Study of tert -amino effect: the role of substituents in isomerization of 5-amino-4-vinyl-3(2 H )-pyridazinones

The thermal isomerization reaction of ortho -vinyl tert -anilines and their heterocyclic analogues via tert -amino effect affords tetrahydropyrido-fused heterocyclic ring systems with a new C-C bond formation between the vinyl and tert -amino groups. A novel series of 5-amino-4-vinyl-3(2 H )-pyridazinone derivatives were prepared to study the role of substituents of the pyridazinone ring and the vinyl group in their isomerization reaction to tetrahydropyrido[2,3-d ]pyridazines. In particular, 6-phenyl and 5-trioxopyrimidinediylmethylene substituents were found to significantly increase the rate of isomerization. Compounds possessing benzyl and methyl groups as amino substituents isomerized with the involvement of the benzyl group. On the basis of experiments with deuterated compounds, an intramolecular pathway was confirmed for the isomerization.


Introduction
Type 2 tert-amino effect, originally the thermal isomerization of ortho-vinyl-tert-anilines with ring closure to quinolines, 1 has been employed for the syntheses of angularly annelated tetrahydropyrido-fused polycyclic ring systems, including derivatives of quinolines and their aza-and diaza-analogues, with biological interest. 2For instance, oxazinoquinolines have recently been claimed to possess remarkable antibacterial properties due to their gyrase inhibitory activity. 3We described the synthesis of annelated analogues of CNS-active pyridazinooxazepines and -thiazepines 4 via type 2 tert-amino effect. 2Several angularly-fused pyrido [2,3-d]pyridazine ring systems were obtained from 5-azacycloalkyl-4-vinylpyridazinones prepared from 5-iodo-2-methyl-3(2H)-pyridazinone 5 in several steps.No examples have however been reported for isomerization of 5-amino-4-vinylpyridazines substituted in the 6position or possessing a dialkylamino group.In this paper, syntheses of such new pyridazinones, and their thermal isomerization to otherwise hardly accessible polycyclic compounds will be reported.
ARKAT USA, Inc.The thermal isomerization reaction via tert-amino effect was generally carried out in dry N,N-dimethylformamide (DMF).The dicyanovinyl compounds 9a, c-e and pyrimidinediylmethylene derivatives 10a-c isomerized at 100 o C to give 11a, c-e and 12a-c, respecitvely, whereas isomerization of dicyanovinyl compound 9b to 11b could only be achieved at reflux temperature.Generally, and in accordance with our previous findings, thermal isomerization of pyrimidinediylmethylene derivatives 10 was significantly faster than that of the respective dicyano derivatives 9.The presence of pyrimidinetrione ring in compounds 10 may facilitate the isomerization reaction by steric and electronic effects: i) making a favorable geometric arrangement for hydrogen migration (cf.reference 2), and ii) efficiently delocalizing the developing negative charge in the transition state.
