Functionalized furans

Balme and coworkers reported on a procedure for the preparation of highly functionalized furans of type 2-940 (Scheme 2.210) [480]. Their approach is based on a nucleophilic Michael addition of propargyl alcohols 2-937 to alkylidene or aryl-idenemalonates 2-938, followed by a palladium-catalyzed cydization via the carban-ion 2-939. The reactions with propargyl alcohol led to the formation of only one di-... 

Recently, Gagosz et al. extended the methodology to other substrates for the synthesis of functionalized furans via Claisen-type rearrangement. The future asymmetric version of the process could be a very useful tool for the synthesis of natural products [101]. 

The DFT study of the 3 + 2-cycloaddition between ketene and TV-silyl-, IV-germyl-, and TV-stannyl-imines shows that the TV-germylimine reaction is a two-step process the TV-stannylimine reaction is a competition between two- and three-step processes whereas the TV-silyl process follows a three-step process44 A new and convenient synthesis of functionalized furans and benzofurans based on 3 + 2-cycloaddition/oxidation has been reported. The cyclization of cyclic 1,3-bis-silyl enol ethers (48) with l-chloro-2,2-dimethoxyethane (49), via a dianion, produced 5,6-bicyclic 2-alkylidenetetrahydrofurans (50), which are readily oxidized with DDQ to 2,3-unsubstituted benzofurans (51) (Scheme 13)45 The Evans bis(oxazoline)-Cu(II) complex catalyses the asymmetric 1,3-dipolar cycloaddition of a -hydroxyenones with nitrones to produce isoxazolidines.46 The... 

Various applications of the method have been reported324,325,325 1 and include the efficient formation of the functionalized furan 388, a precursor of the agylcon 389 of the naturally occurring antibiotic eleutherobin, from the allenic ketone 387 (Scheme 113).328... 

On the basis of this palladium-mediated Michael addition cyclization process, a novel two-step synthetic entry into functionalized furan derivatives 67 has also been devised (Scheme 28). Substitution of benzylidene (or alkyli-dene) malonates for their ethoxymethylene analog (65) as activating olefins gave rise to the formation of the corresponding 2-ethoxy-4-arylidene tetrahy-drofurans 66. An in situ addition of potassium ferf-buloxidc induced a decar-boxylative elimination reaction which was followed by an isomerization of the exocyclic double bond. The entire process successively involved a conjugate addition, a palladium-catalyzed cyclization-coupling reaction, a base-induced eliminative decarboxylation, and finally, a double bond isomerization [73]. 

The copolymerization of furan and 2-methylfuran with dienophiles such as maleic anhydride leads to polymer structures with furan pendent functionality. Furan, 2-methylfuran, and 2,5-dimethylfuran have been copolymerized with acrylic monomers (51,52) and acrylonitrile (52,53). The furan ring of furan, 2-methylfuran, and 2,5-dimethylfuran participates as a diene in a free radical copolymerization with acrylonitrile. The initial step for furan and for 2,5-dimethylfuran is the attachment of an acrylonitrile radical at the 2-position, but for 2-methylfuran, the attack is at the-5-position. Propagation proceeds by the attack of the furan radical on an acrylonitrile molecule, to leave one olefinic bond in the structure derived from the furan ring. If this bond is in the 4,5- or 2,3-position, it may be involved in a second additional reaction by the return of the propagating chain. 

Furans have also been obtained via a related isomerization of terminal epoxyalk-ynes catalyzed by RuCl(Tp)(MeCN)2 in the presence of a base at 80 °C in 1,2-dichlo-roethane. However, in this case their formation is explained by an intramolecular nucleophilic addition of the oxygen atom of the epoxide onto the a-carbon atom of a ruthenium-vinylidene intermediate (Scheme 8.9) [20]. For this reason, the reaction is specific of terminal alkynes. A large variety of functional groups such as ether, ester, acetal, tosylamide, nitrile, are tolerated by the reaction conditions and allow the formation of functionalized furans. 

The opening of halocyclopropanes to allyl systems according to equation 124 can happen thermally or with the assistance of electrophiles and nucleophiles . Some recent examples include an efficient cyclopentenone synthesis (equation 125) ", an electrocyclic opening/cyclization sequence giving functionalized furan and pyran derivatives (equation 126), an elegant total synthesis of the very fast death factor alkaloid ( ) anatoxin and a nice application of the well known nucleophilic opening to the preparation of crystalline methylene aziridines (equation 127) . 

The convenient precursors of unsaturated sugars, dihydrop)Tan or dihydrofuran derivatives, can be also obtained from an appropriately functionalized furan molecule. Two main approaches are used. The first is based on the oxidative rearrangement of furfuryl alcohols (Achma-towicz reaction) [22], the second one involves an acid-catalyzed reaction of aldehydes with 2-trimethyl-silyloxyfuran (Casiraghi reaction) [23] (O Scheme 4). 

Unlike normal all-carbon aryl halides, regioselective Negishi couplings of dihalofu-rans and trihalobenzofurans are synthetically useful. Bach and coworkers have studied both systems extensively and use a variety of cross-coupling reactions to produce functionalized furans and benzofurans. In one example of a selective Negishi reaction,... 

The enantioselective synthesis of aflatoxin was accomplished, and the key step in the synthesis is the asymmetric [3+2] cycloaddition to generate a dihydrobenzo[4>]furan skeleton <05JACS11958>. Another similar type of [3+2] cycloaddition was employed to make functionalized furans and benzo[b]furans <05TL2185>. 

