Saturday, 29 October 2011

Aldehydes from Acyl chlorides, Esters, Nitriles

Aldehydes  can be prepared by mild reduction of acyl chlorides, esters, nitriles. The reducing agents of choice are usually lithium tri-tert-butoxy aluminum hydride (LATB—H) and diisobutylaluminum hydride (DIBAL—H).  low temperature is very crucial for aldehyde conversion otherwise you may end getting an alcohol (over reduced).

Acyl chloride reduction

Acyl chlorides can be reduced by reacting them with lithium tri-tert-butoxyaluminum hydride at −78°C.

Ester and nitrile reduction
You can use diisobutylaluminum hydride to reduce both esters and nitriles to aldehydes.

The mechanism for both of these reactions is very similar to the mechanism for the reduction of acyl chlorides by LATB—H. The first step is an acid-base reaction between an unshared electron pair on oxygen or nitrogen with the aluminum atom of the DIBAL—H. The second step is the transfer of a hydride ion from the DIBAL—H to the carbon atom of the carbonyl or nitrile group. The last step is the hydrolysis of the aluminum complex to form the aldehyde.

Ester reduction mechnaism

Nitrile reduction mechanism

Aldehyde synthesis (via cyanide):

A 200 mL round bottom flask was charged with a magnetic stir bar, 3-ethoxy-2- fluorobenzonitrile (1.000 g, 6.05 mmol), and anhydrous toluene (12.92 ml). The solution was placed under argon and cooled to 0°C with an ice bath. DIBAL-H (7.27 ml, 7.27 mmol) (1M in PhMe) was then added drop wise via syringe and the reaction was allowed to stir to rt overnight. To this mixture was added 10 % HCl until the solution reached a pH of ~ 2. The resulting mixture was then left to stir for 0.5 h. and was then poured into a separatory funnel and extracted with ethyl acetate (2 x 200 mL). The combined organic extract was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude product which was purified via silica gel chromatography (80 g) using ethyl acetate/hexanes (1:4) as eluent to provide pure 3-ethoxy-2-fluorobenzaldehyde (0.810 g, 80 %).
Patent reference: WO2010001169 (Astrazeneca)

Aldehyde synthesis (via ester):
Dissolve the ester (1 equiv) in CH2Cl2. The temperature of the solution should be -78oC. Add DIBAL in THF (1.2 equiv.) to the solution dropwise with a N2 inlet. Stir the resulting mixture at -78oC for 1 hour. Quench the mixture with methanol slowly, and then add brine into the mixture. Separate the organic layer, dry and concentrate. In many cases the residue needs to be purified by column chromatography.

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