Ratiometric fluorescence sensing of fluoride ions by an asymmetric bidentate receptor containing a boronic acid and imidazolium group

Article abstract of DOI:10.1002/ejoc.200900120

The synthesis of the first examples of aoion receptors that utilize boron-fluoride interactions and (C-H)⁺-F～-t:ype ionic hydrogen-bond interactions in. the binding of F ions is reported herein, o-, m-, and p-Phenylboronic acids were linked to

Full text of DOI:10.1002/ejoc.200900120

FULL PAPER
DOI: 10.1002/ejoc.200900120
Ratiometric Fluorescence Sensing of Fluoride Ions by an Asymmetric Bidentate
Receptor Containing a Boronic Acid and Imidazolium Group
Zhaochao Xu,[a] Sook Kyung Kim,[a] Su Jung Han,[a] Chongmok Lee,[a]
Gabriele Kociok-Kohn,[b] Tony D. James,*[c] and Juyoung Yoon*[a,d]
Keywords: Anions / Fluorides / Boron / Heterocycles / Fluorescence
The synthesis of the first examples of anion receptors that
enhanced fluoride binding. The increased binding ability of
the asymmetric bidentate receptor of ortho-boronic acid and
utilize boron–fluoride interactions and (C–H)+···F–-type ionic
hydrogen-bond interactions in the binding of F ions is re- imidazolium towards F– enables it to sense fluoride ions in a
ported herein. o-, m-, and p-Phenylboronic acids were linked
to naphthoimidazolium through a methylene group. On the
basis of fluorescence and 19F NMR studies, we have con-
firmed that the addition of fluoride to a boron center occurs
prior to the formation of (C–H)+···F–-type ionic hydrogen
bond with the imidazolium moiety. More importantly, these
investigations have demonstrated that only the receptor
bearing the ortho-directed boron and imidazolium exhibits
95:5 CH3CN/HEPES aqueous solution. The fluorescence re-
sponses to different anions were also explored; the ortho-bo-
ron-imidazolium receptor displayed ratiometric fluorescence
changes and a high selectivity towards fluoride ions over
other anions (Cl–, Br–, CH3CO2–, HSO4–, and H2PO4–).
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
boron, silicon, tin, and mercury have all emerged.[7] The
fluorescence sensing of fluoride ions using boronic acid was
reported in 1998.[5] Since this first report several other fluo-
rescent systems utilizing the boron–fluoride interaction
have been reported.[6] We developed system A, shown in
Scheme 1, in which the binding of fluoride ions by boronic
acid induced a selective fluorescence enhancement.[6e] More
recently, stable triarylborons with high Lewis acidity were
used as fluoride probes in aqueous or alcohol solvents to
overcome the competitive binding of aqueous protons with
fluoride ions.[8] In particular, diborane receptors have re-
ceived considerable attention because they accept fluoride
more efficiently than monoborane receptors.[9] To increase
the ability of borane-based receptors to capture fluoride
ions from water, Gabbaï et al. developed a series of borane-
containing asymmetric bidentate receptors,[10] for example,
borane with ammonium[11] and borane with phospho-
nium.[12] The ammonium site not only increases the binding
ability with fluoride, but also increases the water-solubil-
ity.[11] Kawachi et al. reported a B/Si bidentate receptor for
fluoride ions.[13] These asymmetric bidentate receptors
could lead to a new design and synthesis of receptors of
fluoride ions that can enhance the binding ability of fluo-
ride ions in aqueous solutions.
