Fluorescent 6-hydroxy- and 6,7-dihydroxy-4-trifluoromethylcarbostyrils and formation of O-carboxymethylated derivatives via O-succinimide esters

Article abstract of DOI:10.1002/jhet.5570450118

(Chemical Equation Presented) Stepwise demethylation of fluorescent 6,7-dimethoxy-3-trifluoromethylcarbostyrils 5 leads to 6-hydroxy derivatives 6 and 6,7-dihydroxyderivative 7. Phenolate formation shifts excitation and emission maxima from 370 and 430 nm to 430 and 480 nm for the anion of 6 and as far as 500 and 580 nm for the dianion of 7. Dependence of fluorescence quantum yield on media and polar structure, varying from 0.02 to 0.51, is discussed. O-Alkylation of 6 with alkyl bromoacetate yields esters of type 8 in good yield. Reactive succinimidoyl (OSu) esters of type 11 were prepared after saponification to acids 9. With amino acids or their esters, peptides and aminoglucose, linking to labeled derivatives 13 or 15 could be achieved under mild conditions in slightly basic aqueous media.

Full text of DOI:10.1002/jhet.5570450118

Jan-Feb 2008
165
Fluorescent 6-Hydroxy- and 6,7-Dihydroxy-4-trifluoro-
methylcarbostyrils and Formation of O-Carboxymethylated
Derivatives via O-Succinimide Esters
Georg Uray, Naresh S. Badgujar, Sona Kováꢀková and Wolfgang Stadlbauer*
Department of Chemistry, Organic and Bioorganic Chemistry, Karl-Franzens University of Graz
Heinrichstrasse 28, A-8010 Graz, Austria/Europe
wolfgang.stadlbauer@uni-graz.at
Received May 18 2007
O
CF3
R4
N
H
CF3
CF3
R2
R3
O
O
O
O
CH3
CH3
O
O
N
R1
O
CH3
N
O
N
O
R1
CH3
6: R1= H, Me; R2 = H
7: R1= Me; R2, R3 = H
8: R2 = CH2COOEt
11: R2 = OSu-ester
5: R1 = H, Me
13: R4-NH = amino acid, peptide
15: R4-NH = carbohydrate
Stepwise demethylation of fluorescent 6,7-dimethoxy-3-trifluoromethylcarbostyrils 5 leads to 6-hydroxy
derivatives 6 and 6,7-dihydroxyderivative 7. Phenolate formation shifts excitation and emission maxima
from 370 and 430 nm to 430 and 480 nm for the anion of 6 and as far as 500 and 580 nm for the dianion of
7. Dependence of fluorescence quantum yield on media and polar structure, varying from 0.02 to 0.51, is
discussed. O-Alkylation of 6 with alkyl bromoacetate yields esters of type 8 in good yield. Reactive
succinimidoyl (OSu) esters of type 11 were prepared after saponification to acids 9. With amino acids or
their esters, peptides and aminoglucose, linking to labeled derivatives 13 or 15 could be achieved under
mild conditions in slightly basic aqueous media.
J. Heterocyclic Chem., 45, 165 (2008).
Luminescence properties of most carbostyrils (quinolin-
compounds showed very good photophysical properties,
such as an absorption maximum close to the visible (ꢀ ꢁ
370 nm), large Stokes shifts (ꢀF ꢁ 450 nm), sufficient high
2(1H)-ones) have the disadvantage of shorter absorption
and emission wavelengths compared with coumarins [1].
Recently we reported systematic studies about the
fluorescence properties of differently substituted carbo-
styrils [2] which revealed that suitable structure elements
shifted the wavelengths up to 440 nm absorption and 540
nm emission maxima: these structure elements were
electron donating substituents such as amino or methoxy
groups in both positions 6 and 7 and an electron deficient
substituent in position 4. Such properties makes them also
interesting to be used in sensor devices utilizing the new
blue laser diodes. In contrast to many other fluorescent
dyestuffs, such push-pull substituted carbostyrils have the
important advantage that they are highly stable against
chemicals (compared with coumarins [3] or fluorescein
type dyes), thermal and photochemical stress (e.g.
compared with azodyes) and they are insensitive to
oxygen quenching (e.g. compared with 1,10-phenan-
throline complexes).
4
extinction coefficients (ꢂ about 10 ) and high fluorescence
quantum yields (ꢃF up to 0.5). The disadvantage of
dimethoxy derivatives in terms of slightly shorter
absorption and emission wavelengths compared with
aminocarbostyrils (ꢀ ꢄ 440 nm absorption and ꢀ ꢄ 540 nm
emission wavelengths) is counterbalanced by advantages
such as largely pH-independent photophysical properties
and high chemical stability.
In this paper we present a strategy of the function-
alization in compounds of type 5 proceeding via a
stepwise ether cleavage of the methoxy groups in position
6 and 7. After functionalization at position 6 using ꢅ-
halogen substituted carboxylates and activation as O-
succinimidoyl (OSu) esters we show the possibility to
label natural substrates such as amino acids and amino-
carbohydrates under mild aqueous conditions.
Furthermore, the effects of variation of the electron
density on the oxygens in position 6 and 7 on lumin-
escence properties are investigated.
