Synthesis and characterization of 5-substituted 8-hydroxyquinoline derivatives and their metal complexes

Article abstract of DOI:10.1016/j.tet.2008.09.081

5-Aminomethyl-8-hydroxyquinoline (QN) was synthesized as a scaffold to generate dimers, trimers, and tetramer metalloquinolates. Starting from QN, a series of 5-substituted 8-hydroxyquinoline derivatives conjugated with small bioactive molecules were synthesized. Absorption and emission spectra indicate that these QN derivatives chelate well with metal ions, which may serve as a new platform to explore the applications of metalloquinolates for a variety of potential applications.

Full text of DOI:10.1016/j.tet.2008.09.081

Tetrahedron 64 (2008) 10986–10995
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and characterization of 5-substituted 8-hydroxyquinoline derivatives
and their metal complexes
,b,
Lihua Li, Bing Xu a
*
a Department of Chemistry, The Hong Kong University of Science & Technology, Clear Water Bay, Hong Kong, China
b Department of Chemistry, Brandeis University, Waltham, MA 02454, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 May 2008
Received in revised form 9 September 2008
Accepted 25 September 2008
Available online 8 October 2008
5-Aminomethyl-8-hydroxyquinoline (QN) was synthesized as a scaffold to generate dimers, trimers, and
tetramer metalloquinolates. Starting from QN, a series of 5-substituted 8-hydroxyquinoline derivatives
conjugated with small bioactive molecules were synthesized. Absorption and emission spectra indicate
that these QN derivatives chelate well with metal ions, which may serve as a new platform to explore the
applications of metalloquinolates for a variety of potential applications.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
8-Hydroxyquinoline
Metalloquinolate
Absorption
Emission
1. Introduction
and might serve as potential drug candidates for treating Parkin-
son’s disease.
8-Hydroxyquinoline, a monoprotic bidentate chelating agent,
has received increased attention recently because its most repre-
sentative metalloquinolate, aluminum tris(8-hydroxyquinoline)
(AlQ3), has served as the emitting material in organic light emitting
diodes (OLEDs).1 Due to their high thermal stability, excellent
electron-transport properties, and unique luminescent proper-
ties,2,3 many derivatives of 8-hydroxyquinoline (for example,
substituted at 2, 5, or 7 position, or coordinated with different
metal ions) have also attracted considerable interest. The impor-
tance of metalloquinolates in analytical chemistry is also well
known.4 In addition, a large number of 8-hydroxyquinoline de-
rivatives have been synthesized and shown to be bioactive. For
example, it was reported that some 8-hydroxyquinoline derivatives
possess antitumor and antimicrobial activities.5 Shen and co-
workers designed and synthesized 7-morpholinomethyl-8-hydro-
xyquinoline, which inhibited the DNA synthesis in HepG2 cells at
micromolar concentrations. Keppler and co-workers investigated
the effect of gallium tris(8-hydroxyquinoline) (GaQ3) on the via-
bility of A549 human malignant lung adenocarcinoma cells and
found that the half-maximal inhibitory concentration (IC50) value
In order to further explore the biological applications of the
metalloquinolates, which combine metal coordination, receptor/
ligand interactions, and luminescent properties, we designed and
synthesized a series of novel 8-hydroxyquinoline derivatives with
substitution at the 5-position (Scheme 1) and examined their
spectral properties and chelating abilities with different metal ions.
We synthesized 5-aminomethyl-8-hydroxyquinoline (QN, 1) as
the scaffold to generate dimers, trimers, and tetramer metal-
loquinolates (2–4). Starting from QN (1), we also synthesized (9H-
fluoren-9-yl)methyl(8-hydroxyquinolin-5-yl)
methylcarbamate
(QFmoc, 5) and (S)-2-[(S)-2-amino-3-phenylpropanamido]-N-((8-
hydroxyquinolin-5-yl)methyl)-3-phenylpropanamide (QFF, 9) and
studied their chelating properties with bivalent and trivalent metal
ions (7,10,11) because they might self-assemble to form fluorescent
hydrogels.6 In addition, we synthesized QN derivatives conjugated
with small bioactive molecules (6, 8,12–17). Absorption and emission
spectra indicate that these QN derivatives maintain good abilities
to chelate metal ions, which may serve as a new platform to explore
the applications of metalloquinolates for various applications.
of GaQ3 was 2.5 mM. Recently, Fridkin and co-workers synthesized
a series of novel iron chelators that contain the 8-hydroxyquinoline
moiety, and these chelators exhibited high antioxidant properties
2. Results and discussion
2.1. Synthesis
Scheme 2 shows the synthesis of 5-aminomethyl-8-hydroxy-
quinoline (QN,1). Derivatization on the 5-position of 8-hydroxyquinoline
* Corresponding author. Tel.: þ1 781 736 5201; fax: þ1 781 736 2516.
E-mail address: bxu@brandeis.edu (B. Xu).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.081

L. Li, B. Xu / Tetrahedron 64 (2008) 10986–10995
10987
NH2
NH2
NH2
NH2
N
N
N
O
N
O
B
H2N
O
O
O
O
N
Li
O
N
M
NH2
M
O
N
N
H2N
N
N
OH
O
1
H2N
H2N
NH2
a
b
c
a
b
c
M Zn Ag Pt
2
M Al In Fe
3
4
H
N
H
O
HN
S
H
H
N
O
O
O
HN
HN
O
O
N
OH
O
5
O
M
N
N
O
N
N
O
M
NH
O
NH
NH
O
O
O
HN
H
O
N
O
H
N
H
N
H
N
S
O
S
O
O
H
O
H
HN
O
H
NH
N
H
N
NH
H
S
a
b
a
b
H
N
M Al In
M Al In
O
OH
6
7
8
NH2
NH
NH2
NH
O
H
O
N
H
N
O
NH2
NH
O
N
O
O
N
O
H
Cu
O
N
N
O
N
In
O
O
N
O
HN
O
O
HN
H2N
N
O
N
H
O
OH
9
HN
H2N
NH
O
N
H
OH
10
11
NH2
O
N
N
N
N
H
HN
NH2
N
O
NH2
H
OH
OH
HO
N
OH
H
N
O
HN
O
O
O
N
N
N
N
OH
OH
OH
12
14
16
O
OH
O
OH
OH
OH
O
O P OH
O
H
H
N
H
N
OH
P
N
OH
OH
N
H
N
H
N
H
OH
O
O
O
O
N
N
OH
OH
OH
13
15
17
Scheme 1. The structures of the 8-hydroxyquinoline derivatives and their metal chelate complexes.