Furan also reacts with benzoquinone (at 20 kbar) to give a 14% yield of the endo adduct and a 15% yield of the exo adduct, along with 71% of unreacted benzoquinone.Better results are obtained with functionalized furans such as 131, which reacted with 4-methyl-2-cyclopentenone at 15 kbar to give a 1 2 mixture of 132/133 in 95% yield (2 days) in Ghosez s synthesis of polyfunctionalized cis-hydrindanones.l35... 

The Diels-Alder reaction of oxazoles with alkynes has become a preferred method for the synthesis of substituted furans with diverse applications. A large number of early examples of this reaction have been tabulated. Activated dienophiles such as acetylenic ketones and esters can be used, although unactivated alkyl, aryl, and silyl alkynes have been used as well. In particular, the reaction of 4-phenyloxazole with substituted acetylenes is frequently used for preparing 3,4-disubstimted furans. Cycloadducts derived from 4-phenyloxazole typically decompose under milder conditions than 4-alkyloxazoles, allowing the synthesis of a wider range of functionalized furans. Several examples are shown below. 

Scheme 50). An alternate approach to the oxindole C3 to C7 bicyclic core found in members of welwitindolinone family has been reported by the Shea and coworkers who set the C3 linkage via a Znl2 promoted coupling of silyl ketene aminal 204 with functionalized furan 205 (Scheme 51) [120]. An intramolecular cycloaddition between C3 tethered furan of 206 and C7 pendant a,p-imsaturated ester closed the bridged oxindole scaffold of 207 in 41% yield. 

There are few general methods for the functionalization of existing furan rings due to their low stability under acidic and aerobic conditions. For this reason, most functionalized furan derivatives are prepared by the cyclization of acyclic precursors using acid, base, or transition metal catalysis. 

Halogenated furans are important intermediates for the synthesis of a number of functionalized furan derivatives through metal-halogen exchange and transition metal-catalyzed cross-coupling reactions, as will be demonstrated throughout this chapter. 

The Feist-Benary and Paal-Knorr syntheses are commonly employed in the preparation of furan ring systems. In special cases where furan derivatives are difficult to prepare by other methods, Diels-Alder and retro-Diels-Alder reactions have become important methods for their synthesis. Finally, transition metal-catalyzed cyclization and cycloisomerization reactions have recently gained significant attention for their utility in the synthesis of highly functionalized furans. Key examples of these syntheses are highlighted in the sections below. 

Metal-catalyzed cyclization/conjugate addition sequences involving substituted propargyl epoxides have also been employed in the synthesis of highly functionalized furans. These reactions are generally catalyzed by... 

Lewis acids have also been used to synthesize highly functionalized furan derivatives with biological signalling capabilities. For example, Sello and co-workers used scandium(III) triflate in their biomimetic synthesis of several signalling molecules of the bacterium Streptomyces. Reaction of methyl 5-methyl-3-oxohexanoate and 2,2-dimethyl-l,3-dioxan-5-one in the presence of scandium (III) triflate in methanol gave the corresponding furan in 60% yield. 

HMF is a suitable precursor for the synthesis of bifunctional furan monomers as summarized in Scheme 4. All these monomers can be used to prepare polycondensates by step-growth reactions with the other corresponding bifunc-tional monomers derived either from petrochemical precursors or from renewable resources. The polycondensates obtained, such as polyesters, polyamides, and polyurethanes, etc. have been characterized [107-113]. Scheme 5 shows another approach for the synthesis of bifunctional monomers through acid-catalyzed condensation of the corresponding mono-functional furan derivatives with an aldehyde... 

The extension of these DA-hased polymerizations to multi-functional furan and/or maleimide monomers naturally leads to crosslinked materials, whose original feature is related to the fact that they can be readily decrosslinked by a simple thermal treatment. Since the first report of a mendable material based on this principle, but applied in cycles [69], several similar studies have appeared in the literature [64] including interesting applications in the realm of thermally removable foams [64] and adhesives [64]. It seems likely that such a simple and useful strategy will continue to draw attention for the preparation of novel intelligent materials. 

Furans represent an important class of electron-rich heterocycles which are useful intermediates in synthetic chemistry and are broadly found as structural motifs of many natural products and pharmaceutically important substances [333]. Since furans are generally less nucleophilic than indoles and pyrroles, their catalytic enantioselective Friedel-Crafts-type conjugate addition has been much less developed so far. Very recently Harada et al. have developed a catalytic system able to achieve good enantioselectivities in the Friedel-Crafts alkylation of electron-rich furans with acychc a,p-unsaturated ketones [334]. As depicted in Scheme 2.117, a//o-threonine-derived oxazaborolidinone 190 (10 mol%) in the presence of V,V-dimethyl benzylamine (10 mol%) as cocatalyst in ether at -40°C, is an efficient catalytic system for the reaction affording the corresponding functionalized furans with good yields and enantioselectivities. 

The same group later found milder Ag-catalyzed reaction conditions and investigated the scope of this transformation for the syntheses of di- and tri-substituted functionalized furans 4. Reactions were performed at room temperature and generally excellent yields of various sensitive furans were achieved (Scheme 8.3) [91]. Syntheses of some furanocycles [92, 93] were accomplished via employment of this protocol. Later, it was found that the cydoisomerization reaction of 3 leading to furans 4 proceeded more efficiently in the absence of CaCOs [94]. 

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