Benzimidazoles amidines

Dibenzo[l,3]diazepines 9, together with amidines and benzimidazoles, are produced by a rearrangement reaction when certain A.A -diarylamide oximes 7 are treated with tosyl chloride. The intermediate 0-tosyl derivatives 8 cannot be isolated.176... 

A catch and release synthesis of tetrazoles and cyclic amidines has been reported making use of solid-supported oximes [94]. When bound sulpho-nyloximes, obtained by reacting polymer supported sulfonyl chloride with oximes, were reacted with nucleophiles, tetrazoles or cychc amidines were obtained (Scheme 19). Alternatively, the use of TMS-CN affords imino nitriles, which have been used as intermediates for the preparation of indoles, 1,2,3,4-tetrahydropyridines, quinoxalines and benzimidazoles. 

Microwave-assisted intramolecular C - N bond formations have also been studied. Substituted benzimidazoles were easily prepared from the corresponding M-(2-bromophenyl)imidoformamides by Brian et al. (Scheme 102) [ 104]. The protocol involved the use of a combination of Pd2 (dba)3 and PPha in a mixture of DME and water using NaOH as the base at 160 °C. It was apphca-ble for electron poor, neutral and rich as well as sterically hindered amidines. The fastest reactions were obtained with an electron withdrawing substituent... 

Cyclocondensation of 3-trifluoroacetyl substituted lactams with cyclic 1,3-bisnucleophiles gives pyrimido[l,2-a]benzimidazoles 21 and l,2,4-triazoloI4,3-a]pyridines 22. The use of amidines yields pyrrolopyrimidines <95JCS(P1)2907 94H(37)915>. 

Das 2-(2-Aryl-2-oxo-ethyl)-l-methyl-benzimidazol VI kann in zwei tautomeren Formen vorliegen. Es entsteht durch Kondensation von 2-(2-Methylamino)-anilin mit 3-Aryl-l,l-bis-[methylthio]-3-oxo-propen. Mit Elektronen-ziehenden Substituenten am Aryl-Rest liegt die Keten-N,N-Acetal-Form V vor, mit Elektronen-reichen Aryl-Resten die Amidin-Form... 

Preparation of the prototype drug departs from the phenylenediamine strategy used in all of the previous examples. Condensation of thiazolo nitrile (53-2) with aniline catalyzed by aluminum chloride affords the amidine addition product (53-3). This is then converted to its reactive A -chloro derivative (53-4) by reaction with sodium hypochlorite. Treatment of that intermediate with a base such as potassium hydroxide leads directly to the cyclization product and thus the benzimidazole thiabendazole (53-6) [56]. The reaction can be rationalized by invoking as the first step the abstraction of chloride to leave behind a nitrene species such as (53-5) this would then readily insert in the CH bond at the ortho position. 

An alternative strategy towards benzimidazole synthesis relies on the palladium-catalysed cyclisation of (2-bromophenyl)amidines. This chemistry has been reported to take place under aqueous reaction conditions, in the presence of sodium hydroxide in sealed microwave vials. The products were isolated by a catch and release method using a strongly acidic ion exchange resin, thereby avoiding conventional chromatographic purification (Scheme 3.14)23. Selectively, N-functionalised benzimidazoles were conveniently prepared by this method. 

Tri-r-b utylaniline is oxidized in acetonitrile to a radical cation. This reacts with pyridine to form 60% 6,8-di-r-butylpyrido[ 1.2 a] benzimidazole (38) by r-buiy 1-transfer to acetonitrile and subsequent dehydrogenation and 25% of the amidine 39. 

Isothiazoles have also been incorporated into a wide range of established drugs including phenothiazines,123 sulfones,121 sulfonamides,3,66,156 thiosemicarbazones,140,157 amidines,158 nitrohetero-cycles,159 and benzimidazoles,160 but this approach does not appear to have resulted in any major improvements. However, many isothiazoles not directly related to known drugs have biological activity, and representatives are listed in Table I, No attempt has been made to include the numerous patents which mention isothiazole derivatives as part of a series, but for which no special claims are made. 

The interaction of perfluoro-5-azanon-4-ene with amidines and 2-amino-benzimidazole occurs with formation of a six-membered heterocycle, giving 2,4-bis(heptafluoropropyl)-6-phenyl-[l,3,5]triazine, 2,4-bis(hep-tafhioropropyl)-6-methyl-[l,3,5]triazine, and a tricyclic compound—2,4-bis(heptafhioropropyl)benz-[4,5]imidazo[l,2-tf][l,3,5]triazine (01IZY457). 

Nitroanilines react with organic cyanides in the presence of dry aluminum chloride. Under the influence of sodium hypochlorite in the presence of a base, the resultant amidines undergo cyclization to the corresponding benzimidazoles (Scheme 2.46) [385-388],... 

