Long-wavelength-absorbing and -emitting carbostyrils with high fluorescence quantum yields

Article abstract of DOI:10.1002/(SICI)1522-2675(19990908)82:9<1408::AID-HLCA1408>3.0.CO;2-Q

Synthesis, absorption and fluorescence spectra, as well as quantum yields of a series of donor-acceptor-substituted carbostyrils (= quinolin- 2(1H)-ones), are reported. Unprecedented strong absorption maxima (ε = 10000-20000) close to the visible spectrum, large Stokes shifts up to 130 nm, and quantum yields up to 0.7 are obtained with derivatives containing donor substituents at C(6) and C(7), and either one Ph substituent at C(3) or one CF₃ residue at C(4). For analytical applications in biochemistry and medicine, N(1)-functionalization, or amidoacylation at C(3) in the case of the CF₃ derivatives, is possible without a concomitant hypsochromic shift of their absorption and emission maxima. Semiempirical molecular-orbital calculations (AM1 for structures, ZINDO for electronic transition energies) prove to be a suitable tool for the prediction of absorption properties of these compounds. The crystal-structure analysis of 6,7-dimethoxy-1-methyl-3- nitro-4-(trifluoromethyl)quinolin-2-(1H)-one (7) (C¹³H₁₁F₃N₂O₅, monoclinic, P2(l)lc, a=12.372(2), b= 12.154(2), c= 10.119(2)A, β= 112.95(2)°) shows that the NO₂ group, squeezed between the CF?₃ and the C=O group, is oriented almost perpendicularly (87.8(4)°) to the ring plane. The intramolecular F ··· N distance between the CF₃ and the NO₂ group is only 2.513(4)A.

Full text of DOI:10.1002/(SICI)1522-2675(19990908)82:9<1408::AID-HLCA1408>3.0.CO;2-Q

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Helvetica Chimica Acta ± Vol. 82 (1999)
Long-Wavelength-Absorbing and -Emitting Carbostyrils with High
Fluorescence Quantum Yields
a
a
b
a
1
by Georg Uray ), Karlheinz S. Niederreiter ), Ferdinand Belaj ), and Walter M. F. Fabian ) )*
a) Institut für Organische Chemie, Karl-Franzens Universität Graz, Heinrichstrasse 28, A-8010 Graz
b) Institut für Anorganische Chemie, Karl-Franzens Universität Graz, Schubertstrasse 1, A-8010 Graz
Synthesis, absorption and fluorescence spectra, as well as quantum yields of a series of donor-acceptor-
substituted carbostyrils (ˆquinolin-2(1H)-ones), are reported. Unprecedented strong absorption maxima (e ˆ
10000 ± 20000) close to the visible spectrum, large Stokes shifts up to 130 nm, and quantum yields up to 0.7 are
obtained with derivatives containing donor substituents at C(6) and C(7), and either one Ph substituent at C(3)
or one CF3 residue at C(4). For analytical applications in biochemistry and medicine, N(1)-functionalization, or
amidoacylation at C(3) in the case of the CF3 derivatives, is possible without a concomitant hypsochromic shift
of their absorption and emission maxima. Semiempirical molecular-orbital calculations (AM1 for structures,
ZINDO for electronic transition energies) prove to be a suitable tool for the prediction of absorption properties
of these compounds. The crystal-structure analysis of 6,7-dimethoxy-1-methyl-3-nitro-4-(trifluoromethyl)qui-
nolin-2-(1H)-one (7) (C13H11F3N2O5, monoclinic, P21/c, a ˆ 12.372(2), b ˆ 12.154(2), c ˆ 10.119(2)Š, b ˆ
112.95(2)8) shows that the NO2 group, squeezed between the CF3 and the CˆO group, is oriented almost
perpendicularly (87.8(4)8) to the ring plane. The intramolecular F ´´´ N distance between the CF3 and the NO2
group is only 2.513(4)Š.
Introduction. ± In a previous publication [1], we described a fairly systematic
investigation into the effect of substituents on the spectral-luminescent characteristics
of quinolin-2(1H)-ones (carbostyrils). The aim of that work was to establish guidelines
for the design of long-wavelength-absorbing and -emitting derivatives with potential
analytic applications in biochemistry and medicine [2]. Such compounds are required
to have high extinction coefficients e and high fluorescence quantum yields FF, ideally
close to 1. Additionally, besides sufficiently large Stokes shifts, absorption maxima
should be close to the visible spectrum. The latter requirement is also supported by the
fact that reasonably priced light-emitting diodes (LEDꢀs) have become available [3] as
excitation sources emitting at ca. 370 nm. A further feature to be fulfilled by
compounds with potential application as, e.g., fluorescence marker in biochemistry or
medicine, is ready functionalization by simple chemical transformations.
