Alkylation benzimidazole derivatives

Benzimidazole, 2-alkoxy-l-methyl-transalkylation, 5, 443 Benzimidazole, 1-alkyl-metal derivatives, 5, 448 reactions... 

The reaction of 4-phenylbut-3-yn-2-one and TV-alkylated benzimidazoles 9 leads to benzo[b [l,4]diazocine derivatives 10 in very low yields.32... 

Hydroxyl-substituted naphthimidazoles, benzothiazoles, benzimidazoles, benzotriazoles, benzoselenazoles and benzoxathiolones may be regarded as substituted phenolic couplers. Compound (121) is a specific example of the latter type which yields intense brown images (51USP2547843). In the absence of hydroxyl groups, alkyl-substituted derivatives of imidazoles or thiazoles may be couplers in their own right by virtue of their active alkyl substituent. 

Imidazoles react with chloroform at high temperature to form azines by carbene insertion and trichloromethyl radicals behave similarly, but carbenes do not always induce ring expansion. In alkaline medium, chlorodifluoromethane converts benzimidazole and its 2-methyl analogue into the 1-difluoromethyl derivatives 365. Dichlorocarbene under basic conditions N-alkylates benzimidazole, and 1-methylbenzimidazole couples under the influence of the same reagent (Scheme 69), perhaps involving initial attack of the carbene at N(3). 

Difluorobenzonitrile and methylthioglycolate cyclize to give 4-fluorobenzo[fe]thiophene [91JFC(54)104]. The reaction of trifluoromethyl-substituted 2,4-dinitrochloro- and 2,6-dinitrochlorobenzene with alkyl thi-oglycolates and amino acid esters at room temperature in the presence of triethylamine follows the same mechanistic concept to yield trifluoromethyl-substituted benzothiazole and benzimidazole derivatives [88JFC(38)327] (Scheme 25). 

Although deprotonation of NHC salts have proven to be an efficient synthetic route, the basic reaction conditions can prove incompatible with certain complex synthesis in a one-pot procedure. Thus, other synthetic strategies to generate free carbene have been developed. Khun reported the synthesis of imidazol-2-ylidenes bearing a small alkyl group on the NHC backbone by potassium reduction of the corresponding thiones (10) (equation 5). This method has also been applied in the synthesis of benzimidazole derivatives, by reduction of the corresponding sulfones with Na/K alloy at room temperature. Synthesis of unsymmetrically substituted... 

Recently, 2-alkyl- and 2-aryl-substituted benzimidazole derivatives 15 have been synthesized from 1,2-diaminobenzene dihydrochloride 13 and its corresponding acids 14 in the presence of polyphosphoric acid using microwave-assisted methods (Scheme 3). The reaction time required for the synthesis of benzimidazole derivatives 15 was reduced to minutes by this method compared to conventional synthesis, which required up to four hours of heating to complete the reaction. Furthermore, it was found that the application of microwave irradiation increased yields by 10-50% (Table 1). It has been... 

All of these derivatives are 1,2-disubstituted benzenes, which are converted by chemical reaction, for example, in aqueous medium with sodium hydroxide or with dimethyl sulfate, into alkyl N-benzimidazol-2-yl-carbamates (Koyamada et ai, 1969 Adams and Wommack, 1970). Thiophanate derivatives themselves are inactive (Nogutsi et al., 1971), but in plants they are converted into benzimidazole derivatives, exerting their effect in this form (Selling et ai, 1970 Vonk and Kaars Sijpesteijn, 1971 Soeda et al., 1972). The lack of activity of 1,3- and l,4-bis(3-alkoxycarbonyl-l-thioureido)benzenescan be explained by their inability to cyclise the benzimidazole ring. Thioallophanic acid derivatives are thus the precursors of alkyl N-benzimidazol-2-yl-carbamates. Further substitutions on the benzene ring decrease the fungitoxicity of the compounds. 

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... 

Solvating reagents such as neutral compounds (e.g., ethers, ketones, alcohols, and esters of carboxylic acids, alkyl phosphates, phosphonates, phos-phinates, phosphine oxides, and phosphine sulfides) and also esters of pyridinecarboxylic acids and certain benzimidazole derivatives that have electron-withdrawing substituents form solvates with extracted neutral species. For example, dialkylpyridine-3,5-carboxylates extract Cu(II) at pH 3 from concentrated chloride solutions ... 

