Pyrido fused-ring systems

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]. 

The synthesis of pyridodiazine ring systems can be classified according to the relative location of nitrogen atoms in the diazine nucleus of the fused ring system as shown in formulas 246-248 for pyrido[v,y-2]pyridazines, pyrido[ ,y- ]pyr-imidines, and pyrido[x,y- ]pyrazines, respectively (Figure 2). Such fused ring systems have been subdivided according to the site of fusion z, that is, whether it is b-d. 

Several papers have been published on the synthesis and properties of fused-ring systems incorporating the 1,4-thiazine structure, mainly pyrido-[2,3-6]-l,4-thiazines, pyrazino[2,3-6]-1,4-thiazines, and pyrimido-[4,5-Z)]-l,4-thiazines, including some sulphur isosteres of dihydropteridines [e.g. (112)]. A detailed account of ring-chain tautomerism in 6-hydroxy-... 

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>. 

The proton affinities of the pyrido[2,3-/ ]pyrazine system for N-1 = 205.56, N-4 = 212.02, and N-5 = 216.32 kcal moP showed that the most basic site is at N-5, which is in agreement with the formation of the quaternary salt derivatives 16-19 as intermediates for the synthesis of imidazopyridopyrazine fused rings <1994H(38)283, 1991JCC675>. 

The tricyclic furo-fused 1,2,4-triazinium salt (74 X= O) reacts with nucleophiles such as sodium hydrogen sulfide, sodium diethyl malonate, or sodium ethyl cyanoacetate to yield the new ring systems thieno[2,3-e pyrido[l,2-Z>]-l,2,4-triazinium perchlorate (74 X= S) and cyclopenta(e]pyrido[ 1,2-b -1,2,4-triazines (75) [94CB1799]. 

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. 

In the case of the benzo-fused pyrido[2,l-c][l,2,4]benzothiadiazine ring system, reduction of the carbonyl group of (206) with lithium aluminum hydride to (207) <91AP(324)317, 72FES670>, and oxidation of a 2,2a-dihydro derivative (208) with mercury (II)-EDTA to (209) have been reported (Scheme 15) <91AP(324)317, 90AP(323)911>. 

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)... 

Pyrido[2,3- pyrimidine bicyclic systems represent interesting fused heterocyclic compounds having pharmacological and biological properties. Their syntheses are well documented in the literature. The pyridine or pyrimidine rings have been used as precursors for constructing the second heterocyclic ring. 

However, Aae can still be used in suitable cases as an indication of conformation, particularly for polycyclic compounds. Thus Aae measurements on TV-CH2X protons may be used to establish the cis or trans nature of the ring fusion in 1,3-heterocyclic systems. For example, the trans-fused perhydro-pyrido[3,2,l-iJ][3,l]benzoxazine (21) shows Aae 0.84 ppm, indicative of the anti-coplanar CH-nitrogen lone-pair geometry, whereas the cis-fused isomer (22), in which the nitrogen lone pair bisects the CH2 group, shows Aae 0.12 ppm.45... 

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). 

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