Based on our results obtained previously [1], we now show that, by judiciously
choosing the substituents, it is possible to obtain long-wavelength-absorbing and
-emitting carbostyril derivatives with high quantum yields. Synthesis and spectral-
luminescence characteristics of 19 selected candidates will be described. Since
computational methods have proved to be useful tools to aid the design of dyes with
special properties [1][4], the experimental results were complemented with semi-
empirical molecular-orbital calculations (AM1 [5], ZINDO [6]). In some cases,
1
)
Tel.: ‡ 43-316-380-8636; Fax: ‡ 43-316-380-9840; e-mail: walter.fabian@kfunigraz.ac.at

Helvetica Chimica Acta ± Vol. 82 (1999)
1409
calculations were performed prior to the synthesis, and experimental results obtained
afterwards proved to be fairly similar to the theoretical predictions. In case of
two potential structures, 21 and 22 (Table 1) the preparation could be even
omitted, because the calculations did not indicate any advantages of these two
compounds.
Table 1. Photophysical Data for Carbostyrils 1 ± 22 (n in cm 1).
Compound
nAbs (exper.)
e
nabs (calc.)
f
nflu (exper.)
FF
Dn
1
2
3
4
5
6
7
8
9
10
11
12c)
13
14
15
16
17
18
19
20
21
22
28900
27200
27300
27200
28300
25500
25400
9000
28500
27200
26900
27000
28600
24700
24700
28400
27500
27300
27200
27200
27400
26400
28500
26700
27000
27400
27900
27100
26900
27000
0.31
0.36
0.63
0.68
0.32
0.41
0.40
0.38
0.44
0.44
0.41
0.30
0.10
0.11
0.85
0.35
0.05
0.22
0.13
0.20
0.20
0.13
25500
22700
23000
23000
22400
0.09
0.59
0.23
0.28
0.04
3400
4500
4300
4200
5900
10400
17400
20800
10200
8810
a
)
)
a
7300
b
)
28600
28300
27100
27700
27900
26100
29000
27200
27200
26800
28300
27100
15100
12800
13000
17200
4100
3500
21100
9500
8100
7200
8000
5900
23200
23200
22100
25381
23500
20500
24200
22900
23100
22700
21100
21900
0.17
0.20
0.45
0.34
0.05
0.33
0.30
0.57
0.12
0.10
0.10
0.11
5400
5100
5000
2319
4400
5600
4800
4300
4100
4100
7200
5200
b
)
)
b
a) No fluorescence. b) Not prepared. c) Not a carbostyril.
Results. ± The structures investigated in the present paper are depicted below. The
choice of these molecules was guided by the following previous findings: i) a MeO
group at C(7) leads to relatively high absorption intensities; ii) the largest batho-
chromic shifts are found for 6-MeO derivatives; iii) high-fluorescence quantum yields
are shown by 3-aryl derivatives; iv) linear benzo annulation has a bathochromic effect
comparable to MeO substitution at C(6). Consequently, 6,7-dimethoxy derivatives,
e.g., 1 ± 11, were promising compounds. Additionally, the CF3 group has proved to be
beneficial for long-wavelength-absorbing and -emitting coumarins [7]. This structural
feature, thus, was also incorporated into most of the investigated compounds.
Functionalization was accomplished either by alkylation at N(1) or via alkylation or
acylation of the 3-NH2 derivatives 8 ± 10 (obtainable from the NO2 compounds 6 and
7). The strongly fluorescent compound 12, which is not a carbostyril, was formed by
coincidence in an attempt to synthesize 11.
Absorption Spectra. For solubility reasons, dimethyl sulfoxide (DMSO) and not
hexane was used throughout as the solvent. Even in this polar medium, most of the
investigated compounds show at least partly resolved vibrational fine structure in their
UV spectra. In the long-wavelength region, usually three peaks were discernible with a

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Helvetica Chimica Acta ± Vol. 82 (1999)
most intense central absorption or one central peak with two shoulders. Therefore, the
data in Table 1 (nAbs(exper.) and e) refer to these central peaks.
First of all, replacement of the Me group at C(4) by CF3 has a profound (1200 ±
1
1800 cm ) bathochromic effect (e.g., 1 vs. 2, 13 vs. 14, 18 vs. its CH3 derivative (n ˆ
1
28000 cm [1]), whereas this structural modification has little effect on e. As
anticipated, the NO2 derivatives 6 and 7 (i.e., acceptor at C(3)) are characterized by
absorption at the longest wavelength among all investigated compounds even ± as

Helvetica Chimica Acta ± Vol. 82 (1999)
1411
evidenced by both the calculations and the X-ray structure determination ± for a nearly
perpendicular arrangement of NO2 with respect to the heterocyclic ring. Reduction of
NO2, yielding the NH2 derivatives 9 and 10, leads to a significant hypsochromic effect
(e.g., 9 vs. 2). Acetylation of 9, giving 11, results in a bathochromically shifted
1
absorption maximum at the desired value of ca. 27000 cm . In addition, 11 has a
reasonably high extinction coefficient (e ˆ 13000). Interestingly, introduction of a third
MeO group has either no effect (20) or results in a blue shift (19). Compounds 1 and 2
demonstrate the importance of the MeO group at C(7) for high absorption intensities
(compare e of these two compounds with those of 13 and 14, resp.). Constraining the
two donor groups at C(6) and C(7) by incorporation into a five-membered ring system
has little effect (16 vs. 2). Methylation at N(1) (9 vs. 10) causes no hypsochromic shift at
1
all. Finally, also included in Table 1 are the calculated transition energies n (cm ) and
oscillator strengths f. Not surprisingly, the largest deviations of calculated from
experimental transition energies are found for compounds 9 and 10, i.e., NH2-
substituted derivatives. In our experience, the effect of NH2 groups on absorption
spectra is significantly underestimated by the ZINDO method [4]. Generally, apart
from 9 and 10, the calculated transition energies closely match the experimental data.