The 6-aryl substituent itself exerted an accelerating effect on the isomerization too.Furthermore, two sets of experiments indicated a particularly strong rate-enhancing effect of its combination with a 4-pyrimidinediyl substituent.The first comparison was made by the reactions of aldehydes 8d and 8e with DMB.These reactions in ethanol at ambient temperature, representing the typical conditions applied for the Knoevenagel condensation with DMB, afforded as isolable products the spiro-substituted derivatives of pyridazino [4,5-c]quinolizine 12d and pyridazino [4',5':5,6]pyrido[2,1-c] [1,4]oxazine 12e ring systems, indicating that their formations were too fast to allow to isolate condensation products of type 10 in pure forms.In the second set of experiments isomerizations of 10a and 10i were compared.The former compound, due to the combined effect of 6-phenyl and 4-pyrimidinediyl substituents, reacted to tricyclic compound 12a much faster than 10i did to 12i.
The important role of 6-phenyl substituent in the isomerization was also apparent from the reactions of compounds 9a and 9i.While compound 9a, possessing a 6-phenyl substituent, could be smoothly isomerized to 11a in DMF at 100 o C, its analogue 9i with no 6-phenyl substituent, did not isomerize even upon prolonged heating (72 h) in DMF, instead, a complex mixture was obtained.No cyclization was achieved by application of AlCl 3 catalyst in refluxing xylene (after a 8-h reaction time, the starting material was completely unchanged, a further boiling resulted in decomposition); and decomposition could only detected in neat at 200 o C. One possible explanation for the rate-accelerating role of the bulky phenyl substituent may be related to its steric buttressing effect. 7The 6-phenyl group may reduce the conformational freedom of the neighboring tert-amino group, thereby favorably influencing both the hydrogen migration and ring closure.
It is noteworthy that isomerization of hexadeuterodimethylamino derivatives 9g and 10g in DMF gave 11g and 12g trideuterated in 1-N-methyl group, and di-and monodeuterated in 2-and 4-positions, respectively, indicating that no deuterium was lost, whereas isomerization of 10a in D 2 O by microwave heating afforded 12a with no deuterium incorporation.These findings definitely prove the intramolecular nature of the rearrangement. 1,2he observation that the dimethylaminopyridazinone 9a isomerized significantly slower than the azacycloalkyl analogues 9c-e can be understood, supposing a two-step mechanism, by the stability difference in the respective iminium intermediates (and thereby the transition states of their formations) obtained via hydride (or sigmatropic hydrogen) migration from the alphacarbon of amino group to the methylene carbon of the pyrimidinediylmethylene substituent. 2For a similar reason, it could be expected that replacement of one of the methyl groups with a benzyl group should accelerate the isomerization with full control of the regiochemistry; in fact, the regioselective type 2 tert-amino effect had already been observed in a few cases. 8eaction of aldehydes 8f and 8h with DMB gave a mixture of condensation and isomerization products 10f + 12f and 10h + 12h, indicating enhancement of isomerization.To make complete the ring closure reaction and to isolate the spirocyclic products 12f, 12h in pure forms, the reaction mixtures were shortly refluxed in ethanol (Schemes 3, 4).Interestingly, the isomerization of 10f exclusively gave 12f, while its regioisomer, compound 13 was not detected at all (Scheme 3).
Similarly, isomerization of the isoquinolinyl derivative 10h led to the formation triazachrysene ring system 12h with no detectable amount of its regioisomer 14 (Scheme 4).

