Room temperature syntheses of entirely diverse substituted β-fluorofurans

Article abstract of DOI:10.1039/c1ob06693e

Synthesis of highly substituted 3-fluorofurans is reported. The sequence began with preparation of tert-butyldimethylsilyl alk-1-en-3-yn-1-yl ethers from 1,4-disubstituted alk-3-yn-1-ones. Subsequent fluorination of alkenynyl silyl ethers with Selectfluor

Full text of DOI:10.1039/c1ob06693e

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Volume 10 | Number 12 | 28 March 2012 | Pages 2341–2488
ISSN 1477-0520
PAPER
Roman Dembinski et al.
Room temperature syntheses of entirely diverse substituted β-fluorofurans
1477-0520(2012)10:12;1-I

Dynamic ArtVicielweALritnicklesOnline
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 2395
www.rsc.org/obc
PAPER
Room temperature syntheses of entirely diverse substituted β-fluorofurans†
Yan Li,a Kraig A. Wheelerb and Roman Dembinski*a
Received 5th October 2011, Accepted 17th November 2011
DOI: 10.1039/c1ob06693e
Synthesis of highly substituted 3-fluorofurans is reported. The sequence began with preparation of tert-
butyldimethylsilyl alk-1-en-3-yn-1-yl ethers from 1,4-disubstituted alk-3-yn-1-ones. Subsequent
fluorination of alkenynyl silyl ethers with Selectfluor gave 2-fluoroalk-3-yn-1-ones in almost quantitative
yield. Subsequent 5-endo-dig cyclizations using chlorotriphenylphosphine gold(I)/silver
trifluoromethanesulfonate (5/5 mol%), N-bromo- or N-iodosuccinimide and gold(I) chloride/zinc bromide
(5/20 mol%), all at room temperature, provided a facile method for the generation of substituted 3-fluoro-,
3-bromo-4-fluoro-, and 3-fluoro-4-iodofurans in good yields. Also, 2,2-difluoroalk-3-yn-1-ones were
prepared by fluorination of alk-3-yn-1-ones under organocatalytic conditions. The structures of (Z)-tert-
butyldimethylsilyl but-1-en-3-yn-1-yl ether, 3-bromo-4-fluorofuran, and 3-fluoro-4-(phenylethynyl)furan
were confirmed by X-ray crystallography.
introduced halogens. Electrophilic cyclization reactions are par-
ticularly attractive since they provide versatile access to different
Introduction
Active pharmaceutical ingredients incorporating the fluorine atom
have found wide applications in the field of medicinal chem-
istry.1,2 Currently, fluorine-containing compounds are leading in
the list of best-selling drugs.3 In fact, fluorofuran or perfluoroalk-
ylfuran fragments have already been embedded within structures
possessing interesting pharmacological properties.4,5 Since the
furan ring constitutes a submotif of medicinal interest,6 corre-
sponding fluorinated molecules are highly sought after building
blocks. Thus, upon considering the pharmaceutical potential, as
well as the limitations of available synthetic methods for 3-fluoro-
furans, we decided to pursue the development of their synthesis.
Halofurans are important derivatives, extensively utilized for
the preparation of acyclic, carbocylic, and heterocyclic com-
pounds. In addition, halofurans provide an opportunity for
further functionalization. In particular, iodo-, bromo-, and also
recently chlorofurans have been useful substrates for a variety of
bond-forming reactions.7–11 In general, approaches to the syn-
thesis of β-halofurans can be divided into substitution reactions
on the furan core and the construction of a furan ring starting
from acyclic precursors.12,13 The later centers on cycloisomeriza-
tion or cyclocondensation reactions and includes halogenation/
cyclizations, and cyclizations of precursors that contain already
halofurans by treatment of the same starting material with differ-
ent halogens.14,15 Usually the electrophile acts as both the cycli-
zation initiator and a halogen donor, thus fostering material
economy. However, fluorine, due to its limited electrophilic char-
acter, is not effective in electrophilic cyclizations.16 So far, pre-
parative access to 3-fluorofurans includes only a few specific
methods; the syntheses usually encompass aggressive conditions
or poor yields.12
Only scarce reports provide a preparative route to β,β′-
fluorohalofurans, which offer an opportunity for further functio-
nalization of fluorofurans. The iodocyclization of gem-difluoroho-
mopropargyl alcohols (2,2-difluoroalk-3-yn-1-ols) can be induced
by iodine monochloride in the presence of a base and microwave
irradiation.7 Subsequent silica gel aromatization of 3,3-difluoro-4-
iodo-2,3-dihydrofurans leads to the 3-fluoro-4-iodofurans. Only
one example of 3-bromo-4-fluorofuran, prepared by a sequential
lithiation/bromination reaction of 3-fluoro-2,5-diphenylfuran, has
been reported with undisclosed preparative yield.17
In order to access a family of β-fluorofurans (1), we elected to
introduce fluorine into an acyclic skeleton and to use 2-fluoro-
alk-3-yn-1-ones (2) as a versatile cyclization starting material
(Scheme 1).18,19 Fluoroalkynone 2 contains one less fluorine
aDepartment of Chemistry, Oakland University, 2200 N. Squirrel Rd,
Rochester, MI 48309-4477, USA. E-mail: dembinsk@oakland.edu
bEastern Illinois University, 600 Lincoln Avenue, Charleston, IL 61920-
3099, USA
†Electronic supplementary information (ESI) available: 1H, 13C, and 19
F
NMR spectra for difluorobutynones 4, silyl ethers 6, and fluorofurans
10–13. CCDC reference numbers 826570, 826571 and 827011. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c1ob06693e
Scheme 1 Retrosynthetic approach to β-fluorofurans.
Org. Biomol. Chem., 2012, 10, 2395–2408 | 2395
This journal is © The Royal Society of Chemistry 2012

View Article Online
atom in comparison to the gem-difluorohomopropargyl alcohol,
hence it should prove to be more versatile and reactive towards
cyclization reactions. This substrate would generate a convergent
synthetic opportunity to also obtain β,β′-fluorohalofurans.
Thus far, the preparations of 2-fluoroalk-3-yn-1-ones 2 have
been reported via the oxidation of 2-fluoroalk-3-yn-1-ols, which
are accessed by a low-yielding ring opening of an oxirane pre-
cursor by a fluoride anion,20 or via a zinc- or indium(III) chlor-
ide-catalyzed reaction of fluoropropargyl halides with carbonyl
compounds.21,22 Therefore, we sought to secure more convenient
access to fluoroalkynones 2 as key starting materials, establish
their cyclization reactions at mild conditions despite the thwart-
ing influence of fluorine atom on their reactivity, and finally,
functionalize the iododerivatives to trisubstituted 3-fluorofurans.
The current results extend our exploration of cycloisomerization
and electrophilic halocyclization reactions.10,23–26 Here we report
our attempts towards the syntheses of a family of substituted
β-fluorofurans 1 from alk-3-yn-1-ones 3.
Scheme 2 Fluorination of butynones 3a,e.
Scheme 3 Synthesis of silyl ethers 6. Procedures: A) LDA (1.1 equiv),
THF, −78 °C to rt, 12 h. B) LDA (1.1 equiv), TMEDA (1.2 equiv),
THF, −78 °C to rt, 12 h. C) DBU (1.1 equiv), NaI (0.2 equiv), aceto-
nitrile, rt, 4 h.
an α-alkoxy carbene derived from aldehyde and N-amino-2,3-
diphenylaziridine derivative,42 or ring opening of furans.43 The
pathway starting from alkynones 3 via enolization has not yet
been reported.
Results and discussion
We sought to develop a more effective fluorofuran synthesis in
terms of halogen atom economy. To introduce a fluorine atom at
the relatively late stage of the synthesis we envisioned direct
fluorination of alk-3-yn-1-ones 3 in a joint α-position to the
alkyne and ketone.27 Monofluorination procedures for regular
ketones at their α-carbon are known.28–30 However, a reaction of
alkynone 3a with NFSI (1 equiv), in the presence of the inor-
ganic base (potassium carbonate), leads to isolation of the
difluoro derivative 4a.31 Since monofluorination of regular
ketones can also be accomplished under organocatalytic con-
ditions,32 an analogous approach was investigated. Unfortu-
nately, the reaction of alkynone 3a with Selectfluor33 (1.1
equiv), in the presence of L-proline (10 mol%) and molecular
sieves, led again to a mixture of monofluoro and difluoro deriva-
tives 2a and 4a (4.5 : 1 ratio) that were difficult to separate.
Since the α-proton of 2a is more acidic than the one in substrate
3a, the product, in the presence of a base, equilibrates to a com-
petitive enolate.
The conversion of alkynone 3a24a to the corresponding
t-butyldimethylsilyl enol ether 6a and its trimethylsilyl lower
homolog was accomplished using a procedure similar to the lit-
erature protocol for regular silyl ether.44 Since 6a was suffi-
ciently stable for isolation by column chromatography, the
remaining silyl enol ethers 6b–h were then prepared as the
t-butyldimethylsilyl derivatives.
Although some of the solid alkynones 3 can be isolated via
crystallization and stored for months in a refrigerator, frequent
instability of liquids or solutions was encountered. The lack of
an effective and timely purification procedure, especially for
compounds 3g and 3h, prompted us to begin the synthesis from
alkynols 5. Since the oxidation of 5 with a Jones reagent is
efficient,38 ketones 3 were used as a crude material in a two step
process (Scheme 3).
The enolate was initially formed via deprotonation of alky-
none 3a with LDA in THF at −78 °C (procedure A, Table 1).
Additional optimization of the preparative procedure was sought.
TMEDA, a bidentate ligand coordinating lithium was added (2
equiv, procedure B), affording the enolate with comparable or
slightly higher yields. The silylation did not proceed with a
higher reaction rate. The substrate with the cyclopropyl alkynyl
group gave a low yield of silyl ether 6b with procedure A (11%,
Table 1, entry 2). Applying conditions B resulted in a complex
reaction mixture without detectable amounts of silyl ether 6b,
presumably due to the sensitivity of the cyclopropyl group
towards the reaction environment. Therefore thermodynamic
conditions (procedure C) for the cyclopropyl-containing sub-
strate were tried. The combination of the cyclopropyl ketone,
DBU (1.1 equiv), TBSCl (1.2 equiv), and NaI (0.2 equiv) in
anhydrous acetonitrile at ambient temperature gave 6b in 60%
yield (two step synthesis starting from 5b, 5 mmol scale). The
substrate with the phenoxymethyl group, derived from glycidol,
was converted to its ether 6h using conditions C as well (55%
yield, Table 1).
Considering the popular use of difluoropropargyl moieties in
synthetic34,35 and biological chemistry36 we took the opportunity
to integrate mild organocatalytic conditions into the preparation
of the difluoro derivatives 4. So far, fluoroalkynones 4 have been
prepared starting from chlorofluorocarbons via gem-difluoroho-
mopropargyl alcohols.37 When the alkynones 3a,e were reacted
with Selectfluor (2.3 equiv) in the presence of L-proline (20 mol
%) and 5 Å molecular sieves (acetonitrile, room temperature),
difluoroalkynones 4a,e were isolated with 63% and 67% yield
(Scheme 2). The convenient access to alkynones 3 include,
among others, oxidation of alkynols 5.38,39
Furthermore, alternative access to fluoroketones 2, in the
absence of a base was pursued. Electrophilic fluorodesilylation
of silyl enol ethers has literature precedence.16,40 However, we
were unable to find a general synthesis of alk-1-en-3-yn-1-yl
silyl ethers 6. So far, synthetic methods for silyl ethers (silyloxy
enynes) of type 6 have only been described for individual com-
pounds. Literature reports include the reaction of an alkynyl
oxirane with BuLi in the presence of TMSCl,41 rearrangement of
2396 | Org. Biomol. Chem., 2012, 10, 2395–2408
This journal is © The Royal Society of Chemistry 2012

