Heteroaromatic ring construction

Best Synthetic Methods Construction of Aromatic and Heteroaromatic Rings... 

Aromatic and heteroaromatic rings are the heart of pharmaceutical design. Several useful methods for monocyclic and polycyclic aromatic ring construction have recently been reported. 

Like other 1,3-dipoles, azomethine ylides were mostly utilized in the ring construction of five-membered nitrogen heteroaromatics by a sequence of cycloadditions to acetylenes and formal oxidation. Thus, azomethine ylides were employed as the synthetic equivalents of nitrile ylides. Other synthetic applications of azomethine ylides, especially the intended utilization of stereochemical characteristics of the azomethine ylide cycloadditions, were quite rare. 

Abstract After a short presentation of major variants of nucleophilic substitution of hydrogen, application of these reactirais to introduction of substituents into aromatic and heteroaromatic rings and construction of heterocyclic systems are discussed. 

Reports discussing the use of quinoxalines as starting materials for the ring construction of different heteroaromatic compounds emerged in 2014. Nguyen and coworkers developed a new method for the generation of the phenazine ring via a base-promoted cyclization of 3-alkynylquinoxaline-2-carbonitriles with CH-acids, such as diethyl malonate, ethyl cyanoacetate. 

The approach to 3-trifluoromethyl-tetrahydro-l,2,4-triazaolo-/4,3-a/-pyrazine (3-trifluoromethyl-l,2,4-triazaolo-piperazine), the heterocyclic portion of the sitagliptin molecule, requires construction of the annulated ring on 2-chloropyrazine 4 to yield the intermediate 7. The latter is selectively hydrogenated in step iv to 8, maintaining the five-membered heteroaromatic ring. 

The most frequent methods for the preparation of 1,5-diheteropentalene systems involve construction of the second heterocyclic ring onto an existing heterocycle. Three new syntheses of iso-condensed heteroaromatic pyrroles and their derivatives... 

Sihcon-based hnkers can be apphed to the immobilization of aromatic and heteroaromatic entities on a sohd support Protodesilylation procedures used to cleave off the combinatorial compounds leave no functional groups on the final products [90-92]. One limitation of this protocol may be the relatively complicated and multistep synthesis of the actual linker unit. Usually, the starting material has to be bound to the hnker unit first, after which the resulting construct is attached to the support material. In addition, the conditions for the protodesilylation depend on the substitution on the arene ring. 

N-Acyliminium ions are versatile intermediates in organic synthesis they not only react with various nucleophiles such as electron-rich aromatic and heteroaromatic compounds but also undergo cycloaddition reactions with unsaturated compounds.It is especially noteworthy that N-acyliminium ions serve as electron-deficient 4t7 components in [4 + 2] cycloaddition with alkenes and alkynes. " This reaction serves as a useful method for the construction of heterocyclic rings containing a nitrogen atom. Acyclic structures containing amino and hydroxyl groups can also be synthesized from the initially formed cyclic compounds. 

The earlier reviews described a number of synthetic approaches to this system. The most generally useful, however, were observed to be those starting with A -aminopyridinium derivatives and constructing the five-membered ring. The chemistry of A -aminoazonium salts, and heteroaromatic N-imines in general, has been reviewed <81AHC(29)73>. Syntheses reported since the publication of the first edition continue to reflect the above-mentioned observation. 

---