The kinetics of the oxidative additions of haloheteroarenes HetX (X=I, Br, Cl) to [Pd(0) (PPh3 )2 ] (generated from [Pd(0) (PPh3 )4 ]) have been investigated in THF and DMF and the rate constants have been determined. In contrast to the generally accepted concerted mechanism, Hammett plots obtained for substituted 2-halopyridines and solvent effects reveal a reaction mechanism dependent on the halide X of HetX: an unprecedented SN Ar-type mechanism for X=Br or Cl and a classical concerted mechanism for X=I. These results are supported by DFT studies.

Reaction of 2-benzyl-5-halopyridazin-3(2H)-ones (3) with Grignard reagents followed by quenching with electrophiles unexpectedly yielded 4,5-disubstituted pyridazin-3(2H)-ones instead of 5-substituted pyridazin-3(2H)-ones. These reactions represent the first examples of cine substitution in which the anionic σ(H)-adduct is quenched by electrophiles (other than a proton) before elimination takes place. Insight into the reaction mechanism led to the direct transformation of 2-benzylpyridazin-3(2H)-one (7) and 2-benzyl-6-chloropyridazin-3(2H)-one (9) into the corresponding C-4 alkyl and aryl derivatives (when Br(2) was used as the electrophile).

The potential of halogen-magnesium exchange reactions, followed by quenching with electrophiles, for the functionalization of the pyridazin-3(2H)-one core was investigated. 2-Benzyl-4-bromo-5-methoxy- (1), 2-benzyl-5-bromo-4-methoxy- (4), and 2-benzyl-4,5-dibromopyridazin-3(2H)-one (10) were selected as readily available model substrates. While 1 and 10 gave exclusively C-4 metalation, a tandem reaction involving nucleophilic substitution via addition elimination and bromine-magnesium exchange was observed with 4.

Selective bromineÀmagnesium exchange on 2-benzyl-5-bromo-4-methoxypyridazin-3(2H)-one could be achieved when MesMgBr was used as reagent. With more nucleophilic RMgCl species (R = Bu, i-Pr, Ph) both nucleophilic additionÀelimination at C-4 and bromineÀmagnesium exchange at C-5 occurred. In 2-benzyl-5-bromopyridazin-3(2H)-one, which does not contain a substituent at C-4, addition could not be suppressed. Less nucleophilic Mg amides (TMPMgCl 3 LiCl) allowed regioselective CÀH magnesiation at the C-4 position in such substrates, as exemplified for 2-benzyl-5-chloro-and 2-benzyl-6-chloropyridazin-3(2H)-one. Quenching of the magnesiated pyridazinones with electrophiles gives access to a variety of hitherto unknown pyridazin-3(2H)-one derivatives.

Zincated pyridazin-3(2H)-ones generated via bromine-magnesium exchange followed by transmetalation using ZnCl(2) or via lactam-directed ortho C4-H zincation with TMPZnCl·LiCl have been synthesized. These in situ created organometallics can be used in Negishi reactions with iodo(hetero)arenes delivering a new approach toward (hetero)arylpyridazin-3(2H)-ones.

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Regioselective nucleophilic additions to pyridazin‐3(2H)‐ones such as (I) followed by quenching with electrophiles allow double functionalization at C‐4 and C‐5 in a single step, when a leaving group is present at C‐5 [→ (IV), (VII), (X)].

Synthesis of (Hetero)arylated Pyridazin-3(2H)-ones via Negishi Reaction Involving ZincatedPyridazin-3(2H)-ones. -The a new approach affords various arylated pyridazinones such as (III), (V), (VII), and (IX) which are of biological interest. Additionally, the formation of dihalogenated pyridazinones is described. -(VERHELST, T.; LIU, Z.; MAES, J.; MAES*, B. U. W.; J. Org. Chem. 76 (2011) 23, 9648-9659, http://dx.doi.org/10.1021/jo201587j ; Dep. Chem., Univ. Antwerp, B-2020 Antwerpen, Belg.; Eng.) -Jannicke 13-182