The above mentioned dyes are frequently used as
fluorescent labels for natural polymers [4]. Recently we
described the introduction of reactive linker groups at the
N1 position of 6,7-dimethoxy-4-trifluoromethyl-carbo-
styrils which allowed labeling of natural substrates such
as amino acids, proteins, amino-carbohydrates or amino-
polysaccharides without any blueshift [5]. These
RESULTS AND DISCUSSION
We started the synthesis of N-alkylcarbostyrils 5a,b
from dimethoxyanilines 4a,b, which were obtained from

166
G. Uray, N. S. Badgujar, S. Kováꢀková and W. Stadlbauer
Vol 45
5:3 ratio, which were separated by dry-flash column
chromatography [10]. Similar results were obtained with
the N-ethyl-derivative 5b, however with lower yields and
worse ratio of 6b; this reaction sequence was not
investigated further. Variation of the concentration of
hydrobromic acid and of the reaction time did not give
significantly other ratios of 6a/7a, but either lower over-
all yields or by-products; complete di-demethoxylation of
5a was achieved when hydroiodic acid was used as the
reagent. N-Unsubstituted carbostyril 5c [2,5] reacted
mainly to the mono-demethylated product and gave 6c in
85% yield. The position of mono-demethoxylation in
compounds 6a and 6c was determined by NMR
experiments. The HMBC experiments showed that
exclusively in both reactions a regioselective 6-mono-
demethylation took place.
The introduction of the linker group was started by
alkylation of 6-hydroxycarbostyril 6a with 2-bromo-
acetate under basic conditions, which gave in 83% yield
the desired 6-quinolinyloxy-acetate 8. A similar reaction
of the N-unsubstituted 6-hydroxycarbostyril 6c gave a
mixture of N- and O-mono- and dialkylated products and
was not investigated further. To study the influence of O-
acylation on fluorescence properties, 6-quinolinyl acetate
10 was prepared from 6-hydroxycarbostyril 6a by
acetylation with acetylchloride.
the commercially available 4-aminoveratrol 1 by a
selective monoalkylation with the corresponding
orthoformates 2 via a Chapman rearrangement [6]. In the
first reaction step the formamides 3 were obtained, which
gave on acidic hydrolysis N-alkyl-3,4-dimethoxyanilines
4 in good yields. This reaction sequence was performed
similar to a text-book procedure [7]; other mono-
alkylation approaches described in the literature did not
show any advantages [8]. The reaction of alkylanilines 4
with isopropyl trifluoroacetoacetate was performed as
described previously [2,5,9] and gave as the intermediates
the corresponding trifluoroaceto-acetanilides. These
intermediates cyclized without isolation on heating with
sulfuric acid as catalyst to give mainly 6,7-dimethoxy-4-
trifluoromethyl-2-quinolones 5a,b, together with a small
amount of the isomer 6,7-dimethoxy-2-trifluoromethyl-4-
quinolones in a 20:1 ratio. Simple recrystallization
afforded pure 2-quinolones 5a,b.
HC(OR1)3
(2a,b)
CH3
CH3
O
O
CH3
CH3
O
O
185 °C, 2.5 h
O
NH2
N
H
59-61 %
R1
3a,b
1
10% aq.HCl
reflux, 90 min
73-90 %
CF3
O
O
CH3
CH3
O
Br
R2
O
CF3
H3C
O
CF3
HO
O
O
O
DMF, K2CO3
35 °C, 4 h
N
H
O
O
CH3
CH3
O
H3C
N
O
H3C
N
O
NH
R1
O
5c
CH3
83 %
CH3
HBr (48%
in water)
8 R2 = Et
9 R2 = H
6a
aq. NaOH/EtOH
20 °C, 5 h
4a,b
85 %
AcOH,
reflux, 10 h
CH3COCl
DMF, K2CO3
20 °C, 5 h
O
O
CH3
60 %
52 %
CF3
F3C
O
CH3
O
80-97 %
CF3
HO
1) 130 °C, 1 h
2) 76% H2SO4, 90 oC, 1 h
N
OH
H3C
H3C
O
CF3
CH3
O
N
R1
O
O
O
O
CH3
CH3
H3C
H3C
61 %
N
C N
HBr (47% in water)
AcOH, reflux, 6-10 h
6a,c
CH3
CH3
O
O
N
O
CH3
+
THF, 0-5 °C, 8 h
O
N
R1
55/30%
R1 = Me
CF3
10
O
O
HO
HO
5a,b
N
O
CF3
N
O
2-7 R1
a Me
b Et
O
CH3
O
H3C
O
N
O
c H
7a
CH3
11
Ether cleavage of N-methyl-dimethoxycarbostyril 5a
with 47 % hydrobromic acid in water gave a mixture of
the mono- and di-demethoxylated products 6a and 7a in a
Next we achieved the preparation of the reactive
succinimidoyl active ester 11 (OSu ester), which has in

Jan-Feb 2008
Fluorescent 6-Hydroxy- and 6,7-Dihydroxy-4-trifluoromethylcarbostyrils
and Formation of O-Carboxymethylated Derivatives via O-Succinimide Esters
167
aqueous solution the advantage of both stability and high
reactivity with amino groups [11]. Hydrolysis of 6-
quinolinyloxy-acetate 8 in aqueous-ethanolic sodium
hydroxide gave in good yields 6-quinolinyloxy-acetic acid
9 which yielded the desired compound 11 after reaction
with N-hydroxysuccinimide/diisopropylcarbodiimide in
dry tetrahydrofurane.
Electronic spectra. Absorption spectra of all new O-
alkyl substituted carbostyrils (including those already
linked to amino acids, peptides and carbohydrates) are
very similar with ꢀmax = 366–377 nm in DMSO and 355-
360 nm in water. In Table 1 are excitation maxima listed
which are for all alkylated species almost equal. We also
found that there is no significant difference to the N-
linked 6,7-dimethoxycarbostyrils described earlier [5].
Interestingly, extinction coefficients are about 10-30%
larger comparing N1-derivatives with the new O6-isomers
varying between 9000 and 13000 in DMSO and 10000-
16000 in water [5]. As also previously observed with
emission spectra of N1-linked derivatives, the new O6
alkylated isomers give maxima in a narrow range around
440 nm in DMSO and 430 nm in water. Hence the
Stokes’ shifts ꢀF = 61-75 nm are sufficiently high and
again similar to the N-linked carbostyrils [5].
