Pyrido-fused system

There are many possibilities for mesomeric betaine formation in the 1,2,4-triazine series, illustrated by the A-methyl-oxo compounds in structures (495)-(498), and in the benzotriazine series by (499). These compounds seem not to have been investigated, however, and the closest example we have found is the pyrido-fused system (500) <77JOC443>. See also Section 6.11.9.1.4. 

Treatment of the quinoxalinylalkanoic acids 5 with alkaline sodium borohydride results in cyclization to give the pyrrolo or pyrido fused systems 6. Although both these products are obtained in high yields, corresponding cyclizations with higher homologues (5, n = 4-6) could not be effected. ... 

Various pyrido-fused systems have shown good antibacterial properties. For example, two types of analogs of linezolid, six imidazo[l,2-a]pyridines and six [l,2,4]triazolo[l,3-a]pyridines, demonstrated good in vitro and in vivo (mouse) potential against methicillin-resistant Staphylococcus aureus and other antibiotic-resistant bacterial strains (13MCL1074). 

All four possible pyridopyrimidine systems, pyrido[2,3-Chemical Abstracts nomenclature is used throughout this Chapter. For the reasons given above (Section 2.15.1), the pyrido[2,3-fused systems, e.g. (5) and (6) (numbering shown), are also known. The linear benzo fused derivatives of pyrido[3,2-[Pg.201]

Both the possible non-bridgehead pyridopyrazines, pyrido[2,3-f ]pyrazine (386) and pyrido[3,4-f ]pyrazine (387), are well known, the numbering being as shown. In the older literature they may be known as pyridino-2, 3 -2,3- and -3, 4 -2,3-pyrazines, as 1,4,5- and 1,4,6-triazanaphthalenes, or as 5- and 6-azaquinoxalines respectively. Some derivatives may also be referred to and numbered as deazapteridines, or as deaza derivatives of various natural products (see Section 2.15.16.3). Of the benzo fused systems, representatives of one angular (388) and two linear (389) and (390) derivatives of the [2,3-f ] system are known, but only the linear benzo fused [3,4-6] system (391). 

Whereas in all previously mentioned inverse cycloaddition reactions [h]-fused pyrido annelated systems are formed, some reactions are described which lead to [c]-pyridine annelated bicyclic systems. 5-(Butynylthio)pyrimidines (R = Ph, NHCOCH3) give on heating at 180°C in nitrobenzene 5-R-2,3-dihydrothieno[2,3-c]pyridines (89T803). 5-Propynyloxymethylpyrimidines also readily undergo cycloaddition into l,3-dihydrofuro[3,4-c]pyridines (89T5151) (Scheme 39). Considerable rate enhancements were observed with quaternized pyrimidinium salts. Whereas... 

Jones et al. [73JCS(P1)968] assume that delocalization over the whole fused system of furo- (6a), pyrido- (304), and thienotropones is minimal because the 1 H-NMR data of their tropone rings are similar even though the electron availability in the heterocyclic rings is very different. However, Jin (92MI2) found differences in the contribution of 0-tt systems of several azolotropones (cf. Section III,A,2,c). 

In the presence of ammonium acetate, one of the Michael-acceptor systems in 4,5-bis(aryl-methylene)-4,5-dihydropyridazine-3,6-(l//,2//)-diones undergoes addition to ethyl cyanoac-etate at 160-170°C26 or malononitrile in refluxing ethanol.25 This is followed by ring closure with the appropriately situated oxo group and ammonia yielding the pyrido-fused moiety in... 

The pyrazine ring is stable to permanganate oxidation, and this accounts for a variety of pyrazinecarboxylic acids that have been prepared from quinoxalines, benzo-fused quinoxalines including phenazines, and pyrido-fused pyrazines . In other fused systems, particularly pter-idines, the pyrimidine ring is easily hydrolyzed under either acidic or basic conditions to give numerous 3-aminopyrazinecarboxylic acid derivatives. 

Further work is required to establish the orientation of two other fused systems derived from pyrido[2,3-h]pyrazines. As the assignment of the phenacyl compound 137 as the 3-oxo derivative is uncertain, the structure of the furo compound 138, obtained on treatment of compound 137 with phosphorus pentoxide in concentrated sulfuric acid at 100° must also... 

Solvent-free Assembly of Pyrido Fused-ring Systems... 

Microwave-assisted solvent-free synthesis of pharmacologically important pyrido fused-ring systems has recently been accomplished and is an improved method for assembly of a variety of pyridopyridazine and quinoline derivatives. Benz-1,3-oxazine formation has also been investigated in dry media using AI2O3-KF as a solid base (Scheme 8.75) [187]. 

Scheme 8.75. MW-assisted synthesis of pyrido fused-ring systems.

The development of a cost-effective microwave-assisted procedure for synthesis of pyrido fused-ring systems, by applying the tert-amino effect, has been described by Van der Eycken and coworkers (Scheme 10.62) [126]. 

True electrophilic substitution is very difficult in pyridopyridazines. For example, the [3,4-d] parent (286) is inert to hot 65% oleum (68AJC1291), and although formation of a 3-bromo derivative (308) was reported in the [2,3-d] series, it seems to have arisen by an addition-elimination reaction via the dibromide (309) (69AJC1745). Attempted chlorination led to ring opening. A similar effect was observed in the [3,4-d] system, where an 8-bromo derivative was obtained (77BSF665), and in iV-oxides of the pyrido[2,3-c]pyridazine and fused pyridazino[3,4-c]isoquinoline series (72JHC351). The formation of (311) from (310)... 

Irradiation of the 3-pyridyltetrazolium salt (367) similarly gives a mixture of 5,6-tetrazolo fused derivatives of these systems (368), which can be converted to the parent systems by various reducing agents (75TL569,56CB563). Use of the 4-pyridyl isomer gave the pyrido[4,3-cjcinnoline anologues. 

The NMR spectra of some derivatives of the benzo fused pyrido[3,4-f ]quinoxaline (1-deazaflavin) (391) system have been recorded (74JCS(P1)1965). 

Lipophilicity and specific hydrophobic surface area were determined by using reversed-phase thin-layer chromatography for fused heterocyclic ring systems including five pyrido[2,iy][l,2,4]triazine derivatives <1998MI64>. 

Synthesis of the ortho- and peri-fused pyrido[3,2,l- 1[l,3,2]benzodiazaphosphorine ring system was accomplished from the quinoline carboxamide derivative 197 by treatment with phosphoryl chloride <1978JHC1169, 1979JHC897>. The iV-chloropropyl derivative 198b could be transformed to the tetracycle 199 (Scheme 27) <1979JHC897>. 

Compounds 39 and 40, in which a pyrazole ring is fused to a pyrido[2,3-2,]pyrazinc, are produced as a 3 2 mixture by reaction of pyridine-2,3-diamine with 3-methyl-l-phenylpyrazoline-4,5-dione (Equation 9) <1999T8475>, and the synthesis of compound 41 (Scheme 11) exemplifies a different approach to the same ring system <1997JCM318, 1997JRM2026>. 

Classical methodology was used to prepare the dibenz[b,f]azepine derivative 21 (R = substituted pyrido[2,3-d]pyrimidine) utilising amide ion formation from dibenz[b,f]azepine itself with sodium hydride and then iV-alkylation with 2,4-diamino-6-bromomethylpyrido[2,3-d]pyrimidine. The bulky bis-fused azepine moiety was required to introduce steric bulk in the system and to study the effect of this on inhibition of the enzyme dihydrofolate reductase <00JHC921>. 

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