New synthesis of (Z)-and (E)-3-styryl-4-quinolones

Article abstract of DOI:10.1055/s-0030-1258042

A novel and efficient route for the synthesis of (Z)-and (E)-3-styryl-4-quinolones is described. Wittig reaction of 4-(chloroquinoline- and quinolone)-3-carbaldehydes with benzylic ylides is the key transformation for this synthetic route. The (Z)-1-methyl-3-styryl-4-quinolone is obtained with high diastereoselectivity from the reaction of 1-methyl-4-quinolone-3- carbaldehyde; while (E)-3-styryl-4-quinolone is prepared through the Wittig reaction of 4-chloroquinoline-3-carbaldehyde followed by acid hydrolysis. Both synthetic routes are efficient regardless of the substituents on the benzylic ylides. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258042

LETTER
2257
New Synthesis of (Z)- and (E)-3-Styryl-4-quinolones
Synthesis of
(
Z
)
-
a
and(
E
)
-
3-S
q
tyryl-4-quin
uolones el S. G. R. Seixas, Artur M. S. Silva,* José A. S. Cavaleiro
Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
Fax +351(234)370084; E-mail: artur.silva@ua.pt
Received 11 June 2010
this type of compound and the reported important biolog-
ical applications of 4-quinolones, a new synthetic route
for the synthesis of (Z)- and (E)-3-styryl-4-quinolones
from 4-(chloroquinoline- and quinolone)-3-carbalde-
Abstract: A novel and efficient route for the synthesis of (Z)- and
(E)-3-styryl-4-quinolones is described. Wittig reaction of 4-(chlo-
roquinoline- and quinolone)-3-carbaldehydes with benzylic ylides
is the key transformation for this synthetic route. The (Z)-1-methyl-
3-styryl-4-quinolone is obtained with high diastereoselectivity from hydes has been developed. The use of these starting mate-
the reaction of 1-methyl-4-quinolone-3-carbaldehyde; while (E)-3-
styryl-4-quinolone is prepared through the Wittig reaction of 4-
rials is very attractive due to the wide range of reactions
in which the formyl group can participate. We already
chloroquinoline-3-carbaldehyde followed by acid hydrolysis. Both
described the use of 4-quinolone-3-carbaldehyde in
synthetic routes are efficient regardless of the substituents on the
Knoevenagel condensations13 and as a dienophile in cy-
benzylic ylides.
cloaddition reactions.14 In this work we will report on the
Key words: 4-chloroquinoline-3-carbaldehyde,
4-quinolone-3-
reactivity of 4-(chloroquinoline- and quinolone)-3-carbal-
dehydes in Wittig reactions with benzylidenetriphe-
nylphosphoranes. The influence of the substituents of the
benzylic ylides, the quinolone protecting groups, and the
quinolone moiety on the reaction yields and Z/E isomeric
ratios will also be described.
carbaldehyde, 3-styryl-4-quinolone, 4-chloro-3-styrylquinoline,
Wittig reaction
4-Quinolone derivatives comprise a large group of nitro-
gen heterocycles that play an important role in the devel-
opment of new drugs. This ring system can be found in a
variety of natural products,1 mainly in compounds from
plants of the Rutaceae family, but the majority of these
derivatives are of synthetic origin. The most explored
property of 4-quinolones is their broad spectrum of anti-
microbial activity, several of them being used as drugs in
the treatment of different kinds of infections;2 certain de-
rivatives are also approved by the WHO as second-line
drugs in the treatment of tuberculosis.3 When appropriate-
ly functionalized they have shown potential in other phar-
macological areas, acting as antitumor4 and antiviral
agents5 and also as CB2 receptor agonists.6
Our first study considered the Wittig reaction of 1-methyl-
4-quinolone-3-carbaldehyde (2a) with benzylidenetriphe-
nylphosphoranes 4a–d. 4-Quinolone-3-carbaldehyde (1)
was prepared by Vilsmeier reaction on 2¢-aminoacetophe-
none, followed by acid hydrolysis of the 4-chloroquino-
line-3-carbaldehyde 7 thus obtained, followed by
methylation with iodomethane in the presence of PS-TBD
as a base to afford 1-methyl-4-quinolone-3-carbaldehyde
(2a).13 The semistabilized ylide 4a was obtained from the
reaction of benzyltriphenylphosphonium chloride 3a with
a molar equivalent of NaH in dry THF, under reflux for 3
hours. The formation of 4a could be observed due to the
