Beta Keto Esters Synthesis Essay

Yong-Heng Luo

School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Haiquan Road, Shanghai, P. R. of China

,

Yuan-Ji Ping

Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, 354 Feng Lin Road, Shanghai 200032, P. R. of China   Email: xuzhenjiang@sioc.ac.cn

,

Zong-Rui Li

Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, 354 Feng Lin Road, Shanghai 200032, P. R. of China   Email: xuzhenjiang@sioc.ac.cn

,

Xin Gu

Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, 354 Feng Lin Road, Shanghai 200032, P. R. of China   Email: xuzhenjiang@sioc.ac.cn

,

Zhen-Jiang Xu*

Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, 354 Feng Lin Road, Shanghai 200032, P. R. of China   Email: xuzhenjiang@sioc.ac.cn

,

Chi-Ming Che*

Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, 354 Feng Lin Road, Shanghai 200032, P. R. of China   Email: xuzhenjiang@sioc.ac.cn

Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, SAR, P. R. of China   Email: cmche@hku.hk

› Author Affiliations

Pyrazolones are important class of heterocyclic ring systems that have been used extensively in pharmaceutical industry [1, 2] due to their numerous applications as analgesic, antipyretic, antiarthritic, uricosuric, anti-inflammatory and antiphlogistic properties. Especially, a pyrazolone derivative (edaravone) [3] acts as a radical scavenger to interrupt the peroxidative chain reactions and membrane disintegrations associated with ischemia [4, 5, 6]. Some of the aryloxypyrazolone derivatives are useful in the treatment of a variety of disorders caused by human immunodeficiency virus and other genetic ailments caused by retroviruses such as acquired immune deficiency syndrome [7]. In addition, these compounds are appropriate precursors for industrial preparation of herbicides [8], liquid crystals [9, 10], dyes [11], thermally stable polymers [12] and colour photographical compounds [13]. Azadienophiles from the chemical oxidation of pyrazolones are acting as suitable substrates for hetero Diels-Alder reactions [14].

Pyrazolones are traditionally synthesized by the reaction of β-keto esters with hydrazine and its derivatives [15, 16, 17, 18, 19, 20, 21]. There are a number of alternative methods to synthesize pyrazolones which are documented in the literature [22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33] but tend to have serious drawbacks such as step-intensive, carbon monoxide usage and sensitive palladium catalysts. These factors revealed that using β-keto esters as an intermediate is the broadest and most efficient way to synthesize pyrazolones. There are methods to synthesize β-keto esters from esters [34, 35, 36, 37] (Claisen condensation) and aldehydes [38, 39], but these methods have main limitation in varying the substituents. Often, a number of methods such as acylation of enolates of malonates [40, 41], acylation of Meldrum's acid [42, 43, 44, 45], mixed malonate esters [46, 47] and bistrimethylsilylmalonate [48, 49] have a chelating effect employed to lock the enolate anion of malonate using lithium and magnesium salts [50, 51]; however, these methods suffer from inconsistent yields in the case of aliphatic acylation. There are methods to synthesize β-keto esters from ketones like caboxylation of ketone enolates [52, 53, 54] using carbon dioxide and carbon monoxide sources in the presence of palladium or transition metal catalysts. Currently, the most general and simple method to synthesize β-keto ester is the reaction of dimethyl or ethyl carbonate with ketone in the presence of strong bases [55, 56]. This method requires long reaction time, use of excessive amount of reagent and inconsistent yield. These factors lead us to develop a simple method to synthesize β-keto esters by changing the base and reagent.

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