View Article Online
Table 1 Synthesis of silyl ethers 6
Yield E/Z
Alkynol 5
R
R′
Procedure 6 [%] ratio46
a
Ph
Ph
p-MeC6H4
c-C3H5
A
B
A
B
C
A
B
C
A
B
A
B
B
A
C
52
60
11
nda
60
28
32
52
65
62
59
68
61
68
55
16 : 84
13 : 87
nd
b
nd
8 : 92
26 : 74
17 : 83
2 : 98
nd
2 : 98
nd
6 : 94
3 : 97
89 : 11b
22 : 78
c
p-FC6H4
p-MeC6H4
d
e
p-BrC6H4
p-BrC6H4
p-MeC6H4
p-t-BuC6H4
Fig. 1 An ORTEP view of 6e illustrating the atom labeling scheme
and thermal ellipsoids (50% probability level). Selected interatomic dis-
tances (Å): Si1–O1 1.6742(14), O1–C2 1.361(2), C2–C3 1.346(3), C2–
C6 1.477(3), C3–C4 1.421(3), C4–C5 1.209(3), C5–C12 1.435(3). Key
angles (°): Si1–O1–C2 130.81(13), O1–C2–C3 122.16(19), C3–C2–C6
123.12(18), O1–C2–C6 114.60(18), C2–C3–C4 124.92(19), C3–C4–C5
178.2(2), C4–C5–C12 176.3(2).
f
g
h
p-CF3C6H4 p-MeC6H4
Et
PhOCH2
Ph
p-MeC6H4
nd = not determined. a Complex reaction mixture. b Tentative E/Z
assignment based upon 1H NMR.
usually require longer acquisition time. Accordingly, we were
not able to observe the relevant CuC signals for the low abun-
dant isomer. Table 2 summarizes the chemical shift trends for
the signals that differentiated both isomers.
The substrate 5g with an ethyl substituent leads to a ketone
with two carbons available for enolization. Under kinetic con-
ditions (procedure A), formation of the conjugated ether 6g was
observed. The ethyl substituted ether 6g was rather unstable;
after a slower silica gel column chromatography a fraction was
collected that was rich in corresponding allenyl ketone.45 Appar-
ently desilylation of silyl ether and isomerization had occurred.
Fast filtration through a plug of deactivated silica gel brought
access to 6g that was still accompanied with a small amount of
allenyl ketone.
The silyl ethers 6a–h were obtained in 52–68% overall yield
(Table 1) after purification by column chromatography. The pro-
longed contact of silyl ethers 6 with silica gel was detrimental to
the yield; the optimum preparative scale was established as
6 mmol (> 1 g). On a smaller scale, such as 0.5 mmol, yields
were usually higher since the chromatography procedure can be
completed more rapidly.
Due to lack of stereochemical E/Z assignments for silyloxy
enynes49 an unequivocal confirmation was sought. Fortunately,
slow evaporation of a hexane/ethyl acetate solution of compound
6e gave a single crystal suitable for X-ray analysis. Inspection of
Fig. 1 reveals the molecular structure of the Z-silyl enol ether 6e.
This result is in agreement with the dominant Z stereochemistry
for silyl ethers derived from phenyl-substituted ketones.47
The fluorination reaction simplified the stereochemical
outcome. Since E and Z stereoisomers presumably produce the
same racemic mixture of 2-fluoroalkynone 2, the mixture of both
stereoisomers was subjected to the reaction. The reaction of 6a
with Selectfluor at room temperature gave a monofluoroketones
2a in almost quantitative yield (Scheme 4).23 Fluoroketone 2b
was also characterized by NMR.
Non-fluorinated alkynones 3 can be converted to furans using
zinc, silver, palladium, and other transition metals-containing
catalysts.24a,51 Unfortunately cycloisomerization of 2a with zinc
chloride etherate or silver nitrate was inhibited by the electron
withdrawing effect of fluorine (Table 3, entry 1 and 2). When
fluoroketone 2 was treated with the (PhCN)2PdCl2 (10 mol %),19
fluorofuran 7a was isolated in 60% yield.
After isolation, the predominance of one stereoisomer was
observed. The structural assignments of regular silyl enol ethers
are frequently based upon the chemical shift of vinyl protons in
the 1H NMR spectrum47,48 or, trustworthier, of allylic carbons in
the 13C NMR spectrum.49,50 However, such an assignment may
not necessarily extrapolate into the sp carbons of a triple bond or
ipso carbons of an aryl ring, which, due to low relaxation,
Table 2 NMR resonances for silyl ethers isomers 6a
Silyl ether 6
Ratio
CvCH major/min
CH3Si major/min
(CH3)3CSi major/min
CvCH major/min
CH3Si major/minor
a
b
c
d
e
f
g
h
87 : 13
92 : 8
98 : 2
98 : 2
94 : 6
97 : 3
89 : 11
78 : 22
5.59/5.38
5.31/5.14
5.52/5.31
5.58/5.39
5.59/5.40
5.68/5.48
4.89/4.93
5.32/5.23
0.17/0.21
0.13/0.16
0.17/0.21
0.18/0.21
0.19/0.21
0.19/0.23
0.22/na
1.03/1.00
1.01/0.97
1.02/0.99
1.02/0.99
1.03/0.99
1.03/1.00
0.96/na
91.0/90.4
91.1/90.8
90.8/nd
91.5/90.4
91.6/nd
92.9/nd
91.7/91.5
90.9/nd
−3.6/−4.3
−3.6/−4.3
−3.5/nd
−3.5/nd
−3.5/−4.3
−3.5/nd
−4.3/−3.6
−3.7/−4.4
0.32/0.17
1.01/0.93
nd = not detected. na = not assigned. a 1H/13C 400/100 MHz, CDCl3, 22 °C, δ, ppm.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 2395–2408 | 2397

View Article Online
seemed to be a logical choice. When Ph3PAuOTf (1 mol%) was
combined with Zn(OTf)2 (5 mol%, DCM, rt) and fluorobuty-
none 2a, the quantitative formation of fluorofuran 7a was
confirmed by 19F NMR. The reaction required 2 h for com-
pletion (Table 3, entry 10). The same reaction time and concen-
tration with 1 mol% Ph3PAuOTf gave only 8% of the
fluorofuran 7a (Table 3, entry 7). The control experiment using
only Zn(OTf)2 (20 mol%, 12 h) showed no conversion of 2a
(Table 3, entry 11). To clarify the role of the counterion, the reac-
tion was carried out with 5 mol% Ph3PAuBF4, and full conver-
sion was observed (Table 3, entry 12). Thus, it can be concluded
that the catalytic system does not depend significantly on the
counterion.56 It is in line with the report that the non-triflate
system Ph3PAuCl/Zn(ClO4)2 is as well an effective catalyst.55
Preparation of alk-3-yn-1-ones (propargyl ketones), the
necessary starting materials, was carried out as described
earlier.24,57 Although we focused on aryl substituents, we also
examined compounds containing one alkyl, and one cycloalkyl
group. The explored substituents of silyl enol ethers 6 include
aryl, ethyl, cyclopropyl, and phenoxymethyl; detailed structures
are provided in Table 1.
Due to the gradual decomposition of the monofluoroketones
during storage in solution and our inability to establish an effec-
tive purification procedure (especially for 2g and 2h), a sequence
of consecutive fluorination and cyclization reactions, starting
from silyl enol ethers 6 and proceeding in the same flask,
without isolation of 2-fluoroalkynones 2 (Scheme 5) was used
for preparative purposes (Table 4). Unfortunately attempted
fluorination of silyl ether 6h gave a complex reaction mixture at
both rt and 0 °C.58 Hence no cyclization reactions with the use
of this compound were pursued.
Scheme 4 Synthesis of 2-fluorobutynone 2a.
Cationic gold compounds show unique activities toward
alkynes, promoting the nucleophilic addition of a variety of
functional groups inter- and intramolecularly. Heterocycle for-
mation via vinyl-gold type intermediates that can be isolated has
already been established.52 Gold catalysts such as AuCl3, AuCl,
and PPh3AuCl have proved effective in the cyclization reac-
tions.53 Although gold(I) and (III) are both carbophilic, their com-
plexes could differ in selectivity for the same reactant. Au(III)
exhibits a thermodynamic preference for heteroatom coordi-
nation over carbon–carbon multiple bonds (and has a relatively
high oxidative potential), while Au(I) increases the relative
strength of coordination to the carbon-carbon multiple bonds.54
The use of AuCl3 (5 mol%) led to the formation of multiple pro-
ducts (Table 3, entry 4). When AuCl (5 mol%) was combined
with 2a in anhydrous DCM at ambient temperature, the reaction
showed no conversion to the fluorofuran in 2 h, although trace
1
amounts of other products were observed in the H NMR and
19F NMR (Table 3, entry 5). An easy-to-handle (air-stable) and
commercially available triphenylphosphine gold(I) chloride was
selected for investigation. The coordination with triphenylpho-
sphine decreases the Lewis acidity of auric salts, and the triphe-
nylphophine gold triflate (Ph3PAuOTf) derivative is a more
dissociated complex with increased electrophilicity at the gold
center. The air stable Ph3PAuOTf was generated in situ from tri-
phenylphosphine gold(I) chloride and silver trifluoromethanesul-
fonate (both 5 mol %), in dichloromethane, at room temperature,
and facilitated almost quantitative conversion of 2a into furan 7a
(Table 3, entry 6).
The electron withdrawing effect of fluorine significantly inhi-
bits not only the cycloisomerization process of fluorinated alky-
nones, but the halocyclization as well. To fine-tune the catalytic
system, optimization was carried out for the bromocyclization
reaction, using fluoroketone 2a as a model compound. The
better stability of formed bromofuran towards gold catalyst along
with the milder halogenation reagent (NBS) provided an advan-
tage over the initial optimization results acquired for the iodocy-
clization reaction.25 The bromination reactions were cleaner;
essentially since only the product and unreacted substrate were
observed.
Lowering the Ph3PAuOTf catalyst load to 1 mol % was inef-
fective due to slow conversion (Table 3, entries 7–9). In further
efforts to reduce the amount of gold/silver catalytic system
increase of enolization was sought by an addition of a co-catalyst
that would be compatible with the gold triflate acting species.55
In order to maintain the presence of the counterion, zinc triflate
Table 3 Catalyst optimization: cycloisomerization of fluorobutynone 2a
Entry
Catalyst
Loading [mol %]
Solvent
Conditions
Yield [%]
1
2
3
4
5
6
7
8
ZnCl2
AgNO3
(PhCN)2PdCl2
AuCl3
AuCl
Ph3PAuCl/AgOTf
Ph3PAuCl/AgOTf
Ph3PAuCl/AgOTf
Ph3PAuCl/AgOTf
Ph3PAuCl/AgOTf + Zn(OTf)2
Zn(OTf)2
100
10
10
5
5
5
1
1
1
DCM
acetone
DCM
acetonitrile
DCM
DCM
DCM
DCM
DCM
DCM
reflux, 3 h
rt, 4 h
rt, 1 h
rt, 30 min
rt, 2 h
rt, 10 min
rt, 10 min
rt, 2 h
rt, 12 h
rt, 2 h
rt, 12 h
rt, 10 min
no reaction
no reaction
60a
ndc
no reaction
95a
trace
8b
9
42a,c
10
11
12
1 + 5
20
5
>98b
DCM
DCM
no reactionb
>98b
Ph3PAuCl/AgBF4
a Isolated product. b Conversion determined by 19F NMR. c Not determined, multiple products observed.
2398 | Org. Biomol. Chem., 2012, 10, 2395–2408
This journal is © The Royal Society of Chemistry 2012

View Article Online
Table 5 Catalyst optimization: bromocyclization of 2-fluorobutynone
2aa
Entry
AuCl [%]
ZnBr2 [%]
Timeb
Yieldc
1
2
3
4
5
6
7
8
—
5
5
—
—
—
—
5
—
—
—
20
20
20
10 min
10 min
1 h
10 min
15 min
11 hd
10
16
19
43
47
>98
97e
>98
100
20
10 min
10 min
a NBS (1.2 equiv), DCM, rt, reaction in 0.05 mmol scale, 0.0025 M.
b Solvent evaporation time not accounted for. c Conversion determined
by the 19F NMR. d The reaction was not monitored throughout the
interval. e Complete conversion, product accompanied by an unidentified
compound at δ −103.0 ppm (3%, 19F NMR).
Scheme 5 Synthesis of fluorofurans 7, 8, and 9 via sequence of fluori-
nation/cyclization.
Bromofurans, as compared to iodo derivatives, are less reac-
tive. Therefore, it was projected that side products would orig-
inate from different reaction pathways of the substrate than from
the follow-up reaction involving the product. As anticipated, side
products were less abundant for bromocyclization process.
Efforts for catalytic system optimization are summarized in
Table 5. The reaction with only NBS (1.2 equiv) gave meager
conversion after 10 min (Table 5, entry 1). The addition of
gold(I) chloride (5 mol%) accelerated the reaction in a minor
way (Table 5, entries 2 and 3). Bromocyclization in the presence
of ZnBr2 (20 mol%) was more effective, with a 43% conversion
after 10 min and almost quantitative conversion after prolonged
time, or with the use of larger amount of the catalyst (Table 5,
entries 4–7). We were delighted to notice that a combination of
gold(I) chloride (5 mol%) and ZnBr2 (20 mol%) gave almost
quantitative conversion within 10 min (entry 8).
noticed. The entire molecule of 8a is nearly planar within
0.12 Å. The maximum atom deviation from the average plane is
0.25 Å for C-16 and C-18.
The gold-catalyzed formation of furans from propargyl
ketones is believed to proceed via an intramolecular, stepwise
mechanism (Fig. 3). Since non-terminal alkynes were used in
this work, the mechanistic pathway can be illustrated using the
coordination of Au to the carbon–carbon triple bond. The role of
zinc is not confirmed at this moment. Although some zinc
halides are excellent catalysts for the cycloisomerization of
regular alkynones 3,24 the fluoroalkynones 2 are reluctant to
proceed under the sole influence of zinc bromide or triflate. The
inability of zinc to act on its own as a cyclization catalyst may
indicate poor π-bond activation. We believe that the role of zinc,
is to increase enolization of alkynones via coordination to the
oxygen atom of a carbonyl group. In electrophilic cyclization
another role of the zinc halide would be to accelerate the release
of electrophile by enhancement of the dissociation of N-halosuc-
cinimide (NXS) into an electrophilic halogen and/or activation
of the halogen towards an electrophilic reaction.
Separation of halofurans from regular furans that could poten-
tially form during the reaction as side or competing products are
difficult to achieve by silica gel column chromatography due to
1
overlapping Rf values. To our delight, we did not observe by H
NMR formation of the non-halogenated fluorofurans 7 in the
halocyclizations post reaction mixtures, which spared a poten-
tially tedious separation of H-furans from halofurans and facili-
tated reasonable yields (Table 4).
The molecular structure of a dihalofuran was confirmed by
X-ray crystallography. Crystallization of compound 8a from
ether gave single crystals suitable for X-ray analysis. Inspection
of Fig. 2 confirms the regiochemistry and reveals the molecular
structure of the expected 3-bromo-4-fluorofuran. No significant
distortion of the furan ring due to the presence of fluorine was
Table 4 Preparation of fluorofurans 7–9a
Furan 7
yield [%]
Bromofuran 8
yield [%]
Iodofuran 9
yield [%]
Silyl ether 6
Fig. 2 An ORTEP view of 8a illustrating the atom labeling scheme
and thermal ellipsoids (50% probability level). Selected interatomic dis-
tances (Å): F1–C3 1.392(3), Br1–C4 1.877(3), O1–C2 1.379(4), O1–C5
1.378(4), C2–C3 1.353(4), C2–C6 1.453(5), C3–C4 1.408(4), C4–C5
1.358(4), C5–C12 1.451(4). Key angles (°): C2–O1–C5 109.0(2), O1–
C2–C3 107.0(3), O1–C2–C6 117.5(3), C3–C2–C6 135.5(3), C2–C3–C4
109.0(3), F1–C3–C2 127.1(3), F1–C3–C4 123.9(3), C3–C4–C5 106.9
(3), Br1–C4–C3 123.2(2), Br1–C4–C5 129.8(2), O1–C5–C4 108.1(3),
O1–C5–C12 115.4(3), C4–C5–C12 136.5(3).
a
b
c
d
e
f
9523,59
92
96
94
92
76
70
68
69
63
—
—
6225
78
72
68
65
89
52
38
—
g
a For R, R′ see Table 1.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 2395–2408 | 2399

