Feist-Benary reaction

The mechanism of the Feist-Benary reaction involves an aldol reaction followed by an intramolecular 0-alkylation and dehydration to yield the furan product. In the example below, ethyl acetoacetate (9) is deprotonated by the base (B) to yield anion 10 this carbanion reacts with chloroacetaldehyde (8) to furnish aldol adduct 11. Protonation of the alkoxide anion followed by deprotonation of the [i-dicarbonyl in 12 leads to... 

Syntheses of trisubstituted furans are much less common than the disubstituted derivatives only one 2,4-disubstituted 3-furoate has been prepared using the Feist-Benary reaction. Combination of chloroacetone (4) with ethyl acetoacetate (9) provides ethyl 2,4-dimethyl-3-furoate (28) in 54-57% yield. The procedure for this... 

The only tetrasubstituted furans that have been prepared using the Feist-Benary reaction are substituted tetrahydrobenzofurans and octahydrodibenzofurans. This strategy was pioneered by Stetter and Chatterjea and applied in a series of total syntheses by Magnus. Stetter demonstrated that 1,3-cyclohexanedione (30) can act as the P-dicarbonyl component and readily combines with either 3-bromo-2-ketobutyric (29) acid or ethyl 2-chloroacetoacetate (32) in the presence of potassium hydroxide to yield tetrahydrobenzofuran derivatives 31 and 33, respectively. ... 

Magnus prepared tetrahydrobenzofuran 37 using a Feist-Benary reaction of ethyl 2-chloroacetoacetate (32) and functionalized 1,3-cyclohexanedione 36. Compound 37 was a key synthetic intermediate in Magnus s synthesis of linderalactone, isolinderalactone, and niolinderalactone. ... 

Several variations of the Feist-Benary reaction furnish substituted furans as products. The following three examples provide synthetically useful alternatives to the standard reaction conditions. One method is based on the reaction of a sulfonium salt with a P-dicarbonyl compound. For example, reaction of acetylacetone (39) with sulfonium salt 38 in the presence of sodium ethoxide yields 81% of trisubstituted furan 40. This strategy provides a flexible method for the preparation of 2,3,4-trisubstituted furans. 

Three other modifications of the standard conditions provide synthetically useful strategies for the preparation of dihydrofurans. One method, called the interrupted Feist-Benary reaction, utilizes milder reaction conditions to stop the final dehydration step. For example, Calter combined bromide 47 with dicarbonyl 48 to produce dihydrofuran 49 as a mixture of diastereomers. He examined the scope and diastereoselectivity of this process and applied this reaction toward the synthesis of the polycyclic core of the zaragozic acids. A method principally designed to yield practical syntheses of cyclic ketodiesters also furnished a dihydrofuran via a variation of the interrupted Feist-Benary reaction. ... 

Although it is far more common to synthesize these substrates using the Feist-Benary reaction (Section 4.1), the Paal-Knorr reaction can also be used to prepare 2,3-disubstituted furans. In a recent example, Castagnoli converted 1,4-ketoaldehyde 40 into furan 41 in 97% yield upon exposure to hot sulfuric acid. ... 

The reaction between the copper derivative of pentafluorobenzene and chloracetyl chloride (ammonia as base) produces a little of the highly stable furan 8, an unusual result that has been regarded very tentatively as a Feist-Benary reaction with Cf,F5COCH2Cl as substrate.48... 

R. Neier et al. synthesized substituted 2-hydroxy-3-acetylfurans by the alkylation of fert-butylacetoacetate with an a-haloketone, followed by treatment of the intermediate with trifluoroacetic acid. When furans are prepared from (3-ketoesters and a-haloketones, the reaction is known as the Feist-Benary reaction. A second alkylation of the C2 alkylated intermediate with various bromoalkanes yielded 2,2-disubstituted products, which upon treatment with TFA, provided access to trisubstituted furans. 

An efficient synthesis of the 7-deoxy zaragozic acid core was deveioped by M.A. Calter and co-workers. The assembly of this complex structure was based on the interrupted Feist-Benary reaction, which produces highiy oxygenated dihydrofuranols that can be isolated. To this end, the sodium enolate of malondialdehyde was reacted with 2-bromo-3-oxo-diethyl succinate in benzene at room temperature to afford 29% of the c/s-dihydrofuranol. This product was converted to the zaragozic acid core in four steps. 

