Phenylthiourea

Submitted by Robert L. Frank and Pawl V. Smith. Checked by Richard T. Arnold and Sherman Sundet. 

In a 500-ml. three-necked flask fitted with a reflux condenser, a mechanical stirrer, and a 100-ml. dropping funnel are placed 17 g. (0.22 mole) of ammonium thiocyanate and 100 ml. of dry acetone (Note 1). Through the dropping funnel is added, with stirring, 28.2 g. (0.2 mole) of benzoyl chloride. After the addition is complete, the mixture is refluxed for 5 minutes. Then a solution of 18.6 g. (0.2 mole) of aniline in 50 ml. of dry acetone is added at such a rate that the solution refluxes gently. The mixture is poured carefully with stirring into 1.5 1. of water, and the resulting yellow precipitate (a-benzoyl- 8-phenylthiourea) is sepa- 

The acetone is dried for at least 48 hours over anhydrous calcium sulfate (Drierite) and distilled just before it is used. 

The preparation of a-phenylthiourea by the procedure described herein has not been reported, although Douglass and Dains have applied the method to the preparation of various substituted phenyl derivatives. 

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Add 0 -5 ml. of phenyl isothiocyanate to the distillate and shake the mixture vigorously for 3-4 minutes. If no derivative separates, crystallisation may be induced by cooling the flask in ice and scratching the walls with a glass rod. Filter off the crude product, wash it with a little 50 per nent. ethanol, and recrystaUise from hot dilute alcohol. (See Table 111,123 for melting points of phenylthiourea derivatives of amines.)... 

Phenylthioureas. Primary and secondary amines react with phenyl isothiocyanate to yield phenylthioureas ... 

Phenylthioureas. Experimental details are given under Aliphatic Amines, Section 111,123, 2. 

Several aspects affect the extent and character of taste and smell. People differ considerably in sensitivity and appreciation of smell and taste, and there is lack of a common language to describe smell and taste experiences. A hereditary or genetic factor may cause a variation between individual reactions, eg, phenylthiourea causes a bitter taste sensation which may not be perceptible to certain people whose general abiUty to distinguish other tastes is not noticeably impaired (17). The variation of pH in saUva, which acts as a buffer and the charge carrier for the depolarization of the taste cell, may influence the perception of acidity differently in people (15,18). Enzymes in saUva can cause rapid chemical changes in basic food ingredients, such as proteins and carbohydrates, with variable effects on the individual. 

Whatever the physiology of odor perception may be, the sense of smell is keener than that of taste (22). If flavors are classed into odors and tastes as is common practice in science, it can be calculated that there are probably more than 10 possible sensations of odor and only a few, perhaps five, sensations of taste (13,21,35—37). Just as a hereditary or genetic factor may cause taste variations between individuals toward phenylthiourea, a similar factor may be in operation with odor. The odor of the steroid androsterone, found in many foods and human sweat, may eflcit different responses from different individuals. Some are very sensitive to it and find it unpleasant. To others, who are less sensitive to it, it has a musk or sandalwood-like smell. Approximately 50% of the adults tested cannot detect any odor even at extremely high concentrations. It is befleved that this abiUty is genetically determined (38). 

I-Cyano-3-phenylurea, first obtained by the alkaline hydrolysis of 5-anilino-3- -toluyl-l,2,4-oxadiazole, has been prepared by tlic condensation of phenyl isocyanate and the sodium salt of cyanamide. However, in these publications an incorrect structural assignment for the product was made. 1-Cyano-3-phenyl-urea is obtained also, together with other products, by warming gently l-cyano-3-phenylthiourea with caustic soda in the presence of ethylene chlorohydrin, or by gradually adding caustic )otash to a boiling solution of 1-phenyldithiobiuret and ethylene clilorohydrin in ethanol. ... 