10988
L. Li, B. Xu / Tetrahedron 64 (2008) 10986–10995
was based on the method proposed by Buckhalter and Leib.7 Sev-
eral papers suggested that the preparation of the free base 19 from
its hydrochloride salt could be carried out by treating the hydro-
chloride salt with sodium hydrogen carbonate (NaHCO3).8 How-
ever, 19 was unstable and readily underwent hydrolysis to form 18,
especially in basic conditions.7 Hence, 18 was prepared as a pre-
cursor for long time storage and converted to 19 by simply reacting
with thionyl chloride before the amination reaction. The conversion
of the chloromethylation product 19 to the aminomethylation
product 1 followed the procedure of amination of benzyl halides by
using hexamine as the amination reagent.9 The reaction of 19 was
carried out at room temperature because it would be converted to
5,50-methylene bis-8-hydroxyquinoline if it was heated under
reflux.7 In the final hydrolysis process, before adjusting the pH
value, large amount of HCl was still present in the solution.
Therefore, when ammonia was added, the heat generated by acid–
base neutralization would cause side reactions. In order to resolve
this problem, methanol was used to wash the hydrolysis product
before adjusting its pH to get the target product, 1.
deprotecting the ethyl groups from the condensation product (21).
All these compounds were purified using reversed-phase HPLC.
Scheme 5 shows the general synthetic route of the coupling of
QN (1) with small bioactive molecules by reacting with the
N-hydroxysuccinimide (NHS) activated esters of the corresponding
carboxylic acids. Compound 17 (QN–Su-Dopa, the conjugate of QN
with the succinic acid derivative of dopamine) was obtained after
deprotecting the benzyl groups from the condensation product 23.
Compound 24 was obtained after deprotecting the Fmoc group
from the condensation product 22. Deprotecting the Boc group
from 24 afforded compound 14 (QG, the conjugate of QN with
glutamate). Reacting 24 with the carboxylic acid analogue of do-
pamine then deprotecting the Boc group yielded QG-Dopa (15). All
of the compounds were purified using reversed-phase HPLC.
The target compounds were characterized by 1H NMR spec-
troscopy, mass spectrometry (MS), UV–vis spectroscopy, and fluo-
rescence spectroscopy. After the conjugates formed, the amino
group of QN (1) was converted to the amide bond, as a result, the
chemical shift of the protons on the methylene group of 1
(d
¼4.1 ppm) moved to down field ( ¼4.6–4.7 ppm), which was
d
a characteristic property in their 1H NMR spectra.
OH
Cl
2.2. Formation of metalloquinolates and their spectral
properties
.
HCHO
HCl (g)
NH3 H2O
SOCl2
N
N
N
By modifying the typical procedures,10,11 we used UV–vis and
fluorescence spectra to examine the formation of the metal-
loquinolates. The photophysical properties of 8-hydroxyquinoline
derivatives have been extensively studied.12 Their absorption
spectra share a common feature: a very intense band lies around
OH
OH
OH
18
(87 %)
19
N
the 250 nm region, which is attributed to a
p–
*
p transition, while
N
N
N
NH2
a less intense and broader band lies at lower energy (above
300 nm). After metal coordination, the peaks usually show red-
shift. The fluorescence properties of metalloquinolates also have
long been known.13 In their fluorescence spectra, hydroxyquinoline
derivatives exhibit a fluorescence band in the 360–520 nm region.
Figure 1 shows the absorption spectra of QN (1) and M(QN)s (2a,
3a–c) obtained in methanol. After 1 chelated with metal ions, the
higher energy transition bands of QN (1) red-shifted from 245 nm
to 259 nm; the lower energy bands red-shifted to a longer wave-
length from the 325 nm of 1. Such red-shifts are characteristic for
metalloquinolates,10,11,14,15 which are 390, 380, 386 nm for Zn(QN)2
(2a),10 Al(QN)3 (3a),10,14,15 and In(QN)3 (3b),10,14 respectively. For
Fe(QN)3 (3c), three bands appear at 375, 460, and 590 nm, which
are characteristic for iron quinolate.15
Figure 2 shows the fluorescent spectra of QN (1), Zn(QN)2 (2a),
Al(QN)3 (3a), and In(QN)3 (3b) in methanol at the similar concen-
tration based on [QN]. The typical shifts of the emission peaks of
metalloquinolates10,13,16 were observed. As the covalent nature of
the metal–ligand bonds increases, the emission shifts to longer
wavelength relative to the emission of QN (1) at 435 nm. As a result,
Al(QN)3 (3a) emits at 511 nm, In(QN)3 (3b) at 542 nm, and Zn(QN)2
(2a) at 558 nm (2a). Although the concentrations of these com-
pounds are similarly based on [QN], metalloquinolates exhibit
obviously enhancement of the fluorescent intensity comparing
.
NH3 H2O
(CH2)6N4
DMSO
HCl (6 M)
N
N
OH
OH
1
(70 %)
Scheme 2. The synthesis of 5-aminomethyl-8-hydroxyquinoline (QN, 1).
As shown in Scheme 3, QN (1) reacted with (9H-fluoren-9-yl)-
methyl chloroformate (Fmoc-Cl) in a mixture of dimethylforma-
mide (DMF) and sodium hydrogen carbonate (NaHCO3) aqueous
solution at room temperature to give QFmoc (5) in 64% yield.
Scheme 4 shows the general synthetic route of coupling of QN
(1) with several small bioactive molecules using 2-(1-hydrox-
ybenzotriazol-1-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate
(HBTU) as the coupling reagent. Compounds 6 (QB, the conjugate of
QN with biotin), 12 (QFA, the conjugate of QN with folic acid), and
16 (QN–Dopa, the conjugate of QN with a carboxylic acid analogue
of dopamine) were obtained directly via HBTU mediated conden-
sation reactions. Compound 9 (QFF, the conjugate of QN with
L
-Phe–L-Phe) was obtained after deprotecting the Fmoc group from
the condensation product (20). Compound 13 (QN–bisP, the con-
jugate of QN with a bisphosphonate derivative) was obtained after
H
N
O
NH2
O
NaHCO3 aq., DMF
+
Cl
O
N
N
5
O
OH
OH
(64 %)
Scheme 3. The synthesis of (9H-fluoren-9-yl)methyl(8-hydroxyquinolin-5-yl) methylcarbamate (QFmoc, 5).