View Article Online
Scheme 6 Cross-coupling reactions of 3-fluoro-4-iodofuran 9a.
Pyridinyl-substituted fluorofuran 12 was obtained in 85% yields.
The coupling with disulfane (diphenyl disulfide), carried out in
reductive conditions,64 produced phenylthio furan 13 with poor
yield (34%). All the couplings required elevated temperature that
was effected by microwaves assistance. The established con-
ditions (80–110 °C, 1–4 h) are comparable to the coupling of
other β-iodofurans (90 °C, 24 h or 110 °C, 0.5–2 h).7,9
Phenylalkynyl fluorofuran 10 gave crystals suitable for study
by X-ray diffraction, which confirmed the structure (Fig. 4). The
crystal structure of 10 shows molecules with nearly planar con-
formations within 0.40 Å. The maximum atom deviations from
Fig. 3 Mechanistic outline for cyclization of alkynones 2 (electrophile/
ketone pathway omitted).
Electrophilic pathways are believed to proceed via halogen
coordination to the triple bond, which could compete with a
gold-activated cyclization via π-bond activation (Fig. 3). As
mentioned earlier, gold(I) complexes are known to be effective
π-electrophilic Lewis acids.54 Thus the mechanism might
include the formation of the intermediate vinylgold species that
is subsequently trapped by electrophilic halogens. The presence
of zinc might also accelerate protonation/halogenation of such an
intermediate. However, the incidence of the reaction (albeit
slow) with sole N-iodo- or N-bromosuccinimide, indicates that
the electrophilic halogen is capable of acting by itself (Table 5
entry 1 and ref. 25). Also, the lack of non-halogenated fluorofur-
ans formation (within detection limit of 1H NMR), when the
cyclization reaction was carried out in the presence of gold/NXS,
may suggest that gold may not act as the cyclization catalyst but
rather as the activator of the NXS.60 It could also be assumed
that the gold/electrophilic pathways may be parallel to each
other, with presumably the electrophilic cyclization proceeding
faster.
Also, a control experiment was conducted to acquire insight
into the participation of a direct iodination reaction of the
cyclized product in the mechanistic process. A non-halogenated,
3-fluorofuran 7a was treated with NIS (1.2 equiv) in the presence
of AuCl/ZnBr2 (5 : 20 mol%, DCM, rt). After 12 h, no iodofuran
7a was detected in the reaction mixture by GC/MS.
The iodine in furan 9a was utilized to prepare an entirely
diverse substituted β-fluorofurans using cross-coupling reactions.
The Sonogashira coupling of 9a gave phenylethynyl fluorofuran
10 with 92% yield (Scheme 6). The Suzuki–Miyaura coupling
reaction with the thiophene-3-boronic acid was confirmed using
classical conditions to produce thiophenylfluorofuran 11 with
92% yield. Lithium N-heterocyclic trialkylborates (trialkoxybo-
rates) were introduced shortly before to facilitate the coupling of
electron-deficient 2-substituted nitrogen-containing hetero-
cycles.61 These organoboron salts, which are commercially avail-
able, provide convenience in handling and use. Applying Cu(I)
enhanced the coupling reaction conditions,62,63 the use of
lithium (pyridin-2-yl)triisopropoxyborate allowed for the intro-
duction of a conventionally unreactive moiety (Scheme 6).
Fig. 4 An ORTEP view of the 10 illustrating atom labeling scheme
and thermal ellipsoids (50% probability level). Selected interatomic dis-
tances (Å): F1–C3 1.3448(19), O1–C2 1.378(2), O1–C5 1.371(2), C2–
C3 1.351(2), C2–C6 1.450(2), C3–C4 1.415(3), C4–C5 1.379(2), C4–
C19 1.423(2), C5–C12 1.454(2), C19–C20 1.198(2), C20–C21 1.436
(2). Key angles (°): C2–O1–C5 108.52(13), O1–C2–C3 107.18(14),
O1–C2–C6 118.09(14), C3–C2–C6 134.73(16), C2–C3–C4 110.13(15),
F1–C3–C2 125.96(16), F1–C3–C4 123.91(15), C3–C4–C5 104.71(15),
C3–C4–C19 125.91(16), C5–C4–C19 129.38(17), O1–C5–C4 109.46
(15), O1–C5–C12 116.19(14), C4–C5–C12 134.35(16), C4–C19–C20
177.8(2), C19–C20–C21 178.0(2).
2400 | Org. Biomol. Chem., 2012, 10, 2395–2408
This journal is © The Royal Society of Chemistry 2012

View Article Online
the average plane are 0.10 and 0.11 Å for C-23 and C-26,
respectively.
a Biotage Initiator reactor equipped with a conventional tempera-
ture IR sensor.
1
New 3-fluorofurans 7–13 (Table 4) were characterized by H,
1
13C, and 19F NMR, IR, (HR)MS. The characteristic H NMR
2,2-Difluoro-4-(4-methylphenyl)-1-phenyl-but-3-yn-1-one (4a)
features for fluorofurans 7a–g include the H-4 signals (doublets
7.08–6.28 ppm with JHF 0.7–1.2 Hz). C–F carbons gave rise in
13C NMR to doublets 153.1–150.2, JCF 243.4–255.6 Hz for
An oven-dried round-bottom flask was charged with 3a
(0.070 g, 0.30 mmol), L-proline (6.9 mg, 0.060 mmol), Selec-
tfluor (0.250 g, 0.700 mmol), and ground 5 Å molecular sieves
(0.50 g). Anhydrous acetonitrile (6 mL) was injected through the
septum. The reaction was stirred at ambient temperature under
nitrogen and monitored by 19F NMR. The reaction was judged
to be complete after 7 days, when mono-fluorinated ketone only
existed in trace amounts. The mixture was diluted with ether
(∼60 mL) and filtered through a Bücher funnel. The filter cake
was washed with ether (20 mL). The combined filtrate was
stirred with 1 N HCl (10 mL) for 1 h. The organic layer was sep-
arated, dried over MgSO4, filtered and concentrated. Silica gel
chromatography (hexane/ethyl acetate 30 : 1) gave 4a as a yellow
oil (0.051 g, 0.19 mmol, 63%). IR (ν, cm−1, film) 2925, 1734,
1718, 1653, 1559. HRMS (DART-TOF) [M + H]+ calcd for
C17H13F2O 271.0935. Found 271.0929. NMR (CDCl3, δ, ppm):
1H 8.23 (d, J = 8.3 Hz, 2H), 7.70–7.64 (m, 1H), 7.58–7.50 (m,
2H), 7.38 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 2.37 (s,
3H); 13C 184.9 (t, J = 30.7 Hz), 134.8, 133.2, 132.4 (t, J = 2.5
Hz), 130.6 (t, J = 2.0 Hz), 129.5, 128.9, 125.7, 116.5 (t, J = 2.9
Hz), 108.4 (t, J = 243.7 Hz), 93.4 (t, J = 6.8 Hz), 79.1 (t, J =
38.2 Hz), 21.9; 19F −88.0.
fluorofurans
7
and 149.2–148.0/152.2–150.8 ppm (JCF
252.0–253.4/250.1–251.7 Hz) for bromo/iodofurans 8/9, respect-
4
ively. Longer range couplings, including JCF, were observed.19
The neighboring β-carbons (δ 100.0–99.0/89.9–89.6/
57.4–56.9 ppm) showed 2JCF 20.1–20.6/21.3–21.6/24.8–25.1 Hz
for 7/8/9, respectively. Observed 19F NMR signals for atoms
attached to the furan ring were in a close range (163.0–158.9,
163.8–160.8, 159.0–155.3 ppm, 7/8/9). Mass spectra for 7–13
exhibited intense molecular ion peaks and appropriate isotopic
patterns. Accurate elemental analyses and/or HRMS spectra were
obtained.
Conclusion
In summary, we have demonstrated that Z-butenynyl silyl ethers
6 can be successfully accessed from butynones 3, and their
monofluorination with Selectfluor leads to 2-fluorobutynones 2.
Furthermore, 2-fluorobutynones 2 undergo cycloisomerization in
the presence of chlorotriphenylphosphine gold/silver trifluoro-
methanesulfonate and halocyclization becomes effective when
N-halosuccinmides are used in combination with gold(I) chlor-
ide/zinc bromide. The synthetic method proved to be best suited
for aryl substituents at α- (C-2 and C-5) furan positions. This
way 3-fluoro-, 3,4-bromofluoro-, and 3,4-fluoroiodofurans 7, 8,
and 9 were obtained with good yields and characterized. The
relatively short reaction times (10 min) and mild conditions (rt)
provide an appealing alternative to the currently available
methods, also from the standpoint of halogen atom economy.
These methods avoid the loss of halogens in the synthetic
pathway, facilitate the regioselective introduction of fluorine
within two available β positions, and also allows for the intro-
duction of substituents such as cycloalkyls that are not easily
carried out by other methods. However, due to the stability of
aryl substituted alkynones the method is best suited for com-
pounds with aryl substituents. The dual catalyst methodology
proves the mild Lewis acid aids the cyclization catalyzed by the
gold catalyst. Additionally, difluorobutynones 4 were prepared
by direct fluorination of ketones 3.
1-(4-Bromophenyl)-4-(4-(tert-butyl)phenyl)-2,2-difluorobut-3-yn-
1-one (4e)
Procedure analogous to 4a: From 3e (0.107 g, 0.300 mmol); 4e
was obtained as a yellow solid (0.078 g, 0.20 mmol, 67%). IR
(ν, cm−1, film) 2925, 2234, 1718, 1653, 1559. HRMS
(DART-TOF) Calcd for [M + H]+ C20H18BrF2O 391.0509.
Found 391.0522. NMR (CDCl3, δ, ppm): 1H 8.09 (AA′XX′, J ≈
8.7 Hz, 2H),65 7.68 (AA′XX′, J ≈ 8.7 Hz, 2H),65 7.42 (AA′XX′,
J ≈ 8.3 Hz, 2H),65 7.38 (AA′XX′, J ≈ 8.3 Hz, 2H),65 1.31 (s,
9H); 13C 184.0 (t, J = 30.8 Hz), 154.6, 132.4, 132.3 (t, J = 2.4
Hz), 132.0 (t, J = 2.0 Hz), 130.5, 130.0, 125.9, 116.3 (t, J = 2.9
Hz), 108.2 (t, J = 244.0 Hz), 93.8 (t, J = 6.6 Hz), 78.8 (t, J =
38.2 Hz), 35.3, 31.3; 19F −88.2.
Preparation of silyl ethers (6)
Procedures A and B. The flask was charged with homopro-
pargyl alcohol 5a (1.42 g, 6.00 mmol) and acetone (30 mL).
Jones reagent (3.0 M, 3.0 mL, 9.0 mmol) was added at 0 °C
(water/ice bath). The reaction was stirred for 20 min at ambient
temperature, quenched with iPrOH (2.0 mL), and concentrated
under vacuum. The residue was diluted with ether (100 mL) and
filtered through a Büchner funnel. The filter cake was rinsed
with ether (2 × 20 mL). The combined organic solutions were
washed with brine (20 mL), 5% NaHCO3 (20 mL), dried over
MgSO4, and concentrated to yield the ketone 3a as a yellow
solid which was used for the next step without further purifi-
cation. The flask containing the crude ketone 3a was charged
with anhydrous THF (30 mL) under nitrogen. LDA (2.0 M,
Experimental section
General experimental details
Dichloromethane was collected from the Innovative Technology
PS-MD-6 solvent purification system. N-bromosuccinimide
(Avocado) was recrystallized from water. Other reagents were
used as received. Column chromatography was carried out on
silica gel (Dynamic Adsorbents, 32-63 μ). The NMR chemical
shifts are reported: 1H (400 MHz) and 13C (101 MHz) relative to
CDCl3/acetone-d6, 7.26/2.05 ppm and 77.16/29.9 ppm respect-
ively, and 19F (376 MHz) relative to CFCl3 as external standard.
The microwave reactions were carried out using capped vials in
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 2395–2408 | 2401