Introduction
Anions play a fundamental role in a wide range of chemi-
cal and biological processes, and considerable effort has
been devoted to the development of abiotic receptors for
anionic species.[1] Among them, fluoride is the smallest
anion with a high charge density and a hard Lewis basic
nature, which results in unusual chemical properties. Fluo-
ride ions are biologically important anions because of their
role in, for example, dental care[2] and the treatment of os-
teoporosis.[3] In this regard, the sensing of fluoride ions has
attracted growing attention.[1,4–6]
In a number of cases, hydrogen-bonding between the N–
H of urea, pyrrole, or a naphthalimide group and the fluo-
ride ion is the mechanism of recognition.[4] Electron-de-
ficient Lewis acid coordination by orbital overlap has also
received considerable attention and receptors containing
[a] Department of Chemistry and Nano Science, Ewha Womans
University,
Seoul 120-750, Korea
Fax: +82-3277-3284
E-mail: jyoon@ewha.ac.kr
[b] Bath Chemical Crystallography, University of Bath,
Bath, BA2 7AY, UK
[c] Department of Chemistry, University of Bath,
Bath, BA2 7AY, UK
The imidazolium group has also been actively studied for
the recognition of anions.[14] The imidazolium group can
interact strongly with anions through a (C–H)+···X–-type
ionic hydrogen bond, as shown in system B (Scheme 1).
E-mail: t.d.james@bath.ac.uk
[d] Department of Bioinspired Science, Ewha Womans University,
Seoul 120-750, Korea
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Ratiometric Fluorescence Sensing of Fluoride Ions
Results and Discussion
Synthesis and Characterization
Compounds 1, 2, and 3 were synthesized as the ortho,
meta, and para derivatives, respectively. Compound 4 was
prepared as a reference compound. The synthetic method
for the preparation of compounds 1–4 is summarized in
Scheme 2. 1H-Naphtho[2,3-d]imidazole (5) was synthesized
by following a published procedure.[16] 2,3-Diaminonaph-
thalene was heated at reflux in formic acid for 4.5 h. The
solution was evaporated to dryness and the residue was dis-
solved in boiling water, treated with charcoal, and filtered.
The hot filtrate was treated with conc. ammonia and on
cooling the precipitate was collected. 1-Methyl-1H-naph-
tho[2,3-d]imidazole (6) was synthesized in 91% yield by the
reaction of 1H-naphtho[2,3-d]imidazole (5) with iodome-
thane in THF at 0 °C followed by stirring for 1 h at room
temperature. This intermediate was then treated with o-, m-
,
or p-(bromomethyl)phenylboronic acid and 1-(bro-
momethyl)benzene in acetonitrile at reflux for 24 h. The re-
action mixtures were subsequently treated with a saturated
aqueous KPF6 solution to give the compounds 1–4 in 55–
60% yields. All these compounds were fully identified by
1H and 13C NMR spectroscopy and HRMS.
Scheme 1. Sensing systems A, B, and C.
More attractively, the imidazolium group has also shown
the ability to sense anions in aqueous solution.[15] Encour-
aged by the idea of asymmetric bidentate receptors, we have
synthesized the first receptors bearing boronic acid and an
imidazolium group as fluorescent receptors for the fluoride
Fluoride Recognition Studies in Acetonitrile
Of the probes illustrated in Scheme 2, compound 1 is ex-
ion. In our new system C, the naphthoimidazolium group pected to show the strongest binding with F– due to the
was utilized for anion-binding and also as a fluorescent re- proximity of the boronic acid and imidazolium, increasing
porter. To test the potential of the borane-imidazolium sys- the likelihood that the boronic acid and imidazolium can
tem to bind fluoride ions, o-, m-, and p-phenylboronic acids bind the same fluoride ion. Compounds 2 and 3 are antici-
were selected instead of triarylboron and linked to the pated, in comparison with 1, to provide a favorable geome-
naphthoimidazolium through a methylene group for an try of the boronic acid and imidazolium to bind F– ions.
easy synthesis. The results are presented herein.
The control compound 4 can clearly be used to test the
Scheme 2. Synthesis of compounds 1–4.
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rationality of our design, that is, that a bidentate receptor of
boronic acid and imidazolium improves the binding ability
towards F– compared with a single binding site.