NH2
COOR2
R3
O
R3
(12a-c)
O
R2
N
H
CF3
N-methylmorpholine/DMF
or pH=7 buffer/aq. DMSO
20 °C, 14 h
O
O
O
H3C
N
O
CH3
49-75%
13a-c
12-13 R2 R3
a
b
c
Et Ph
H
H
Ph
Unexpectedly, fluorescence quantum yields, which
were found in DMSO to have values of ꢁF = 0.34 and
0.47 for “standard” 6-O-methylcarbostyrils 5a and 5c,
were lowered in water for the N-methyl derivative 5a by
about 50% (Table 1). The same trend was observed in
water for 6-O-CH2CO linked derivatives 8, 11 and 13a-c,
with values of ꢁF = 0.08–0.14 (vs. 0.11– 0.27 for the N1-
analogues). As an exception, the glucosamine derivative
15 emitted 30% stronger than the N1-analogue. In
contrast, in DMSO measured differences in quantum
yields were found to be individually different between N1
and O6 derivatives, sometimes better in O6 derivatives (8
and 15), and significantly smaller for OSu ester 11 (0.14
vs. 0.40).
-CO-NH-CH2-CO-NH-CH2COOH
11
NH2
HO
OH .HCl
O
OH
O
(14)
OH
O
OH
N
CF3
H
HO
N-methylmorpholine,
aq. DMF, 20 °C, 14 h
O
HO
OH
H3C
O
N
O
54%
CH3
15
Linkage of fluorescent dyes with biopolymers such as
proteins or polysaccharides is a method used for many
purposes; e.g. refs [4b,4i,11b,12], and was already
successfully applied with similar N1-linked carbostyrils
[5]. The reaction of OSu ester 11 with phenylalanine ester
12a or phenylalanine 12b was performed either in
dimethylformamide as the solvent and N-methyl-
morpholine as basic catalyst, or in aqueous dimethyl-
sulfoxide as the solvent and pH 7 buffer as the base. It
afforded in all cases in about 49-75% yield the
carbostyrils 13a or 13b, linked with the amino group of
phenylalanine derivative. In the same manner, the
tripeptide glycyl-glycyl-glycine (13c) reacted both in
DMF and in aqueous DMSO solution with OSu-ester 11
to the peptide linked carbostyril 13c in 54-56% yield.
Aminoglucose (14) gave with 11 in 54 % yield the
glucose-linked carbostyril 15.
Spectral data of acetyloxycarbostyril 10 were explored
because the structure could serve as a model compound in
enzymatic hydrolysis (e.g. the activity of hydrolases in
water). Comparison of 10 with 5a and 6a shows that both
excitation and emission spectra suffered a blue-shift of
about 20-38 nm (see Table 1). The epsilon values are
rather high (11600 in DMSO and 14100 in water),
however the quantum yields are low with about 0.03 both
in DMSO and water.
Interesting are the electronic spectra of 6-hydroxy- and
6,7-dihydroxycarbostyrils
6 and 7 (Figure 1).
Monophenol 6, fluorescing in DMSO solution just as 6,7-
dialkylated analogues, shows in water only about 6% of
the DMSO quantum yield (0.02). The anion, however
shows the “usual” water quantum yield of 0.16, absorbing
at 395 nm and emitting at 465 nm. A study of the pH-
dependence of 6a (Figure 2) revealed a pKa of about 8.3,
well in the range of expectation [13]. Interestingly, a
recent publication dealing with the excited state “super”
acidity of 6-hydroxyquinoline-N-oxides describes the
photoisomerization to 6-hydroxyquinoline-2-ones via
adiabatic photo-induced proton transfer confirming the
photo stability of carbostyrils [14]. Carbostyril 6c, having
It must be emphasized that all these linking reactions
could be carried out at conditions which prevent any
renaturation of natural products: the reaction temperature
was in all cases 20 °C, which is an important and
necessary fact when natural products are used as
substrates. A further important fact is that all linking
reactions with amino acids and peptides could be
performed at biochemical conditions in aqueous
dimethylsulfoxide as the solvent and with aq. pH7 buffer.

168
G. Uray, N. S. Badgujar, S. Kováꢀková and W. Stadlbauer
Vol 45
a second dissociable group at NH1/OH2, has the best
quantum yield of all investigated compounds (0.50) in
DMSO and is again quenched in water. 6,7-Dihydroxy-
carbostyril 7a has in water and DMSO equal fluorescence
properties, but the monoanion of 6a and the dianion of 7a
(both measured at pH = 13) have very weak fluorescence.
However, measured in DMSO with the addition of traces
of powdered potassium hydroxide, monoanion of 6a and
dianion of 7a show values of unprecedented redshift in
the carbostyril series (Figure 1). Excited at 490 nm,
emission of 7a2- occurs with a quantum efficiency of 0.02
at 580 nm (monoanion 430 nm and 490 nm, quantum
efficiency 0.07).
interesting substrates under mild conditions. Quantum
yields of the new OCH2CO- in comparison to N-CH2CO-
linked products are in some cases lower. They are
understandable considering the double push function in
position 6 and 7 being more sensible to ionic quenching
phenomena. In these cases, comparison of experimental
data lead to better understanding of the complicated
fluorescence decay pathways.
