Ether Cleavage Re‐Investigated: Elucidating the Mechanism of BBr₃‐Facilitated Demethylation of Aryl Methyl Ethers

Abstract

One of the most well-known, highly utilized reagents for ether cleavage is boron tribromide (BBr3), and this reagent is frequently employed in a 1:1 stoichiometric ratio with ethers. Density functional theory calculations predict a new mechanistic pathway involving charged intermediates for ether cleavage in aryl methyl ethers. Moreover, these calculations predict that one equivalent of BBr3 can cleave up to three equivalents of anisole, producing triphenoxyborane [B(OPh)3] prior to hydrolysis. These predictions were validated by gas chromatography analysis of reactions where the BBr3:anisole ratio was varied. Not only do we confirm that sub-stoichiometric equivalents may be used for ether demethylation, but the findings also support our newly proposed three cycle mechanism for cleavage of aryl methyl ethers.

An insight into the metabolism of New Psychoactive Substances : Structural elucidation of urinary metabolites of synthetic cannabinoids and fentanyl analogues using synthesized reference standards

“…The use of BBr3 is a well-known method for demethylation of aryl methyl ethers. 264 The hypothesis was that the use of one equivalent of BBr3 would result in the demethylation of one methyl ether, which would yield a mixture of compounds C7 and C8 (Scheme 16). Contrary to that hypothesis, both methyl ethers were demethylated and compound C6 was the exclusive product.…”

In vitro and in vivo trypanocidal activities of 8‐methoxy‐3‐(4‐nitrobenzoyl)‐6‐propyl‐2H‐cromen‐2‐one, a new synthetic coumarin of low cytotoxicity against mammalian cells

“…On the other hand, a new methylene carbon signal was observed at 26.6 ppm in the 13 C spectrum. Derivative 10 was obtained by an O ‐demethylation reaction with coumarin 3 carried out by aluminum chloride in dry dichloromethane, as an adaptation of a well‐known methodology . The loss of methyl group could be perceived by the absence of typical methoxyl signals in NMR spectra.…”

“…Derivative 10 was obtained by an O-demethylation reaction with coumarin 3 carried out by aluminum chloride in dry dichloromethane, as an adaptation of a well-known methodology. [28] The loss of methyl group could be perceived by the absence of typical methoxyl signals in NMR spectra. Finally, coumarin 11 was achieved by a classical ketone reduction made by sodium borohydride in alkaline media.…”

Exploring the biotransformation of N-(2-hydroxyphenyl)-2-propylpentanamide (an aryl valproic acid derivative) by CYP2C11, using in silico predictions and in vitro studies

“…Dihydroxylated derivatives were obtained by the deprotection of the methoxy groups of the respective intermediates ( 2a and 2b ). [ 25 ] Compounds 2a and 2b (1.0 eq) were dissolved in DCM anh. and cooled to −15°C, and then, boron tribromide (BBr 3 , 10.0 eq) dissolved in DCM anh.…”