropriate alkynyliodonium salts 119 (R = long alkyl chain or other group with C-H bond available at C5) with various relatively hard nucleophiles. Typical nucleophiles used to initiate these selective cyclizations are enolate, azide, sulfinate, tosylamide, thioamide and some other anions. 

But the more heteroatoms, the more alternatives. We could disconnect the enamine first 27a and the C-S bond second 31. This suggests a reasonable a-halo-ketone 33 and an unstable-looking imine 32. Fortunately this is just a tautomer of the thioamide 34. Though thioketones are unstable, thio-amides are stable thanks to extra conjugation. 

Enethiolates are soft nucleophiles which react in a conjugate fashion with Michael acceptors [1, 128, 129]. Thioamide enethiolates are a borderline case... 

Bifunctional nucleophilic reagents, such as ketones, enamines, / -diketones and their derivatives, amidines, thioureas, thioamides, dithiocar-bamates, and others, are very often employed in cyclizations with azine derivatives, resulting in the formation of annelated five-membered cycles (84UK1648 85KGS1011). The structure of all these 1,3-dinucleophiles feature a double bond conjugated with an anionic center or with a heteroatom bearing the lone pair of electrons (Scheme 5). 

Simple thioaldehydes and thioketones are too unstable to exist and attempts at their preparation lead to appalling smells (Chapter 1). The problem is the poor overlap between the 2sp2 orbital on carbon and the 3sp2 orbital on sulfur as well as the more or less equal electronegativities of the two elements. Stable thiocarbonyl compounds include dithioesters and thioamides where the extra conjugation of the oxygen or nitrogen atom helps to stabilize the weak C-S bond. 

Conjugate addition of lithium enolates to a,/3-unsaturated thioamides is also promoted by the addition of 1-2 equiv. of HMPT. ... 

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