[110-00-9]  · C4H4O  · Furan  · (MW 68.08)

(versatile four-carbon synthon;1 aromatic heterocycle which exhibits reactivity towards various electrophiles2 and electrophilic carbon radicals;3 2-monolithio4a or 2,5-dimetalated furan derivatives can be readily generated and transmetalated;4 ene employed for [2 + 2] photochemical1d,5 and [2 + 3] dipolar cycloadditions;6 diene widely used for [4 + 2] Diels-Alder1e and [4 + 3] dipolar cycloadditions;7 can be oxidized by a number of reagents such as singlet oxygen8)

Physical Data: mp -85.6 °C; bp 31.4 °C; fp -35 °C; n20D 1.421;9c d204 0.9514 g cm-3.9a,b

Solubility: sol ethanol, ether, benzene, acetone; slightly sol chloroform; insol water.9a

Form Supplied in: commercially available as a water-white liquid in >99% purity (GC); usually a trace of 2,6-di-t-butyl-p-cresol (BHT) added as an inhibitor of oxidation.

Purification: shaken with aq 5% KOH, dried with CaSO4 or Na2SO4, then distilled under nitrogen, from KOH or sodium, immediately before use.10

Analysis of Reagent Purity: GC; IR (neat) 1592, 1485, 1380, 1172, 1061, 869, 744, 601 cm-1;11a 1H NMR (CDCl3) d 6.39 (2H), 7.44 (2H);11b,c 13C NMR (CDCl3) d 109.7, 142.8.11d

Handling, Storage, and Precautions: on EPA Extremely Hazardous Substances List; reported in EPA TSCA Inventory.12 The vapors are anesthetic; can be absorbed through skin.12 Use in a fume hood.

Electrophilic Substitution Reactions.

Synthesis of 2-Halo-, Acyl-, Cyano-, Sulfonyl-, and Carbonyloxyfurans.

Furan is an electron-rich, aromatic heterocycle which readily undergoes electrophilic substitution reactions with a wide range of electrophiles. Therefore furan serves as a convenient starting material for the preparation of various substituted furans, including halo, acyl/formyl, cyano, and other heteroatom substituted furans.1 The C-2 position is generally more susceptible than C-3 towards electrophiles, presumably due to the extended conjugation of the intermediate cation generated by the addition of an electrophile at the former. However, the ratio of the C-2/C-3 products appears to be highly dependent upon the type of electrophile and the reaction conditions. For example, acylation of furan with Acetic Anhydride and Tin(IV) Chloride in dichloromethane gives C-2/C-3 products in ratios of 6800 and 800 at 25 and 75 °C, respectively. However, the reaction with acetyl trifluoroacetate at 75 °C results in a C-2/C-3 product ratio of 6000.13 The acetylation can also be achieved cleanly at the C-2 position in excellent yield with Acetyl p-Toluenesulfonate.14 Other electrophilic substitution reactions of furan at the C-2 position include: bromination (Br2, DMF) (eq 1),15 cyanation (OCNSO2Cl, DMF),16 Vilsmeier formylation (Me2NCHO, POCl3),17 sulfonation (SO3.py),18 and carbonylation (PdCl2,Hg2+, Cu2+/CO/ROH).19

Synthesis of Alkylfurans.

Alkyl-substituted furans can be prepared by electrophilic substitution reactions of furan. For example, furan undergoes the Mannich reaction with aminals, a-amino ethers, and bis(alkoxymethyl)alkylamines under Lewis acid catalysis to give 2-(N,N-dialkylamino)methyl derivatives of furan (eq 2).20 Furan can also add to the b-carbon of enones in the presence of Iodotrimethylsilane (eq 3).21 In addition, Ag+ has been reported to induce allylation of furan with 1,3-bis(phenylseleno)propene (eq 4)22a or cyclopropyl halides (eq 5).22b It should be noted that this Ag+-catalyzed allylation of furan, illustrated in eq 4, has been shown to proceed with high stereoselectivity where the configuration of the stereochemically pure (Z)- or (E)-allylating agent is retained in the product.22a An arenecarbonylmolybdenum has been employed as a catalyst for the t-butylation of furan at C-2.23

Radical-Mediated Substitution Reactions.