1

L. Li, B. Xu / Tetrahedron 64 (2008) 10986–10995
10989
H
N
R
HBTU, DIEA
DMSO, DMF
+
1
R
OH
N
OH
O
O
OH
O
N
N
NH
H
HN
H
N
H
N
12
6
HN
R =
(66 %)
(59 %)
N
NH2
S
HO
O
O
O
OH
OH
16
(41 %)
H
N
O
OEt
O P OEt
OEt
O
20
O
O
NH
21
N
H
P
OEt
(49 %)
O
O
O
Piperidine
1) TMSB 2) H2O
CHCl3
Acetone
OH
9
O P OH
OH
NH
NH
O
(57 %)
13
N
P
O
H
OH
(73 %)
O
O
O
Scheme 4. The general synthetic route of coupling of QN (1) with small bioactive molecules using HBTU as the coupling reagent.
with that of the monomer 1, and the complexes of trivalent metal
ions (3a and 3b) show higher enhancement than that of divalent
metal ions (2a). As the same group of metal ions, fluorescence in-
tensity decreases with the increase of atomic number. For example,
the emission of Al(QN)3 (3a) has higher intensity than that of
In(QN)3 (3b). Figure 3 shows the fluorescent spectra of QN (1) at
different Al3þ concentrations. A significant enhancement of the
fluorescence is observed with the increase of the Al3þ
concentrations.
Besides using Zn, Al, In, and Fe as the metal centers to generate
metalloquinolates, we also studied other metal ions, such as Ag and
Pt. Silver/platinum-containing antibiotics were widely studied for
decades.17 The self-assembly of a silver(I) polymer based on de-
rivatives of 8-hydroxyquinoline18 and an organogelator con-
structed using an 8-hydroxyquinoline/platinum(II) chelate3,19 have
been reported recently. In order to explore the self-assembly of
8-hydroxyquinoline derivatives in water for generating novel an-
tibiotics, we designed silver–QN and platinum–QN templates. It is
known that the peaks of metalloquinolates at lower energy
(above 300 nm) usually show red-shifts after metal co-
ordination.10,11,14,15,20 Based on this property, the synthesis can be
monitored using UV–vis absorption spectra.
(4), in which only oxygen atoms of QN coordinated to the central
boron atom. The emission peak of 4 (451 nm) is about 60 nm blue
shifted comparing with that of Al(QN)3 (3a) (511 nm) (Fig. 6), as the
similar trend as the results reported by Tao.21 However, 4 is un-
stable in water. As shown in Figure 7, after treating 4 with water, the
absorption peak of 4 was just the same as that of QN (1), indicating
a decomposition of 4 to its precursor 1 in water.
In our research on the small molecule hydrogels, we have suc-
cessfully demonstrated hydrogelators based on Fmoc,22 Nap,23 and
Phe–Phe.24 In order to explore the hydrogelation generated via the
interactions of metalloquinolates for searching potential hydro-
gelator moieties, we synthesized QFmoc (5) and QFF (9), and
studied their chelating properties with bivalent and trivalent metal
ions. Figure 8 shows the fluorescent spectra of QN (1), QFmoc (5),
and Al(QFmoc)3 (7a). Compound 5, the Fmoc derivative of 1, ex-
hibits the same emission peak (434 nm) as 1 (435 nm), and the
typical shift of the emission peaks of metalloquinolates10,13,16 also
shows on the aluminum chelate complex 7a (538 nm). Figures 9
and 10 show the UV–vis spectra of the chelating process of Cu(II)
and In(III) with QFF (9). The characteristic absorption peaks com-
pletely red-shifted from the 321 nm of 9 to 400 and 390 nm for
Cu(QFF)2 (10) and In(QFF)3 (11), respectively, after 2 h, indicating
a fast and complete conversion.
Using silver acetate as the source of silver, Ag(QN)2 (2b) was
produced in DMF. UV–vis spectra of the reaction process indicated
a high conversion of QN (1) to 2b, which was stable in basic con-
dition (Fig. 4). According to the reported procedure,3 synthesis of
Pt(QN)2 (2c) was carried out in a basic solution containing K2PtCl4.
UV–vis spectra indicated a modest conversion (Fig. 5).
Unfortunately, both 5 and 9 could not form hydrogels before or
after chelating with the metal ions (Cu2þ and In3þ). The possible
reasons could be: (i) the 8-hydroxyquinoline platform contains
a nitrogen and a hydroxyl moiety on the 8-hydroxyquinoline ring
that might disfavor efficient
p–p interactions between the rings;
Besides generating the dimers and trimers, we also synthesized
a tetramer of QN. According to a reported tetramerization of
8-hydroxyquinoline derivative constructed with boron, which was
a blue electroluminescence material,21 we synthesized LiB(QN)4
(ii) in the complexes of trivalent metal ions, the three 8-hydroxy-
quinoline rings around the central metal result in nonplanar
arrangment,25 which disfavors the packing of the QN to form
nanofibers; (iii) in the complexes of divalent metal ions, their

10990
L. Li, B. Xu / Tetrahedron 64 (2008) 10986–10995
H
N
O
R'
DIEA, DMF
+
1
R' O N
N
O
OH
O
O
O
O
O
O
O
23
22
R' =
N
NH
H
(73 %)
O
O
H2, Pd/C
DMSO
Diethylamine
DMF
OH
OH
O
O
O
24
(56 %)
17
(86 %)
O
N
H
O
NH2
OH
1)
TFA
O
HO
OH
O
NH2
HBTU, DIEA, DMSO
OH
2) TFA
O
O
14
(82 %)
O
OH
OH
15
HN
(34 %)
OH
O
Scheme 5. The general synthetic route of coupling of QN (1) with small bioactive molecules by reacting with the NHS activated esters of corresponding carboxylic acids.
square-planar chelate structures would favor gel formation. How-
ever, the 8-hydroxyquinoline moiety might be too hydrophilic to
form a hydrogel.
In order to explore the potential applications of 8-hydroxy-
quinoline systems, we also synthesized QN derivatives conjugated
with small bioactive molecules, such as biotin,26 folic acid,27
bisphosphonates,28 and glutamate.29 Spectral properties of those
conjugates were studied as the preliminary information for further
exploration. Figure 11 shows the fluorescent spectra of these QN
derivatives. These conjugates exhibit similar emission peaks as QN
(435 nm). QB (6) emits peak at 430 nm, QFA (12) at 455 nm, QN–bisP
(13) at 446 nm, and QG (14) at 441 nm. The fluorescent spectrum of
Al(QB)3 (8a) (Fig.12) and the UV–vis spectra of the chelating process
Figure 2. The fluorescent spectra (lex¼325 nm) of QN (1), Zn(QN)2 (2a), Al(QN)3 (3a),
and In(QN)3 (3b) in methanol at room temperature and at the concentration (based on
QN) of 1.149, 1.161, 0.928, and 1.079 mM for 1, 2a, 3a, and 3b, respectively.
