Fused-Ring Heterocycles

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. 

In addition to the synthesis of industrially important azo dyes using heteroaromatic diazo components, intramolecular azo coupling reactions of heterocyclic diazonium ions also have interesting synthetic uses, because they lead to new fused-ring heterocycles, as shown by the diazotization of 2-amino-3-arylbenzimidazoles (12.7) in which, without isolation of the diazonium ion, a 1,2,4-triazine ring is formed (Kolodyazhnaya et al., 1973). Further examples of intramolecular azo couplings were reviewed by Tisler and Stanovnik (1980), and very extensively (403 references ) by Kishimoto et al. (1990). 

Aube took advantage of an intramolecular Schmidt reaction of azide 129 to provide the fused ring heterocyclic lactam 130 as a key step in a total synthesis of (+)-aspidospermidine... 

JOC2083). The rearrangement does involve presumably the base-promoted ejection of the bridging nitrogen atom, followed by lactam formation and aromatization. Other fused ring heterocycles have also been generated by this chemistry (Scheme 43). 

Fused ring heterocycles, prepared by cyclization of substrates with a tethered nitrogen nucleophile, have been used in the synthesis of amino sugars and aminocyclitols. The examples shown in Table 28 make use of imidate-type functionality (equation 101) to insure nucleophilic attack by nitrogen. The bro-mocyclization of N,W-dialkylaminomethyl ethers of 2-cyclohexen-l-ol to form bicyclic oxazolidine derivatives has been reported also.228b... 

The reaction of 2-mercapto-5-(phenylazo)-4,6-dimethylpyridine-2-carbonitrile with appropriate halogeno compounds yields S-alkylated products which can be cyclised to yield pyridothieno-pyrimidines (61a) or -triazines (61b) [94PS(90)85]. Related reactions have been employed to yield further fused ring heterocycles [95PS(104)143]. 

The properties of fused-ring heterocycles are generally similar to those of the simple heterocycles. Fused heterocyclic compounds are common in nature, and they are also used as drugs to treat a wide variety of illnesses. Figure 16-17 shows some fused heterocycles that occur naturally or are synthesized for use as drugs. 

Title Phenylethynyl and Styryl Derivatives of Imidazole and Fused Ring Heterocycles... 

Reactions of potentially high synthetic utility are intramolecular azo coupling reactions of heterocyclic diazonium ions to give new fused-ring heterocycles. Some examples are given in (25-27) . The use of heterocyclic diazo compounds in organic synthesis has recently been reviewed by Ti ler and Stanovink ,... 

B. C. Sekhar Cyclic 1,3-diones and their derivatives as versatile reactive intermediates in the synthesis of condensed fused ring heterocycles 2004JHC807... 

With a-di ketones 1- and 2-amino- and 1,2- and 1,5-diaminoimidazoles condense to give fused-ring heterocycles, with initial attack at the C-amino function. An N-amino group can be removed by treatment with nitrous acid. Oxidation of quaternary salts of 1-aminoimidazoles gives azoimidazolium salts, while manganese dioxide converts 1,2-di-aminoimidazoles into triazoles and triazines (see Section IV,D). 

Five-Membered Unsaturated Heterocycles 1151 Structures of Pyrrole, Furan, and Thiophene 1152 Electrophilic Substitution Reactions of Pyrrole, Furan, and Thiophene 1153 Pyridine, a Six-Membered Heterocycle Electrophilic Substitution of Pyridine Nucleophilic Substitution of Pyridine Fused-Ring Heterocycles 1158 Nucleic Acids and Nucleotides 1160 Structure of Nucleic Acids 1163 Base Pairing in DNA The Watson-Crick Model Nucleic Acids and Heredity 1166 Replication of DNA 1167... 

Reactions with aromatic binucleophiles form fused ring heterocycles (00T7267). Thus, when the reaction is performed with 2-aminothiophenol, compound 99 is converted into 2-trifluoroacety 1-4/7-1,4-benzothiazine (identified by X-ray crystallography) (Scheme 106). In the case of thioethanolamine hydrochloride, the product is 2-trifluoroacetyl-47/-1,4-thiazine. 

Ab initio dipole moments are also available for numerous other heterocyclic compounds (heterocycles with fused rings, heterocycles with two or more heteroatoms, etc.). 

Cyclic acetals of ketoses are important and useful compounds. Among other applications, they can be used as intermediates in the synthesis of numerous, useful sugar derivatives and as substrates for studies of conformational principles in fused-ring, heterocyclic A personal contribution by the author. 

Ethoxymethylene-2-phenyl-5(4H)-oxazolone (26) has been shown to be a useful synthon for the synthesis of a range of fused-ring heterocycles by its reactions with suitable aminoheterocycles. Examples include the pyrazolopyrimidines (27) and (28) and others (Scheme 5) [93H(35)9S5]. 

The purines are another biologically important class of fused-ring heterocycles. They contain a pyrimidine ring fused to an imidazole ring. 

---