Inverse electron-demand Diels-Alder reactions pyridazine

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. ... 

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>. 

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>. 

Inverse electron demand Diels-Alder reactions of 1,2,4,5-tetrazines with alkynes produce pyridazines directly with the elimination of nitrogen and retention of the substituents on the acetylene thus, tributylstannylacetylenes give pyridazines with a 4-tributylstannyl substituent (Scheme 24). 

A strained azo-bridged tricyclic system (1) undergoes a selective retro inverse electron-demand Diels-Alder reaction on heating, leading through a cascade of tautomeric and sigmatropic shifts to the pyridazine derivative (2) (Scheme 2).16 The proposed mechanism was supported by quantum chemical calculations and experimental evidence. 

Employment of pyrido[3,4-d]pyridazine derivatives (18) as azadienes in inverse electron-demand Diels-Alder reactions with 1-pyrrolidino-l-cyclopentene, or its six-membered homologue, provides a good route to the isoquinolines (19) after aromatization of the dihydroisoquinoline intermediates (Equation (2)) <92TL7173>. 

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. 

A pyridazine ring can be formed in a cycloaddition reaction of diazo compounds or diazonium salts, with alipahtic or cyclic azo compounds. It can also be formed by cycloaddition of various 1,2,4,5-tetrazines and dienophiles in inverse electron demand Diels-Alder reactions. As shown later, this synthetic approach has been used extensively and with success in the 1980s. 

Tetrazine derivatives have been used widely in making pyridazines by inverse electron-demand Diels-Alder reactions with dienophiles (see Scheme 10), followed by loss of nitrogen from the usually unstable intermediate if the dienophile has a triple bond or potential triple bond properties, the final pyridazines will be aromatic. From the coordination chemistry point of view 3,6-dipyridin-2 -yl-l,2,4,5-tetrazine and dimethyl 1,2,4,5-tetrazinedicarboxylate and their analogs are probably the most useful starting compounds for making relevant ligands. 

In 2002, Bodwell and Li reported an elegant and efficient total synthesis of strychnine based on an intramolecular inverse-electron-demand Diels-Alder reaction that involves a pyridazine as diene. The required cyclophane 91 was built up via hydroboration of A-[2-(l-allyl-l/7-indol-3-yl)ethyl]-6-iodopyridazin-3-amine (90) followed by an intramolecular sp —sp coupling reaction [55]. 

The parent pyrido[2,3-d]pyridazine has been used as an azadiene in inverse-electron-demand Diels-Alder reactions with pyrrolidin-l-ylalkenes. After the aromatization of the intermediate dihydroquinolines by elimination of pyrrolidine this represents a route to 6,7-disubstituted quinolines.155... 

Phenyl- and 5,8-diphenylpyrido[3,4-c/]pyridazine, as well as ethyl 5,8-diphenylpyrido[3,4-r/]-pyridazine-7-carboxylate, have been used as azadienes in inverse-electron-demand Diels-Alder reactions with 1-pyrrolidinocyclopent-l-ene or its six-membered homolog. After the aroma-tization of the intermediate dihydroisoquinolines by acid-catalyzed elimination of pyrrolidine or piperidine, this represents a route to isoquinolines 9.141- 164... 

Two atypical reactions of tetrazines involve a dienatnine and a dihydropyridine. Acyclic diena-mines react with two molecules of 3,6-diaryl-l,2,4,5-tetrazines to give a mixture of 3,6-diaryl-pyridazines and the corresponding 4-dialkylamino derivatives (Scheme 112) reaction proceeds by cycloaddition to the terminal double bond and then to the enamine double bond by a second tetrazine to give the postulated intermediate (149), followed by loss of nitrogen and, finally, aromatization is achieved by an unusual carbon-carbon cleavage to give the two products <87H(26)337>. The expected inverse electron demand Diels-Alder reaction between the Ar-methyl-l,4-dihyropyridine (150) and... 