The emission spectroscopy and fluorescence titration ex-
periments with F– were performed in acetonitrile solution
(Figure 1). The emission spectrum of free 1 displays a broad
band with a maximum at 440 nm. When F– was added pro-
gressively to a solution of 1, a significant decrease in the
440 nm emission was observed with the appearance of a
blue-shifted emission band centered at 372 nm, which was
attributed to the formation of a 1–F– complex and in-
creased in intensity, and a clear isoemission point at
406 nm. Thus, 1 is a ratiometric fluorescent probe for F–,
which means that changes in the ratio of the intensities of
the emission at two wavelengths are observed. Ratiometric
fluorescent probes permit signal-rationing and thus they in-
crease the dynamic range and provide built-in correction
for monitoring environmental effects.[17] Figure 2a shows
the dependence of the ratio of the emission intensities at
372 and 440 nm (I372/I440) on the concentration of F–,
which correlates directly with the amount of F–. The ad-
dition of F– to a solution of 1 causes a blue-shift of the
emission from 440 to 372 nm, which leads to a significant
color change. This color change allows 1–F– to be readily
distinguished by the naked eye (Figure 2b), and probe 1
thus combines the sensitivity of fluorescence with the con-
venience and aesthetic appeal of a colorimetric assay.[17a]
With the addition of F–, compounds 2 and 3 showed
only slight changes in emission even with more than
130 equiv. of F–. Compound 4 displayed a similar fluores-
cent response, but needs larger amounts of F– than 1. As
shown in Figure 2 (a), for compound 1, the addition of
7 equiv. of F– saturates the fluorescent changes. On the
other hand, a larger amount of F– (Ͼ11 equiv.) is needed
in the case of 4 for saturation, notably with a weaker blue-
shifted fluorescence intensity. Because the communicating
source of the fluorescence is the naphthoimidazolium
group, the blue-shifted emission should result from the in-
teraction between naphthoimidazolium and the fluoride
ion. Naphthoimidazolium is a donor–acceptor system and
undergoes internal charge transfer (ICT) from naphthalene
to imidazolium upon excitation by light, with imidazolium
playing the role of acceptor.[18] When F– interacts with
imidazolium, the electron-withdrawing ability of imid-
azolium would be reduced and an anion-induced blue-shift
in emission would be expected. Thus, we can conclude that
1 displays a stronger (C–H)+···F–-type ionic hydrogen bond
than the other three compounds 2–4.
Two questions arise regarding these systems. First, be-
tween the boron–fluoride interaction and the (C–H)+···F–-
type ionic hydrogen bond, which interaction occurs first?
Secondly, does the ortho derivative 1 display enhanced bind-
ing with the fluoride ion compared with compounds 2 and
3?
To answer these questions, a study by 19F NMR spec-
troscopy in CD3CN was performed at –10 °C. Figure 3
shows the 19F NMR spectra of phenylboronic acid, 4, and
1 upon the addition of F–. James and co-workers have pre-
Figure 1. Fluorescent emission spectra for compounds 1–4 in the
presence of different concentrations of F– (0–130 equiv.; at intervals
of 0.5 equiv.) in CH3CN. a) 1; b) 2; c) 3; d) 4. The excitation wave-
length was 323 nm. The concentrations of 1–4 were all 10 µ.
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Ratiometric Fluorescence Sensing of Fluoride Ions
Figure 2. a) Ratiometric calibration curve for I372/I440 as a function
of F– concentration. [1] = [2] = [3] = [4] = 10 µ. b) Emission
observed from a solution of 1 and 1–F–.
viously reported the 19F NMR spectroscopic data of phen-
ylboronic acid in 33% methanol/D2O (v/v) at 0 °C upon
the addition of fluoride ions.[5] The experimental curves in
Figure 2 (a) and the NMR spectroscopic data in Figure 3
(c) assume the formation of the trifluoroboronate of 1 with
fluoride (Scheme 3). As shown in Figure 3 (a), the peaks at
–138.5 and –115.9 ppm, appeared upon the addition of F–
–
and correspond to –B(OH)F2 and free F–, which was con-
firmed by James and co-workers. It is notable that, even
with excess fluoride ions, –B(OH)F2– is the most stable spe-
cies of phenylboronic acid in CH3CN upon the addition of
fluoride ions. In Figure 3 (b), the peaks for (C–H)+···F– (or
F2H) and free F– can be observed at –150.9 and
–115.4 ppm, respectively. With these references, it is easy to
explain the 19F NMR spectra of 1 shown in Figure 3 (c).
