Weinreb amide formation

What is Weinreb amide formation?

Weinreb et al. reported the reaction in 1977, which involves the preparation of N-methoxyl-N-methyl amides from N,O-dimethyl hydroxylamine in the presence of a coupling reagent such as AlMe3. This reaction is commonly referred to as the Weinreb amide formation, and the corresponding amides are called Weinreb amides.

Weinreb amide formation - general reaction scheme - Weinreb amides - AlMe3
Weinreb amide formation
  • R = alkyl, aryl
  • Peptide coupling reagent = AlMe3, BMPI, BOP, BOP-Cl, CMPI, DCC, DMTMM, PyBOP,
    PyBrOP, TBTU, PivCl, etc. (see list of acronyms)

This coupling reagent have been widely used in organic synthesis as it is an important acylation reagent equivalent to an acyl group, and only ketone is formed during the reaction of the amide with alkyl lithium or Grignard reagent. This is due to the exceptional stability of the addition intermediate to the nucleophile, which arises from chelation between the metal cation and the oxygen atoms of the alkoxide and N-methoxy group.

When treated with a reducing reagent, such as LiAlH4 or NaBH4, only aldehyde is produced, and such transformation is known as the Weinreb aldehyde synthesis. The N-methoxy group can facilitate the nucleophilic attack, which is evidenced by the preparation of ynones from Weinreb amides and alkynyllithium. Weinreb amides are also superior to lactone during the acylation of vinyl anion. Various methods have been developed for the preparation of Weinreb amides, including the treatment of carboxylic acid and N,O-dimethyl hydroxylamine hydrochloride with different coupling reagents. However, AlMe3, the most commonly used coupling reagent, is not suitable for large-scale preparation, and many other coupling reagents have been used as alternatives.

Higher yields of ketones can be obtained from Weinreb amides with smaller protecting groups on the N-carbamate than those carrying larger protecting groups. It is also worth mentioning the important improvement in the preparation of β-amino ketones with high diastereoselectivity from N-sulfinyl β-amino Weinreb amides.

References

Basha, A.; Lipton, M. and Weinreb, S., Tetrahedron Lett., 1977, 48, 4171

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