Pyridazines 1,2-Diazines

Pyridazines, 1,2-diazines, substituted with additional electron-withdrawing substituents participate in well-defined inverse electron demand [4 -I- 2] cycloadditions with electron-rich dienophiles. - In nearly all reports, cycloaddition occurs across C-3/C-6 of the 1,2-diazine nucleus, and the regioselectivity of the reaction can be predicted based on the 1,2-diazine substitution pattern [Eq. (14)]. 

Exceptions to this generalization are restricted to the reactions of ynamines with electron-deficient 1,2-diazines, where both C-3/C-6 and C-4/N-l 1,2-diazine cycloaddition have been observed [Eq. (15)].  

The number and position of electron-withdrawing substituents on the 1,2-diazine nucleus control the mode and regioselectivity of the ynamine 1,2-diazine cycloaddition, and in each case studied, only one reaction product was detected. Much of this work is summarized in Table lO-III. 

Intramolecular Diels-Alder reactions of unactivated and highly substituted alkenyP and alkynyP 1,2-diazines have been explored [Eq. (16)]. 

The reaction is sensitive to the diene/dienophile spacer as well as subtle features apparently important for substrate/product stability under the reaction conditions (200-230°C). Table 10-IV summarizes the intramolecular Diels-Alder reactions of 1,2-diazines. These observations have found application in the total synthesis of the cAMP phosphodiesterase inhibitors PDE-I and PDE-II (24), constituting the central and right-hand segments of the potent antitumor antibiotic CC-1065 [Eq. (17)].  

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Pyridazine (1,2-diazine) exhibits a weak fluorescence in solutions at room temperature,73 but no phosphorescence appears in hydrogen and rare gas matrices at 4.2°K. The intersystem crossover was shown to be 103-105 times as slow (at low temperatures) in pyridazine as in pyrazine or pyrimidine.84,85 Very efficient radiationless processes of deactivation must be considered again. 

Pyridazine (1,2-diazine) (1) and its benzo analogs cinnoline (1,2-diazanaphthalene) or benzo[c]pyridazine (2) and phthalazine (benzo[rf]pyridazine) (3) have been known since the nineteenth century. Although the basic synthetic principles and reactivity were investigated in the early years, interest in these compounds was not very intense, compared with pyrimidines and their bicyclic analogs, as they were not found in nature. However, during the last three decades intensive research has been stimulated because many derivatives have found application as a result of their biological activity. 

This section deals with molecules derived from the diazines C4H4N2 pyrazine (1,4-diazine 7), pyrimidine (1,3-diazine 8) and pyridazine (1,2-diazine 9). 

In this section we shall present and compare different computational strategies one can adopt to simulate the effect of the environment on spectroscopic properties of solvated systems. In particular, as a representative example, we shall summarize the results of two studies [30,31] we have published in the last years on the environment effects on the nitrogen nuclear shieldings of a specific class of molecular systems containing sp2-type nitrogens three diazines, also known as pyridazine (1,2-diazine), pyrimidine (1,3-diazine) and pyrazine (1,4-diazine). 

Regiospecific inverse electron demand Diels-Alder reactions of enamines with 1,3-diazines or 1,2,3- and 1,2,4-triazines (see Section IH.D.l), which on elimination of HCN or Nj, 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 pyrimidines (1,3-diazines) and pyridazines (1,2-diazines). Examples of the use of this methodology are the preparation of the pyrimidine substituted benzomorphane 356 (equation 77) and the pyridazine 359 (equation 78), intermediate in the total synthesis of cis- and trans-trikentrin... 

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