Excluding these two molecules, the mean deviation between experimental and
1
calculated wave numbers is ca. 400 cm . In contrast, as has also been observed in
our previous paper, oscillator strengths f are only moderately correlated with extinction
coefficients. Nevertheless, f still appears to be a useful quantity for a rough estimate of
absorption intensities. Clearly, the computational procedure used is of predictive value
for absorption spectra. Thus, synthesis of compounds 21 and 22 was not attempted,
since according to the calculations (see Table 1) these two molecules are not expected
to be superior to 20.
Fluorescence Spectra. Experimental fluorescence maxima n, quantum yields FF as
well as Stokes shifts Dn are also collected in Table 1. Most important, for several of the
investigated compounds, fluorescence quantum yields above 0.5 are obtained. Low
values for FF are shown by compounds containing H or Me instead of CF3 at C(4), e.g.,
1, 5, and 13, those lacking the 7-MeO substituent (13 and 14), or benzo-annulated
derivatives 17 and 18. The bathochromic shift induced by CF3 groups on fluorescence
1
maxima is even more pronounced (2000 ± 3000 cm ) than for absorption spectra.
1
Stokes shifts are in the range 4000 ± 5000 cm . Unusually large Stokes shifts are found
for 4-Ph derivative 5, which may be caused by a reduction of the Ph torsion in the first
electronic excited state, and, especially, for trimethoxy derivative 19. Thus, in contrast
to the absorption maximum, introduction of the third MeO group significantly shifts
the emission to longer wavelengths. Unfortunately, this substitution leads to a
substantial loss in fluorescence quantum yields. Introduction of an NH2 group at
C(3) causes not only a hypsochromic shift, but also a reduction in FF (compare 2 with
1
9). An unusually low Stokesꢀ shift, of 2300 cm is found for accidentally prepared,
strongly fluorescent compound 12, which is, however, not a carbostyril.
Crystal and Molecular Structure of 7. The NO2 group is squeezed between the CF3
group and the CˆO group, and is thereby oriented almost perpendicularly (87.8(4)8) to
the ring plane (see Fig.) and is not coplanar as observed in nitrobenzene [8] or in
other ortho-unsubstituted aromatic NO2 compounds. By the CF3 group, the NO2
group is strained towards the CˆO group: the bonding angle C(2) C(3) N(3) is

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Helvetica Chimica Acta ± Vol. 82 (1999)
Figure. Plot of a molecule of compound 7 showing the atomic numbering scheme. The probability ellipsoids are
drawn at the 50% probability level, the H-atoms are drawn with arbitrary radii (ORTEP [31]).
diminished from 116.88 in quinolin-2(1H)-one [9] to 111.3(2)8 in 7, the intra-
molecular F(41) ´´´ N(3) contact is only 2.513(4)Š compared to the sum of the van
der Waals radii of 3.02Š [10]. The corresponding calculated (AM1) structural
parameters closely match the experimental ones (C(2) C(3) N(3) O(31) ˆ 89.08,
F(41) C(41) C(4) C(3) ˆ 0.68, C(2) C(3) N(3) ˆ 113.48, F(41) ´´´ N(3) ˆ
2.514 Š). Selected bonding parameters are given in Table 2.
A search in the Cambridge Crystallographic Database [11] for ortho-substituted
nitro-trifluoromethyl compounds yielded 5 hits with the following torsion angles t
corresponding to F(41) C(41) C(4) C(3) in 7: if the CF3 group is encompassed by
two NO2 groups, j t j ranges from 91.4 to 95.98 [12][13]; in one compound, the CF3
group is cis-oriented with a C F bond towards the NO2 group (t ˆ 7.98 [14]) as in 7
[t ˆ 1.6(5)8], in one compound trans with t ˆ 178.48 [14], and in one compound t ˆ
80.98 [15]. In these compounds, the torsion angles corresponding to
O(31) N(3) C(3) C(4) in 7 range from 36.2 to 53.38 if the ring is unsubstituted at
the other side of the NO2 group [12][13][15], but range from 90.2 to 91.48 if the ring is
substituted at both sides of the NO2 group [14].