Figure 2: UV-Absorption of 6a at 365 nm at pH 5 – 11
EXPERIMENTAL
Melting points were determined using a Stuart SMP3 Melting
1
Point Apparatus in open capillary tubes. H 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 (ꢀ) 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, Austria. 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 spectrofluorometer (150-W Xe lamp, 6
selectable slits: 1.5, 3, 5, 10, 15, 20 nm, R452-01 photo-
multiplier; monochromator: ion-blazed holographic concave
grating F/2.5); concentration: < 10-5 mol/L. Determination of
quantum yields: emission signals were set in relation to the
known signal of quinine sulphate at pH 1. Analytical hplc was
performed 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 μm) column, running an acetonitrile/water
gradient (30-100% acetonitrile).
Figure 1: Absorption (a) and emission (b) spectra of 5a and the anions
of 6a and 7a in DMSO.
All reactions were monitored by thin layer chromatography
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.
CONCLUSION
All these findings reveal that easily prepared N1-
protected 6-hydroxy-7-methoxy-4-trifluoromethyl-carbo-
styrils lead to interesting derivatives with tunable
fluorescence properties, useful to label biological

Jan-Feb 2008
Fluorescent 6-Hydroxy- and 6,7-Dihydroxy-4-trifluoromethylcarbostyrils
and Formation of O-Carboxymethylated Derivatives via O-Succinimide Esters
169
Table 1
Photophysical Data for the Electronic Excitation (exc) and Fluorescence (flu) of Carbostyrils 5-15; solvent temperatures: 25 °C; ꢁ in nm.
ꢂ
ꢂ
ꢁexc
ꢁflu
ꢃF
ꢃF
ꢁexc
ꢁflu
ꢃF
ꢃF
No.
(DMSO)
(water)
(DMSO)
(DMSO)
(DMSO)
N1*
(water)
(water)
(water)
N1*
5a
365
368
9700
9400
435
0.34
0.47
0.33
0.29
0.50
0.16
0.41
0.22
0.03
0.14
0.33
0.27
0.28
0.29
365
365
361
395
358
354
354
360
345
356
354
354
365
354
10100
10400
10200
9000
428
428
430
465
460
420
420
428
397
426
420
420
420
420
0.16
0.45
0.02
0.16
0.03
0.13
0.08
0.11
0.03
0.14
0.10
0.13
0.14
0.13
5c
6a
6a
6c
438
450
470
450
455
430
450
410
438
430
433
433
433
380
9100
-
400
10000
9600
377+400
384
9900
7a
8
9600
9900
365
10400
10800
11600
10500
11300
13500
9600
0.31
0.32
11700
12900
14100
12100
12600
15600
11400
13400
0.21
0.27
9
380
10
11
350
376
0.40
0.33
0.36
0.33
0.22
0.25
0.25
0.22
0.26
0.11
13a
13b
13c
15
366
366
371
366
11300
* Quantum yields of N1-isomer 6-methoxy-1-alkyl-carbostyrils [5]
1
3,4-Dimethoxyaniline (1): This compound is commercially
hplc purity 95%; lit. bp: 153-155 °C (12 mm Hg) [8g]; H nmr
(CDCl3): ꢀ 2.81 (s, 3 H, NMe), 3.81 and 3.84 (2 s, 2x3 H, 2
OMe), 6.16 (d, J = 6.1 Hz, 1 H, 1 ArH), 6.25 (s, 1 H, 2-H), 6.78
(d, J = 8.5 Hz, 1 H, 1 ArH); MS: m/z (%) = 167 (100) [M].
N-Ethyl-3,4-dimethoxybenzenamine (4b). A mixture of the
formamide 3b (8.00 g, 38.5 mmol) and 10% hydrochloric acid
(50 mL) was brought to reaction and worked-up as described for
4a. The yield was 6.22 g (90%) of a yellow-brown liquid, hplc
purity 96%, bp 150-154 °C/15 mbar; lit. bp: 145-151 °C (6-8
mm Hg) [8e], 116-119 °C (2.5 mm Hg) [8d]; ir: 3380 m, 2960 s,
2930 s, 2900 sh, 2830 m, 1620 s, 1595 m cm-1; 1H nmr (CDCl3):
ꢀ 1.10 (t, J = 7.5 Hz, 3 H, ethyl-CH3), 2.92 (q, J = 7.5 Hz, 2 H,
ethyl-CH2), 3.65 and 3.71 (2 s, 2x3 H, 3-OMe and 4-OMe), 5.11
(s, 1 H, NH), 6.02 (d, J = 7.5 Hz, 1 H, 1 ArH), 6.30 (s, 1 H, 2-
H), 6.72 (d, J = 7.3 Hz, 1 H, 1 ArH); MS: m/z (%) = 181 (100)
[M].
6,7-Dimethoxy-1-methyl-4-trifluoromethylquinolin-2(1H)-
one (5a). To isopropyl 4,4,4-trifluoroacetoacetate (10.30 g, 52
mmol) at 130 °C in an open flask dimethoxyaniline 4a (4.34 g,
26 mmol) was added dropwise under stirring; the reaction
mixture was kept for 1 hour at this temperature and then cooled
to 40-45 °C. The excess ester was removed i. vac. to give N-
methyl-N-(4,4,4-trifluoroacetoacetyl)-3,4-dimethoxyanilide as a
yellow oily residue. The intermediate was cyclized without
isolation: 76% sulfuric acid (9 mL) was added to the reaction
mixture while keeping the temperature below 95 °C. After 1
hour at 90 °C, the reaction mixture was cooled to room
temperature, water (300 mL) was added with stirring, and a light
yellow-green precipitate was formed, which was filtered and
washed with water until neutral to afford 7.20 g (97%) of light
yellow prisms, mp 230-231 °C (ethanol); ir: 3550-3450 s, 1662
s, 1624 w, 1599 m, 1561 w cm-1; 1H nmr (CDCl3): ꢀ 3.77 (s, 3 H,
NMe), 3.96 and 4.04 (2 s, 2x3 H, 6-OMe and 7-OMe), 6.84 (s,
3-H), 7.00 (s, 8-H), 7.22 (s, 5-H); uv (DMSO): ꢁmax (nm) = 365;
(water): 365. Anal. Calcd. for C13H12F3NO3 (287.24): C, 54.36;
H, 4.21; N, 4.88. Found: C, 54.49; H, 4.18; N, 4.89.
available.
