Preparations of Isothiocyanates

Preparation of Isothiocyanates.—A conventional synthetic method is illustrated in the preparation of AT-(isothiocyanato-acyl)-amino-acids, e.g. S C N (CH2) C0 NHCHR C02H, starting from the peptide trimethyl-silyl ester treatment with CSg and an alkyl chloroformate gives an alkoxycarbonyl dithiocarbamate which readily cyclo-eliminates COS and alkanol. Acylation of an amino-acid trimethylsilyl ester with SCN--(CH2) C0 C1 provides an alternative route cyclization of an a-isothio-cyanato-acid (158) to a 2-thio-oxazolidone (159) occurs readily in solution,  

A novel pyrolysis sequence (161) - (162) - MeNCS has been studied the overall reaction is brought about at lower temperature (100 C) with the N-phenyl analogue of (161). 

Boerma-Markerink, J. C. Tagt, H. Meyer, J. Wildeman, and A. M. van Leusen, Synth. Comm., 1975, 5, 147. 

Although a good deal of variety in structure is conceivable with bifunctional isothiocyanates, preparative methods are generally routine. An example is the conversion of ClaFCSCl through several steps into ClaFCSNCS.  

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Altanserin (100) is a representative of the thiaquinazolinones. This serotonin antagonist is said to prevent gastric lesions. One method for preparation of this compound involves first preparation of isothiocyanate derivative 99, by reacting 4-fluorobenzoylpiperidine with 2-bromoethylamine and then converting the intermediate to the isothiocyanate with thionyl chloride and base. Condensation of 99 with methyl anthranilate (98) probably proceeds initially to a thiourea. Cyclization by ester-amide interchange leads to altanserin (100) [28]. 

A preponderance of the transition-metal pseudohalogen complexes reported in the literature are prepared in aqueous media. Several oxidation states of many transition metals are either unstable in the presence of water or form only oxygen-coordinated species. Thus, these metal ions will not form pseudohalogen complexes in the normal manner. The following method, using polar, nonaqueous solvents is suitable for the preparation of isothiocyanate complexes of several of these ions. As an example of the preparation of such complexes, the synthesis of potassium hexakis(isothiocyanato)niobate(V) is described. 

Dithiocarbamic salts are suitable starting materials for the preparation of isothiocyanic esters (mustard oils), their reactions with heavy-metal salts,771 chloroformic esters,772 phosgene,768 carbodiimides,805 phosphorus oxychloride,806 aryl cyanates,732 or sodium hypochlorite807 usually giving good yields. Reaction of amines 808,809 or their hydrochlorides with thiophosgene810 is also generally applicable. 

Preparation of isothiocyanic esters from dithiocarbamic salts ... 

Treatment of triethylammonium dithiocarbamates with a 2-chloro-l-methyl-pyridinium salt provides a convenient method for the preparation of isothiocyanates (Scheme 24), °... 

Preparation of Isothiocyanates. Ethoxycarbonyl isothiocyanate (18), useful as a synthetic reagent for heterocyclic syntheses, can be prepared in excellent yield from the reaction of ethyl chloroformate (16) with sodium thiocyanate (17) using quinoline as a base catalyst (eq 9). Only trace amounts of the isomeric thiocyanates are formed in the reaction. In the absence of the base catalyst, only a moderate (65%) yield of the desired product is obtained, along with significant (10%) contamination by the isomeric ethoxycarbonyl thiocyanate. Pyridine can also be used as the catalyst here however, it reacts faster, which sometimes leads to undesired byproduct formation. 

Indeed, this transformation has been developed into a procedure for the preparation of isothiocyanates from primary amines using hydrogen peroxide as the dehydrosulfurization reagent. It proceeds via the thiuram disulfide, although concentrations of the latter are always kept low (Fig. 8) (85). 

Figure 8. Proposed route for the preparation of isothiocyanates from primary amines.

Classically, perhaps the most widely used method for the preparation of isothiocyanate involves the reaction of amines with carbon disulfide in the presence of a base such as ethanolic aqueous ammonia or sodium hydroxide to form the appropriate salt of a dithiocarbamate. The conversion of a dithiocarbamate to an isothiocyanate may be carried out by a variety of reagents such as copper sulfate, ferrous sulfate, zinc sulfate, or lead nitrate. A procedure involving the use of lead nitrate for the general preparation of isothiocyanates has been described. This reaction involves the reactions shown in Eqs. (15) and (16). 

A quite general reaction for the preparation of isothiocyanates involves the use of thiophosgene. Since this material is a liquid, its handling is somewhat simpler than that of phosgene used in the synthesis of isocyanates. Its toxicity is believed to be as great as that of phosgene, if not greater. 

Preparations of Isothiocyanates.—Preparations from isocyanides have been studied by several groups, showing that aryl isocyanides with elemental... 

The HSAB pattern may also be reversed by steric effects a Japanese patent describes the preparation of 3-(4-R-thiazolyl-2)thioallophanic acid esters (151) by reaction between 2-amino-4-R-thiazoles (4-R = H or low alkyl) and isothiocyanate formic acid ester (Scheme 96) (309). 

Substitution of alkaline cyanates by isocyanates allows the preparation of 3-substituted hydantoias, both from amino acids (64) and amino nitriles (65). The related reaction between a-amino acids and phenyl isothiocyanate to yield 5-substituted 3-phenyl-2-thiohydantoiQS has been used for the analytical characterization of amino acids, and is the basis of the Edman method for the sequential degradation of peptides with concomitant identification of the /V-terminal amino acid. 

