Pyridazines cycloadditions

Pyridazine carboxylates and dicarboxylates undergo cycloaddition reactions with unsaturated compounds with inverse electron demand to afford substituted pyridines and benzenes respectively (Scheme 45). 

An intramolecular [4 + 2] cycloaddition is represented by a thermal conversion of allylphenoxy- and allyloxyphenoxy-pyridazines into xanthenes (80CPB198). 

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... 

The other main source of various pyridopyridazines from pyridines are the [4 + 2] cycloaddition reactions, already mentioned (Section 2.15.8.3), between vinylpyridines and azodicarboxylic esters (79T2027, 79KGS639) or triazolidinediones e.g. 78KGS651). 2-Vinyl-pyridines gave reduced pyrido[3,2-c]pyridazines (370), 4-vinylpyridines gave [3,4-c] analogues, whilst 2-methyl-5-vinylpyridine furnishes a mixture of the [2,3-c] and [4,3-c] compounds. Yields are low, however, and these remain curiosities for practical synthetic purposes. 

The only recorded synthesis of this type from a pyridazine involves the [4 + 2] cycloaddition of the lactim ether (374) with l,2,4,5-tetrazine-3,6-dicarboxylic ester, which proceeds with loss of nitrogen and methanol from the intermediate adduct to give the pyrido[2,3-t/]pyridazine (375) (77AP936). 

There are several useful syntheses which effectively commence with the cycloaddition of oxygen, a nitroso compound, an azo compound or a sulfinylamine to a 1,3-diene leading to the corresponding 1,2-dioxins, 1,2-oxazines, pyridazines or 1,2-thiazines. Examples of the transformation of these adducts into five-membered heterocycles are shown in Scheme 114 together with leading references. 

Pyridazine-3,6-dione, 3,6-dihydro-[4- 2] cycloaddition, 3, 38 ring contraction, 4, 148 synthesis, 3, 38... 

Asymmetric dipolar cycloaddition of azomethine imines derived from diazoal-kane-pyridazine cycloadducts 98JHC1187. 

Dipolar cycloadditions of diazoalkanes to pyridazines 98JHC1187. 3(2//)-Pyridazinones in modem synthetic andmedicinal chemistry 98JHC1075. 

Ab initio Hartree-Fock and density functional theory calculations were performed to study the transition state geometry in intramolecular Diels-Alder cycloaddition of azoalkenes 55 to give 2-substituted 3,4,4u,5,6,7-hexahydro-8//-pyrido[l,2-ft]pyridazin-8-ones 56 (01MI7). 

The reaction of oxepin with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate affords a 2 1 mixture of products 9 a and 10, whose formation can be rationalized by a [4+2] and a [4 + 6] cycloaddition, followed by nitrogen extrusion.235 With 2,7-dimethyloxepin, only dimethyl 6,8-dime-thy 1-2.4a-dihydrooxepino[4,5-c/]pyridazine-l,4-dicarboxy late (9b) as product of the [4 + 2] cycloaddition can be isolated.235 236... 

The reaction of several substituted imidazo[4,5-c/]-, pyrazolo[3,4-r/]- and triazolo[4,5-zf]pyrid-azines 3 with ynamines, in competition with [4 + 2] cycloaddition, leads to [2 + 2] derivatives 4, which rearrange to l,2-diazocines5.7 8 The reaction seems to be sensitive to the substituents, as replacement of the electron-withdrawing group R on the pyridazine ring of the pyrazolo compound (A = N, B = CH) by chlorine completely inhibits both the [4 + 2] and [2 + 2] cycloaddition reactions. The X-ray structure of the imidazo derivative 5 (R = Ms, A = CH, B = N) reveals a tub conformation of the eight-membered ring. 

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

Palladium-catalyzed [3+3] cycloaddition of (2-(acetoxymethyl)-2-propenyl)-trimethylsilane with azomethine imi-nes, for example, l-benzylidene-3-oxopyrazolidin-l-ium-2-ides, leading to appropriately substituted hexahydro-7-methylene-177-pyrazolo[l,2- ]pyridazin-l-ones has been reported <2006JA6330>. 

A 1,2-diazetidine has been proposed as an intermediate in the reaction of pyridazine-3,6-dione (12) with styrene.87 The observed product was thought to arise from addition of water to the 1,2-diazetidine, although the alternative more likely explanation involving a dipolar intermediate (cf. Scheme 5) was apparently not considered. In the photochemical reaction of styrene with DEAZD, a 1,2-diazetidine structure was tentatively assigned to a minor product.88 Attempted photochemical [2 + 2] cycloaddition of DEAZD to other olefins failed to give any 1,2-diazetidines.88... 

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... 

Photoproducts arising by a [3 + 2] cycloaddition of s-triazolo[4,3-b]-pyridazine (269) to alkenes have been described.222 Addition to cyclohexene, for example, led to the formation of adducts 270 and 271, and the proposed mechanism is outlined in Scheme 8. The reaction has been extended to include addition to cis- and rans-hex-3-ene,223 cyclooctene,224 and furan.225... 

