Tetrahydropyridazines

Thermal decomposition of cis- and rans-3,6-dimethyl-3,4,5,6-tetrahydropyridazines affords propene, cis- and trans-1,2-dimethylcyclobutanes and 1-hexene. The stereochemistry of the products is consistent with the intermediacy of the 1,4-biradical 2,5-hexadienyl. The results indicate that thermal reactions of cyclic azo compounds and cyclobutanes of similar substitution proceed with similar stereospecificity when compared at similar temperatures (79JA2069). 

The screening was performed against different sources of PRs. PR isolated from human bone tissue was the most sensitive for this class of compounds. In contrast to marketed steroidal PR agonists, these compounds showed significant differences in the binding to other sources of PRs like T47D human breast carcinoma cells or receptor preparations from rabbit uterus. It was concluded that this effect could eventually lead to tissue-specific PR ligands. 

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Finally, several naturally occurring depsipeptide antibiotics containing the 2,3,4,5-tetrahydropyridazine or the hexahydropyridazine system have to be mentioned. In Japan, antrimycin (132, R = Me) has been isolated from Strepto-myces xanthocidicus MG125-CF1, which in vitro shows antibacterial activity (Mycobacterium smegmatis MIC 12.5 /rg/ml Mycobacterium tuberculosis MIC 50 /rg/ml) [366]. 

Stoodley developed an asymmetric synthesis of (5A)-2,3,4,5-tetrahydropyridazine-3-carboxylic acid (see Section 8.01.6.4). The ring construction was achieved via cycloaddition of dienes 295 bearing a tetraacetyl /3-D-glucopyranosyl moiety for chiral induction with azodicarboxylates (Equation 73) <1999J(P1)2591>. 

CHEC(1984) <1984CHEC(2)1> and CHEC-II(1996) <1996CHEC-II(6)1> covered examples of the cycloaddition reaction of diazoalkenes with alkenes yielding 2,3,4,5-tetrahydropyridazines. The diazadiene is normally generated in situ from an a-halogenated hydrazone with the assistance of base. 

More recently, Xi et al. 68 described the synthesis of conformationally rigidified dipeptides incorporating 2-acyl-2,3,4,5-tetrahydropyridazine-3-carboxylic acids 14 and hypothesized, although did not experimentally test, that these dipeptides could be utilized to enforce p-turns (Scheme 8). 

Scheme 8 2-Acyl Derivatives of 2,3,4,5-Tetrahydropyridazine-3-carboxylic Acids1681...

Cycloaddition reaction of diazadienes (generated in situ from an -halogenated hydrazone) with alkenes yielding 2,3,4,5-tetrahydropyridazines followed by aromatization is a general synthetic approach to substituted pyridazines (e.g., 131) a representative example is shown in Scheme 67 <1995TL5703>. 

Cyclic azomethine imines 2,2-dimethyl-4-oxo-3,4-dihydro-2/-/-pyrrolium-l-anilide (70) and 3,3-dimethyl-5-oxo-l-phenyl-2,3,4,5-tetrahydropyridazin-l-ium-2-... 

The asymmetric synthesis of hexahydro- and tetrahydropyridazines can be achieved from either 1- or 2-hetero-substituled 1.3-dienes, provided that the heteroatom is linked to a chiral auxiliary. The diene ( , )-7, bearing D-glucose as chiral auxiliary, reacts with dialkyl diazenedicar-boxylates to give the cycloadducts 8 as single diastereomers ( ll NMR)5. From one adduct obtained using di-/er/-butyl diazenedicarboxylate, (35 )-2,3,4,5-tetrahydropyridazine-3-car-boxylic acid was satisfactorily prepared and isolated as the trifluoroacetic acid salt 9. 

Treatment of amino ester 67 with WBOC oxaziridine 65a afforded a-hydrazino carboxylic acid 68 in 72% yield <1998JOC6421>. This compound is a precursor to (33, 43)-4-hydroxy-2,3,4,5-tetrahydropyridazine-3-carboxylic acid, important structural units found in the potently antitumor antibiotic luzopeptins. 

Diphenyl-2,3,4,5-tetrahydropyridazine (XLIX) is structurally similar to a benzyl-hydrazone of propiophenone, and accordingly, a four-eletron polarographic wave is observed in acid solution with formation of L [306]. The electrode reaction is as follows ... 

Hexahydro derivatives 283 are favored when 3 mol of LAH are allowed to react with 2,3,4,5-tetrahydropyridazin-3-ones (281). Use of less reducing... 

