Oxidative ipso substitution of 2,4-difluoro-benzylphthalazines: identification of a rare stable quinone methide and subsequent GSH conjugate. | LitMetric
In vitro metabolite identification and GSH trapping studies in human liver microsomes were conducted to understand the bioactivation potential of compound 1 [2-(6-(4-(4-(2,4-difluorobenzyl)phthalazin-1-yl)piperazin-1-yl)pyridin-3-yl)propan-2-ol], an inhibitor of the Hedgehog pathway. The results revealed the formation of a unique, stable quinone methide metabolite (M1) via ipso substitution of a fluorine atom and subsequent formation of a GSH adduct (M2). The stability of this metabolite arises from extensive resonance-stabilized conjugation of the substituted benzylphthalazine moiety. Cytochrome P450 (P450) phenotyping studies revealed that the formation of M1 and M2 were NADPH-dependent and primarily catalyzed by CYP3A4 among the studied P450 isoforms. In summary, an unusual and stable quinone methide metabolite of compound 1 was identified, and a mechanism was proposed for its formation via an oxidative ipso substitution.
The fleeting existence of aryl carbanion intermediates in the bulk phase prevents their direct observation and spectroscopic measurement. In sharp contrast, we report the direct interception of such unstable species at the air-water interface of microdroplets. We observed the transformation of three types of aryl acids (benzoic, phenylsulfinic, and phenylboronic acids) into phenyl carbanion (Ph) in water microdroplets, as examined by mass spectrometry.
A series of compounds with the general formula AMBO (A=Zn, Ba, Pb; B=Pb, Ba, Zn, Cu) related to the kotoite structure has been prepared employing high-temperature solid state methods. The substitution of transition elements in place of Zn ions resulted in colored compounds. The optical absorption spectra could be explained based on Tanabe-Sugano diagram and allowed d-d transitions.
Herein, we report the first example of Cu-promoted β -hydroxylation of substituted benzophenones using a bidentate directing group (DG) and HO as an oxidant. In addition to the new C-O bond formed, the -oxidation induces a very unusual 1,2-rearrangement of the iminyl group to the vicinal γ position. This transformation is highly dependent on the substrate utilized (favored for 4-methoxy-substituted benzophenones) and on the DG used (2-picolylamine leads to selective γ-C-H functionalization, while β -oxidation requires 2-(2-aminoethyl)pyridine).
Oxidative cleavage of aromatic C(sp)-O bond is important to the conversion of biomass and plastic wastes into value-added chemicals. Here we put forward the oxidative cleavage of para-C-O bonds in phenolic compounds in use of oxoammonium salts as oxidant and water as the oxygen source. The mechanism is that oxoammonium cation activates water to form hydroxy-oxoammonium adduct and thus realizes the ipso-substitution of 4-alkoxyphenol, which is proved by substituent effect, isotope labelling experiments, and kinetic analysis.
The high nitrogen content and diverse reactivity of malononitrile are widely harnessed to access nitrogen-rich fine chemicals. Although the facile substitutions of malononitrile can give structurally diverse quaternary carbons, their access to enantioenriched molecules, particularly chiral amines that are prevalent in bioactive compounds, remains rare. Here we report a cobalt-catalysed desymmetric reduction of disubstituted malononitriles to give highly functionalized β-quaternary amines.