Figure 1. The absorption spectra of QN (1) and M(QN)s (2a, 3a–b) in methanol at room
temperature.

L. Li, B. Xu / Tetrahedron 64 (2008) 10986–10995
10991
Figure 5. The absorption spectra for monitoring the synthesis of Pt(QN)2 (2c). (a)
Before adding K2PtCl4; (b) 5 h after adding K2PtCl4, rt; (c) 22 h, 80 ꢀC; (d) 24 h, 80 ꢀC.
Figure 3. The fluorescent spectra (lex¼350 nm) of QN (1) in ethanol (0.200
mM) at
room temperature upon addition of increasing amounts of Al3þ ions. The ratio of Al3þ
to QN (1) is (a) 0, (b) 0.03, (c) 0.04, (d) 0.08, (e) 0.17, and (f) 0.33.
(RP-HPLC) was carried out with Waters 600 Controller and 996
of In(QB)3 (8b) (Fig.13) exhibit the typical shift of the emission10,13,16
photodiode Array Detector, using XTerra RP18 C18 7 mm columns
and absorption10,11,14,15,20 peaks of metalloquinolates.
for both analytical and preparative purposes. HPLC elution
employed linear gradients of [0.1% trifluoroacetic acid (TFA) in
water] and [0.1% TFA in acetonitrile]. 1H NMR and 31P NMR spectra
were obtained on a 300 MHz Bruker ARX 300 in DMSO-d6 or D2O.
Mass spectra were obtained on a Finnigan TSQ7000 System. UV–vis
spectra were obtained on a Varian Cary 50 Scan UV–Visible spec-
trophotometer. Fluorescent spectra were taken on a Perkin–Elmer
LS-55 luminance spectrometer. Transmission electron micrograph
(TEM) was done on a JEOL 2010 transmission electron microscope,
operating at 200 kV.
3. Conclusion
In summary, starting from 5-aminomethyl-8-hydroxyquinoline
(QN, 1), we have synthesized a series of 8-hydroxyquinoline de-
rivatives that can chelate with different metal ions and conjugate
covalently with various small molecules for the further exploration
of their potential applications. According to their absorption and
emission spectra, these conjugates maintain good abilities to che-
late metal ions, suggesting that QN would potentially serve as
a useful scaffold to construct multivalent receptors, a subject is
being investigated.
4.2. Synthesis
4.2.1. 5-Hydroxymethyl-8-hydroxyquinoline (18)
A mixture of 7.37 g (0.0508 mol) of 8-hydroxyquinoline, 16 mL
(0.526 mol) of concentrated hydrochloric acid, and 8 mL
(0.290 mol) of 37% formaldehyde was treated with hydrogen
chloride gas and stirred overnight. The solvent was stripped off and
then treated with 15 mL of water. The pH value was adjusted to 10
by using ammonia. The mixture was filtered and dried to give the
title compound 18 (7.71 g, 87%) as a white solid; mp 138–140 ꢀC. IR
4. Experimental
4.1. General
Chemical reagents and solvents were used as received from
commercial sources unless otherwise stated. Reversed-Phase HPLC
Figure 4. The absorption spectra for monitoring the synthesis of Ag(QN)2 (2b). (a)
Before adding silver acetate; (b) 4 h after adding silver acetate; (c) after adjusting pH to
8; (d) after adjusting pH to 10.
Figure 6. The fluorescent spectra (lex¼325 nm) of QN (1), Al(QN)3 (3a), and LiB(QN)4
(4) in methanol at room temperature.

10992
L. Li, B. Xu / Tetrahedron 64 (2008) 10986–10995
Figure 9. The absorption spectra for monitoring the synthesis of Cu(QFF)2 (10). (a)
Before adding CuCl2 (pH¼5.6); (b) 2 h after adding CuCl2; (c) 20 h after adding CuCl2;
(d) after adjusting pH to 10.
Figure 7. The absorption spectra of (a) QN (1) and (b) water treated LiB(QN)4 (4) in
methanol at room temperature.
(cmꢁ1): 3031, 2726, 1578, 1522, 1430, 1338, 1000. 1H NMR
using ammonia. The mixture was filtered and dried to give the title
compound 1 (710 mg, 70%) as a yellow solid; mp 98–99 ꢀC. IR
(cmꢁ1): 3292, 3018, 2653, 1560, 1508, 1457, 1298, 1077. 1H NMR
(300 MHz, DMSO-d6)
d
(ppm): 8.85 (1H, d, J¼4.1 Hz, Ar–H), 8.51
(1H, d, J¼8.5 Hz, Ar–H), 7.57 (1H, dd, J¼8.5, 4.1 Hz, Ar–H), 7.40 (1H,
d, J¼7.8 Hz, Ar–H), 7.00 (1H, d, J¼7.8 Hz, Ar–H), 4.82 (2H, s,
ArCH2OH). HRMS: [MþH]þ calcd for C10H10NO2: 176.0712, found:
176.0699.
(300 MHz, DMSO-d6)
d
(ppm): 8.84 (1H, d, J¼4.1 Hz, Ar–H), 8.55
(1H, d, J¼8.5 Hz), 7.57 (1H, dd, J¼8.5, 4.1 Hz, Ar–H), 7.42 (1H, d,
J¼7.8 Hz, Ar–H), 7.01 (1H, d, J¼7.8 Hz, Ar–H), 4.10 (2H, s, ArCH2NH2).
HRMS: [MþH]þ calcd for C10H11N2O: 175.0871, found: 175.0955.
4.2.2. 5-Aminomethyl-8-hydroxyquinoline (QN, 1)
Compound 18 (1.03 g, 5.87 mmol) was treated by 30 mL of thi-
onyl chloride. The mixture was stirred at room temperature for 6 h.
