DOI: 10.1002/adsc.201000411

Gold(I)-Catalyzed Cycloisomerization of 2-Fluoroalk-3-yn-1-ones:Synthesis of 2,5-Substituted 3-Fluorofurans

Yan Li,a Kraig A. Wheeler,b and Roman Dembinskia,*a Department of Chemistry, Oakland University, 2200 N. Squirrel Rd., Rochester, Michigan 48309-4477, USA

Fax: (+1)-248-370-2321; e-mail: dembinsk@oakland.edub Department of Chemistry, Eastern Illinois University, 600 Lincoln Avenue, Charleston, Illinois 61920-3099, USA

Received: May 25, 2010; Revised: September 11, 2010; Published online: October 26, 2010

Supporting information for this article is available on the WWW underhttp://dx.doi.org/10.1002/adsc.201000411.

Abstract: Fluorination of 1,4-disubstituted tert-bu-tyldimethylsilyl but-1-en-3-yn-1-yl ethers with Se-lectfluor gives 2-mono-fluorobut-3-yn-1-ones. Sub-sequent 5-endo-dig cyclization in the presence ofchlorotriphenylphosphine gold(I)/silver trifluorome-thanesulfonate (both 5 mol%, dichloromethane)under ambient conditions, provides a facile methodfor the generation of mainly 2,5-diaryl-substituted3-fluorofurans in high yields (89–96%). The struc-ture of 2-(4-bromophenyl)-3-fluoro-5-(4-methylphe-nyl)furan was confirmed by X-ray crystallography.

Keywords: alkynes; cyclization; fluorine; furans;gold; oxygen heterocycles

2,5-Diarylfurans exhibit interesting biological activity.Compounds such as 1a or 1b (Figure 1) serve as DNAintercalating agents and are known to bind to theRNA duplex or stem regions.[1] 5-Hydroxymethyl-2-thienyldiphenylfuran derivative, 1c, suppresses cell

growth as an inhibitor of the p53-MDM2 interac-tion.[2] Pentamidine (DB289, 1d) is a prodrug of fura-midine (DB75, 1e) that has demonstrated good effica-cy against African trypanosomiasis, pneumonia, aswell as malaria in clinical trials.[3]

Active pharmaceutical ingredients containing fluo-rine have found a wide application in medicinalchemistry.[4,5] Over the past half century, fluorinateddrugs represent 5–15% of the total number oflaunched drugs worldwide with a noticeable increasein recent years.[6] Since the furan ring constitutes asubmotif encountered in lead compounds, the corre-sponding fluorinated molecules are potentiallysought-after building blocks. Indeed, fluorofuran orperfluoroalkylfuran fragments have already been em-bedded within structures possessing important phar-macological properties.[7] For example, an analogue oftrovirdine (2, Figure 1) reveals high anti-HIV-1 activi-ty.[8] Upon considering the pharmaceutical potential,as well as the limitations of available synthetic meth-ods for 2,5-diaryl-3-fluorofurans, we decided topursue the development of their synthesis.

Synthetic methods leading to b-fluorofurans includelimited options.[7,9] The lithiation of 3-bromofuran de-rivative and its subsequent reaction with N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (NFSI) gives 3-fluoro-2-octylfuran with poor yield.[10] Rearrangementof gem-difluorocyclopropyl aryl ketones (1-aryloyl-2,2-difluorocyclopropanes) offers a method for thepreparation of 3-fluoro-2,5-diarylfurans with goodyield.[11] However, a high reaction temperature(216 8C) is required to effectively accomplish this pro-cess. Analogously, acid-catalyzed hydrolysis of gem-di-fluorocyclopropyl acetals and ketals such as 3 pro-ceeds at 110 8C to afford 3-fluoro-2,5-diphenylfuranswhen the electron-donating group in the p-position ofthe phenyl ring is present. Acetals with electron-with-drawing groups in the p-position of the aromatic ringgive a mixture of fluorofurans and gem-difluorocyclo-Figure 1. Examples of biologically-active furans.