The peak at –134.5 ppm was observed first with 1 equiv. of
–
F–, corresponding to –B(OH)F2 . Very importantly, upon
the addition of Ն2 equiv. of F–, a peak at –144.4 ppm,
–
which corresponds to –BF3 , began to appear at the ex-
pense of the –B(OH)F2– peak, which disappeared after add-
ing 3 equiv. of F–. The peak at –118.1 ppm corresponds to
the free fluoride peak. As shown in Figure 2 (a), the ad-
dition of Ն2 equiv. of F– induced the blue-shifted fluores-
cence of 1. This means that there is a (C–H)+···F–-type ionic
hydrogen-bond interaction between imidazolium and
Figure 3. 19F NMR spectra of solutions of fluoride ion in CD3CN
with a) phenylboronic acid, b) compound 4, and c) compound 1.
–
–BF3 . This suggests that the boron binds to F– first, and
then the binding is strengthened with the cooperation of
naphthoimidazolium. We may ascribe the nonexistence of
the (C–H)+···F– interaction between imidazolium and
–B(OH)F2– to hydrogen-bonding between imidazolium and
B–OH, which may prevent B–F from accessing the imid-
azolium.
To gain further proof for the above conclusion, the 19F
NMR spectra of 2 and 3 were also recorded upon the ad-
dition of F–. Unfortunately, the solutions of 2–PF6 and 3–
PF6 emulsified upon addition of F–. Therefore, we studied
2–Br and 3–Br by 19F NMR spectroscopy. Figure 4 shows
the 19F NMR spectra of 3 upon the addition of F–. The
meta adduct 2–Br displayed similar 19F NMR spectra to
those of the para adduct 3–Br. The peak at –133.9 ppm was
observed first with 2 equiv. of F–, which corresponds to
–
–B(OH)F2 , as confirmed by analogy with the spectra of Scheme 3. The binding of 1 to fluoride ions.
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phenylboronic acid (Figure 3, a). Upon the addition of pearance of ipc was not observed with the para adduct 3
Ն3 equiv. of F–, peaks at –143.9 and –144.1 ppm began to upon addition of 3 equiv. of F– and 17% of the reduction
–
appear, which correspond to –BF3 . The peak at current still remained even upon the addition of 5 equiv. of
–106.5 ppm corresponds to the free fluoride ion. Notably, F–. These results also support unequivocally the proposal
–
with this amount of F–, the peak arising from –B(OH)F2
that fluoride-binding can be enhanced with the ortho-di-
–
still exists alongside the peaks of –BF3 , which are quite rected boron.
weak. That means compound 3 has a much weaker ability
to bind three fluoride ions than compound 1. Thus, we can
Table 1. Relative change of cathodic peak current (ipc) at –1.6 V vs.
SCE for 1 and 3 upon the addition of F–.[a]
be clear why the addition of the fluoride ions does not cause
a blue-shift of the fluorescence of 2 and 3. These results also
suggest that F– adds to the boron prior to the formation of
the hydrogen bond with the imidazolium moiety, and more
importantly the presence of boronic acid at the meta or para
position does not increase the strength of F–-binding. Based
on the variation of the fluorescence, the binding constants
K3 for 1–3 and K for 4 with F– were estimated to be 5.1
(Ϯ 0.2)ϫ105, 6.7 (Ϯ 0.2)ϫ103, 5.7 (Ϯ 0.2)ϫ103, and 1.1
(Ϯ 0.2)ϫ104 –1, respectively.[19] Based on Figures 1, 3, and
the binding constants, we can say that the adjacent boronic
acid (ortho) facilitates the interaction of the fluoride ion
with imidazolium, whereas the more distant boronic acids
(meta and para) inhibit the F–-binding process with imid-
azolium. This is reasonable because boronic acid and naph-
thoimidazolium are competitors for binding F–. They bind
F– cooperatively under favorable circumstances, but also
they can be mutually exclusive of F–-binding under unfa-
vorable situations.
