A new route to 5,6‐diarylpyridazin‐3‐ones by metalation and cross‐coupling of pyridazines

Abstract

Starting from 3,6‐dichloropyridazine, a new route is described to antihypertensive 5,6‐diarylpyridazin‐3‐ones. This pathway comprises the regioselective metalation followed by a substitution of the trimethylsilyl moeity. The introduction of iodine by another metalation allowed the cross coupling of arylboronic acids. The 6‐methoxy group was then cleaved to afford the pyridazinones.

Functionalization of diazines and benzo derivatives through deprotonated intermediates

“…25 It was noted that using the in situ trapping method metalation also occurred regioselectively next to the methoxy group. 26 When one of the chloro groups was replaced with a methoxyethoxy, using LDA or LTMP in THF at -70 °C gave a mixture of both possible lithio compouds 23 Butyllithium surprisingly gave better results than LTMP when used to functionalize 6-chloro-1,4dimethoxyphthalazine. Metalation solely occurred at the 7-25 position, leading to the compounds 5.…”

Palladium-Catalyzed Reactions on 1,2-Diazines

“…Both substrates can be easily obtained from 15 by a selective substitution of one chlorine atom, and their 3-aryl derivatives are useful intermediates in the pyridazine chemistry and are often themselves interesting due to their biological activities. In an attempt to develop novel neuropeptide Y5 receptor antagonists, Suzuki reaction of N-(6-chloropyridazin-3-yl)-2-(2-naphthyl)acetamide (43) with arylboronic acids was studied in the presence of Pd(PPh 3 ) 4 catalyst and aqueous Na 2 CO 3 solution [15]. 4-Carboxyphenylboronic acid could also be used on this substrate but in this case, 50% aqueous acetonitrile was used as the solvent [12].…”

“…Also Quéguiner showed chemoselective Suzuki arylation involving an iodine and chlorine atom on a pyridazine nucleus (Scheme 16) [43]. In a first Suzuki reaction, C-5 selective arylation of 4-acetyl-6-chloro-5-iodo-3methoxypyridazine (146) could be obtained using only a slight excess of arylboronic acid.…”

Palladium catalyzed reactions on chloropyridazines

“…The success of these palladium-catalyzed reactions is highly dependent on the substrate, the organometallic reagent or amine, the base (if present) and the ligand that is used for the palladium catalyst. For example, we [32] and others [23,24,33] described smooth Suzuki arylations on chloropyridazines with in situ generated Pd(0)(PPh 3 ) 2 catalyst, while the same substrates with the same catalytic system usually give moderate to bad results in the Sonogashira alkynylation [34][35][36].…”

“…Since the incorporation of nitrogen in the benzene ring also decreases the electron density of the π-system, there is a good chance to perform palladium-catalyzed reactions on chloropyridazines with triarylphosphines (e.g., PPh 3 ) as the ligands of the catalyst. In the literature examples of Suzuki-reactions on chlorinated pyridines [19], quinolines [20], pyrazines [21], triazines [22], and even on pyridazine derivatives [23,24], do support this idea.…”