Thiocarbamoyl isothiocyanates

Cycloaddition Reactions. In [2+2] cycloaddition reactions with car-bodiimides sometimes [2+4] cycloadducts are produced as coproducts. Examples include the reaction of phenylcarbonyl isocyanate, phenylcarbonyl isothiocyanate and thiocarbamoyl isothiocyanate with carbodiimides to give [2+4] cycloadducts, discussed in Section 5.3.1. In the current section, mainly [2+4] cycloaddition of carbodiimides as dienophile with dienes derived from oxoketenes, generated in situ or masked oxoketenes, especially 2,3-diones investigated by Kollenz and his coworkers are discussed. 

Thiocarbamoyl isothiocyanate reacts with cyclic enamines to form a fused thiazinethione under mild conditions a mechanism has been suggested for this unusual cyclization. The reactions of isothiocyanates have been reviewed [3990]. 

A miscellany of papers dealing with the potency of the thioureido neighbouring group in nucleophilic substitution processes, the complexing ability of thioureas towards macrocyclic polyethers, and the cycloaddition reactions of thiocarbamoyl isothiocyanates (190) with ketens, ketenimines, imines, isocyanates, carbodi-imides, and isonitriles also deserve attention. 

In an extension of this work, analogous [4 + 2] and [4+1] cycloadditions of thiocarbamoyl isothiocyanates (161) have been examined. Their interaction with isocyanides under restrained conditions yields 2-amino-5-imino-2-thiazoline-4-thiones (162) as deeply coloured stable... 

In a similar reaction, ethylthiocarbonyl isothiocyanate reacts with diphenylketene to give the [4+2] cycloadduct. Thiocarbamoyl isothiocyanates react with ketenes and ketenimines in a similar fashion (see Chapter 4, Sections 4.1 and 4.3) ". ... 

The dimerization of carbonyl-, thiocarbonyl-, imidoyl- and thiocarbamoyl isothiocyanates proceeds in a [4-1-2] cycloaddition reaction (see Section 3.3.2.2). Carbonyl isothiocyanates also readily undergo [4-1-2] cycloaddition reactions with aliphatic and aromatic azomethines, the former being considerably more reactive. For example, phenylcar-bonyl isothiocyanate reacts with benzylidenemethylamine 184 to give a [4-1-2] cycloadduct 185... 

Cycloadditions The [4+2] cycloaddition reactions of carbodiimides with phenyl-carbonyl isocyanate, phenylcarbonyl isothiocyanate and thiocarbamoyl isothiocyanate have been discussed above. In the dimerization reactions the functional carbodiimides react as both the diene and the dienophile. Unsaturated carbodiimides, generated in situ, can be trapped with N=N bond- or C=N bond-containing substrates. 

Several thioureas have been synthesized by ring-opening reactions of heterocyclic compounds such as l,3-dithiolan-2-thiones, 5-arylimino-l,2,4-dithiazolidine-3-thiones, benzoxazole-2-thiones, and 3,1-benzo-thiazine-4-thione derivatives. Similarly, the action of triphenylphosphine on 5-amino-l,2,4-dithiazolo-3-thiones gave thiocarbamoyl isothiocyanates (304). Other thioureas have been obtained by thermolytic decarbonylation of 2-amino-5(4H)-thiazolones and by treatment of 4,5,6,7-tetrahydro-cyclopenta-l,3-dioxin-4-one" and 3-nitrophthalic anhydride with thiourea. ... 

Condensation of 165 with ethoxymethylenemalononitrile gave 171, and with ethyl ethoxymethylenecyanoacetate or methyl bis(methylmercapto)-methylene cyanoacetate it yielded 172 (80AP108). The reaction of 172 with urea, thiourea, and benzyl nitrile afforded 173 (91PHA98). Treatment of hydrazino derivatives 165 with alkyl, aryl, or aralkyl isothiocyanates yielded (86JHC1731) 3-(/V-substituted-thiocarbamoyl)-hydrazino[l,2,4]triazino[5,6-b]indoles which have been evaluated for in vitro antimicrobial activity (Scheme 36). 

An acylation on the thiophene ring occurs when 58 is allowed to react with either acetyl isothiocyanate or phenyl isothiocyanate to form the corresponding thiocarbamoyl derivatives 59a and 59b, respectively (Equation 23) <1997IJB612>. 

