Displacement phthalazine

An ingenious synthesis of 1-arylisoindolcs has been developed by Vebor and Lwowski, based upon the reaction of an o-phthalimido-methylbenzophenone (41, R = aryl) with hydrazine (Table IV). The benzophenone is prepared by a Friedel-Crafts reaction with o-phthalimidomethylbenzoyl chloride (40). The mechanism of isoindole formation can be represented sehematically by a sequence involving attack by hydrazine at the imide to give the ring-opened hj drazide (42), followed by cyclization to phthalazine-l,4-dione (44) with displacement of the o-aminomethylbenzophenone (43). Intramolecular condensation of the latter can lead, via the isoindolenine... 

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. 

Phthalazines commonly possess adrenergic activity. One such, carbazeran (77), is a cardiotonic agent. Its patented synthesis involves nucleophilicaromatic displacement of chiorophthal-azine derivative 7 with piperidinyl carbamate 76 to give carbazeran (77)... 

Dihydralazine (67-3) is the less important of the two phthalazine antihypetensive agents its preparation is however recorded first because of its simplicity. Thus, reaction of phthaUiydrazide (67-1) with phosphorus oxychloride leads to the by now very famihar conversion of the amide functions to enol chlorides (67-2). The displacement of halogen by hydrazine leads directly to the antihypertensive agent dihydralazine (67-3) [76]. 

Halogens are displaced by sulfur nucleophiles as in the phthalazine analogue (24) (67T681). In the thiation of the fused uracil (25) the higher reactivity at C-4, for the reasons discussed above, can be used to effect selective thiation in this position (78CPB2497). 

The possible involvement of an ANRORC mechanism in the nucleophilic displacement of halogen by hydrazine from a series of 3-halopyridazines and 4-halophthalazines was studied using N labelling and mass spectral analysis. With pyridazine substrates the ANRORC mechanism operated to the extent of 17-30%, but it was not observed at all with the phthalazines <83JHC1259>. 

As alternatives to the chloro compounds for substrates in nucleophilic displacement reactions, phenoxy compounds and cyclic amides and cyclic thioamides have been used. It appears that 2-phenoxyquinoxaline is significantly less reactive than the corresponding cinnoline or phthalazine derivatives and only gives a negligible yield of 2-aminoquinoxaline when heated with ammonium acetate. However the phenoxyquinoxaline 1 is converted in high yield into the aminoquinoxaline 2 on treatment with this reagent. ... 

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 . ... 

Of these and related displacement reactions to produce phthalazines with oxygen-joined substituents, only alcoholysis and phenolysis have been used extensively. The following classified examples involve both nuclear and extra-... 

Note Acylphthalazines have been made by primary synthesis (see Chapter 8), Reissert-type additions to simple phthalazines (Section 9.1.3), oxidation of alkylphthalazines (Section 9.2.2), displacement of halogeno substituents (Section 10.3.4), acylation of tautomeric phthalazinones (Section 11.1.2.2), oxidation of extranuclear hydroxyphthalazines (Section 11.2.2), or as illustrated in these examples. 

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