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propyl ketones, with a predominance of the latter.The hydrolysis of ketals containing electron-with-drawing groups yields ketones such as 4 as the sole ormajor products.[12] For example, using this method,compound 5a was obtained in only 2% yield(Scheme 1).[12]

Heterocyclizations reactions are more appealing.[13]

Quite recently silver nitrate-catalyzed cyclization ofgem-difluorohomopropargyl alcohols to 3,3-difluoro-2,3-dihydrofurans has been reported.[14] Subsequentelimination of hydrogen fluoride via silica gel chroma-tography yields the corresponding 3-fluorofurans.However, non-aromatic 3,3-difluoro-2,3-dihydrofuransalso remain as the final product, dependent on thesubstituents.[15] Similarly, treatment of difluorohomo-propargyl alcohols with potassium tert-butoxide orDBU at an elevated temperature provides 3-fluoro-furans.[16]

The starting materials for this method, gem-difluoro ACHTUNGTRENNUNGhomopropargyl alcohols, are prepared by asynthesis involving chlorofluorocarbons such as bro-mochlorodifluoromethane,[17] and similar to the gem-difluorocyclopropyl derivatives, the elimination of hy-drogen fluoride is required. Thus, we sought to devel-op a more effective fluorofuran synthesis in terms ofhalogen atom economy. Our recent efforts to explorethe application of cycloisomerization reactions result-ed in the efficient synthesis of furans and furanopyri-midine nucleosides.[18,19] Relevant electrophilic halo-cyclization reactions from our laboratory have alsobeen reported.[20] Here we present our attempts to es-tablish a synthesis of b-fluoro-substituted furans frombut-3-yn-1-ones. The potential of a biological applica-tion moved the focus to model diaryl substituents.

Our initial effort to facilitate electrophilic flurocyc-lization of butynone 6a with Selectfluor,[21] in a similarmanner as for iodo-, bromo-, and chlorocycliza-tions,[20] was not successful. This result came as no sur-prise, since the electrophilic character of fluorine isthe lowest within the halogens, and formal electro-philic reactions of fluorine presumably involve alter-native mechanisms.[22] Reports of fluorocyclization re-

actions are mainly limited to activated alkenes.[23] Foralkynes, the leading reference presents a gold-cata-lyzed cyclization/fluorination sequence that yields amixture of fluorinated and non-fluorinated com-pounds, which may be difficult to separate.[24] More-over, the exposure of furan to Selectfluor may facili-tate an oxidative ring opening, as it has been reportedfor attempted direct fluorination of furans.[25] Thus,we decided to introduce fluorine into an acyclic skele-ton, and to investigate the metal-catalyzed cycloiso-merization of 2-fluoroalk-3-yn-1-ones.[26,27] The prepa-rations of 2-fluoroalk-3-yn-1-ones that have so farbeen reported include the oxidation of 2-fluorobut-3-yn-1-ol, obtainable by a low-yielding ring opening ofan epoxide precursor by a fluoride anion,[28] or a zincor indium ACHTUNGTRENNUNG(III) chloride-catalyzed reaction of fluoro-propargyl chlorides with carbonyl compounds.[29]

Considering the availability of alk-3-yn-1-ones,[18]

we envisioned their direct fluorination in a joint alphaposition to the alkyne and ketone. Although an arrayof a-monofluorination procedures is available for reg-ular ketones,[30] a reaction of alkynone 6a with NFSI(1 equiv.), in the presence of potassium carbonate, ledto the difluoro derivative 7 (Scheme 2). Such resultsmay be attributed to further rapid fluorination of themonofluoro derivative, which is more prone to H ab-straction/enolization and effectively competes withthe starting ketone. Similarly Peng and Shreeve haveobserved formation of the difluoro product whenelectronically akin cyano keto derivative (a-benzoyl-ACHTUNGTRENNUNGacetonitrile) was treated with sodium hydride/Selec-fluor (1 equiv.).[31]

Thus, an alternative fluorination procedure in neu-tral conditions that would avoid the presence of thebase was sought. Conversion of ketone 6a[18] to thecorresponding tert-butyldimethylsilyl enol ether 8awas accomplished by following the literature proto-col.[32] To our delight, reaction of 8a with Selectfluorat room temperature gave a monofluoro ketone 9 inalmost quantitative yield (Scheme 3).

Cycloisomerization of 9 was attempted next. Con-version of non-halogenated but-3-yn-1-ones to furansmay be quantitatively accomplished within minutes atroom temperature using simple Lewis acids such aszinc chloride; other transition metals are also effec-tive.[18,33] Unfortunately, the electron-withdrawingeffect of fluorine significantly inhibits the cycloisome-rization process of fluorinated butynones.[34] Treat-

Scheme 1. Acid-catalyzed hydrolysis of gem-difluorocyclo-propyl ketal 3.[12]

Scheme 2. Fluorination of butynone 6a.

