New and Facile Approach for the Synthesis of (E)‐α,β‐Unsaturated Esters and Ketones

Abstract

Preparation of (E)-a,b-unsaturated esters and ketones is an important task in organic synthesis.[1] Such esters and ketones are excellent building blocks for the synthesis of a plethora of synthetic and natural products.[2] The most versatile and widely used methods are the Wittig reaction [3] with aldehydes by using alkoxycarbonylmethylene(triphenyl)phosphoranes and the Horner-Wadsworth-Emmons [4] procedure using trialkyl phosphonoacetates with stronger bases. These methods generate stoichiometric amounts of byproducts, namely triphenylphosphine oxide and phosphate salts. Decarboxylative Knoevenagel-type reactions employing malonic acid half esters [5] and the olefination of aldehydes with ethyl diazoacetate [6] (EDA) are alternative methods reported for the synthesis of (E)-a,b-unsaturated esters. The synthesis of (E)-a,b-unsaturated ketones involves the reaction of aromatic aldehydes with aromatic ketones, alkynes and the Grignard reaction of unsaturated aromatic nitriles.[7] The Knoevenagel condensation is an important reaction for the synthesis of a,b-unsaturated compounds; aromatic aldehydes afforded (E)-a,b-unsaturated esters and salicylaldehydes afforded 3-substituted coumarins [8] with b-ketoesters in the presence of base. Generally, the condensation of carbonyl compounds with active methylene substrates containing trifluoroacetoacetate substituents seldom gives the condensation product; however, it has been reported that the reaction of benzaldehyde with ethyl-4,4,4-trifluoroacetoacetate in the presence of piperidine in toluene under reflux conditions afforded ethyl (E)-3-phenyl-2-(2,2,2-trifluoroacetyl)-2-propenoate in low yields. [9] As part of our ongoing efforts in developing approaches for the synthesis of various heterocyclic compounds with potential biological applications, [10] we recently reported the synthesis of methyl (E)-3-(2-chloro-5-methyl-3-pyridyl)-2-propenoate [11] by adopting Horner-Wadsworth-Emmons (HWE) reaction conditions and synthesized new Knoevenagel products. Herein, we report a new, general, and practical method for the synthesis of (E)-a,b-unsaturated esters and ketones by Aldol-adduct elimination under basic conditions. Treatment of 2-chloro-5-methylnicotinaldehyde (1 q) with ethyl-4,4,4-trifluoroacetoacetate (2 a) in CH 2 Cl 2 in the presence of piperidine at room temperature for 4-6 h gave the geometrically selective E product 3 qa instead of the condensation product (Scheme 1).The result surprised and encouraged us to search for the best reaction conditions. The optimization of the reaction conditions was first examined with the use of mostly basic catalysts, namely 1,4-diazabicycloA C H T U N G T R E N N U N G [2.2.2]octane (DABCO), 4-dimethylaminopyridine (DMAP), imidazole, triethylamine, NaOMe, pyridine, and picoline, and we found that the reaction did not take place under these basic conditions. However, when we studied the use of piperidine with various solvents we found that CH 2 Cl 2 was the solvent of choice in terms of yield, reaction time, and selectivity ...

Copper‐Catalyzed C−H Oxygenation of Benzoxepine‐4‐carboxylates: Facile Synthesis and Photophysical Properties of Naphtho[2,1‐d]oxazoles and Benzo[c]phenoxazines

“…As part of our ongoing research on heterocyclic chemistry, we have studied the reaction of carbonyl compounds/salicylaldehydes with various β‐ketoesters. The reaction of carbonyl compounds with ethyl 4,4,4‐trifluoro‐3‐oxobutanoate in the presence of piperidine provided a series of ( E )‐α,β‐unsaturated esters and ketones . The reaction of salicylaldehydes with 3‐oxobutanoates provided various heterocyclic compounds –.…”

Ambient Cross-linking System Based on the Knoevenagel Condensation Reaction between Acetoacetylated Sucrose and Aromatic Dicarboxaldehydes

“…Since the Knoevenagel condensation reaction was first reported by Emil Knoevenagel in 1894, 1 the Knoevenagel condensation reaction has been increasingly used and has become an important C–C bond formation reaction. 2−5 It has been used to obtain a variety of compounds, such as synthetic natural products, 6 drugs, 7 fine chemicals, 8 functional polymer materials, 9 and so forth.…”