The mycotoxin patulin was synthesized via the oxidation of a disubstituted furan in the laboratory of M. Tada. The required 2,3-disubstituted furan was conveniently prepared via the Feist-Benary reaction of acetonedicarboxylic acid dimethyl ester and chloroacetaldehyde in the presence of pyridine. Subsequent functional group modification and oxidation of this furan finally gave the natural product. 

Bisagni, E., Marquet, J. P., Andre-Louisfert, J., Cheutin, A., Feinte, F. 2,3-Disubstituted furans and pyrroies. i. Extension of the Feist-Benary reaction to P-diketones. New synthesis of 3-acyiated furans and pyrroies. Bull. Soc. Chim. Fr. 1967, 2796-2780. 

Apart from acting as effective Lewis base catalysts, the quinuclidine structure of cinchona alkaloids can also participate in the other cycloaddition reaction by a different catalytic mechanism. Calter et al. described an interesting asymmetric interrupted Feist-Benary reaction between ethyl bromopyruvates and cyclohexadione. They proposed that the protonated cinchona alkaloid would perform as a Bronsted acid to form hydrogen-bonding interaction with a-ketoester moiety, rendering it more electrophilic toward attack by either the enol or enolate of cydohexandione. Then intramolecular alkylation would afford the formal [3 + 2] cycloadduct (Scheme 10.12) [16]. 

Scheme 10.12 Catalytic mechanism for the asymmetric interrupted Feist-Benary reaction.

The condensation reaction of (3-dicarbonyl compounds with a-haloketones to generate hydroxydihydrofuran is known as an interrupted Feist-Benary reaction. Calter et al. reported an enantioselective version of this reaction [26]. The aldol reaction of diketone with a-bromo-a-ketoester followed by cyclization proceeded in the presence of dimeric cinchona alkaloid catalyst to give cyclized product in high yield with high ee... 

Calter, M.A., Phillips, R.M. and Flaschenriem, C. (2005) Catal3ftic, asymmetric, interrupted Feist-Benary reactions. Journal of the American Chemical Society, 127, 14566-14567. 

The base-catalyzed reaction of j8-ketoesters with a-halogenoketones (Feist-Benary reaction) <02CB 1545,11CB493 > yields 3-alkoxycarbonylfurans (23) (Scheme 16). Usually the reaction starts with an aldol condensation if in the first step an alkylation of the ) -carbonyl compound takes place, the reversed regiochemistry is observed <68JH05>. 

Several tetrasubstituted furan derivatives have been prepared by the Feist-Benary reaction. For example, Stetter and Lauterbach demonstrated that 1,3-cyclohexanedione could serve as a P-dicarbonyl in combination with ethyl 2-chloroacetoacetate in the presence of potassium hydroxide to yield the corresponding fused tetrasubstituted furan derivative in good yield. ... 

Magnus and co-workers extended on work by Stetter and Lauterbachr to produce an intermediate common to the natural products linderalactone, isolinderalactone and neolinderalactone. Compounds of this class have been shown to exhibit a host of biological properties including analgesic, anti-inflammatory, antiemetic, antibacterial and antiviral. The Feist-Benary reaction of ethyl 2-chloroacetoacetate and 5-(methoxymethyl)-5-methylcyclohexane-l,3-dione in the presence of potassium hydroxide gave the desired tetrasubstituted furan in 57% yield. 

This reaction has been modified by temporarily terminating the reaction to obtain the dihydrofuran derivatives. In addition, this reaction has been carried out under an acidic conditions, such as in the presence of TFA, and by using 10% EtsN as the base. Moreover, o, j0-dichloroethyl ether has been used to substitute for the a-halo ketones. Other modifications include the reaction of dicarbonyl compounds with acetylenes and aldehydes. Furthermore, a general preparation of five-membered heterocycles, including furans—although not related to the Feist-Benary reaction—is also considered as a relevant modification. ... 

Other references related to the Feist-Benary reaction are cited in the literature. 

Example 3, Ionic liquid-promoted interrupted Feist-Benary reaction ... 

Example 4, interrupted Feist-Benary reaction of a-tosyloxy-acetophenones... 

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