N-(3,4-Dimethoxyphenyl)-N-methylformamide (3a). A
mixture of 3,4-dimethoxyaniline (1) (29.90 g, 195 mmol),
trimethyl orthoformate (2a) (32.0 g, 300 mmol) and
concentrated sulfuric acid (1.5 g) was slowly heated under
stirring to 103-105 °C and the formed methanol was distilled
over a short Vigreux column. During 2.5 hours the bath
temperature was increased to 170-185 °C until no more
methanol was formed, then the mixture was kept at this
temperature for further 60 min, and then cooled to 50 °C.
Distillation under reduced pressure (bp 180-190 °C/15 mbar)
afforded a yield of 23.2 g (61%) of a yellow oil, hplc purity
94%; ir: 3550-3450 m, 2960-2910 s, 2836 s, 1673 s, 1596 s,
1516 s cm-1; 1H nmr (CDCl3): ꢀ 3.28 (s, 3 H, NMe), 3.89 (s, 6 H,
2 OMe), 6.69 (s, 1 H, 2-H), 6.73 (d, J = 8.6 Hz, 1 H, 1 ArH),
6.85 (d, J = 8.4 Hz, 1 H, ArH), 8.36 (s, 1 H, CH=O); MS: m/z
(%) = 195 (80) [M].
N-(3,4-Dimethoxyphenyl)-N-ethylformamide (3b). A
mixture of 3,4-dimethoxyaniline (1) (10.00 g, 65 mmol) and
triethyl orthoformate (2b) (18.0 g, 120 mmol) were brought to
reaction and worked up as described for 3a. Distillation (bp 145-
148 °C/10 mbar) gave a yield of 8.07 g (59%) of a yellow-
1
orange liquid, hplc purity 93%; H nmr (CDCl3): ꢀ 1.23 (t, J =
7.1 Hz, 6 H, ethyl-CH3), 3.15 (q, J = 7.5 Hz, 2 H, ethyl-CH2),
3.80 and 3.85 (2 s, 2x3 H, 3-OMe and 4-OMe), 6.18 (d, J = 6.2
Hz, 1 H, 1 ArH), 6.24 (s, 1 H, 2-H), 6.79 (d, J = 8.4 Hz, 1 H, 1
ArH), 8.30 (s, 1 H, CH=O); MS: m/z (%) = 209 (76) [M].
3,4-Dimethoxy-N-methylbenzenamine (4a). A mixture of
the formamide 3a (22.5 g, 115 mmol) and 10% hydrochloric
acid (70 mL) was stirred and heated under reflux for 90 min.
Then the mixture was cooled to room temperature, neutralized
and saturated with potassium carbonate. The amine separated as
colorless oil and was extracted with diethylether (6 x 70 mL),
the ether phase was washed with ice/water (80 mL) and dried
over potassium carbonate. The solvent was removed i. vac. and
the orange product distilled under reduced pressure (bp 153-155
°C, 15 mbar) to yield 14.0 g (73%) of a slightly yellow liquid,
1-Ethyl-6,7-dimethoxy-4-trifluoromethylquinolin-2(1H)-
one (5b). A mixture of isopropyl 4,4,4-trifluoroacetoacetate

170
G. Uray, N. S. Badgujar, S. Kováꢀková and W. Stadlbauer
Vol 45
(7.33 g, 37 mmol), dimethoxyaniline 4b (2.99 g, 16.5 mmol) and
76% sulfuric acid (7 mL) was brought to reaction and worked-up
as described for 5a to afford 3.98 g (80%) of colorless prisms,
mp 166.4-166.9 °C (ethanol); ir: 2980 w, 2930 w, 1660 s, 1630
1 H, 3-H), 7. 97 (s, 1 H, 8-H), 7.13 (s, 1 H, 5-H), 9.75 and 10.30
(b, 2x1 H, 6-OH and 7-OH); ir: 3450 b, m, 3083 m, 1649 m,
1590 m cm-1; uv (DMSO): ꢁmax (nm) = 384; (water): 354. MS:
m/z (%) = 259 (39) [M], 255 (16). Anal. Calcd. for C11H8F3NO3
(259.19): C, 50.98; H, 3.11; N, 5.40. Found: C, 51.24; H, 3.02;
N, 5.67.
1
m, 1600 w cm-1; H nmr (CDCl3): ꢀ 1.41 (t, J = 7.1 Hz, 3 H,
ethyl-CH3), 4.04 and 4.38 (s, 2x3 H, 6-OMe and 7-OMe), 4.41
(q, J = 7.2 Hz, 2 H, ethyl-CH2), 6.87 (s, 1 H, 3-H), 6.99 (s, 1 H,
8-H), 7.22 (s, 1 H, 5-H); uv (DMSO): ꢁmax (nm) = 370; (water):
360. Anal. Calcd. for C14H14F3NO3 (301.27): C, 55.82; H, 4.68;
N, 4.65. Found: C, 56.01; H, 4.60; N, 4.58.
Ethyl (7-Methoxy-1-methyl-2-oxo-4-trifluoromethyl-1,2-
dihydroquinolin-6-yloxy)acetate (8). A mixture of 6-hydroxy-
quinolone 6a (273 mg, 1 mmol) and potassium carbonate (200
mg, 14 mmol) in dry dimethylformamide (5 mL) was stirred for
35 min at room temperature. Then ethyl bromoacetate (167 mg,
1 mmol) was added dropwise and the reaction mixture was
heated to 35 °C for 4 hours. The mixture was then poured into
water (50 mL) and stirred for 1 hour. The solid was filtered by
suction and washed with water which afforded 296 mg (83%) of
6,7-Dimethoxy-4-trifluoromethylquinolin-2(1H)-one (5c).
