Furan synthesis, from 1,4-dicarbonyl

Although nearly all Paal-Knorr condensations produce di-, tri-, or tetrasubstituted furans, it is possible to use this reaction to generate monosubstituted furans. Molander demonstrated the utility of this method with his synthesis of 2-(methyldiphenylsilyl)furan (11) from dicarbonyl 10. ... 

Scheme 3b). It is instructive at this point to reiterate that the furan nucleus can be used in synthesis as a progenitor for a 1,4-dicarbonyl. Whereas the action of aqueous acid on a furan is known to provide direct access to a 1,4-dicarbonyl compound, exposure of a furan to an alcohol and an acid catalyst should result in the formation of a 1,4-diketal. Indeed, when a solution of intermediate 15 in benzene is treated with excess ethylene glycol, a catalytic amount of / ara-toluenesulfonic acid, and a trace of hydroquinone at reflux, bisethylene ketal 14 is formed in a yield of 71 %. The azeotropic removal of water provides a driving force for the ketalization reaction, and the presence of a trace of hydroquinone suppresses the formation of polymeric material. Through a Finkelstein reaction,14 the action of sodium iodide on primary bromide 14 results in the formation of primary iodide 23, a substance which is then treated, in crude form, with triphenylphosphine to give crystalline phosphonium iodide 24 in a yield of 93 % from 14.

The approach also allows the synthesis of furans by employing ethoxymethylene malonate, followed by an eliminative decarboxylation. This method was used by Balme for a formal synthesis of the antitumor lignan burseran (6/1-294), starting from 6/1-290,6/1-291 and 6/1-292 via the furan 6/1-293 (Scheme 6/1.78) [139], Furans as 6/1-298 can also be obtained by Pd-catalyzed reaction of 2-propynyl-l,3-dicarbonyls 6/1-295 with aryl halides 6/1-296 in DMF, using potassium carbonate as base, as shown by Arcadi, Cacchi and coworkers (Scheme 6/1.79) [140]. 

As depicted in the following scheme, in the presence of sodium iodate and pyridine, several 5,6-dihydroxylated benzofuran derivatives were synthesized via an oxidation-Michael addition of P-dicarbonyl compounds to catechols in a one-pot procedure <06TL2615 06JHC1673>. A novel additive Pummerer reaction of 2-benzo[fc]furan sulfilimines with carbon nucleophiles derived from P-dicarbonyl compounds was also employed to the synthesis of 2,3-disubstituted benzo[b]furans <06TL595>. 

Substituted furan formation by an indirect cyclization of 1,4-dicarbonyl derivatives has also been adopted as a key step in the synthesis of 3-oxa-guaianolides. Although 1,4-dicarbonyl compounds have been traditionally considered as the direct precursors for furans, treatment of 1,4-dicarbonyl compounds having a tertiary acetoxy group with p-toluenesulfonic acid leads to only 11% yield of an alkenylfurans as derived from a cyclization/acetoxy-elimination route. The following scheme shows an alternative multi-step conversion of the 1,4-dicarbonyl that leads to a more acceptable yield of the acetoxyfuran . 

Standard heterocyclic syntheses tend to have a name associated with them and it is simply not worth while learning these names. Few chemists use any but the most famous of them we will mention the Knorr pyrrole synthesis, the Hantzsch pyridine synthesis, and the Fischer and Reissert indole syntheses. We did not mention that the synthesis of furans from 1,4-dicarbonyl compounds is known as the Feist-Benary synthesis, and there are many more like this. If you are really interested in these other names we suggest you consult a specialist book on heterocyclic chemistry. 

Furans with suitable substituents in the 2-position can also be converted into phenols. These can be transformed into a 1,4-dicarbonyl system by 2,5 oxidation and ring opening. This system can then condense intramolecularly into a six-membered ring.333 334 The synthesis of m-hydroxybenzoic acid in 26% yield from furfuryl chloride288 is an example of this ... 

Takei utilized a furan as the synthetic equivalent of a 1,4 dicarbonyl compound in his synthesis of pyrenophorin as described in Scheme 4.6. ° Thus butenolide 28, obtained by Michael addition of butenolide 27 to methyl vinyl ketone, was silylated to provide the silyloxyfuran. Treatment with lead tetraacetate followed by aqueous hydrolysis gave 29 in 55% yield. Protection of the ketones as dimethyl ketals followed by selective removal of the C-7 ketal and reduction gave seco acid 30. Dimerization and hydrolysis gave a mixture of 9 and 18 (17% from 29). 

The ring synthesis of five-membered heterocycles has been extensively investigated, and many and subtle methods have been devised. Each of these three heterocyclic systems can be prepared from 1,4-dicarbonyl-compounds, for furans by acid-catalysed cyclising dehydration, and for pyrroles and thiophenes by interaction with ammonia or a primary amine, or a source of sulfur, respectively. 

As illustrations of the variety of methods available, the three processes below show (i) the addition of isonitrile anions to a,P-unsaturated nitro-compounds, with loss of nitrous acid to bring about aromatisation, (ii) the interaction of thioglycolates with 1,3-dicarbonyl-compounds, for the synthesis of thiophene 2-esters, and (iii) the cycloaddition/cycloreversion preparation of furans from oxazoles. 

The hydrolysis (or alcoholysis) of furans involves nucleophilic addition of water (or an alcohol) to an initially formed cation, giving rise to open-chain 1,4-dicarbonyl-compounds or derivatives thereof. This is in effect the reverse of one of the general methods for the construction of furan rings (18.13.1.1). Suc-cindialdehyde cannot be obtained from furan itself, presumably because this dialdehyde is too reactive under conditions for hydrolysis, but some alkyl-furans can be converted into 1,4-dicarbonyl products quite efficiently, and this can be viewed as a good method for their synthesis, and of cyclopentenones derived from them. ° Other routes from furans to 1,4-dicarbonyl compounds are the hydrolysis of 2,5-dialkoxy-tetrahydro-furans (18.1.1.4) and by various oxidative procedures (18.2). 

Synthesis of furans by base catalyzed condensation of an a-halocarbonyl compound with an enol, derived from a 1,3-dicarbonyl compound (see 1st edition). 

Figure 4. A. Synthesis of enamino carbonyl derivatives from 1,3-dicarbonyl compounds and amines [51], B. Reaction of furan with a,/0-unsaturated carbonyl compounds [52].

Synthesis of 1,4-dicarbonyl compounds and cyclopentenones from furans , Piancatelli, G., D Auria, M., and D Onofrio, F., Synthesis, 1994, 867. 

Other interesting methods can generate furans. One method treats an allylic diol such as 125 with pyridinium chlorochromate (PCC see Chapter 17, Section 17.2.3), in an oxidative-cyclization process, to give 3-ethylfuran, 126. Thiophene derivatives can also be prepared from 1,4-dicarbonyl compounds. A Paal-Knorr thiophene synthesis reacts 2,4-hexanedione (115) with phosphorus pentasulfide (P4S10) to give 2,5-dimethylthiophene, 127. 

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