Disubstituted-pyridazines

Direct chlorination of 3,6-dichloropyridazine with phosphorus pentachloride affords 3,4,5,6-tetrachloropyridazine. The halogen is usually introduced next to the activating oxo group. Thus, 1,3-disubstituted pyridazin-6(l//)-ones give the corresponding 5-chloro derivatives, frequently accompanied by 4,5-dichloro compounds as by-products on treatment with chlorine, phosphorus pentachloride or phosphoryl chloride-phosphorus pentachloride. 

Disubstituted pyridazine-3,6(l//,2//)-diones add halogens to the 4,5-double bond, followed by dehydrohalogenation to give 4-halo derivatives. 1,2-Disubstituted 5-bromopyridazine-3,6(l//,2F0 diones react with bromine to give the corresponding 4,5-dibromo derivative. The Mannich reaction with 2-arylpyridazin-3(2//)-one occurs at position 4. 

Mannich reaction with pyridazinone 1-oxides takes place at the a- or y-positions relative to the iV-oxide group, in contrast to the reaction in the pyridazinone series, where N-substituted products are formed. Pyridazin-3(2FT)-one 1-oxide gives first the corresponding 6-substituted derivative with excess of the reagents, 4,6-disubstituted products are obtained. When position 6 is blocked the corresponding 4-dialkylaminomethyl derivatives are obtained. 

Some 4,5-disubstituted pyridazines exhibit ring-chain isomerism involving heterospiro compounds. For example, 5-(o-aminophenylcarbamoyl)pyridazine-4-carboxylic acid exists in a zwitterionic form in the solid state, but in a solution of DMSO it is almost exclusively 3, 4 -dihydro-3 -oxospiro[pyridazine-5(2//),2 (l //)-quinoxaline]-4-carboxylic acid (134). The equilibrium is strongly influenced by the nature of the solvent, the substituents on the pyridazine ring and the nucleophilicity of the group attached to the phenyl ring (Scheme 48) <80JCS(P2)1339). 

AK(30)26l). 2-Acetoxyfuran-3(2i/)-ones react with hydrazine to give 3,6-disubstituted-4-ethoxycarbonylpyridazin-4(li/)-ones (184) as the main product, but with mono-substituted hydrazines in addition to these pyridazines anhydro-5-hydroxypyridazinium hydroxide (185) derivatives and some pyrazole derivatives are also formed (Scheme 102) (79JOC3053). The... 

Hydroxyphthalazin-l(2//)-one is obtained in a smooth reaction between phthalic anhydride and hydrazine hydrate and this is again the starting compound for many 1-substituted and/or 1,4-disubstituted phthalazines. The transformations of 1,4-dichloro-phthalazine, which is prepared in the usual manner, follow a similar pattern as shown for pyridazines in Scheme 110. On the other hand, phthalonitrile is the preferential starting compound for amino- and hydrazino-phthalazines. The most satisfactory synthesis of phthalazine is the reaction between a,a,a, a -tetrachloro-o-xylene and hydrazine sulfate in sulfuric acid (67FRP1438827), alt iough catalytic dehalogenation of 1-chloro- or 1,4-dichloro-phthalazine or oxidation of 1-hydrazinophthalazine also provides the parent compound in moderate yield. 

A variety of 3,6-disubstituted pyridazines have been quatemized and the structures of the salts determined by unambiguous synthesis, degradation, or reactivity, On the basis of these data the following... 

Synthesis of 3,5-disubstituted pyridazines by regioselective [4 + 2] cycloadditions with ethynyltributyltin and subsequent replacement of the organotin substituent [160]... 

A common method to synthesize pyridazines remains the inverse electron-demand Diels-Alder cycloaddition of 1,2,4,5-tetrazines with electron rich dienophiles. [4 + 2]-Cycloadditions of disubstituted 1,2,4,5-tetrazine 152 with butyl vinyl ether, acrylamide, phenylacetylene, and some enamines were performed to obtain fully substituted pyridazines 153 . This reaction was accelerated by electron withdrawing groups, and is slowed by electron donating groups, R1 and R2on the tetrazine. 

Intermolecular cross aldolization of metallo-aldehyde enolates typically suffers from polyaldolization, product dehydration and competitive Tishchenko-type processes [32]. While such cross-aldolizations have been achieved through amine catalysis and the use of aldehyde-derived enol silanes [33], the use of aldehyde enolates in this capacity is otherwise undeveloped. Under hydrogenation conditions, acrolein and crotonaldehyde serve as metallo-aldehyde enolate precursors, participating in selective cross-aldolization with a-ketoaldehydes [24c]. The resulting/ -hydroxy-y-ketoaldehydes are highly unstable, but may be trapped in situ through the addition of methanolic hydrazine to afford 3,5-disubstituted pyridazines (Table 22.4). 

