Synthetically important 3-alkoxyfurans can be prepared efficiently via treatment of acetal-containing propargylic alcohols (obtained from the addition of 3,3-diethoxypropyne to aldehydes) with 2 mol% gold catalyst in an alcohol solvent at room temperature. The resulting furans show useful reactivity in a variety of subsequent transformations

Foster, RW

Hailes, HC

Pennell, MN

Sheppard, TD

Tame, CJ

Turner, PG

UCL Discovery

1302 | Chem. Commun., 2014, 50, 1302--1304 This journal is©The Royal Society of Chemistry 2014Cite this:Chem. Commun., 2014,50, 1302Gold catalysed synthesis of 3-alkoxyfurans atroom temperature†Matthew N. Pennell,a Robert W. Foster,a Peter G. Turner,b Helen C. Hailes,aChristopher J. Tameb and Tom D. Sheppard*aSynthetically important 3-alkoxyfurans can be prepared eﬃcientlyvia treatment of acetal-containing propargylic alcohols (obtainedfrom the addition of 3,3-diethoxypropyne to aldehydes) with 2 mol%gold catalyst in an alcohol solvent at room temperature. The resultingfurans show useful reactivity in a variety of subsequent transformations.Furans are important structural motifs which appear in a widearray of natural products, biologically active compounds andpharmaceuticals.1 They also have potential uses in the constructionof conjugated polymers for applications such as organic electronics.2As a consequence, the synthesis of polysubstituted furans hasattracted considerable interest. Recent synthetic approacheshave included a number of transition-metal catalysed cyclisationreactions3 mediated by a variety of catalysts4–8 including systemsbased on palladium,4 rhodium,5 ruthenium6 and silver.7 Overthe past few years, the use of homogeneous gold catalysts forfacilitating the addition of nucleophiles to carbon–carbonmultiplebonds has emerged as a very powerful synthetic method9 and anumber of gold-catalysed approaches to the synthesis of hetero-cyclic aromatic rings,10 including simple furans,11 have beenreported. Simple 3-alkoxyfurans such as 3-methoxyfuran arehighly electron rich systems which show useful reactivity,12and have found application in natural product synthesis13 aswell as in the construction of polysubstituted tetrahydrofurans.14However, the chemistry of more complex 3-alkoxyfurans has notbeen widely explored, largely as a consequence of their syntheticinaccessibility.15 Herein, we describe a gold-catalysedmethod for thesynthesis of a wide variety of 3-alkoxyfurans from readily availablepropargylic alcohols, via a process that allows straightforward varia-tion of substituents both on the furan ring and the alkoxy group.We have recently reported that the gold-catalysed rearrange-ment of propargylic alcohols to enones (the Meyer–Schusterrearrangement) proceeds at room temperature in toluene, inthe presence of a small amount of alcohol additive (MeOH orEtOH).16 During the course of our study into the scope of thisreaction, we observed that attempted rearrangement of acetal-containing propargylic alcohol 1a (Scheme 1, R1 = 4-CF3C6H4)Scheme 1 Gold-catalysed synthesis of 3-ethoxyfurans and 3-methoxyfurans.a 600 mg scale reaction. b Clean conversion of the aldehyde in propargylicalcohol 1o into the dimethylacetal occurred under the reaction conditions.a Department of Chemistry, University College London, 20 Gordon St, London,WC1H 0AJ, UK. E-mail: tom.sheppard@ucl.ac.uk; Fax: +44 (0)7679 7463;Tel: +44 (0)7679 2467b GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage,Herts, SG1 2NY, UK† Electronic supplementary information (ESI) available: Experimental proce-dures, spectroscopic data for all compounds and 1H and 13C NMR spectra fornovel compounds. See DOI: 10.1039/c3cc48290aReceived 29th October 2013,Accepted 11th December 2013DOI: 10.1039/c3cc48290awww.rsc.org/chemcommChemCommCOMMUNICATIONThis journal is©The Royal Society of Chemistry 2014 Chem. Commun., 2014, 50, 1302--1304 | 1303gave a mixture of the expected enone 2a and 3-ethoxyfuran 3a,where the alcohol additive had become incorporated.17 Giventhe importance of polysubstituted furans in a wide variety ofapplications, we sought to optimise this transformation.18Pleasingly in ethanol furan 3a was formed in 89% yield withcomplete selectivity. With these optimised conditions in hand, thesynthesis of a wide range of 3-ethoxyfurans and 3-methoxyfuranswas then explored. High yields (68–98%) of the correspondingfurans 3 and 4were obtainedwith a selection of propargylic alcohols1a–1o. A wide range of aromatic groups can be incorporated at the2-position of the furan ring, including electron deficient (1a, 1h,1m), electron rich (1c, 1n) and sterically encumbered (1f ) benzenerings, as well as thiophene (1i) and furan (1j) rings. Propargylicalcohols containing aliphatic groups were also smoothly convertedinto the corresponding 2-alkyl furans (1b, 1d, 1g, 1k). Whenmethanol was used as the reaction solvent, direct solvolysis togenerate the 3-methoxyfurans 4 occurred selectively over formationof 3-ethoxyfurans 3, which could potentially