Imidazole fused-ring systems

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. ... 

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 synthesis of naphthimidazo[2,l-fe]thiazol-3(2//)-ones, in which a 4-thiazolidinone nucleus has fused to both naphth[2,3-d]imidazole and naphth[l,2-c/]imidazole ring systems, has been reported. 

Benzimidazole is a fused aromatic imidazole ring system where a benzene ring is fused to the 4 and 5 positions of an imidazole ring. Benzimidazoles are also known as benziminazoles and 1,3-benzodiazoles [1,2]. They possess both acidic and basic characteristics. The NH group present in benzimidazoles is relatively strongly acidic and also weakly basic. Another characteristic of benzimidazoles is that they have the capacity to form salts. Benzimidazoles with unsubstituted NH groups exhibit fast prototropic tau-tomerism, which leads to equihbrium mixtures of asymmetrically substituted compounds [1]. 

Wentrup and co-workers have carried out systematic flash vacuum thermolysis studies with a series of fused tetrazoles. Investigations of the isomeric tetrazolo[l,5- ]pyrazine 17 and tetrazolo[l,5-f]pyrimidine 20 showed that, in both cases, ring contraction takes place to afford imidazoles in high yields, but isotope labeling experiments revealed that the mechanisms of the openings of the two ring systems are different <2002JOC8538>. 

There are many heterocyclic molecules in which 1,3,4-thiadiazoles are fused to other ring systems. For example, Molina et al. developed a procedure for building a thiadiazole ring on to a properly substituted imidazole moiety (Scheme 29). Reaction of l-amino-2-methylthio-4-phenylimidazole (161) with triphenylphosphine dibromide in dry benzene furnished the 2-methylthio-4-phenyl-l-triphenylphosphoranylidenamino imidazole (162) in a 95% yield. With aroyl chlorides at elevated temperature, this gave the 2-aryl-6-phenylimidazo[2,l-Z ][l,3,4]thiadiazoles (164) in yields between 50% and 70% via the imidoyl chloride intermediate (163) which could be isolated and shown to cyclize to the thiadiazole. The method developed for the imidazole ring was also applicable to the thiadiazolotriazine ring system <88H(27)1935). 

The nomenclature for fused 5 5 systems is generally related to the two fused component heterocyclic rings as indicated above for imidazo[4,5-rf]imidazole (1), although compounds are sometimes named as hetero derivatives of pentalene. Heterocycles which are not fully conjugated can be named as dihydro, tetrahydro, etc., derivatives of the fully conjugated parent system or as hetero derivatives of the saturated parent hydrocarbon. For example heterocycle (6) can be named as a tetraaza bicyclo[3.3.0]octane. 

It is easily possible to continue to insert nitrogen atoms into fused ring systems and some important compounds belong to these groups. The purines are part of DNA and RNA and are treated in Chapter 49, but simple purines play an important part in our lives. Coffee and tea owe their stimulant properties to caffeine, a simple trimethyl purine derivative. It has an imidazole ling fused to a pyrimidine ring and is aromatic in spite of the two carbonyl groups. 

The three part so-called cocktail used to treat HIV positive patients typically comprise a proteinase inhibitor, such as those discussed in Chapter 1 a nucleoside-based reverse transcriptase inhibitor, such as those in Chapter 6, and a non-nucleoside inhibitor of reverse transcriptase (NNRTI). Most of the compounds in the first two classes share a good many structural features with other agents in the class. Chemical structures of the various NNRTIs on the other hand have little in common. Capravirine (103), is notable in the fact that it fails to include any of the fused ring systems that provide the nucleus for other compounds in this class. Chlorination of 3-methylbutyraldehyde (94) provides one of the components for building the imidazole ring. For bookkeeping purposes, the condensation of 94 with 0-benzyl glyoxal and ammonia can be... 

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