Conclusion. ± Although carbostyrils offer the advantage of greater thermal and
chemical stability over the corresponding coumarins, they have attracted considerably
less interest as potential analytical reagents. Their major disadvantages were their
shorter-wavelength absorption and emission, diminished sensitivity to substituents, and
their comparatively low fluorescence quantum yields [16]. In the present paper, we
have shown that it is possible, by judiciously choosing the nature and position of
substituents, to synthesize long-wavelength-absorbing and -emitting carbostyril deriv-

Helvetica Chimica Acta ± Vol. 82 (1999)
1413
Table 2. Selected Bond Lengths [Š] and Bond Angles [8] for 7 (for numbering of atoms, see the Figure)
N(1) C(2)
C(3) C(4)
C(10) C(5)
C(6) C(7)
C(8) C(9)
N(1) C(9)
C(2) O(2)
N(3) O(31)
C(4) C(41)
C(41) F(42)
C(6) O(6)
C(7) O(7)
1.377(3)
1.359(4)
1.420(4)
1.420(4)
1.411(4)
1.404(3)
1.233(3)
1.218(3)
1.509(4)
1.328(4)
1.362(3)
1.358(3)
C(2) C(3)
C(4) C(10)
C(5) C(6)
C(7) C(8)
C(9) C(10)
N(1) C(11)
C(3) N(3)
N(3) O(32)
C(41) F(41)
C(41) F(43)
O(6) C(61)
O(7) C(71)
1.450(4)
1.444(4)
1.368(4)
1.372(4)
1.406(4)
1.470(3)
1.481(3)
1.223(3)
1.328(3)
1.335(4)
1.425(3)
1.434(4)
C(2) N(1) C(9)
C(9) N(1) C(11)
N(1) C(2) O(2)
C(2) C(3) C(4)
C(4) C(3) N(3)
C(3) C(4) C(41)
C(5) C(6) O(6)
C(6) O(6) C(61)
C(8) C(7) O(7)
C(3) N(3) O(31)
O(31) N(3) O(32)
C(4) C(41) F(42)
C(11) N(1) C(2) O(2)
C(2) C(3) N(3) O(31)
N(3) C(3) C(4) C(41)
C(5) C(6) O(6) C(61)
123.4(2)
C(2) N(1) C(11)
N(1) C(2) C(3)
C(3) C(2) O(2)
C(2) C(3) N(3)
C(3) C(4) C(10)
C(10) C(4) C(41)
C(7) C(6) O(6)
C(6) C(7) O(7)
C(7) O(7) C(71)
C(3) N(3) O(32)
C(4) C(41) F(41)
C(4) C(41) F(43)
O(2) C(2) C(3) N(3)
C(2) C(3) N(3) O(32)
C(3) C(4) C(41) F(41)
C(8) C(7) O(7) C(71)
116.7(2)
119.8(2)
123.2(3)
125.0(2)
123.7(2)
121.9(2)
125.8(3)
117.5(2)
125.1(3)
118.2(3)
125.2(3)
111.6(3)
0.8(4)
114.5(2)
122.3(2)
111.3(2)
118.1(2)
120.0(2)
115.0(2)
114.5(3)
118.7(2)
116.5(3)
113.9(3)
111.7(3)
1.3(4)
87.3(3)
4.1(4)
6.8(4)
89.0(3)
1.6(5)
6.2(5)
atives with sufficiently high absorption intensities (extinction coefficients e) and
fluorescence quantum yields FF. Specifically, derivatives containing a CF3 group at
C(4) and MeO groups at C(7) show excellent photophysical properties. In addition, the
MeO substituent at C(6) is required for absorption and emission at sufficiently long
wavelengths. Evidently, compound 2, analogue type 16, and especially compounds of
type 11, derived from precursor 9, ideally fulfill the requirements outlined in the
introduction (labs ꢀ 370 nm; lF ꢀ 450 nm; sufficiently high absorption intensity and
fluorescence quantum yield, possibility to form linkages without decrease in wave-
length). However, it should also be noted that carbostyrils with substitution patterns as
in 4 and 15 exhibit outstanding photophysical data (see Table 1) which could be used for
further exploration.
Experimental Part
General. Chemicals and reagents were purchased from Aldrich or Fluka, and used without further
purification. M.p.: Gallenkamp Melting Point Apparatus, model MPD-350, in open capillary tubes. IR Spectra:
Perkin-Elmer 298 spectrophotometer, in KBr pellets. 1H-NMR Spectra: Varian XL-200 at 200 MHz or a Bruker
at 360 MHz, in the solvents indicated, chemical shifts (d) in ppm rel. to internal TMS. Microanalyses were
performed on a Fisons elemental analyzer model EA 1108.
General Procedure for the Synthesis of Compounds 1, 2, 13, 14, 16 ± 20. Substances were prepared according
to the Knorr synthesis [17]. Ethyl 3-oxobutanoate (2 equiv.) was heated in an open flask to the boiling point, and
the primary arylamine (1 equiv.) was added slowly. The contents of the flask were stirred occasionally to

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Helvetica Chimica Acta ± Vol. 82 (1999)
facilitate removal of the alcohol formed, and heating was continued for 30 min after all of the arylamine had
been added. On cooling the mixture, a dark liquid formed, which was concentrated under reduced pressure to
remove the excess of ester. The residual oil, representing the corresponding 3-oxo-arenecarboxamide, was not
crystallized, but used directly for the ring closure. To this oil, 76% H2SO4 or 10% P2O5 in MeSO3H was added,
and the mixture was heated carefully to 90 ± 958. Fumes developed at this temp., indicating that the reaction had
begun. After the reaction subsided (the temp. of the mixture must not exceed 958), the mixture was heated at
958 for 10 min, then cooled to 608 and poured into H2O. The precipitate formed was isolated and finally
recrystallized from alcohol.