This compound was prepared according to ref. [5].
6-Hydroxy-7-methoxy-1-methyl-4-trifluoromethyl-quin-
olin-2(1H)-one (6a). A mixture of dimethoxyquinolone 5a (1.44
g, 5 mmol) and hydrobromic acid (47% in water, 10 mL, 60
mmol) in glacial acetic acid (15 mL) was heated under reflux,
until starting material was dissolved. The mixture was then
heated for further 6-8 hours until no starting material could be
detected (checked by TLC monitoring). Then the mixture was
cooled to room temperature, poured into ice/water (250 mL) and
filtered by suction. The yellow precipitate (1.10 g, 85%) was
purified by dry column flash chromatography [10] (Merck silica
gel 60 H; elution with chloroform). The yield was 0.71 g (55%)
of pale yellow prisms, mp 245-246 °C (chloroform); ir: 3156 w,
1
colorless needles, mp 133-134 °C (ethanol); H nmr (CDCl3): ꢀ
1.31 (t, J =7.07 Hz, 3 H, ester-Me), 3.76 (s, 3 H, NMe), 4.05 (s,
3 H, 7-OMe), 4.29 (q, J =7.04 Hz, 2 H, ester-CH2), 4.74 (s, 2 H,
6-OCH2), 6.86 (s, 1 H, 3-H), 7.00 (s, 1 H, 8-H), 7.27 (s, 1 H, 5-
H ); ir: 3450 b, 2983 s, 1757 s, 1662 s, 1624 w, 1603 m, 1561 w
cm-1; uv (DMSO): ꢁmax (nm) = 365; (water): 354. Anal. Calcd.
for C16H16F3NO5 (359.30): C, 53.49; H, 4.49; N, 3.90. Found: C,
53.54; H, 4.46; N, 3.90.
(7-Methoxy-1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydro-
quinolin-6-yloxy)acetic acid (9). To a solution of 6-quino-
linyloxyacetate 8 (343 mg, 1 mmol) in dry tetrahydrofurane (7
mL), 1 M aq. sodium hydroxide (4 mL) was added and the
mixture stirred at room temperature for 5 hours. Then the
solvent was removed i. vac., the residue dissolved in ice/water
(50 mL) and neutralized with conc. hydrochloric acid to pH = 6.
The solid was filtered by suction and washed with water to
afford 200 mg (60%) of colorless prisms, mp 255-256 °C
(acetonitrile); 1H nmr (DMSO-d6): ꢀ 3.70 (s, 3 H, NMe), 4.00 (s,
3 H, 7-OMe), 4.73 (s, 2 H, 6-OCH2), 6.91 (s, 1 H, 3-H), 7.04 (s,
1 H, 8-H), 7.12 (s, 1 H, 5-H); ir: 3450 b, 2929 b, 1724 s, 1650 s,
1626 w, 1575 s, 1529 m cm-1; uv (DMSO): ꢁmax (nm) = 380;
(water): 360. Anal. Calcd. for C14H12F3NO5 (331.25): C, 50.76;
H, 3.65; N, 4.23. Found: C, 50.72; H, 3.54; N, 4.20.
1
3089 m, 1658 s, 1632 w, 1586 m cm-1; H nmr (DMSO-d6): ꢀ
3.67 (s, 3 H, NMe), 3.97 (s, 3 H, 7-OMe), 6.86 (s, 1 H, 3-H),
7.05 (s, 1 H, 8-H), 7.21 (s, 1 H, 5-H), 9.65 (s, 1 H, OH, D2O
exchangeable); uv (DMSO): ꢁmax (nm) = 380, 308; (water): 361;
MS: m/z (%) = 273 (90) [M]. Anal. Calcd. for C12H10F3NO3
(273.21): C, 52.75; H, 3.69; N, 5.13. Found: C, 52.74; H, 3.53;
N, 5.09.
6-Hydroxy-7-methoxy-4-trifluoromethylquinolin-2(1H)-
one (6c). Dimethoxyquinolone 5c (1.37 g, 5 mmol) was brought
to reaction with hydrobromic acid (47% in water, 5 mL, 30
mmol) in glacial acetic acid (5 mL) as described for 6a. Then the
mixture was cooled to room temperature, poured into ice/water
(300 mL) and filtered by suction. The residue was dissolved in
0.1 M aq. sodium hydroxide, extracted with diethylether (300
mL) and acidified with hydrochloric acid to pH = 2-3. The
precipitate was filtered by suction, washed with water and
purified by dry column flash chromatography [10] (Merck silica
gel 60 H; elution with chloroform/acetone 9:1), which afforded
1.10 g (85%) of colorless prisms, mp 292-295 °C (ethyl acetate);
ir: 3200-2850 m, 1665 s, 1638 sh, 1607 m, 1523 s cm-1; 1H nmr
(DMSO-d6): ꢀ 3.84 (s, 3 H, 7-OCH3), 6.72 (s, 1 H, 3-H), 6.93 (s,
1 H, 8-H), 7.06 (s, 1 H, 5-H), 9.52 (s, 1 H, OH), 12.03 (s, 1 H,
NH); 13C nmr (DMSO): ꢀ 56.3 (7-OMe), 98.9 (8-C), 107.0 (4a-
C), 108.3 (5-C), 118.3 (3-C), 123.6 (q, J = 270 Hz, CF3), 135.4
(8a-C), 136.4 (q, 27 Hz, 4-C) 143.6 (C-6), 152.7 (7-C), 160.3 (2-
C=O); HMBC (CDCl3): ꢀ13C-ꢀ1H = 118.3-6.72 (3-C), 108.3-
7.06 (5-C), 152.7-3.84 (7-C), 98.9-6.93 (8-C); uv (DMSO): ꢁmax
(nm) = 377; (water): 358; MS: m/z (%) = 260 (15), 259 (80)
[M], 244 (100), 215 (8). Anal. Calcd. for C11H8F3NO3 (259.19):
C, 50.98; H, 3.11; N, 5.40. Found: C, 50.63; H, 3.04; N, 5.26.
