Syntheses of novel (E)-N-methyl-2-styryl-4-quinolones

Article abstract of DOI:10.1055/s-0028-1083530

Two new synthetic routes for (E)-N-methyl-2-styryl-4-quinolones have been established, both starting from (E)-2′-cinnamoylaminoacetophenones. In the first, (E)-2′-cinnamoylaminoacetophenones are cyclized and then methylated, while in the second they are m

Full text of DOI:10.1055/s-0028-1083530

LETTER
2593
Syntheses of Novel (E)-N-Methyl-2-styryl-4-quinolones
S
ynthese
s
of Nove
n
l
(
E
)-
N
-Meth
d
yl-2-styryl-4
r
-quinolo
e
nes ia I. S. Almeida, Vera L. M. Silva, Artur M. S. Silva,* Diana C. G. A. Pinto, José A. S. Cavaleiro
Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
Fax +35(12)34370084; E-mail: artur.silva@ua.pt
Received 10 July 2008
vi
Abstract: Two new synthetic routes for (E)-N-methyl-2-styryl-4-
quinolones have been established, both starting from (E)-2¢-cin-
namoylaminoacetophenones. In the first, (E)-2¢-cinnamoylamino-
R
R
O
R
acetophenones are cyclized and then methylated, while in the
Me
N
Me
second they are methylated followed by in situ cyclization.
N
C
Key words: ketones, quinolones, cyclization, N-methylation
+
+
NMe
O
O
7a–c
5a–d
A wide variety of clinical applications has been approved
v
O
8a–d
for quinolones, including treatment for respiratory, gas-
trointestinal, and gynecologic infections, sexually trans-
mitted diseases, chronic osteomyelitis, prostatitis, and
some skin, bone, and soft tissue infections.1 Particularly,
iv
3"
6"
R
4"
2"
3'
6'
4'
R
2'
β
5"
8
1"
NH2
2-aryl-4-quinolones are known for their wide range of
β
α
5'
O
1'
H
pharmacological properties, exhibiting antibacterial,1–3
i
ii
C
9
N
α
2
antiplatelet,4 antitumoral,5 antimitotic, and anticancer ac-
tivity.2,3 They are also known for their capacity to act as
inhibitors of in vitro tubulin polymerization,2,3,6 and act-
ing as cytotoxic agents5 and cardiovascular protectors.7,8
3'
6'
CO2H
4'
NH
2'
7
6
O
3
2
1
5'
1
10
4
1'
5
O
O
4a–d
Despite the structural analogy of 2-styryl-4-quinolones
with 2-aryl-4-quinolones and 2-styrylchromones, until
now they have not been reported in the literature. As de-
scribed above, 2-aryl-4-quinolones have been the subjects
of several studies; while the syntheses and biological ac-
tivity of 2-styrylchromones have been extensively studied
by our group.9 Now we are interested in the synthesis of
the analogous (E)-2-styryl-4-quinolones 4 and 5. The cy-
clization of 2¢-cinnamoylaminoacetophenones seems to
be a suitable method to obtain these compounds. The at-
tempts to prepare (E)-2¢-cinnamoylaminoacetophenones
3a–d from 2¢-aminoacetophenones and appropriate cin-
namoyl chlorides in pyridine were not very successful, re-
sulting in poor yields (ca. 20%). Therefore these
compounds 3a–d10 were prepared in moderate yields (46–
65%) through the condensation of 2¢-aminoacetophenone
(1) with the appropriate cinnamic acid derivatives 2a–d in
the presence of DCC and 4-pyrrolidinopyridine
(Scheme 1). The base-induced cyclization of 3a–d under
classical heating conditions11,12 or microwave irradiation
(MW)13,14 led to the desired (E)-2-styryl-4-quinolones
4a–d15 in very good yields (74–91%), except for the nitro
derivative 4d (Scheme 1). Our attempts to obtain deriva-
tive 4d under classical heating failed and under MW this
derivative was only obtained in low yield (25%).
3a–d
iii
R
2a–d
R
R
Me
N
N
+
OMe
O
6a–c
5a–c
a: R = H, b: R = OMe, c: R = Cl, d: R = NO2
Scheme 1 Reagents and conditions: (i) DCC, 4-pyrrolidinopyri-
dine, CH2Cl2, r.t., 6–8 d; (ii) classical heating: t-BuOK, anhyd THF,
80 °C, 4 h; MW: t-BuOH, NaOH, 120 °C, 18 min; (iii) classical hea-
ting: NaH, anhyd THF, MeI, r.t., 5 h; MW: NaH, anhyd THF, MeI,
1.5 h; (iv) classical heating: NaH, anhyd THF, MeI, r.t., 24 h; MW:
NaH, anhyd THF, MeI, 25 °C, 30 min, then 50 °C, 1 h; (v) Me2SO4,
anhyd DMF, t-BuOK, r.t. (only for 3d); (vi) classical heating:
t-BuOK, anhyd THF, 80 °C, 4 h (only for 8d).
Our ongoing research project on the reactivity of (E)-2-
styryl-4-quinolones 4a–d requires the protection of their
NH group. N-Alkyl-4-quinolones can be prepared by two
main methods: (i) starting from N-alkylaniline derivatives
and elaboration of the latter to N-alkyl-4-quinolones or (ii)
by direct alkylation of 2-aryl-4-quinolones.16,17 We decid-
ed to study the direct N-methylation of 4a–c using methyl
iodide or dimethyl sulfate as alkylating agents in alkaline
medium. The optimal conditions were obtained by treat-
SYNLETT 2008, No. 17, pp 2593–2596
x
x
.x
x
.2
0
0
8
Advanced online publication: 01.10.2008
DOI: 10.1055/s-0028-1083530; Art ID: D26608ST
© Georg Thieme Verlag Stuttgart · New York