appearance of an orange color and, after the addition of 1-
methyl-4-quinolone-3-carbaldehyde (2a), the solution
turned colorless; after which the reaction mixture was
refluxed for 3 hours. This reaction afforded a mixture of
(Z)- and (E)-1-methyl-3-styryl-4-quinolones 5a and 6a
(Table 1, Scheme 1) in good yields. The Z-isomer was the
more abundant, as expected from the reaction of semista-
bilized ylides with sterically crowded carbonyl com-
pounds.15
3-Styryl-4-quinolones are compounds structurally similar
to 3-aryl-4-quinolones and are the aza-analogues of 3-
styryl-4-chromones. 3-Aryl-4-quinolones or azoisofla-
vones, which are less studied than the corresponding 2-
aryl-derivatives, have shown inhibitory activity against P-
glycoprotein7 and EGFR tyrosine kinase,8 antiplatelet,9
and cytotoxic activity against human cancer cell lines;10
while 3-styryl-4-chromones have shown antifungal and
antibacterial activities.11
In order to understand the influence of the N-protecting
group of the quinolone in the reactivity of the 3-formyl
group of the 4-quinolone-3-carbaldehyde in the Wittig re-
action, we carried out the same reaction but using the tol-
uenesulfonyl protecting group as an electron-withdrawing
substituent. 1-Tosyl-4-quinolone-3-carbaldehyde (2b)
was prepared in good yield by the reaction of 4-quinolo-
ne-3-carbaldehyde (1) with p-toluenesulfonyl chloride in
acetone using potassium carbonate as base.16 The reaction
of 1-tosyl-4-quinolone-3-carbaldehyde (2b) with ylide 4a
also yielded a mixture of (Z)- and (E)-3-styryl-1-tosyl-4-
To the best of our knowledge, the only synthetic route for
the synthesis of 3-styryl-4-quinolones was recently de-
scribed by our group and it involves the Heck reaction of
3-iodo-4-quinolones with styrene derivatives under clas-
sical heating conditions and under MW irradiation.12 This
methodology only allows the preparation of the E-diaste-
reomer of 3-styryl-4-quinolone. Following our interest in
SYNLETT 2010, No. 15, pp 2257–2262
x
x
.x
x
.2
0
1
0
Advanced online publication: 12.08.2010
DOI: 10.1055/s-0030-1258042; Art ID: D14610ST
© Georg Thieme Verlag Stuttgart · New York

2258
R. S. G. R. Seixas et al.
LETTER
quinolones 5e and 6e in moderate yields, with the Z-iso-
mer being the major product as expected.
Table 1 Reaction Conditions and Yields in the Wittig Reaction of 1-
Methyl-4-quinolone-3-carbaldehyde (2a) and 1-Tosyl-4-quinolone-3-
carbaldehyde (2b) with Benzylidenetriphenylphosphoranes 4a–d
The results of the reaction of both 4-quinolone-3-carbal-
dehyde derivatives 2a and 2b with p-nitrobenzylidene-
triphenylphosphorane 4d were analogous to that
described with the ylide 4a. Better yields and easier puri-
fication were observed in the reaction of 1-methyl-4-quin-
olone-3-carbaldehyde (2a); while the reaction of 1-tosyl-
4-quinolone-3-carbaldehyde (2b) took less time, although
no significant difference in the Z/E isomeric ratios was
observed. The purification of 1-tosyl-derivatives 5e,f17
and 6e,f18 was more difficult, and these compounds
proved to be more unstable in solution under light than the
corresponding 1-methyl-derivatives 5a,d and 6a,d.19
These results led us to consider the Wittig reaction of 1-
methyl-4-quinolone-3-carbaldehyde (2a) with ylides 4b
and 4c, obtaining in both cases a diastereomeric mixture
of (Z)- and (E)-1-methyl-3-styryl-4-quinolones 5b,c and
6b,c (Table 1, Scheme 1).20 The Z-isomer was always the
most abundant isomer independent of the starting ylide.
RCHO Ylide synthesis
Reaction timeafterTotal yield Z/E ratio
the addition of 2 (%)
of 5/6
2a
2a
2a
2a
2a
2a
2b
2b
2b
4a: 3 equiv, 3 h
4b: 3 equiv, 3 h
4b: 3 equiv, 3 h
4c: 3 equiv, 1 h
4c: 3 equiv, 1 h
4d: 1.5 equiv, 3 h
4a: 1.5 equiv, 3 h
4a: 3 equiv, 3 h
4d: 1.5 equiv, 3 h
3 h
3 h
78
48
77
54
79
96
47
52
73
70:8
44:4
21 h
4 h
68:9
43:11
64:15
72:24
38:9
21 h
3 h
3 h
4 h
46:6
1.5 h
69:4
in good yields (Table 2, Scheme 2).20 These reactions
took less time that the corresponding reactions with 1-
methyl-4-quinolone-3-carbaldehyde (2a), the global
yields were slightly better in the case of ylides 4a,b and
the Z-diastereomer was once again the most abundant one,
although the Z/E ratio was lower.