6,7-Dihydroxy-1-methyl-4-trifluoromethylquinolin-2(1H)-
one (7a). This compound was obtained from dimethoxy-
quinolone 5a (1.44 g, 5 mmol) and hydrobromic acid (47% in
water, 10 mL, 60 mmol) following to the procedure of 6a. After
separation of 6a by dry column flash chromatography [10]
(Merck silica gel 60 H), elution with acetone afforded 0.39 g
(30%) of pale yellow prisms of 7a, mp 323-325 °C
(chloroform); 1H nmr (DMSO-d6): ꢀ 3.56 (s, 3 H, NMe), 6.78 (s,
7-Methoxy-1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydro-
quinolin-6-yl acetate (10). A mixture of 6-hydroxyquinolone 6a
(273 mg, 1 mmol) and potassium carbonate (200 mg, 14 mmol)
in dry DMF (6 mL) was stirred at room temperature for 35 min.
Then acetylchloride (39 mg, 0.5 mmol) was added and the
reaction mixture stirred at room temperature for 5 hours. Then
the mixture was poured into water (50 mL) and stirred for 1
hour. The solid was then filtered by suction and washed with
water which afforded 83 mg (52%) of colorless needles, mp
1
174-175 °C (methanol); H nmr (CDCl3): ꢀ 2.36 (s, 3 H, Me of
acetyl), 3.76 (s, 3 H, NMe ), 3.99 (s, 3 H, 7-OMe), 6.87 (s, 1 H,
3-H ), 7.00 (s, 1 H, 8-H ), 7.51 (s, 1 H, 5-H); ir: 3455 b, 1764 s,
1676 s, 1627 sh, 1616 m, 1603 m, 1560 w, 1528 m cm-1; uv
(DMSO): ꢁmax (nm) = 350, 311; (water): 345. Anal. Calcd. for
C14H12F3NO4 (315.25): C, 53.34; H, 3.84; N, 4.44. Found: C,
53.44; H, 3.48; N, 4.36.
1-(7-Methoxy-1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydro-
quinolin-6-yloxy)acetyloxypyrrolidine-2,5-dione (11). N-
Hydroxysuccinimide (58 mg, 0.5 mmol) was added slowly
whilst stirring to a solution of 6-quinolinyloxyacetic acid 9 (165
mg, 0.5 mmol) in dry tetrahydrofurane (20 mL) at 0 °C. Then
1,3-diisopropylcarbodiimide (63 mg, 0.5 mmol) was added
dropwise at 0-5 °C and the mixture then stirred for 8 hours. The
formed solid was separated by suction filtration, washed well

Jan-Feb 2008
Fluorescent 6-Hydroxy- and 6,7-Dihydroxy-4-trifluoromethylcarbostyrils
and Formation of O-Carboxymethylated Derivatives via O-Succinimide Esters
171
with dry tetrahydrofurane and stirred in dry ethanol (10 mL) at
20 °C for 30 min to remove N,N'-diisopropylurea formed as by-
product during the reaction. Suction filtration afforded 130 mg
mmol) were brought to reaction and worked-up as described for
13a (method A). The yield was 35 mg (56%) of colorless
prisms, mp 238-239 °C (ethyl acetate). Method B: OSu-ester 11
(53 mg, 0.125 mmol) and glycyl-glycyl-glycine (12c) (24 mg,
0.125 mmol) were brought to reaction and worked-up as
1
(61%) of colorless prisms, mp 212-213 °C (ethanol); H nmr
(CDCl3): ꢀ 2.88 (s, 4 H, 2 CH2 of succinimide), 3.76 (s, 3 H,
NMe), 4.06 (s, 3 H, 7-OMe), 5.06 (s, 2 H, 6-OCH2), 6.86 (s, 1 H,
3-H), 7.00 (s, 1 H, 8-H), 7.46 (s, 1 H, 5-H); ir: 3537 m, 3454 m,
1813 w, 1783 w, 1738 s, 1652 m, 1625 w, 1585 m, 1528 m cm-1;
uv (DMSO): ꢀmax (nm) = 376, 307; (water): 356. MS: m/z (%) =
429 (28), 428 (62) [M], 345 (100). Anal. Calcd. for
C18H15F3N2O7 (428.32): C, 50.48; H, 3.53; N, 6.54. Found: C,
50.37; H, 3.43; N, 6.18.
1
described for 13a (method B). The yield was 33 mg (54%); H
nmr (DMSO-d6): ꢀ 3.70 (s, 3 H, NMe ), 3.73-3.74 (d, J = 5.5 Hz,
4 H, 2 peptide-CH2), 3.81-3.82 (d, J = 5.2 Hz, 2 H, peptide-
CH2), 4.01 (s, 3 H, 7-OMe), 4.59 (s, 2 H, 6-OCH2 ), 6.91(s, 1H,
3-H ), 7.13 (s,1 H, 8-H ), 7.17 (s, 1 H, 5-H), 8.17 (t, J = 5.5 Hz,
1 H, NH), 8.26 (t, J = 5.7 Hz, 1 H, NH), 8.30 (t, J = 5.4 Hz, 1 H,
NH); ir: 3378 w, 3357 w, 3299 w, 1655 s, 1529 m cm-1; uv
(DMSO): ꢀmax (nm) = 371, 309; (water): 365. Anal. Calcd. for
C20H21F3N4O8 (502.41): C, 47.81; H, 4.21; N, 11.15. Found: C,
48.01; H, 3.87; N, 11.10.
