Pyridazines acylation

When nitration of pyridazine iV-oxides is carried out with acyl nitrates (prepared in situ from acyl chlorides and silver nitrate) the reaction takes place at the /3-position relative to the iV-oxide group. Under these circumstances only mononitro derivatives are formed. For example, nitration of pyridazine 1-oxide with acetyl nitrate yields 3-nitropyridazine 1-oxide (17%) and 5-nitropyridazine 1-oxide (0.8%), whereas with benzoyl nitrate a better yield of 5-nitropyridazine 1-oxide is obtained. 

A substituted acyl amino group can be introduced by reaction of pyridazine 1-oxide with A-phenylbenzonitrilium hexachloroantimonate 3-A-benzoylanilinopyridazine is formed (75JOC41). 

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). 

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

Protonated pyridazine is attacked by nucleophilic acyl radicals at positions 4 and 5 to give 4,5-diacylpyridazines. When acyl radicals with a hydrogen atom at the a-position to the carbonyl group are used, the diacylpyridazines are mainly converted into cyclo-penta[ f]pyridazines by intramolecular aldol reactions (Scheme 43). 

Side-chain lithiation with lithium diisopropylamide and subsequent alkylation or acylation is a practical method for the preparation of various alkyl-, alkenyl- and acyl-methyl-pyridazines 78CPB2428, 78CPB3633, 79CPB916) (Scheme 47). 

Pyrazolo[3,4-d]pyridazines (555) can be prepared readily from hydrazines and pyrazoles substituted in positions 4 and 5 with an acyl and an ester group, or with two ester groups. 4,5-Pyrazolinediones have been used as starting materials for the synthesis of the quinoxaline derivatives (548) (see above) and of pyrazolo[3,4-e][l,2,4]triazines (556)... 

Pyridazine, 3-alkylidene-2,3-dihydro-synthesis, 3, 28 Pyridazine, alkylthio-synthesis, 3, 27 Pyridazine, 3-alkynyl-synthesis, 3, 28 Pyridazine, amino-acylation, 3, 35 diazotization, 3, 35 reaction... 

Pyridazine-3(2H)-thione, 4,5,6-triphenyl-ring contraction, 3, 29 Pyridazineth lones acylation, 3, 37 glycosides... 

Pyridazin-6(IH)-one, 3,4,5-trihalo-nucleophilic substitution, 3, 25 Pyridazinones acylation, 3, 16 alkoxy... 

Addition of A-mesityl benzimidazolyl carbene 720 to an a,/3-unsaturated aldehyde generates a homoenolate intermediate that undergoes an addition/acylation sequence with azomethine imine 719 to afford (3R, 5S, 6S )-177-pyrazolo[l,2- ]pyridazine-l,8(5//)-diones 721 with excellent diastereoselectivity. Compound 721 (Ar = R = Ph) treated with sodium hydoxide in methanol or benzylamine provided nearly quantitatively, ring-opened products 722a and 722b, respectively (Scheme 116) <2007JA5334>. 

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]. 

Moreover, there are several patents and reports on cephalosporins and 7-alkoxy derivatives thereof, which are characterized by a pyridazine-derived substituent attached to the thiazine ring. Some typical examples are given in formulae (126) [347-356], (127) [357], (128) [358], (129) [359, 360] and (130) [355, 361-363] in which R1 represents a variable acyl group. 

Treatment of pyrazoles 14a-d with hydrazine hydrate affords py-razolo[3,4-(3npyridazines 15a-d. However, an attempt to convert 16 into a pyrazolo[3,4-i/]pyridazine resulted in acyl group cleavage and the formation of 17 (Scheme 2) (77HCA2171). 

The synthesis of 2-acylpyridazin-3(2//)-ones has been discussed in Section 8.01.5.5.3. These compounds have been used as mild acylating reagents for amines <2002S733>. Symmetrical and unsymmetrical 1,3,4-oxadiazoles were also synthesized starting from these 2-acyl(or aroyl)pyridazin-3(2//)-ones <2003S560>. 

Preparations of pyridazino[3,4- [l,3]oxazines by ozonolysis of pyrrolo[2,3-b]pyridazine-3-carboxylates and from the reaction of A -(4-ethoxycarbonylpyridazin-3-yl)phosphinimines with acyl halides were described in CHEC-II(1996) <1996CHEC-11(7)737>. A simpler form of the latter approach has now been reported <1994CC2451>, wherein the 1-A -oxide of 3-aminocinnoline-4-carboxylic acid undergoes cyclization with acetic anhydride (Equation 126). The isomeric pyridazino[4,3-, [l,3]oxazines have been prepared in a similar manner (Equation 127) <1997PHA838>. 

The structure of the pyridazine-based antidepressant agent minaprine (34-6) departs markedly from both the older tricyclic drugs and the more recent selective serotonin re-uptake inhibitors. There is evidence that the compound acts via a dopa-mimetic route. Friedel-Crafts acylation of benzene with itaconic anhydride (34-1) leads to the keto-acid (34-2). Condensation with hydrazine leads to the formation of the hydrazine and hydrazide bonds the double bond shifts into the ring to give the fully unsaturated pyridazinone (34-3) this is then converted to the chloride (34-4) in the usual way. The displacement of halogen by the amine on 3-(A -morpho-lino)propylamine (34-5) affords (34-6) [36]. 

Nitration of pyridazine A-oxides with acyl nitrates prepared from acyl chlorides and silver nitrate also occurs at the (3-position relative to the /V-oxide group. Thus, pyridazine 1-oxide yields 3-nitropyridazine 1-oxide. 

Tetrahydroxypyridazino[4,5-djpyridazine is prepared by condensing tetraethyl ethylenetetracarboxylate with hydrazine (72JCS(P1)953). Condensation of hydrazine with ethyl 5-acyl-4-pyridazinecarboxylates (159) gives pyridazino[4,5-J]pyridazin-l(2H)-ones (160) bearing an alkyl or aryl substituent at the 4-position. Pyridazines (159) are prepared by the homolytic acylation of ethyl 4-pyridazinecarboxylate (79M365). 

Diethyl pyrimidin6-4,5-dicarboxylates react readily with hydrazine to give pyrimido-[4,5-df]pyridazine-5,8-diones (72CPB1513). In a similar manner the acyl pyrimidines (202) react with hydrazines to give the products (203) (76BSF1549). Hydrazines also react with... 

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