The solvent was stripped off to give 5-chloromethyl-8-hydroxy-
quinoline (19) as a yellow solid. Compound 19 (1.13 g, 5.87 mmol)
was dissolved in 45 mL of DMSO (dried). Hexamine (1.60 g,
11.4 mmol) was added into the yellow solution. The mixture was
stirred at room temperature overnight, then filtered to remove the
white solid (hexamine). The yellowish green filtrate was dried to
give a green solid, then was dissolved into 25 mL of 6 M HCl. The
yellow solution was stirred at room temperature for about two
days. The solvent was stripped off and the yellow solid was washed
by 12 mL of methanol and then filtered. The filtrate was evaporated
and washed by 8 mL of methanol again. The combined solid was
dissolved in 20 mL of water. The pH value was adjusted from 4 to 10
4.2.3. (9H-Fluoren-9-yl)methyl(8-hydroxyquinolin-5-yl)-
methylcarbamate (QFmoc, 5)
QN (1) (209 mg, 1.19 mmol) was dissolved in 15 mL DMF, fol-
lowed by the addition of NaHCO3 (150 mg, 1.79 mmol) aqueous
solution.
(9H-Fluoren-9-yl)methyl
chloroformate
(333 mg,
1.29 mmol) was dissolved in 4 mL of DMF, then was added drop-
wise to the reaction solution. The reaction was stirred overnight;
20 mL of water was added. A yellow solid was precipitated and
filtered out; 10 mL of methanol and 10 mL of diethyl ether were
used to wash it to give the title compound 5 (301 mg, 64%) as
a yellow solid; mp 124–126 ꢀC. IR (cmꢁ1): 3286, 3083, 2780, 1701,
1599, 1512, 1397, 1314, 1185, 1017. 1H NMR (300 MHz, DMSO-d6)
d
(ppm): 8.85 (1H, d, J¼3.3 Hz, Ar–H), 8.49 (1H, d, J¼8.3 Hz, Ar–H),
Figure 10. The absorption spectra for monitoring the synthesis of In(QFF)3 (11). (a)
Before adding InCl3 (pH¼5.6); (b) 2 h after adding InCl3; (c) 24 h after adding InCl3; (d)
after adjusting pH to 10.
Figure 8. The fluorescent spectra (lex¼325 nm) of QN (1), QFmoc (5), and Al(QFmoc)3
(7a) in methanol at room temperature.

L. Li, B. Xu / Tetrahedron 64 (2008) 10986–10995
10993
Figure 11. The fluorescent spectra (lex¼325 nm) of QN (1), QB (6), QFA (12), QN–bisP
(13), and QG (14) in methanol at room temperature.
Figure 13. The absorption spectra for monitoring the synthesis of In(QB)3 (8b). (a)
Before adding InCl3 (pH¼5.6); (b) 2 h after adding InCl3; (c) 18 h after adding InCl3; (d)
after adjusting pH to 10.
7.87 (2H, d, J¼7.4 Hz, Ph), 7.66 (2H, d, J¼7.3 Hz, Ph), 7.58 (1H, dd,
J¼8.3, 3.3 Hz, Ar–H), 7.41–7.25 (5H, m, Ph, Ar–H), 7.01 (1H, d,
J¼7.7 Hz, Ar–H), 4.53 (2H, s, ArCH2), 4.33 (2H, d, J¼6.3 Hz,
CHCH2CO), 4.20 (1H, t, J¼6.3 Hz, CHCH2CO). HRMS: [MþH]þ calcd
for C25H21N2O3: 397.1552, found: 397.1465.
(CH)2CHNH), 4.08–4.05 (1H, m, (CH)2CHNH), 3.05–2.99 (1H, m,
CH2CHCH), 2.80 (1H, dd, J¼12.5, 4.9 Hz, SCHaHbCH), 2.56 (1H, d,
J¼12.5 Hz, SCHaHbCH), 2.09 (2H, t, J¼7.2 Hz, COCH2CH2), 1.54–1.24
(6H, m, COCH2CH2CH2CH2CHS). HRMS: [MþH]þ calcd for
C20H25N4O3S: 401.1647, found: 401.1694.
4.2.4. QN–biotin conjugate (QB, 6)
QN (1) (87.4 mg, 0.502 mmol) and
D
-(þ)-biotin (123 mg,
4.2.5. (S)-2-[(S)-2-Amino-3-phenylpropanamido]-N-((8-
hydroxyquinolin-5-yl)methyl)-3-phenylpropanamide (QFF, 9)
0.504 mmol) were dissolved in 5 mL of DMSO (dried). The mixture
was cooled to 0 ꢀC and HBTU (252 mg, 0.664 mmol) in 2 mL of DMF
(dried) was added, followed by N,N-diisopropylethylamine (DIEA)
(0.41 mL, 2.4 mmol). The mixture was allowed to rise to room
temperature and stirred overnight. The reaction was quenched by
adding dropwise 30 mL of acetone. A yellow solid was precipitated
and filtered out; 10 mL of acetone was used to wash it once. The
QN (1) (69.8 mg, 0.401 mmol) and Fmoc-L-Phe-L-Phe-OH
(215 mg, 0.403 mmol) were dissolved in 5 mL of DMSO. HBTU
(226 mg, 0.595 mmol) in 1 mL of DMF was added to the solution,
followed by 0.30 mL (1.7 mmol) of DIEA. After stirring overnight,
8 mL of piperidine was added and stirred for another 6 h. The sol-
vent was stripped off, and the crude product was purified using RP-
crude product was purified by RP-HPLC to give the title compound
25
6 (133 mg, 66%) as a yellow solid; mp 199–201 ꢀC; [
a]
þ46 (c 0.3,
HPLC to give the title compound 9 (107 mg, 57%) as a yellow solid;
D
25
mp 185–188 ꢀC; [
a
]
þ6.8 (c 0.5, MeOH). IR (cmꢁ1): 3282, 3052,
MeOH). IR (cmꢁ1): 3282, 3075, 2933, 2863, 1670, 1560, 1399, 1313,
D
2963, 2667, 1636, 1560, 1508, 1455, 1374, 1240, 1077. 1H NMR
1191, 1127. 1H NMR (300 MHz, DMSO-d6)
d
(ppm): 8.85 (1H, d,
(300 MHz, D2O)
d
(ppm): 8.87 (1H, d, J¼4.0 Hz, Ar–H), 8.29 (1H, d,
J¼4.1 Hz, Ar–H), 8.44 (1H, d, J¼8.5 Hz, Ar–H), 8.24 (1H, t, J¼5.3 Hz,
ArCH2NHCO), 7.58 (1H, dd, J¼8.5, 4.1 Hz, Ar–H), 7.36 (1H, d,
J¼7.8 Hz, Ar–H), 7.01 (1H, d, J¼7.8 Hz, Ar–H), 6.37 (2H, d, J¼15.6 Hz,
CHNHCO), 4.59 (2H, d, J¼5.3 Hz, ArCH2NHCO), 4.30–4.26 (1H, m,
J¼8.6 Hz, Ar–H), 7.60 (1H, dd, J¼8.6, 4.0 Hz, Ar–H), 7.41–7.28 (5H, m,
Ph, Ar–H), 7.19–7.09 (6H, m, Ph), 6.91 (1H, d, J¼7.6 Hz, Ar–H), 4.47
(2H, s, ArCH2), 4.36 (1H, t, J¼5.7 Hz, CH2CH), 4.22 (1H, t, J¼5.8 Hz,
CH2CH), 3.14–3.08 (2H, m, PhCH2CH), 2.73–2.65 (2H, m, PhCH2CH).
