One-step synthesis of O-benzyl hydroxamates from unactivated aliphatic and aromatic esters

Journal of Organic Chemistry

Volumn 70, Issue 17, 2005, Pages 6925-6928

  Gissot, Arnaud ^a   Volonterio, Alessandro ^a   Zanda, Matteo ^a  

^a POLITECNICO DI MILANO   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACIDS; DERIVATIVES; ESTERS; ISOMERIZATION; STEREOCHEMISTRY; SYNTHESIS (CHEMICAL);

EPIMERIZATION; O-BENZYL HYDROXAMATES; ONE-STEP SYNTHESIS; RACEMIZATION;

AROMATIC COMPOUNDS;

ALIPHATIC COMPOUND; ALPHA AMINO ACID; ANION; AROMATIC COMPOUND; CARBON; ESTER; HYDROXAMIC ACID DERIVATIVE; HYDROXYLAMINE; O BENZYL HYDROXAMATE DERIVATIVE; O BENZYL HYDROXYLAMINE; PEPTIDE; UNCLASSIFIED DRUG;

ARTICLE; CHEMICAL REACTION; CHIRALITY; EPIMERIZATION; LOW TEMPERATURE; RACEMIZATION; SYNTHESIS;

ESTERS; HYDROXAMIC ACIDS;

EID: 23644438030     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo0509713     Document Type: Article

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18. A classical protocol for the synthesis of Weinreb amides consists of the treatment of methyl or ethyl esters with the anion of N,O-dimethyl hydroxylamine. This concept is thus not new, but as we shall see later, the conditions employed for the synthesis of Weinreb amides are not suitable for the synthesis of O-Bn hydroxamates. For examples of synthesis of Weinreb amides directly from esters, see: (a) Davis, F. A.; Rao, A.; Carroll, P. J. Org. Lett. 2003, 5, 3855-3857.
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23. Since n-BuLi is always present in excess to deprotonate the final hydroxamate, this side reaction is unavoidable even if the ester is added last to the anion of O-Bn-hydroxylamine (result not shown). In turn, this result shows that if the use of n-BuLi or Grignard reagents to deprotonate N,O-dimethylhydroxylamine constitutes a powerful method to synthesize Weinreb amides from esters, this strategy cannot be utilized with O-Bn-hydroxylamine (which has an additional proton) to form hydroxamic acid derivatives, as addition of the base to the ester will always compete with deprotonation.
24. An intense red color was observed upon addition of the ester to the lithiated O-Bn hydroxylamine. This color might indicate the formation of a charge-transfer complex that perturbs the reaction. Unfortunately, an even poorer yield was obtained with KH at 20 °C instead of LiHMDS and no reaction was observed with TEA (5 equiv) in refluxing THF.
25. Deprotonation α to the ester does take place as evidenced by the formation of the Claisen condensation product from ethyl hydrocinnamate when LiHMDS was slowly added to the mixture of ester and O-benzylhydroxylamine at -78 °C in THF (result not shown).
26. 3/MeOH mixture as eluent.
27. D identical to that reported in the literature for the enantiopure compound (see Supporting Information).
28. Prior deprotonation of the NH-Cbz or NH-Boc groups may prevent the amino acid from undergoing additional deprotonation at the stereogenic center.