N— compounds used as acid inhibitors include heterocyclic bases, such as pyridine, quinoline and various amines. Carassiti describes the inhibitive action of decylamine and quinoline, as well as phenylthiourea and dibenzyl-sulphoxides for the protection of stainless steels in hydrochloric acid pickling. Hudson e/a/. refer to coal tar base fractions for inhibition in sulphuric and hydrochloric acid solutions. Good results are reported with 0-25 vol. Vo of distilled quinoline bases with addition of 0 05m sodium chloride in 4n sulphuric acid at 93°C. The sodium chloride is acting synergistically, e.g. 0-05m NaCl raises the percentage inhibition given by 0-1% quinoline in 2n H2SO4 from 43 to 79%. Similarly, potassium iodide improves the action of phenylthiourea . 

Nucleophilic addition of the peptide terminai amino group to p nenyi isothiocyanate (PITC) gives an /V-phenylthiourea derivative. 

Acid-catalyzed cyctization of the phenylthiourea yields a tetrahedral intermediate. .. 

There are amines such as A-methylnitroamine, that are too weakly nucleophilic to be able to form covalent adducts with arenediazonium ions. The products of the latter appear to be those of salts ArNJ N(N02)CH3, as found by Baranchik et al. (1957). Amides also appear not to be sufficiently nucleophilic, but thioamides are, as is shown by the reaction of A-phenylthiourea in the presence of NaOH (Scheme 13-12 Nesynov et al., 1970). First a (probably homolytic) phenylation-de-diazoniation takes place, followed by A-coupling. Selenourea also reacts a mixture of products is formed, which indicates a reaction of the same type as with thiourea (Nesynov and Aldokhina, 1976). 

One group which could have utility in this context is the thiourea group (Fig. 17). Unfortunately, repeated attempts to generate the dianion via directed lithiation of A(,-dimethyl-Ar-phenylthiourea were unsuccessful. Again, bromo compounds came to the rescue. The 2-bromo derivative could be deprotonated (N-... 

The dearrangement of phenylthiourea may be demonstrated very simply by heating a small quantity of the material in a test-tube. It undergoes a violent decomposition slightly above its melting-point, the odors of ammonia, of aniline, and of phenyl mustard oil may be detected, and the residue which consists largely of sym.-diphenylthiourea gives with ferric chloride the a ed color characteristic of thiocyanic acid. 

The ligands N-[bis(isopropoxy)thiophosphoryI]thiobenzamide and N-[bis(isopro-poxy)thiophosphoryl]-N -phenylthiourea can be deprotonated with the acetylacetonate gold(III) derivative [Au(C6F5)2(acac)] [26] giving the corresponding pentafluorophenyl complexes with the ligand acting as a chelate one [192]. 

Substituted thioureas have been extensively studied over the decades. Reaction of CoX2 (X = C1, Br) with substituted phenylthioureas yield a range of complexes involving halide and thiourea as ligands, characterized by spectroscopy and thermogravimetric analysis.503 Both [Co(Rtu)4(OH2)2]2+ (Rtu = thiourea, phenylthiourea, allylthiourea) and [Co(Rtu)2(OH2)4]2+ (Rtu = diphenylthiourea) have been prepared and characterized as low-spin octahedral species.504 The octahedral bis(phenylthiourea)bis(dithiolate)cobalt(II) complex, one of a number of complexes of phenylthiourea, chlorophenylthiourea and bis(diphenylphospinothioyl)methane prepared and characterized,505 proved the most biologically active of those tested. 

An improved procedure for preparing urea derivatives involves reaction of isocyanates or isothiocyanates with 4(5)-aminoimidazole (25 R = H) in tetrahydrofuran solution [92JCS(P1)2779]. A THF solution of 4(5)-aminoimidazole (25 R=H) generated in situ and then treated with the appropriate reagent gave either lV-imidazole-4-yl-AT-phenylurea (56 X = 0) (32%) or AT-imidazoM-yl-A/ -phenylthiourea (56 X = S) (21%). 

The oxidation of acetylthiourea and phenylthiourea to afford the corresponding 1,2,4-thiadiazoles has been reported using [bis(acyloxy)iodo]arenes as the oxidants. The proposed mechanism involves the formation of a polyvalent iodine compound 74. After the elimination of iodobenzene, the 1,6-dip he nyl-dithioformamidine 75 is formed, which is set up to undergo a further oxidation to give the bis 3,5-diamino-l,2,4-thiadiazole 76 (Scheme 7) <2003T7521>. 

