Cross-conjugated mesomeric betaines play an important role in heterocyclic synthesis. They can act as 1,4-dipoles in cycloaddition reactions or can be rearranged at higher temperatures to thermodynamically more stable compounds [2,3,4]. The rearrangement of cross-conjugated mesomeric pyrimidines has been extensively studied. When substituted on nitrogen with an aryl substitutent they can be rearranged to 2,3-disubstited 4-quinolones via unsaturated ?-lactame intermediates [2,3,5] (type A rearrangements [3])or via 2-oxoketenes to 4-hydroxy-2-quinolones (type B rearrangements [2]) [2,3,4,6]. In this paper we want to present type B rearrangements of pyridazino[2,3-a]pyrimidines in which the intermediate 2-oxoketene has two possibilities for ringclosure reactions to lead to thermodynamically more stable compounds. The thermolysis of pyrido[1,2-a]pyrimidines has been described before [6]. For this investigation two typs of pyridazino[2,3-a]pyrimidines were required. One with (the usual) electron-deficient pyridazine moiety (4) and one with with an electron rich pyridazine nucleus (7), i.e. with a high electron density at position 9 to allow an electrophilic attack of the expected ketene intermediate. The synthesis of the mesoionic compounds 4 and 7 requires the 2-amino-pyridazines 3 and 6. These compounds are readily available from the chloropyridazines 2 and 5 with the appropriate amine in boiling 1-propanol [7] or by heating in the amine itself without solvent [8], see Table 1. Compounds 2 (R=Me, Ph) were obtained from the corresponding lactams 1 in refluxing phosphorus oxychloride [7], while 3-chloro-5-hydroxy-6-phenyl-pyridazine 5 (which is an intermediate in the commercial synthesis of the herbicide PYRIDATE�) was provided by CHEMIE LINZ AG [9].
The mesomeric betaines 4 and 7 were prepared from the amines 3 and 6 with the help of substituted bis-(2,4,6-trichlorophenyl)-malonates (AME?s, magic malonates) [10] by standard procedures. In order to prevent early thermal rearrangement we have choosen refluxing chlorobenzene (b.p. 132 �C) as reaction solvent. We have prepared 30 compounds of type 4 and 6 compounds of type 7 (see Table 2).
For preliminary testing of the rearrangement behavior of these mesoions we have selected two compounds of each series (Scheme 2). From the first series we have selected two compounds (4r,ab) both with a meta-methoxy group in the N1-phenyl substituent in order to facilitate an electrophilic attack of the intermediate ketene at the para-position at the phenyl group. As expected, heating of 4r,ab in boiling diphenyl ether (b.p. 250�) lead to the 4-hydroxy-2-quinolones 9a,b (A) in 77% and 82% yield, respectively. The spectroscopic data suggest that compounds 9 exist (due to the formation of a hydrogen bridge between the OH group and a pyridazine nitrogen atom) predominatly in their tautomeric 2-hydroxy-4-quinolone form B. The outcome of the reaction is in complete analogy to the rearrangement of mesomeric pyrido[1,2-a]pyrimidines leading to N-pyridyl substituted 4-hydroxy-2-quinolones as describend by Lube [6]. Preliminary experiments (DSC) have shown that the presence of a methoxy group in para-position of the intermediate 2-oxo-ketene 8 seems not to be essential for the reaction pathway. Quite different results are obtained in the thermolysis reaction of 8-hydroxy-pyridazino[2,3-a]pyrimidines 7b,d . Under identical reaction conditions (boiling diphenyl ether) the pyrido[2,3-c]pyridazines 11a,b are formed. The presence of the enol moiety in the intermediate ketene 10 makes the pyridazine nucleus more favorable for an electrophilic attack than the phenyl substituent at N, regardless if unsubstituted or bearing a chloro substituent. The structural formulas of the 2-oxo-ketenes 8 and 10 present the situation just after ringopening. However, they can existist in several rotameric or tautomeric (e.g. 10) forms which are for instance required for the electrophilc ringclosure reactions. For more information on 2-oxo-ketenes see the review by C. Wentrup [4]. It should be mentioned that formula 11 represents only one structure of potential tautomeric isomers. The outcome of this reaction was not surprising since we have shown earlier [9,11] that at N1 unsubstituted pyridazino[2,3-a]pyrimidines rearrange also at 250� to pyrido[2,3-a]pyridazines. In this case there is no other other nucleophilic postion available. The results obtained demonstrate that mesomeric pyridazino[2,3-a]pyrimidines undergo ringopening at temperatures above 200� to 2-oxo-ketenes and that stabilization of these intermediates is directed by the nucleophilicity of the available C-atoms. EXPERIMENTAL 3-Chlor-6-methylpyridazine 2a A mixture of 50 mmol of the pyridazone 1a and 20mL phosphorus oxychloride was heated for 30 min under reflux. After cooling the phosporoxychloride was removed by destillation and the residue poored into ice-water. The solution was made alkaline and a yellow precipitate was filtered by suction. The filtrate was extracted twice with diethylether , dried with sodium sulfate and evaporated to dryness to yield 34% of 2a. 3-Chlor-6-phenylpyridazine 2b A mixture of 1 mol ofthe pyridazone 1b and 400 mL phosphorus oxychloride was heated for 1 hour under reflux. After cooling the solution was carefully poured into ice-water. The precipitate was filtered off and washed sometimes with water until the motherlique becomes neutral. The yield was 97%. General procedure for the synthesis of 3,6-substituted pyridazinones 3 A mixture of 10 mmol of the 3-chloropyridazinons 2a,b and 10 mmol of the corresponding aniline was heated in 30 mL of 1-propanol for 2-7 hours under reflux. After cooling the mixture was evaporated to dryness and the residue was trituated with diluted Na 2CO3-solution. The precipitate was filtered by suction , washed with water and recrystallized.General procedure for the synthesis of 3,6-substituted 5-hydroxy-pyridazinones 6 A mixture of 10 mmol of the 3-chloro-5-hydroxy-6-phenyl-pyridazinone 5 and 20 mmol of the corresponding aniline was heated in 60 mL of 1-propanol for 2-20 hours under reflux. After cooling the precipitated product was filtered by suction. Table 1 Experimental and Physical Data for Compounds 3
and 6
awithout solvent; after cooling
trituation with methanol General procedure for the synthesis of pyridazino[2,3-a]pyrimidin-1-ium-2-olates 4 and 7 A mixture of the 3,6-substitued pyridazinone 3 or the 3,6-substiuted 5-hydroxypyridazinone 6 and 12 mmol bzw. 20 mmol (for compounds 6) of the corresponding bis�2,4,6-trichlorophenylmalonate was heated in 50 mL of chlorobenzene for 1-5 hours under reflux. After cooling the solution was trituated with petrolether . The precipitate was filtered off and recrystallized. Table 2 Experimental and Physical Data for Compounds
4 and 7
General Procedure for the synthesis of the rearranged pyridazino[2,3-a]pyrimidin-1-ium-2-olates 9 and 11 2 mmol of the pyridazino[2,3-a]pyrimidin-1-im-2-olate was heated in diphenylether for 1 hour under reflux. After cooling to about 40-50�C the solution was trituated with petrolether.The precipitate was filtered by suction and recrystallized. Table 3 Experimental and Physical Data for Compounds 9
and 11
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