Enethiolates

Note 2. Propargyl bromide itself also reacts with ammonia and therefore the interval between the addition of this compound and its conversion with the enethiolate should be kept as short as possible. Inverse addition was applied if propargyl bromide is added to the enthiolate solution, the primary product partly isomerizes into H2C=C(5C2Hs)SCH=C=CH2 under the catalytic influence of the enethiolate. 

Recently, Hoff and Blok report the reductive ring opening of 4-methyl-A-4-thiazoline-2-thione anion (80) (Scheme 39) (204) when treated with two equivalents of sodium in liquid amonia. Treatment of the prop-enethiolate (83) by 4N aqueous HCl affords 4-methylthiazole. The... 

The mercapto form is much more strongly favored than is the hydroxy form for the corresponding oxygen compounds. A pertinent comparison in this respect is the greatly reduced inclination of enethiols to tautomerize to the corresponding thiocarbonyl compounds, in contrast to the facile ketonization of vinyl alcohols. 

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. " ... 

Diphenylcyclopropene thione shows analogous reactivity24S,246J forming 2-azonia-bicyclo(3,l,0)hex-3-enethiolates-3 (371, X=S) at low temperatures and thioamides (372, X=S) at elevated temperatures. 

Tautomeric equilibria. The presence of a hydrogen at the a carbon near the thione group induces the thione-enethiol tautomerism, Scheme 1, where C=S turns into the more stable C S single bond.1,2,3 Calculated enolization enthalpies4,5 show that C=0 is stronger than C=S. 

In contrast with the normal behaviour of aliphatic thioketones, 3-exo,3 -exo-(lR,l R)-bithiocamphor cannot exist as enethiol, since the latter is obtained by reduction of its 1,2-dithiine, immediately stabilized by 1,5-prototropic rearrangement.6... 

Thiamine (vitamin B,) in the presence of Me2T10H (435). Here the kinetics are much affected, through coordination of TIMeJ to the sulfur of the thiamine in its enethiolate form. 

There appears to be little reported work on S-nitrosation reactions of simple thioke-tones. Thiocamphor when treated with /50-amyl nitrite in fact gives the oxime58 (formerly called a isonitroso compounds), presumably via the tautomeric form of the thione, i.e. the enethiol. In this respect the reaction is very similar to the reactions of ketones59 which give oximes or C-nitroso compounds via the enol intermediates60. 

Diborneo-l,2-dithiin 25 was synthesized from (R)-thiocamphor 212 via disulfide oxidation (of the enethiol form) and Cope rearrangement to the bis-thiocamphor, which was deprotonated employing NaH/DMF to form the dienolate and then finally oxidized with K3[Ee(CN)6] (Scheme 58) <1995T13247, 1994TL1973> only the racemic dithiin derivative 25 was obtained. 

Attempts to generate thiocamphor (5)-methylide (44) by the addition of diazomethane to thiocamphor and subsequent N2-elimination from the [3-1-21-cycloadduct 43 led to enethiol ether 45 via a 1,4-H shift (Scheme 5.17). The formation of an unstable intermediate 43 was proposed on the basis of the proton nuclear magnetic resonance ( H NMR) spectrum of the crude mixture. The postulated intermediate 44 could not be intercepted by dipolarophiles or methanol, and did not undergo electrocyclization to give the corresponding thirrane (41). 

Acidic compounds of type R—XH, which are able to protonate thiocarbonyl ylides, also undergo 1,3-addition leading to products of S,S-, S,0-, or 5,A-acetal type (Scheme 5.20). Thiophenols and thiols add smoothly to thiocarbonyl ylides generated from 2,5-dihydro-l,3,4-thiadiazoles (36,38,86,98,99). Thiocamphor, which exists in solution in equilibrium with its enethiol form, undergoes a similar reaction with adamantanethione (5)-methylide (52) to give dithioacetal 53 (40) (Scheme 5.21). Formation of analogous products was observed with some thiocarbonyl functionalized NH-heterocycles (100). 

