Synthesis of alpha-hydroxy ketones

α-hydroxy ketones are important intermediates in organic synthesis. Various methods available for the synthesis of α-hydroxy ketones are described herein.

Hi Friends, in this article we will learn about α-hydroxy ketones synthesis. Here we will discuss Corey-Seebach reaction, Benzoin condensation, Davis Oxidation and Rubottom Oxidation.

Introduction

The α-hydroxy ketones also known as acyloin are important intermediates in organic synthesis. For example the hydroxyl group can be converted in to halide, azide amine functionality. The carbonyl moiety is used for nucleophilic addition, reduction or reductive amination reactions. 

Following are the methods which are used in organic synthesis.

Acyloin condensation

It is a reductive coupling of two carboxylic esters using metallic sodium to yield an α-hydroxy ketone. 

Mechanism

• Step 1: Oxidative ionisation of carbonyl bond of ester due to sodium atom.
• Step 2: Coupling of two free radical molecules (Step 2).
• Step 3: Elimination of two alkoxy groups to form 1,2-diketone.
• Step 4: Oxidative ionisation of carbonyl bond to produce sodium enodiolate.
• Step 5: Neutralization of enodiolate with water to form enodiol, further tautomerization gives α-hydroxy ketone. 

   Examples

Corey-Seebach reaction

The process was developed by Elias James Corey and Dieter Seebach in 1965. It is four step synthesis strategy used for preparation of a-hydroxy ketones.

Step 1: Reaction of aldehyde and dithiol under acidic conditions to form 1,3-dithiane. They are stable in acidic and basic reaction condition.

Step 2: Lithiation of 1,3-dithiane by using BuLi. This is also known as masked acyl anion.

Step 3: Nucleophilic addition of lithiated 1,3-dithiane on carbonyl compound to form secondary/ tertiary alcohol.

Step 4: Hydrolysis of 1,3-dithiane to offer α-hydroxy ketone.

   Example

Benzoin condensation

The Benzoin condensation is a carbon-carbon bond forming reaction. In this reaction two aldehydes reacts in presence of base catalyst to produce α-hydroxyketone compound. The benzoin condensation was first reported in 1832 by Justus von Liebig and Friedrich Wöhler. This reaction is used for synthesis of benzoin by using benzaldehyde; hence the name given “Benzoin condensation”. It is an example of addition reaction. In this reaction a thiazolium salt may also be used as the catalyst.

 Mechanism

The mechanism of Benzoin condensation consists of six steps;

Step 1: Addition of cyanide anion (nucleophile) on carbonyl carbon of aldehyde to form alkoxide ion.

Step 2: Proton transfer to form cyanohydrine.

Step 3: Abstraction of acidic proton of cyanohydrine by base to form a nucleophile.

Step 4: Addition of nucleophile on second molecule of aldehyde to form alkoxide ion.

Step 5:  Proton transfer to produce new alkoxide ion.

Step 6: Regeneration of catalyst due to removal of leaving group to form α-hydroxy ketone compound. 

Let’s recap the complete mechanism.

Complete mechanism

Examples

A thiazolium salt may also be used as the catalyst in this reaction.

Davis Oxidation

Davis oxidation is the two steps synthesis for α-hydroxy ketone compound.  This reaction was developed by American chemist Franklin A. Davis. In this process first step is formation of enolate under strong basic conditions.  The second step is nucleophilic addition of enolate on 2-(phenylsulfonyl)-3-phenyloxaziridine; also known as Davis reagent. 

Mechanism

Let’s see the mechanism of addition of enolate on Davis reagent.

Step 1: The enolate attacks on oxaziridine to produce hemiaminal intermediate. 

Step 2: The hemiaminal intermediate cleaves to form sulfinimine and the corresponding α-hydroxy ketone compound. 

Example

Rubottom Oxidation

This reaction is reported independently by A.G. Brook George M. Rubottom. It is the reaction of silyl enol ethers with mCPBA to produce α-hydroxy ketone.

Mechanism

In this reaction silyl enol ether oxidises to form epoxide intermediate.

Step 1: The epoxide intermediate rearranges to give α-keto silyl ether species.

Step 2: Hydration of α-keto silyl ether leads to the formation of α-hydroxy ketone product. 

 

Example

To summaries this article, we have learned five different methods for the preparation of a-hydroxy ketones. They are Acyloin condensation, Corey-Seebach reaction, Benzoin condensation, Davis Oxidation and Rubottom Oxidation. From the above methods Benzoin condensation, Davis Oxidation and Rubottom Oxidation are more efficient and frequently used in organic synthesis.

That's all for this topic. Thank you..!