Weinreb's salt (N,O-dimethylhydroxylamine·HCl)

Technical Specifications

Product Description & Scientific Applications

N,O-Dimethylhydroxylamine hydrochloride is the salt from which N-methoxy-N-methylamides — Weinreb amides — are made, and its value in synthesis follows entirely from the behaviour of those amides. Coupling the free base, liberated from the hydrochloride, to a carboxylic acid derivative installs the N-methoxy-N-methyl group; the resulting Weinreb amide reacts with a single equivalent of an organometallic or hydride nucleophile and then stops. The methoxy oxygen and the carbonyl oxygen chelate the metal to form a stable five-membered tetrahedral intermediate that does not collapse until aqueous work-up, so the electrophilic carbonyl is masked during the reaction and over-addition is suppressed. This is the property that distinguishes the reagent: an ester or acid chloride treated with a Grignard or organolithium reagent tends to add twice and give a tertiary alcohol, whereas the corresponding Weinreb amide delivers the ketone cleanly at one addition.

Applications

The two classic transformations exploit that controlled single addition:

• Ketone synthesis — organolithium and Grignard reagents convert Weinreb amides to ketones, giving unsymmetrical ketones without the tertiary-alcohol by-product; the same chelation control underlies newer triazinylamide variants developed for sequential double substitution.
• Aldehyde synthesis — diisobutylaluminium hydride reduces Weinreb amides to aldehydes rather than over-reducing to the alcohol; where an α,β-unsaturated ester must be spared, it is protected in situ so that DIBAL-H reduces the α,β-unsaturated Weinreb amide to the α,β-unsaturated aldehyde and the ester is then recovered.
• Amide preparation — the amides are prepared directly from carboxylic acids by coupling the salt with reagents such as the triazine reagent DMT-MM, which furnishes Weinreb amides in high yields.
• C-Acylation and solid-phase synthesis — because the amide is a protected, non-over-adding acyl unit, it serves as a C-acylation reagent in natural-product total synthesis and, on solid support, lets a single resin-bound Weinreb amide precursor be released either as a C-terminal peptide aldehyde or as a hydroxamate.

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