F– [equiv.]
1
3
0
1
2
3
5
1.00
0.94
0.41
0.00
0.00
1.00
1.00
0.94
0.78
0.17
[a] Cathodic peak potential (Epc) was –1.63 and –1.50 V vs. S.C.E.
for 1 and 3, respectively.
Two crystal structures related to 3–Br were obtained, as
shown in Figure 5; the OH groups were replaced with
OCH3 as the crystals were grown in methanol. Figure 5 (a)
represents a compound (3-OMe) in which one of the OH
groups has been replaced with OCH3 and the other forms
Figure 4. 19F NMR spectra of 3–Br with fluoride ion in CD3CN.
a) 1 equiv. of F–; b) 2 equiv. of F–; c) 3 equiv. of F–; d) 5 equiv. of
F–.
Cyclic voltammetry (CV) experiments were also per-
formed (Table 1 and Figure 1 of the Supporting Infor-
mation). The cathodic peak current (ipc) for the ortho ad-
duct 1 decreased to less than half (–1.63 V vs. SCE) upon
addition of 2 equiv. of F–, which can be attributed to the
interaction of the fluoride ion with the imidazolium group.
With 3 equiv. of F–, 1 did not show any significant re-
Figure 5. X-ray crystal structures of a) 3-OMe and b) 3-2OMe-F–
duction current. On the other hand, such a virtual disap- and unit cells of c) 3-OMe and d) 3-2OMe-F–.
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Ratiometric Fluorescence Sensing of Fluoride Ions
a hydrogen bond with Br–. In the unit cell, imidazolium (C–
H)+ forms a hydrogen bond with methanol, methanol then
interacts with Br–, and Br– interacts with –B(OH) (Figure 5,
c). On the other hand, Figure 5 (b) represents a structure
(3-2OMe-F) in which the boron bears two OCH3 groups
and a fluoride. The unit cell displays π-stacking between
the naphthoimidazolium moieties (Figure 5, d).
The fluorescence titration of 1 against various anions
was conducted to examine its selectivity. The addition of
–
–
–
Cl–, Br–, CH3CO2 , HSO4 , and H2PO4 produced only a
nominal change in the fluorescence spectra of 1 due to their
low affinity with probe 1. Figure 6 shows the dependence
of the intensity ratios (I372/I440) on the anions. The results
show that probe 1 has a high selectivity for F–.
Figure 6. The responses of 1 to various anions in fluorescence ti-
tration.
Studies of Fluoride Recognition in Aqueous Solution
Probe 1 is a bidentate receptor containing a boronic acid
and naphthoimidazolium that exhibits enhanced fluoride-
binding. The increased ability of the boronic-based receptor
to bind F– may enable 1 to capture fluoride ions from aque-
ous solution.
To explore the F–-binding ability of 1 in aqueous solu-
tion, the fluorescence responses of 1 in the presence of F–
were examined in different ratios of acetonitrile/water. In
1–5% water, 1 exhibits a blue-shifted emission centered at
372 nm due to binding with F–. Figure 7 displays the fluo-
rescence responses of 1–4 to F– in CH3CN/HEPES (95:5)
solution. With the addition of F–, the emission of 1 at
440 nm first increases and then displays the same response
as that in 100% acetonitrile. The other three compounds
showed only slight fluorescence changes on addition of F–
because of their weak ability to bind F– in aqueous solu-
tion. As the percentage of water increased (Ͼ5%), 1 can no
longer capture fluoride ions and nominal changes in the
fluorescence were observed. In aqueous solution, it may be
difficult for the methylene-bridged imidazolium and bo-
ronic acid to bind the same fluoride ion, because of the
Figure 7. Fluorescent emission spectra of compounds 1–4 in the
presence of different concentrations of F– (0–100 equiv., rising in
steps of 10 equiv.) in CH3CN/HEPES (95:5, 0.5 , pH 7.4). a) 1;
b) 2; c) 3; d) 4. The excitation wavelength was 323 nm. The concen-
trations of 1–4 were all 10 µ.