Study of the reduction of 2,3,4,5-tetrahydropyridazine-3-ones, which can be regarded as cyclic acylhydrazines, with lithium aluminum hydride revealed that, in proportions varying with conditions, 1,4,5,6-tetrahydropyridazines, hexahydropyridazines, and/or 1,4-dihydropyridazines are formed. Although 3,6-diphenyl-4,5-dihydropyridazine has been isolated and is reasonably stable, related 4,5-dihydro analogs readily dimerize or trim-... 

The mass spectral fragmentation of many pyridazines was investigated. " Studies of fragmentation of 2,3,4,5-tetrahydropyridazin-3-ones revealed that four principal fragmentation paths can be observed i.e., loss... 

Antrimycins (cirratiomycins are the same substances) are linear polypeptide antibiotics (from Streptomyces xanthocidicus and St. ciratus) containing in the central part (3S)-2,3,4,5-tetrahydropyridazine-3-carboxylic acid. Syntheses of this acid have been developed (91CL1953 93S809) and the total synthesis of antrimycin Dv was described [92JCS(CC)1186],... 

The amino nitrogen of 2,3,4,5-tetrahydropyridazines behaves normally and reacts with methyl isothiocyanate to give the 2-(Af-methylthiocarbamoyl) derivative <84JHC889>. Similarly, both 1,2,3,6-tetrahydropyridazine and its 1 -ethoxycarbonyl derivative react with arylisocyanates (Scheme 43) to give high yields of aryl carbamoyl derivatives <93JHC45>. 

Oxidation of adjacent enantiomeric piperazic acids in the cyclic peptide (88) with air or hypochlorite (89MI 601-01 > gave the corresponding peptide containing two 2,3,4,5-tetrahydropyridazine-... 

The synthesis of pyridazine derivatives from hydrazones includes the thermal cyclization of 2-arylhydrazono-3-oxo-5-phenyl-4-pentenenitriles (readily obtained from ethyl cinnamate by condensation with acetonitrile followed by Japp-Klingemann type reactions) to l-aryl-3-cyano-6-phenyl-5,6-dihydro-4(l//)-pyridazinones (Scheme 85) <86JHC93>, and base-induced cyclization of a hydrazone of a 4-chloro-l-arylbutan-l-one to prepare a 2,3,4,5-tetrahydropyridazine (Scheme 85) <88JHC1543>. An earlier route to 6-carboxy-5-hydroxy-2-phenyl-3(2//)-pyridazinone via condensation of benzenediazonium chloride and dimethyl acetonedicarboxylate has been adapted to give a series of aryl derivatives either as esters (by thermal cyclization) or as acids (by cyclization with hydroxide). Both cyclizations proceed in high overall yield (Scheme 86) and decarboxylation of the acids also proceeds in high yield <89JHC169>. 

The total synthesis of 3(S)-carboxy-4(S)-hydroxy-2,3,4,5-tetrahydropyridazine, the unusual amino acid constituent of luzopeptin A, in 32% overall yield from malonaldehyde dimethyl acetal utilizes regioselective ring opening of a chiral epoxide (114), (Scheme 94). Immediate acidification of the relatively unstable intermediate hydrazono acid with trifluoroacetic acid gives the product in 65% yield from (114) the cw-isomer was made as a racemate <89JOC3260>. 

Tetrahydropyridazines are produced by cycloaddition of azoalkenes, derived from hydra-zones of ethyl bromopyruvate, with electron rich alkenes (Scheme 101). Good yields are obtained... 

Pyridazine derivatives are not commonly found in nature but those that do occur include the monamycin and cirratiomycin antibiotics, and luzopeptin A, a dimeric cyclic depsipeptide which intercalates with DNA and has antibiotic and antitumor activity. These compounds contain hexa-hydro- or tetrahydropyridazine residues which, in the case of luzopeptin A and the cirratiomycins, is present as the novel amino acid unit 3(S)-carboxy-4(S)-hydroxy-2,3,4,5-tetrahydropyridazine <89JOC3260>. 

Carboxy-2-(p-methylbenzoyl)ethyl]thio-5,6,7,8-tetrachloro-4-(3,4-dimethyl-phenyl)phthalazine (27) with hydrazine hydrate gave 5,6,7,8-tetrachloro-l-(3,4-dimethylphenyl)-4-(3-oxo-6-p-tolyl-2,3,4,5-tetrahydropyridazin-4-ylthio) phthalazine (28) (substrate, Et2), hot synthonj. portionwise reflux, 6h ... 

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