In the previous examples, the sulfur atom acted as a nucleophile. Electron-deficient sulfur species such as sulfenyl ion and its equivalents (e.g. disulfide/Lewis acid complexes, sulfenic acids, sulfenyl halides, sulfonium ions, sulfines, etc.), can also serve as an electrophile. Oxidative ring closure of enethiols (a-thioketocarboxylic acid) (124), which proceeds via disulfides, produces thiophenes (125) in good yields (86EUP158380, 88JHC367). 

Certain divinyl disulfides (a) are readily available by oxidation of dithioic esters in basic solution (Scheme 9). Heating (a R = Me or Ph) in toluene converted it to a mixture of the 3,4-disubstituted 2,5-di(methylthio)thiophene (b) and the corresponding 5-methylthio-2-thiophenethiol (c). Addition of potassium f-butoxide to the toluene resulted in a nearly quantitative yield of the thiol (c), but further addition of methyl iodide in a second step converts (c) to (b) so that the yield of either product can be maximized (74RTC258). The mechanism is the same as that shown in Scheme 7 (Scheme 9). Photolysis of enethiol esters gives divinyl sulfides such as those shown in Scheme 7, and these form thiophenes under the conditions of photolysis (77JOC1142). 

An interesting variation of the Dieckmann cyclization involves vinylogous activation of a methyl group in a 2-butenyl ester. Reaction of an a-halo ester with the enethiol formed by treatment of an acetoacetic ester, which may be substituted at the a-position, with hydrogen sulfide produces (92) in satisfactory yield. Treatment of these compounds with sodium in benzene produced the 4-hydroxythiophene-2-acetic acids (94) (40JCS1385). The product undoubtedly involved the intermediate (93), in which the activated methyl goup has condensed with the ethoxycarbonyl group in typical Claisen fashion. 

However, for aliphatic low-molecular-weight members of this class, oligomerization and/or polymerization, formation of gem-dithiols and enethiolization are often observed. The purification steps can be tedious and the obtention of pure products difficult. There is still a need for progress in this field. Although much less used, another general method whose scope appears important [127] involves the reaction of ketimine... 

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). 

The thiophilic addition of aliphatic Grignard reagents to dithioesters deserves some comment. Although they are less reactive than organolithium compounds, their reactions are selective. With enethiolizable dithioesters, enethiolization cannot be avoided with the organolithium species, and at low temperatures this can become exclusive [332]. Enethiolization does not interfere in the case of the less... 

With thioamides few results are available. Only carbophilic additions have been reported [329, 358]. This mode of addition of organolithiums was used for novel syntheses of unsymmetrical ketones and a-alkylated amines. Although enethiolization of aliphatic thioamides by alkyllithiums limits the scope of these synthetic routes the yields are good and reactions simple to run [358]. 

Again for synthetic applications, thio- and dithioesters are particularly useful. Their enethiolates are easily generated [120]. Potassium and lithium amides and LDA can be conveniently used, and deprotonate the dithioesters quantitatively in THF at -78°C. Methyllithium under the same conditions also acts as a base and not as a nucleophile, and it has the advantage that its conjugate acid is the totally inert methane. 

The enethiolates (2) present interesting aspects. Some are mentioned below (see [120] for a discussion and appropriate references) ... 

Under kinetic conditions the enethiolates (2) of cis geometry are formed preferentially and are configurationally stable. 

The addition reaction of enethiolates towards Michael acceptors has been investigated (for reviews, see [120, 362]). It was established that lithium dithioester enethiolates undergo regioselective 1,4-addition with a wiik ... 

The stereochemical aspects of the Michael addition of lithium dithioester enethiolates in the challenging acyclic series have been examined [362]. A stereospecific addition of a c/s-enethiolate to an ( )-enone furnishes the anti isomer (6). 

With a,p-disubstituted enuiies an unexpected mode of stereocontrol was evidenced [365, 366]. Syn products (7) were obtained by addition of the lithium enethiolate of methyl dithioacetate to an a,3-disubstituted enone via diastereoselective auto-protonation of the intermediate enolate generated in the 1,4 addition. 

A good stereospecificity has also been demonstrated for the reaction of m-enethiolates with aldehydes [359,360]. 

---