View Article Online
tert-Butyl({[1-(4-fluorophenyl)-4-(4-methylphenyl)but-1-en-3-
yn-1-yl]oxy})dimethylsilane (6c). Procedure C. From 5c (1.52 g,
6.00 mmol). Obtained 6c (1.14 g, 3.12 mmol, 52%) as a white
solid, a mixture of E/Z isomers in a 2 : 98 ratio.46 Calcd for
C23H27FOSi: C, 75.37; H, 7.42. Found: C, 75.55; H, 7.57. IR (ν,
cm−1, KBr) 2955, 2856, 2189, 1506, 1104, 816, 784. UV-vis (ε,
M−1cm−1; ether; 3.7 × 10−5 M) 226 (16 000), 313 (29 000). MS
(EI, m/z): 366 (30%, M+), 309 (100%, M+ − tBu). NMR
3.6 mL, 7.2 mmol) was added dropwise at −78 °C and the reac-
tion was stirred for 20 min followed by addition (for procedure
B only) of anhydrous TMEDA (1.80 mL, 12.0 mmol). The reac-
tion was stirred at −78 °C for 10 min and TBSCl (1.08 g,
7.20 mmol) in anhydrous THF (30 mL) was injected in small
portions. The reaction was stirred at ambient temperature for
12 h. After concentration under vacuum, silica gel column
chromatography (hexane/ethyl acetate 50 : 1) gave silyl ether 6a
as a white solid (1.23 g, 3.53 mmol, 60%).
1
(CDCl3, δ, ppm): H 7.56–7.50 (m, 2H), 7.35 (dt, J = 8.1, 1.6
Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 7.07–7.00 (m, 2H), 5.52 (s,
0.98H, Z-isomer), 5.31 (s, 0.02H, E-isomer), 2.36 (s, 3H), 1.02
(s, 9H), 0.21/0.17 Z/E (s, 6H); 13C{1H}(signals for Z-isomer)
163.3 (d, J = 248.6 Hz), 159.0, 138.0, 134.4 (d, J = 3.2 Hz),
131.3, 129.3, 127.7 (d, J = 8.3 Hz), 121.3, 115.4 (d, J = 21.7
Hz), 94.4, 90.8, 86.6, 26.0, 21.7, 18.7, −3.5.
Procedure C. To the homopropargyl alcohol 5b (1.12 g,
6.00 mmol) in acetone (30 mL) Jones reagent (3.0 M, 3.0 mL,
9.0 mmol) was added at 0 °C. The reaction was stirred for
20 min at ambient temperature. The reaction was quenched with
iPrOH (2 mL) and concentrated under vacuum. The residue was
diluted with ether (80 mL) and filtered through a Büchner
funnel. The filter cake was rinsed with ether (2 × 20 mL). The
combined organic solutions were washed with brine (20 mL)
and 5% NaHCO3 (20 mL). The filtrate was dried over MgSO4,
filtered and concentrated to yield the propargyl ketone as a
yellow oil, which was used for the next step without further
purification. The flask containing the propargyl ketone was
charged with NaI (0.300 g, 2.00 mmol) and TBSCl (0.990 g,
6.60 mmol in glovebox). Anhydrous acetonitrile (30 mL) was
injected through the septum. To the above homogeneous solution
DBU (0.99 mL, 6.6 mmol) was added dropwise at 0 °C (water/
ice bath). The reaction mixture was stirred at 0 °C for 4 h (TLC).
After concentration under vacuum, silica gel column chromato-
graphy (hexane) gave 6b as a yellow oil (1.07 g, 3.58 mmol,
60%).
{[1-(4-Bromophenyl)-4-(4-methylphenyl)but-1-en-3-yn-1-yl]
oxy}(tert-butyl)dimethylsilane (6d). Procedure B. From 5d
(1.88 g, 6.00 mmol). Obtained 6d (1.58 g, 3.70 mmol, 62%) as
a white solid, a mixture of E/Z isomers in a 2 : 98 ratio.46 Calcd
for C23H27BrOSi: C, 64.63; H, 6.37. Found: C, 64.88; H, 6.40.
IR (ν, cm−1, KBr) 2927, 2858, 1484, 894, 784. UV-vis (ε,
M−1cm−1; ether; 3.2 × 10−5 M) 230 (17 000), 319 (37000). MS
(EI, m/z): 426 (20%, M+), 369 (100%, M+ − tBu). NMR
(CDCl3, δ, ppm): 1H 7.48 (dt, J = 8.8, 2.0 Hz, 2H), 7.41 (dt, J =
8.8, 2.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz,
2H), 5.58 (s, 0.98H, Z-isomer), 5.39 (s, 0.02H, E-isomer), 2.36
(s, 3H), 1.02 (s, 8.82H, Z-isomer), 0.99 (s, 0.18H, E-isomer),
0.21 (s, 0.12H, E-isomer), 0.18 (s, 5.88H, Z-isomer); 13C{1H}
(signals for Z-isomer) 158.8, 138.2, 137.1, 131.6, 131.3, 129.3,
127.4, 123.1, 121.2, 94.9, 91.5, 86.5, 26.0, 21.7, 18.7, −3.5.
tert-Butyldimethyl{[4-(4-methylphenyl)-1-phenylbut-1-en-3-
yn-1-yl]oxy}silane (6a). Procedure B. Obtained 6a as a white
solid, a mixture of E/Z isomers in a 13 : 87 ratio.46 Calcd for
C23H28OSi: C, 79.26; H, 8.10. Found: C, 79.45; H, 8.51. IR (ν,
cm−1, KBr) 2927, 2856, 2186, 1349, 1103, 816, 787, 765, 694.
UV-vis (ε, M−1cm−1; ether; 3.6 × 10−5 M) 227 (17 000),
314 (28 000). MS (EI, m/z): 348 (30%, M+), 291 (100%,
{[1-(4-Bromophenyl)-4-(4-tert-butylphenyl)but-1-en-3-yn-1-yl]
oxy}(tert-butyl)dimethylsilane (6e). Procedure B. From 5e
(2.14 g, 6.00 mmol). Obtained 6e (1.92 g, 4.08 mmol, 68%) as a
white solid, a mixture of E/Z isomers in a 6 : 94 ratio.46 Calcd
for C26H33BrOSi: C, 66.51; H, 7.08. Found: C, 66.61; H, 7.08.
IR (ν, cm−1, KBr) 2929, 2855, 2195, 1252, 1093, 1009, 894,
835, 784. UV-vis (ε, M−1cm−1; ether; 3.2 × 10−5 M) 228
(20 000) sh, 320 (37 000). MS (EI, m/z): 470 (20%, M+), 413
1
[M − tBu]+). NMR (CDCl3, δ, ppm): H 8.04–7.99 (m, 0.28H),
7.58–7.52 (m, 1.72H), 7.42–7.31 (m, 5H), 7.16–7.09 (m, 2H),
5.59 (s, 0.86H, Z-isomer), 5.38 (s, 0.14H, E-isomer), 2.36 (s,
2.58H), 2.35 (s, 0.42H), 1.03 (s, 7.74H, Z-isomer), 1.00 (s,
1.26H, E-isomer), 0.21 (s, 0.84H, E-isomer), 0.17 (s, 5.16H,
Z-isomer); 13C{1H}(signals for Z-isomer) 160.0, 138.2, 138.0,
131.3, 129.3, 129.0, 128.4, 126.0, 121.4, 94.4, 91.0, 86.8, 26.1,
21.7, 18.8, −3.6.
1
(100%, M+ − tBu). NMR (CDCl3, δ, ppm): H 7.54–7.31 (m,
8H), 5.59 (s, 0.94H, Z-isomer), 5.40 (s, 0.06H, E-isomer), 1.33
(s, 9H), 1.03 (s, 8.46H, Z-isomer), 0.99 (s, 0.54H, E-isomer),
0.21 (s, 0.36H, E-isomer), 0.19 (s, 5.64H, Z-isomer); 13C{1H}
(signals for Z-isomer) 158.7, 151.3, 137.2, 131.6, 131.1, 127.4,
125.5, 123.1, 121.2, 95.0, 91.6, 86.5, 35.0, 31.4, 26.0, 18.7,
−3.5.
tert-Butyl[(4-cyclopropyl-1-phenylbut-1-en-3-yn-1-yl)oxy]
dimethylsilane (6b). Procedure C. Obtained 6b as a yellow oil, a
mixture of E/Z isomers in a 8 : 92 ratio.46 Calcd for C19H26OSi:
C, 76.45; H, 8.78. Found: C, 76.27; H, 8.70. IR (ν, cm−1, film)
2930, 2858, 2217, 1339, 1257, 1088, 841, 783, 763, 695. MS
(EI, m/z): 298 (20%, M+), 241 (100%, [M − t-Bu]+). NMR
(CDCl3, δ, ppm): 1H 7.52–7.43 (m, 2H), 7.34–7.28 (m, 3H),
5.31 (d, J = 1.8 Hz, 0.92H, Z-isomer), 5.14 (d, J = 2.0 Hz,
0.08H, E-isomer), 1.49–1.34 (m, 1H), 1.01 (s, 8.30H, Z-isomer),
0.97 (s, 0.70H, E-isomer), 0.86–0.74 (m, 4H), 0.16 (s, 0.51H,
E-isomer), 0.13 (s, 5.49H, Z-isomer); 13C{1H}(signals for
Z-isomer) 159.6, 138.3, 128.8, 128.3, 125.8, 98.2, 91.1, 73.5,
26.0, 18.7, 8.5, 0.90, −3.6.
tert-Butyldimethyl{[4-(4-methylphenyl)-1-[4-(trifluoromethyl)
phenyl]but-1-en-3-yn-1-yl]oxy}silane (6f). Procedure B. From 5f
(0.610 g, 2.00 mmol). Obtained 6f (0.510 g, 1.22 mmol, 61%)
as a white solid, a mixture of E/Z isomers in a 3 : 97 ratio.46
Calcd for C24H27F3OSi: C, 69.20; H, 6.53. Found: C, 69.43; H,
6.67. IR (ν, cm−1, KBr) 2930, 1323, 1125, 1068, 814, 781. UV-
vis (ε, M−1cm−1; ether; 3.3 × 10−5 M) 225 (20 000), 323
(29 000). MS (EI, m/z): 416 (10%, M+), 359 (100%, M+ − tBu).
NMR (CDCl3, δ, ppm): 1H 7.66 (d, J = 8.4 Hz, 2H), 7.61 (d, J =
8.4 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H),
5.68 (s, 0.97H, Z-isomer), 5.48 (s, 0.03H, E-isomer), 2.37 (s,
3H), 1.03 (s, 8.73H, Z-isomer), 1.00 (s, 0.27H, E-isomer), 0.23
2402 | Org. Biomol. Chem., 2012, 10, 2395–2408
This journal is © The Royal Society of Chemistry 2012