Thioureas give thioxo analogues of a variety of the above syntheses (52JOC542), although these thioxo products are usually prepared from isothiocyanates (Section 2.15.5.2.1). Examples are known in the pyrido-[2,3-[Pg.225]

The method is generally applicable to the preparation of aryl isothiocyanates. Using this procedure, the submitters have prepared the following isothiocyanates, with the yields and times of refluxing indicated phenyl, 44%, 8 hours o-chlorophenyl, 46, 8 -bromophenyl, 73, 8 j>-biphenylyl, 49, 6 /3-naphthyl, 70, 10 9-phenanthryl, 70, 10 1-pyrenyl, 72, 10. 

The reaction of the enamines of cyclic ketones with alkyl isocyanates, acyl isocyanates, phenyl isothiocyanates, and acyl isothiocyanates has also been reported 112). The products are the corresponding carboxamides. The products from the isothiocyanates have been utilized as intermediates in the preparation of various heterocyclic compounds 113). 

Further investigation on this type of thiazole synthesis in subsequent years led to the preparation of 5-aminothiazoles in which the 2-position was varied through reaction of the aminonitrile with salts and esters of dithioacids, carbon disulfide, carbon oxysulfide, and isothiocyanates. 

It is worth noting that the 2-pyridone 42 (99MI1) and thione 43 (88H(27)733), which could react in either of the two ways as shown, with an isocyanate or isothiocyanate and with a nitrile respectively, actually give a one-carbon insertion. There is a case of formation of 2,3 and 3,4 bonds in the preparation of 8-hydroxy-triazolopyridine 44 (83MI1). 

There is virtually no recent literature on quinoxaline cyanates or isocyanates, and most of what little there is on quinoxaline thiocyanates, isothiocyanates, or nitrones has been covered already the preparation of thiocyanatoquinoxalines from halogenoquinoxalines (Section 4.4.1) the conversion of the thiocyanatoquinoxalines into alkoxyquinoxalines (Section 4.4.1), into quinoxalinethiones (Section... 

Ammonia and primary and secondary amines can be added to isocyanates to give substituted ureas. Isothiocyanates give thioureas. This is an excellent method for the preparation of ureas and thioureas, and these compounds are often used as derivatives for primary and secondary amines. Isocyanic acid (HNCO) also gives the reaction usually its salts (e.g., NaNCO) are used. Wohler s famous synthesis of urea involved the addition of ammonia to a salt of this acid. "... 

Most 1,3-diazepine syntheses employ the insertion of a single carbon fragment between the two nitrogen atoms. This is further exemplified by the use of tosyl isocyanate and methyl isothiocyanate in the preparation of the bicyclic imidazo[4,5-e][l,3]diazepines 46 and the imidazo[4,5-rf][l,3]diazepines 47 respectively <96JHC855, 96JCS(P1)2257>. 

A recent paper from Katritsky summarises all the preparations of achiral dissymmetrical thioureas and proposes a new one, based on l-(alkyl/arylthio-carbamoyl)benzotriazoles, which act as masked isothiocyanates. As described in the previous section, other N-heterocyclic derivatives can be used instead... 

Fehlhammer, W. P. et al., Z. Naturforsck, 1983, 38B, 547 In the first stage of the preparation of bis(triphenylphosphine)palladium(II) isothiocyanate, a large deficiency of aqueous palladium nitrate must be added with rapid stirring to an excess of sodium azidodithioformate solution to avoid the precipitation of explosive palladium(II) azidodithioformate. 

Fig. 20.1. Confocal images of whole mounts of the ovijector region of A suum stained with phalloidin-tetramethylrhodamine isothiocyanate (TRITC) to show muscle and with an anti-RFamide antiserum coupled to fluorescein isothiocyanate (FITC) to show FaRPergic nerves. (A) Main ventral nerve cord encircles opening of ovijector where it meets the body wall and is immunopositive for FaRPs. (B) Flat-fixed preparation of the ovijector showing circular muscles and tracts of parallel FaRPergic nerves (arrows). (C) Detail of the circular muscle of ovijector and associated nerves (arrows). (D) A FaRPergic cell body is localized in the ventral nerve cord at junction with ovijector and provides innervation to ovijector muscle.

A straightforward preparation of pyrimidinones and pyrimidinethiones 45 involved reaction of isocyanates or isothiocyanates with the readily available starting material 44, which had previously been described by the same authors. A particularly interesting application was the use of sugar isothiocyanates to give nucleosides. Nucleophilic displacements of the sulfur groups in the products were also reported <06EJO634>. 

In the preparation of 15 nm core-shell fluorescent silica particles, Ow et al. (2004) reported that the naked core (2.2 nm) alone produced a fluorescence intensity of less than the free dye in solution, presumably due to dye quenching. However, upon addition of the outer silica shell around the core, the brightness of the particles increased to 30 times that of the free dye (using tetramethylrhodamine-5-(and 6)-isothiocyanate (TRITC)). They speculate that shell may protect the core from solvent effects, as evidenced by a lack of spectral shift upon changing the solvent in which the particles are suspended. 

Yen and Chu subsequently also disclosed a related Pictet-Spengler reaction involving tryptophan and ketones for the preparation of 1,1-disubstituted indole alkaloids [417]. In the approach shown in Scheme 6.234, tryptophan was reacted with numerous ketones (12 equivalents) in toluene in the presence of 10 mol% of trifluoroacetic acid catalyst. Using microwave irradiation at 60 °C under open-vessel conditions, the desired products were obtained in high yields. Compared to transformations carried out at room temperature, reaction times were typically reduced from days to minutes. Subsequent treatment with isocyanates or isothiocyanates led to tetrahydro-/8-carbolinehydantoins. 

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