Phthalazine reduction

Reduction of 3-aryl-4-oxo-4//-pyrido[2,l-fl]phthalazine-l-carboxamides with sodium cyanoborohydride in acidified methanol or lithium borohy-dride in tetrahydrofuran afforded 6,7-dihydro derivatives 47 (R = H) (88EUP294599). 

The reductions of cinnolines and phthalazines were discussed in Part I, Section IV,B (Ring Contractions) or V,D. 1-Methylisoindole (190) has since been isolated as a hydrochloride from reduction in hydrochloric acid of 1-methylphthalazine with strict control of the potential to avoid further reduction to methylisoindoline (191). Purification requires acidic conditions the free base turned quickly to a tar299,300 [Eq. (113)]. 

Oxazines, which are readily prepared from enamines and a-bromokctoximes, are reductively converted to pyrroles in good yields by iron carbonyls (Scheme 116) (81CL869). The reductive conversion of cinnolines to indoles or indolines (71JCS(C)3088> and of phthalazines to isoindoles or phthalimidines (70ACS1867) may occasionally be of synthetic value. 

The reduction course of substituted phthalazines depends on the substituents. Thus, 1-methylphthalazine (158) in alkaline solution... 

LAH converts l-alkylpyridazin-6-ones (60) into the corresponding 1,6-dihydropyridazines (57 R = Me, R = H), whereas excess reagent reduces 4,5-dihydropyridazin-6-ones (61) to a mixture of 1,4,5,6-tetrahydro- (62) and hexahydro-pyrazines (63).2 Cinnolines (64) and phthalazines (66) both undergo ring opening during cathodic reduction, giving diamines (65) and (67), respectively. ... 

Many 1,2-diazines undergo N-N-bond cleavage upon electroreduction, eventually resulting either in reductive ring opening or in ring contraction, e.g. of the type pyridazine —> pyrrole [111] or phthalazine —> isoindole [112],... 

Similar ring contractions in which the nitrogen-nitrogen bond is cleaved are found in the reductive ring contractions of pyridazines to pyrroles [148, 149], phthalazines to isoindoles [150], 5,6-diphenyl-1,2,4-triazinones to imidazolones [151], benzo-l,2,4-triazines to benzimidazoles [71], benzo-l,2,3-triazinone to indazolone [la, 152], benzo-l,2,3-triazin-3-oxide to indazole [la], benzo-2,3-diazepines to isoquinolines [153], benzo-l-pyrano-[4,3-e ]-as-triazin-3-one to benzopyranoimidazolone [154], and 2-methyl-4,5-dihydropyridazin-3-ones to pyrrolin-2-ones [155]. 

In alkaline solution phthalazine is reduced polarographically in a two-electron reduction, but in a preparative reduction it is possible to isolate mostly dimerized products, resulting from a one-electron reduction, or 1,2-dihydrophthalazine (LIII), depending on the conditions LIII is reducible at a more negative potential to 1,2,3,4-... 

Alper2 has used this same system for reduction of the carbon-nitrogen double bond. Thus treatment of phthalazine (1) with Fe3(CO)12 in refluxing methanol-benzene for... 

The polarographic reduction of quinoxaline and its derivatives has been studied by a number of workers. Half-wave electrode potentials are pH dependent and over the pH range of 1 to 10, Ei has been reported to vary from —0.254 to -0.863 The half-wave electrode potential in anhydrous dimethylformamide is — l.bOV for quinoxaline, —1.06 V for cinnoline, —1.41V for phthalazine, and —1.22 V for quinazoline. The benzodiazines are more easily reduced than the corresponding diazines, thus pyrazine has a half-wave electrode potential of -1.57V. Pyridine with a half-wave potential of —2.15 V is still more difficult to reduce. The reversible reduction potential of quinoxaline as determined by cyclic voltammetry is -1.097 V. The observed energy differences between azine and radical anion are well correlated with the results of CNDO and SCF iT-electron calculations. 

Irradiation of the diazines phthalazine and quinoxaline in acidified alcohols is thought to result in electron transfer from solvent to the excited state of the diazinium cation.81 In strongly acidic methanol, reduction of phenazine may involve electron transfer from solvent to the excited singlet phenazinium dication.62 A-Methylphenazine undergoes photoreduction, often accompanied by dealkylation to phenazine, on irradiation in alcohols.8 ... 

Reduction of quinoxaline with potassium borohydride in acetic acid gives an excellent yield of l,4-diethyl-l,2,3,4-tetrahydroquinoxaline phthalazine reacts similarly, and other carboxylic acids can be used. ... 

Phthalazine (5) underwent reduction by the borane-pyridine complex in acetic acid to give 2-acetyl-1,2,3,4-tetrahydrophthaIazine (6) (reflux, 5 min 57%), conceivably a potential source of 1,2,3,4-tetrahydrophthaIazine. 

Phthalazine (9) was reduced by triiron dodecacarbonyl to give 1,2-dihydrophtha-lazine (10) [Fe3(CO)i2, MeOH, PhH, reflux, 12 h 54%] the same substrate (9) underwent photoreduction to give a separable mixture of 1,2-dihydro-phthalazine (10) and l,l, 2,2 -tetrahydro-l,l -biphthalazine (11) (PPOH, hv, 5-8 h yields and the electrochemical reduction of phthalazine has... 

Unsubstituted phthalazine has been used extensively as a substrate for a variety of reactions. Simple reduction has been covered in Section 9.1.1, and other reactions are illustrated by the following examples, grouped alphabetically for convenience. 

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