6,7-Dimethoxy-4-methylquinolin-2(1H)-one (1): obtained from ethyl acetoacetate and 3,4-dimethoxyani-
line. Yield: 88%. Colorless prisms. M.p. 2408 (MeOH) ([18]: m.p. 236 ± 2378).
6,7-Dimethoxy-4-(trifluoromethyl)quinolin-2(1H)-one (2): obtained from ethyl 4,4,4-trifluoroacetoacetate
and 3,4-dimethoxyaniline. Yield: 50%. Colorless prisms. M.p. 2728 (EtOH). IR: 1675, 1625, 1560, 1520, 1460,
1
1430, 1320, 1270, 1245. H-NMR ((D6)DMSO): 3.80 (s, MeO C(6)); 3.85 (s, MeO C(7)); 6.80 (s, H C(3));
7.00 (m, H C(5), H C(8)); 12.15 (s, NH). Anal. calc. for C12H10F3NO3: C 52.75, H 3.69, N 5.13, O 17.57,
F 20.86; found: C 52.95, H 3.50, N 5.07.
6,8-Dimethoxy-4-methylquinolin-2(1H)-one (13): obtained from ethyl acetoacetate and 2,4-dimethoxyani-
line. Yield: 47%. Brown prisms. M.p. 231 ± 2338 (EtOH). IR: 1645, 1620, 1605, 1460, 1395, 1380, 1360, 1275,
1215. 1H-NMR ((D6)DMSO): 2.40 (s, Me C(4)); 3.85 (s, MeO C(6)); 3.90 (s, MeO C(8)); 6.45 (s, H C(3));
6.75 (s, H C(5)); 6.80 (s, H C(7)); 10.50 (s, NH). Anal. calc. for C12H13NO3: C 65.74, H 5.98, N 6.39, O 21.89;
found: C 65.41, H 6.00, N 6.36.
6,8-Dimethoxy-4-(trifluoromethyl)quinolin-2(1H)-one (14): obtained from ethyl 4,4,4-trifluoroacetoace-
tate and 2,4-dimethoxyaniline. Yield: 88%. Yellow prisms. M.p. 1968 (EtOH). IR: 1675, 1615, 1465, 1410, 1360,
1320, 1275. 1H-NMR ((D6)DMSO): 3.85 (s, MeO C(6)); 4.00 (s, MeO C(8)); 6.70 (s, H C(3)); 7.05
(s, H C(5)); 7.10 (s, H C(7)); 11.55 (s, NH). Anal. calc. for C12H10F3NO3: C 52.75, H 3.69, N 5.13, O 17.57,
F 20.86; found: C 52.60, H 3.48, N 5.01.
6,7-(Methylenedioxy)-4-(trifluoromethyl)quinolin-2(1H)-one (16): obtained from ethyl 4,4,4-trifluoroace-
toacetate and 3,4-methylenedioxyaniline. Yield: 58%. Colorless prisms. M.p. 288 ± 2908 (DMSO). IR: 1665,
1565, 1500, 1475, 1450, 1430, 1405, 1360, 1315. 1H-NMR ((D6)DMSO): 6.18 (s, OCH2O); 6.80 (s, H C(3)); 6.95
(s, H C(5)); 7.05 (s,H C(8)); 12.22 (s, NH). Anal. calc. for C11H6F3NO3: C51.38, H 2.35, N 5.45, O 18.66,
F 22.16; found: C 51.31, H 2.18, N5.37.
4-(Trifluoromethyl)benzo[g]quinolin-2(1H)-one (17): obtained from ethyl 4,4,4-trifluoroacetoacetate and
2-naphthylamine. Yield: 48%. Colorless prisms. M.p. 274 ± 2768 (EtOH). IR: 1670, 1585, 1545, 1525, 1485, 1465,
1425, 1400, 1310, 1265, 1250. 1H-NMR ((D6)DMSO): 7.20 (s, H C(3)); 7.50 ± 7.80 (m, H C(7), H C(9),
H
C(10)); 8.05 (m, H C(8)); 8.20 (m, H C(6)); 8.40 (m, H C(5)); 12.80 (s, NH). Anal. calc. for
C14H8F3NO: C 63.88, H 3.06, N 5.32, O 6.08, F 21.65; found: C 63.75, H 2.96, N 5.25.
4-(Trifluoromethyl)benzo[h]quinolin-2(1H)-one (18): obtained from ethyl 4,4,4-trifluoroacetoacetate and
naphthalen-1-amine. Yield: 75%. Yellow prisms. M.p. 2888 (MeOH) ([19]: m.p. 304 ± 3058).
