Benzimidazole-2-acetate, reaction with

A method [116] was developed for determining formate as benzimidazole after reaction with o-phenylenediamine at 130 °C for 2 h in 1M perchloric acid. The benzimidazole was extracted from the reaction mixture with ethyl acetate/ethanol (9 1, v/v). The HPLC system was a Cjg column, isocratic elution with a mixture of phosphate buffer (pH 2.1) and acetonitrile, and detection at 267 nm. This procedure was employed to determine the formate concentration in human urine and rat liver and urine, and to measure the activity of formaldehyde dehydrogenase [116]. 

Aryl-5,6-dihydrobenzo[4,5]imidazo[l,2-C]-quinazolines Isatoic anhydride could also be reacted with amino-, hydroxyl- or thiolanilines to form 2-(2-aminophenyl)benz-imidazoles, oxazoles or thiazoles, Scheme 5.38. In the case of 2-(2-aminophenyl)benzimidazoles (X=N), the product was formed after 3 min at 150°C in acetic acid. The products could subsequently be further elaborated 6-aryl-5,6-dihydrobenzo[4,5]imidazo[l,2-C]quinazolines, a four ring system, was formed by treatment of the 2-(2-aminophenyl) benzimidazole (X=N) with different aldehydes in acetic acid at 150°C for 5 min (J. Westman, and K. Orrling, Personal Chemistry, Uppsala, Sweden, unpublished results). Fifteen compounds were synthesised in 20-75% overall yield. This 3 + 5 min procedure should be compared to the conventional heating protocol developed by Devi and co-workers57, where each reaction step was run overnight to eventually afford the products in only 30-50% yield. 

The benzo derivative (128) reacts as a thiocarbonyl ylide. Addition of N-(p-tolyl)maleimide gives a mixture of the exo (71%) and endo (16%) adducts (129 Ar=p-tolyl), which in hot acetic acid eliminate hydrogen sulfide giving the pyrido[l,2-a]benzimidazole (130 Ar=p-tolyl). Analogous 1 1 cycloadducts (131) are formed with dimethyl maleate, dimethyl fumarate, methyl crotonate and methyl acrylate. In contrast to the transformation (129) —> (130), treatment of the adducts (131 R = H, Me) with hot acetic acid gives the tetracyclic compounds (133) via the benzimidazole derivatives (132 R = H, Me). Reaction with alkynic 1,3-dipolarophiles gives pyrido[l,2-a]benzimidazole (134) by desulfurization of the primary adducts (80CL1369). 

Under alkaline conditions, alkyl nitrites nitrosate imidazoles that possess a free NH group, at the 4-position. Nitrosation of 3,5-dimethylpyrazoles gives the 4-diazonium salt by further reaction of the nitroso compound with more NO+. 4-Nitrosopyrazoles 188 can be used as spin traps. 5-Pyrazolinones are nitrosated readily at the 4-position. Imidazo[l,2-tf] benzimidazoles are nitrosated with NaN02 in acetic acid giving 3-nitrosoderivatives 189. Nitrosation of 2-(dimethyla-mino)thiazoles under acid conditions gives 5-nitroso-derivatives 190. 3-Alkyl-5-acetamidoisothiazoles undergo 4-nitrosation. 

The (l-methylimidazol-2-yl)thioglycolic acid 52 can be converted into the ring-fused mesoionic system 53 by reaction with acetic anhydride (Scheme 33) <1979JOC3803>. The thioether 54 with ethanolic sodium ethoxide gives the 3-benzylthiazolo[3,2- ]benzimidazole 55 (Scheme 34). 

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. 

In the uncondensed imidazoles the standard method reacts an a-aminocarbonyl compound with a thiocyanate (see Section 4.1 and Table 4.1.1). If a 2-alkylthioimidazole is required directly, one can combine an N-alkyT or A -arylcarbonimidodithioate in refluxing acetic acid with the aminocarbonyl substrate (see Section 4.1 and Scheme 4.1.3). Alternatively, reaction between thiourea and a two-carbon synthon (ot-hydroxy-, a-halogeno-, a-dicarbonyl) leads to imidazoline-2-thiones (see Section 4.3). In sulfuric acid, 3-butynylthiourea cyclizes to 4,5-dimethylimidazolin-2-thione (see Section 2.2.1). 1-Substituted 2-methylthioimidazoles can be made, albeit in rather poor yields, from appropriately substituted 2-azabutadienes (see Section 3.2 and Scheme 3.2.3), and 2-arylthioimidazoles are available in moderate yields from benzyl isocyanides and arylsulfenyl chlorides (see Section 4.2 and Scheme 4.2.12). Ring transformations of 5-amino-2-alkylaminothiazoles and 2-acylamino-5-aminothiazoles may have occasional applications (see Section 6.1.2.7). The ease with which a thiol group or imidazole or benzimidazole can be alkylated, in comparison with the annular nitrogens, usually makes it more convenient to prepare alkylthioimidazoles from the thiols (or thiones). 

The vicinal position of nucleophilic amino and strongly electrophilic nitroso groups makes A -aryl-2-nitrnsoanilines 413 (Wrobel and Kwast 2007, 2010) very interesting starting materials for domino reactions with properly eqmpped dipolar parmers, leading to a variety of heterocyclic systems. The reactions of these compounds with comparatively acidic sulfones (Scheme 2.75, route a) or acetates and phosphonoacetates (Scheme 2.75, route b) appeared to be efficient ways of the synthesis of benzimidazoles 414 (Wrobel et al. 2011) and quinoxalin-2(lff)-ones 415 (Wrobel et al. 2013). 

Oxidation of aliphatic C-H groups with HP is efficiently catalysed by cis-a-aminopyridine manganese complexes in the presence of acetic acid. The reaction demonstrated excellent efficiency (up to TON = 970), site selectivity, and stereospecificity (up to >99%). Manganese(II) and iron(II) complexes based on ligands with a rigid, chiral diamine derived from proline and two benzimidazoles (2) were synthesized and applied in epoxidation reaction with aqueous HP. Mn-complex catalyses the epoxidation of olefins. Isolated yields of 60-99% and up to 95% ee were obtained with 0.01-0.2mol% catalyst loading. The turnover frequencies and turnover numbers reached 59,000 h and 9600, respectively. Iron(II) complex exhibited a... 

A series of benzimidazole and benzimidazolone derivatives from the Janssen laboratories has provided an unusually large number of biologically active compounds, particularly in the area of the central nervous system. Reaction of imidazolone itself with isopropenyl acetate leads to the singly protected imidazolone derivative 51. Alkylation of this with 3-chloro-l-bromopropane affords the functionalized derivative Use of this... 

An analogous sequence leads to the anthelmintic agent, etibendazole (50). Reaction of the benzophenone 47, which can be obtained by acylation of o-nitroaniline with g-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-methylthiourea gives the benzimidazole etibendazole (50) fl6]. 

Arylations of amines and nitrogen-containing heterocycles require the presence of a copper catalyst, usually 10% copper(ll) acetate. For example, the reaction of 4-MeC6H4Pb(OAc)3 with the benzimidazole 20 affords the arylation product 21 in 98% yield.39 40 Similarly, the arylation of the amino groups of heteroaromatic compounds 22 and 23 gives rise to the corresponding products 24a and 25 in good to excellent yields (Equations (7)-(9)).41 42... 

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