View Article Online
(s, 0.18H, E-isomer), 0.19 (s, 5.82H, Z-isomer); 13C{1H}(signals
for Z-isomer) 158.2, 141.6, 138.4, 131.4, 130.8 (q, J = 32.5 Hz),
129.4, 126.0, 125.5 (q, J = 3.8 Hz), 124.3 (q, J = 271.8 Hz),
121.0, 95.6, 92.9, 86.2, 26.0, 21.7, 18.7, −3.5.
5-Cyclopropyl-3-fluoro-2-phenylfuran
(7b). From
6b
(0.150 g, 0.500 mmol). Obtained 7b (0.092 g, 0.46 mmol, 92%)
as a yellow oil. Calcd for C13H11FO: C, 77.21; H, 5.48. Found:
C, 76.75; H, 6.40. IR (ν, cm−1, neat) 2924, 1653, 1636, 1559,
1457, 1424, 668. MS (EI, m/z): 202 (M+). NMR (δ, ppm): H
1
tert-Butyldimethyl[(6-phenylhex-3-en-5-yn-3-yl)oxy]silane (6g).
Procedure A. From 5g (1.05 g, 6.03 mmol). Silica gel was
washed with 1% Et3N/eluent (v/v).Obtained 6g (1.18 g,
4.12 mmol, 68%) as a yellow oil, a mixture of E/Z isomers in a
89 : 11 ratio.46 IR (ν, cm−1, film) 2931, 2859, 2201, 1594, 1490,
1293, 871, 840. MS (EI, m/z): 286 (10%, M+), 229 (100%, [M
− tBu]+). NMR (CDCl3, δ, ppm): 1H 7.42–7.38 (m, 2H),
7.33–7.24 (m, 3H), 4.93 (s, 0.11 H, Z-isomer), 4.89 (s, 0.89 H,
E-isomer), 2.48 (q, J = 7.5 Hz, 2H), 1.13 (t, J = 7.5 Hz, 3H),
0.96 (s, 9H), 0.22 (s, 6H); 13C 168.4, 131.1, 128.5, 127.4, 124.7,
91.7, 87.5, 87.3, 27.5, 25.8, 18.4, 11.6, −4.3.
(acetone-d6) 7.64–7.58 (m, 2H), 7.48–7.40 (m, 2H), 7.29–7.23
(m, 1H), 6.28 (d, J = 0.8 Hz, 1H), 2.04–1.96 (m, 1H), 1.02–0.96
(m, 2H), 0.91–0.85 (m, 2H); 13C (acetone-d6) 156.2 (d, J = 9.0
Hz), 150.7 (d, J = 252.0 Hz), 134.9 (d, J = 20.6 Hz), 130.2 (d,
J = 5.0 Hz), 129.8, 127.6 (d, J = 1.3 Hz), 123.7 (d, J = 5.3 Hz),
99.3 (d, J = 20.2 Hz), 10.1 (d, J = 1.3 Hz), 7.6; 19F (CDCl3)
−163.0.
3-Fluoro-2-(4-fluorophenyl)-5-(4-methylphenyl)furan
(7c).
From 6c (0.184 g, 0.500 mmol). Obtained 7c (0.125 g,
0.480 mmol, 96%) as a white solid, mp 100–101 °C. Calcd for
C17H12F2O: C, 75.55; H, 4.48. Found: C, 75.50; H, 4.60. IR (ν,
cm−1, KBr) 2921, 1635, 1507, 1403, 1234, 826, 792. MS (EI,
tert-Butyldimethyl{[5-(4-methylphenyl)-1-phenoxypent-2-en-
4-yn-2-yl]oxy}silane (6h). Procedure C. From 5h (1.60 g,
6.00 mmol). Obtained 6h (1.26 g, 3.30 mmol, 55%) as a yellow
solid, a mixture of E/Z isomers in a 22 : 78 ratio.46 Calcd for
C24H30O2Si: C, 76.14; H, 7.99. Found: C, 76.08; H, 8.11. IR (ν,
cm−1, KBr) 2929, 2857, 2198, 1378, 1237. MS (EI, m/z): 378
1
m/z): 270 (M+). NMR (δ, ppm): H (acetone-d6) 7.85–7.78 (m,
2H), 7.77–7.70 (m, 2H), 7.32–7.25 (m, 4H), 7.02 (d, J = 0.84
Hz, 1H), 2.36 (s, 3H); 13C (acetone-d6) 162.7 (dd, J = 245.7, 2.1
Hz), 151.8 (d, J = 9.8 Hz), 151.3 (dd, J = 252.0, 1.7 Hz), 139.4,
135.5 (d, J = 20.8 Hz), 130.5, 128.3 (d, J = 2.1 Hz), 126.4 (dd, J
= 5.2, 3.0 Hz), 126.3 (dd, J = 8.1, 5.3 Hz), 124.7, 116.9 (d, J =
22.1 Hz), 99.7 (d, J = 20.3 Hz), 21.4; 19F (CDCl3) −114.8,
−163.0.
1
(30%, M+), 229 (100%). NMR (CDCl3, δ, ppm): H 7.36–7.29
(m, 4H), 7.12 (d, J = 8.0 Hz, 2H), 7.04–6.91 (m, 3H), 5.32 (s,
0.78H, Z-isomer), 5.23 (s, 0.22H, E-isomer), 4.84 (s, 0.44H, E-
isomer), 4.44 (s, 1.56H, Z-isomer), 2.36 (s, 3H), 1.01 (s, 6.85H,
Z-isomer), 0.93 (s, 2.15H, E-isomer), 0.32 (s, 4.49H, Z-isomer),
0.17 (s, 1.51H, E-isomer); 13C{1H}(signals for Z-isomer) 158.4,
157.0, 138.0, 131.3, 129.8, 129.3, 121.5,121.2, 114.9, 93.3,
90.9, 85.2, 69.1, 25.9, 21.7, 18.6, −3.5.
2-(4-Bromophenyl)-3-fluoro-5-(4-methylphenyl)furan
(7d).
From 6d (0.214 g, 0.500 mmol). Obtained 7d (0.155 g,
0.468 mmol, 94%) as a white solid, mp 110–112 °C. HRMS
(DART-TOF) Calcd for [M]+ C17H12BrFO: 330.0056. Found:
330.0265. IR (ν, cm−1, KBr) 2923, 1636, 1499, 1395, 824, 790.
MS (EI, m/z): 331 (M+). NMR (δ, ppm): 1H (acetone-d6)
7.76–7.59 (m, 6H), 7.27 (d, J = 7.9 Hz, 2H), 6.98 (d, J = 0.7
Hz, 1H), 2.35 (s, 3H); 13C (acetone-d6) 152.3 (d, J = 9.0 Hz),
152.0 (d, J = 253.7 Hz), 139.6, 135.3 (d, J = 20.6 Hz), 133.0,
130.5, 128.9 (d, J = 4.9 Hz), 128.2 (d, J = 2.1 Hz), 125.9 (d, J =
5.4 Hz), 124.8, 121.2 (d, J = 2.3 Hz), 100.0 (d, J = 20.4 Hz),
21.4; 19F (CDCl3) −160.8.
2-Fluoroalk-3-yn-1-ones (2): general procedure
A 100 mL round-bottom flask was charged with ether 6
(0.500 mmol), Selectfluor (0.195 g, 0.550 mmol), and aceto-
nitrile (10 mL). The mixture was stirred at ambient temperature
(22 °C) and monitored by TLC (hexane/EtOAc 8 : 2; usually for
1 h). Solvent was removed by rotary evaporation and the residue
was kept under oil pump vacuum for 30 min. DCM (60 mL) was
added and the mixture was stirred for 10 min. The solid was
filtered off (fritted funnel) and the filter cake was washed with
DCM (20 mL). Solvent was removed from the combined filtrates
by rotary evaporation to give crude 2.
2-(4-Bromophenyl)-5-(4-tert-butylphenyl)-3-fluorofuran (7e).
From 6e (0.235 g, 0.500 mmol). Obtained 7e (0.172 g,
0.461 mmol, 92%) as a white solid, mp 72–73 °C. Calcd for
C20H18BrFO: C, 64.36; H, 4.86. Found: C, 64.64; H, 4.95. IR
(ν, cm−1, KBr) 2959, 1636, 1395, 831, 820. MS (EI, m/z): 373
(M+). NMR (δ, ppm): 1H (acetone-d6) 7.80–7.74 (m, 2H),
7.73–7.64 (m, 4H), 7.54–7.49 (m, 2H), 7.03 (d, J = 0.8 Hz, 1H),
1.34 (s, 9H); 13C (acetone-d6) 152.7, 152.2 (d, J = 8.8 Hz),
152.0 (d, J = 253.6 Hz), 135.4 (d, J = 20.6 Hz), 133.0, 128.9
(d, J = 5.0 Hz), 128.1 (d, J = 2.1 Hz), 126.8, 125.9 (d, J = 5.4
Hz), 124.7, 121.2 (d, J = 2.3 Hz), 100.0 (d, J = 20.1 Hz), 35.4,
31.6; 19F (CDCl3) −160.7.
4-Cyclopropyl-2-fluoro-1-phenylbut-3-yn-1-one
(2b). NMR
(CDCl3, δ, ppm): 1H 8.12–8.05 (m, 2H), 7.66–7.60 (m, 1H),
7.54–7.48 (m, 2H), 5.98 (dd, J = 49.5, 2.1 Hz, 1H), 1.35–1.24
(m, 1H), 0.86–0.69 (m, 4H); 19F −177.8 (d, J = 49.5 Hz).
3-Fluorofurans (7): general procedure
Crude 2 (obtained from 6 as described above) was dissolved in
DCM (10 mL). To the solution, Ph3PAuCl (0.013 g,
0.025 mmol) and AgOTf (0.0065 g, 0.025 mmol) were added
and the mixture was stirred vigorously in the dark (the flask was
wrapped in Al foil) for 10 min. The residue was concentrated by
rotary evaporation and purified by silica gel column chromato-
graphy (hexane).
3-Fluoro-5-(4-methylphenyl)-2-[4-(trifluoromethyl)phenyl]
furan (7f). From 6f (0.208 g, 0.500 mmol). Obtained 7f
(0.142 g, 0. 444 mmol, 89%) as a white solid, mp 132–133 °C.
Calcd for C18H12F4O: C, 67.50; H, 3.78. Found: C, 67.22; H,
3.67. IR (ν, cm−1, KBr) 2926, 1634, 1410, 1339, 1165, 1108,
1
1072, 840, 792. MS (EI, m/z): 320 (M+). NMR (δ, ppm): H
(acetone-d6) 7.82 (d, J = 8.2 Hz, 2H), 7.97 (d, J = 8.2 Hz, 2H),
Org. Biomol. Chem., 2012, 10, 2395–2408 | 2403
This journal is © The Royal Society of Chemistry 2012

