Enethiols, synthesis

The mechanism of the condensation in Part D probably involves thioformylation of the metallated isocyanoacetate followed by intramolecular 1,1-addition of the tautomeric enethiol to the isonitrile. This thi2izole synthesis is analogous to the formation of oxazoles from acylation of metallated isonitriles with acid chlorides or anhydrides. " Interestingly, ethyl formate does not react with isocyanoacetate under the conditions of this procedure. Ethyl and methyl isocyanoacetate have been prepared in a similar manner by dehydration of the corresponding N-formylglycine esters with phosgene and trichloromethyl chloroformate, respectively. The phosphoryl chloride method described here was provided to the submitters by Professor U. Schollkopf and is based on the procedure of Bohme and Fuchs. The preparation of O-ethyl thioformate in Part C was developed from a report by Ohno, Koi/.uma, and Tsuchihaski. " ... 

It must be noted that this selective synthesis of enethiols from thioketones is restricted to cases for which regio- and stereoselective deprotonation occurs, as was achieved above with the symmetrical thiones (2a)-(2d). 

Enethiols 61 are tautomerically stable isomers of thioketones 60 and, in contrast to enols, enethiols have been isolated and characterized. This method provides a route for the selective synthesis of enethiols by deprotonation of 60 and quenching with trimethylchlorosilane, since under these conditions no isomerization takes place. 

The absence of a convenient method for the preparation of enethiolisab-le thioketones prompted us to fulfil this need. The development of aliphatic thioketones has so far been mostly restricted to examples with steric protection, such as thiocamphor and adamantanethione. Among the difficulties for a general synthesis of aliphatic and acyclic thioketones were easy enethiolisation (enethiols are stable tautomers with thermodynamic stabilities close to those of the thione form), oligomerisation, and susceptibility to air oxidation. They were solved by the adaptation of a former German reac-... 

This study was complemented by a selective synthesis of the tautomeric enethiols [77]. Aliphatic thioketones were deprotonated by LDA, silylated, and the resulting silyl vinyl sulfides were smoothly converted to enethiols by simple addition of methanol. These are stable compounds which do not equilibrate with thioketones, this behaviour probably related to the extremely mild conditions of the (easy) cleavage of the silicon-sulfur bond. 

The main class of electrophiles which reacts on the sulfur atom of enethiolates are alkyl halides. This was applied by Vallee and Tchertchian [121] in a one pot synthesis of hydroxy-ketenedithioacetals which elegantly uses the preceding features. Deprotonation of alkyl dithioacetates by LDA at -78 °C provided enethiolates which were treated by aldehydes. Comparable to the case of enolates, the aldol reaction takes place on the carbon atom. When water is added to the reaction mixture, 3-hydroxyalkanedithioates are obtained. However, if the quench is replaced by an alkyl halide addition, hydroxyketenedithioacetals are obtained. Formation of these compounds... 

The aldol reaction of dithioester enethiolates has been used for the synthesis of dithiolactones [123], chiral substrates for the Claisen rearrangement [124, 125], and oxathianes [126]. Thioamide enethiolates may be employed in this reaction as well as shown with /Tthiolactams [26], or with a precursor of the antitumour agent vinblastine [127]. 

It is interesting to note that nonsilylated enethiols have only been prepared as mixtures with their isomeric thioketones.4a,c The first selective synthesis of aliphatic enethiols was performed by Metzner52 by deprotonation of enethiolizable thioke-tones 42 with LDA and reaction of the enethiolates with trimethylsilylchloride. The subsequent methanolysis of silyl vinyl sulfides 43 afforded enethiols devoid of isomeric thioketones. Treatment of the enethiolates with various proton sources afforded instead mixtures of thioketones and enethiols (Scheme 31). 

Enethiols are reactive molecules and therefore useful starting materials in syntheses. They are acyl anion equivalents and good Michael acceptors. Addition of a thiol to the double bond, followed by Horner-Wittig reaction and then hydrolysis, constitutes a regioselective synthesis of a-sulphenyl ketones (equation 97). 

Synthesis.—All attempts to prepare simple aliphatic thioaldehydes have until now been unsuccessful, as only the cyclic trimers or less well-defined polymeric substances have been obtained. However, Brandsma has now reported that ajS-unsaturated sulphides (1) are cleaved by alkali metals in liquid ammonia to produce the corresponding enethiols (2) in high yields. For R = H, the products (2) represent the simple aliphatic thioaldehydes (3) in what is evidently their more stable tautomeric enethiol form. Apparently the pure enethiols (2 R = H) showed no tendency to... 

Synthesis.—Simple aliphatic and alicyclic thioketones are prepared easily and in high yields by the same method > as described in the preceding section for the preparation of the enethiol tautomers of simple aliphatic... 

Synthesis.— Thioketones (or enethiols) react with sulphur and carbon disulphide in DMF in the presence of triethylamine to give both 1,2-dithiole-3-thiones and l,3-dithiole-2-thiones thus heptane-4-thione yields 4-ethyl-5-propyl-l,2-dithiole-3-thione (1) and 4-ethyl-5-propyl-l,3-dithiole-2-thione (2). 5-Phenyl-4-styryl-l,2-dithiole-3-thione has been prepared by application of the well-known keten mercaptal synthesis, and some aryl-1,2-dithiole-3-thiones have been obtained, conventionally, by hi -temperature reactions of arylalkanes with sulphur. ... 

Barton and his group have prepared the interesting new di-t-butyl thio-ketone (7) in high yield by reaction of carbon disulphide with the lithium salt of the corresponding ketone imine. Independently, Ohno and his co-workers have published an analogous synthesis of this non-enethiolizable thioketone (7). Aliphatic thiones and, possibly, enethiols have been obtained by reaction of arylimines with benzoic anhydride and a stream of hydrogen sulphide. Treatment of a vinyl chloride with sodium monosulphide led to the isolation of thio-dimedone (8 R = H), which has an enethiol ketone structure. Basic hydrolysis... 

Synthesis.— The condensation of acetonitrile with ethyl thionoformate by means of butyl-lithium has been reported to yield thioformylacetonitrile (1) after subsequent treatment of the intermediate lithium salt (2) with hydrochloric acid. The thioaldehyde could not be isolated, but it was reasonably stable in solution in the tautomeric enethiol form (3), and was characterized as its stable S-methyl derivative (4). Several new, stable thioaldehydes, (5) and (6), have been synthesized by solvolysis of the VUsmeier salts (7) and (8) with aqueous sodium hydrogen sulphide. Some deuteriated analogues of (6) were similarly prepared from the corresponding salts (9). The thioaldehydes (10) were isolated as amorphous solids from the cycloaddition reaction of l,2-dithiole-3-thione with propiolic acid or its... 

Dieckmann cyclization of (21a) gave, depending upon conditions, either (21b) or (21c) predominantly. These compounds were transformed into the thiophens (21d) and (21e). The acid-catalysed reaction of (22) with hydrogen sulphide at -35 °C leads via the enethiol to ethyl 2,5-dimethyl thiophen-3-carboxylate as the main product. The monoacetals of substituted succinaldehyde (23), which are conveniently prepared through hydro-formylation of a -unsaturated aldehyde acetals with trans-bis(triphenyl-phosphine)carbonyl chlororhodium(i) as catalyst, have been used for the synthesis of optically active 3-substituted thiophens (from optically active a/3-unsaturated aldehyde acetals) through the acid-catalysed reaction with... 

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