Conclusions
We have reported the synthesis of novel fluoride recep-
flexibility of 1. A rigid geometry of boron and the adjacent tors bearing two distinct recognizing groups, boronic acid
imidazolium can be expected to bind the same fluoride ion and an imidazolium moiety. The ortho compound 1 dis-
in aqueous solution. Related studies are in progress.
played a selective and ratiometric fluorescence change on
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addition of fluoride ions. Based on the fluorescence and 19
F
Synthesis of 2: By following the same procedure as that used for 1,
combining 6 (100 mg, 0.55 mmol) and 3-(bromomethyl)phenylbo-
ronic acid (180 mg, 0.81 mmol) produced 2 (152 mg, 60% yield) as
a white solid. 1H NMR (DMSO, 250 MHz): δ = 4.23 (s, 3 H), 5.88
(s, 2 H), 7.45 (m, 1 H), 7.70 (m, 3 H), 7.83 (d, J = 7.4 Hz, 1 H),
7.96 (s, 1 H), 8.20 (m, 4 H), 8.60 (s, 1 H), 8.69 (s, 1 H), 10.09 (s, 1
H) ppm. 13C NMR (DMSO, 62.5 MHz): δ = 33.46, 50.0, 110.94,
111.09, 126.63, 128.01, 128.20, 129.93, 130.82, 131.15, 132.85,
133.78, 134.30, 146.90 ppm. HRMS (FAB): calcd. for
C19H18BN2O2 [M – PF6]+ 317.1461; found 317.1462.
NMR studies, we confirmed that the addition of fluoride
to the boron center occurs prior to the formation of the
(C–H)+···F–-type ionic hydrogen bond with the imid-
azolium moiety. More importantly, these investigations have
demonstrated that only the receptor bearing the ortho-di-
rected boron and imidazolium exhibits enhanced fluoride
binding. This increased ability of the boronic-based recep-
tor to bind F– allows 1 to be used as a fluoride ion sensor
in aqueous solution.
Synthesis of 3: By following the same procedure as that used for 1,
combining 6 (100 mg, 0.55 mmol) and 4-(bromomethyl)phenylbo-
ronic acid (180 mg, 0.81 mmol) produced 3 (140 mg, 55% yield) as
a white solid. 1H NMR (DMSO, 250 MHz): δ = 4.20 (s, 3 H), 5.87
(s, 2 H), 7.54 (d, J = 8.0 Hz, 2 H), 7.68 (t, J = 4.2 Hz, 2 H), 7.84
(d, J = 8.0 Hz, 2 H), 8.17 (s, 2 H), 8.23 (m, 2 H, B-OH), 8.54 (s, 1
H), 8.66 (s, 1 H), 10.06 (s, 1 H) ppm. 13C NMR (DMSO,
62.5 MHz): δ = 33.95, 50.29, 111.38, 111.60, 127.14, 127.62, 128.70,
130.33, 131.30, 131.65, 135.09, 136.07, 147.48 ppm. HRMS (FAB):
calcd. for C19H18BN2O2 [M – PF6]+ 317.1461; found 317.1466.
