Preparation Methods and Condensation reaction of Ethyl propionylacetate

Ethyl propionylacetate is a reactive methylene-type compound that exists as a clear, colorless to pale yellow liquid at room temperature and under atmospheric pressure, exhibiting high chemical reactivity and significant nucleophilicity. Ethyl propionylacetate is insoluble in water but readily soluble in most organic solvents such as ethyl acetate and dichloromethane. Ethyl propionylacetate can be prepared from ethyl acetoacetate as the starting material through a series of chemical reactions, and this compound is primarily employed as an organic synthetic intermediate and as a fundamental chemical raw material for pharmaceutical molecules. Notably, studies have reported that ethyl propionylacetate can be utilized in the synthesis of the insecticidal drug molecule dinotefuran.

Preparation Methods

Researchers have reported a preparation method for ethyl propionylacetate, which is synthesized starting from ethyl acetoacetate as the raw material. In this process, ethyl acetoacetate is subjected to condensation with propionyl chloride in dichloromethane as the solvent in the presence of a catalyst, thereby affording ethyl α-acetylpropionylacetate as an intermediate. This intermediate is then hydrolyzed in aqueous ammonia to remove the acetyl group, followed by acidification with hydrochloric acid, to finally obtain the desired product, ethyl propionylacetate. The ethyl propionylacetate produced by this method consistently achieves a purity of over 98%. Compared with existing techniques in the art, the present invention offers several distinct advantages: the starting materials are readily available and inexpensive, the reaction conditions are mild, the operation is safe and straightforward, the product quality is stable, and the overall process is well suited for large-scale industrial production.

Preparation of flufenerim

To investigate the biological activity of the insecticide flufenerim, its synthetic route was explored and accompanied by bioactivity assays. In this study, ethyl propionylacetate served as one of the key starting materials, along with sulfonyl chloride, 4-trifluoromethoxybenzyl bromide, and sodium cyanide, to prepare flufenerim through a multi-step sequence. The overall yield of the reaction was 40%, and the structure of the target compound was confirmed by nuclear magnetic resonance (NMR) spectroscopy. Bioassay results indicated that the compound exhibits promising insecticidal activity against Plutella xylostella (diamondback moth) and Myzus persicae (green peach aphid) at low dosages, while also demonstrating moderate activity against Mythimna separata (oriental armyworm) and Tetranychus cinnabarinus (carmine spider mite). Notably, ethyl propionylacetate proved to be a readily accessible and reactive building block in this synthetic pathway, and its utilization underscores the practical value of ethyl propionylacetate in constructing complex heterocyclic pharmacophores for agrochemical development.

Condensation reaction

The ketone carbonyl group in the structure of ethyl propionylacetate can undergo condensation reactions with amine compounds under basic conditions to afford the corresponding enamine or imine derivatives.

Figure1: The Condensation reaction of ethyl propionylacetate

To an oven-dried sealed tube equipped with a magnetic stirring bar and containing a suspension of anhydrous magnesium sulfate (15 mmol) in absolute ethanol (20 mL) were added the ethyl propionylacetate (12 mmol) and aniline (10 mmol), after which an acetic acid solution (0.2 mmol) was introduced dropwise into the mixture. A reflux condenser was then attached to the apparatus, and the resulting reaction mixture was stirred at 90 °C in an oil bath, with the progress of the reaction being closely monitored by thin-layer chromatography at regular intervals. Upon completion as indicated by TLC analysis, the reaction was quenched by the addition of water, and the mixture was subsequently extracted with ethyl acetate. The organic and aqueous layers were carefully separated, and the aqueous phase was subjected to two additional extractions with fresh portions of ethyl acetate to ensure complete recovery of the desired product. The combined organic extracts were then dried over anhydrous magnesium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to afford a crude residue. This crude material was finally purified by column chromatography to obtain the pure product.[1]

Reference

[1] Shen, Peng; et al, Dual Gold/Silver Catalysis: 3-Alkynylpyrroles via a Tandem C(sp2)-H Alkynylation/N-Alkynylation, Organic Letters (2026), 28(22), 6998-7003.