Compounds which are of interest in this context include 4-oxadiazolylpyrid-azines (35, R = cyclopropyl, Et) [117], 6-aryloxy-2-hydroxyalkyI-3(27/)-pyri-dazinones [118], 3-halo-6-hydrazinopyridazines of type (36, R = substituted amino) [119], Ar-2-isoxazolylmethyl-substituted 3-iminopyridazines (37) [ 120], carbamates derived from 3,6-bis(hydroxymethyl)-4-pyridazinones (38, R = alkyl, Ph) [121], and iminodihydropyridazine derivatives (39, R1 = acyl R2 = H,MeS R3 = aryl) [122, 123]. In Hungary, antidepressant activity has been observed with some 3,6-disubstituted pyridazines of type (40) [124]. 

Dioximes are known to generate isoxazoles and related compounds when oxidized with IBTA. However, these reactions are of limited use because of formation of side products. For example, oxidation of dioximes of /B-diketones 159 gives rise to a mixture of 3,5-disubstituted oxazoles 160 and pyrazole-di-N-oxides 161 (82MI1). In another case, oxidation of dioximes 162 affords a mixture of the isomeric dihydroisoxazolo-isoxazoles 163 and pyridazine dioxides 164 (76S837 79JOC3524 82MI1). 

Examples of the 3-lithiation of both 2- and 2,6-disubstituted chloro- and methoxypyrazines, as well as 2-thiomethylpyrazine are known (88S881 90JOC3410 91JHC765, 91JOM(412)301] (Scheme 117). As with pyridazine, LiTMP has so far been the only base employed, and this same base system has also recently been used for the directed metalation of pyrazine... 

As a rule, the annular nitrogen atoms in 1,3,4-thiadiazoles are very reactive towards electrophiles as shown by facile alkylation reactions and quaternary salt formation. A thorough study on the quaternization of 2,5-disubstituted thiadiazoles, and its comparison with pyridazines has been published <84CHEC-i(4)545>. Electrophilic attack by benzyl chloride on 2-aminothiadiazole to give (44) in a regiospecific manner was utilized in the synthesis of an antiviral candidate <92MI 4io-oi>. 

Figure 4 Structure and numbering of 4,6-disubstituted 3-methyiisoxazoio[3,4-c/ pyridazin-7(6H)-ones.

Several other azolopyridazine ring systems have been prepared by similar approaches <2002FA89, 2002JHC329, 2001MOL203, 2000MOL1187>. For example, 6-substituted imidazo[4,5-tf pyridazin-7-ones are obtained from the reaction of 1,2-disubstituted 4-aroylimidazole-5-carboxylates and hydrazines <2002JHC329>. 

Two approaches to pyridazino[3,4- ][l,4]-oxazines by nucleophilic displacement of 3,4-disubstituted pyridazines were reported in CHEC-11(1996) <1996CHEC-11(7)737>, and two further reports of the use of this approach have appeared since <2001JMT(545)75, 2003JMT(666)625>. A further approach has also appeared, involving cyclization of a 2-[4-aminopyridazin-3-yloxy]acetic acid, as exemplified in Equation 128 <2002ZN(B)668, 2003JMT(666)625>. 

The H NMR spectrum of 2-methylpyrazino[2,3-d]pyridazine reveals a singlet at 5 9.76 for both the H-5 and H-8 protons. The H-2 proton absorbs at 5 9.17. The HNMR spectrum for 5,8-dichloropyrazino[2,3-d]pyridazine exhibits a singlet at 5 9.42 for both the H-2 and H-3 protons. Spectral data for several other 5,8-disubstituted derivatives of this ring system all give a singlet for the two H-2 and H-3 protons at 5 9.1-9.4 (66JHC512). 

Dichloropyrimido[4,5- ]pyridazines react readily with amines, potassium hydrosulfide, sodium azide (72CPB1528) and alkoxides (72CPB1522) to give the corresponding disubstituted amines, thiones, azides and alkoxides, respectively. Hydrolysis of the starting compounds (88) with 1% sodium hydroxide yields a mixture of the chloro products (89) and (90) (72YZ1312). 

Compounds containing this ring system are prepared by the reaction of 3,4-disubstituted pyridazines with hydrazine. 6-Methylpyridazine-3,4-dicarbaldehyde (150) condenses with hydrazine to give 3-methylpyridazino[4,5-c]pyridazine (151) (73JHC1081). 5-Oxo and 5,8-dioxo substituted pyridazino[4,5-c]pyridazines are prepared in like manner by condensing ethyl 3-formylpyridazine-4-carboxylates and diethyl pyridazine-3,4-dicarboxylates, respectively, with hydrazine. Pyridazine-3,4-dicarbonitrile (152) also reacts with hydrazine to give the diamino heterocycle (153) (67JHC393). 

All preparations of this ring system involve the condensation of hydrazine and substituted hydrazines with functionally disubstituted pyridazines. The unsubstituted ring compound (6) is prepared by reducing diethyl pyridazine-4,5-dicarboxylate with LAH to give the dialdehyde (156). This intermediate product is not isolated but is reacted immediately with hydrazine to give the desired ring system (6) (67CC1006). 

Most pyrimido[4,5-d]pyridazines are prepared from 4,5-disubstituted pyridazine precursors. The versatile intermediate pyrimido[4,5-cf]pyridazine-2,4-dione (85) can readily be formed in high yield from pyridazine-4,5-dicarboxamide (196) by reaction with sodium hypobromite in a Hofmann type reaction (68JHC53). 

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