This concept was applied to the intramolecular alkylation of imidazole and benzimidazole derivatives (Scheme 19.86) [121]. Preliminary results showed that while the Wilkinson catalyst was effective for this transformation, standard ruthenium catalysts were unreactive. Further screening using [RhCl(coe)2]2 as the rhodium source with various phosphine ligands revealed that electron-rich ligands such as PCyj yielded the best results. As the reaction was found to be more efficient in the presence of the Lewis or Bronsted acid, an optimized protocol was devised through the use of [HPCyjKQ] imder microwave irradiation [122]. Mechanistic studies showed that the reaction is zero order in substrate and first order in catalyst. 

Peterson et al. has reported photochemical reactivity of imidazole-fused cyclic enediynes [22]. Irradiation of degassed enediyne solutions with 450W low-pressure Hg lamp with a quartz filter gave benzimidazole derivatives in yields that were dependent on the nature of solvent and substituents at the alkyne termini (Scheme 30.9). The cycloaromatized product was obtained in the highest yields (26-64%) for R=Ph, with the best yield obtained using THF as solvent. Yields for the two alkyl substituted enediynes (R=Me and Bu) depended very strongly on the solvent. The cyclic... 

Catalyhc Zn0 H202 (0.1 mmol lmL/2 mmol of the substrate) has been explored [91] for the synthesis of benzimidazole and quinoxaline derivahves at room temperature (Scheme 62). o-Phenylenediamines have been shown to react with variety of aliphatic as well as aromatic aldehydes resulting in substituted benzimidazoles in high yields. The reactions are completed within 20 min in case of aromatic aldehydes whereas the aliphatic ones need 1 h for complete conversion. Replacing aldehydes with 1,2-diketones results in the synthesis of quinoxaline derivatives within 10 min (Scheme 62). Zinc acetate has also been used as a catalyst for solvent-free synthesis of benzimidazole derivatives at room temperature with approximately 90% yields. The solvent-free reaction is carried out using substituted o-phenylenediamines and aldehydes (both aryl and alkyl) [92] (Scheme 62). 

Sun et al. reported a diversity-oriented tactic to access the benzo[d]oxazol-5-yl-lH-benzo[d]imidazole 64 on IL support (Scheme 24). The authors coupled 4-hydroxy-3-nitrobenzoic acid onto IL-immobilized o-phenylenediamine 58 that underwent ring closure to furnish benzimidazole derivatives 60. Further hydrogenation of the nitro group to an amine followed by the reaction with 1,1-thiocarbonyldiimidazols resulted into IL tagged-benzoxazol 63. In order to generate skeletal diversity, S-alkylation with alkyl and aryl bromides was carried out. Cleavage of 64 from IL support was done by treatment with sodium methoxide in methanol imder microwave irradiation [127]. 

Reaction of carboxylic acids with o-phenylenediamine leads to 2-alkyl-benzimidazoles which have properties suitable for identification (21, 22), i.e., they crystallize well and have sharp melting points which are not too close to each other (formic acid derivative, mp, 172—173 °C stearic acid derivative, 93.5—94.7 °C). Another advantage consists in their forming another series of derivatives they can be converted to picrates,... 

Benzimidazole Derivatives - The activity of hydroxy benzyl benzimidazole (HBB) against picornaviruses has been a stimulus to continued study of its derivatives. 2-(alpha-Amino benzyl)benzimldazole (ABB) and 1-phenyl ABB were significantly effective in reducing cytopathic effect of ECHO-12 virus at nontoxic concentrations. Alkylation or acetylation of the amino function resulted in loss of antiviral activity. The presence of a 5- or 1-methyl group in the N-methylamino series Increased the activity against ECHO-12. The addition of a phenyl substituent in the 1-position of the alpha nethoxy and alpha-amino derivatives of HBB also Increased the activity against the ECHO viruses. 

Alkylation of the cyclization product 115 and the following hydrolysis gave 9-alkyl substituted 6-oxo-6,9-dihydroimidazo[4,5-/i]quinoline-7-carboxylic acid derivatives 119, compounds useful as antibacterials (no data) [80JAP(K)1], 4(7)-Aminobenzimidazole can react with 1,3-diketones as a bidentate nucleophile, but with 2,4-pentanedione in glacial acetic acid it gives a Combes product, l//-6,8-dimethylimidazo[4,5-/i]quinoline 120, accompanied by 4(7)-acetamido-benzimidazole (91T7459). 

By using basicity data, Ridd and Smith- showed that 5-nitro- and 5-chloro-benzimidazole and their 2-methyl analogs exist essentially as mixtures of equivalent amounts of 29 and 30, and, in agreement with this ratio, 5-substituted benzimidazoles form comparable amounts of 1- and 3-derivatives on alkylation,- showing earlier alkylation ratios- to be erroneous. There are, however, other factors which can lead to the predominance of one tautomeric form. Basicity measurements indicate that 31 is preferred to the alternative non-hydro-... 

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... 

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