Syntheses and fluorescent properties of 2-amino substituted 6,7-dimethoxy-4-(trifluoromethyl)quinolines

Article abstract of DOI:10.1002/jhet.109

(Chemical Equation Presented) 2-Amino-substituted 6,7-dimethoxy-4- trifluoromethyl-quinolines were synthesized from the 2-oxo compound 1 via 2-chloroquinoline 2 and aminated with anilines or benzylamine to give highly fluorescent molecules 4, 5. 2-Aminoqu

Full text of DOI:10.1002/jhet.109

May 2009
Syntheses and Fluorescent Properties of 2-Amino Substituted
6,7-Dimethoxy-4-(trifluoromethyl)quinolines
415
Wolfgang Stadlbauer,* Appasaheb B. Avhale, Naresh S. Badgujar,
and Georg Uray
Department of Chemistry, Organic and Bioorganic Chemistry, Karl-Franzens University of Graz,
Heinrichstrasse 28, A-8010 Graz, Austria/Europe
*E-mail: wolfgang.stadlbauer@uni-graz.at
Received December 4, 2008
DOI 10.1002/jhet.109
Published online 7 May 2009 in Wiley InterScience (www.interscience.wiley.com).
2-Amino-substituted 6,7-dimethoxy-4-trifluoromethyl-quinolines were synthesized from the 2-oxo
compound 1 via 2-chloroquinoline 2 and aminated with anilines or benzylamine to give highly fluores-
cent molecules 4, 5. 2-Aminoquinoline 8 was obtained via azidation of 2–6, reaction to the phosphazene
7, and hydrolysis. 4-Ethoxycarbonyl derivative 4b is suitable for linking appropriate biomolecules. The
construction of a linking group was achieved by conversion of 4b via carboxylic acid 9 to the reactive
O-succinimide ester 10, which reacts easily with amino acids or peptides to amides 11 and 12. The fluo-
rescent properties were investigated and are comparable with derivatives of 1.
J. Heterocyclic Chem., 46, 415 (2009).
INTRODUCTION
to high-quantum yields. The functionalization to O-suc-
cinimidyl (OSu) esters at N-1 and 6-O and labelling of
biopolymers such as peptides and carbohydrates was
carried out without any blue-shift, resulting in absorbing
close to the visible range and emitting in aqueous solu-
tion at 430–450 nm, suitable for biochemistry and
medicine.
Coumarins and carbostyrils with push-pull systems
are studied extensively as fluorescent dyes [1]. However,
many carbostyrils (2-quinolones) show disadvantages in
luminescence properties compared with coumarins
because of shorter absorption and emission wavelengths
[2]. Recently, we reported a series of studies about the
fluorescence properties of differently substituted carbos-
tyrils [3] with suitable structure elements which shifted
the wavelengths up to 440 nm absorption and 540 nm
emission maxima. These structure elements were elec-
tron donating substituents such as amino or methoxy
groups in both positions 6 and 7 and an electron defi-
cient substituent in position 4. Such properties make this
compound class also interesting for the use in sensor
and electroluminescence devices [4,5]. The advantage of
3,4-dimethoxycarbostyril derivatives was shown recently
in their use as fluorescence resonance energy transfer
systems [6], in the study of luminescence resonance
transfer techniques [7a] and incorporated in a time
resolved pH sensor as covalently attached europium
complex [7b].
After the variation of substituents at positions 4, 6,
and 7, we report in this article about the investigation
on the synthesis and properties of 2-aminoquinolines
III[3g]. In contrast to type II structures [3b], 2-amino-
quinolines III have a possible tautomeric 2-imino struc-
ture IV as potential fluorescent compounds (Scheme 1).
