Pyridazines general

In general, pyridazine can be compared with pyridine. It is completely miscible with water and alcohols, as the lone electron pairs on nitrogen atoms are involved in formation of hydrogen bonds with hydroxylic solvents, benzene and ether. Pyridazine is insoluble in ligroin and cyclohexane. The solubility of pyridazine derivatives containing OH, SH and NH2 groups decreases, while alkyl groups increase the solubility. Table 1 lists some physical properties of pyridazine. 

The electron impact mass spectrometric fragmentations of (E)-3- and ( )-4-styryl-pyridazines show that the intensity ratio of the M and (M -1)" ions, the general degree of fragmentation and the elimination pathways of nitrogen are the most characteristic features distinguishing between the two isomeric compounds (81JHC255). 

A very useful procedure for introducing a cyano group into a pyridazine ring is the Reissert-type reaction of the A/-oxide with cyanide ion in the presence of an acyl halide or dimethyl sulfate. The cyano group is introduced into the a-position with respect to the A-oxide function of the starting compound. The yields are, however, generally poor. In this way, 6-cyanopyridazines (111) can be obtained from the corresponding pyridazine 1-oxides (Scheme 33). 

The reactivity of halogens in pyridazine N- oxides towards nucleophilic substitution is in the order 5 > 3 > 6 > 4. This is supported by kinetic studies of the reaction between the corresponding chloropyridazine 1-oxides and piperidine. In general, the chlorine atoms in pyridazine A-oxides undergo replacement with alkoxy, aryloxy, piperidino, hydrazino, azido, hydroxylamino, mercapto, alkylmercapto, methylsulfonyl and other groups. 

Halogenated pyridazines are generally inert as arylating agents in Friedel-Crafts reactions. The only example is the reaction of 3,6-dichloropyridazine with resorcinol and hydroquinone to give 3-aryl-6-chloropyridazines. 

Homolytic acylation of ethyl pyridazine-4-carboxylate is a convenient general method for preparation of 4-acylpyridazines (Scheme 42) (79M365). 

Since the pyridazine ring is generally more stable to oxidation than a benzene ring, oxidation of alkyl and aryl substituted cinnolines and phthalazines can be used for the preparation of pyridazinedicarboxylic acids. For example, oxidation of 4-phenylcinnoline with potassium permanganate yields 5-phenylpyridazine-3,4-dicarboxylic acid, while alkyl substituted phthalazines give pyridazine-4,5-dicarboxylic acids under essentially the same reaction conditions. 

Pyridazinecarbohydrazides are prepared in the normal way from an ester or acid chloride and hydrazine or a substituted hydrazine, generally in good yields. Pyridazines with two ortho alkoxycarbonyl groups give cyclic hydrazides with hydrazine, which are pyridazinopyridazines. 

Scheme 59). If phenyliodoso bistrifluoroacetate is used as the oxidizing agent the major product is an isoxazoloisoxazole, but pyridazine 1,2-dioxides are formed in minor amounts together with other products. With lead tetraacetate, in general, pyridazine 1,2-dioxides are the major products. 

A large number of pyridazines are synthetically available from [44-2] cycloaddition reactions. In one general method, azo or diazo compounds are used as dienophiles, and a second approach is based on the reaction between 1,2,4,5-tetrazines and various unsaturated compounds. The most useful azo dienophile is a dialkyl azodicarboxylate which reacts with appropriate dienes to give reduced pyridazines and cinnolines (Scheme 89). With highly substituted dienes the normal cycloaddition reaction is prevented, and, if the ethylenic group in styrenes is substituted with aryl groups, indoles are formed preferentially. The cycloadduct with 2,3-pentadienal acetal is a tetrahydropyridazine derivative which has been used for the preparation of 2,5-diamino-2,5-dideoxyribose (80LA1307). 

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

This synthetic appproach has been used in a few cases for the preparation of pyridazines from diazo compounds and cyclopropenes. In general, cycloadducts (176) are formed first and these rearrange in the presence of acid or alkali to pyridazines (Scheme 98) (69TL2659, 76H(5)40l). Tetrachlorocyclopropene reacts similarly and it was found that the stability of the bicyclic intermediates is mainly dependent on substitution (78JCR(S)40, 78JCR(M)0582>. 

