Thioureas acylation

Reaction of 2-aminothiazoles with alkyl isocyanates yields 2-thiazolylureas (256) (Scheme 153) (479-483). This reaction is general and works with acyl isocyanates (484. 485). These heterocyclic ureas are also prepared by the reaction of H2O on 2-thia2olylcyanamide (486) or by action of HjOj on the corresponding thiourea (303, 481). 

N-monosubstituted thioureas also react with a-haJoacids or esters to give stable compounds of type 126, in which R is aryl or acyl. When R is alkyl such as an allyl group (85), isomer 125 is formed (Scheme 60). 

Disubstitution of 2,4-dichloropyrimidine with thiourea proceeds more readily than with hydrosulfide ion, principally because the former intermediate (229) contains the activating, cationic acylated thio group compared to the highly anionized mercapto group in the latter reaction. 

Although the antithyroid activity of compounds incorporating an enolizable thioamide function was discussed earlier, this activity was in fact first found in the pyrimidine series. The simplest compound to show this activity, methylthiouracil (80) (shown in both enol and keto forms), is prepared quite simply by condensation of ethyl acetoacetate with thiourea.Further work in this series shows that better activity was obtained by incorporation of a lipophilic side chain. Preparation of the required dicarbonyl compound starts with acylation of the magnesium enolate of the unsyrametrically esterified malonate, 81, with butyryl chlo-... 

In a typical synthesis, reduction of the nitro group in starting material 75 leads to the corresponding diamine 76. Reaction with intermediate 11 obtained by acylation of the methyl ether of thiourea with methyl chioroformate, leads directly to fenbendazole (78). ... 

An acylated glycosyl halide, such as a 2,3,4,6-tetra-O-acetyl derivative, is treated with thiourea. The resulting pseudothiouronium salt is hydrolyzed with aqueous potassium carbonate to give the 2,3,4,6-tetra-0-acetyl-l-thio-(3-D-glucopyranose,48 which then is alkylated. 

Chemical synthesis and characterization of palm oil-based difatty acyl thiourea. Journal of Oleo Science 59, 229-233. 

Some chiral mono-, acyl- and di-thioureas have been used as ligand for the Rh-catalysed asymmetric hydroformylation of styrene. Although thiourea ligands form inactive systems with [Rh(COD)Cl]2 as the catalyst precursor, in standard conditions (40 °C, 40 bar CO -l- H2 1/1), the cationic Rh complex [Rh(COD)2]Bp4 combined with monothioureas as the ligand showed moderate to good activity (Scheme 29) [114]. 

Koch, K. R. Sacht, C. Grimmbacher, T. Bourne, S. New Ligands for the platinum-group metals deceptively simple coordination chemistry of N-acyl-N -alkyl and N-acyl-N, N -dialkyl-thioureas. S. Afr. J. Chem. 1995, 48, 71-77. 

Koch, K. R. New chemistry with old ligands N-alkyl- and N,N-dialkyl-N -acyl(aroyl)thioureas in co-ordination, analytical and process chemistry of the platinum group metals. Coord. Chem. Rev. 2001, 216, 473 188. 

Reactions of (benzotriazol-l-yl)carboximidamides and acyl- or arylamino-carbonyl(benzotriazol-l-yl)carboximidamides with hydrogen sulfide give the corresponding thioureas and tV-acylthioureas or tV-carbamoylthioureas, respectively (Scheme 47).128... 

The cyclizations to obtain cyclic thioureas have been performed using thiocarbonyldiimidazole.232 Reaction of methyl acetoacetate, thiourea and an aliphatic aldehyde in the presence of the zinc iodide (Znl2) was studied. Under the normal pressure, reaction has not been occurred whereas at high pressure (300 MPa) conditions 3,4-dihydropyrimidine-2-thione was obtained only in 10% yield.233 The same one-pot three-component cyclocondensation reaction in the presence of iodide (I2) provides a variety of 3,4-dihydropyrimi-dine-2-thione in high yields.234 Condensation reaction of thioureas with a,p-unsaturated ketones in the presence of the sodium methoxide in methanol affords 3,4-dihydropyrimidine-2-thione derivatives.235,236 Acylation of N,N -disubstituted thioureas with methyl malonyl chloride followed by base-catalysed cyclization leads in the formation of l,3-disubstituted-2-thiobarbituric acids (Scheme 78).237... 

