Benzimidazole isothiocyanate

The dibromo derivatives 125a and 126a have been prepared by reaction of the unsubstituted amine 125c and the methanesulphonate salt of 126c with excess bromine in acetic acid. Amines 125b and 126b have been converted to the isothiocyanates 125 and 126 by reaction with thiophosgene in a biphasic chloroform-bicarbonate system. The radiochemical purity and the specific radioactivity of the isothiocyanate 125 were 99.9% and 27.4 Ci mmol -1, respectively. The benzimidazole isothiocyanate 126 has been prepared with >95% radiochemical purity and with specific activity of 16.3 Ci mmol -1. 

The cyclization to the desired head-to-tail linked bis-benzimidazoles could also be performed utilizing aryl or alkyl isothiocyanates with N, N -dicyclohexylcarbodiimidc (DCC) [82]. Upon completion, the insoluble N,N -dicyclohexylthiourea formed had to be removed by filtration and the desired PEG-bound products were precipitated by the addition of diethyl ether. The results were essentially the same as those of the cyclizations with the above mentioned aldehydes. 

Carbon disulfide, the all sulfur equivalent of isothiocyanates, was found to react with benzimidazole 127 very rapidly under microwave irradiation to produce 128 <00TL5857>. 

Triazines now are widely used as pesticides. Scheme 107 shows one approach to this class of compounds, which consists in the conversion of the iminophosphorane of 2-aminobenzimidazole (301). After alkylation of the benzimidazole ring, treatment with two equivalents of isothiocyanate affords cyclization to l,3,5-triazino[l,2-a]benzimidazole (302) (92S297). 

Bis(benzimidazol-2-yl)disulfide (214) treated with phenyl isothiocyanate gives the 1,2,4-dithiazole derivative (215) as a result of electrophilic attack by the isothiocyanate group on the nitrogen atom... 

In general, benzimidazole-2-methyl carbamate derivatives (28) can be synthesized by the reaction of an appropriate diamine (26) with 1,3-dicarbo-methoxy-5-methylisothiourea (27) [43], This is the most general and economic synthesis for benzimidazole carbamates. However, the same reaction was less than satisfactory when the aza analogues of o-phenylenediamines (29) were used. In order to synthesize the aza analogues of mebendazole (2) or flubendazole (3), the reactions of methoxycarbonyl isothiocyanate (30) with a wide variety of diamines such as 3,4-diaminopyridines, 4,5-diaminopyrimi-dines, o-phenylenediamines have been investigated in the presence of dicyclo-hexylcarbodiimide [44, 45] and were found to be quite successful in the synthesis of carbamates (31). 

A library of 2-(arylamino)benzimidazoles was prepared in a microwave-accelerated cyclocondensation of PEG-supported orffto-phcnylenediamines 31 with isothiocyanates, followed by the product cleavage from polymer support [55,56]. The quantitative cyclization required either microwave heating (in an open vessel system) for 10 min or reflux in MeOH for 4 hours (Scheme 20). The use of a soluble PEG matrix substantially simplified the... 

It is a general rule that imidazoles and benzimidazoles are resistant to Friedel-Crafts reactions. This is not surprising since such basic compounds must be markedly deactivated in the presence of Lewis acids. Imidazolin-2-ones appear to be an exception and apparently possess sufficient activation to react. Reactions between imidazoles and Af-methylfor-manilide and phosphoryl chloride are also unproductive. With 4,5-diphenylimidazole, phenyl isocyanate at 80 °C gives products of both N- and C-substitution, but in boiling nitrobenzene only the latter (86) is formed. 2-Methyl-4-phenylimidazole gives (87) under the same conditions, and 1,3-diphenylimidazolium perchlorate is transformed by potassium t-butoxide into a ylide which reacts at C-2 with phenyl isothiocyanate. Sufficient activation is present in l-methyl-2-phenyl-4-phenylaminoimidazole for it to react by substitution at C-5 with acetic anhydride (71JOC3368). 

Bis(benzimidazoyl)disulfide (319) undergoes cycloaddition with isocyanates and also with phenyl-isothiocyanate to give 2,3-dihydro[l,2,4]thiadiazolo[4,5-fl]benzimidazol-3-ones (320 Y = O) and the 3-thione (320 Y = S), respectively (Equation (95)) <83T23ii>. 

The isocyanate moiety of 2-substituted 2,3-dihydro-[l,2,4]thiadiazolo[4,5-a]benzimidazol-3-ones (393) is exchangeable with Other isocyanates or a carbodiimide giving rise to a formal exchange of the 2-substituent as in (394) (Equation (134)). With isothiocyanates 2-substituted 2,3-dihydro[l,2,-4]thiadiazolo[4,5-fl]benzimidazole-3-thiones (395) and/or 3-imino-3//-[l,2,4]dithiazolo[4,3- I]ben-zimidazoles (396) are formed (see Section 8.05.4.3). The reaction with carbon disulfide results in the formation of 3//-[l,3,4]-dithiazolo[4,5-u]benzimidazole-3-thione (397). All these exchange products react with isocyanates and are reconverted into compounds (393). 

Cyclization to the desired head-to-taU-linked bis-benzimidazoles can also be performed by reaction of aryl or alkyl isothiocyanates with N,N -dicyclohexylcarbodi-imide (DCC) [83]. In a closely related and more recent study by the same group, mercury chloride was used as a catalyst to perform cyclization to the benzimidazoles [84]. Another application of the bis-hydroxylated polymer support PEG 6000, microwave-accelerated liquid-phase synthesis of thiohydantoins, has been reported [85, 86]. 

Cycloaddition and cyclization routes were used to access certain 1,3-diazines. The 4+2 cycloaddition reaction of 4-(N-allyl-N-aryl)amino-l,3-diaza-l,3-butadienes with vinyl-, isopropenyl-, and chloroketene led to pyrimidinone-fused pyrimidinones <97T13841>. Cis-cyclopenta[d]pyrimidines were derived from cis-2-amino-l-cyclopentanecarboxylates by cyclization with KOCN and KSCN <97JHC1211>. 2-Thioxopyrido[3, 2 4,5]thieno[3,2-r/]pyrimidin-4(3//)-ones 19 were prepared by cyclocondensation of 2-carbethoxy-3-amino-4-phenyl-6-substituted-thieno[2,3-/)]pyridines and isothiocyanates <97JHC937>. Thiazolyl-benzimidazoles derived from 2-cyanomethyl-l//-benzimidazole and 2,3-dihydrothiazole-2-(3//)-thiones were cyclized to the corresponding thiazolo[4,5-r/]pyrimidines <97PHA346>. Reductive cyclization of 6-cyanomethyl-5-nitropyrimidines afforded 7-alkyl-5//-pyrrolo[3,2-r/]pyrimidines and 6-amino-7,7-dialkyl-7//-pyrrolo[3,2-rf]pyrimidines <97T391>. 7-Methyl-5-alkyl-2-vinyl-pyrazolo[3,4-r/]pyrimidine-4,6(5//,7//)-diones arose from cyclization and alkylation of... 

Aminoperimidines. Phenyl isothiocyanate added to a soln. of the equimolar amount of 1,8-naphthalenediamine in toluene, and after a few min. of an exothermic reaction refluxed 6 hrs. -> 2-aniIinoperimidine. Y 84%. Also 2-amino-benzimidazoles by a modified procedure (cf. Synth. Meth. 25, 363) s. D. Kiffer, Bl. 2970, 2377. 

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