R2
H
N
for compounds 3 and 4:
3a, 4a R2 = H
3b, 4b R2 = Cl
3c, 4c R2 = OEt
3d, 4d R2 = NO2
CHO
H2C
O
PPh3X
NaH
R2
The next step in our strategy was the hydrolysis of the (Z)-
and (E)-4-chloro-3-styrylquinolines 8a–d and 9a–d. We
began with the hydrolysis the (Z)-4-chloro-3-styrylquino-
1
3a–d
R1
N
(i)
(iii)
(ii)
R2
R2
R1
N
O
R2
R2
5a–f
(iii)
+
NaH
R1
CHO
H2C
(i)
N
PPh3X
N
HC
O
PPh3
3a–d
HC
2a,b
4a–d
PPh3
2a R1 = Me
2b R1 = Ts
Cl
4a–d
O
N
R2
8a–d
+
(i)
6a–f
For compounds 5 and 6:
5a, 6a R1 = Me; R2 = H
CHO
N
5b, 6b R1 = Me; R2 = Cl
5c, 6c R1 = Me; R2 = OEt 5d, 6d R1 = Me; R2 = NO2
Cl
5e, 6e R1 = Ts; R2 = H
5f, 6f R1 = Ts; R2 = NO2
7
Cl
O
S
a R2 = H
b R2 = Cl
R2
c R2 = OEt
d R2 = NO2
Ts =
Me
9a–d
O
Scheme 2 Reagents and conditions: (i) dry THF, reflux, N2.
Scheme 1 Reagents and conditions: (i) MeI, PS-TBD, dry THF, 40
°C, N2; (ii) K2CO3, ClTs, acetone, r.t.; (iii) dry THF, reflux, N2.
Table 2 Reaction Conditions and Yields in the Wittig Reaction of
4-Chloroquinoline-3-carbaldehyde (7) with Benzylidenetriphenyl-
phosphoranes 4a–d
In parallel, we studied an alternative means of synthesiz-
ing the 3-styryl-4-quinolones by Wittig reaction of the
semistabilized ylides 4a–d with 4-chloroquinoline-3-carb-
aldehyde 7 in order to obtain 4-chloro-3-styrylquinolines
8a–d and 9a–d that, after hydrolysis, would generate the
desired 3-styryl-4-quinolones. Using this strategy we
could eliminate the N-protection step of the quinolone.
The Wittig reaction of 4-chloroquinoline-3-carbaldehyde
7 with benzylidenetriphenylphosphoranes 4a–d gave the
(Z)- and (E)-4-chloro-3-styrylquinolines 8a–d21 and 9a–d22
Ylide synthesis
Reaction time after Total yield Z/E ratio
the addition of 7
(%)
of 8/9
55:36
60:29
50:28
65:28
4a: 3 equiv, 3 h
4b: 3 equiv, 3 h
4c: 3 equiv, 1 h
4d: 1.5 equiv, 3 h
0.75 h
4.5 h
1 h
91
89
78
1 h
93
Synlett 2010, No. 15, 2257–2262 © Thieme Stuttgart · New York

LETTER
Synthesis of (Z)- and (E)-3-Styryl-4-quinolones
2259
line 8a in 40% of aqueous formic acid, firstly at room tem-
perature and then at 55 °C but only traces of the
corresponding quinolone were observed. At the reflux
conditions complete hydrolysis was achieved (Scheme 3)
but a simultaneous isomerization of the (Z)-3-styryl-4-
quinolone 10a to the thermodynamically more stable E-
isomer 11a was observed (Table 3). Isomerization was
also observed when using a lower concentration of formic
acid (10%) at reflux temperature (Table 3). Using hydro-
chloric acid as a stronger acid, in order to avoid heating
and retain the configuration of the initial compound, did
not work because the hydrolysis was again only efficient
at reflux temperature (Table 3). The isomerization pro-
cess was observed for all the (Z)-3-styryl-4-quinolone de-
rivatives 10a–d being faster in the case of the p-ethoxy
derivative 10c and slower for the p-nitro derivative 10d
(Table 3).
Table 3 Reaction Conditions and Yields in the Hydrolysis of (Z)-4-
Chloro-3-styrylquinolines 8a–d
Quinoline
[Acid]
Temp
Reaction Yield of
time (h) 10/11 (%)
40% HCOOH
10% HCOOH
HCl 1 M
reflux
reflux
reflux
reflux
reflux
reflux
reflux
23
23
48
18
18
18
18
0/69
21/55a
0/81
8a R2 = H
8a R2 = H
40% HCOOH
40% HCOOH
40% HCOOH
40% HCOOH
9/78a
9/76a
0/92
8b R2 = Cl
8c R2 = OEt
8d R2 = NO2
25/74a
a Calculated yields based on the 1H NMR integration of H-a and H-b.