Furan undergoes substitution reactions with electrophilic carbon radicals to provide 2-alkyl substituted furans (eq 6).3 These radicals are generated from dialkyl malonates with Ce4+,3 triethyl methanetricarboxylate with Mn3+,24a Fe2+/H2O2 in DMSO,24b or ethyl iodoacetate with triethylborane.24c

Cross-Coupling Reactions.

Two major types of cross-coupling reactions have been reported in conjunction with the synthesis of arylated furans. Thus the photochemical coupling of furan with 2-bromo- or -iodo- (eq 7)25a or 4-iodopyridine25b produces the corresponding coupled products in moderate yield. Other five-membered heterocycles such as thiophenes and pyrroles also undergo similar reactions.25 Interestingly, the direct aryl coupling reaction of furan can also be achieved in the presence of a Pd0 catalyst with aryl bromides bearing an electron-withdrawing group (moderate yield) or 1-naphthyl bromide (low yield) at elevated temperatures (eq 8).26a It is noteworthy that although similar Pd0-catalyzed cross-coupling reactions with a wide variety of aromatic, benzyl, and cinnamyl bromides can be effected using 2-lithio- or 2-furylzinc chloride in generally higher yield,26b these require prior generation of the organometallic reagent. While the use of the Palladium(II) Acetate-Copper(II) Acetate catalyst system results in facile alkenylation reactions of furan at the a-position with methyl acrylate and acrylonitrile, the yields of the reactions are generally low with frequent complication due to the formation of the 2,5-dialkenylated products.27 However, if the Pd(OCOPh)2-catalyzed reaction of furan with ethyl acrylate is carried out in the presence of t-butyl perbenzoate (postulated to act as a hydrogen acceptor), ethyl 3-(2-furyl)acrylate is obtained in 53% yield with virtually no formation of the dialkenylated product.28

Organometallic Compounds.

Lithiated furans are presumably one of the most widely employed organometallic species in synthesis.4a Furan can be readily monolithiated at C-2 with n-Butyllithium and it can be dimetalated at C-2 and 5 either by careful control of reaction conditions using n-BuLi (to 2,5-dilithiofuran)4b or with the use of the Schlosser-Lochmann reagent (n-BuLi/BuOK)29 (presumably to 2,5-dipotassiofuran) (eq 9).4c These metalated furans can react with a variety of electrophiles4a including TMSCl,4a CO2,4a epoxides,4a ketones,4a,30a and aldehydes.4a,30b Additionally, 2-lithiofuran can also be readily transmetalated to the corresponding organometallic species such as organoboron ate complexes,31a lithium 2-furyltellurolate,31b and di(2-furyl)zinc (eq 10).31c Possibly the most useful of such C-2 organometallic furan species may be the higher-order cuprates, which can effectively undergo conjugate addition reactions at low temperatures onto enones (eq 11), as well as additions to epoxides and aldehydes, all under Lewis acid catalysis.32

Cycloaddition Reactions.

Furan is known to undergo various types of cycloaddition reactions. It functions as an ene and participates in [2 + 2] and [2 + 3] cycloadditions under photochemical and thermal conditions, respectively. With an embedded cyclic conjugated diene system in it, furan also functions as a diene that undergoes various [4 + 2] and [4 + 3] cycloaddition reactions.1

[2 + 2] Cycloaddition Reactions as an Ene.

It has been well established5 that carbonyl compounds can be added to furan in a highly regioselective [2 + 2] fashion under photochemical conditions, providing relatively unstable 2,7-dioxabicyclo[3.2.0]hept-3-ene compounds (eq 12).5c These bicyclic oxetanes can be isomerized smoothly by acid treatment to 3-substituted furans (eq 12).5c

[2 + 3] Cycloaddition Reactions as an Ene.