Apart from a short section in an early book on phthalazines (53HC(5)198), the only previous general account of significance occurs in a chapter in a now dated volume on fused pyridazines, which covers work up to 1969 (73HC(27)968), and which also includes bridgehead nitrogen derivatives not relevant to this review. A later review (75MI21504) does exist but is in Japanese. 

The nucleophilic substitution reactions in pyrido-[2,3-f>]- and -[3,4-f ]-pyridazines in general follow the usual pattern of polyaza heterocycles. Oxo groups in the 2-, 3- and 6-positions of [2,3-f ]-ones, and in the 2- and 3-positions of [3,4-f ]-ones have been... 

The reaction of a-oxophenylhydrazones with 2-amino-1,1,3-tricyanopropene and diethyl 1-cyano-2-aminopropene-l,3-dicarboxylate has been shown to afford polyfunctionally substituted pyridazines and cinnolines <96JCR(S)434>. A study of haloazodienes has led to a new, general... 

The Diels-Alder reaction is a useful way of synthesizing six-membered carbocyclic rings. Since ADC compounds are usually better dienophiles than the corresponding C=C compounds, the Diels-Alder reaction provides a good general route to pyridazines, and their reduced derivatives. Although vast numbers of examples of Diels-Alder reaction involving ADC compounds have been reported, not many of these have been aimed specifically at heterocyclic synthesis. 

This review has attempted to bring together the reactions of ADC compounds which are useful in heterocyclic synthesis, and to develop the general trends that have so far appeared in their reactivity. Thus, in general, ADC compounds are more powerful dienophiles than the corresponding C=C compounds, particularly when the azo bond is in the cis configuration. However, they are also more reactive as enophiles and electrophiles, and may react as such even in cases where Diels-Alder (or other) cycloaddition is formally possible, and where the corresponding C=C compounds do react as dienophiles. Nevertheless, despite this added complication, the major use of ADC compounds has been as dienophiles in the synthesis of pyridazines... 

A number of pyridazines have been prepared by standard condensations of enediones with hydrazine but a general synthesis of the intermediate enediones is notable. This involved iodine-copper exchange of an iodoenone 3, followed by reaction of the resulting cuprate with acid chlorides. However, only a few of these enediones were actually converted into pyridazines <06OL1941>. 

To corroborate the proposed mechanism, the catalytic reductive aldol coupling of acrolein with phenyl glyoxal monohydrate was performed under 1 atmos. elemental deuterium. Exposure of the aldol product to excess hydrazine in situ results in formation of the pyridazine, which incorporates precisely one deuterium atom in a manner consistent with the general mechanism proposed in Scheme 22.4 (Scheme 22.9). 

Generalized valence bond interaction energies were computed for mono/poly-nitrogenous five- and six-membered heterocycles.203 Results that diverged from those obtained by other methods were obtained only for poly-nitrogenous systems such as pyridazine, benzotriazole, and tetrazole, which may confirm Bird s earlier finding123 204 that electron delocalization is not a stand-alone and direct measure of aromaticity for nitrogenous heterocyclic compounds. 

In Japan, a variety of heterocyclylaminophenylpyridazinones as represented by the general formula (29) have been prepared and investigated [89-92]. Structure-activity relationships have been discussed [92] additional classes of compounds in which the heterocyclic substituent is separated from the aminophenyl ring by a carbon chain have been patented [93,94]. From these studies, a novel class of pyridazine-derived cardiotonics and vasodilators has emerged. 

It is not surprising to see that most of the bio-active compounds discussed in this review are 1,2-diazine derivatives bearing heteroatom substituents either at C-3 or at C-3 and C-6, since pyridazinones and pyridazinediones, utilized as intermediates in the synthesis of such derivatives, have been known for a long period and are generally conveniently accessible. On the other hand, there are so far only a few examples of pyridazine-derived pharmacological agents in which the parent system is linked to a functionalized carbon side-chain only. This may be attributed to the fact that many of the required synthetic building blocks had remained unexplored until very recently [15,173,438-441]). 

---