RESULTS AND DISCUSSION
For our study, we selected 6,7-dimethoxy-4-trifluoro-
methyl-2-quinolone 1 as the starting compound, with
methoxy groups as the donor and a trifluoromethyl
group as the acceptor substituents. The synthesis of the
carbostyril ring system was achieved by cyclocondensa-
tion of 3,4-dimethoxyaniline with trifluoro-methyl-aceto-
acetate as described recently [3b,c]. The conversion of
the 2-oxo group to the reactive 2-chloro moiety in com-
pound 2 was achieved with phosphoryl chloride. Con-
ventional heating required a reaction time of 12 h and
produced many by-products. The application of
In our earlier articles [3a–f], we described the synthe-
sis of highly fluorescent push-pull substituted carbostyr-
ils (type I) with donor substituents at positions 6 and 7
and acceptor substituents at position 4 having widely pH
independent properties, large Stokes shifts and medium
C
V
2009 HeteroCorporation

416
W. Stadlbauer, A. B. Avhale, N. S. Badgujar, and G. Uray
Vol 46
Scheme 1
NMR signals of NH ranged between 5.2 and 10.9 ppm
with chloroform as the solvent.
Using suitable substituted derivatives such as 4-(2-
quinolinylamino)benzoate 4b (R2 ¼ COOEt) allowed
the introduction of linker groups attached at the phenyl
ring at the amino/imino-position 2. For the construction
of linker groups to aminogroups of natural products, a
reactive O-succinimide ester (OSu-ester) was planned
because OSu-esters attached to heterocycles are known
to be easily available, stable, and useful to link to bio-
logical samples. The synthesis was achieved by saponifi-
cation of the ethyl ester group of 4b to the free carbox-
ylic acid 9 in ethanolic sodium hydroxide solution, and
re-esterification with N-hydroxysuccinimide in the pres-
ence of carbodiimide, which gave the active OSu ester
10 in good yields.
The OSu ester 10 reacted smoothly under biological
conditions in buffered aqueous DMSO solution below
50ꢀC with biomolecules such as aminoacids and pep-
tides. We synthesized two fluorescence marked
microwave heating allowed the isolation of chloroquino-
line 2 after 30 min with similar yields but better purity
(Scheme 2).
The conversion of the 2-chloro group in 2 to a free 2-
amino group was achieved in a three step reaction by
exchange of the 2-chloro substituent against the 2-azido
group in dimethylformamide at 80ꢀC using Kryptofix-5
as catalyst, to give 2-azidoquinoline 6. According to IR
spectra the azide 6A exists predominantly in its tauto-
meric tetrazolo structure 6T similar as shown in many
investigations [8]. The Staudinger reaction with triphe-
nylphosphane gave the corresponding phosphazene 7,
which is hydrolyzed by acid catalysis with hydrochloric
acid in water/methanol to give the free 2-aminoquino-
line 8 in an overall yield of about 67%. The aminoqui-
noline 8, however, did not show sufficient fluorescent
properties for further applications, probably caused by
the predominant tautomeric amino-structure of type III,
so this way was not continued.
Scheme 2
On the other hand, 2-arylamino and 2-benzyl-amino-
quinolines 4a-c and 5, which were obtained from the 2-
chloro derivative with the appropriate anilines 3a-c or
benzylamine in a one step reaction in 62–66% yield,
showed good fluorescence properties (possibly deriving
from the formation of a tautomeric imino structure in
the state of fluorescence excitation); see Table 1. Sur-
prisingly, the benzylamino derivative 5 showed similar
fluorescence properties as the arylamino derivatives 4,
which means, that the influence of the aryl group
attached to the 2-amino group (forming an azomethine-
type structure as imino tautomer) has no remarkable
influence on luminescence properties. However, products
with substituted benzylamines were not stable enough
for further investigation (Scheme 3).
Spectral assignment of 4 and 5 to an amino- or im-
ino-structure was not possible, because differences
caused by solvent influences are strong and the 1H
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2009
Syntheses and Fluorescent Properties of 2-Amino Substituted
6,7-Dimethoxy-4-(trifluoromethyl)quinolines
417
Table 1
Photophysical data for UV spectra, the electronic excitation (exc), and fluorescence (flu) of carbostyrils 4–12.
a
No.