View Article Online
3-Bromo-4-fluoro-5-(4-fluorophenyl)-2-(4-methylphenyl)furan
(8c). From 6c (0.183 g, 0.500 mmol). Obtained 8c (0.125 g,
0.358 mmol, 72%) as a white solid, mp 103–105 °C. Calcd for
C17H11BrF2O: C, 58.48; H, 3.18. Found: C, 58.32; H, 3.50. IR
(ν, cm−1, KBr) 2922, 1508, 1406, 1233, 945, 828, 812. MS (EI,
7.80–7.74 (m, 2H), 7.36–7.28 (m, 2H), 7.08 (d, J = 0.7 Hz, 1H),
2.38 (s, 3H); 13C (acetone-d6) 153.2 (d, J = 8.8 Hz), 153.1 (d,
J = 255.6 Hz), 139.9, 134.9 (d, J = 20.4 Hz), 133.3 (d, J = 3.8
Hz), 130.6, 128.9 (qd, J = 33.3, 1.9 Hz), 128.0 (d, J = 2.2 Hz),
126.9 (q, J = 3.9 Hz), 125.4 (q, J = 271.2 Hz), 125.0, 124.4 (d,
J = 5.5 Hz), 99.9 (d, J = 20.1 Hz), 21.4; 19F (CDCl3) −63.0
(3F), −158.9 (1F).
1
m/z): 348 (100%, M+). NMR (δ, ppm): H (acetone-d6) 7.96 (d,
J = 8.3 Hz, 2H), 7.87–7.81 (m, 2H), 7.36 (d, J = 8.2 Hz, 2H),
7.35–7.28 (m, 2H), 2.39 (s, 3H); 13C (acetone-d6) 163.2 (dd, J =
247.2, 2.2 Hz), 148.5 (dd, J = 252.0, 2.2 Hz), 147.2 (d, J = 3.8
Hz), 140.2, 135.4 (d, J = 19.3 Hz), 130.5, 127.3 (d, J = 1.5 Hz),
126.8 (dd, J = 8.5, 5.0 Hz), 126.2, 125.4 (dd, J = 5.1, 3.1 Hz),
117.1 (d, J = 22.4 Hz), 89.6 (d, J = 21.5 Hz), 21.4; 19F (CDCl3)
−163.0, −113.5.
2-Ethyl-3-fluoro-5-phenylfuran (7g). From 6g (0.143 g,
0.500 mmol). Obtained 7g (0.049 g, 0.26 mmol, 52%) as a col-
1
orless oil. NMR (acetone-d6, δ, ppm): H 7.71–7.64 (m, 2H),
7.45–7.37 (m, 2H), 7.33–7.26 (m, 1H), 6.83 (d, J = 1.2 Hz, 1H),
2.73 (qd, J = 7.6, 1.8 Hz, 2H); 1.27 (t, J = 7.6 Hz, 3H); 13C
150.3 (d, J = 9.2 Hz), 150.2 (d, J = 243.4 Hz), 140.0 (d, J =
25.9 Hz), 131.5 (d, J = 2.1 Hz), 129.7, 128.6, 124.1, 99.0 (d, J =
20.6 Hz), 18.9 (d, J = 3.1 Hz), 12.4 (d, J = 1.7 Hz).
3-Bromo-5-(4-bromophenyl)-4-fluoro-2-(4-methylphenyl)furan
(8d). From 6d (0.214 g, 0.500 mmol). Obtained 8d (0.139 g,
0.339 mmol, 68%) as a white solid, mp 101–103 °C. Calcd for
C17H11Br2FO: C, 49.79; H, 2.70. Found: C, 50.05; H, 2.84. IR
(ν, cm−1, KBr) 2923, 1636, 1488, 1397, 944, 821. MS (EI, m/z):
3-Bromo-4-fluorofurans (8) and 3-fluoro-4-iodofurans (9):
general procedure
1
410 (100%, M+). NMR (δ, ppm): H (acetone-d6) 8.00–7.94 (m,
2H), 7.76–7.69 (m, 4H), 7.39–7.34 (m, 2H), 2.40 (s, 3H); 13C
(acetone-d6) 149.2 (d, J = 253.3 Hz), 147.6 (d, J = 4.3 Hz),
140.4, 135.2 (d, J = 19.2 Hz), 133.2, 130.5, 127.9 (d, J = 5.1
Hz), 127.2 (d, J = 1.4 Hz), 126.3 (d, J = 4.9 Hz), 126.3, 122.3
(d, J = 2.2 Hz), 89.7 (d, J = 21.6 Hz), 21.5; 19F (CDCl3)
−160.8.
The flask containing crude 2 (obtained from 6 as described
above) was charged with N-halosuccinimide (NIS 0.135 g,
0.600 mmol or NBS, 0.107 g, 0.600 mmol) and anhydrous
DCM (7.0 mL). The mixture was stirred for a few minutes to
become homogeneous, then anhydrous ground ZnBr2 (0.0225 g,
0.100 mmol) was added followed immediately by AuCl
(0.0058 g, 0.025 mmol) in anhydrous DCM (3.0 mL). The
mixture was stirred vigorously at ambient temperature for
10 min. The reaction was quenched by adding saturated sodium
thiosulfate aqueous solution (10 mL) and stirred for few
minutes. DCM (60 mL) was added. The organic layer was separ-
ated, dried over MgSO4, filtered, and concentrated under reduced
pressure. The product was purified by silica gel column chrom-
atography (hexane).
3-Bromo-5-(4-bromophenyl)-2-(4-tert-butylphenyl)-4-fluor-
ofuran (8e). From 6e (0.235 g, 0.500 mmol). Obtained 8e
(0.148 g, 0.327 mmol, 65%) as a white solid, mp 122–123 °C.
Calcd for C20H17Br2FO: C, 53.13; H, 3.79. Found: C, 53.68; H,
3.85. IR (ν, cm−1, KBr) 2959, 1653, 1636, 832, 817, 668. MS
(EI, m/z): 452 (100%, M+). NMR (δ, ppm): 1H (acetone-d6)
8.04–7.97 (m, 2H), 7.75–7.68 (m, 4H), 7.63–7.56 (m, 2H), 1.38
(s, 9H); 13C (acetone-d6) 153.4, 149.2 (d, J = 253.4 Hz), 147.6
(d, J = 4.3 Hz), 135.2 (d, J = 19.1 Hz), 133.2, 127.9 (d, J = 5.1
Hz), 127.2, 126.7, 126.3 (d, J = 5.1 Hz), 126.2, 122.2 (d, J = 2.1
Hz), 89.8 (d, J = 21.4 Hz), 35.5, 31.5; 19F (CDCl3) −160.8.
3-Bromo-4-fluoro-2-(4-methylphenyl)-5-phenylfuran
(8a).
From 6a (0.175 g, 0.500 mmol). Obtained 8a (0.103 g,
0.311 mmol, 62%) as a white solid, mp 75–76 °C. Calcd for
C17H12BrFO: C, 61.65; H, 3.65. Found: C, 61.95; H, 3.82. IR
(ν, cm−1, KBr) 2924, 1636, 1499, 943, 817, 760, 687. MS (EI,
m/z): 330 (100%, M+). NMR (δ, ppm): 1H (acetone-d6)
8.00–7.94 (m, 2H), 7.82–7.75 (m, 2H), 7.57–7.49 (m, 2H),
7.42–7.33 (m, 3H), 2.39 (s, 3H); 13C (acetone-d6) 148.8 (d, J =
252.4 Hz), 147.1 (d, J = 4.4 Hz), 140.2, 136.1 (d, J = 19.0 Hz),
130.4, 130.1, 129.0 (d, J = 1.4 Hz), 128.8 (d, J = 5.0 Hz), 127.4,
126.2, 124.6 (d, J = 5.0 Hz), 89.6 (d, J = 21.5 Hz), 21.4; 19F
(CDCl3) −162.2.
2-Cyclopropyl-4-fluoro-3-iodo-5-phenylfuran (9b). From 6b
(0.150 g, 0.500 mmol). Obtained 9b (0.115 g, 0.350 mmol,
70%) as a white solid, mp 61–62 °C. Calcd for C13H10FIO: C,
47.59; H, 3.07. Found: C, 47.55; H, 3.25. IR (ν, cm−1, KBr)
3010, 1636, 1494, 1417, 997, 760. MS (EI, m/z): 328 (100%,
1
M+). NMR (δ, ppm): H (CDCl3) 7.62–7.54 (m, 2H), 7.43–7.36
(m, 2H), 7.26–7.21 (m, 1H), 2.02–1.94 (m, 1H), 1.09–0.97 (m,
4H); 13C (acetone-d6) 154.8 (d, J = 6.1 Hz), 150.8 (d, J = 251.2
Hz), 134.9 (d, J = 21.0 Hz), 129.8, 129.2 (d, J = 5.2 Hz), 128.2,
123.9 (d, J = 5.1 Hz), 57.4 (d, J = 24.8 Hz), 10.3, 7.7; 19F
(CDCl3) −159.0.
3-Bromo-2-cyclopropyl-4-fluoro-5-phenylfuran (8b). From 6b
(0.150 g, 0.500 mmol). Obtained 8b (0.110 g, 0.391 mmol,
78%) as a white soft solid. IR (ν, cm−1, neat) 2925, 1638, 1497,
1428, 1002, 759. MS (EI, m/z): 280 (100%, M+). HRMS
(DART-TOF) Calcd for [M + H]+ C13H11BrFO 280.9977. Found
280.9978. NMR (δ, ppm): 1H (CDCl3) 7.62–7.55 (m, 2H),
7.43–7.36 (m, 2H), 7.26–7.22 (m, 1H), 2.04–1.94 (m, 1H),
1.09–0.98 (m, 4H); 13C (acetone-d6) 151.8 (d, J = 4.5 Hz),
148.0 (d, J = 252.5 Hz), 134.8 (d, J = 19.7 Hz), 129.9, 129.2 (d,
J = 5.1 Hz), 128.4 (d, J = 1.4 Hz), 124.0 (d, J = 5.1 Hz), 89.9
(d, J = 21.3 Hz), 9.0, 7.3; 19F (CDCl3) −163.8.
3-Fluoro-2-(4-fluorophenyl)-4-iodo-5-(4-methylphenyl)furan
(9c). From 6c (0.183 g, 0.500 mmol). Obtained 9c (0.135 g,
0.341 mmol, 68%) as a white solid, mp 98–99 °C. Calcd for
C17H11F2IO: C, 51.54; H, 2.80. Found: C, 51.94; H, 3.21. IR (ν,
cm−1, KBr) 2919, 1701, 1653, 1508, 837, 817. MS (EI, m/z):
1
396 (100%, M+). NMR (δ, ppm): H (acetone-d6) 8.03–7.97 (m,
2H), 7.85–7.78 (m, 2H), 7.39–7.26 (m, 4H), 2.40 (s, 3H); 13 C
(acetone-d6) 163.1 (dd, J = 246.6, 2.2 Hz), 151.5 (dd, J = 250.1,
2404 | Org. Biomol. Chem., 2012, 10, 2395–2408
This journal is © The Royal Society of Chemistry 2012

View Article Online
2.2 Hz), 149.7 (d, J = 6.0 Hz), 140.2, 135.5 (d, J = 21.2 Hz),
130.3, 128.0 (d, J = 1.3 Hz), 126.9, 126.7 (dd, J = 8.2, 5.1 Hz),
125.5 (dd, J = 5.1, 3.5 Hz), 117.1 (d, J = 22.2 Hz), 56.9 (d, J =
25.1 Hz), 21.4; 19F (CDCl3) −157.6, −113.7.
of ethyl ether (50 mL) and concentrated under vacuum. The
residue was purified by silica gel flash chromatography
(hexanes) to give 10 as a white solid (0.080 g, 0.23 mmol, 92%),
mp 132–133 °C. IR (ν, cm−1, KBr) 3032, 2919, 2218, 1636,
819, 755, 668. MS (EI, m/z): 352 (100%, M+). HRMS
(DART-TOF) Calcd for [M + H]+ C25H18FO: 353.1342. Found:
2-(4-Bromophenyl)-3-fluoro-4-iodo-5-(4-methylphenyl)furan
(9d). From 6d (0.214 g, 0.500 mmol). Obtained 9d (0.158 g,
0.346 mmol, 69%) as a white solid, mp 104–106 °C. Calcd for
C17H11BrFIO: C, 44.67; H, 2.43. Found: C, 45.12; H, 2.49. IR
(ν, cm−1, KBr) 2920, 1700, 1653, 1559, 940, 824. MS (EI, m/z):
1
353.1330. NMR (CDCl3, δ, ppm): H 8.07 (d, J = 8.3 Hz, 2H),
7.82–7.77 (m, 2H), 7.64–7.57 (m, 2H), 7.49–7.38 (m, 5H),
7.34–7.28 (m, 3H), 2.42 (s, 3H); 13C 151.6 (d, J = 4.8 Hz),
149.4 (d, J = 258.9 Hz), 139.1, 135.1 (d, J = 18.6 Hz), 131.8,
129.6, 129.0, 128.9, 128.7, 128.6, 127.7, 127.6 (d, J = 1.5 Hz),
125.0, 123.9 (d, J = 5.1 Hz), 123.2, 97.6 (d, J = 17.4 Hz), 96.9,
78.3 (d, J = 2.5 Hz), 21.7; 19F −161.7.
1
456 (100%, M+). NMR (δ, ppm): H (acetone-d6) 8.04–7.99 (m,
2H), 7.75–7.68 (m, 4H), 7.40–7.34 (m, 2H), 2.40 (s, 3H); 13C
(acetone-d6) 152.2 (d, J = 251.5 Hz), 150.2 (d, J = 5.9 Hz),
140.4, 135.3 (d, J = 20.8 Hz), 133.2, 130.3, 128.0 (d, J = 5.4
Hz), 127.9 (d, J = 1.4 Hz), 126.9, 126.3 (d, J = 5.1 Hz), 122.0
(d, J = 2.4 Hz), 57.0 (d, J = 24.9 Hz), 21.4; 19F (CDCl3)
−155.3.
3-Fluoro-5-(4-methylphenyl)-2-phenyl-4-(thiophen-3-yl)furan
(11)
2-(4-Bromophenyl)-5-(4-tert-butylphenyl)-3-fluoro-4-iodofuran
(9e). From 6e (0.235 g, 0.500 mmol). Obtained 9e (0.156 g,
0.313 mmol, 63%) as a white solid, mp 143–144 °C. Calcd for
C20H17BrFIO: C, 48.12; H, 3.43. Found: C, 48.22; H, 3.33. IR
(ν, cm−1, KBr) 2958, 1653, 1559, 1395, 940, 832, 816, 668. MS
(EI, m/z): 498 (100%, M+). NMR (δ, ppm): 1H (acetone-d6)
8.10–8.05 (m, 2H), 7.77–7.69 (m, 4H), 7.64–7.59 (m, 2H), 1.38
(s, 9H); 13C (acetone-d6) 153.4, 152.2 (d, J = 251.7 Hz), 150.2
(d, J = 5.9 Hz), 135.4 (d, J = 21.1 Hz), 133.2, 128.0 (d, J = 5.1
Hz), 127.9 (d, J = 1.5 Hz), 126.8, 126.6, 126.3 (d, J = 5.1 Hz),
122.0 (d, J = 2.2 Hz), 57.1 (d, J = 24.9 Hz), 35.5, 31.5; 19F
(CDCl3) −155.3.
A 10 mL microwave reaction vial was charged with the iodo-
furan 9a (0.095 g, 0.25 mmol), 3-thiophene-3-boronic acid
(0.064 g, 0.50 mmol), Pd(PPh3)4 (0.029 g, 0.025 mmol), and
Na2CO3 (0.053 g, 0.50 mmol). The reaction vial was sealed,
evacuated and backfilled with nitrogen (Schlenk line, three
times). Under nitrogen protection, degassed toluene (5 mL),
EtOH (0.5 mL) and H2O (0.2 mL) were injected into the vial
successively. The reaction vial was submitted to microwave
irradiation with stirring (110 °C, 2 h), and monitored by TLC
analysis of an aliquot of the reaction solution. The reaction
mixture was transferred to a separatory funnel with the aid of
ether (60 mL) and washed with brine (10 mL). The organic layer
was dried over MgSO4, filtered and concentrated under vacuum.
The residue was purified by silica gel column chromatography
(hexane) to give 11 as a white solid (0.077 g, 0.23 mmol, 92%),
mp 79–81 °C. Calcd for C21H15FOS: C, 75.42; H, 4.52. Found:
C, 75.89; H, 4.88. IR (ν, cm−1, KBr) 2924, 2854, 1495, 1442,
820, 759. MS (EI, m/z): 334 (100%, M+). NMR ( CDCl3, δ,
3-Fluoro-4-iodo-5-(4-methylphenyl)-2-[4-(trifluoromethyl)
phenyl]furan (9f). From 6f (0.208 g, 0.500 mmol). Obtained 9f
(0.085 g, 0.19 mmol, 38%) as a white solid, mp 79–81 °C. IR
(ν, cm−1, KBr) 2924, 2853, 1616, 1407, 1326, 1164, 1107,
1070, 839, 816. MS (EI, m/z): 446 (100%, M+). HRMS
(DART-TOF) Calcd for M+ C18H11F4IO: 445.9791. Found:
1
1
ppm): H 7.83–7.77 (m, 2H), 7.56–7.50 (m, 2H), 7.49–7.42 (m,
445.9772. NMR (δ, ppm): H (acetone-d6) 8.06–8.00 (m, 2H),
3H), 7.39 (dd, J = 5.0, 3.0 Hz, 1H), 7.33–7.28 (m, 1H),
7.21–7.15 (m, 3H), 2.39 (s, 3H); 13C 148.8 (d, J = 255.9 Hz),
146.4 (d, J = 6.0 Hz), 138.6, 135.4 (d, J = 19.6 Hz), 129.6 (d,
J = 2.8 Hz), 129.5 (2C), 129.2 (d, J = 5.0 Hz), 129.0 (2C),
128.2, 127.3, 126.4 (2C), 125.9, 124.2 (d, J = 2.1 Hz), 123.8 (d,
J = 5.2 Hz, 2C), 110.5 (d, J = 16.1 Hz), 21.6;66 19F −164.0.
7.97 (d, J = 8.2 Hz, 2H), 7.85 (d, J = 8.3 Hz, 2H), 7.37 (d, J =
8.0 Hz, 2H), 2.40 (s, 3H); 13C (acetone-d6) 153.2 (d, J = 253.5
Hz), 150.9 (d, J = 5.9 Hz), 140.7, 134.9 (d, J = 20.7 Hz), 132.3
(d, J = 5.3 Hz), 130.3, 129.5 (q, J = 32.4 Hz), 127.7 (d, J = 1.3
Hz), 127.0, 127.0 (q, J = 3.9 Hz), 125.3 (q, J = 271.3 Hz), 124.8
(d, J = 5.5 Hz), 57.1 (d, J = 25.0 Hz), 21.4; 19F (CDCl3)
−153.4, −63.1.
2-[4-Fluoro-2-(4-methylphenyl)-5-phenylfuran-3-yl]pyridine (12)
3-Fluoro-5-(4-methylphenyl)-2-phenyl-4-(phenylethynyl)furan
(10)
A 10 mL microwave reaction vial was charged with the iodo-
furan 9a (0.095 g, 0.25 mmol), lithium (pyridin-2-yl)triisoprox-
yborate (0.110 g, 0.400 mmol), Pd(PPh3)4 (0.029 g,
0.025 mmol), CuCl (0.0025 g, 0.025 mmol), Cs2CO3 (0.098 g,
0.30 mmol), and ZnCl2 (0.034 g, 0.25 mmol, loaded in glove-
box). The reaction vial was sealed, evacuated and backfilled with
nitrogen (Schlenk line, three times). Under nitrogen protection,
anhydrous degassed DMF (2 mL) was injected into the vial. The
reaction vial was submitted to microwave irradiation with stirring
(110 °C, 2 h), and monitored by TLC analysis of an aliquot of
reaction solution. After completion, the reaction mixture was
transferred to a flask with the aid of ethyl ether (60 mL) and
washed with brine (10 mL). The organic layer was separated,
A 10 mL microwave reaction vial was charged with the iodo-
furan 9a (0.095 g, 0.25 mmol), PdCl2(PPh3)2 (0.018 g,
0.025 mmol), and CuI (4.8 mg, 0.025 mmol). The reaction vial
was sealed, then evacuated-backfilled with nitrogen (Schlenk
line, three times). Under nitrogen protection, degassed toluene
(5 mL) and Et3N (0.10 mL, 0.75 mmol) were injected into the
vial. Then phenylacetylene (80 μL, 0.73 mmol) was injected to
the reaction. The reaction vial was submitted to microwave
irradiation with stirring (80 °C, 1 h). After 9a had been con-
sumed, as judged by TLC analysis of an aliquot of reaction sol-
ution, the reaction mixture was transferred to a flask with the aid
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 2395–2408 | 2405