Hydrolysis of (E)-4-chloro-3-styrylquinolines 9a–d in re-
fluxing 40% formic acid for 18 hours gave the corre-
sponding (E)-3-styryl-4-quinolones 11a–d23 in good
yields without need of purification (Table 4). Thus we
carried out the hydrolysis of the diastereomeric mixture of
(Z)- and (E)-4-chloro-3-styrylquinolines derivatives 8a–d
and 9a–d for extended reaction times (24 h) aiming to
synthesize only the E-diastereomer. Indeed, both Z- and
E-isomers 8a–d and 9a–d yielded only (E)-3-styryl-4-
quinolones 11a–d in good yields with the exception of the
4¢-nitro-derivatives 8d and 9d that required 48 hours
(Table 4).24
6.67–6.93 ppm) appear at higher frequency values than
those of H-b (d = 6.58–6.66 ppm), and the stereochemis-
try of the vinylic system was established as cis based on
the typical coupling constant values (3JH-a–H-b = 12.1–12.2
Hz). In the 1H NMR spectra of (Z)-4-chloro-3-styrylquin-
olines 8a–d the resonances of H-b (d = 6.88–6.96 ppm)
appear at higher frequency values than those of H-a (d =
6.67–6.82 ppm) with exception of the p-nitro derivative
3
8d and the coupling constant values of JH-a–H-b = 12.0–
12.1 Hz confirm the cis configuration of the vinylic sys-
tem. The cis configuration of 5a–d and 8a–d was support-
ed by the NOE cross peaks observed between the signals
of H-a and H-b and also between H-2¢,6¢ and that of H-2
and H-b. A weak cross peak can be observed between the
signals of H-2 and H-a which indicates a free rotation
around the C3–Ca bond.
R2
R2
H
N
(i)
N
Table 4 Reaction Conditions and Yields in the Hydrolysis of (E)-4-
Chloro-3-styrylquinolines 9a–d and of the Diastereomeric Mixture of
(Z)- and (E)-4-Chloro-3-styrylquinolines 8a–d/9a–d
O
10a–d
Cl
Quinoline
Reaction time (h) Yield of 11 (%)
a R2 = H
8a–d
b R2 = Cl
c R2 = OEt
d R2 = NO2
9a R2 = H
18
18
18
18
24
24
24
48
86
90
85
99
93
91
86
93
(i)
9b R2 = Cl
8
5
H
N
8
5
9c R2 = OEt
9d R2 = NO2
8a/9a R2 = H
8b/9b R2 = Cl
8c/9c R2 = OEt
8d/9d R2 = NO2
N
9
2
9
7
6
2
3
7
6
(i)
β
2'
5'
β
3
2'
1'
4
1'
3'
4'
10
3'
4'
10
4
α
α
Cl
O
6'
R2
6'
R2
5'
9a–d
11a–d
Scheme 3 Reagents and conditions: (i) HCOOH 40%, reflux.
All the new synthesized compounds were characterized
by a range of NMR techniques (1H, 13C, HSQC, HMBC,
and NOESY), MS, and elemental analysis (or HRMS).
The most important features of the 1H NMR spectra of 3-
styryl-4-quinolones 5a–d, 6a–d, and 11a–d and 4-chloro-
3-styrylquinolines 8a–d and 9a–d are the resonances of
their vinylic protons. In the case of (Z)-1-methyl-3-styryl-
4-quinolones 5a–d the resonances assigned to H-a (d =
1
In the H NMR spectra of the (E)-3-styryl-4-quinolones
6a–d and 11a–d the resonances of H-b (d = 7.54–7.92 and
7.71–8.01 ppm) appear at higher frequency than those of
H-a (d = 7.02–7.24 and 7.07–7.48 ppm). These signals ap-
pear as doublets with high coupling constant values
(3JH-a–H-b = 16.1–16.4 Hz) indicating a trans configuration
Synlett 2010, No. 15, 2257–2262 © Thieme Stuttgart · New York

2260
R. S. G. R. Seixas et al.
LETTER
Yang, J.-S.; Kuo, C.-L.; Lo, C.; Lin, J.-P.; Hsia, T.-C.; Lin,
J.-J.; Lai, K.-C.; Kuo, H.-M.; Huang, L.-J.; Kuo, S.-C.;
Wood, W. G.; Chung, J.-G. J. Orthop. Res. 2009, 27, 1637.