UV (kmax
)
e
kexc
kflu
Stokes shift
UF
4a
4b
4c
5
384
392
398
375
391
393
393
392
9500
13400
18000
8600
380
380
394
380
380
380
380
378
450
433
440
440
433
417
432
433
70
53
46
60
53
37
52
53
0.152
0.100
0.182
0.297
0.072
0.100
0.060
0.033
9
10200
9900
9900
10
11
12
9000
Solvent: DMSO, Solvent temperatures: 25 ꢀC; k in nm.
a Wavelength of excitation.
examples, the phenylalanine derivative 11 and the gly-
cyl-glycyl-glycin 12 linked at the amino group of the
amino acid with the linker molecule.
which were high for any N1-alkylated analyte of type I
[3b,c], decreased from UF ¼ 0.1 in the ester 4b to UF ¼
0.03–0.06 in linked 2-amino analogues 11,12. Ester 4c
shows a higher e value because of the asymmetric struc-
ture, which causes changes in dipole properties.
Electronic spectra. Absorption spectra of recently
synthesized 4-(trifluoromethyl)carbostyrils [3b,c] were
rather similar with kmax ꢁ 350–380 nm in DMSO or
water; there was also no great difference between NH-
and N-alkyl derivatives, which means, that in all cases
the tautomeric amide group (N1-C2) of structure I is
predominant. In the 2-amino/imino series (structures III/
IV) comparable absorption wavelengths were obtained
(Table 1): The UV wavelengths are slightly higher
(375–398 nm), the Stokes’ shifts are in the region 50–
70 nm. However, the fluorescence quantum yields,
CONCLUSION
We could show that the conversion of the carbostyril
1 to its 2-aza analogues 4 and 5 can be achieved in
good yields to obtain subsequently OSu ester 10 with
comparable fluorescence spectral properties, however,
with too low-quantum yield values for the use in analyt-
ical tasks. From the 6,7-dimethoxy-4-(trifluoro-methyl)-
carbostyril series until now investigated, only N1-alky-
lated carbostyrils of structure type I [3c] gave quantum
yields high enough for this purpose.
Scheme 3
EXPERIMENTAL
Melting points were determined using a Stuart SMP3 Melt-
1
ing Point Apparatus in open capillary tubes. H NMR and 13C
NMR spectra were recorded on a Bruker AMX 360 instrument
(360 or 90 MHz) or on a Bruker Avance DRX 500 instrument
(500 or 125 MHz). Chemical shifts are given in ppm (d) from
the internal TMS standard. IR spectra were recorded using a
Mattson Galaxy Series FTIR 7020 instrument with potassium
bromide discs. Elemental analyses were performed at the
Microanalytical Laboratory of the University of Vienna, Aus-
tria. Mass spectra were obtained from a HP 1100 LC/MSD
mass spectral instrument (positive or negative APCI ion
source, 50–200 V, nitrogen). UV/Vis spectra were recorded on
a Shimadzu UV/Vis scanning spectrophotometer UV-2101 PC;
concentration: 0.01 mg/mL. Excitation and emission spectra
were recorded using a Shimadzu RF-5001 PC spectrofluorome-
ter, concentration: 0.001 mg/mL. Determination of quantum
yields: emission signals were set in relation to the known sig-
nal of quinine sulfate at pH 1. Analytical HPLC was per-
formed on a Shimadzu LC 20 system equipped with a diode
array detector (215 and 254 nm) on a Pathfinder AS reversed
phase (4.6150 mm, 5 lm) column, running an acetonitrile/
water gradient (30–100% acetonitrile).