HRMS: [MþH]þ calcd for C28H29N4O3: 469.2240, found: 469.2162.
4.2.6. QN–folic acid conjugate (QFA, 12)
QN (1) (29.8 mg, 0.171 mmol) and folic acid (77.1 mg,
0.175 mmol) were dissolved by ultrasonic in 8 mL of DMSO to get
a deep yellow solution. HBTU (87.7 mg, 0.231 mmol) in 1 mL of
DMF was added to the solution, followed by 0.12 mL (0.69 mmol) of
DIEA. The resultant clear yellow solution was stirred overnight and
concentrated. The crude product was purified by RP-HPLC to give
the title compound 12 (60.2 mg, 59%) as a yellow solid; mp 223–
þ14 (c 0.1, MeOH). IR (cmꢁ1): 3254, 3065, 2780, 1701,
25
225 ꢀC; [
a]
D
1605,1508,1406,1298,1185. 1H NMR (300 MHz, DMSO-d6)
d (ppm):
8.83 (1H, d, J¼4.0 Hz, Ar–H), 8.62 (1H, s, Ar–H), 8.41 (1H, d,
J¼8.6 Hz, Ar–H), 8.29 (1H, t, J¼5.6 Hz, ArCH2NHCO), 8.04 (1H, d,
J¼6.9 Hz, CHNHCO), 7.63 (2H, d, J¼7.9 Hz, Ph), 7.53 (1H, dd, J¼8.6,
4.0 Hz, Ar–H), 7.37 (1H, d, J¼7.7 Hz, Ar–H), 6.99 (1H, d, J¼7.7 Hz, Ar–
H), 6.92 (1H, t, J¼5.7 Hz, PhNHCH2Ar), 6.62 (2H, d, J¼7.9 Hz, Ph),
4.59 (2H, d, J¼5.6 Hz, ArCH2NHCO), 4.47 (2H, d, J¼5.7 Hz,
PhNHCH2Ar), 4.38–4.32 (1H, m, CH2CHNHCO), 2.22 (2H, t, J¼6.9 Hz,
COCH2CH2), 1.95–1.89 (2H, m, COCH2CH2CH). HRMS: [MþH]þ calcd
for C29H28N9O6: 598.2163, found: 598.2190.
Figure 12. The fluorescent spectra (lex¼325 nm) of QB (6) and Al(QB)3 (8a) in meth-
anol at room temperature.

10994
L. Li, B. Xu / Tetrahedron 64 (2008) 10986–10995
25
4.2.7. N1-((8-Hydroxyquinolin-5-yl)methyl)-N4-(3,3-
di(ethoxyphosphono)propyl)succinamide (21)
(36.1 mg, 82%) as a yellow solid; mp 153–155 ꢀC; [
MeOH). IR (cmꢁ1): 3246, 3076, 2938, 1718, 1684, 1560, 1458, 1399,
1202. 1H NMR (300 MHz, DMSO-d6)
(ppm): 8.93 (1H, d, J¼4.2 Hz,
a
]
þ7.5 (c 0.2,
D
QN (1) (23.6 mg, 0.136 mmol) and 3-(3,3-di(ethoxypho-
sphono)propylcarbamoyl)propanoic acid (57.4 mg, 0.133 mmol)
were dissolved in 5 mL of DMSO to get a yellow solution. HBTU
(72.9 mg, 0.192 mmol) in 1 mL of DMF was added to the solution,
followed by 0.12 mL (0.69 mmol) of DIEA. The reaction was stirred
overnight and concentrated. The crude product was purified by RP-
HPLC to give the title compound 21 (38.3 mg, 49%) as a yellow solid;
mp 280 ꢀC (decomp.). IR (cmꢁ1): 3313, 3022, 2906, 2740, 1684,
1654, 1508, 1474, 1299, 1240, 1084, 1006. 1H NMR (300 MHz, DMSO-
d
Ar–H), 8.59 (1H, d, J¼8.4 Hz, Ar–H), 8.20 (1H, t, J¼5.3 Hz, ArCH2
-
NHCO), 7.69 (1H, dd, J¼8.4, 4.2 Hz, Ar–H), 7.49 (1H, d, J¼7.8 Hz, Ar–
H), 7.11 (1H, d, J¼7.8 Hz, Ar–H), 4.65 (2H, d, J¼5.3 Hz, ArCH2NHCO),
3.77 (1H, t, J¼4.7 Hz, COCHCH2), 2.24 (2H, t, J¼4.7 Hz,
CH2CH2COOH), 1.95–1.88 (2H, m, CHCH2CH2). HRMS: [MþH]þ calcd
for C15H18N3O4: 304.1297, found: 304.1213.
4.2.11. 4-((8-Hydroxyquinolin-5-yl)methylcarbamoyl)-4-(3-(3,4-
dihydroxyphenyl)propanamido)butanoic acid (QG–Dopa, 15)
d6)
d
(ppm): 8.94 (1H, d, J¼4.1 Hz, Ar–H), 8.74 (1H, d, J¼8.4 Hz, Ar–
H), 8.35 (1H, t, J¼5.0 Hz, ArCH2NHCO), 7.89 (1H, t, J¼5.5 Hz,
CH2NHCO), 7.77 (1H, dd, J¼8.4, 4.1 Hz, Ar–H), 7.48 (1H, d, J¼7.8 Hz,
Compound 24 (27.2 mg, 0.0758 mmol) and 15.6 mg of 3-(3,4-
dihydroxyphenyl)propionic acid (0.0856 mmol) were dissolved in
5 mL of DMSO to get a yellow solution. HBTU (40.0 mg, 0.106 mmol)
in 1 mL of DMF was added to the solution, followed by 0.06 mL
(0.3 mmol) of DIEA. The reaction was stirred overnight and con-
centrated. Acetone was added and then filtered. The solid was
dissolved in 2 mL of DMSO, followed by adding 10 mL of TFA. After
stirring overnight, the solvent was stripped off, and the crude
Ar–H), 7.16 (1H, d, J¼7.8 Hz, Ar–H), 4.63 (2H, d, J¼5.0 Hz, ArCH2
-
NHCO), 4.03 (8H, q, J¼6.7 Hz, CH2Me), 3.20–3.16 (2H, m,
NHCH2CH2), 2.27 (4H, s, COCH2CH2CO), 1.89–1.79 (3H, m,
CH2CH2CH), 1.22 (12H, t, J¼6.7 Hz, Me). 31P NMR (300 MHz, DMSO-
d6)
d
(ppm): 23.5 (s). HRMS: [MþH]þ calcd for C25H40N3O9P2:
588.2240, found: 588.2247.