2594
A. I. S. Almeida et al.
LETTER
ment of 4a–c with an excess of methyl iodide in the pres- quinolone 5a (the obtained yield are almost the sum of
ence of sodium hydride and using anhydrous THF as those of 5a + 8a obtained before). The application of this
solvent, under classical heating conditions or microwave procedure to (E)-2¢-cinnamoylaminoacetophenones 3b,c
irradiation.18 Under both these conditions the reaction af- allowed the synthesis of 5b,c in good yields (66–86%)
forded the desired (E)-N-methyl-2-styryl-4-quinolones with 7b,c also being isolated in very small amounts (2–
5a–c18 as main products in moderate yields (47–55%) but 4%; Table 2).
also the O-methylated19 derivatives 6a–c in low yields
(13–18%; Scheme 1, Table 1).
Since the beneficial effect of microwave activation on the
reactions resulting in higher yields and shorter reaction
time is well documented22 we decided to explore this
Table 1 N-Methylation of (E)-2-Styryl-4-quinolones 4a–c under
Classical Heating Conditions and Microwave Irradiation
technique to enhance the efficiency of the methylation
of (E)-2¢-cinnamoylaminoacetophenone (3a; Scheme 1,
Classical heating
MW
Table 3). After several attempts we have found that the
use of 1.5 molar equivalents of sodium hydride and two
molar equivalents of methyl iodide and irradiation of the
mixture for 1.5 hours were the conditions that provided
the best results (5a was obtained in 67% yield). The scope
of the reaction was next investigated under the optimized
MW conditions. We tried the methylation of derivatives
3b and 3c but unfortunately the results were not good
(Table 3). The desired N-methyl-2-styryl-4-quinolones
5b,c were obtained in low yields (21–23%), due to a high
degradation of the reaction mixture. Some starting mate-
rial was also recovered. Attempts to use a higher amount
of methyl iodide (2.5 molar equiv) and/or to reduce the re-
action time to 40 minutes (after 30 min stirring with NaH)
and the addition of base (NaH) and methyl iodide at the
same time were also unsuccessful.
Compound R
Yield of 5 Yield of 6 Yield of 5 Yield of 6
(%)
55
(%)
16
(%)
50
(%)
18
4a
4b
4c
H
OMe
Cl
53
17
52
13
47
18
48
16
To circumvent the problem of the nonregioselectivity of
direct methylation of 4a–c, we attempted to convert sub-
strates 3a–c into their N-methyl derivatives 8a–c aiming
to perform the in situ cyclization of the latter to 5a–c. A
variety of conditions was explored with (E)-2¢-cinnamoyl-
aminoacetophenone (3a) to optimize conditions for the
desired N-methylation (Table 2). Firstly 3a was treated
with 1.5 equivalents of sodium hydride in anhydrous THF
for 30 minutes at room temperature followed by quench-
ing with 1.5 equivalents of methyl iodide to afford 7a
(2%),20 the expected derivative 5a as the major product
(37%) and also compound 8a as minor product (29%) af-
ter 18 hours reaction time. We also recovered 21% of
starting material 3a.
Table 3 N-Methylation of (E)-2¢-Cinnamoylaminoacetophenones
3a–c Followed by in situ Cyclization under MW Irradiation
Compound
NaH
MeI
Yield of 5 Yield of 7
(equiv)
(equiv)
(%)
42a
67
(%)
3a; R = H
1.5
1.5
1.5
1.5
1.5
2.0
2.0
2.0
4
3a; R = H
18
Considering these results we made some modifications to
the procedure21 (by increasing the amount of base to 2.5
equivalents and the reaction time from 18 h to 24 h) which
led to high yields of 5a (68%; Table 2). Under these cir-
cumstances we were able to convert almost quantitatively
the intermediate 8a into the desired N-methyl-2-styryl-4-
3b; R = OMeb
23
traces
7
3c; R = Cl
21
a Starting material 3a (30%) was recovered.
b Compound 8b (8%) was also isolated.
Table 2 N-Methylation of (E)-2¢-Cinnamoylaminoacetophenones
3a–c Followed by in situ Cyclization under Classical Heating Condi-
tions
The above described methylation methodology of 3a–c
under classical heating conditions was efficient for the
synthesis of 5a–c but it was not the case for the synthesis
of 5d. In this case the methylation did not occur and we
only recovered starting material 3d. Consequently we at-
tempted another method and we were able to optimize the
procedure to obtain the desired compound 5d. This new
procedure starts with the methylation of 3d with dimethyl
sulfate (3 equiv) in anhydrous DMF in the presence of po-
tassium tert-butoxide (3 equiv) at room temperature, with
8d23 being obtained in 47% yield. The cyclization of 8d
with potassium tert-butoxide as described for (E)-2¢-cin-
namoylaminoacetophenones 3a–c, under classical heating
conditions,12 afforded (E)-N-methyl-2-(4-nitrostyryl)-4-
quinolone (5d)24 in 37% yield.
Compound
NaH
MeI
Yield of Yield of 7 Yield of 8
(equiv)
(equiv) 5s (%) (%)
(%)
3a; R = H
1.5 + 1.0
after 8 h
1.5
1.5
1.5
1.5
68
traces
–
3b; R = OMe 1.5 + 1.0
66a
86
2
4
4
–
–
2
after 16 h
3c; R = Cl
3c; R = Cl
1.5 + 1.0
after 16 h
1.5 + 1.0
after 19 h
67b
a Starting material 3b (24%) was recovered.
b Starting material 3c (8%) was recovered.
Synlett 2008, No. 17, 2593–2596 © Thieme Stuttgart · New York