Journal of Heterocyclic Chemistry
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W. Stadlbauer, A. B. Avhale, N. S. Badgujar, and G. Uray
Vol 46
Microwave-assisted syntheses were carried out in an Emrys
was heated for 3 h to 130ꢀC. The mixture was cooled, the
formed solid filtered by suction, washed with ethanol
(100 mL), and dried. The yield was 0.252 g (62%), yellow
needles, m.p. 188–189ꢀC (ethanol); IR: 3266 m, 1684 s, 1601
Synthesizer at 2450 MHz (Biotage AB, Uppsala). All reactions
were monitored by thin layer chromatography (TLC) on 0.2-
mm silica gel F-254 (Merck) plates using UV light (254 and
366 nm) for detection. Common reagent-grade chemicals are
either commercially available and were used without further
purification or prepared by standard literature procedures. All
optical measurements were performed using analytical grade
solvents.
m, 1570 w, 1536 m cmꢂ1 1H NMR (CDCl3): d 3.97, 4.02,
;
and 4.07 (3 s, 9H, 3 OMe), 6.98 (t, J ¼ 8.3 Hz, 1H, ArH),
7.17 (s, 1H, ArH), 7.24 (s, 1H, ArH), 7.33 (s, 1H, ArH), 7.60
(t, J ¼ 8.1 Hz, 1H, ArH), 8.07 (d, J ¼ 8.3 Hz, 1H, ArH), 9.19
(d, J ¼ 8.6 Hz, 1H, ArH), 10.96 (s, 1H, NH); MS: m/z (%) ¼
407 (20, M þ 1), 406 (100, M), 375 (15), 374 (33); Anal.
Calcd. for C20H17F3N2O4 (406.36): C, 59.12; H, 4.22; N, 6.89;
Found C, 58.83; H, 4.56; N, 6.54.
2-Chloro-6,7-dimethoxy-4-(trifluoromethyl)quinoline
(2)
Method A. A mixture of 6,7-dimethoxy-4-(trifluoromethyl)-
quinolone (1) [3c] (2.73 g, 10 mmol) and phosphoryl chloride
(7.60 g, 50 mmol) was heated under reflux for 12 h. The reac-
tion mixture was cooled to room temperature and poured onto
crushed ice (250 g) and kept for 30 min. The solid obtained
was filtered by suction, washed with excess of water to afford
2.65 g (91% yield) of colorless needles.
Method B. A mixture of 6,7-dimethoxy-4-(trifluoromethyl)-
quinolone (1) (0.273 g, 1 mmol) and phosphoryl chloride (3.0 g,
20 mmol) was heated at 120ꢀC for 30 min by microwave irradia-
tion in a sealed tube. After cooling to room temperature, the reac-
tion mixture was worked up as described in method A. The yield
was 0.260 g (90%), colorless needles, m.p. 134–136ꢀC (ethanol);
IR: 3468 m, 2978 w, 1619 m, 1593 m cmꢂ1; 1H NMR (CDCl3):
d 4.05 (2 s, 6H, 2 OMe), 7.29 (s, 1H, 3-H), 7.43 and 7.56 (2 s,
2H, ArH); Anal. Calcd. for C12H9ClF3NO2 (291.66): C, 49.42;
H, 3.11; N, 4.80; Found C, 49.21; H, 2.90; N, 4.58.
N-Benzyl-6,7-dimethoxy-4-(trifluoromethyl)quinolin-2-amine
(5). A mixture of 2-chloroquinoline 2 (0.291g, 1 mmol) and
benzylamine (0.214 g, 2 mmol) was heated for 3 h to 130ꢀC.