The cycloaddition reactions of the novel 3-methylsulfrnyl-6-methylthio- 37 and 3-(benzyloxycarbonyl)amino-6-methylsulfinyl- 38 -1,2,4,5-tetrazine to afford the corresponding pyridazines 39-40 proceeded with a regioselectivity opposite to expected and complementary to that observed for the corresponding sulfides <06JOC185>. 

The cycloaddition of acetylenes to 3,6-di(pyridin-2-yl)-l,2,4,5-tetrazines to give the corresponding di(pyridin-2-yl) pyridazines was considerably accelerated under microwave assisted conditions <06JOC4903>. 

The [4+2] cycloaddition of dimethyl-1,2,4,5-tetrazine-3,6-dicarboxylate 41 with ketene A, O-acetals or cyanamide yielded tetrafunctionalized pyridazines 42 or 1,2,4-triazine 43 respectively. Treatment of 42-43 with zinc dust in AcOH afforded pyrrole 44 or imidazole 45 derivatives <06S1513>. 

N-Heteroaromatic compounds like pyridine, pyridazine, pyrazine, isoquinoline, and their derivatives42,250 react with diphenyl cyclopropenone in a formal (3+2) cycloaddition mode to the C=N bond of the heterocycle. As expected from the results discussed earlier (p. 67), the reaction is initiated by attack of nitrogen at the cyclopropenone C3 position and followed by stabilization of the intermediate betaine 390 through nucleophilic interaction of the Cl/C3 bond with the activated a-site of the heterocycle, giving rise to derivatives of 2-hydroxy pyrrocoline 391—394). In some cases, e.g. diphenyl cyclopropenone and pyridine42, further interaction with a second cyclopropenone molecule is possible under the basic conditions leading to esters of type 392. 

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. 

Similarly, [4 + 2]-cycloadditions were used to prepare the pyridazine moiety in fused tetraheterocyclic azepine 155 syntheses. In this reaction, the 1,2,4,5-tetrazines 154 function both as the 47t-components and the oxidizing agents thereby requiring four equivalents of tetrazine for optimal yield. . 

Cycloaddition reactions of nitrile oxides with 5-unsubstituted 1,4-dihydro-pyridine derivatives produced isoxazolo[5,4-Z>]pyridines in moderate to good yield. In each case examined, the reaction produced only a single isomer, the structure of which was assigned by NMR spectra and confirmed by X-ray diffraction analysis of 102 (270). A study of the cycloaddition behavior of substituted pyridazin-3-ones with aromatic nitrile oxides was carried out (271). Nitrile oxides undergo position and regioselective 1,3-dipolar cycloaddition to the 4,5-double bond of pyridazinone to afford 3a,7a-diliydroisoxazolo 4,5-<7]pyridazin-4-ones, for example, 103. 

The inverse-electron-demand Diels-Alder reaction of 3,6-dichloro[l,2,4,5]tetrazine with alkenes and alkynes provides the synthesis of highly functionalized pyridazines. ° Also, the 4 + 2-cycloaddition reactions of the parent [l,2,4,5]tetrazine with donor-substituted alkynes, alkenes, donor-substituted and unsubstituted cycloalkenes, ketene acetals, and aminals have been investigated. ... 

Hexahydropyrido[l,2-6]pyridazin-8-ones 178 and a 2,3-tetramethylene derivative were formed on the intramolecular cycloaddition of 177, formed in situ by dehalogenation of hydrazones of the hex-5-enoic acid derivatives 176 [87JCS(P1)2511]. Intramolecular cycloaddition of hydrazones 179 in... 

Elimination of nitrogen from Diels-Alder adducts of certain heteroaromatic rings has been useful in the synthesis of substituted aromatic compounds.224 Pyridazines, triazines, and tetrazines react with electron-rich dienophiles in inverse-electron-demand cycloadditions. The adducts then rearomatize with loss of nitrogen and the dienophile substituent.225... 

Since the publication of CHEC-II(1996) <1996CHEC-II(6)1>, in which thermally induced [4+2] cycloadditions have been reviewed, significant progress has been realized in this strategy, especially for the synthesis of polycyclic heterocycles. Cyclophanes 12 containing pyridazine and indole units were used for the synthesis of pentacyclic compounds 13 via a thermally induced transannular inverse-electron-demand Diels-Alder reaction (Equation 2) <20020L127, 2002AGE3261>. 

Similarly, mono- and bicyclic 1,2-diazines tethered to indole dienophiles by only one alkylene chain 14 afford tetra-and pentacyclic condensed carbazoles 15. Unactivated pyridazines undergo these thermally induced [4+2] cycloaddition reactions only very sluggishly. However, the examples with the more activated electron-deficient pyridazines, especially pyridazine diesters and pyridazino[4,5-, pyridazindiones, demonstrate the synthetic usefulness of this strategy for the construction of polycyclic carbazoles (Equation 3) <2004T6495>. 

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