Pyrimidine-fused systems, synthesis

The cleavage of fused pyrazines represents an important method of synthesis of substituted pyrazines, particularly pyrazinecarboxylic acids. Pyrazine-2,3-dicarboxylic acid is usually prepared by the permanganate oxidation of either quinoxalines or phenazines. The pyrazine ring resembles the pyridine ring in its stability rather than the other diazines, pyridazine and pyrimidine. Fused systems such as pteridines may easily be converted under either acidic or basic conditions into pyrazine derivatives (Scheme 75). 

Pyrimidine-fused Systems.—The Gewald synthesis of thiophen analogues of anthranilic acid has opened the synthetic route to pyrimidine-fused thiophens. The interest in this field is mainly due to the potential pharmacological properties of these systems. Condensation of (603) with forma-mide at 200 °C yields (604). Similarly, (605) was prepared from 3-amino-2-methoxycarbonylthiophen or from its formamide derivative. Derivatives of (604) were also obtained by cyclization of the 2-amino-3-carboxamide... 

Pyrimidine-fused Systems.—o-Aminothiophencarboxylic acid derivatives have been extensively used for the synthesis of thienopyrimidine derivatives. Thus the mercapto-derivatives (464) have been synthesized by... 

The varied biological activity of coumarins fused with a benzopyrano pyrimidines ring system [1-6] has continued to stimulate a great deal of interest in the development of new methodologies for the synthesis of multi-substituted [ 1 ]benzopyranopyrimidines. 

Purines, Pteridines, and Related Systems.— This year has seen the development, particularly by Japanese workers, of several new and modified procedures for the synthesis of purines and other fused pyrimidine ring systems. Especially useful as precursors for these syntheses are the arylidene derivatives (241 X = NH2 or OH) and the 6-amino-azo-compounds (240 X = N). The amino-azo-compounds are cyclized directly to purine derivatives (242) on fusion with arylamines, " or,... 

Amongst other fused seven-membered ring systems, the synthesis of novel [l,2,5]selena (and [l,2,5]thia)diazolo[3,4-e][l,4]oxazepines from fused pyrimidine precursors has been described by Ueda and co-workers <00JHC1269>. 

Pyrimidine annulated heterocycles fused at positions 5 and 6 to uracil were synthesized via a three-step sequence starting from uracil 63 [20]. Firstly, the reaction with 3-bromocyclohexene gave the AT-allyl-vinyl core system 64 in 80% yield. Upon heating 64 in EtOH in the presence of HCl, aza-Claisen rearrangement gave rise to the C-cyclohexenyl uracil 65 in 38% yield. Final bromination ( 66) and dehydrogenation steps ( 67) allowed synthesis of the desired tricyclic fused uracil systems (Scheme 15). 

When the synthesis of a heterocyclic system containing a diazole fused onto l,2,3-triazin-4-one (e.g., imidazo[4,5-i [l,2,3]tnazin-4-one (Section 10.13.9.1.l(i)) and pyrazolo[3,4-rf [l,2,3]triazin-4-one (Section 10.13.9.1.1(ii))) or 1,2,3-triazole fused onto pyrimidin-4(7)-(di)one (e.g., [l,2,3]triazolo[4,5-rf pyrimidin-4(7)-(di)one (Section 10.13.9.1.l(iv))) is required, the synthesis of the six-membered ring is the most reliable method. There are several recent accounts of six-membered annulations onto 1,2,3-triazoles to give [l,2,3]triazolo[4,5-r/ pyrimidines (Section 10.13.9.1.l(iv)), which are valuable alternatives to 1,2,3-triazole annulation using nitrosation techniques <1996CHEC-II(7)489>. 

The sulfur can be reductively removed by one of the many methods utilized for sulfur heterocycles. For the fused pyrimidine (703) zinc in acetic acid can be used (64JOC2135). In the 7-formylamino analogue (704), however, Raney nickel in aqueous ethanol was the best reagent for the reductive cyclization to form adenines (705) (78JOC960). It has been pointed out that nucleophilic substitution at C-7 in the [l,2,5]thiadiazolo[3,4-d]pyrimidine system easily takes place. This makes the compounds (704) readily available as key substances in this convenient approach to the synthesis of 9-substituted adenine derivatives. 

The three diazines, pyridazine, pyrimidine, and pyrazine are stable, colourless compounds that are soluble in water. The three parent heterocycles, unlike pyridine, are expensive and not readily available and so are seldom used as starting materials for the synthesis of their derivatives. There are only four ways in which a benzene ring can be fused to a diazine cinnoline, phthalazine, quinazoline and quinoxaline are the bicyclic systems thus generated. 

One review of a synthetic nature covered new routes to pyridazino-fused ring systems <04SL1123>. In addition to this, there were two reviews focusing on specific medicinal applications of some diazines. One covered the design, synthesis and SAR of 5-[(l-substituted) alkyl (or vinyl)] pyrimidine nucleosides as potential inhibitors of herpes viruses <04MI2749>, and the other described 4-thiophenoxy-N-(3,4,5-trialkoxyphenyl)pyrimidine-2-amines as potent and selective inhibitors of the T-cell p561ck tyrosine kinase <04MI747>. 

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