The reaction mixture was cooled to room temperature, the
formed solid filtered, dissolved in water (100 mL), and brought
to pH 13 with conc. aq. sodium hydroxide solution. The aque-
ous solution was extracted with diethylether (3 ꢃ 30 mL), the
ether solution taken to dryness under reduced pressure and the
oily product purified by dry flash column chromatography [9]
using toluene as eluent. The yield was 0.224 g (62%), pale
yellow needles, m.p. 98–99ꢀC (ethanol); IR: 3435 s, 3253 m,
1
1632 s, 1514 m cmꢂ1; H NMR (CDCl3): d 3.98 and 4.02 (2
s, 6H, 2 OMe), 4.71 (d, J ¼ 5.8 Hz, 2H, CH2), 5.04 (s, 1H,
NH), 6.84 (s, 1H, ArH), 7.18 (s, 2H, ArH), 7.31–7.43 (m, 5H,
PhH); MS: m/z (%) ¼ 363 (25, M þ 1), 362 (100, M), 361
(12, M ꢂ 1), 272 (8); Anal. Calcd. for C19H17F3N2O2
(362.35): C, 62.98; H, 4.73; N, 7.73; Found C, 62.79; H, 4.57;
N, 7.72.
6,7-Dimethoxy-N-phenyl-4-(trifluoromethyl)quinolin-2-amine
(4a). A mixture of 2-chloroquinoline 2 (0.291 g, 1 mmol) and
aniline (4a) (0.186 g, 2 mmol) was heated for 3 h to 130ꢀC.
The reaction mixture was cooled to room temperature, the
formed solid filtered and digested with diethylether (100 mL).
The ether solution was taken to dryness under reduced pres-
sure and the oily residue purified by dry flash column chroma-
tography [9] using toluene as the eluent. The yield was 0.230
g (66%), pale yellow needles, m.p. 147–148ꢀC (ethanol); IR:
7,8-Dimethoxy-5-(trifluoromethyl)tetrazolo[1,5-a]quinoline
(6). A suspension of 2-chloroquinoline 2 (0.291 g, 1 mmol),
sodium azide (0.260 g, 4 mmol), and Kryptofix-5 (0.01 g) in
dimethylformamide (7 mL) was heated under TLC monitoring
for about 80 h to 75–80ꢀC. Then the mixture was cooled to
room temperature and poured into ice/water (100 mL), the
formed solid filtered by suction and washed with cold water
(100 mL). The yield was 0.240 g (80%), brownish needles,
m.p. 237–239ꢀC (ethanol); IR: 1617 w, 1528 m, 1505 w
3438 m, 3385 s, 1630 m, 1618 m, 1599 m cmꢂ1 1H NMR
,
(CDCl3): d 4.00 and 4.03 (2 s, 6H, 2 OMe), 6.92 (s, b, 1H, 2-
NH), 7.11–7.17 (m, 2H, ArH), 7.21–7.27 (m, 2H, ArH), 7.38
(t, J ¼ 7.5 Hz, 2H, ArH), 7.54 and 7.57 (2 s, 2H, ArH);Anal.
Calcd. for C18H15F3N2O2 (348.33): C, 62.07; H, 4.34; N, 8.07;
Found C, 62.02; H, 4.16; N, 7.95.
cmꢂ1 1H NMR (CDCl3): d 4.08 and 4.18 (2 s, 6H, OMe),
;
7.51 (s, 1H, ArH), 8.18 (s, 1H, ArH), 8.23 (s, 1H, ArH); MS:
m/z (%) ¼ 299 (14, M þ 1), 298 (100, M), 272 (13); Anal.
Calcd. for C12H9F3N4O2 (298.23): C, 48.33; H, 3.04; N, 18.79;
Found: C, 48.08; H, 3.01; N, 18.48.