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ment of fluorobutynone 9 with zinc chloride, even inan equimolar amount and at an elevated temperature,did not lead to conversion (Table 1). Similarly, resultsacquired using silver nitrate, an effective cycloisome-rization catalyst frequently cited by Marshall�sgroup,[35] did not warrant further attention (entry 2).When a small preparative scale amount of fluoroketone 9 was treated with the palladium catalyst,(PhCN)2PdCl2 (10 mol%),[26] in dichloromethane, for-mation of 5a was noticed after 1 h. Fluorofuran 5awas isolated, after work-up by a silica gel shortcolumn chromatography in 60% yield (Table 1,entry 3).

In a continued search for a more reactive cycloiso-merization catalyst, we turned our attention togold.[36] Gold compounds are successful in the alkyneactivation and cyloisomerization processes,[37] and fa-cilitate heterocycles formation via vinyl-gold inter-mediates that can even be isolated.[38] When fluoroketone 9 was treated with gold ACHTUNGTRENNUNG(III) chloride, the for-mation of fluorofuran was observed by TLC, butwithin minutes a complex post-reaction mixture wasobtained. Concluding that the reactivity of gold ACHTUNGTRENNUNG(III) istoo high, we turned our attention to the chlorotriphe-nylphosphine gold(I), an easy-to-handle (air-stable)and commercially available complex. The chlorotri-phenylphosphine gold, in combination with silver tri-fluoromethanesulfonate (both 5 mol%), in dichloro-methane, at room temperature, facilitated almostquantitative conversion of 9 into furan 5a (Scheme 3).

Due to the gradual decomposition of the monofluoroketones such as 9 over prolonged storage and our in-ability to establish an effective purification procedure,we decided to use a sequence of consecutive fluorina-tion and cyclization reactions, starting from silyl enolethers 8 and proceeding in the same flask, withoutisolation of 2-fluorobutynones (Scheme 4).

Preparation of but-3-yn-1-ones (propargyl ketones),the necessary starting materials, was carried out as de-scribed earlier.[18] Although we focused on aryl sub-stituents, we also examined compounds containingone alkyl, and one cycloalkyl group. The exploredsubstituents of silyl enol ethers 8 include phenyl, p-tolyl, p-halophenyls, p-trifluoromethylphenyl, ethyl,and cyclopropyl; detailed structures are provided inTable 2.

New 3-fluorofurans 5 were characterized by 1H, 13C,and 19F NMR, IR, mass, and UV-vis spectroscopy.The characteristic NMR features for aryl and alkylsubstituted furans 5a–g include the 1H H-4 signals(doublets 7.08–6.28 ppm with JH,F 0.7–1.2 Hz), 13C C-3/C-4 (doublets 153.1–150.2/100.0–99.0 ppm, JC,F

243.4–255.6/20.1–20.6 Hz). Longer range JH,F and JC,F

were observed.[28] Acquired 19F NMR spectra showedagreement with literature data (at C-3, 158.9–163.0 ppm).[39] Mass spectra for 5a–g exhibited intensemolecular ions. Most solid furans gave accurate ele-mental analyses.

The molecular structure of a representative furanwas confirmed by X-ray crystallography. Crystalliza-tion of compound 5c from ether gave single crystalssuitable for X-ray analysis.[40] Inspection of Figure 2reveals the molecular structure of the expected 2,5-disubstituted 3-fluorofuran. No significant distortionof the furan ring due to the presence of fluorine was

Scheme 3. Synthesis of 3-fluorofuran 5a.

Table 1. Catalyst optimization: cycloisomerization of 2-fluorobutynone 9.

Entry Catalyst Loading [mol%] Solvent Conditions Yield [%]

1 ZnCl2 100 CH2Cl2 reflux, 3 h no reaction2 AgNO3 10 ACHTUNGTRENNUNG(CH3)2CO r.t., 4 h no reaction3 ACHTUNGTRENNUNG(PhCN)2PdCl2 10 CH2Cl2 r.t., 1 h 60[a]

4 AuCl3 5 CH3CN r.t., 30 min multiple products5 Ph3PAuCl/AgOTf 5 CH2Cl2 r.t., 10 min 95[a]

6 Ph3PAuCl/AgOTf 1 CH2Cl2 r.t., 12 h 42[a,b]

[a] Isolated product.[b] Incomplete reaction after 1 h; multiple products found after 12 h.