A series of 1-aminoalkanediphosphonic acids has been reported by the treatment of the N-phenylthiourea derivatives of a>-diethoxyphos-phinoylaldehydes with triphenyl phosphite.343 This constitutes an approach toward the analogues of aspartic and glutamic acid in which both carboxylate sites have been replaced by phosphonic acid functions. A similar approach has also been reported to be of use for the preparation of (diphenyl ester) phosphonate analogues of ornithine, lysine, and homolysine.344345... 

To a solution of triphenyl phosphite (6.2 g, 0.02 mol) and thiomethoxy-acetaldehyde (2.25 g, 0.025 mol) in glacial acetic acid (18 ml), powdered N-phenylthiourea was added in a single portion. The reaction mixture was stirred at room temperature for 30 min and then for 30 min at 80°C. After the mixture was cooled to room temperature, water (5 ml) was added and the solution was maintained at room temperature for 10 h. The precipitate was removed by suction filtration, washed with 1 1 acetic acidtwater (2 x 10 ml), dried over potassium hydroxide in an evacuated dessicator, and recrystallized from chloroform/ methanol. In this manner there was isolated pure 0,0-diphe-nyl 2-methylthio-l-(iV-phenylthioureido)ethylphosphonate (8.61 g, 94%) of mp 136 to 138°C, which exhibited spectra and analytical data in accord with the proposed structure. 

Pedersen (1971) reported on a number of crystalline complexes with thiourea and similar molecules and found that the solubility of dibenzo-18-crown-6 [11] in methanol is enhanced by urea and thiourea. The latter observation precludes the possibility of the solid complexes being urea or thiourea inclusion compounds. Factors that are of importance in the complex formation are ring size (dibenzo-12-crown-4 did not form complexes), and steric hindrance in the complex caused by the guest molecule. Thiourea, N-phenylthiourea, and 2-thiazolidinethione form complexes but N,N,N -trimethylurea, thiocarbanilide and N-methylthiazolidinethione do not. 

The conversion of symmetrical into unsymmetrical thioureas is exemplified by the formation of Af-cyclohexyl-Af -phenylthiourea when yV,iV-diphenyl thiourea is heated with cyclohexylamine and triethylamine in acetonitrile367. Carbonylation of lithium piperidide in the presence of tellurium generates the lithium carbamotellurate 307, which is trapped as the 7V-ethyl carbamotellurate 308 by ethyl bromide368. 

The preparation of phenylguanidine from ammonia and phenylthiourea was claimed [112] in 1879 but the authenticity of the product has been questioned... 

S- and Se-donor ligands. The e.s.r. and electronic spectra of [Co(sacsac)2] and [Co(sacsac)2L] (sacsac = dithioacetylacetonate, L = py or piperidine) have been studied, and a polarographic study of [Co(sacsac)J (n = 2 or 3) in acetone has shown the complexes to have a well-defined capacity to accept one or two electrons in a reversible stepwise manner. The magnitude of the potentials and their reversible nature suggest that isolation of cobalt-sacsac complexes of low formal oxidation states should be possible." Co complexes of l,5-bis-(2-methylmercaptoethylthio)pentane are both hydrated and polymeric, and thermal decomposition in air or nitrogen leads to oxida tion to Co . Ethylenethiourea (etu) and tetramethylthiourea (tmtu) form the complexes [Co(etu) ](N03)2 and [Co(tmtu) ](C10 )2, which are tetrahedral, and [Co(etu)2(N03)2] and [Co(tmtu)2(N03)2] which have distorted octahedral co-ordination. 3-Diphenylphosphinothioyl-l-phenylthiourea, -1,1-diethyl-thiourea, and -1,1-dimethylthiourea form complexes with Co in which the ligands are bidentate. ... 

A reducing reagent such as DTT or 2-ME can be used instead of phenylthiourea. 

The Co(II) -phenylthiourea-borax buffer system has been studied applying CSV at HMDE [69]. An irreversible peak observed at —1.5 V was attributed to the catalytic hydrogen evolution. The first reduction step, combined with the adsorptive accumulation of herbicide metribuzin at mercury electrode, has been used for its determination by adsorptive stripping voltammetry [70]. 

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