Ethyl 4-{[6,7-dimethoxy-4-(trifluoromethyl)quinolin-2-yl]
amino}benzoate (4b). A mixture of 2-chloroquinoline 2 (2.91
g, 10 mmol) and ethyl 4-aminobenzoate (3b) (3.30 g, 20
mmol) was heated for 3 h to 130ꢀC. The reaction mixture was
cooled to room temperature, the formed solid filtered by suc-
tion, washed with ethanol (100 mL), and dried. The yield was
2.85 g (65%), yellow needles, m.p. 210–211ꢀC (ethanol); IR:
6,7-Dimethoxy-4-(trifluoromethyl)-N-(triphenylphosphora-
nylidene)quinolin-2-amine (7). A mixture of tetrazolo[1,5-
a]quinoline 6 (0.298 g, 1 mmol), and triphenylphosphane
(0.524 g, 2 mmol) in toluene (8 mL) was heated under TLC
monitoring for about 22 h under reflux. The solvent was
removed under reduced pressure and the oily residue triturated
with cyclohexane. The formed solid was filtered by suction,
and washed with cyclohexane until the excess of triphenyl-
phosphane was removed. The yield was 0.260 g (87%), brown-
ish prisms, m.p. 183–184ꢀC (methanol); IR: 1606 m, 1509 m
3357 s, 3215 m, 2926 m, 1682 s, 1619 m, 1602 s cmꢂ1 1H
;
NMR (CDCl3): d 1.39 (t, J ¼ 7.5 Hz, 3H, Me), 4.02 and 4.07
(2 s, 6H, 2 OMe), 4.35 (q, J ¼ 7.1 Hz, 2H, CH2), 6.96 (s, 1H,
NH), 7.16 (s, 1H, ArH), 7.24 (s, 1H, ArH), 7.29 (s, 1H, ArH),
7.73 (d, J ¼ 7.5 Hz, 2H, ArH), 8.07 (d, J ¼ 7.5 Hz, 2H,
ArH); MS: m/z (%) ¼ 421 (21, M þ 1), 420 (100, Mþ);Anal.
Calcd. for C21H19F3N2O4 (420.39): C, 60.00; H, 4.56; N, 6.66;
Found C, 59.92; H, 4.28; N, 6.65.
Methyl 2-{[6,7-dimethoxy-4-(trifluoromethyl)quinolin-2-
yl]amino}benzoate (4c). A mixture of 2-chloroquinoline 2
(0.291 g, 1 mmol) and methyl anthranilate (0.302 g, 2 mmol)
cmꢂ1 1H NMR (CDCl3): d 3.88 and 3.93 (2 s, 6H, 2 OMe),
;
6.67 (s, 1H, ArH), 7.14 (s, 1H, ArH), 7.37 (s, 1H, ArH), 7.44–
7.48 (m, 6H, ArH), 7.52–7.56 (m, 3H, ArH), 7.86–7.92 (m,
6H, ArH); Anal. Calcd. for C30H24F3N2O2P (532.51): C,
67.67; H, 4.54; N, 5.26; Found: C, 67.94; H, 4.65; N, 5.06.
6,7-Dimethoxy-4-(trifluoromethyl)quinolin-2-amine (8). A
mixture of N-(triphenylphosphoranylidene)quinolin-2-amine 7
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Syntheses and Fluorescent Properties of 2-Amino Substituted
6,7-Dimethoxy-4-(trifluoromethyl)quinolines
419
(0.532 g, 1 mmol) and conc. hydrochloric acid (7 mL) in
methanol (8 mL) was heated under TLC monitoring for 5 h
under reflux. The reaction mixture was cooled to room temper-
ature, the formed solid filtered by suction and washed with
excess of water until pH of 7 was reached. The yield was
0.262 g (96%), yellowish green crystals, m.p. 283–284ꢀC
(ethanol); IR: 3345 s, 3090 s, 1680 s, 1647 m, 1618 w, 1520
prisms, m.p. 272–273ꢀC (acetone); IR: 3366 w, 2933 m, 1647
w, 1625 w, 1603 s, 1575 w cmꢂ1 1H NMR (CDCl3): d 3.33
;
and 3.41 (2 dd, J ¼ 5.7 and 13.9 Hz, 2H, CH2), 3.99 and 4.05
(2 s, 6H, 2 OMe), 5.09 (dd, 5.8 and 6.7 Hz, 1H, CH), 6.87 (d,
J ¼ 5.9 Hz, 1H, amide-NH), 7.18–7.24 (m, 6H, ArH),
7.30 and 7.33, (2 s, 2H, ArH), 7.37 (d, J ¼ 8.2 Hz, 2H, ArH),
7.75 (d, J ¼ 8.3 Hz, 2H, ArH), 10.20 (s, 1H, 2-NH); MS: m/z
(%) ¼ 541 (11, M þ 2), 540 (47, M þ 1), 539 (100, M), 538
(35, M ꢂ 1), 391 (14); Anal. Calcd. for C28H24F3N3O5
(539.52): C, 62.34; H, 4.48; N, 7.79; Found C, 61.91; H, 4.37;
N, 7.63.