Although the enediamine form is predominant, the amidine tautomers exist in some the imidazole and benzimidazole forms in the crystals, whereas in solution, tautomeric equilibrium between 13 and 13 has been observed33 (equation 1). The equilibrium is affected by the substituent X, and electron-withdrawing chlorine of 13 favors the... 

The formation of benzimidazoles by cyclization of aryl amidines can be accomplished in a number of ways, but is usually carried out under anhydrous conditions in the presence of a base. Thus cyclizations of (45 R = OH) induced by benzenesulfonyl chloride in pyridine or triethylamine generally give yields of greater than 60%. The more direct process of oxidizing the parent compounds (45 R = H) with sodium hypochlorite under basic conditions gives even higher yields (70-98%). Intermediates in these reactions are the )V-haloamidines (45 R = C1) a nitrene intermediate may be involved or merely dehydrochlorination with concomitant cyclization (Scheme 25). Alternative cyclization procedures include oxidation of the parent amidines (45 R = H) by manganese dioxide or lead tetraacetate and thermal... 

Under oxidative or acidic conditions, or merely by heating the reagents, appropriately functionalized aryl-amidines or -guanidines cyclize to 1-alkyl or 1-aryl-benzimidazoles [51, 52]. If guanidines are employed. 

A mixture of the triazoline (10 mmol) and triethyl phosphite (20 ml) is refluxed (10-30h) under an inert atmosphere. When the amidine intermediate is no longer detectable (TLC, 40% ethyl acetate-cyclohexane) the solution is rotary evaporated, and the crude residue is chromatographed on a silica gel column using the same solvent as for TLC. The first fraction (minor) is unchanged amidine the second fraction contains the benzimidazole (2) in 60-95% yield. 

Amidines 1170 substituted with electron-rich aromatic rings undergo an oxidative intramolecular cyclization process to give A-substituted benzimidazoles 1172. The reaction proceeds well in MeCN with CAN or electrochemical oxidation and probably involves the cationic intermediate 1171 (Scheme 285) <1996JOC3902>. 

Trifluoroethanimidamines (amidines) undergo a two-electron electrochemical oxidation leading either to 2-trifluoromethyl benzimidazoles via intramolecular nucleophilic substitution or to p-benzoquinone imine derivatives by external nucleophilic addition depending on the reaction conditions [Eq. (21)] [137]. Another study of the indirect electrochemical amidine oxidation has been published by Lessard [138]. 

A palladium-catalyzed W-arylation reaction provided a novel synthesis of benzimidazoles 5 from (o-bromophenyl)amidine precursors 4 under microwave irradiation. The route was found to be flexible with respect to various substituents and allows for the preparation of highly substituted benzimidazoles, including W-substituted examples (Scheme 1) [23]. The method was later improved and optimized to achieve the rapid formation of benzimidazoles in high yield [24]. It has been found that 50% aqueous dimethyl ether (DME) is an optimal solvent for the reaction and that catalyst loading of palladium can be reduced to 1 mol %. 

Copper Catalysts Brasche and Buchwald reported a direct Cu-catalyzed C—H functionalization and C—N bond-forming approach which provides benzimidazoles from readily available amidines (Equation 11.40) [79]. The new method requires only inexpensive reagents, such as copper( 11) acetate, acetic acid, and oxygen, and tolerates a variety of useful functional groups. 

Benzimidazoles and an Imidazoquinoline. - Aryl sulphimides p-RC6H4NSMe2 (R = Cl, Br, or NO2) react with nitrile oxides ArCNO to yield mixtures of benzimidazole A -oxides (300) and 1,2,4-benzoxadiazines (301). The betaine (302) results from the action of Chloramine T on benzimidazoline-2-thione. A -Phenylcarbimide dichloride, PhN=CCl2, reacts with the amidine... 

Amination of azaheteroaryl bromides and chlorides has also been reported to be smoothly executed within 10 min by use of standard reaction conditions and microwave irradiation [118]. Benzimidazoles have been prepared by Brain and Steer via intramolecular cyclization using an amidine moiety as the N-nucleophile [119]. The reaction was rapid and high yielding, and in combination with a catch and release strategy featuring capture of the benzimidazole on an acidic resin in the... 

Scheme 15.57. Palladium-catalyzed intramolecular amidination producing different benzimidazoles.

Since the previously reported 6-acetamidopyrrolo[l,2-a]benzimidazole (APBI) has a stmcture similar to the makaluvamines and showed a similar topoisomerase activity. Skibo et al. prepared the imidazoquinoxaline analogs, which possess the ethylene tether and an amidine moiety, and are similar to the makaluvamines (Scheme 11). However, they showed a weaker activity than makaluvamine H [57,58]. 

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