Benzoic Acid Catalyzed Aldol‐Type Condensation of Aldehydes with Ethyl Diazoacetate: Highly Diastereoselective Products with Chiral Aldehydes

Abstract

Benzoic acid catalyzed aldol‐type condensation of aldehydes with ethyl diazoacetate (EDA) under neat conditions at room temperature to afford β‐hydroxy‐α‐diazo carbonyl compounds in good to excellent yields is reported. Furthermore, the condensation of EDA with sugar‐derived aldehydes under the same conditions afforded the adducts in excellent yields and high diastereoselectivities.

Ethyl diazoacetate synthesis in flow

“…Considering the importance of EDA in a wide variety of reactions e.g. cyclopropanation, X–H insertion, cycloaddition and ylide formation [13,15], and more recently, in the synthesis of valuable compound classes such as β-keto esters [16] and β-hydroxy-α-diazocarbonyl compounds [17], we aimed to develop an inherently safe continuous-flow EDA process using microreactor and separation technology.…”

“…In-line phase separation was thought to greatly enhance the usefulness of the EDA flow synthesis. Therefore, the outlet of the microreactor was directly connected to membrane-based phase separator to obtain EDA in the organic phase, which in principle can then be immediately used for either batch [13,15] or continuous-flow [16–17] follow-up reactions. Straightforward scale-up or scale-out of microreactor technology renders this method viable for industrial application.…”

Carboxylate catalysis: a mild catalytic O-silylative aldol reaction of aldehydes and ethyl diazoacetate

“…In 1976, Evans and co-workers described a mild Osilylative variant which required the use of TMS-activated diazoacetate and catalytic KCN/18-cr-6. 5 Even milder methods employing, among others, DBU , or benzoic acid 9 as catalysts have been disclosed. With metal phenolates or organometallic bases, the reaction has also been rendered enantioselective.…”

Brønsted Acid/Lewis Acid Cooperatively Catalyzed Addition of Diazoesters to 2H‐Chromene Acetals

“…13 Several novel organic transformations were developed by using BINOL-phosphoric acid under various reaction condition. 14 α-Unsubstituted diazocarbonyl compounds, which are generally considered as a carbene precursors, 15 can be coupled with various electrophiles as nucleophiles, 16 such as aldehydes 17 and imines 18 with the retention of diazo moiety under Brønsted acid catalyzed reaction condition. However, to the best of our knowledge, the use of nucleophilic diazoacetates additions to oxocarbeniums has not been reported.…”