m cmꢂ1 1H NMR (DMSO-d6): d 3.87 and 3.94 (2 s, 6H,
;
OMe), 7.09 (s, 1H, ArH), 7.32 (s, 1H, ArH), 7.38 (s, 1H,
ArH), 8.62 (s, b, 2H, NH2); Anal. Calcd. for C12H11F3N2O2
(272.23): C, 52.95; H, 4.07; N, 10.29; Found: C, 52.65; H,
3.78; N, 10.02.
N-(4-{[6,7-Dimethoxy-4-(trifluoromethyl)quinolin-2-yl]am-
ino}benzoyl)glycylglycylglycine (12). To a solution of glycyl-
glycyl-glycine (38 mg, 0.2 mmol) in dimethyl-sulfoxide/water
(9:1, 2.5 mL), a solution of OSu-ester 10 (98 mg, 0.2 mmol)
in dimethylsulfoxide/water (9:1, 2.5 mL) was added dropwise
at room temperature. Then aq. pH 7 buffer (0.75 mL) was
added, the mixture stirred for 14 h at 50ꢀC, poured into water
(25 mL), and then acidified with conc. hydrochloric acid to pH
¼ 1–2. A solid separated, which was filtered by suction and
washed with excess of water to afford 75 mg (53%) of yellow
prisms, m.p. 238–239ꢀC (acetone); IR: 3338 s, 3306 s, 3117
m, 3088 m, 2961 w, 2925 m, 1721 s, 1662 s, 1625 w, 1605 s,
4-{[6,7-Dimethoxy-4-(trifluoromethyl)quinolin-2-yl]amino}
benzoic acid (9). A mixture of 4-(quinolin-2-yl)aminobenzoate
4b (0.420 g, 1 mmol) and 1M aq. sodium hydroxide solution
(2 mL) in ethanol (20 mL) was heated for 7 h under reflux,
then the solvent was removed under reduced pressure and the
residue dissolved in water (10 mL) under cooling. The mixture
was acidified with conc. hydrochloric acid to pH ¼ 1–2, the
resulting precipitate filtered by suction and washed with excess
of water. The yield was 0.310 g (80%), yellow prisms, m.p.
275–276ꢀ C (ethyl acetate); IR: 3457 s, 2940 w, 1677 s, 1624
w, 1600 s, 1526 s cmꢂ1 1H NMR (DMSO-d6): d 3.87 and
;
1
3.96 (2 s, 6H, 2 OMe), 7.10 (s, 1H, ArH), 7.36 (s, 1H, ArH),
7.38 (s, 1H, ArH), 7.91 (d, J ¼ 8.6 Hz, 2H, ArH), 8.04 (d, J
¼ 8.6 Hz, 2H, ArH), 9.95 (s, 1H, NH), 12.54 (s, 1H, OH);
MS: m/z (%) ¼ 393 (18, M þ 1), 392 (100, M), 377 (12);
Anal. Calcd. for C19H15F3N2O4 (392.34): C, 58.17; H, 3.85; N,
7.14; Found: C, 57.82; H, 3.76; N, 7.00.
