Thioamide side chain

If the substrate contained a thioamide side chain (e.g., 160), then the thioamide intramolecularly intercepted the sulfenic acid resulting in the unstable disulfide (161) which slowly lost sulfur to yield the thiazoline (162) (Micetich et al., 1976 Tanida et al., 1975b). 

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. 

Although the antithyroid activity of compounds incorporating an enolizable thioamide function was discussed earlier, this activity was in fact first found in the pyrimidine series. The simplest compound to show this activity, methylthiouracil (80) (shown in both enol and keto forms), is prepared quite simply by condensation of ethyl acetoacetate with thiourea.Further work in this series shows that better activity was obtained by incorporation of a lipophilic side chain. Preparation of the required dicarbonyl compound starts with acylation of the magnesium enolate of the unsyrametrically esterified malonate, 81, with butyryl chlo-... 

Insertion of a thioamide (0[CSNH]) bond into a peptide backbone with noncoordinating side chains increases distinctly the coordination ability of the peptide toward Ni11. The thioamide sulfur is a much more potent donor than the carbonyl-O and it is a basic donor for Ni11 ion coordination around physiological pH.1764... 

On treatment with phosphorus pentasulfide, 4-amino-5-thio-477-[l,2,4]triazoles 86 are converted into 6-aryl-3-(2-aminophenyl)[l,2,4]triazolo[3,4-4][l,3,4]thiadiazoles 3. This transformation is presumed to involve three steps first, the transformation of the amide into the thioamide second, transfer of the thioaroyl group from the phenylamino side chain to the iV-amino group of the triazole ring and, finally, cyclodehydrosulfurization leading to 3 (Equation 21) <1989LA1055>. 

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). 

Side-chain amides (Asn, Gin) are reactive towards thionylating reagents, but in their absence appropriately protected peptides can be converted into thioamide peptides. Examples of short, singly thionylated peptides are given in Table 1. 

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. 

It is interesting to note that, due to the reversible character of the cycloaddition, isomerization favoring the product which is thermodynamically more stable may occur and an appropriate side-chain substituent may participate. For example, the thiazolo [4,5-b] quinoxalines 55, formed in the reaction of quinoxalinium salts with thioamides under kinetically controlled conditions, are able to undergo two different isomerizations (Scheme 45). When compound 55 contains an aryl group at C-2 (R2 = aryl) and this compound is heated in an ethanolic solution, the thiazoloquinoxaline 57 is formed. In the case of R2 = CH3, the methyl group participates in the isomerization process, yielding pyrrolo [2,3-b]quinoxalin-2-thione 58 (Scheme 45) (85KGS396). 

The very small amount of steroid that reaches the bloodstream from a topically administered drug can at least in theory cause some of the typical corticoid side-effects. This has occasioned research on corticoids that contain weak links that will lead to deactivation of the steroid by serum enzymes. The drug fluticasone (32-6) acts as a typical anti-inflammatory and antiallergic corticoid even though the side chain on ring D consists of a thioamide instead of a 2-hydroxyacetyl function. That thioamide provides the weak link that causes the drug to be destroyed by serum enzymes. As a result, fluticasone powder is used extensively in inhalers for treating asthma. 

At the side-chain. Thiazole phosphonium salts (105 R=alkyl,Ar,R1= alkyl,Ar,amino,X=C1, Br) [prepared from acylvinylphosphonium salts and thioamides] undergo nucleophilic displacement with MeO" to form ethers (106) or ylide formation with nBuLi. Subsequent reactions of the ylides are reported122. 2-Acetonylthiazole... 

The 3 -isobut5Toylamino-thymidine derivative (117), on the other hand, reacts with 1 equiv of LR in the side chain to form the thioamide (118). Phosphite esters which are used as intermediates in solid-phase synthesis of oligonucleotides are converted into the corresponding phosphorothioates (119). Interestingly, LR can also be used as a potent catalyst for the s)uithesis of nucleosides. Tetramethylglycoluril (120) is readily converted to the monothiono- (121) or the dithionoglycolurU (122) depending on the applied molar amount of LR. ... 

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