Tetrahydropyridazines synthesis

There are some recent examples of this type of synthesis of pyridazines, but this approach is more valuable for cinnolines. Alkyl and aryl ketazines can be transformed with lithium diisopropylamide into their dianions, which rearrange to tetrahydropyridazines, pyrroles or pyrazoles, depending on the nature of the ketazlne. It is postulated that the reaction course is mainly dependent on the electron density on the carbon termini bearing anionic charges (Scheme 65) (78JOC3370). 

Ley developed an efficient tandem organocatalytic synthesis of chiral dialkyl 3-alkyl-l,2,3,6-tetrahydropyridazine-1,2-dicarboxylates 272 from /3-oxohydrazines 271. Compound 271 was obtained from commercially available achiral aldehydes and dialkyl azodicarboxylates using (6)-pyrrolidinyl tetrazole as the chiral catalyst. This synthesis proceeds with good to excellent yields (58-89%) and enantioselectivities (69-99% ee). The highest ee values are obtained for the most bulky di-/-butyl azodicarboxylate and the shortest branched aldehydes (Scheme 67) <2006SL2548>. 

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>. 

The substrate for the synthesis of cyclobutanes by elimination of molecular nitrogen is the 3,4,5,6-tetrahydropyridazine skeleton 1. The most important methods for obtaining these compounds are the hetero Diels-Alder reaction of suitable dienes with azo dienophiles followed by oxidative hydrolysis of the adducts, and the oxidation of six-membered cyclic hydrazines (see Houben-Weyl, Vol. E16d, pp 1-111 and ref 1). 

This method of nitrogen elimination from tetrahydropyridazines is frequently used in the synthesis of polycyclic systems. The thermolysis, as well as photolysis, of 2,3-diazabicy-clo[2.2.1]hept-2-enes gave bicyclo[2.1.0]pentanes via intermediate formation of cyclopenta-1.3-diyl, from which bicyclic compounds with one three-membered and one four-membered segment are formed this type of reaction is discussed in Houben-Weyl, Vol. E17b, pp 1089-1108 and 1163-1166. 

A number of methods for the synthesis of piperazic acid (7) and related derivatives are currently available as a result of growing interest in natural product chemistry and in their potential in medicinal chemistry. Their chemistry and conformational properties have been comprehensively reviewed. 2451 Racemic piperazic acid is obtained by condensation of penta-2,4-dienoic acid with phthalazinedione and subsequent reductive deprotection of the resulting A,A -bis(phthaloyl)-l,2,3,6-tetrahydropyridazine-3-carboxylic acid.12431 Resolution of racemic piperazic acid is achieved by fractional crystallization of the ephedrine salt of Nl-(benzyloxycarbonyl)piperazic acid from ethyl acetate. 246,2471 A typical route to enantiomerically pure (3S)-piperazic acid 56 starts from chiral 2-amino-5-hydroxyvaleric acid 55 as shown in Scheme 12.1248 Convenient stereoselective syntheses have been reported for 5-hydroxy- and 5-chloropiperazic acids as important constituents of natural cyclic peptides and depsipep-tides.1249,2521... 

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). 

Eeduction with sodium and ethanol has been used in the synthesis of hexahydropyridazine which is obtained together with 1,4-diaminobutane. Similarly, reduction of 3-(p-tolyl)-pyridazine gave besides the corresponding hexahydropyridazine also a substituted pyrrolidine. 3,6-Dimethylpyridazine, when reduced in this way, can give its dihydro or hexahydro analog.In all other cases of pyridazine reductions, no dihydro- and tetrahydropyridazines have been isolated, probably on account of their more ready reduc-ibility compared to aromatic pyridazines. 

Synthesis of 1,2-disubstituted perhydro-3,6-pyridazinediones and 6-(S-carboxybutyl)-4,5-dihydro-3(2Zf)-pyridazinone is reported. Tetrahydropyridazines were also synthesized from 3 2H)-pyridazinones by reduction with LiAlH4. ... 

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. 

Schmidt and his coworkers have cleaved the N—N bond of tetrahydropyridazines (20) with sodium in liquid ammonia as a step in the synthesis of 4-aminolyxose derivatives. Leblanc and coworkers have used carbohydrate-derived glycals as two-electron components in cycloadditions to dibenzyl azodicar-boxylate the adducts (e.g. 21 in Scheme 15) were subjected to methanolysis and the N—N bond was then cleaved using Raney nickel. ... 

Pyridazines, synthesis from hydrazines 84H(22)1821. A -Tetrahydropyridazines, mechanism of thermal and photodecomposi-... 

In other examples of the use of azo compounds in pyridazine synthesis, dialkyl azodicarboxylates undergo cycloaddition with dienes to give 1,2,3,6-tetrahydropyridazines. Azobis(formamidine) reacts similarly. Diethyl azodicarboxylate also reacts with furans to give an adduct which is transformed into a pyridazine by acid. In a photochemical synthesis,... 

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 method can be extended successfully to the synthesis of a 1,2-oxazine, by reacting 2-fluoro-l-(trimcthylsiloxy)buta-1,3-diene with nitrosobenzene.85 A similar diene 29 containing the trif-luoromethyl moiety instead of fluorine reacts with a variety of dienophiles, e.g. dienophile 30 affords the 1,2,3.6-tetrahydropyridazine derivative 31.86... 

TMSCN//7-toluenesulfonyl chloride is much more effective than TMSCN/benzoyl chloride for the preparation of Reissert compounds from pyridazine and methylpyridazines 4-methylpyridazine reacts exclusively at N-2/C-3. Some of the Reissert compounds undergo facile tautomerism on silica gel, but treatment of the crude compounds with DBU provides an efficient synthesis of 3-cyanopyridazines in about 75% overall yield (Scheme 20). With sodium borohydride instead of DBU, competing reductions give a mixture of the pyridazine and tetrahydropyridazine nitriles <86H(24)793>. 

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>. 

A convenient synthesis of pyridazine-3,4-dicarboxylic acid based on [4 + 2] cycloaddition of an electron deficient diazadiene has been developed (Scheme 102) and carried out on a molar scale. The azadiene is generated in situ from the precursor (124) (prepared from diethyl oxaloacetate and methyl carbazate followed by chlorination with sulfuryl chloride) and trapped with ethyl vinyl ether. The regiospecific cycloaddition gives the tetrahydropyridazine (125) as a mixture of cis and trans isomers which, with bromine in acetic acid, are transformed into diethyl pyridazine-3,4-dicar-boxylate. Saponification gives the diacid in an overall yield of 52% <90JHC579>. In a similar approach from the readily available ethyl 2-chloro-3-oxobutanoate, an efficient route to ethyl 3-methylpyridazine-4-carboxylate has been developed which gives the product in 56% overall yield. This route is claimed to be a practical alternative to the radical ethoxycarbonylation of pyridazines <91JHC1043>. 

Pyrroles tetrahydropyridazines, LDA in THF converts aromatic ketazines into dianions, which on hydrolytic work-up are converted into either pyrroles or tetrahydropyridazines, depending on the substrate. In the Piloly pyrrole synthesis ketazines are converted into pyrroles by treatment with ZnCIa or HCI. Examples ... 

Zhu and Chiba applied a TEMPO-mediated allylic C—H amination involving alkenyl hydrazones to the synthesis of tetrahydropyridazines 8 and dihydrophthalazines 9 (Scheme 5) (140BC4567). Optimal reaction conditions were found to be treatment of the respective hydrazone with 3 equivalents of TEMPO in A/,N-dimethylformamide (DMF) at 130°C, giving the corresponding products in moderate-to-high yields. 

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