Isothiocyanates react with many nucleophiles, but only the products with amines (thiocarbamoyl derivatives) are stable.16 Although the increased specificity is desirable, the reaction with the amino group changes the charge on the protein, and this may be needed in order to maintain the activity or the conformation, or both. The linkage formed is alkali-labile, and, as with the azo derivatives, the aromatic ring is a liability. 

Thiazetidines may be prepared by alkylation of the sodium salts obtained conveniently by thiocarbamoylation of the sulfonamides 191 with isothiocyanates in the presence of sodium hydride in DMF. Alkylation with bromo-chloromethane or dibromomethane yields the substituted 2-imino-l,3-thiazetidines 41 <2002SUL105>. 

Phenoxyacetophenone was thiocarbamoylated by treatment with phenyl isothiocyanate in the presence of potassium /frt-butoxide and methyl iodide to afford 1,3-thiazetidine derivative 192 in 28% yield <1996SUL1> (Scheme 62). 

Thiocarbamoylation of malonic acid derivatives with phenyl isothiocyanate gives the sodium salts 193 which are not isolated. Alkylation of these salts in situ using dibromomethane or bromochloromethane yields the 1,3-thiazetidine derivatives 40 (Scheme 63) <2005MI499>. 

Bromoethylamine (460) reacts with methyl isothiocyanate (461) giving an intermediate thiazolidine (462) which adds further to methyl isothiocyanate yielding the 3-AT-methyl-thiocarbamoyl-2-methyliminothiazolidine (463 Scheme 261). The interaction of 2-... 

Azine approach. 6-Aminouracils are attacked by electrophiles at C-5. With an isothiocyanate as electrophile a thiocarbamoyl derivative (156) is formed which undergoes oxidative cyclization. Sometimes a minor product, the thiazole (158), may be formed via the thiourea intermediate (157). The course of the reaction may perhaps be rationalized on the HSAB principle the hard iso thiocyanate electrophile has to choose between the hard nucleophilic centre at C-5 or the soft nucleophilic centre at 6-NH2. Isothiocyanates of aminosugars have also been used in these reactions (79CPB1147). 

A new synthetic route to tetraaminoethene derivatives developed by Gorls and coworkers95 involves a reduction/substitution sequence the oxalic amidines, 123, were reduced with lithium under sonication affording 124, and the subsequent addition of phenyl isothiocyanate, 125, afforded the anionic bis(thiocarbamoyl) derivatives 126. Treatment of 126 with methyl iodide gave, in a nearly quantitative yield, the isothiourea derivative 127 (Scheme 40)96. 

Additions of hydrazoic acid to carbon-sulphur double bonds may conceivably be of the general type outlined in equation (88) but do not constitute a synthetic route to azides. Recent corrections to the earlier literature relating to this field are, however, noteworthy. It was originally suggested that thiocarbamoyl azides " (193) were obtained from organic isothiocyanates and hydrazoic acid. The spectroscopic studies of Lieber and co-workers " have now established that the products are in fact thiatriazoles (194). The reactions of sodium azide with isothiocyanates , and carbon disulphide , which were also previously considered to furnish organic azides, have now been shown to produce the heterocyclic compounds 195 and 196 respectively. 

Other preparative routes to isothiocyanates involve reaction of amines with carbon disulfide and alkali and subsequent treatment of the dithiocarbamate (112) with phosgene or ethyl chloroformate. Alternatively, the dithiocarbamate may be reacted with mercury(II) chloride or lead tetranitrate (Scheme 61). Amines can also be reacted with thiophosgene or N,N-diethyl thiocarbamoyl chloride (113) (Scheme 61). 

It appears quite probable that this reaction occurs by the same mechanism as the reaction of nitrous acid with thiosemicarbazides and of sodium azide with isothiocyanates. The primary reaction product is a thiocarbamoyl azide (CCXIII) to which, however, the cyclic structure of a 5-amino-l,2,3,4-thiatriazole (CCXIV) is attributed. In alkaline medium these compounds rearrange to the corresponding 1 -substituted-Zla-tetrazoline-5-thiones (CCXII) 236, 237). A survey of these compounds, prepared from the dithiocarbamic acid esters, is given in Table 33. 

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