Imidazoles imidazole-fused ring system

Many methods were developed for the synthesis of imidazole fused-ring systems. The different structural types are listed in the table given below. 

Imidazole-fused ring systems Imidazole-fused ring types... 

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... 

Transformation of 1-carbamyltriazolines 49a to fused-ring systems (51) has been achieved through cyclization reaction with 1,l -carbonyldi-imidazole at 120°C for 1 hr (Scheme 22) (84ABC2913, 84JOC1073). 

The drag Fadrozole (9.61), which is an inhibitor of the enzyme aro-matase and used for the treatment of estrogen-dependent neoplasms, is an example of a fused imidazole derivative. The ring system is... 

Another novel fused-ring system is synthesized by reacting the aza Diels-Alder adducts, 24 and 25, with ethyl isothiocyanatoformate followed by base treatment of the resulting thiourea, thus providing l,3-dihydro-2/f-imidazole-2-thione 98 in 48% overall yield. Subsequent desulfurization with Raney nickel in ethanol provides the novel strained imidazole 99 in 29% yield ... 

Heterocyclic amines are compounds that contain one or more nitrogen atoms as part of a ring. Saturated heterocyclic amines usually have the same chemistry as their open-chain analogs, but unsaturated heterocycles such as pyrrole, imidazole, pyridine, and pyrimidine are aromatic. All four are unusually stable, and all undergo aromatic substitution on reaction with electrophiles. Pyrrole is nonbasic because its nitrogen lone-pair electrons are part of the aromatic it system. Fused-ring heterocycles such as quinoline, isoquinoline, indole, and purine are also commonly found in biological molecules. 

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 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>. 

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