Scheme 4. Synthesis of 3-fluorofurans 5 via the sequence offluorination/cycloisomerization of 8.

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Gold(I)-Catalyzed Cycloisomerization of 2-Fluoroalk-3-yn-1-ones

noticed. The entire molecule of 5c is nearly planarwithin 0.17 �. The maximum atom deviations fromthe average plane are 0.33 and 0.32 � for C-10 and C-14, respectively.

In summary, we have demonstrated that 2-fluoro-but-3-yn-1-ones can be successfully obtained by mon-ofluorination of the but-1-en-3-yn-1-yl silyl etherswith Selectfluor, and that chlorotriphenylphosphinegold/silver trifluoromethanesulfonate is an efficientcatalyst for the cycloisomerization of the 2-fluorobut-3-yn-1-ones. The methods proved to be most effectivefor aryl substituents (C-2 and C-5 of furan). The rela-tively short reaction time and mild conditions (roomtemperature) provide an appealing alternative to thecurrently available methods, especially from thestandpoint of halogen atom economy. This methodavoids the loss of halogens in the synthetic pathway,facilitates the regioselective introduction of fluorinewithin two available beta positions, and also allowsfor the introduction of substituents such as cycloalkylsthat are not easily carried out by other methods. De-termination of scope of the reaction with alkyl-only

substituents is the subject of further investigations inour laboratory.

Experimental Section

General Remarks

Selectfluor {1-chloromethyl-4-fluoro-1,4-diazoniabicyclo-ACHTUNGTRENNUNG[2.2.2]octane bis(tetrafluoroborate), Air Products andChemicals}, chlorotriphenylphosphine gold(I) (Strem), andsilver trifluoromethanesulfonate (Aldrich), were used as re-ceived and handled in the air. Column chromatography wascarried out on silica gel (Dynamic Adsorbents, 32–63 m). 1H,13C, and 19F NMR spectra were recorded on a BrukerAvance III 400 spectrometer (400, 100, and 376 MHz, re-spectively). The chemical shifts are reported in d (ppm)values (1H and 13C relative to CDCl3/acetone-d6, 7.26/2.05 ppm and 77.16/29.9 ppm, respectively), and 19F relativeto CFCl3 (external standard). IR spectra were recordedusing a Varian 3100 Excalibur spectrometer.

2-Fluoro-4-(4-methylphenyl)-1-phenylbut-3-yn-1-one(9)

The flask was charged with silyl enol ether 8a (0.175 g,0.500 mmol), Selectfluor (0.195 g, 0.550 mmol), and acetoni-trile (10 mL). The mixture was stirred at ambient tempera-ture for about 1 h and monitored by TLC (hexanes/EtOAc,8:2). Solvent was removed by rotary evaporation and theresidue was kept under oil pump vacuum for 30 min. Di-chloromethane (60 mL) was added and the mixture wasstirred for 10 min. The solid was filtered off (fritted funnel)and washed with dichloromethane (20 mL). Solvent was re-moved from the combined filtrates by rotary evaporation togive crude 9 as yellow oil that may slowly solidify in a freez-er. IR (film): n= 2956, 2928, 2222, 1713, 1510, 1450, 1218,1066, 943, 845, 817, 688, 667 cm�1; 1H NMR (CDCl3): d=8.16 (d, J=7.4 Hz,), 7.67–7.61 (m, 1 H), 7.55–7.49 (m, 2 H),7.33 (d, J=8.0 Hz, 2 H), 7.12 (d, J=8.0 Hz, 2 H), 6.26 (d, J=49.0 Hz, 1 H), 2.34 (s, 3 H); 13C NMR (CDCl3): d= 189.9 (d,J=21.8 Hz), 140.2, 134.4, 133.0, 132.1 (d, J=2.9 Hz), 129.6(d, J=2.1 Hz), 129.3, 128.9, 118.0 (d, J=4.1 Hz), 93.4 (d, J=10.4 Hz), 83.5 (d, J=184.6 Hz), 80.5 (d, J=25.8 Hz), 21.7;19F NMR (CDCl3): d= �179.2 (d, J=49.0 Hz).

Table 2. Preparation of 3-fluorofurans 5.