5,6,7-Trimethoxy-4-(trifluoromethyl)quinolin-2(1H)-one (19): obtained from ethyl 4,4,4-trifluoroacetoace-
tate and 3,4,5-trimethoxyaniline. Yield: 44%. Grey prisms. M.p. 231 ± 2338 (EtOH). IR: 1675, 1615, 1550, 1500,
1480, 1445, 1415, 1385, 1365. 1H-NMR ((D6)DMSO): 3.87 (s, MeO C(6)); 3.94 (s, MeO C(5), MeO C(7));
6.88 (s, H C(3)); 6.90 (s, H C(8)); 12.08 (s, NH). Anal. calc. for C13H12F3NO4: C 51.48, H 4.00, N 4.62,
O 21.10, F 18.80; found: C 51.42, H 3.90, N 4.57.
6,7,8-Trimethoxy-4-(trifluoromethyl)quinolin-2(1H)-one (20): obtained from ethyl 4,4,4-trifluoroaceto-
acetate and 2,3,4-trimethoxyaniline. Yield: 43%. Grey prisms. M.p. 242 ± 2448 (EtOH). IR: 1675, 1615, 1500,
1465, 1420, 1355, 1320, 1275. 1H-NMR (CDCl3): 3.90 (s, MeO C(7)); 3.97 (s, MeO C(6)); 4.08 (s, MeO C(8);
6.90 ± 7.05 (m, H C(3), H C(5)); 10.00 (s, NH). Anal. calc. for C13H12F3NO4: C51.48, H 4.00, N 4.62, O 21.10,
F 18.80; found: C 51.38, H 3.89, N 4.55.
6,7-Dimethoxy-3-phenylquinolin-2(1H)-one (3): obtained from 2-chloro-6,7-dimethoxy-3-phenylquinoline
(0.72 g, 2.4 mmol) in glacial AcOH and H2O according to the procedure described in [20]. Yield: 0.45 g (66%).
Colorless prisms. M.p. 242 ± 2448 ([21]: m.p. 2648).
6,7-Dimethoxy-3-(4-methoxyphenyl)quinolin-2(1H)-one (4): obtained from 2-chloro-6,7-dimethoxy-3-(4-
methoxyphenyl)quinoline (0.72 g, 2.4 mmol) in glacial AcOH and H2O according to the procedure described in
[20]. Yield: 0.53 g (87%). Colorless prisms. M.p. 247 ± 2498 ([22]: m.p. 2508).
6,7-Dimethoxy-4-phenylquinolin-2(1H)-one (5): obtained from 3,4-dimethoxyaniline (2.4 g, 16 mmol) and
ethyl 3-oxo-3-phenylpropanoate (3.7 g, 19 mmol) according to the procedure described in [23]. Yield: 0.15 g
(30%). Colorless prisms. M.p. 2628 (EtOH). IR: 1655, 1515, 1440, 1415, 1355, 1260, 1230, 1210, 1120. 1H-NMR

Helvetica Chimica Acta ± Vol. 82 (1999)
1415
((D6)DMSO): 3.60 (s, MeO C(6)); 3.85 (s, MeO C(7)); 6.25 (s, H C(3)); 6.80 (s, H C(8)); 6.95
(s, H C(5)); 7.40 ± 7.65 (m, H C(2), H C(3), H C(4), H C(5), H C(6) of Ph); 11.70 (s, NH). Anal. calc.
for C17H15NO3: C 72.58, H 5.37, N 4.98, O 17.06, found: C 72.48, H 5.40, N 4.94.
6,7-Dimethoxy-3-nitro-4-(trifluoromethyl)quinolin-2(1H)-one (6). First 35 ml of cooled 40% HNO3 and
then 17.5 ml of a cold soln. containing HNO3/H2SO4 1.0 :1.2 were added dropwise to 3.50 g (12.81 mmol) of 6,7-
dimethoxy-4-(trifluoromethyl)quinolin-2(1H)-one under N2 while cooling with an ice-water bath. The mixture
was warmed and stirred 35 min at r.t., then poured into 175 ml of cold H2O. After 25 min at 08, the formed
precipitate was isolated and washed with H2O. The product was purified by flash column chromatography (silica
gel 60 from Fluka, particle size 35 ± 70 mm; CH2Cl2/acetone 9 :1). Yield: 2.57 g (8.08 mmol; 63%). Yellow solid.
M.p. 2708 (acetone). IR: 1670, 1625, 1550, 1515, 1460, 1430, 1360, 1310, 1295, 1260, 1250, 1210, 1180. 1H-NMR
((D6)DMSO): 3.80 (s, MeO C(6)); 3.85 (s, MeO C(7)); 7.00 (s, H C(5), H C(8)); 12.15 (s, NH). Anal. calc.
for C12H9F3N2O5: C 45.29, H 2.85, N 8.80, O 25.14, F 17.91; found: C 45.52, H 2.59, N 8.55.