product was purified using RP-HPLC to give the title compound 15
25
4.2.8. N1-((8-Hydroxyquinolin-5-yl)methyl)-N4-(3,3-bisphosphono
propyl)succinamide (QN–bisP, 13)
(11.9 mg, 34%) as a yellow solid; mp 182–184 ꢀC; [
a
]
þ7.0 (c 0.2,
D
MeOH). IR (cmꢁ1): 3311, 3068, 2928, 2870, 1718, 1654, 1508, 1458,
Compound 21 (19.2 mg, 0.0327 mmol) was dissolved in 4 mL of
chloroform, followed by adding 0.07 mL (0.5 mmol) of trime-
thylsilyl bromide (TMSB). The reaction was stirred overnight and
the solvent was evaporated under vacuum. Then, acetone with
a small amount of water was added and stirred for another 30 min.
After removing the organic solvent, hexane and chloroform were
used to wash it and separated by extraction. The aqueous layer was
collected and dried. The crude product was purified by RP-HPLC to
give the title compound 13 (11.4 mg, 73%) as a yellow solid; mp
300 ꢀC (decomp.). IR (cmꢁ1): 3345, 3040, 2898, 2836, 2726, 2645,
1684, 1618, 1578, 1522, 1430, 1372, 1280, 1246, 1162, 1083, 1000. 1H
1264,1136,1021. 1H NMR (300 MHz, DMSO-d6)
d
(ppm): 8.89 (1H, d,
J¼4.1 Hz, Ar–H), 8.57 (1H, d, J¼8.5 Hz, Ar–H), 8.34 (1H, t, J¼5.3 Hz,
ArCH2NHCO), 7.97 (1H, d, J¼5.7 Hz, CHNHCO), 7.65 (1H, dd, J¼8.5,
4.1 Hz, Ar–H), 7.42 (1H, d, J¼7.8 Hz, Ar–H), 7.08 (1H, d, J¼7.8 Hz, Ar–
H), 6.61–6.55 (2H, m, Ph), 6.42 (1H, d, J¼7.9 Hz, Ph), 4.62 (2H, d,
J¼5.3 Hz, ArCH2NHCO), 4.23–4.18 (1H, m, NHCHCH2), 2.71–2.59
(4H, m, PhCH2CH2CO), 2.34–2.14 (4H, m, CHCH2CH2COOH). HRMS:
[MꢁH]þ calcd for C24H24N3O7: 466.1614, found: 466.1484.
4.2.12. 3-(3,4-Dihydroxyphenyl)-N-((8-hydroxyquinolin-5-
yl)methyl)propanamide (QN–Dopa, 16)
NMR (300 MHz, DMSO-d6)
d
(ppm): 8.93 (1H, d, J¼3.9 Hz, Ar–H),
QN (1) (26.5 mg, 0.152 mmol) and 3-(3,4-dihydrox-
yphenyl)propionic acid (27.1 mg, 0.149 mmol) were dissolved in
4 mL of DMSO to get a yellow solution. HBTU (75.5 mg, 0.199 mmol)
in 1 mL of DMF was added to the solution, followed by 0.10 mL
(0.57 mmol) of DIEA. The reaction was stirred overnight and con-
centrated. The crude product was purified using RP-HPLC to give
the title compound 16 (20.4 mg, 41%) as a yellow solid; mp 117–
118 ꢀC. IR (cmꢁ1): 3309, 3068, 2930, 2863, 1654, 1560, 1508, 1458,
8.68 (1H, d, J¼7.9 Hz, Ar–H), 8.44 (1H, t, J¼5.2 Hz, ArCH2NHCO), 7.92
(1H, t, J¼5.7 Hz, CH2NHCO), 7.72 (1H, dd, J¼7.9, 3.9 Hz, Ar–H), 7.59
(1H, d, J¼7.6 Hz, Ar–H), 7.30 (1H, d, J¼7.6 Hz, Ar–H), 4.67 (2H, d,
J¼5.2 Hz, ArCH2NHCO), 3.22–3.18 (2H, m, NHCH2CH2), 2.26 (4H, s,
COCH2CH2CO), 1.91–1.74 (3H, m, CH2CH2CH). 31P NMR (300 MHz,
DMSO-d6)
476.0988, found: 476.1002.
d
(ppm): 20.6 (s). MS: [MþH]þ calcd for C17H24N3O9P2:
1264,1136,1021. 1H NMR (300 MHz, DMSO-d6)
d (ppm): 8.93 (1H, d,
4.2.9. tert-Butyl 4-((8-hydroxyquinolin-5-yl)methylcarbamoyl)-4-
aminobutanoate (24)
J¼4.0 Hz, Ar–H), 8.66 (1H, d, J¼7.5 Hz, Ar–H), 8.28 (1H, t, J¼5.5 Hz,
ArCH2NHCO), 7.79 (1H, dd, J¼7.5, 4.0 Hz, Ar–H), 7.35 (1H, d,
J¼7.8 Hz, Ar–H), 7.12 (1H, d, J¼7.8 Hz, Ar–H), 6.58–6.53 (2H, m, Ph),
6.38 (1H, d, J¼8.1 Hz, Ph), 4.61 (2H, d, J¼5.5 Hz, ArCH2NHCO), 2.64
(2H, t, J¼7.2 Hz, COCH2CH2), 2.32 (2H, t, J¼7.2 Hz, CH2CH2Ph). MS:
[MþH]þ calcd for C19H19N2O4: 339.1345, found: 339.1321.