Entry Enol Ether R R’ Furan Reaction Time [min] Yield [%]a

1 8a C6H5 p-Me-C6H4 5a[12] 60 + 10 952 8b p-F-C6H4 p-Me-C6H4 5b 60 + 10 963 8c p-Br-C6H4 p-Me-C6H4 5c 60 + 10 944 8d p-Br-C6H4 p-t-Bu-C6H4 5d 60 + 10 925 8e p-CF3-C6H4 p-Me-C6H4 5e 60 + 60 896 8f Et C6H5 5f[16] 60 + 30 527 8g C6H5 c-C3H5 5g 60 + 10 92

[a] Reactions were carried out on a 0.50 mmol scale with 0.55 mmol of Selectfluor in acetonitrile, and 0.025 mmol ofPh3PAuCl and AgOTf in CH2Cl2, at room temperature.

Figure 2. An ORTEP view of the 5c illustrating atom label-ing scheme and thermal ellipsoids (50% probability level).Selected interatomic distances (�): F�C3 1.339(6), O1�C21.371(6), O1�C5 1.389(6), C2�C3 1.355(7), C2�C6 1.455(7),C3�C4 1.389(8), C4�C5 1.359(7), C5�C12 1.469(7). Keyangles (deg): C2�O1�C5 107.0(4), O1�C2�C3 107.5(4), O1�C2�C6 116.8(4), C3�C2�C6 135.7(5), C2�C3�C4 110.4(4),F�C3�C2 125.9(5), F�C3�C4 123.7(5), C3�C4�C5 105.3(4),O1�C5�C4 109.9(5), O1�C5�C12 116.2(4), C4�C5�C12133.9(4).

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3-Fluoro-5-(4-methylphenyl)-2-phenylfuran (5a)[12]

To a solution of the crude 9 from the reaction above in di-chloromethane (10 mL), chlorotriphenylphosphine gold(I)(0.013 g, 0.025 mmol) and silver trifluoromethanesulfonate(0.0065 g, 0.025 mmol) were added. The mixture was stirredvigorously in the darkness (the flask was wrapped in Al foil)for 10 min. The solvent was removed by rotary evaporationthe residue was purified by silica gel column chromatogra-phy (hexanes) to give 5a as a white solid; yield: 0.120 g(0.476 mmol, 95%), mp 93–95 8C; anal. calcd. for C17H13FO:C 80.93, H 5.19; found: C 80.72, H 5.44; IR (KBr): n= 2923,1631, 1501, 1428, 1150, 821, 792, 668 cm�1; MS (EI): m/z =252 (M+, 100%); 1H NMR (acetone-d6): d=7.80–7.70 (m,4 H), 7.52–7.45 (m, 2 H), 7.35–7.25 (m, 3 H), 7.00 (d, J=0.7 Hz, 1 H), 2.36 (s, 3 H); 13C NMR (acetone-d6): d= 151.7(d, J= 9.1 Hz), 151.6 (d, J=252.3 Hz), 139.3, 136.2 (d, J=20.5 Hz), 130.5, 129.9, 129.8 (d, J= 5.2 Hz), 128.4 (d, J=2.2 Hz), 128.1 (d, J= 1.2 Hz), 124.7, 124.2 (d, J=5.2 Hz),99.7 (d, J=20.3 Hz), 21.4; 19F NMR (CDCl3): d=�162.0.

Supporting Information1 H, 13C, and 19F NMR spectra for new fluorofurans 5 andcrystallographic tables for 5c are available as Supporting In-formation.

Acknowledgements

We are indebted to the donors of the Petroleum ResearchFund (ACS-PRF#46094) administered by the AmericanChemical Society and to Oakland University and its ResearchExcellence Program in Biotechnology for the support of thisresearch. The National Science Foundation (NSF) awards(CHE-0821487 and CHE-0722547) are also acknowledged.Y.L. is grateful for the Provost�s Graduate Student ResearchAward. We are grateful to Dr. Robert Syvret (Air Productsand Chemicals) for the generous supply of Selectfluor.

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[40] Crystals of 5c (transparent plate, colorless) were grownfrom the ether by slow evaporation. CCDC 775673contains the supplementary crystallographic data forthis paper. These data can be obtained free of chargefrom The Cambridge Crystallographic Data Centre viawww.ccdc.cam.ac.uk/data_request/cif.

2766 asc.wiley-vch.de � 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2010, 352, 2761 – 2766

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