Facile Synthesis of β-Keto Esters from Methyl Acetoacetate and Acid Chloride:  The Barium Oxide/Methanol System¹

Abstract

The synthesis of β-keto esters has been performed in good yield by reacting excess methyl acetoacetate with barium oxide, acylating the resulting barium complex with acid chloride, and then cleaving the r-acyl β-keto ester with methanol at a mild temperature. Using this new procedure, various β-keto esters were prepared. Thus, methyl 4-phenyl-3-oxobutanoate, methyl 3-phenyl-3-oxopropionate, methyl 4-cyclohexyl-3-oxobutanoate, and methyl 3-oxooctadecanoate were prepared from methyl acetoacetate and the corresponding acid chloride in 69%, 84%, 67%, and 74% yields, respectively. β-Keto esters are known to be useful as intermediates in the synthesis of drugs, ceramides, biodegradable polymers, etc., and there have been reported a number of syntheses for β-keto esters. 2 For example, recently, Benetti et al. 2d reviewed the synthesis of β-keto esters. In this review, numerous procedures were reported; in particular, the acylation of an acetoacetic ester at the C2 carbon, a well-known process, was discussed in detail. As the base component to be employed in this acylation process, NaH, NaNH 2 , or alkali metal alcoholates are usually used. 3,4 However, the achieved yields are only of the order of 30-40%, because the β-keto ester formed during the condensation reaction has a higher reactivity than the starting compounds to be converted, which can lead to numerous secondary reactions. As an improvement in the base component in the reaction for condensing

Synthesis and biological evaluation of dihydropyrano-[2,3-c]pyrazoles as a new class of PPARγ partial agonists

“…All starting hydrazines were purchased from commercial suppliers. The corresponding β-keto esters were synthesized either according to Yuasa and Tsuruta [ 19 ] or by deprotonation of esters and subsequent reaction with ethyl acetate [ 20 ]. Aldehydes were all purchased or prepared in one step from 14 according to the procedure described for the synthesis of 15 .…”

A Process in Need Is a Process Indeed: Scalable Enantioselective Synthesis of Chiral Compounds for the Pharmaceutical Industry

“…Synthesis of a single enantiomer of 3 seems less demanding than that of viracept 1 and its central four‐carbon intermediates such as 10 (Schemes and ), 32 c (Scheme ), and 34 (Scheme ), because 3 possesses only one stereogenic center (Figure 1). However, it is ironic that scalable processes to access either ( R )‐ or ( S )‐ 3 are few notwithstanding various synthetic methodologies explored so far, which actually cover the following alternatives: 1) resolution of (±)‐ 3 14–17 via diastereomeric salt formation with basic resolving agents;14b, 15, 18 2) kinetic resolution of (±)‐ 3 and its methyl ester via lipase‐catalyzed enantioselective O‐acetylation;14a, 19, 20 3) asymmetric bioreduction of β ‐keto acid;16, 20a 4) asymmetric reduction of β ‐keto ester over chiral metal/complex catalysts;14c, 21–23 5) stereoselective functionalization through Sharpless' asymmetric epoxidation24 and dihydroxylation;25 6) stereoselective construction of homoallyl alcohol through Brown's asymmetric allyboration;26 7) chiral pool synthesis starting from ( S )‐ β ‐hydroxy‐ γ ‐butyrolactone27 or ( S )‐epichlorohydrin 4. Thus, the scope and limitation intrinsic to each methodology will be discussed from the pragmatic viewpoint in the sections that follow.…”

“…Saponification eventually provided (±)‐ 3 in a three‐step overall yield of 65 % from 39 14a. Except for Meldrum's acid‐based synthesis, there are other approaches to prepare (±)‐ 3 , such as the Reformatsky reaction to prepare ethyl ester of (±)‐ 3 from ethyl bromoacetate and dodecanal,15 γ ‐alkylation of a dianion generated from methyl acetoacetate with decyl halide to give 42 ,16 and acylation of a barium chelate complex of methyl acetoacetate with acid chloride 17…”

A Process in Need Is a Process Indeed: Scalable Enantioselective Synthesis of Chiral Compounds for the Pharmaceutical Industry.

“…The most typical approach to (AE)-3 started with acylation of Meldrum×s acid 39 with dodecanoyl chloride 40 to give 41, [14] which, on methanolysis, was converted to b-keto ester 42 in 72 % overall yield from 39 (Scheme 7 acid-based synthesis, there are other approaches to prepare (AE)-3, such as the Reformatsky reaction to prepare ethyl ester of (AE)-3 from ethyl bromoacetate and dodecanal, [15] galkylation of a dianion generated from methyl acetoacetate with decyl halide to give 42, [16] and acylation of a barium chelate complex of methyl acetoacetate with acid chloride. [17] Resolution of (AE)-3 into (R)-3 by diastereomeric salt formation was effected using chiral amine as the resolving agent, such as (1S,2R)-l-ephedrine (44), [14b] (R)-d-a-methylb-phenethylamine (45), [15] and dehydroabietylamine (46). [18] Resolution efficiency reported for each resolving agent is as follows: 44, 50% ee and 25 % overall yield after twofold recrystallization; 45, no data for optical purity or overall yield for a single recrystallization step; 46, 95 % ee and 24 % overall yield after twofold recrystallization.…”