Weinreb ketone synthesis

What is Weinreb ketone synthesis?

The reaction that forms ketones by treating Weinreb amides (amides of N-methyl-N-methoxy hydroxylamine) with various carbanions (e.g., Grignard reagents, alkyl lithium, lithium enolate, phosphonium ylides) followed by hydrolysis was first reported by Nahm and Weinreb in 1981. This reaction is commonly known as the Weinreb ketone synthesis or Weinreb acylation. The reduction of the Weinreb amide by hydride, such as LiAlH4 and DIBAL-H (see list of acronyms), results in the production of aldehydes, which is referred to as the Weinreb amide reduction.

Weinreb ketone synthesis - general reaction scheme
Weinreb ketone synthesis
  • R = alkyl, aryl
  • Alternative nucleophile: R’-MgBr, lithium enolate, etc.
Weinreb amide reduction - general reaction scheme
Weinreb amide reduction

Several examples of the Weinreb ketone synthesis include the formation of alkynones from lithiated alkynes, α-dicarbonyl compounds with the lithium salt of 1,3-dithiane, β-ketoesters from the lithium enolate of esters, methyl ketones with methyllithium and ethyl ketones from ethyl magnesium bromide, α-chloromethyl ketones with both methyllithium and chloroiodomethane, allyl ketone from the allyl Grignard reagent, and α,β-unsaturated ketones from vinyl Grignard reagents or propen-2-yl lithium. The high chemoselectivity of this reaction in forming either ketones or aldehydes is due to the remarkable stability of intermediate alkoxide caused by the chelation of metal cation with alkoxide oxygen and an oxygen atom of the N-methoxy group. As a result, over addition of a carbanion to carbonyl moiety, which is common in the reaction between a Grignard reagent and an acyl halide or ester, does not occur with the Weinreb amides.

The effect of metal cation chelation can be observed from the better results of ketones obtained with Grignard reagents than with the corresponding lithium reagents due to the coordination of magnesium. However, the alkoxide oxygen anion may react further with certain neighboring functional groups to form alternative products rather than the expected ketones, as seen in the reaction of lithium enolate of t-butyl acetate with the Weinreb amide of proline having a β-cyano group on the α-nitrogen atom. During the reduction of Weinreb amides of α-amino acids and peptides to aldehydes, no free aldehyde was detected before the quenching of the reaction mixture, and only one aldehyde was observed after the workup, indicating the absence of epimerization (or racemization) from optically active amides. The reduction by DIBAL-H usually gives a cleaner reaction than that from LiAlH4 reduction, although some over reduction by DIBAL-H has been reported for the reduction of the corresponding benzyl ester but not for the reduction of the Weinreb amides.

Ketones can also be prepared from the N,N-dimethylamide; however, the yields of ketones from the Weinreb amides are generally higher, likely due to the higher nucleophilicity of the Weinreb amides compared to the corresponding methyl ester.

The stability of the Weinreb amide group allows it to survive under different reaction conditions, such as the Wittig olefination, DDQ oxidation to remove p-methoxybenzyl (PMB) group, Moffatt-Swern oxidation (COCl)2/ DMSO/Et3N, and Takai olefination CHI3/CrCl2.

Example

Weinreb ketone synthesis is a method for the synthesis of ketones using the reaction of a carboxylic acid and a halide, typically a chloride, in the presence of a strong base, such as lithium diisopropylamide (LDA). Here is an example reaction:

Example:
2-Butanone synthesis via Weinreb ketone synthesis

Reactants:

Acetic acid
2-chloropropane
Lithium diisopropylamide (LDA)
Reaction:
Acetic acid and 2-chloropropane are added to a solution of LDA in a polar solvent such as THF. The mixture is stirred at room temperature for a period of time, typically several hours. The reaction proceeds via a nucleophilic addition of the carboxylate anion to the halide, followed by deprotonation of the intermediate to form the ketone product.

2-chloropropane + Acetic acid + LDA -> 2-Butanone + HCl

The product 2-Butanone is purified by distillation and collected.

Mechanism of reaction

In this mechanism, the metal chelation occurs during the addition of a carbanion to the carbonyl group of the Weinreb amides, resulting in a stable intermediate. Moreover, the N,O-dimethyl hydroxylamine is released, upon hydrolysis and ketone is produced, as shown. In the figure acidic hydrolysis is emphasized so that the N,O-dimethylhydroxylamine can be readily cleaved from the intermediate. Thus, no neutral N,O-dimethylhydroxylamine can react with the resultant ketone to form enamine again.

Weinreb ketone synthesis mechanism
Reaction mechanism of Weinreb ketone synthesis

The mechanism of the Weinreb ketone synthesis can be written as the following steps:

Step 1 – Protonation of the carboxylic acid to form a carboxylic acid salt: The carboxylic acid (in this example acetic acid) is protonated by the lithium diisopropylamide (LDA) to form the carboxylic acid salt.

H-COOH + Li+ N(CH2CH2CH3)2 → H-COO-Li+ N(CH2CH2CH3)2

Step 2 – Nucleophilic addition of the carboxylate anion to the halide: The carboxylate anion (H-COO) acts as a nucleophile, and attacks the electrophilic carbon atom of the halide (in this example 2-chloropropane), forming a tetrahedral intermediate.

H-COO-Li+ N(CH2CH2CH3)2 + Cl-CH2CH2CH3 → H-COO-CH2CH2CH3 + Li+ N(CH2CH2CH3)2Cl

Step 3 – Deprotonation of the intermediate: The tetrahedral intermediate is deprotonated by the lithium diisopropylamide (LDA) to form the final product, the ketone (in this example 2-butanone) and the byproduct HCl.

H-COO-CH2CH2CH3 + Li+ N(CH2CH2CH3)2Cl → 2-Butanone + Li+ N(CH2CH2CH3)2 + HCl

The mechanism is a generalization of the reaction, and it can vary depending on the specific conditions and reagents used.

References

Nahm, S., and Weinreb, S. M. (1981). N-methoxy-n-methylamides as effective acylating agents. Tetrahedron Letters, 22(39), 3815-3818. https://doi.org/10.1016/S0040-4039(01)91316-4

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