occur via incorporationof an ethoxy group derived from the acetal group. Many functionalgroups including an alkene (1g), a nitrile (1h), a halide (1l), an ester(1m), and even a free phenol (1n) were compatible with the reaction.In the case of the aldehyde containing substrate 1o, concomitantformation of the corresponding dimethylacetal 4o was observed.The synthesis of furan 3b was performed on a 600 mg scale withoutdifficulty to give the alkyl furan in 85% yield.The synthesis of more complex 3-alkoxyfurans was thenexplored, by incorporation of other alcohols in the furanformation reaction (Scheme 2). Primary (5b, 6b, 7b), secondary(8b) and tertiary (9b) alcohols were incorporated eﬃciently,including functionalised examples such as allyl alcohol (6b)and ethylene glycol (7b).It was also possible to construct a conjugated bis-(3-alkoxy-2-furyl)benzene 4p in excellent yield by gold-catalysed reaction ofbis-propargylic alcohol 1p with MeOH (Scheme 3). The conjugatedtriaryl unit in 4p is reminiscent of the oligofuran systems currentlybeing investigated for a variety of applications in organic electronics.2Interestingly, propargylic alcohol 1q containing a nearby alkene unitunderwent tandem alcohol addition/ene-yne cyclisation to give fusedcyclohexylfurans 10 in excellent yield, with incorporation of thealcohol on the cyclohexane ring. This provides a rapid assembly ofthe fused furan–cyclohexane motif present in the terpene naturalproduct furadysin.19Appropriate control experiments18 were performed todemonstrate that the gold catalyst was required for the furanformation, and that the reaction was unlikely to be catalysed byBrønsted acid (Tf2NH)20 or silver salts (AgNTf2).16b,21 The furanformation reaction potentially proceeds via regioselective gold-catalysed addition of the alcohol to the alkyne to generate vinylgold intermediate 11 (Scheme 4). Loss of ethanol can then leadto allenyl ether 12 which can undergo further activation by goldto give oxonium ion 13. Oxonium ion 13 can then be attackedby the nearby alcohol to generate dihydrofuran intermediate 14which will evolve to the furan 3 after protodeauration and loss ofethanol. An alternative pathway which proceeds via Lewis-acidactivation of the acetal to generate oxonium ion 15, followed byconjugate addition of the alcohol to give 12, can also beenvisaged. However, this seems less likely given the fact thatthe furan formation does not readily occur in the presence of asimple Brønsted acid catalyst.18The electron-rich 3-alkoxyfurans are highly reactive, andcare should be taken during the isolation of these compoundsin order to prevent decomposition of the products via atmo-spheric oxidation.18 The reactivity of these furan systems cannevertheless be readily harnessed in a variety of other usefultransformations (Scheme 5). Furan 4b readily underwent aDiels–Alder reaction with N-methylmaleimide at room temperatureto generate the cycloadduct 16 as a 2 : 1 mixture of separablestereoisomers in excellent overall yield (94%). Treatment of themajor diastereoisomer with TFA led to stereoselective cyclisationto give the polycyclic ether 17 in 69% yield. Cyclohexyl fusedfuran 10b gave tertiary amine 18 in 92% yield upon reaction withEschenmoser’s salt.12a We were also able to promote Claisenrearrangement22 of the allyloxyfuran 6b by heating at reflux intoluene to generate 2,2-disubstituted 3-furanone 19 in 80% yield.Electrophilic bromination23 of furan 3e proceeded in 75% yieldScheme 2 Incorporation of diﬀerent alcohols in the 3-alkoxyfuran for-mation reaction with 1b.Scheme 3 Synthesis of polycyclic furans.Scheme 4 Possible mechanism for the gold-catalysed conversion ofpropargylic alcohols 1 to furans 3.Communication ChemComm1304 | Chem. Commun., 2014, 50, 1302--1304 This journal is©The Royal Society of Chemistry 2014to give bromide 20, providing a useful building block for cross-coupling reactions.In summary, we have developed a mild gold-catalysedmethod for the formation of synthetically useful 3-alkoxyfuranswhich enables these versatile molecules to be prepared in two stepsfrom readily available aldehydes, alcohols and 3,3-diethoxypropyne.The reaction gives access to a wide range of 3-alkoxyfurans in goodto excellent yield, and the products can be used in subsequenttransformations to access more complex structures.We would like to acknowledge the Engineering and PhysicalSciences Research Council (EP/E052789/1 and EP/G040680/1)and GlaxoSmithKline (CASE award, PhD studentship supportand supply of selected aldehydes) for supporting this work.Notes and references1 H. N. C. Wong, P. Yu and C.-Y. Yick, Pure Appl. Chem., 1999,71, 1041.2 (a) O. Gidron, Y. Diskin-Posner and M. Bendikov, J. Am. Chem. 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Gold catalysed synthesis of 3-alkoxyfurans at room temperature

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Gold catalysed synthesis of 3-alkoxyfurans at room temperature

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