Ethyl 2-[2-(7-Methoxy-1-methyl-2-oxo-4-trifluoromethyl-
1,2-dihydroquinolin-6-yloxy)-acetylamino]-3-phenylpro-
pionate (13a). Method A: A solution of OSu-ester 11 (53 mg,
0.125 mmol) in dimethylformamide (1 mL) was added dropwise
to a solution of ethyl 2-amino-3-phenylpropanoate (12a) (24 mg,
0.125 mmol) in dimethylformamide (1 mL), and then N-
methylmorpholine (0.01 mL) was added. The reaction mixture
was stirred at 20 °C for 14 hours and poured into water (10 mL),
filtered and washed with water to afford 31 mg (49%) of
colorless prisms, mp 145-146 °C (ethyl acetate). Method B: A
solution of OSu-ester 11 (53 mg, 0.125 mmol) in aq. dimethyl-
sulfoxide (90%, 2 mL) was added dropwise to a solution of
(D,L)-phenylalanine (12a) (24 mg, 0.125 mmol) in aq.
dimethylsulfoxide (90%, 2 mL). Then pH7 buffer (1 mL) was
added, the reaction mixture stirred at 20 °C for 14 h, poured into
water (20 mL) and acidified with a few drops of conc.
hydrochloric acid. The solid was filtered and washed with water,
then dried and washed again with ethyl acetate to afford 39 mg
2-(7-Methoxy-1-methyl-2-oxo-4-trifluoromethyl-1,2-dihydro-
quinolin-6-yloxy)-N-(2,4,5-trihydroxy-6-hydroxymethyltetra-
hydropyran-3-yl)-acetamide (15): A solution of OSu-ester 11
(53 mg, 0.125 mmol) in dimethylformamide (2 mL) was added
dropwise to a solution of D-glucosamine hydrochloride (16) (27
mg, 0.125 mmol) in dimethylformamide/water (9:1, 2 mL), and
then N-methyl-morpholine (0.01 mL) was added. The reaction
mixture was stirred at 20 °C for 14 hours and poured into water
(25 mL), stirred for 1 hour at 20 °C, the solid filtered by suction
and washed with water to afford 33 mg (54%) of colorless
1
prisms, mp 260-261 °C; H nmr (CF3COOD): ꢀ 4.66 (s, 3 H,
NMe), 4.72 (s, 3 H, 7-OMe), 4.78 (m, 2 H, 7'-CH2), 4.83-4.95
(m, 3 H, 4', 5', 6'-H), 5.41 (s, 2 H, 6-OCH2), 5.69 (m, 1 H, 3'-H)
5.98 (d, J = 3.2 Hz, 1 H, ꢂ-H), 7.91 (s, 1 H, 3-H ), 8.10 (s, 2 H,
5-H, 8-H); ir: 3536 w, 3484 w, 3350 w, 3305 m, 1663 s, 1597 m,
1530 m cm-1; uv (DMSO): ꢀmax (nm) = 375, 309; (water): 355;
MS: m/z (%) = 472 (47) [M], 416 (100), 349 (55). Anal. Calcd.
for C20H23F3N2O9 (492.41): C, 48.79; H, 4.71; N, 5.69. Found:
C, 48.73; H, 4.59; N, 5.61.
1
(62%) of colorless prisms ; H nmr (CDCl3): ꢁ 1.26 (t, J = 6.83
Hz, 3 H, ester-CH3), 3.17 (d, J = 5.6 Hz, 2 H, Ph-CH2), 3.77 (s, 3
H, NMe), 3.91 (s, 3 H, 7-OCH3), 4.20 (q, J = 7.2 Hz, 2 H, ester-
CH2), 4.59 (s, 2 H, 6-OCH2), 4.97 (dd, J = 5.1 and 5.3 Hz, 1 H,
NCH), 6.80 (s, 1 H, 3-H), 7.01 (s, 1 H, 8-H ), 7.13 (m, 2 H, 5-H
and Ph-H ), 7.22 (s, 4 H, PhH), 7.49 (d, J = 7.7 Hz, 1 H, NH); ir:
3411 m, 1730 m, 1672 s, 1611 w, 1530 m cm-1; uv (DMSO):
ꢀmax (nm) = 366; (water): 354. Anal. Calcd. for C25H25F3N2O6
(506.48): C, 59.29; H, 4.98; N, 5.53. Found: C, 59.24; H, 4.86;
N, 5.48.
Acknowledgements. This research project was supported by
scholarships from the Austrian Exchange Service Academic /
Cooperation and Mobility Unit (N. S. B.) and the CEEPUS
network (S. K.).
2-[2-(7-Methoxy-1-methyl-2-oxo-4-trifluoromethyl-1,2-
dihydroquinolin-6-yloxy)-acetylamino]-3-phenylpropionic
acid (13b). Method A: OSu-ester 11 (53 mg, 0.125 mmol) and
(D,L)-phenylalanine (12b) (21 mg, 0.125 mmol) were brought to
reaction and worked up as described for 13a (method A) to
afford 35 mg (58%) of colorless prisms, mp 232-233 °C (ethyl
acetate). Method B: OSu-ester 11 (53 mg, 0.125 mmol) and
(D,L)-phenylalanine (12b) (21 mg, 0.125 mmol) were brought to
reaction and worked up as described for 13a (method B) to
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afford 45 mg (75%) of 13b; H nmr (CF3COOD): ꢁ 3.75-3.82
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