Scheme 4
Constitution of 12f and 12h could be unambiguously proven by nmr data.The regiochemistry is determined by the migration aptitudes of hydrogens.In both cases, isomerization took place with the involvement of one of the benzylic hydrogens leading to the more stabilized iminium double bond in the dipolar intermediates 10fA vs. 10fB, and 10hA vs. 10hB, and in the respective transition states.
In summary, isomerization of novel series of 4-vinyl-5-aminopyridazinones via type 2 tertamino effect led to the formation of new pyridopyridazines in moderate to high yields, indicating some new features and wide synthetic scope of the reaction.In particular, a phenyl substituent located ortho to the tert-amino group and a cyclic electron-withdrawing vinyl substituent may significantly accelerate the reaction.
While the intramolecular nature of the rearrangement reactions was confirmed by deuteration experiments, and some new information could be provided on the scope of type 2 tert-amino effect.Although, we feel that a step-wise mechanism may operate in the formation of tetrahydropyridine ring, a concerted mechanism for the ring formation could not be fully excluded.This question and to find new extensions of the reaction will challenge our further work.

Experimental Section
General Procedures.All melting points were determined on a Kofler apparatus, and are uncorrected.The IR spectra were recorded on a Perkin-Elmer 1600 FTIR instrument in potassium bromide pellets.The 1 H NMR spectra were recorded at ambient temperature in the solvent indicated, using the 2 H signal of the solvent as the lock and tetramethylsilane as the internal standard.Chemical shifts (δ) are given in ppm and coupling constants (J) in Hz.Bruker AM at 200 MHz and Varian Mercury Plus spectrometer at 400 MHz were used. 13C NMR spectra were recorded on the same spectrometers at 50 and 100 MHz, respectively.The assignments of 13 C NMR spectra were supported by DEPT-135 spectra.All new compounds gave satisfactory elementary analytical data (C, H, N); these analyses were performed on a Carlo Erba Elemental Analyzer Model 1012 apparatus.Mass spectrometric experiments were performed on a reverse geometry VG-ZAB-2SEQ instrument (in case of compounds 9a, 9c, 9e, 9g, 9i, 10a, 10b, 10g, 11a, 11g, 12a and 12g).Fast atom bombardment (FAB) ionization with 30kV Cs + ions was used, samples were dissolved in CHCl 3 and put on the probe using DHB matrix.Accelerating voltage was 8 kV.Microwave irradiation experiments were carried out a monomode CEM-Discover MW reactor in the standard configuration as delivered, including proprietary software.The experiments were executed in a MW process vial (10mL) with control of the temperature by infrared detection.After completion of the reaction, the vial was cooled to 50 o C via air jet cooling.For flash column chromatography Kieselgel 60 (Aldrich, 0.040-0.063mm silica gel) was used; for TLC analysis Silica gel 60 F 254 (Merck) plates were applied.Solvent mixtures used for chromatography are always given in a vol/vol ratio.The reagents were obtained from commercial sources and used as received.Solvents were dried and distilled prior to use.Compounds 5 6 and 6 5 were prepared according to the literature procedures cited.

General procedure for preparation of aldehydes (8) by Vilsmeier-Haack reaction. Typical example
A solution of 7a (0.0044 mol) in anhydrous DMF (8 mL) was cooled by ice-water bath.A solution of POCl 3 (1.3 mL) in anhydrous DMF (3.1 mL) was added dropwise to the mixture 0-6 o C. The reaction mixture was allowed to warm to room temperature, and was heated at 60 o C for 6 hours (monitored by TLC).After evaporation of the solvent (under 60 o C in vacuo), ice (30 g) was added to the brown oily residue and the mixture was allowed to warm to room temperature.Then it was made alkaline with aqueous 40 % sodium hydroxide (pH=8) and the resulting solution was extracted with chloroform (5x30 mL).The combined organic phases were dried over anhydrous magnesium sulphate.The solvent was evaporated in vacuo to give the crude product (in this case 8a) which was purified by column chromatography and/or (re)crystallization.

General procedure for the synthesis of malononitriles (9a-h). Typical example
To a solution of aldehyde (0.005 mol) 8 in ethanol (10 ml), malononitrile (0.005) and 1-2 drops of piperidine were added.The mixture was stirred at room temperature until the starting material had been consumed (monitored by TLC).The precipitated product was then filtered off, washed with ethanol, diethyl ether and hexane.The crude product was purified by flash column chromatography with a mixture of dichloromethane and ethyl acetate (1:1) as the eluent.
ARKAT USA, Inc.      : 312.Based on the comparison of spectra of 9g to those of 9a, it was confirmed that no deuterium was lost (>98% deuterium).

General procedure for the isomerization of vinyl compounds 9: preparation of compounds 11
Compound 9 (0.005 mol) in anhydrous DMF (10 ml) was heated at 100 o C (in case of compound 9b and 9g at 155 o C) until the starting material had been consumed (monitored by TLC).After evaporation of the solvent in vacuo, water (5 mL) was added to the oily residue, and the mixture was extracted with chloroform (3x5 mL).The combined organic phases were dried over anhydrous magnesium sulphate.The solvent was evaporated in vacuo, and the crude product was purified by column chromatography or crystallization.In case of compounds 11a, 11b and 11d, the precipitated crystals were filtered off and washed with water (3x2 mL).The crude product was purified by column chromatography or crystallization.