View Article Online
dried over MgSO4, filtered and concentrated under vacuum. The
residue was purified by silica gel flash chromatography (hexane/
ethyl acetate 30 : 1) to give 12 as a white solid (0.070 g,
0.22 mmol, 85%), mp 80–82 °C. Calcd for C22H16FNO: C,
80.23; H, 4.90. Found: C, 80.12; H, 5.37. IR (ν, cm−1, KBr)
2920, 1640, 1592, 1416, 816, 763. MS (EI, m/z): 329 (100%,
M+). NMR (CDCl3, δ, ppm): 1H 8.75 (ddd, J = 4.9, 1.8, 0.9 Hz,
1H), 7.85–7.80 (m, 2H), 7.75 (pseudo td J = 7.7, 1.8 Hz, 2H),
7.58–7.53 (m, 2H), 7.52–7.43 (m, 3H), 7.32–7.27 (m, 2H), 7.15
(d, J = 8.0 Hz, 2H), 2.37 (s, 3H); 13C 150.4 (d, J = 3.5 Hz),
150.2, 148.7 (d, J = 257.0 Hz), 147.9 (d, J = 5.7 Hz), 138.8,
136.7, 135.7 (d, J = 19.4 Hz), 129.3, 129.1 (d, J = 4.9 Hz),
129.0, 127.8 (d, J = 1.3 Hz), 127.4 (d, J = 1.0 Hz), 126.6, 125.0
(d, J = 2.0 Hz), 123.9 (d, J = 5.3 Hz), 122.8, 115.1 (d, J = 14.8
Hz), 21.6; 19F −164.5.
of this research. The National Science Foundation (NSF) awards
(CHE-0821487, CHE-1048719, and CHE-0722547) are also
acknowledged. Y. L. is grateful for the Provost’s Graduate
Student Research Award. We also thank Dr Robert Syvret (Air
Products and Chemicals), Dr Bruno François (Simafex, France),
and Frontier Scientific, Logan, Utah, for a generous supply of
Selectfluor, N-iodosuccinimide, and boronic acid/lithium triiso-
propoxyborate salt (LTBS), respectively.
References
1 E. P. Cormier, M. Das, and I. Ojima, Approved Active Pharmaceutical
Ingredients Containing Fluorine, in Fluorine in Medicinal Chemistry and
Chemical Biology,ed. I. Ojima, Wiley-Blackwell, Chichester, 2009, pp.
525–603.
2 J.-P. Bégué and D. Bonnet-Delpon, Bioorganic and Medicinal Chemistry
of Fluorine,John Wiley & Sons, New York, 2008, pp. 279–351.
3 Wikipedia, the free encyclopedia, List of bestselling drugs, http://en.wiki-
pedia.org/wiki/List_of_bestselling_drugs (accessed August 30, 2011).
4 Review: O. Serdyuk, A. Butin and V. Abaev, J. Fluorine Chem., 2010,
131, 296–319.
3-Fluoro-5-(4-methylphenyl)-2-phenyl-4-(phenylsulfanyl)furan
(13)
A 10 mL microwave reaction vial was charged with the iodo-
furan 9a (0.095 g, 0.25 mmol), diphenyl disulfide (0.055 g,
0.25 mmol), PdCl2(dppf) (0.019 mg, 0.025 mmol), and zinc
dust (0.030 g, 0.50 mmol). The reaction vial was sealed, evacu-
ated and backfilled with nitrogen (Schlenk line, three times).
Under nitrogen protection, anhydrous degassed THF (2.5 mL)
was injected into the vial. The reaction vial was submitted to
microwave irradiation with stirring (110 °C, 4 h). The reaction
mixture was filtered through a Bücher funnel with the aid of
ether (60 mL) and the filtrate was washed with brine (10 mL).
The organic layer was dried over MgSO4, filtered and concen-
trated under vacuum. The residue was purified by silica gel
column chromatography (hexanes) to give 13 as a white soft
solid (0.031 g, 0.086 mmol, 34%). IR (ν, cm−1, KBr) 2924,
1653, 1559. HRMS (DART-TOF) Calcd for [M + H]+
C23H18FOS: 361.1062. Found: 361.1055. NMR (CDCl3, δ,
5 A. S. Cantrell, P. Engelhardt, M. Högberg, R. S. Jaskunas,
N. G. Johansson, C. L. Jordan, J. Kangasmetsä, M. D. Kinnick, P. Lind,
J. M. Morin Jr., M. A. Muesing, R. Noreén, B. Öberg, P. Pranc,
C. Sahlberg, R. J. Ternansky, R. T. Vasileff, L. Vrang, S. J. West and
H. Zhang, J. Med. Chem., 1996, 39, 4261–4274.
6 See for example: (a) J. R. Thomas and P. J. Hergenrother, Chem. Rev.,
2008, 108, 1171–1224; (b) N. Issaeva, P. Bozko, M. Enge,
M. Protopopova, L. G. G. C. Verhoef, M. Masucci, A. Pramanik and
G. Selivanova, Nat. Med., 2004, 10, 1321–1328; (c) X. Ming, W. Ju,
H. Wu, R. R. Tidwell, J. E. Hall and D. R. Thakker, Drug Metab.
Dispos., 2009, 37, 424–430; (d) M. M. Nyunt, C. W. Hendrix,
R. P. Bakshi, N. Kumar and T. A. Shapiro, Am. J. Trop. Med. Hyg., 2009,
80, 528–535.
7 S. Arimitsu, J. M. Jacobsen and G. B. Hammond, J. Org. Chem., 2008,
73, 2886–2889.
8 See for example: (a) M. Hussain, R. A. Khera, N. T. Hung and P. Langer,
Org. Biomol. Chem., 2011, 9, 370–373; (b) S. A. Schweizer and T. Bach,
Synlett, 2010, 81–84.
9 A. S. Karpov, E. Merkul, T. Oeser and T. J. J. Müller, Eur. J. Org. Chem.,
2006, 2991–3000.
10 A. Sniady, M. S. Morreale, K. A. Wheeler and R. Dembinski,
Eur. J. Org. Chem., 2008, 3449–3452.
11 C.-H. Cho and R. C. Larock, ACS Comb. Sci., 2011, 13, 272–279.
12 R. Dembinski, Y. Li, D. Gundapuneni and A. Decker, Synthesis of
β-Halofurans, in Halogenated Heterocycles: Synthesis and Use, ed.
J. Iskra, Topics in Heterocyclic Chemistry Series, Springer, Heidelberg,
2011, vol. 27, ch. 3, pp. 63–98.
13 Representative reviews for synthesis of furans: (a) H. N. C. Wong, X.-
L. Hou, K.-S. Yeung and H. Huang, Five-Membered Heterocycles:
Furan. InModern Heterocyclic Chemistry, J. Alvarez-Builla, J. J. Vaquero
and J. Barluenga, Eds., Wiley-VCH: Weinheim, 2011, Vol. 1, Ch. 6, 533–
592; (b) N. T. Patil and Y. Yamamoto, Arkivoc, 2007, 10, 121–141;
(c) S. F. Kirsch, Org. Biomol. Chem., 2006, 4, 2076–2080;
(d) R. C. D. Brown, Angew. Chem., Int. Ed., 2005, 44, 850–852.
14 (a) B. Godoi, R. F. Schumacher and G. Zeni, Chem.Rev., 2011, 111,
2937–2980; (b) For a general review on the cyclizations of alkynes
see: K. Gilmore and I. V. Alabugin, Chem. Rev., 2011, 111, 6513–
6556.
15 Recent representative advances: (a) S. Ali, H.-T. Zhu, X.-F. Xia, K.-G. Ji,
Y-F. Yang, X-R. Song and Y.-M. Liang, Org. Lett., 2011, 13, 2598–2601;
(b) H.-T. Zhu, K.-G. Ji, F. Yang, L.-J. Wang, S.-C. Zhao, S. Ali, X.-Y. Liu
and Y.-M. Liang, Org. Lett., 2011, 13, 684–687; (c) A. Sperança,
B. Godoi, M. D. Costa, P. H. Menezes and G. Zeni, Tetrahedron Lett.,
2011, 52, 388–391; (d) R. Sanz, A. Martínez, P. García-García,
M. A. Fernández-Rodríguez, M. A. Rashid and F. Rodríguez, Chem.
Commun., 2010, 46, 7427–7429; (e) K.-G. Ji, H.-T. Zhu, F. Yang,
A. Shaukat, X.-F. Xia, Y.-F. Yang, X.-Y. Liu and Y.-M. Liang, J. Org.
Chem., 2010, 75, 5670–5678; (f) B. Crone, S. F. Kirsch and K.-
D. Umland, Angew. Chem., Int. Ed., 2010, 49, 4661–4664;
(g) R. F. Schumacher, A. R. Rosário, A. C. G. Souza, P. H. Menezes and
1
ppm): H 8.01 (d, J = 8.3 Hz, 2H), 7.82–7.75 (m, 2H), 7.46 (t,
J = 7.8 Hz, 2H), 7.33–7.14 (m, 8H), 2.39 (s, 3H); 13C 152.6 (d,
J = 4.5 Hz), 150.4 (d, J = 255.5 Hz), 139.4, 136.5, 136.0, 135.6
(d, J = 19.9 Hz), 129.6 (2C), 129.4 (2C), 129.0 (2C), 127.7,
127.2 (d, J = 1.5 Hz), 127.1 (2C), 126.2, 126.1 (2C), 123.8 (d,
J = 5.1 Hz, 2C), 102.7 (d, J = 20.3 Hz), 21.6; 19F −160.5.
Crystallography
Crystals of 6e (transparent prism, colorless) were grown by evap-
oration of hexanes/ethyl acetate (20 : 1) solution. Crystals of 8a
(transparent needle, colorless) were grown from the ether by
slow evaporation. Crystals of 10 (transparent needle, colorless)
were grown from the pentane by slow evaporation. CCDC
826570, 826571, and 827011, respectively (see the supplemen-
tary crystallographic data for this paper†).
Acknowledgements
Acknowledgment is made to the donors of the Petroleum
Research Fund (ACS-PRF#46094) administered by the Ameri-
can Chemical Society and to Oakland University and its
Research Excellence Program in Biotechnology for the support
2406 | Org. Biomol. Chem., 2012, 10, 2395–2408
This journal is © The Royal Society of Chemistry 2012

