Feist-Benary

The Feist-Benary furan synthesis occurs when an a-halocarbonyl (1) reacts with a P-dicarbonyl (2) in the presence of a base. The resulting product (3) is a 3-furoate that incorporates substituents present in the two starting materials. ... 

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. ... 

Chatteijea showed that cyclic ot-halocarbonyls are acceptable substrates for the Feist-Benary furan synthesis by combining 1-chlorocyclohexanone (34) with 1,3-cyclohexanedione (30) to yield octahydrodibenzofuran 35. ... 

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 modifications of the Feist-Benary furan synthesis have been reported and fall into two general classes 1) reactions that yield furan products 2) reactions that yield dihydrofuran products. One variant that furnishes dihydrofiirans uses substrates identical to the traditional Feist-Benary furan synthesis with a slight modification of the reaction conditions. The other transformations covered in this section involve the combination of P-dicarbonyls with reagents that are not simple a-halocarbonyls. Several reactions incorporate a-halocarbonyl derivatives while others rely on completely different compounds. 

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. 

Step reaction provides an excellent alternative to the traditional Feist-Benary protocol for the synthesis of 2-substituted 3-furoates. 

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. ... 

The final variation of the Feist-Benary furan synthesis encompasses reactions of 1,3-dicarbonyls with 1,2-dibromoethyl acetate (52). For example, treatment of ethyl acetoacetate (9) with sodium hydride followed by addition of 52 at 50°C yields dihydrofuran 53. The product can be easily converted into the corresponding 2-methyl-3-furoate upon acid catalyzed elimination of the acetate, thus providing another strategy for the synthesis of 2,3-disubstituted furans. 

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. ... 

D. From Feist-Benary Synthesis (Haloketone Reactions).174... 

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... 

Dicarbonyl compounds can be converted into furans by methods other than the classical Feist- Benary method, the essential feature of which is alkylation by a haloketone or similar species. A curious variation is provided by the use of trichloronitroethene, Cl2C=CCIN02, which condenses with two moles of a 1,3-dicarbonyl compound by Michael addition followed by elimination of two chloride ions the third chloride is lost at the aroma-tization step so that, for example, methyl 3-oxobenzenepropanoate is converted into the nitrofuran 38."... 

Finally, Scharf and Wolters report a method said to be superior to both the Paal-Knorr synthesis (starting materials more easily accessible) and the Feist-Benary synthesis (freer choice for 3-substituent). Thermal rearrangement-elimination by alkylated dioxolanes at 230 C gives alkyl substituted furans. Yields can be nearly quantitive since the only serious by-products also give the furans under proton-catalyzed thermolysis (Scheme 25).124 Photochemical methods are outlined in Section VII. 

Feist-Benary cyclo-condensation of (2,4-dioxobutylidene)-phosphoranes with a-chloroacetone gave rise to substituted furfuryl phosphonium salts, which underwent subsequent Wittig reactions to afford alkenylfurans in good yields as can be seen below <06JOC8045>. 

Shea, K. M. Feist—Benary Furan Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 160-167. (Review). 

Reactions of the Feist-Benary type have been applied to the synthesis of thiophenes (140 — 141) (75ZC100). The use of a-halocarbonyl halides provides an entree to 3-furanones (142 — 143) (73RTC73I). 

Furan carboxylic acids are usually prepared by ring synthesis using the Feist-Benary and Paal-Knorr methods (Section 3.12.2.2). However, furancarboxylic acids can also be prepared by reaction of lithiofurans with carbon dioxide. A convenient source of furan-3-carboxylic acid (517) is the commercially available diethyl furan-3,4-dicarboxylate (518) (71S545). 

The construction of the furan ring in a Feist-Benary type reaction starting from 4-hydroxy-6-methylpyran-2-one (66) has also proved to be useful for the synthesis of furo[3,2-c]pyridines (Scheme 14) (75JHC461, cf. 71BSF4041). Quite recently the synthesis of the hitherto unknown furo[3,2-c]pyridin-3-ols has been described (79LA371). 4-Hydroxypyridine-3-carboxylates (e.g. 69), which are available from diketene and /3-aminocrotonic esters, react with a-halogenoketones in the presence of potassium carbonate to give compounds of type 70. 

The method described has some features in common with the well-known, but apparently little-used, Feist-Benary furan synthesis,1 which uses an a-haloketone in place of the sulfonium salt. Acetylenic bromides suitable for preparing the sulfonium salts are readily available by well-documented procedures involving acetylenic organometallic compounds. 

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