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of the vinylic system. For the (E)-4-chloro-3-styrylquino-
lines 9a–d the resonances of H-a (d = 7.49–7.81 ppm) ap-
pear at higher frequency values than those of H-b (d =
7.28–7.38 ppm) and the larger constant coupling values
(3JH-a–H-b = 16.5–16.6 Hz) confirm the trans configura-
tion. The 2D NOESY spectra of 6a–d, 9a–d, and 11a–d
supported this assignment since cross peaks between the
signals of H-b and those of H-2 and H-2¢,6¢ and of H-a
with those of H-2 and H-2¢,6¢ were observed indicating, as
in the case of the Z-isomers, a free rotation around the C3–
Ca bond. For the (E)-4-chloro-3-styrylquinolines 9a–d
the NOE cross peak between the signals of H-a and H-2 is
very weak. The 1H NMR spectra of (E)-3-styryl-4-quino-
lones 11a–d possess a broad singlet at high frequency
(d = 12.11–12.33 ppm) due to the resonance of the N–H
proton while the (E)-1-methyl-3-styryl-4-quinolones 6a–
d contain a singlet (d = 3.84–3.92 ppm) due to the reso-
nance of the N-methyl protons.
(5) (a) Lucero, B. A.; Gomes, C. R. B.; Frugulhetti, I. C. P. P.;
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In conclusion, a new and efficient methodology for the
synthesis of (Z)- and (E)-3-styryl-4-quinolones has been
developed. In the first approach, we prepared with high
diastereoselectivity and in good yields (Z)-1-methyl-3-
styryl-4-quinolones by performing a Wittig reaction of 1-
methyl-4-quinolone-3-carbaldehyde with benzylic ylides.
Alternatively, Wittig reaction of 4-chloroquinoline-3-carb-
aldehyde with the same benzylic ylides followed by acid
hydrolysis allowed us to obtain (E)-3-styryl-4-quinolones
in very good yields and with total diastereoselectivity.
Acknowledgment
Thanks are due to the University of Aveiro, FCT and FEDER for
funding the Organic Chemistry Research Unit and the Project
POCI/QUI/58835/2004. Raquel S. G. R. Seixas also thanks FCT for
her PhD Grant (SFRH/BD/30734/2006).
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(8) Hadjeri, M.; Barbier, M.; Ronot, X.; Mariotte, A.-M.;
Boumendjel, A.; Boutonnat, J. J. Med. Chem. 2003, 46,
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(14) Seixas, R. S. G. R.; Silva, A. M. S.; Pinto, D. C. G. A.;
(2) (a) Oliphant, C. M.; Green, G. M. Am. Fam. Physician 2002,
65, 455. (b) Alós, J.-I. Enferm. Infecc. Microbiol. Clin.
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Eldere, J.; Tulkens, P. M. Clin. Microb. Infect. 2005, 11,
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(15) (a) Kolodiazhnyi, O. I. Phosphorous Ylides – Chemistry and
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(16) Optimized Experimental Procedure
To a suspension of 4-quinolone-3-carbaldehyde (1, 1.16
mmol, 200.9 mg) in acetone (20 mL), anhyd K2CO3 (2.32
Synlett 2010, No. 15, 2257–2262 © Thieme Stuttgart · New York

LETTER
mmol, 320.6 mg) was added, and the mixture was stirred at
Synthesis of (Z)- and (E)-3-Styryl-4-quinolones
c and 19 mg, 0.78 mmol for reaction with 3d) and the
2261
r.t. for 30 min. p-Toluenesulfonyl chloride (1.74 mmol,
331.7 mg) was then added, and the mixture was stirred at r.t.
for 3 h. After that time, the K2CO3 was filtered off, washed
with acetone (2 × 20 mL), and the filtrate was concentrated.
The residue was purified by silica gel column
chromatography, first using CH2Cl2 as eluent (to remove the
excess of p-toluenesulfonyl chloride) and then a mixture of
CH2Cl2–acetone (5:1). The solvent was evaporated to
dryness and the solid recrystallized from a mixture of
CH2Cl2–light PE to give 1-tosyl-4-quinolone-3-
appropriate phosphonium halide 3a–d (1.56 mmol for 3a–c
and 0.78 mmol for 3d) in refluxing dry THF (20 mL) was
stirred for the requisite time (Tables 1 and 2). The appear-
ance of an orange colour and the disappearance of the
suspension of phosphonium salt indicated the ylide
formation. Subsequently, the appropriate 3-carbaldehyde
2a,b and 7 (0.52 mmol) was added, and reflux was continued
for the time noted in Tables 1 and 2. After cooling to r.t., the
reaction mixture was poured onto ice (20 g) and H2O (20
mL), and the pH value was adjusted to 5 with dilute HCl. In
the case of precipitation, the solid was filtered off, washed
with H2O (3 × 50 mL), dissolved in CHCl3 (50 mL), washed
with H2O (2 × 50 mL), and the organic solvent evaporated to
dryness. If no solid precipitated, the organic layer was
extracted with CHCl3 (3 × 50 mL), and the solvent was
evaporated to dryness. In all the cases, the residues were
dissolved in CH2Cl2.
carbaldehyde (2b) as a white solid (1.15 mmol, 376.4 mg,
99%).