Fragmentation of an adduct with release of a nitrile, CO2 or N2 are most common and the latter provide an irreversible method for the formation of a new diene or aromatic compound. Cycloaddition of a pyran-2-one or a 1,2-diazine (pyridazine) with an alkyne gives an intermediate bridged compoimd that loses CO2 or N2 to generate a benzene derivative (see Scheme 3.46). Many other aromatic and heteroaromatic compounds can be prepared likewise. For example, a synthesis of lavendamycin made use of the inverse electron demand Diels-Alder reaction between the 1,2,4-triazine 116 and the enamine 117, followed by in situ elimination of pyrrolidine and retro Diels-Alder reaction, releasing N2 and the substituted pyridine 118 (3.88). 2... 

Another very popular and efficient method to synthesize pyridazines remains the inverse electron demand Diels-Alder reactions of 1,2,4,5-tctrazines with electron rich dienophiles. Wan and Snyder reported the (4 + 2]-cycloaddition of the readily available tetrazine 121 with A-protected 2-aminoimidazole 120 to obtain pyridazine 122 (86%). Subsequent deprotection and decarboxylation gave 123, the structure originally assigned to zarzissine, a cytotoxic marine natural product <01T5497>. Zarzissine was then reassigned as the imidazole(4,5-bjpyrazine 124. 

As mentioned earlier in Section 6.2.4.1, pyridazines also react readily with electron-rich dienophiles to undergo inverse electron demand Diels-Alder reaction <01TL7929>. 

A new electron acceptor, 6-alkylpyrrolo[3,4-4]pyridazine-5,7-dione (PPD) 10, was prepared by Ye and collaborators via an inverse electron demand Diels—Alder reaction (Scheme 6) (140L6386).The authors synthesized both furan- and thiophene-ligated 6-alkylpyrrolo[3,4-first step of this synthesis involved treatment of either 2-cyanofuran or 2-cyanothiophene with hydrazine and sulfur in ethanol, followed by addition of isoamyl nitrite to form the respective tetrazine.The 5-positions of either the furan rings or the thiophene rings were then bro-minated with N-bromosucciriiinide (NBS) in DMF at 100 After stirring... 

Wang, et al. reported an organocatalylic direct inverse electron demand Diels-Alder reaction of ketones 140 with l,2,4,5-tetrazinesl41, Scheme 3.46 [62]. Examination of the results of catalyst screening revealed that L-proline seems to be the best organocatalyst tried in this process. Several steps were involved in the cascade reactions inverse electron demand Diels-Alder reaction of 1,2,4,5-tetrazines 141 with the enamines, derived from ketones and L-proline, followed by a subsequent retro-Diels-Alder process to extrude and elimination to afford pyridazines 142. 

Scheme 1 a Normal electron-demand and inverse electron-demand Diels-Alder reaction, b Tetrazine bioorthogonal reaction. The reaction product is pyridazine if the dienophile is an alkyne... 

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]. 

Haider N, Mereiter K, Wanko R (1994) Inverse-electron-demand Diels-Alder reactions of condensed pyridazines, 4. Synthesis and cycloaddition reactions of L4-bis(trifluoromethyl) pyrido[3,4-d]pyridazine. Heterocycles 38 1845-1858... 

Haider N., Wanko R. Inverse-Electron-Demand Diels-Alder Reactions of Condensed Pyridazines, 5. l,4-Bis(trifluoromethyl)pyridazino[4,5-d]indole as an Azadiene . - Heterocycles, 1994, v. 38, p. 1805-1811. 

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. 

Electron-deficient heteroaromatic systems such as 1,2,4-triazines and 1,2,4,5-tetrazines easily undergo inverse electron demand Diels-Alder (lEDDA) reactions. 1,2-Diazines are less reactive, but pyridazines and phthalazines with strong electron-withdrawing substituents are sufficiently reactive to react as electron-deficient diazadienes with electron-rich dienophiles. Several examples have been discussed in CHEC-II(1996) <1996CHEC-II(6)1>. This lEDDA reaction followed by a retro-Diels-Alder loss of N2 remains a very powerful tool for the synthesis of (poly)cyclic compounds. 

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