Pyrimido 4,5,i/ pyridazines

Nucleophilic reactivity at positions 5 and 8 of pyrimido[4,5-i pyridazines was reviewed in CHEC(1984) <1984CHEC(3)329> and in CHEC-II(1996) <1996CHEC-II(7)737>. More recently, the preparation and amination of a 4-chloro species (Scheme 15) has been reported, although details given are limited <1998W098/35967>. 

Thiazolyl)pyrimido[4,5-i/]pyridazines have been prepared by utilizing the reaction of the active methylene compound 46 with benzenediazonium chloride (Scheme 24) to give a hydrazone, which cyclizes spontaneously <1999JPR147>. A further approach described recently <2002HAC108> involves reaction of the malononitrile derivative 47 with a further equivalent of malononitrile, forming a pyrimidine with a suitably disposed hydrazine, which cyclizes on exposure to strong base (Scheme 25). 

Dihydro-2,5,8-trisubstituted pyrimido[4,5-alkyl halides or alkyl sulfates and sodium hydride in DMF (72YZ1316). If this reaction is carried out with benzyl bromide and sodium hydride, the 1,4-bisbenzyl product can be obtained (73YZ1043). Alkylation of (91) with ethylmagnesium bromide gives the dialkylated product (92) (75CPB1488). 

Pyrimido[4,5-d]pyridazines with a further annulated ring are formed from hydroxyalkyl-amino-substituted pyrimido[4,5-tf]pyridazines.52 Thus. 6-chloro-9-phenyl-2,3-dihydroimidazo-[l,2-6]pyrimido[4,5-(i]pyridazine (11) is obtained from the (hydroxyethyl)amino-substituted compound 10.52... 

Pyrimido[4,5-c]pyridazine-5,7-diones cleavage, 3, 344 synthesis, 3, 356, 357 Pyrimido[4,5-[Pg.810]

In the manner already described i vide supra) for pyridazinopyridazines, pyrimido[4,5-f]pyridazines can be formed by reaction of a 4-hydrazinopyrimidine with a dialkyl acetylenedicarboxylate (Scheme 19) in principle, an indazole side product is possible, but this is not observed in practice <1999TL1793>. 

IR spectral data for several pyrimido[4,5-cf]pyridazines have been reported (68JHC845). A comparison of UV data for several 8-amino substituted 5-chloro-2-phenylpyrimido-[4,5-d]pyridazines and 5-amino substituted 8-chloro-2-phenylpyrimido[4,5-(i]pyridazines has been made. The p.Ka values for these compounds have also been reported (Table 3) (76BSF1549). Hiickel MO calculations have been made (66JSP(19)25). 

Pyrimido[4,5-d]pyridazine derivatives are readily cleaved under both acidic and basic conditions. Reaction of 2-phenyl-5,8-dimorpholinopyrimido[4,5-hydrochloric acid gives a mixture of four isolated products 2-phenyl-8-morpholinopyrimido[4,5-d]pyridazin-5(6//)-one (96), 4-hydroxy-6-morpholinopyridazin-3(2jy>one (97), 4-amino-5-formyl-3,6-dimorpholinopyridazine (98) and benzoic acid (99). 

Thirteen diazinodiazines without bridged heteroatom are theoretically possible. All of these have been reported in the literature. There are (i) four pyridazinopyridazines, namely pyridazino-[4,3-c]pyridazine (A), pyridazino[3,4-c]pyridazine (B), pyridazino[4,5-c]pyridazine (C), and pyridazino[4,5-[Pg.738]

The most important experimental data concerning NMR, IR, and UV spectroscopy have been reported in CHEC-I. Much information about structure, reactivity, and the most popular synthetic approaches to pyrimido[4,5-c]pyridazines has been reported in a review by Wamhoff, Dzenis, and Hirota <92AHC(55)129>. In addition an AMI SCF-MO study has been published <88JOC3900>. 

The most common synthetic approach by a Hofmann-type reaction of pyridazine-4,5-dicarboxamide or the cyclization of a / -enamino ester with guanidine or formamide have been reported in CHEC-I. Some new strategies have been developed. A novel and simple way to pyrimido[4,5-c/]pyridazines is the coupling of a functionalized pyrimidine (e.g. (60)) with benzenediazonium chloride to the arylhydrazone derivative (e.g. (61)) which cyclizes to the pyrimidopyridazine (62) (Scheme 11) <82JCS(P1)2667>. 

The reaction of 5,8-dimorpholino-2-phenylpyrimido[4,5-c/]pyridazine (1) with Grignard reagents proceeds with formation of various 4-substituted derivatives 262 which can be dehydrogenated to the corresponding fully conjugated pyrimido[4,5-r/]pyridazine systems (see Section 7.4.6.I.2.)61... 

Pyrimido[l,2-a][l,8]naphthyridines synthesis, 2, 599 Pyrimido[5,4-c]oxadiazine purine synthesis from, 5, 591 Pyrimido[4,5-6][ 1,4]oxazine synthesis, 3, 312 Pyrimido[2,1 -i]pteridine structure, 3, 284 Pyrimido[5,4-g]pteridine structure, 3, 284 Pyrimidopurines, 5, 566 Pyrimido[4,5-c]pyridazine, aryl- H NMR, 3, 335... 

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