6,7-Dimethoxy-1-methyl-3-nitro-4-(trifluoromethyl)quinolin-2(1H)-one (7). Compound
6
(400 mg,
1.26 mmol), dimethyl sulfate (212 mg; 1.68 mmol), and K2CO3 (3.0 g, 22 mmol) were refluxed in acetone
(120 ml) for 4 h. Filtration and evaporation of the solvent gave a mixture of N- and O-methylated products
(80 :20), which were separated by flash column chromatography (silica gel 60 from Fluka, particle size 35 ±
70 mm; CH2Cl2/acetone 9 :1). Yield: 230 mg (0.69 mmol; 55%) of 7 (the O-methylated product was not further
investigated). M.p. 2548 (CH2Cl2/acetone 9 :1). IR: 1650, 1615, 1550, 1520, 1460, 1430, 1390. 1H-NMR (CDCl3):
3.85 (s, MeO C(6)); 3.95 (s, MeO C(7)); 4.10 (s, Me N); 6.87 (s, H C(8)); 7.28 (s, H C(5)). Anal. calc. for
C13H11F3N2O5: C 47.00, H 3.34, N 8.43; found: C 47.12, H 3.31, N 8.40.
3-Amino-6,7-dimethoxy-4-(trifluoromethyl)quinolin-2(1H)-one (9). A suspension of 1.08 g (3.39 mmol) of
6 in 200 ml of abs. EtOH was reduced by shaking with H2 at 50 psi (3.4bar, 3.4 ´ 105 Pa) and 508 for 24 h, in the
presence of PtO2 (50 mg). The soln. was filtered, evaporated, and the residue was recrystallized from toluene.
Yield: 0.83 g (2.88 mmol; 85%). Yellow solid. M.p. 2218 (EtOH). IR: 3520, 3405, 1620, 1615, 1580, 1515, 1470,
1
1430, 1375, 1345, 1275, 1230, 1140, 1095. H-NMR ((D6)DMSO): 3.75 (s, MeO C(6)); 3.80 (s, MeO C(7));
6.15 (s, NH2 C(3)); 6.90 (s, H C(8)); 6.95 (d, H C(5)); 12.10 (s, NH). Anal. calc. for C12H11F3N2O3: C 50.01,
H 3.85, N 9.72, O 16.65, F 19.77; found: C 50.28, H 3.79, N 9.49.
3-Amino-6,7-dimethoxy-1-methyl-4-(trifluoromethyl)quinolin-2(1H)-one (10). A suspension of 230 mg
(0.69 mmol) of 7 in 40 ml of abs. EtOH was reduced by shaking with H2 at 50 psi (3.4 bar, 3.4 ´ 105 Pa) and 508
for 24 h, in the presence of PtO2 (10 mg). The soln. was filtered and evaporated. Yield: 200 mg (0.66 mmol;
96%). Yellow solid. M.p. 1918 (EtOH). IR: 3490, 3390, 1620, 1555, 1530, 1470, 1450, 1410, 1365, 1300, 1270,
1235, 1160. 1H-NMR ((D6)DMSO): 3.81 (s, MeO C(6)); 3.90 (s, MeO C(7)); 3.96 (s, Me N(1)); 5.48
(s, NH2 C(3)); 6.80 (s, H C(8)); 7.18 (d, H C(5)). Anal. calc. for C13H13F3N2O3: C 51.66, H 4.34, N 9.27;
found: C 51.75, H 4.32, N 9.35.
N-[6,7-dimethoxy-2-oxo-4-(trifluoromethyl)-1H-quinolin-3-yl]acetamide (11).
A mixture of 50 mg
(0.17 mmol) of 9 and 35 mg (0.35 mmol) of Ac2O in 2 ml of abs. pyridine was refluxed in the presence of 4-
pyrrolidinopyridine (10 mg) under Ar for 1 h. The formed precipitate was washed with CH2Cl2 and dried at 608.
Yield: 35 mg (0.11 mmol; 61%). Yellow solid. M.p.: dec. above 3208 (CH2Cl2). IR: 3250, 1655, 1520, 1450, 1420,
1365, 1325, 1290, 1270, 1250. 1H-NMR ((D6)DMSO): 2.10 (s, Me CO); 3.82 (s, MeO C(6)); 3.88
(s, MeO C(7)); 6.97 (s, H C(8)); 7.09 (s, H C(5)); 9.60 (s, NH C(3)); 12.50 (s, NH). Anal. calc. for
C14H13F3N2O4: C 50.91, H 3.97, N 8.48; found: C 51.01, H 3.89, N 8.43.
6,7-Dimethoxy-2-methyl-9-(trifluoromethyl)[1,3]oxazolo[5,4-b]quinoline (12): obtained from 9 (100 mg,
0.35 mmol), Ac2O (2.0 ml, 21 mmol), and I2 (5 mg) according to the procedure described in [24]. Yield: 90 mg
(0.29 mmol, 83%). Colorless solid. M.p. 2318 (DMSO). IR: 1625, 1580, 1490, 1435, 1350, 1335, 1280, 1255, 1225,
1215. 1H-NMR ((D6)DMSO): 2.70 (s, Me C(2)); 3.92 (s, MeO C(7)); 3.98 (s, MeO C(6)); 7.35 (s, H C(5));
7.60 (s, H C(8)). Anal. calc. for C14H11F3N2O3: C 53.85, H 3.55, N 8.97; found: C 53.86, H 3.52, N 8.92.
