Pyridazino pyridazin-1 -ones

Pyridazino[4,5 -c]isoquinoIine, 6-aryI-synthesis, 3, 244 Pyridazino[3,4-c]isoquinoIines alkylation, 3, 238 JV-oxide, 3, 327 synthesis, 3, 247-248 Pyridazino[4,3-c]isoquinolines synthesis, 3, 247 Pyridazino[4,5-c]isoquinolines alkylation, 3, 238 Pyridazin-3(2H)-one, 6-acryIoxy-polymers, 1, 288... 

Partial saturation of the pyridazino ring of 3-acylamino-4//-pyrimido[l,2-A pyridazin-4-ones and the pyrazino ring of 3-acylamino-4//-pyrazino[l,2-tf]pyrimidin-4-ones in EtOH/AcOH system using Pd/C catalyst, resulted in the respective 6,7,8,9-tetrahydro derivatives in good yields <2000JHC783>. 

The linearly condensed pyridazino[6,l-A]quinazolines can be synthesized by tandem [6+0 (a)] cyclizations, forming the pyrimidine and the pyridazine rings in the same step. Thus, 1,2,3,4-tetrahydro-10//-pyridazino[6, l+]quinazolin-2,10-dione 108 was prepared by thermal cyclization of 106 or 107 (Scheme 12) <1999RJ0286, 1998RJ0534>. Heating/ra r-2-amino-l-cyclohexanecarbohydrazide with 3-(/>-chlorobenzoyl) propionic acid in toluene, the appropriate 2-(/<-chlorophenyl)-3,4,5 ,6,7,8,9,9 -octahydro-10//-pyridazino[6,l- ]quinazolin-10-one was prepared in 35% yield <1998JHC201>. 

A special class of synthesis is the utilization of retro-Diels-Alder (RDA) reactions. A double RDA sequence was used to prepare the pyrimido[l,2-A]pyridazin-3-one 118. In this versatile method both reactants of the parent compound were constructed from cyclopentadiene. The parent compound 117 contains two norbornene units and decomposes on heating in toluene in a double RDA reaction leaving two double bonds in the target heterocycle. Similarily, the parent compound 119 decomposes in a single RDA reaction to yield the benzologue, pyridazino[6,l-3]-quinazolin-10-one 120 (Scheme 13) <2000SL67>. 

Pyridazines continued to play a central role in the construction of new biologically active compounds. 2,7-Dihydro-3//-pyridazino 5,4,3-17 acridin-3-ones were synthesized as cytotoxic agents <05BMC1969> and 6-(5-chloro-3-methylbenzofuran-2-sulfonyl)-2//-... 

Bischler-Napieralski cyclization of pyridazin-6-one 134 with POCI3, and subsequent hydrogenation of the cyclized product 135 over Pt02, gave rise to 2,3,4,6,7,llZ -hexahydro-l//-pyridazino[6,l-fl]isoquinoline (51) (75CPB3056). Treatment of Reissert compound 136 with NaH gave 116-cyano-l, 2,3,116-tetrahydro-4//-pyrido[2,l-fl]phthalazin-4-one (137) (80JHC433). 

Similarly, mono- and bicyclic 1,2-diazines tethered to indole dienophiles by only one alkylene chain 14 afford tetra-and pentacyclic condensed carbazoles 15. Unactivated pyridazines undergo these thermally induced [4+2] cycloaddition reactions only very sluggishly. However, the examples with the more activated electron-deficient pyridazines, especially pyridazine diesters and pyridazino[4,5-, pyridazindiones, demonstrate the synthetic usefulness of this strategy for the construction of polycyclic carbazoles (Equation 3) <2004T6495>. 

Substituted 3,5-dihydro-4//-pyridazino[4,5-, ]indol-4-ones 50 <2001H(55)1105, 2002T10137> and 2,5-dihydro-l/7-pyridazino[4,5-7]indol-l-ones 52 <2006T121> have been synthesized from 5-(2-aminophenyl)pyridazin-3(2/0-ones 49 and 4-(2-aminophenyl)pyridazin-3(27/)-ones 51, respectively. For this purpose diazotization of the amino groups was followed by a nucleophilic substitution with sodium azide affording aryl azides. Upon heating of these compounds, the ring-closed products were obtained most probably via the formation of an electrophilic nitrene (Scheme 10). 

Pyridazino[4,5-, pyridazin-l(277)-one 82 shows a similar behavior as pyridazin, 5-dicarbonitrile 77 since it is a pyridazine derivative with electron-withdrawing groups at C-4 and C-5 too. Haider used this fused pyridazine for the synthesis of cycloalkene annelated phthalazin-l(2//)-ones 83 in good yields (54-87%) (Scheme 17) <1995H(41)2519>. 

Pyrazino[2,3-d]pyridazine-5,8-dione (420) can be prepared from pyrazine-2,3-dicarboxylic acid anhydride (419). Condensation of hydrazine with ethyl 5-acylpyridazine-4-carboxylates (421) gives pyridazino[4,5-d]pyridazin-l(2//)-ones (422) (79M365). 

Tetrahydroxypyridazino[4,5-djpyridazine is prepared by condensing tetraethyl ethylenetetracarboxylate with hydrazine (72JCS(P1)953). Condensation of hydrazine with ethyl 5-acyl-4-pyridazinecarboxylates (159) gives pyridazino[4,5-J]pyridazin-l(2H)-ones (160) bearing an alkyl or aryl substituent at the 4-position. Pyridazines (159) are prepared by the homolytic acylation of ethyl 4-pyridazinecarboxylate (79M365). 

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]

There are only a few experimental data available. One x-ray crystal structure determination and one Huckel MO calculation were reported in CHEC-I. Now there are more theoretical data available. With the AMI SCF-MO method some pyridazino[4,3-c]pyridazine derivatives have been calculated <88JOC3900>. New quantum chemical calculations <90MI 719-01) and some more experimental data are reported <85KGS1428>. 

A rather similar method was reported by Matsuo et al. <78JAP(K)53002497, 87JA2717). 4-Chloro-5-(2-hydroxyethylamino)-3(2//)-pyridazin-3-ones (138) were converted upon treatment with base to the corresponding pyridazino[4,5-6][l,4]oxazinones (139). The ring closure fails for compound (138 R = H) (Equation (17)). 

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