Pyridazines reactions with enamines

The slightly lower lowest unoccupied molecular orbital (LUMO) energy of pyrido[3,4-r71pyridazine 5 compared to its isomer [2,3-r7] 6, calculated by the AMI method <1985JA3902>, explained the shorter time required for the pyrido[3,4-r7j-pyridazine to complete the [4+2] cycloaddition reaction with cyclic enamines of different ring sizes <1995M211, 2001ARK21>. 

Reaction of enamines with A-carbamidohydrazones (222) gives a mixture of pyridazine derivatives (88G187). A new general synthesis of... 

For steric reasons, the reaction of enamines with 1,4-diarylpyridazino-[4,5-d]pyridazines (260) takes place only with the unsubstituted pyridazine ring (91T3959). Numerous enamines were used in the reaction with 260. Among other products, a series of phthalazine derivatives was obtained. An efficient approach to isoquinoline derivatives is based on the reaction... 

Regiospecific inverse electron demand Diels-Alder reactions of enamines with 1,3-diazines or 1,2,3- and 1,2,4-triazines (see Section III.D.l), which on elimination of HCN or N2, respectively, produce a pyridine ring, can be used with 1,3,5-triazines and 1,2,4,5-tetrazines as a useful method for the synthesis of pyrimidines214-216 (1,3-diazines) and pyridazines217-219 (1,2-diazines). Examples of the use of this methodology are the preparation of the pyrimidine substituted benzomorphane 356 (equation 77)219 and the pyridazine 359 (equation 78), intermediate in the total synthesis of cis- and trans-trikentrin A216. 

The most useful procedure utilises a 1,4-keto-ester giving a dihydro-pyridazinone, which can be easily dehydrogenated to the fully aromatic heterocycle, often by C-bromination then dehydrobromination alternatively, simple air oxidation can often suffice. 6-Aryl-pyridazin-3-ones have been produced by this route in a number of ways using an a-amino nitrile as a masked ketone in the four-carbon component, or by reaction of an acetophenone with glyoxylic acid and then hydrazine. Friedel-Crafts acylation using succinic anhydride is an alternative route to 1,4-keto-acids, reaction with hydrazine giving 6-aryl-pyridazinones. Alkylation of an enamine with a phenacyl bromide prodnces 1-aryl-l,4-diketones, allowing synthesis of 3-aryl-pyridazines. ... 

Pyridine spiro compounds 221 were prepared by reacting 188 with cyanothioacetamide. Reaction of 188 with enamines yielded 222. Alkylidenemalononitriles were cyclized with aromatic diazonium chlorides to yield pyridazines. Cyanoacetamide was dimerized to 223 and reacted with phenyldiazonium chloride to yield the pyridazine 224. ... 

Recently, Rusinov et al. reported unexpected formation of cyclopenta[4,5]imidazo[l,2-3]-l,2,4,5-tetrazines 321 in the reactions of r-tetrazine hydrazones 319 with enamines 320 in methanol. When carried out in acetonitrile, these reactions produced the expected cyclopenta[4,5]pyridazines 322 (Scheme 76) <2003HC039>. 

Ketone 167 reacted with morpholine and p-TosOH to yield enamine 169, which undergoes Diels-Alder reaction with tetrazine 142 to yield the isolable intermediate 170. Aromatization occurs easily on further treatment of 170 with p-TosOH in boiling benzene leading to N-protected tricyclic pyridazines 171 (2002BMC1 Scheme 30). 

It was described in Sect. 7.8 of this chapter that chain-fluorinaled diazines can be synthesized using inverse-electron-demand Diels-Alder reactions. Some of the fused pyridazines can also undergo analogous reactions with electron-rich alkenes. In particular, Diels-Alder reactions of pyridopyrazine 1259 were smdied. It was found that 1259 reacted with enamines to give quinoline derivatives (e.g. 1260) (Scheme 291) [790]. Reaction of 1259 with ketene N,S-acetal 1261 led to a mixture of regioisomers 1262 and 1263, whereas reaction with A-methylindole gave complex mixture of products 1264-1267 (Scheme 292) [791]. 

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... 

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. 

These authors found that the tetrazinylhydrazone derivative 46 when reacted with pyrrolidinoenamine 47 in methanol yields the cyclopenta-fused derivative of the title ring system 48 in 94% yield. A similar transformation was carried out successfully by using morpholine-enamine in somewhat poorer yield. When the transformation was tried in acetonitrile as a solvent, a totally different reaction was observed a regular Diels-Alder reaction between the tetrazine ring and the enamine double bond (of inverse electron demand) took place to yield pyridazines. 

Pyrido[2,3-, pyridazine derivatives 48 have been synthesized by refluxing equimolar amounts of an appropriate 5-benzylidene-2,2-dimethyl-l,3-dioxane-4,6-dione 47 with 5-amino-6-phenylpyridazin-3(2/7)-one 46 in methanol or a methanol acetic acid mixture. The electron-poor carbon atom of the polarized carbon-carbon double bond of 47 is the electrophile attacking C-4 of the 5-aminopyridazinone 46. Imino-enamine tautomerization of the intermediate is followed by ring closure and subsequent loss of acetone and carbon dioxide affording the reaction products 48 as stable crystalline solids in 70-90% yield (Scheme 9) <2000T2473>. 

The [4 + 2] heteio Diels-Alder reaction of in sifti-generated chlorodiazadienes 127 with various electron rich dienophiles (such as enamines) yielded a series of substituted pyridazines 128 after aromatization <99JHC301>. In this publication. South noted that the use of trichlorohydrazones 126 (X = Cl) gave rise to chloro-substituted pyridazines 128, although not through the [4 + 2] mechanism. 

As previously noted, Haider and co-workers reported inverse electron demand Diels-Alder reactions of various enamines 130 with an appropriately substituted pyridazine 129 as a method for phthalazine synthesis as well (see section 6.2.4.3) <99SC1577>. 

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