The reactions of 5-acyl-2,2-dimethyl-4,6-dioxo-l, 3-dioxanes (1373) with urea, thiourea, sulfamide, hydroxylamine, or 1-substituted hydrazines gave monocyclic six- and five-membered heterocycles (1374-1378) in good yields [79JAP(K) 106466],... 

The acyl-Pictet-Spengler reaction is also catalyzed by chiral thiourea derivative 6 to provide M-acetyl p-carbolines in high enantioselectivities. Notably, thiourea derivatives can activate not only electronically distinct imine derivatives such as N-alkyl and N-Boc imines but also a weakly Lewis basic N-acyhminium ion with high enantioselectivity using a chiral hydrogen bond donor (Scheme 12.4). 

The Pictet-Spengler reaction is the method of choice for the preparation of tetrahydro-P-carbolines, which represent structural elements of several natural products such as biologically active alkaloids. It proceeds via a condensation of a carbonyl compound with a tryptamine followed by a Friedel-Crafts-type cyclization. In 2004, Jacobsen et al. reported the first catalytic asymmetric variant [25]. This acyl-Pictet-Spengler reaction involves an N-acyliminium ion as intermediate and is promoted by a chiral thiourea (general Brpnsted acid catalysis). 

When the 3-thiourea derivative (59) was heated in boiling ethanol for 3 h, and then the evaporated reaction mixture was treated with 10% NaOH solution at 100°C for 20 min, anhydro 2-methyl-3-mercapto-4-hydroxy-5,6,7,8-tetrahydro[l,2-6]pyridazinium hydroxide (61) was obtained (71CPB159). The mercapto group was alkylated with benzyl bromide and was treated with HgCla in boiling ethanol to yield the 3-chloromercurithio derivative. Anhydro 3,4-dihydroxy-2-methyl-5,6,7,8-tetrahydropyrido[l,2-f ]pyridazinium hydroxide (62) was O-acylated with acetic anhydride, but the structure of the product was not elucidated (71CPB159). 

An analogous sequence leads to the anthelmintic agent, etibendazole (50). Reaction of the benzophenone 47, which can be obtained by acylation of g-nitroaniline with p-fluorobenzoyl chloride, with ethylene glycol leads to acetal 48. Sequential reduction of the nitro group and cyclization of the resulting diamine (49) with N,N-dicarbomethoxy-S-methyl thiourea gives the benzimidazole etibendazole (50) fl6]. 

Acetazolamide Acetazolamide is 5-acetamido-l,3,4-thiadiazole-2-sulfonamide (9.7.5). The synthesis of acetazolamide is based on the production of 2-amino-5-mercapto-l,3, 4-thiadiazole (9.7.2), which is synthesized by the reaction of ammonium thiocyanate and hydrazine, forming hydrazino-N,N -( ji-(thiourea) (9.7.1), which cycles into thiazole (9.7.2) upon reaction with phosgene. Acylation of (9.7.2) with acetic anhydride gives 2-acetylamino-5-mercapto-l,3,4-thiadiazol (9.7.3). The obtained product is chlorinated to give 2-acetylamino-5-mercapto-l,3,4-thiadiazol-5-sulfonylchloride (9.7.4), which is transformed into acetazolamide upon reaction with ammonia (9.7.5) [24,25]. 

Most of the now synthetically used quantitative cascade reactions involve an initial substitution step. That is quite clear for the reactions of acyl hahdes with thioureas to give 2-aminothiazoliiun salts. The 3-cascade consists of substitution to form the thiuronium salt, specific cychzation with the more nucleophihc of the amino groups, and elimination of water. In all reported cases, the water of reaction is taken up by the product crystal and it can be removed by heating to about 80 °C in a vacuiun. For example, if the thioureas 162 and phenacyl bromide 217 are stoichiometrically ball-milled at room temperature for 30 min, quantitative yields of the pure products 428 are obtained in all cases after drying at 0.01 bar at 80 °C [ 10] (Scheme 67). The free bases 429 can be obtained by trituration of 428 with NaHCOj solution. Furthermore, the thioureido-acet-amides 275 react correspondingly with 217 to give quantitative yields of the salts 430 from which the free bases can be obtained by NaHCOj trituration [96]. 

Pyrrole-containing thiourea derivatives 52 and 53 were developed and optimized for hydrogen-bonding activation of N-acyliminium ions [76] in the acyl-Pictet-Spengler [202, 205] (Schemes 6.50 and 52) and acyl-Mannich reaction [204] (Scheme 6.51). List et al. extended the applicability of this thiourea type to... 

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