Pyridazines Diels-Alder reactions

While enamines are poor dienophiles for Diels-Alder reactions, their addition to tetrazines has provided a route to pyridazines (595). 

Another interesting scavenger is polymer-supported anthracene, developed by Porco for the scavenging of dienophiles [109]. An example of its application to the synthesis of a complex 5,8-dihydro-(l,2,4)triazolo[l,2-a]pyridazine-l,3-diones via hetero-Diels-Alder reaction followed by removal of the excess of triazole-3,5-dione under microwave irradiation is depicted in Scheme 24. For this particular example, moving from thermal heating (toluene, 100 °C) to a microwave-assisted protocol (DCE, 150 °C) reduced scavenging time from 3 h to just 15 min. 

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. 

Bis-l,2,4-triazole-3,5-diones such as 110 have also been used in Diels-Alder reactions, and give bispyridazines.171 The pyridazine derivative 111 is formed in quantitative yield from PTAD and 2,7-dimethyl-2,3,5,6-octatetraene,172 and the azadiene, 4-aza-l,3,5-triphenylpenta-2,4-diene, also reacts readily with PTAD to give 112.173 There are many other examples of Diels-Alder additions of ADC compounds to simple acyclic dienes which proceed entirely as expected the above selection has been limited to reactions of synthetic potential and with novel features. 

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. 

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>. 

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>. 

Only two examples of the synthesis of pyrrolo[3,4-r-]pyridazines that begin with a pyridazine have been reported. The first involves a Diels-Alder reaction. Thus pyridazine 88 under thermal conditions provides the heterodiene 89 intermediate with loss of CO2, which is trapped / situ with A -phenyldiazamaleimide to form 90 in the yields shown (Scheme 8) <20010L3647>. Alternatively, the thiadiazole 1,1-dioxide 91 can produce 89 by loss of SO2. 

Furo[3,4-J]pyridazines have also been used in Diels-Alder reactions (331a with maleic anhydride, acrylic acid, 1,4-naphthoquinone, dibenzoyl-ethylene, 1,4-benzoquinone, benzo[c]furandione ° 331c with maleic anhydride) 331a has been shown to be more reactive than 331c. 1,3-Diphenylfuro[3,4-b]quinoxaline (335) has been obtained from phthalide 334 (Eq. 17) as a green crystalline, quite stable solid (mp 244-246°C). In DMSO (deep blue solution), 335 reacts instantaneously with such dienophiles... 

Tetrazines react with alkenes to give bicycles (403) which lose nitrogen to give the 4,5-dihydropyridazine (404). This can either tautomerize to a 1,4-dihydropyridazine, be oxidized to the aromatic pyridazine, or undergo a second Diels-Alder reaction to give (405). Many heterocycles can act as the dienophiles in such reactions for example thiophene gives (406). The reaction is also used to trap unstable compounds, for example, 2-phenylbenzazete (407) as compound (408). 

The most important synthetic methods involve condensation of hydrazine, hydroxylamine or hydrogen peroxide with a 1,4-oxygenated carbon chain, and these procedures are particularly useful for the preparation of pyridazines and 1,2-oxazines. Other methods include Diels-Alder reactions of a diene with an azo or nitroso compound. 

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). 

The carbocyclic ring of substituted indolines can be constructed by intramolecular Diels-Alder reactions of 2-(Af-pent-3-ynylamino)pyridazines (Scheme 10) (84JOC2240). 

Finally, a Diels-Alder reaction with inverse electron demand, in which the thiophene acts as the 27r-component, has been reported (78AP728). Tetrazinedicarboxylic ester adds to thiophenes to give the adduct (290) loss of nitrogen from this is followed by oxidation, yielding the thieno[2,3-rf]pyridazines (291) in 10-15% yield. With 2,5-dimethyl-thiophene as the substrate, aromatization is blocked, and the product (292) is obtained in 57% yield. 

Another pathway which is often used in the preparation of this ring system involves the Diels-Alder reaction. 3,6-Pyridazinedione (139) is known to be exceptionally reactive toward dienes. This dienophile readily condenses with butadiene, 2,3-dimethylbutadiene and coumalic acid to give the respective Diels-Alder adducts (140). 3,6-Pyridazinedione is also reported to decompose with evolution of nitrogen gas at temperatures below 0 °C, giving the pyridazino[l,2-a]pyridazine-l,4,6,9-tetrone (44) as the major product (62JA966). 

Pyridazines and their partially saturated analogs have been prepared on insoluble supports by Diels-Alder reaction of electron-rich alkenes or alkynes with 1,2,4,5-tetrazines (Entries 1-3, Table 15.27). The mechanism of this reaction is outlined in Figure 15.15. An additional approach, also based on the Diels-Alder reaction, is the cycloaddition of azo compounds to 1,3-dienes (Entries 4 and 5, Table 15.27). The resulting tetrahydropyridazines (Entry 4) have been used as constrained 3-strand mimetics for the discovery of new protease inhibitors [323], An example of the N-alkylation of hexahydropyridazines on solid phase is given in Section 10.3. 

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. 

---