Fused-Imidazole Rings

There are several reported syntheses of this 4,5-di-substituted imidazole. A published route from an academic group prepared the imidazole from 1,4-di-nitroimidazole. The proposed mechanism for this transformation is nucleophilic addition (cine addition) of cyanide to the 

A more direct route involves the treatment of a-amino-cyano-amide with a protected formamidimide. The reaction is reported to take place at ambient temperature and provide good yields of the 1,4,5-tri-substituted and more appropriately functionalized imidazole, which is subsequently transformed into temozolomide.  

Another pharmaceutically important fused-imidazole ring system is the popular sleeping aid medication zolpidem. Bromination of 4-methylacetophenone and condensation with methylated 2-amino pyridine provides the fused-imidazole in good overall yield. Note that the ring nitrogen on the aminopyridine reaction reacts with the bromide carbon. Mannich-type alkylation at the unsubstituted 5-position provides the dimethylaminomethyl substituent in good yield. Further elaboration yields zolpidem.  

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The synthesis of this ring system by condensation of 3,4,5-triamino-l,2,6-thiadiazine-l,1-dioxide with formic acid equivalents to give the fused imidazole ring dates back to the review by Montgomery and Secrist <1984GHEC(5)607>. This methodology was extended to cyclocondensation reactions of 3,4,5-triamino-l,2,6-thiadia-zine-1,1-dioxide with electrophiles such as methyl chloroformate and carbon disulfide to yield 6-oxo 98 and 6-thioxo 99 derivatives of 4-aminoimidazo[4,5-d-l,2,6-thiadiazine-2,2-dioxide respectively (Scheme 72) <1999BMC1617>. 

The removal of the iV-etheno group from the fused imidazole ring of tricycle 102 was achieved using rV-bromosuccin-imide (NBS) in 1 1 DMF-water to yield the 2-azanucleoside (pyrazolo[3,4-4][l,2,3]triazine) 103 (Scheme 79) <2004JOC4695, 20050BC1714>. An analogous tricycle transformation to imidazo[4,5-r7 [l,2,3]triazines has been reported earlier <1996CHEC-II(7)489>. 

The removal of the W-etheno group from the fused imidazole ring of tricycles, diimidazo[l,2-rt4, 5 -r ][l,2,3]tria-zines and imidazo[l,2-f]pyrazolo[4,3-i ][l,2,3]triazines, is a reliable method for making imidazo[4,5-rf [l,2,3]triazines <1996CHEC-II(7)489> and pyrazolo[3,4-r/ [l,2,3]triazines, respectively (Section 10.13.10.1.2). 

The thioamide function also provides the entry for the construction of a fused imidazole ring, though the sequence is somewhat more complex due to the need to form a new carbon-carbon bond. Reaction of the thioamide (18-1) with methylamine proceeds to give the corresponding amidine this is transformed into a good leaving group by conversion to the A-nitroso derivative (18-2) by treatment with nitrous... 

The fusion of an additonal heterocyclic ring onto the above benzodiazepine restores at least partial agonistic activity. The benzodiazepine nucleus is built exactly as above using L-proline (20-2) instead of sarcosine to afford (20-3). The fused imidazole ring is again added by condensation with an isocyanoacetate, in this case the tert-butyl ester. This then affords bretazenil (20-4) [24], a compound that displays some antianxiety activity. 

Acylation of the theophylline diamine intermediate (26-6) with phenylacetyl chloride affords the corresponding amide (28-2). Base catalyzed cyclization then leads to the purine (28-3) that now includes a quite lipophilic benzyl group on the fused imidazole ring. The molecule is then provided with a side chain that incorporates basic nitrogen, arguably to improve water solubility. The anion from (28-3) is thus first alkylated with bromochloroethane to afford the chloroethyl product (28-4). The displacement of chlorine with ethanolamine affords the bronchodilator bamifylline (28-5) [28]. 

An analysis of conformational flexibility of pyrimidine ring in related molecules (purine, aminopyrimidine, and unsubstituted pyrimidine (Scheme 21.4)) indicates that the flat character of the potential energy surface around minimum is a general property of pyrimidine ring. A presence of amino group and fused imidazole ring only promotes increase of conformational flexibility of heterocycle. 

Substituents on the benzene ring can play some part in subsequent electrophilic substitution reactions, but the situation is not a simple one. As can be seen in Scheme 93 the normal meta directing effect of a nitro substituent can be offset by the directional effect of the fused imidazole ring, as can the usual ortho-para directing effect of bromo. 

Halogens attached to pyrazine react readily with 2>aminopyridine with the formation of a doubly fused imidazole ring. 2-Aminopyridines carrying alkyl or alkoxy groups react at ambient temperature while two halogen atoms or a nitro group inhibit the cyclization. 

Compounds with a peri-fused imidazole ring to the purine ring 257 were only little studied. Their synthesis involved an intramolecular alkylation of 8-alkyl- or 8-aryl-9-(2-mesyloxyethyl)-l-methyl-purinediones 260b. The necessary intermediates 260b were achieved by hydrogenation of the 6-[2-(hydroxyethyl)-amino]-3-methyl-5-nitroso-pyrimidinedione 258 to 5-amino-6-[2-(hydroxyethyl)amino] compound 259 further reactions with the respective ortho-carboxylates and mesyl chloride gave 8-alkyl- or 8-aryl-9-(2-hydroxyethyl)-purinediones 260 or 261 (98CCC407) (Scheme 76). 

A well-known purine is the central nervous stimulant (CNS) caffeine (9.134), which is found in coffee and chocolate. Its synthesis (Scheme 9.77) illustrates the technique of forming the fused imidazole ring of purines. It was noted in Chapter 4 that diaminobenzenes reacted with carboxylic acids or esters to form benzimidazoles this process is known as the Phillips synthesis. It is this reaction that is used to fuse imidazoles to pyrimidines. Here, the process is known as the Traube purine synthesis. The initially formed purine is tri-methylated with methyl chloride and base to form caffeine (9.134). Note that under these conditions it is the 7-nitrogen that is methylated. 

The carbonylation of indolines at the 7-position with ethylene and carbon monoxide has been achieved when a 2-pyridyl group is substituted at the indoline nitrogen atom (eq 6). Fused imidazole rings in 1,2-disubstitutedbenzimdazoles also serve as the directing group to selectively undergo direct carbonylation at the 4-position (eq7).i2... 

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