Benzimidazole, 6- alkylation

The reactivity of seven resin-bound thiophenol esters toward 3,4-dimethoxy-phenethylamine (42) was consistent with the trend seen in n-butylamine cleavage reactions i.e. benzimidazole > alkyl > aromatic. However, the rate constant for the same thiophenol esters with 3,4-dimefhoxyphenethylamine was decreased by two to three fold compared with that with n-butylamine. The rate constant of ben-... 

Examples of phase-transfer catalysis applications include methylation of benzimidazole in 38yo yield <81AJC1729>, benzylation (76% yield) and tritylation (80%) of the same substrate <85H(23)2895>, and other benzimidazole alkylations <91BSF255>. Tetrabutylammonium sulfate has been used in the aminoalkylation of imidazole (60%) and benzimidazole (50%) with 2-chloroethylamine <91SC535>, while methylene-l,r-diimidazole and other di-imidazoles and -benzimidazoles were made with the appropriate dichloroalkane under phase transfer conditions <83JHC1245, 88JHC771,92H(34)1365>. See also <83CHE1141 >. 

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

Benzimidazole, 2-amino-5-bromo-l-methyl-diazo coupling, 5, 429 Benzimidazole, 2-amino-6-bromo-1 -methyl-diazo coupling, 5, 429 Benzimidazole, 2-amino-1-ethyl-alkylation, 5, 438 Benzimidazole, 2-amino-1-methyl-acylation, 5, 438 bromination, 5, 429 tautomerism, 5, 368 Benzimidazole, 4-amino-2-methyl-diazo coupling, 5, 429 Benzimidazole, 2-aroyl-mass spectra, 5, 360 Benzimidazole, 1-aryl-metallation, 5, 448 reactions... 

Benzimidazole, 2,6-dimethyl-4-nitro-alkylation, 5, 389-390 Benzimidazole, IV-ethyl-sensitizing dyes... 

Benzimidazole, l-methyl-2-trichloromethyl-substitution reactions, 5, 432 Benzimidazole, naphthoyl-, 1, 327 Benzimidazole, 5-nitro-alkylation, 5, 390 Benzimidazole, 6-nitro-1-oxide... 

Benzimidazole-2-carboxylic acid decarboxylation, 5, 435 Benzimidazole-3-carboxylic acid, 1-hydroxy-ethyl ester synthesis, 6, 407 Benzimidazoles acidity, 5, 50, 385, 386 acylation, 5, 71, 391, 402, 417 2V-alkyl-... 

Benzimidazole-2-thione, l-( -D-ribofuranosyl)-tautomerism, 5, 368 Benzimidazolethiones tautomerism, 5, 368 Benzimidazole-2-thiones alkylation, 5, 444 synthesis, 5, 458... 

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... 

As noted earlier (see Chapter 10), 4-acyl piperidines separated from benzimidazole by a three carbon chain often show antipsychotic activity. The heterocycle can apparently be replaced by a pyridopyrimidine ring. Thus alkylation of piperidine 41 with halide 42 affords pirenperone (43). ... 

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... 

Another interesting example of dehydrative C-C coupling involves the alkylation of benzimidazole 36 with allyl alcohol 37, which is catalysed by complex 39 [15], The reaction is believed to proceed by alkene complex formation with the allyl alcohol 37 with loss of water from the NH proton of the NHC ligand and OH of the allyl alcohol to give an intermediate Ji-allyl complex. The initially formed 2-allylbenzimidazole isomerises to a mixture of the internal alkenes 38 (Scheme 11.9). 

Schulz, W. G. Nieman, R. A. Skibo, E. B. Evidence for DNA phosphate backbone alkylation and cleavage by pyrrolo[l,2-a] benzimidazoles, small molecules capable of causing sequence specific phosphodiester bond hydrolysis. Proc. Natl. Acad. Sci. USA 1995, 92, 11854-11858. 

It is quite certain that the two cobalamin species with coordinated and free benzimidazole are in rapid equilibrium. However, the ligands bound to the lower coordination site are apparently not always easily displaced. As mentioned above, Brodie and Poe (130) have found that in DMSO, a water molecule is firmly bound to the sixth coordination position of alkyl cobinamides. Thus, even though DMSO is a good Lewis base, it will not easily displace water from the primary coordination sphere of the cobalt. 

Fig. 35. (a) Correlation between the photolysis rate of halomethyl-cobalamins and the electronegativity of the alkyl ligand. (The electronegativity values are shown as the sums of the Pauling electronegatives of the atoms attached to the methyl carbon.) (b) Correlation between pKa for displacement of benzimidazole and alkyl group electronegativity for a series of halomethyl-cobalamins... 

Whereas pyrrole was reported not to give N/H insertion by ketocarbenoids, such a reaction mode does occur with imidazole Copper-catalyzed decomposition of ethyl diazoacetate at 80 °C in the presence of imidazole gives ethyl imidazol- 1-ylacetate exclusively (93 %) small amounts of a C-alkylated imidazole were obtained additionally under purely thermal conditions 244). N/H insertion also takes place at benzimidazole 245 a). The reaction is thought to begin with formation of an N3-ylide, followed by N1 - C proton transfer leading to the formal N/H insertion product. Diazomalonic raters behave analogously however, they suffer complete or partial dealkoxycarbonylation under the reaction conditions 244) (Scheme 34). N-alkylation of imidazole and benzimidazole by the carbenoids derived from co-diazoacetophenone and 2-(diazoacetyl)naphthalene has also been reported 245 b>. 

Imidazolines are also formed in silver cyanide-catalyzed cyclization of alkyl isocyanides with aliphatic diamines (Scheme 103).169 This simple synthesis can be applied in a general way with difunctional nucleophiles and has been used to prepare benzimidazoles, oxazoles, thiazoles, and oxazines.169 It is suggested that transient carbene complexes are formed in these reactions (cf. 87 in Scheme 103) but further work is required to ascertain the mechanism and scope of these processes. 

The scope of the silver cyanide-catalyzed reaction of difunctional nucleophiles with alkyl isocyanides has been described in the earlier section on imidazoles an example of the use of this simple approach in benzimidazole synthesis is illustrated in Scheme 105.169... 

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. 

The alkylation of the G-H bonds occurs even in the CH=N moiety of five-membered heteroaromatic compounds such as thiazoles, benzimidazoles, and oxazoles (Equation (25)).26,26a This intermolecular alkylation without chelation assistance is very interesting. 

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