(17) Analytical Data for (Z)-4¢-nitro-3-styryl-1-tosyl-4-
quinolone (5f)
Mp 144–146 °C. 1H NMR (300.13 MHz, CDCl3): d = 2.42
(s, 3 H, 4¢¢-CH3), 6.86 (AB, 1 H, J = 12.3 Hz, H-b), 6.89
(AB, 1 H, J = 12.3 Hz, H-a), 7.29 (d, 2 H, J = 8.3 Hz, H-
3¢¢,5¢¢), 7.43 (ddd, 1 H, J = 0.9, 7.2, 8.0 Hz, H-6), 7.48 (d, 2
H, J = 8.6 Hz, H-2¢,6¢), 7.48 (d, 2 H, J = 8.3 Hz, H-2¢¢,6¢¢),
7.61 (ddd, 1 H, J = 1.7, 7.2, 8.8 Hz, H-7), 8.14 (d, 1 H,
J = 8.8 Hz, H-8), 8.17 (d, 2 H, J = 8.6 Hz, H-3¢,5¢), 8.35 (d,
1 H, J = 0.6 Hz, H-2), 8.40 (dd, 1 H, J = 1.7, 8.0 Hz, H-5)
ppm. 13C NMR (75.47 MHz, CDCl3): d = 21.7 (4¢¢-CH3),
118.1 (C-8), 119.4 (C-3), 124.0 (C-3¢,5¢), 125.83 (C-10),
125.85 (C-6), 126.7 (C-a), 127.5 (C-5 and C-2¢¢,6¢¢), 129.7
(C-2¢,6¢), 130.1 (C-b), 130.4 (C-3¢¢,5¢¢), 132.8 (C-7), 133.4
(C-1¢¢), 136.3 (C-9), 136.9 (C-2), 144.1 (C-1¢), 146.5 (C-4¢),
146.8 (C-4¢¢), 177.4 (C-4) ppm. ESI+-MS: m/z (%) = 447.1
(100) [M + H]+, 469.1 (9) [M + Na]+. ESI+-HRMS: m/z calcd
for [C24H18N2O5S + H]+: 447.10092; found: 447.10011.
(18) Analytical Data for (E)-4¢-Nitro-3-styryl-1-tosyl-4-
quinolone (6f)
For the reaction of 1-methyl-4-quinolone-3-carbaldehyde
(2a) the residue was purified by silica gel column
chromatography with a mixture of CH2Cl2-EtOAc (4:1),
leading to the isolation of two products, in each case. The
components with the higher Rf value were identified as (E)-
1-methyl-3-styryl-4-quinolones 6a–d with the slower
eluting components being (Z)-1-methyl-3-styryl-4-
quinolones 5a–d. These compounds were recrystallized
from a mixture of CH2Cl2–light PE. For the reaction of 1-
tosyl-4-quinolone-3-carbaldehyde (2b) the residue was
purified by preparative TLC with a mixture of light PE–
EtOAc (4:1), in the case of 5e and 6e, and with a mixture of
light PE–EtOAc (2:1), in the case of 5f and 6f. In both cases,
the component of higher Rf value was identified as (E)-3-
styryl-1-tosyl-4-quinolones 6e,f with the second being the
(Z)-3-styryl-1-tosyl-4-quinolones 5e,f. For the reaction of 4-
chloroquinoline-3-carbaldehyde (7), the residue was
purified by silica gel column chromatography, eluting with a
mixture of light PE–EtOAc (7:1 to 4:1), leading to the
isolation of two products, in each case. In this case, the
component of higher Rf value was identified as (Z)-4-chloro-
3-styrylquinolines 8a–d and the second as (E)-4-chloro-3-
styrylquinolines 9a–d. These compounds were
Mp 219–220 °C. 1H NMR (300.13 MHz, CDCl3): d = 2.41
(s, 3 H, 4¢¢-CH3), 7.29 (d, 1 H, J = 16.6 Hz, H-a), 7.34 (d, 2
H, J = 8.8 Hz, H-3¢¢,5¢¢), 7.44 (ddd, 1 H, J = 0.8, 7.2, 8.0 Hz,
H-6), 7.61 (ddd, 1 H, J = 1.7, 7.2, 8.7 Hz, H-7), 7.69 (d, 2 H,
J = 8.8 Hz, H-2¢,6¢), 7.79 (d, 2 H, J = 8.8 Hz, H-2¢¢,6¢¢), 7.89
(d, 1 H, J = 16.6 Hz, H-b), 8.21 (d, 1 H, J = 8.7 Hz, H-8),
8.24 (d, 2 H, J = 8.8 Hz, H-3¢,5¢), 8.43 (dd, 1 H, J = 1.7, 8.0
Hz, H-5), 8.84 (s, 1 H, H-2) ppm. 13C NMR (75.47 MHz,
CDCl3): d = 21.8 (4¢¢-CH3), 118.1 (C-8), 119.6 (C-3), 124.1
(C-3¢,5¢), 126.0 (C-6), 126.2 (C-a), 126.3 (C-10), 126.9 (C-
2¢,6¢), 127.6 (C-2¢¢,6¢¢), 127.7 (C-5), 129.0 (C-b), 130.5 (C-
3¢¢,5¢¢), 132.8 (C-7), 133.5 (C-1¢¢), 135.8 (C-9), 136.7 (C-2),
144.2 (C-1¢), 146.8 (C-4¢ and C-4¢¢), 177.0 (C-4) ppm. ESI+-
MS: m/z (%) = 447.1 (100) [M + H]+. ESI+-HRMS: m/z
calcd for [C24H18N2O5S + H]+: 447.10092; found:
447.10023.