5,7-Dimethoxy-3-phenylquinolin-2(1H)-one (15): obtained from 2-chloro-5,7-dimethoxy-3-phenylquino-
line (0.20 g, 0.67 mmol) in glacial AcOH and H2O according to the procedure described in [20]. Yield: 0.14 g
(74%). Colorless prisms. M.p. 2438 (CHCl3/acetone 7 :3). IR: 2930, 2840, 1660, 1630, 1615, 1570, 1515, 1475,
1
1455, 1440, 1410, 1395. H-NMR ((D6)DMSO): 3.85 (s, MeO C(5)); 3.95 (s, MeO C(7)); 6.40 (s, H C(6));
6.50 (s, H C(8)); 7.30 ± 7.50 (m, H C(3), H C(4), H C(5) of Ph); 7.70 (d, H C(2), H C(6) of Ph); 8.05
(s, H C(4)); 11.85 (s, NH). Anal. calc. for C17H15NO3: C 72.59, H 5.37, N 4.98, O 17.06, found: C 72.47; H 5.30;
N 4.88.
Absorption and Fluorescence Spectra. Solvents for UV and fluorescence spectra were purified by
distillation. UV/VIS Spectra were recorded on a Shimadzu UV/VIS scanning spectrophotometer UV-2101PC.
Excitation and emission spectra were obtained with a Shimadzu RF-5001PC spectrofluorophotometer. It is

1416
Helvetica Chimica Acta ± Vol. 82 (1999)
fitted with a 150-W Xe lamp operated as a continuous wave source, slits selectable in 6 steps to produce spectral
bandwidths of 1.5, 3, 5, 10, 15, and 20 nm, and an R452-01 photomultiplier. Excitation and emission
monochromators: ion-blazed holographic concave grating F/2.5.
UV Spectra were recorded at a concentration of 10 mg/ml, excitation and emission spectra at a
concentration of 1 mg/ml. For the determination of quantum yields, emission signals were set in relation to the
emission signal of 3 under the same conditions (slit, solvent, temp., and concentration). Compound 3 has a
quantum yield, according to [25], of 0.020. Emission spectra are uncorrected.
X-Ray Crystal-Structure Determination of 7. Crystal data and measurement conditions are summarized in
Table 3. The diffraction data were collected by w scans on a modified Stoe four-circle diffractometer at r.t. The
structure was solved by direct methods (SHELXS-97 [26]) and refined by full-matrix least-squares techniques
against F2 (SHELXL-97 [27]) until the parameter shifts became zero. The non-H-atoms were refined with
anisotropic displacement parameters. The H-atoms of the Me groups were refined with common isotropic
displacement parameters for the H-atoms of the same group and idealized geometry with C H distances of
0.96 Š.
Table 3. Crystallographic Data for Compound 7
Formula
C13H11F3N2O5
332.24
298
Formula weight [g/mol]
Temperature [K]
Crystal size [mm]
Crystal system
Space group
a [Š]
b [Š]
c [Š]
b [8]
V [Š3]
0.55 Â 0.50 Â 0.10
monoclinic
P21/c (No. 14)
12.372(2)
12.154(2)
10.119(2)
112.95(2)
1401.1(4)
4
Z
F(000)
1calc [g cm
l [Š]
m (MoKa) [mm
Vmax [8]
680
1.575
0.71069
0.146
25
3
]
1
]
No. of measured reflections
No. of independent reflections
No. of observed reflections
Criterion for observed reflections
Refinement (on F2)
3169
2457
1573
I > 2s(I)
Full-matrix
213
0.0544
0.1269
No. of parameters refined
R1 ˆ S k Fo j j Fc k /S j Fo j
wR ˆ {S[w(Fo2 Fc2)2]/S[w(Fo2)2]}1/2
S ˆ {S[w(Fo2 Fc2)2]/(Nref Npar)}1/2
1.073
0.158, 0.161
3
Max. and min. D1 [eŠ
]
Crystallographic data (excluding structure factors) for the structure reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as deposition No. CCDC-118478. Copies of the data
can be obtained, free of charge, on application to the CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax:
‡44 (1223) 336033; e-mail: deposit@ccdc.cam.ac.uk).
Computational Procedures. Starting structures of the investigated compounds were created with the aid of
the SYBYL molecular-modeling package [28]. Semiempirical molecular-orbital calculations were done by the
MOPAC [5] program packages. Geometries for ground states were completely optimized (keyword PRECISE)
by the semiempirical AM1 [5] Hamiltonian with the eigenvector following the routine in [29]. Based on the
AM1-optimized structures, electronic transition energies were calculated by the ZINDO method [6]. Solvent
effects (DMSO, n ˆ 1.479, D ˆ 45.0) were treated with the self-consistent reaction-field approximation [30].

Helvetica Chimica Acta ± Vol. 82 (1999)
1417
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Received May 14, 1999