Aldehyde 2-substituted thiosemicarbazones

In an early investigation [70LA(731)142], it was supposed that the equilibrium 88A 88B exists in acidic solutions of aldehyde and ketone 2-substituted thiosemicarbazones [for a detailed review, see (93KGS991)]. Later, it was shown (79JHC1273) that acetone thiosemicarbazone 88 (R1 = R2 = Me R3 = R4 = H) and its 2-methyl (R3 = Me) and 4-methyl (R4 = Me) derivatives exist as open-chain isomers in (CD3)2SO solution, but as cyclic isomers 88B in CF3COOD. According to this investigation, the 2,4-dimethyl-substituted derivative exists solely as the cyclic tautomer 88B (R1 = R2 = R3 = R4 = Me) in both of these solvents. 

Synthesis of 2-heterocyclic thiosemicarbazones can be summarized in three reaction sequences following the lead of Klayman et al. [5]. Condensation of equimolar quantities of a thiosemicarbazide and a 2-heterocyclic aldehyde or ketone in an alcoholic solvent is represented by Eq. (1). The product s superscripts refer to positions of substitution in the thiosemicarbazone moiety in accord with lUPAC. 

The treatment of the 2-(4-chloromethylthiazol-2-yl)hydrazone of a heteroaromatic aldehyde (196) (formed as an intermediate in the reaction of some thiosemicarbazones with 1,3-dichloroacetone) with acetic anhydride gives rise to 3-hetaryl-substituted 2-acetyl-5-chloromethyl-2,3-dihydro-thiazolo[2,3-c][ 1,2,4]triazoles (197) (Scheme 17) <92JIC596>. 

This reaction was first reported by Hantzsch and Weber in 1887. It is the formation of thiazole derivatives by means of condensation of a-haloketones (or aldehydes) and thioamides. Therefore, it is generally known as the Hantzsch thiazole synthesis. In addition, other names, including the Hantzsch synthesis, Hantzsch reaction, and Hantzsch thiazole reaction are also used from time to time. Besides thioamides, other thio-ketone derivatives such as thiourea, dithiocarbamates, and ketone thiosemicarbazone can also condense with a-halo ketones (or aldehydes) to form thiazoles. This reaction occurs because of the strong nucleophilicity of the sulfur atom in thioamides or thioureas, and normally gives excellent yields for simple thiazoles but low yields for some substituted thiazoles, as of dehalogenation. This reaction has been proven to be a multistep reaction, and the intermediates have been isolated at low temperatures, in which the dehydration of cyclic intermediates seems to be the slow step. It is found that a variety of reaction conditions might result in the racemized thiazoles that contain an enolizable proton at their chiral center, and it is the intermediate not the final product that is involved in the racemization. Therefore, some modifications have been made to reduce or even eliminate the epimeriza-tion upon thiazole formation. In addition, this reaction has been modified using a-tosyloxy ketones to replace a-haloketones. ... 

An extensive presentation of biological data produced by a total of 33 pyridine aldehyde thiosemicarbazones has been described [32]. This report also included data on 26 isoquinoline carboxaldehyde thiosemicarbazones and 45 other heterocyclic aldehyde thiosemicarbazones. However, no attempt was made to correlate structure with activity. Recently, a series of 5-substituted analogues of (4) has been reported [33] which included various esters of 5-hydroxymethyl-pyridine thiosemicarbazone. 5-Acetoxymethyl (57b) and 5-isonicotinoyl (570 derivatives were found to be active antineoplastic agents. The acetoxymethyl derivative (57b) was markedly active against the Ehrlich ascites carcinoma, leukemia L-1210, and leukemia C-1498, while moderately effective against Nakahara-Fukuoka sarcoma and inactive against adenocarcinoma 755. The iso-... 

Oxidation of 4-acetoxy-l-methylisoquinoline (76) with selenium dioxide produced the corresponding 1-carboxaldehyde, which upon acid hydrolysis yielded the 4-hydroxy derivative. Treatment of heterocyclic aldehydes with thio-semicarbazide produced the desired thiosemicarbazones. In general, the 4-substituted derivatives were less effective than (1) as antineoplastic agents against Sarcoma 180 ascites cells in mice however, the sodium salt of the 4-hydroxy derivative was considerably more efficacious than (1) against the L-1210 lymphoma. 

The condensation of thiosemicarbazones and maleic anhydride to thiazole derivatives has been successfully extended to thiocarbono-hydrazones of aromatic aldehydes and acetophenone (265). Their fusion with maleic anhydride affords a series of substituted thiazolidines of type (266). ... 

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