Experimental Section
General Procedures and Materials: Unless otherwise noted, materi-
als were obtained from commercial suppliers and were used with-
out further purification. Flash chromatography was carried out on
silica gel 60 (230–400 mesh ASTM; Merck). Thin-layer chromatog-
raphy (TLC) was carried out by using Merck 60 F254 plates with a
thickness of 0.25 mm. Preparative TLC was performed by using
Merck 60 F254 plates with a thickness of 1 mm. Melting points were
measured by using a Büchi 530 melting point apparatus. 1H and
13C NMR spectra were recorded by using Bruker 250 MHz or Var-
ian 500 MHz spectrometers. Chemical shifts are given in ppm and
coupling constants (J) in Hz. UV absorption spectra were obtained
with a UVIKON 933 Double Beam UV/Vis spectrometer. Fluores-
cence emission spectra were obtained with a RF-5301/PC spectro-
fluorophotometer (Shimadzu). Phenylboronic acid was purchased
from Aldrich.
Synthesis of 4: By following the same procedure as that used for
1, combining 6 (100 mg, 0.55 mmol) and benzyl bromide (130 mg,
0.76 mmol) produced 4 (147 mg, 64% yield) as a white solid. 1H
NMR (DMSO, 250 MHz): δ = 4.22 (s, 3 H), 5.90 (s, 2 H), 7.47 (m,
3 H), 7.68 (m, 4 H), 8.21 (m, 2 H), 8.61 (s, 1 H), 8.68 (s, 1 H),
10.18 (s, 1 H) ppm. 13C NMR (DMSO, 62.5 MHz): δ = 32.34,
48.58, 109.76, 109.95, 116.95, 125.44, 127.03, 127.12, 127.49,
127.76, 128.65, 129.63, 129.96, 132.82, 145.79 ppm. HRMS (FAB):
calcd. for C19H17N2 [M – PF6]+ 273.1392; found 273.1388.
Supporting Information (see also the footnote on the first page of
1
this article): H and 13C NMR, and CV data.
Synthesis of 6: NaH (330 mg, 8.3 mmol, 60% in mineral oil) was
added to a mixture of 5[16] (690 mg, 4.1 mmol) in THF (20 mL) at
0 °C. After the reaction mixture had been stirred for 20 min at 0 °C,
iodomethane (960 mg, 6.3 mmol) was added. After additional stir-
ring for 1 h at room temperature, water (50 mL) was added to the
reaction mixture and the mixture extracted with CHCl3. The or-
ganic layer was then separated, dried with anhydrous magnesium
sulfate, and concentrated under reduced pressure. Purification by
flash chromatography on silica gel (CH2Cl2/MeOH = 100:1) af-
forded 6 (680 mg, 91%) as a pale-yellow solid; m.p. 152–154 °C.
1H NMR (CDCl3, 250 MHz): δ = 3.52 (s, 3 H), 7.28 (m, 2 H), 7.47
(s, 1 H), 7.76 (m, 2 H), 7.86 (m, 1 H), 8.15 (s, 1 H) ppm. 13C NMR
(CDCl3, 62.5 MHz): δ = 30.92, 105.13, 117.09, 123.49, 124.43,
127.48, 128.52, 129.97, 130.44, 135.07, 143.78, 147.51 ppm. HRMS
(FAB): calcd. for C12H11N2 [MH]+ 183.0922; found 183.0925.
Acknowledgments
This work was supported by Korea Science and Engineering Foun-
dation (KOSEF) National Research Lab (NRL), funded by the Ko-
rean Government (MOST) (Grant R04-2007-000-2007-0), the Ko-
rea Research Foundation (KRF) (Grant KRF-2004-005-C00093)
and the World Class University (WCU) (R31-2008-000-10010-0)
program. S. K. K. thanks the Korea Research Foundation (KRF)
(2007-000-C00054) and the Brain Korea 21 (BK21). We also
acknowledge a Royal Society International Joint Project (IJP) for
funding exchanges between the UK and Korea.
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Synthesis of 1: A mixture of 6 (100 mg, 0.55 mmol) and 2-(bro-
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(10 mL) was heated at reflux for 24 h under N2. After cooling to
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Received: February 4, 2009
Published Online: April 30, 2009
Eur. J. Org. Chem. 2009, 3058–3065
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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