SYNTHESIS OF ETHYL 3-OXOPENTANOATE (Ethyl propionylacetate)

• Prepare the ethoxy magnesium diethyl malonate derivative from 13g (0.53 mol) of magnesium and 80g (0.5 mol) of diethyl malonate. 

• Then add with vigorous stirring a solution of 49g (46 ml, 0.53 mol) of propanoyl chloride in 50 ml of anhydrous ether. 

• Reflux the reaction mixture for 30 minutes and then cool and acidify with 60 ml of dilute sulphuric acid. 

• Separate the ether layer, extract the residual aqueous solution with two 50 ml portions of ether. 

• Wash the combined organic phases with water, dry over anhydrous sodium sulphate and remove the ether on a rotary evaporator. 

• Add to the residue 8g of naphthalene-2-sulphonic acid monohydrate and heat the mixture slowly to 200 °C in an oil bath. 

• A vigorous evolution of gas sets in at about 120°C; when gas evolution has subsided, cool the reaction mixture and dissolve it in about 150 ml of ether. 

• Wash the ethereal extract with four 25 ml portions of 10 per cent sodium carbonate solution and then with water; back extract the combined aqueous solutions with three 25 ml portions of ether. 

• Dry the combined ether extracts with anhydrous sodium sulphate, remove the ether on a rotary evaporator and distil the residue under reduced pressure. 

• Collect the ethyl 3-oxopentanoate as a fraction of b.p. 100-105 °C/22 mmHg; the yield is 34g (47%).

Cognate preparation: General procedure for the acylation of the dianion of ethyl hydrogen malonate (1)

• To 250 ml of tetrahydrofuran (distilled from sodium/benzophenone under nitrogen prior to use) under nitrogen with stirring is added 13.47g (0.1 mol) of monoethyl malonate (2) and several milligrams of 2,2'-bipyridyl as an indicator. 

• After cooling to — 70 °C, butyllithium (hexane) is added slowly while allowing the temperature to rise to c. - 5 °C near the end of the addition (~ 130 ml of 1.6 m solution, 0.2 mol). 

• After the pink indicator persists at — 5°C the heterogeneous solution is recooled to — 65 °C and the acid chloride (0.057 mol) is added dropwise over 5 minutes.

• After the appropriate reaction time (3), the reaction solution is poured into 400 ml of ether and 200 ml of 1 M hydrochloric acid. 

• After mixing and separating the aqueous phase, the organic phase is washed with 2 x 100 ml of saturated sodium hydrogen carbonate solution and 100 ml of water, dried over anhydrous sodium sulphate and concentrated to yield the 𝛃-keto ester.

Notes to keep in mind:

1. Ethyl hydrogen malonate may be prepared from diethyl malonate by controlled hydrolysis with potassium hydroxide.

2. The following acid chlorides have been used and the reaction times are given in parentheses: Pr·COCl (5 minutes); Me₂CH·CH₂COCl (5 minutes); Bu·COCl (5 minutes); Ph·CH₂COCl (5 minutes); and Ph·COCl (30 minutes).