Furan undergoes [2 + 3] cycloaddition reactions upon exposure to nitrile oxides generated in situ under high dilution conditions, giving rise to dipolar cycloaddition products in moderate yield (eq 13).6 These regioselectively produced adducts have been employed in the synthesis of a number of amino-polyols including nojirimycin.6a

[4 + 2] Cycloaddition Reactions as a Diene.

The use of furan as a diene in intermolecular Diels-Alder reactions represents one of the most common applications of furan in synthesis, providing a highly versatile means for new C-C bond formation and for further synthetic manipulations.1d,e However, often these Diels-Alder reactions involving furan as a diene are sluggish, presumably due to its aromatic nature. Some otherwise difficult furan Diels-Alder reactions have been reported to be mediated by high pressure.33 The initial report on the acceleration of furan Diels-Alder reactions with the use of catalytic quantities of the Lewis acid Zinc Iodide34 has been followed by similar observations of rate acceleration by a number of other catalysts. These include BF3.OEt2,35a Cu(MeCN)4(BF4),35b Cy3Sn(MeCN)2SbF6-,35c chromatography adsorbents,35d and K-10 bentonite clay doped with Fe3+ or AlCl3.35e There is even a report describing observed acceleration of a Diels-Alder reaction between furan and maleic anhydride when the reaction is performed in an ultracentrifuge.35f

Furan has been shown to undergo Diels-Alder reactions with activated allenic compounds36 with high regio- and stereoselectivity (eq 14).36e In addition, the Diels-Alder reactions with certain acetylenic compounds are also known.37 Trapping of highly reactive arynes,38 Dewar furans,39 and strained bridgehead alkenes40 with furan in a [4 + 2] Diels-Alder fashion is well documented. Particularly, reactions of furan with a variety of in situ-generated arynes followed by the aromatization of the 1,4-endoxide rings of the resulting cycloadducts constitute a well-established method for the synthesis of polyarenes (eqs 15 and 16).38

Asymmetric Diels-Alder reactions of furan with dienophiles have been developed for the synthesis of optically active 7-oxabicyclo[2.2.1]hept-5-ene derivatives, key intermediates for the synthesis of physiologically significant natural products. Diastereoselectivity is achieved with the use of a chiral oxazaborolidine as the catalyst (eq 17)41a or optically active dienophiles41b,c (eq 18).41b

[4 + 3] Cycloaddition Reactions as a Diene.

Furan reacts with dipolar species generated from 2-oxyallyl cations generated from a,a“-polybromo ketones7,42 or a,a-dialkoxy ketones (via their a“-enol TMS ethers)43 to form 8-oxabicyclo[3.2.1]oct-6-en-3-ones (eq 19).7,42 These [4 + 3] cycloadducts can be readily converted to cycloheptanones,7 tropones,7,43 highly substituted cycloheptane systems,44 or even to substituted tetrahydrofuran compounds such as ribose.7 Many of these have served as key synthetic precursors to a number of natural cyclic and acyclic compounds.7,44

Oxidation Reactions.

Electron rich furan is readily oxidized by a number of oxidizing agents.1b One of the most frequently employed reagents for the oxidation of furan is singlet Oxygen,8,45a generating the six-membered endoperoxide by a [4 + 2] cycloaddition reaction followed by its rearrangement or solvolysis to give rise to a variety of products.45a,b Treatment of furan with Dimethyldioxirane results in the formation of the extremely unstable malealdehyde through oxidative ring opening (eq 20).45c Under anodic oxidation conditions, furan produces 2-acetoxyfuran, which can be trapped by several kinds of electrophiles to form 4-substituted butenolides (eq 21).45d

Carbenoid Reactions.

Other synthetically useful reactions include carbenoid addition to form 2-oxabicyclo[3.1.0]hex-3-ene systems.46 The reaction of vinylcarbenoids with furan provides two products (eq 22).47 These results may be rationalized invoking a nonsynchronous cyclopropanation mechanism that leads to two possible dipolar transition states.47,48

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Masato Koreeda & Wu Yang

The University of Michigan, Ann Arbor, MI, USA

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