View Article Online
G. Zeni, Org. Lett., 2010, 12, 1952–1955; (h) N. Fei, Q. Hou, S. Wang,
H. Wang and Z. J. Yao, Org. Biomol. Chem., 2010, 8, 4096–4103;
(i) S. Mehta and R. C. Larock, J. Org. Chem., 2010, 75, 1652–1658;
( j) C.-H. Cho, B. Neuenswander and R. C. Larock, J. Comb. Chem.,
2010, 12, 278–285.
41 A. Denichoux, F. Ferreira and F. Chemla, Org. Lett., 2004, 6, 3509–
3512.
42 A. Padwa, D. J. Austin, Y. Gareau, J. M. Kassir and S. L Xu, J. Am.
Chem. Soc., 1993, 115, 2637–2647.
43 (a) A. V. Anisimov, G. N. Murina, L. V. Mozhaeva, N. B. Kazennova and
E. A. Viktorova, Chem. Heterocycl. Compd., 1984, 20, 599–601; Khim.
Geterotsikl. Soed., 1984, 744–746; (b) K. Atsumi and I. Kuwajima,
J. Am. Chem. Soc., 1979, 101, 2208–2211.
16 Formal electrophilic reactions of fluorine presumably involve alternative
mechanisms: T. Umemoto, S. Fukami, G. Tomizawa, K. Harasawa,
K. Kawada and K. Tomita, J. Am. Chem. Soc., 1990, 112, 8563–8575.
17 P. Li, Z. Chai, G. Zhao and S.-Z. Zhu, Synlett, 2008, 2547–2551.
18 For conversion of 2,5-substituted 3-fluorofurans into 2,3,5-substituted
see: (a) P. Li, J.-W. Gu, Y. Ying, Y.-M. He, H.-F. Zhang, G. Zhao and S.-
Z. Zhu, Tetrahedron, 2010, 66, 8387–8391; (b) P. Li, Z. Chai, G. Zhao
and S.-Z. Zhu, Tetrahedron, 2009, 65, 1673–1678.
44 (a) I. Fleming and I. Paterson, Synthesis, 1979, 736–738;
(b) H. O. House, L. J. Czuba, M. Gall and H. D. Olmstead, J. Org.
Chem., 1969, 34, 2324–2336.
45 Phenylhexa-4,5-dien-3-one. Yellow oil. IR (ν, cm−1, film) 2929, 1937,
1
1910, 1715, 1684, 1456, 699. NMR (CDCl3, δ, ppm): H 7.40–7.29 (m,
19 3-Fluorofuran-containing fatty ester was obtained using a similar reaction
catalyzed by (PhCN)2PdCl2 in propylene oxide in 50% yield:
M. S. F. Lie Ken Jie, M. M. L. Lau and C. N. W. Lam, Lipids, 2003, 38,
1293–1297.
20 M. S. F. Lie Ken Jie, M. M. L. Lau, C. N. W. Lam, M. S. Alam,
J. O. Metzger and U. Biermann, Chem. Phys. Lipids, 2003, 125, 93–101.
21 H. L. Sham and D. A. Batebenner, J. Chem. Soc., Chem. Commun.,
1991, 1134–1135.
5H), 6.64 (d, J = 6.4 Hz, 1H), 6.16 (d, J = 6.4 Hz, 1H), 2.75–2.58 (m,
2H), 1.09 (t, J = 7.4 Hz, 3H); 13C 215.3, 201.1, 131.4, 129.3, 128.4,
127.5, 100.4, 98.8, 33.1, 8.6.
46 The ratio was calculated based upon 1H NMR integration of the vinyl
protons.
47 C. H. Heathcock, C. T. Buse, W. A. Kleschick, M. C. Pirrung, J. E. Sohn
and J. Lampe, J. Org. Chem., 1980, 45, 1066–1081. When the phenyl
group is attached to the carbonyl function in regular ketones, the use of
LDA usually promotes a dominance of Z versus E isomer.
48 D. A. Evans, K. M. Hurst and J. M. Takacs, J. Am. Chem. Soc., 1978,
100, 3467–3477.
22 B. Xu and G. B. Hammond, J. Org. Chem., 2006, 71, 3518–3521.
23 Y. Li, K. A. Wheeler and R. Dembinski, Adv. Synth. Catal., 2010, 352,
2761–2766.
24 (a) A. Sniady, A. Durham, M. S. Morreale, A. Marcinek, S. Szafert,
T. Lis, K. R. Brzezinska, T. Iwasaki, T. Ohshima, K. Mashima and
R. Dembinski, J. Org. Chem., 2008, 73, 5881–5889; (b) A. Sniady,
A. Durham, M. S. Morreale, K. A. Wheeler and R. Dembinski, Org.
Lett., 2007, 9, 1175–1178; (c) P. Wyrębek, A. Sniady, N. Bewick, Y. Li,
A. Mikus, K. A. Wheeler and R. Dembinski, Tetrahedron, 2009, 65,
1268–1275.
25 Y. Li, K. A. Wheeler and R. Dembinski, Eur. J. Org. Chem., 2011, 2767–
2771.
26 (a) A. Sniady, K. A. Wheeler and R. Dembinski, Org. Lett., 2005, 7,
1769–1772; (b) M. S. Rao, N. Esho, C. Sergeant and R. Dembinski, J.
Org. Chem., 2003, 68, 6788–6790.
27 Effort to facilitate electrophilic fluorocyclization of butynone 3a with
Selectfluor was unsuccessful.
28 F. A. Davis and P. V. N. Kasu, Org. Prep. Proced. Int., 1999, 31, 125–
143.
29 G. Verniest, E. Van Hende, R. Surmont and N. De Kimpe, Org. Lett.,
2006, 8, 4767–4770.
30 For the synthesis of α-fluoro ketones from alkynes see: T. de Haro and
C. Nevado, Adv. Synth. Catal., 2010, 352, 2767–2772.
31 Matching observations has been reported for fluorination of enamines:
W. Peng and J. M. Shreeve, J. Org. Chem., 2005, 70, 5760–5763.
32 D. Enders and M. R. M. Hüttl, Synlett, 2005, 991–993.
33 G. S. Lal, G. P. Pez and R. G. Syvret, Chem. Rev., 1996, 96, 1737–1756.
34 (a) S. Arimitsu and G. B. Hammond, Synthesis of gem-Difluorinated
Heterocycles Using a Difluoropropargyl Molecular Scaffold, in Fluori-
nated Heterocycles, ed. A. A. Gakh and K. L. Kirk, ACS Symposium
Series 1003, American Chemical Society, Washington, DC, 2009; pp.
135–162; (b) S. Arimitsu and G. B. Hammond, Chim. Oggi, 2010, 28,
20–22; (c) S. Arimitsu, B. Fernandez, C. del Pozo, S. Fustero and
G. B. Hammond, J. Org. Chem., 2008, 73, 2656–2661.
35 See for example: J.-C. Kizirian, N. Aiguabella, A. Pesquer, S. Fustero,
P. Bello, X. Verdaguer and A. Riera, Org. Lett., 2010, 12, 5620–5623.
36 For examples see: (a) C. Dai, L. Wang, J. Sheng, H. Peng,
A. B. Draganov, Z. Huang and B. Wang, Chem. Commun., 2011, 47,
3598–3600; (b) E. M. Sletten, H. Nakamura, J. C. Jewett and
C. R. Bertozzi, J. Am. Chem. Soc., 2010, 132, 11799–11805;
(c) S. T. Laughlin, J. M. Baskin, S. L. Amacher and C. R. Bertozzi,
Science, 2008, 320, 664–5667.
49 H. J. Reich, R. C. Holtan and C. Bolm, J. Am. Chem. Soc., 1990, 112,
5609–5617.
50 For assignments with the use of a NOE experiment, see ref. 41.
51 Y. Lu, F. Song, X. Jia and Y. Liu, Prog. Chem., 2010, 22, 58–70 (in
Chinese).
52 (a) A. S. K. Hashmi, T. D. Ramamurthi and F. Rominger, Adv. Synth.
Catal., 2010, 352, 971–975; (b) L.-P. Liu and G. B. Hammond,
Chem.–Asian J., 2009, 4, 1230–1236; (c) A. S. K. Hashmi, A. Schuster
and F. Rominger, Angew. Chem., Int. Ed., 2009, 48, 8247–8249;
(d) D. Weber, M. A. Tarselli and M. R. Gagné, Angew. Chem., Int. Ed.,
2009, 48, 5733–5736; (e) L.-P. Liu, B. Xu, M. S. Mashuta and
G. B. Hammond, J. Am. Chem. Soc., 2008, 130, 17642–17643.
53 Representative recent reviews: (a) H. Huang, Y. Zhou and H. Liu, Beil-
stein J. Org. Chem., 2011, 7, 897–936; (b) M. Rudolph and
A. S. K. Hashmi, Chem. Commun., 2011, 47, 6536–6544;
(c) Y. Yamamoto, I. D. Gridnev, N. T. Patil and T. Jin, Chem. Commun.,
2009, 5075–5087; . For the gold-catalysed cycloisomerisation of propar-
gyl ketones see: (d) A. S. K. Hashmi, L. Schwarz, J.-H. Choi and
T. M. Frost, Angew. Chem., Int. Ed., 2000, 39, 2285–2288; . See also:
(e) S. Hummel and S. F. Kirsch, Beilstein J. Org. Chem., 2011, 7, 847–
859.
54 (a) Y. Yamamoto, J. Org. Chem., 2007, 72, 7817–7831; (b) Y. Xia,
A. S. Dudnik, V. Gevorgyan and Y. Li, J. Am. Chem. Soc., 2008, 130,
6940–6941; . For a recent theoretical insight into the activity of gold cata-
lysts see: (c) A. S. K. Hashmi, M. Pernpointner and M. M. Hansmann,
Faraday Discuss., 2011, 152, 179–184.
55 For another combination of
a Au/Zn catalyst see: A. S. Demir,
M. Emrullahoğlu and K. Buran, Chem. Commun., 2010, 46, 8032–8034.
56 In addition, the participation of triflic acid (HOTf, which would be deliv-
ered from a metal triflate catalyst) in the catalytic cycle could be con-
sidered. However, reaction with sole triflic acid (10 mol %) led to the
decomposition of the fluoroketone and formation of the multiple products
including regular furan 7a.
57 To diminish formation of the enolate anion that increases partition of the
product in the water phase, 5% NaHCO3 was used instead of saturated
Na2CO3 in an extraction step.
58 Selectfluor has been reported as the mediator for many types of reactions,
for example see: (a) S. Stavber and M. Zupan, Acta Chim. Slov., 2005,
52, 13–26; (b) S. Stavber, Molecules, 2011, 16, 6432–6464. Also, the
ether 6h possesses a skeleton that would be potentially vulnerable to the
aromatic Claisen rearrangement.
37 S. Arimitsu, B. Fernández, C. del Pozo, S. Fustero and G. B. Hammond,
J. Org. Chem., 2008, 73, 2656–2661.
38 (a) A. Sniady, M. S. Morreale and R. Dembinski, Org. Synth., 2007, 84,
199–208; Org. Synth., 2009, Coll. Vol. 11, 794–801; (b) See also ref.
24a, and references therein.
39 A. S. Dudnik, Y. Xia, Y. Li and V. Gevorgyan, J. Am. Chem. Soc., 2010,
132, 7645–7655.
59 W. Xu and Q.-Y. Chen, Org. Biomol. Chem., 2003, 1, 1151–1156.
60 For selected NBS/gold catalytic systems see: (a) F. Mo, J. M. Yan,
D. Qiu, F. Li, Y. Zhang and J. Wang, Angew. Chem., Int. Ed., 2010, 49,
2028–2032; (b) A. Leyva-Pérez, P. Rubio-Marqués, S. S. Al-Deyab, S.
I. Al-Resayes and A. Corma, ACS Catal., 2011, 1, 601–606.
40 (a) V. Gouverneur and B. Greedy, Chem.–Eur. J., 2002, 8, 766–771 and
references therein (b) E. Differding and H. Ofner, Synlett, 1991, 187–
189; (c) G. S. Lal, J. Org. Chem., 1993, 58, 2791–2796; (d) Y. Guo,
G.-H. Tao, A. Blumenfeld and J. M. Shreeve, Organometallics, 2010, 29,
1818–1823.
61 (a) K. L. Billingsley and S. L. Buchwald, Angew. Chem., Int. Ed., 2008,
47, 4695–4698; (b) L. Ackermann and H. K. Potukuchi, Synlett, 2009,
2852–2856; See also: (c) A. N. Cammidge, V. H. M. Goddard, H. Gopee,
N. L. Harrison, D. L. Hughes, C. J. Schubert, B. M. Sutton, G. L. Watts
and A. J. Whitehead, Org. Lett., 2006, 8, 4071–4074.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 2395–2408 | 2407

View Article Online
62 J. Z. Deng, D. V. Paone, A. T. Ginnetti, H. Kurihara, S. D. Dreher,
S. A. Weissman, S. R. Stauffer and C. S. Burgey, Org. Lett., 2009, 11,
345–347.
63 http://www.frontiersci.com/index.php?module/Pages&func/display&pa-
geid/18&cat/Chemistry.
64 S. Fukuzawa, D. Tanihara and S. Kikuchi, Synlett, 2006, 2145–2147.
65 Six peaks exhibiting a splitting pattern of pseudo triplet of doublet were
observed. The estimated values were determined as νA = ½ (δ2+ δ5), JAX
≈ δ2− δ5.
66 One signal is obscured.
2408 | Org. Biomol. Chem., 2012, 10, 2395–2408
This journal is © The Royal Society of Chemistry 2012