QN (1) (71.0 mg, 0.408 mmol) and Fmoc–Glu(OtBu)–NHS
(209 mg, 0.401 mmol) were dissolved in 10 mL of DMF, followed by
adding 0.30 mL (1.7 mmol) of DIEA. After stirring overnight,10 mL of
diethyl aminewas added and stirredfor another 4 h. The solvent was
stripped off, and the crude product was purified using RP-HPLC to
give the title compound 24 (80.5 mg, 56%) as a yellowsolid; mp 127–
4.2.13. N1-(3,4-Bis(benzyloxy)phenethyl)-N4-((8-hydroxyquinolin-
5-yl)methyl)succinamide (23)
25
130 ꢀC; [
a
]
D
ꢁ8.6 (c 0.5, MeOH). IR (cmꢁ1): 3398, 2978, 1727, 1698,
1541, 1450, 1367, 1292, 1153, 1062. 1H NMR (300 MHz, DMSO-d6)
3-(3,4-Bis(benzyloxy) phenethylcarbamoyl)propanoic acid
(99.1 mg, 0.229 mmol) and 27.0 mg (0.235 mmol) of NHS were
dissolved in 3 mL of DMF, followed by adding 54.5 mg
(0.264 mmol) of DCC. After stirring overnight, DCU was filtered out
and the filtrate containing the NHS ester was used for the next step
without further purification. QN (1) (39.4 mg, 0.226 mmol) was
added to the solution, followed by adding 0.2 mL of DIEA. The re-
action was stirred overnight and concentrated. The crude product
was purified using RP-HPLC to give the title compound 23 (98.6 mg,
73%) as a yellow solid; mp 154–157 ꢀC. IR (cmꢁ1): 3302, 3065, 2929,
1636, 1509, 1426, 1382, 1270, 1131, 1025. 1H NMR (300 MHz, DMSO-
d
(ppm): 8.92 (1H, d, J¼4.3 Hz, Ar–H), 8.61 (1H, d, J¼7.8 Hz, Ar–H),
8.16 (1H, t, J¼5.6 Hz, ArCH2NHCO), 7.71 (1H, dd, J¼7.8, 4.3 Hz, Ar–H),
7.50 (1H, d, J¼7.6 Hz, Ar–H), 7.12 (1H, d, J¼7.6 Hz, Ar–H), 4.69 (2H, d,
J¼5.6 Hz, ArCH2NHCO), 3.76 (1H, t, J¼4.8 Hz, COCHCH2), 2.18 (2H, t,
J¼5.2 Hz, CH2CH2CO),1.95–1.87 (2H, m, CHCH2CH2),1.35 (9H, s, Me).
HRMS: [MþH]þ calcd for C19H26N3O4: 360.1923, found: 360.1838.
4.2.10. 4-((8-Hydroxyquinolin-5-yl)methylcarbamoyl)-4-
aminobutanoic acid (QG, 14)
Compound 24 (52.0 mg, 0.145 mmol) was dissolved in 5 mL of
methanol, followed by adding 10 mL of trifluoroacetic acid (TFA).
After stirring overnight, the solvent was stripped off, and the crude
product was purified using RP-HPLC to give the title compound 14
d6)
d
(ppm): 8.84 (1H, d, J¼3.2 Hz, Ar–H), 8.43 (1H, d, J¼7.6 Hz, Ar–
H), 8.30 (1H, t, J¼5.4 Hz, ArCH2NHCO), 7.87 (1H, t, J¼5.5 Hz,
CH2NHCO), 7.56 (1H, dd, J¼7.6, 3.2 Hz, Ar–H), 7.44–7.29 (11H, m,

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10. Lytle, F. E.; Storey, D. R.; Juricich, M. E. Spectrochim. Acta 1973, 29A, 1357–1369.
11. Moeller, T. Ind. Eng. Chem., Anal. Ed. 1943, 15, 346–349.
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Devol, I.; Larrey, B.; Valeur, B. J. Phys. Chem. B 1997, 101, 7786–7793; (c) Prodi, L.;
Bargossi, C.; Montalti, M.; Zaccheroni, N.; Su, N.; Bradshaw, J. S.; Izatt, R. M.;
Savage, P. B. J. Am. Chem. Soc. 2000, 122, 6769–6770.
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Marshall, B.; Levy, S. B.; Bennett, S.; Billard, L. Antimicrob. Agents Chemother.
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B. S. J. Chem. Soc., Dalton Trans. 2001, 2429–2434.
Ar–H, Ph), 7.00 (1H, d, J¼7.8 Hz, Ar–H), 6.96–6.93 (2H, m, Ph), 6.70
(1H, d, J¼7.5 Hz, Ph), 5.06 (4H, s, PhCH2O), 4.58 (2H, d, J¼5.4 Hz,
ArCH2NHCO), 3.21–3.14 (2H, m, NHCH2CH2), 2.57 (2H, t, J¼7.3 Hz,
CH2CH2Ph), 2.31 (4H, s, COCH2CH2CO). HRMS: [MþH]þ calcd for
C36H36N3O5: 590.2655, found: 590.2501.
4.2.14. N1-(3,4-Dihydroxyphenethyl)-N4-((8-hydroxyquinolin-5-
yl)methyl)succinamide (QN–Su-Dopa, 17)
Compound 23 (57.3 mg, 0.0973 mmol) was dissolved in 10 mL of
DMSO, and 50 mg of the catalyst (10% Pd on charcoal) was added
under nitrogen atmosphere. The reaction proceeded at room tem-
perature under hydrogen atmosphere overnight. After removing
the catalyst by filtration, the solution was concentrated to dryness.
The crude product was purified by RP-HPLC to give the title com-
pound 17 (34.1 mg, 86%) as a yellow solid; mp 185–187 ꢀC. IR
(cmꢁ1): 3297, 3068, 2930, 1654, 1554, 1516, 1431, 1212, 1130, 1041.
1H NMR (300 MHz, DMSO-d6)
d
(ppm): 8.85 (1H, d, J¼4.2 Hz, Ar–H),
8.40 (1H, d, J¼7.2 Hz, Ar–H), 7.56 (1H, dd, J¼7.2, 4.2 Hz, Ar–H), 7.34
(1H, d, J¼7.8 Hz, Ar–H), 7.03 (1H, d, J¼7.8 Hz, Ar–H), 6.62–6.56 (2H,
m, Ph), 6.37 (1H, d, J¼7.6 Hz, Ph), 4.55 (2H, s, ArCH2), 3.14 (2H, t,
J¼5.8 Hz, CH2CH2Ph), 2.56 (2H, t, J¼5.8 Hz, CH2CH2Ph), 2.30 (4H, s,
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Acknowledgements
The authors thank RGC (6094/02P) for the financial support.
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