1568 w, 1531 s cmꢂ1; H NMR (DMSO-d6): d 3.76–3.78 (m,
4H, 2 CH2), 3.87 (s, 3H, OMe), 3.90 (d, J ¼ 5.4 Hz, 2H,
CH2), 3.97 (s, 3H, OMe), 7.11 (s, 1H, ArH), 7.35 and 7.39 (2
s, 2H, ArH), 7.88 (d, J ¼ 8.6 Hz, 2H, ArH), 8.01 (d, J ¼ 8.3
Hz, 2H, ArH), 8.17–8.24 (m, 2H, amide-NH), 8.64 (t, J ¼ 5.3
Hz, 1H, amide-NH), 9.91 (s, 1H, 2-NH); MS: m/z (%) ¼
564 (14, M þ 1), 563 (42, M), 507 (17), 450 (25), 449
(100), 392(85); Anal. Calcd. for C25H24F3N5O7 (563.49):
Calcd. C, 53.29; H, 4.29; N, 12.43; Found C, 53.63; H, 4.29;
N, 12.56.
1[(4-{[6,7-Dimethoxy-4-(trifluoromethyl)quinolin-2-yl]am-
ino}benzoyl)oxy]pyrrolidine-2,5-dione (OSu-ester) (10). N-
Hydroxysuccinimide (0.115 g, 1 mmol) was added slowly with
stirring at 0ꢀC to a solution of 4-(quinolin-2-yl)amino-benzoic
acid 9 (0.392 g, 1 mmol) in dry tetrahydrofuran (20 mL).
Then N,N-diisopropylcarbodiimide (0.125 g, 1 mmol) was
added dropwise with stirring at 0–5ꢀC which formed a yellow-
ish-white precipitate. This mixture was stirred further at 0–5ꢀC
for 14–15 h. The solvent was removed under reduced pressure
and the solid residue obtained was digested in dry tetrahydro-
furan (10 mL), filtered and washed well with dry tetrahydrofu-
ran. Then the solid was stirred in dry ethanol (50 mL) at room
temperature for 30 min to remove N,N-diisopropylurea formed
during the reaction. Suction filtration afforded 0.288 g (59%)
of OSu-ester, pale yellow prisms, m.p. 268–269ꢀC (ethanol);
IR: 3435 s, 3340 s, 3212 m, 1765 s, 1723 s, 1618 w, 1598 s,
1578 w cmꢂ1;1H NMR (CDCl3): d 2.93 (s, 4H, 2 CH2), 4.03
and 4.09 (2 s, 6H, 2 OMe), 7.22 (s, 1H, ArH), 7.25 (s, 1H,
ArH), 7.33 (s, 1H, ArH), 7.77 (d, J ¼ 8.4, 2H, ArH), 8.16 (d,
J ¼ 8.6, 2H, ArH); MS: m/z (%) ¼ 490 (25, M þ 1), 489
(100, M), 392 (10); Anal. Calcd. for C23H18F3N3O6 (489.41):
C, 56.45; H, 3.71; N, 8.59; Found: C, 56.44; H, 3.89; N, 8.30.
N-(4-{[6,7-Dimethoxy-4-(trifluoromethyl)quinolin-2-yl]am-
ino}benzoyl)phenylalanine (11). To a solution of (D,L)pheny-
lalanine (38 mg, 0.2 mmol) in dimethyl-sulfoxide/water (9:1,
2.5 mL), a solution of OSu-ester 10 (98 mg, 0.2 mmol) in
dimethylsulfoxide/water (9:1, 2.5 mL) was added dropwise at
room temperature. Then aq. pH 7 buffer (0.75 mL) was added,
the mixture stirred for 14 h at 50ꢀC, poured into water (25
mL) and then acidified with conc. hydrochloric acid to pH ¼
1–2. A solid separated, which was filtered by suction and
washed with excess of water to afford 85 mg (63%) of yellow
Acknowledgments. This research was supported by scholar-
ships from the Austrian Exchange Service/Academic Coopera-
tion and Mobility Unit (N.S.B. and A.B.A).
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