Phthalazine amination

The catalytic effect of protons has been noted on many occasions (cf. Section II,D,2,c) and autocatalysis frequently occurs when the nucleophile is not a strong base. Acid catalysis of reactions with water, alcohols, mercaptans, amines, or halide ions has been observed for halogeno derivatives of pyridine, pyrimidine (92), s-triazine (93), quinoline, and phthalazine as well as for many other ring systems and leaving groups. An interesting displacement is that of a 4-oxo group in the reaction of quinolines with thiophenols, which is made possible by the acid catalysis. 

The much more reactive 2,3-dihydro-l,4-phthalazine 248, on reaction with five equivalents of benzylamine, HMDS 2, and (NH4)2S04 for 24 h at 160°C, furnishes the bis-aminated product 249 in 87% yield [27] (Scheme 4.26). 

The silylation-amination of 5,10-dihydroxy-l,4-dioxo-l,2,3,4-tetrahydroben-zo[g]phthalazine 281 for 27 h at 170 °C with excess N(2-aminoethyl)piperidine 282 and HMDS 2 proceeds with catalytic amounts of Ts0H-H20 to afford, via the activated persilylated intermediate in which the sensitive phenolic hydroxy groups are protected, the 1,4-bis-amine 283 in 67% yield. All conventional efforts with POCI3, PCI5, or SOCI2 to convert 281 into the corresponding 1,4-dichloro compound, to be followed by amination, resulted in failure [86] (Scheme 4.35). 

H2ase = hydrogenase Hbsms = 4-mercapto-3,3-methyl-l-phenyl-2-thiabutane Scys = cysteine thiolate psnet = bis(5-(diphenylphosphino)-3-thiapentanyl)amine bdptz = 1,4-bis (2,2 -dipyridylmethyl)phthalazine OTs = / -toluenesulfo-nate tmen = A,A,A, Ai -tetramethylethylenediamine AA = acetohydroxamate anion [PhTt ] = phenyltris((tert-butyl-thio)-methyl)borate bipy = bipyridine. 

In principle, the interaction of a phosphorus(III) ester with an co-haloalkylamine should lead to an (co-aminoalkyl)phosphonic diester or a phosphinic acid analogue (Scheme 11). Such examples in the classical Michaelis-Arbuzov mould have been widely reported, but success in their outcome depends on the relative nucleophilicities of nitrogen and phos-phorus(III) centres towards the displacement of halogen. The interaction of triethyl phosphite and a halogen-substituted tertiary amine, such as 2-chloroethyldiethylamine, does not lead to a phosphonic diester, and in this particular case the product is a piperazinium diquaternary salt. However, successful Michaelis-Arbuzov reactions have been carried out between the bis(bromomethyl)phthalazines 130 (to both the mono- and di-phosphonic acid stages) and the series of [co-(2-cyano-4-pyridine)alkyl]phosphonic diesters 132 (n = 1-4) have been prepared from the 4-pyridinealkyl bromides 131 as precursors to the phosphonoalkylpiperidinecarboxylic acids 133 . ... 

They are made by reaction of OSO4 in aqueous solution or emulsion of the amine L to give 0s04 L (L = pyridine, pyridazine, quinuclidine (NC,H,3), phthalazine and iso-... 

The conversion of these substrates into phthalazines is interesting rather than useful in its present state of development. The lead tetracetate oxidation of 4,7-diphenyl-17/-1,2,3-triazolo[4,5-tf]pyridazin-l-amine (301) in the presence of 2,3,4,5-tetraphenyl-l-cyclopentadienone (302) gave 1,4,5,6,7,8-hexaphenylphtha-lazine (303) [reactants, CaO, CH2CI2, Pb(OAc)4 portionwise, 20°C, min 20% see original with respect to mechanism]. ... 

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