recrystallized from a mixture of CH2Cl2–light PE.
(21) Analytical Data for (Z)-4-Chloro-4¢-ethoxy-3-styryl-
quinoline (8c)
Mp 89–91 °C. 1H NMR (300.13 MHz, CDCl3): d = 1.38 (t,
3 H, J = 7.0 Hz, 4¢-OCH2CH3), 3.97 (q, 2 H, J = 7.0 Hz, 4¢-
OCH2CH3), 6.67 (d, 1 H, J = 12.0 Hz, H-a), 6.72 (d, 2 H,
J = 8.7 Hz, H-3¢,5¢), 6.88 (d, 1 H, J = 12.0 Hz, H-b), 7.09 (d,
2 H, J = 8.7 Hz, H-2¢,6¢), 7.64 (ddd, 1 H, J = 1.3, 6.9, 8.3 Hz,
H-6), 7.73 (ddd, 1 H, J = 1.4, 6.9, 8.3 Hz, H-7), 8.04 (d, 1 H,
J = 8.3 Hz, H-8), 8.28 (dd, 1 H, J = 1.4, 8.3 Hz, H-5), 8.63
(s, 1 H, H-2) ppm. 13C NMR (75.47 MHz, CDCl3): d = 14.8
(4¢-OCH2CH3), 63.4 (4¢-OCH2CH3), 114.5 (C-3¢,5¢), 122.2
(C-a), 124.0 (C-5), 126.5 (C-10), 127.6 (C-6), 128.2 (C-1¢),
129.5 (C-8), 129.8 (C-7), 129.9 (C-3), 130.3 (C-2¢,6¢), 133.6
(C-b), 140.5 (C-4), 147.2 (C-9), 151.3 (C-2), 158.8 (C-4¢)
ppm. ESI+-MS: m/z (%) = 310.1 (100) [M + H]+. Anal.
Calcd (%) for C19H16ClNO (309.8): C, 73.66; H, 5.21; N,
4.52. Found: C, 73.55; H, 5.23; N, 4.55.
(19) Analytical Data for (E)-1-Methyl-4¢-nitro-3-styryl-4-
quinolone (6d)
Mp >300 °C. 1H NMR (300.13 MHz, CDCl3): d = 3.92 (s, 3
H, N-CH3), 7.24 (d, 1 H, J = 16.1 Hz, H-a), 7.45 (d, 1 H,
J = 8.5 Hz, H-8), 7.47 (ddd, 1 H, J = 1.2, 7.4, 7.8, H-6), 7.62
(d, 2 H, J = 8.8 Hz, H-2¢,6¢), 7.72 (ddd, 1 H, J = 1.5, 7.4, 8.5
Hz, H-7), 7.81 (s, 1 H, H-2), 7.92 (d, 1 H, J = 16.1 Hz, H-b),
8.19 (d, 2 H, J = 8.8 Hz, H-3¢,5¢), 8.57 (dd, 1 H, J = 1.5, 7.8
Hz, H-5) ppm. 13C NMR (75.47 MHz, CDCl3): d = 41.1 (N-
CH3), 115.4 (C-8), 117.4 (C-3), 124.1 (C-3¢,5¢), 124.5 (C-6),
126.3 (C-b), 126.5 (C-2¢,6¢), 127.0 (C-10), 127.5 (C-5),
127.6 (C-a), 132.3 (C-7), 139.3 (C-9), 143.7 (C-2), 145.2 (C-
1¢), 146.3 (C-4¢), 176.3 (C-4) ppm. ESI+-MS: m/z
(%) = 307.1 (100) [M + H]+, 329.1 (5) [M + Na]+. ESI+-
HRMS: m/z calcd for [C18H14N2O3 + H]+: 307.10772; found:
307.10785.
(22) Analytical Data for (E)-4-Chloro-4¢-ethoxy-3-styryl-
quinoline (9c)
Mp 154–155 °C. 1H NMR (300.13 MHz, CDCl3): d = 1.45
(t, 3 H, J = 7.0 Hz, 4¢-OCH2CH3), 4.08 (q, 2 H, J = 7.0 Hz,
4¢-OCH2CH3), 6.94 (d, 2 H, J = 8.8 Hz, H-3¢,5¢), 7.29 (d, 1
H, J = 16.5 Hz, H-b), 7.49 (d, 1 H, J = 16.5 Hz, H-a), 7.56
(d, 2 H, J = 8.8 Hz, H-2¢,6¢), 7.64 (ddd, 1 H, J = 1.1, 7.0, 8.3
Hz, H-6), 7.71 (ddd, 1 H, J = 1.4, 7.0, 8.3 Hz, H-7), 8.09 (dd,
(20) Optimized Experimental Procedure
A mixture of NaH (37 mg, 1.56 mmol for reaction with 3a–
Synlett 2010, No. 15, 2257–2262 © Thieme Stuttgart · New York

2262
R. S. G. R. Seixas et al.
LETTER
1 H, J = 1.1, 8.3 Hz, H-8), 8.26 (dd, 1 H, J = 1.4, 8.3 Hz, H-
5), 9.18 (s, 1 H, H-2) ppm. 13C NMR (75.47 MHz, CDCl3):
d = 14.8 (4¢-OCH2CH3), 63.6 (4¢-OCH2CH3), 114.8 (C-
3¢,5¢), 120.0 (C-a), 124.4 (C-5), 126.4 (C-10), 127.9 (C-6),
128.37 (C-2¢,6¢), 128.40 (C-3), 129.2 (C-1¢), 129.5 and 129.6
(C-7 and C-8), 132.7 (C-b), 138.9 (C-4), 147.4 (C-9), 148.1
(C-2), 159.5 (C-4¢) ppm. ESI+-MS: m/z (%) = 310.1 (100)
[M + H]+. Anal Calcd for C19H16ClNO (309.8): C, 73.66; H,
5.21; N, 4.52. Found: C, 73.82; H, 5.22; N, 4.50.
NH) ppm. 13C NMR (75.47 MHz, DMSO-d6): d = 116.5
(C-3), 118.4 (C-8), 123.6 (C-6), 125.1 (C-a), 125.2 (C-b),
125.4 (C-5 and C-10), 127.4 (C-2¢,6¢), 128.6 (C-3¢,5¢), 130.9
(C-4¢), 131.5 (C-7), 137.5 (C-1¢), 138.6 (C-9), 139.2 (C-2),
175.2 (C-4) ppm. ESI+-MS: m/z (%) = 282.0(100) [M + H]+.
ESI+-HRMS: m/z calcd for [C17H12ClNO + H]+: 282.06802;
found 282.06801.
(24) Optimized Experimental Procedure
A suspension of a mixture of (Z)- and (E)-4-chloro-3-
styrylquinoline 8a–d and 9a–d (0.19 mmol) in 40% aq
formic acid (6 mL) was refluxed for the appropriate time
(Table 4). The resulting suspension was cooled in ice for 30
min, the pH value adjusted to 5 with Na2CO3, and the
precipitate formed was filtered off and washed with H2O.
The pure (E)-3-styryl-4-quinolone derivatives 11a–d were
collected as a white solids (11a–c) or an orange solid (11d)
without the need for further purification.
(23) Analytical Data for (E)-4¢-Chloro-3-styryl-4-quinolone
(11b)
Mp >300 °C. 1H NMR (300.13 MHz, DMSO-d6): d = 7.23
(d, 1 H, J = 16.3 Hz, H-a), 7.37 (dd, 1 H, J = 7.5, 7.8 Hz, H-
6), 7.41 (d, 2 H, J = 8.4 Hz, H-3¢,5¢), 7.53 (d, 2 H, J = 8.4 Hz,
H-2¢,6¢), 7.58 (d, 1 H, J = 7.9 Hz, H-8), 7.67 (dd, 1 H,
J = 7.5, 7.9 Hz, H-7), 7.82 (d, 1 H, J = 16.3 Hz, H-b), 8.21
(d, 1 H, J = 7.8 Hz, H-5), 8.29 (s, 1 H, H-2), 12.19 (br s, 1 H,
Synlett 2010, No. 15, 2257–2262 © Thieme Stuttgart · New York

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