LETTER
Syntheses of Novel (E)-N-Methyl-2-styryl-4-quinolones
2595
(6) Li, L.; Wang, H.-K.; Kuo, S.-C.; Wu, T.-S.; Lednicer, D.;
Lin, C. M.; Hamel, E.; Lee, K.-H. J. Med. Chem. 1994, 37,
1126.
(7) Lee, H.-Z.; Lin, W.-C.; Yeh, F.-T.; Wu, C.-H. Eur. J.
Pharmacol. 1998, 354, 205.
All the new synthesized (E)-2-styryl-4-quinolones 4a–d
and their N-methyl derivatives 5a–d and 7a–c have been
characterized by NMR spectroscopy. The most noticeable
1
feature in their H NMR spectra is the singlet due to the
resonance of the NH proton at d = 11.52–11.61 in the case
of quinolones 4a–d. This signal is not observed in the
spectra of the N-methylated derivatives 5a–d and 7a–c; in
this case a singlet is observed due to the resonance of the
methyl group at dH = 3.83–3.86. The resonance of the ole-
finic proton H-3, appears as a singlet at d = 6.32–6.39 for
4a–d and more deshielded at d = 6.53–6.54 for 5a–d. The
absence of this signal in the spectra of derivatives 7a–c is
the main criterion for distinguishing them from com-
pounds 5a–d.
(8) Su, M. J.; Chang, G. J.; Kuo, S.-C. Br. J. Pharmacol. 1993,
110, 310.
(9) (a) Santos, C. M. M.; Silva, A. M. S.; Cavaleiro, J. A. S. Eur.
J. Org. Chem. 2003, 4575. (b) Silva, A. M. S.; Pinto, D. C.
G. A.; Cavaleiro, J. A. S.; Lévai, A.; Patonay, T. Arkivoc
2004, (vii), 106. (c) Silva, V. L. M.; Silva, A. M. S.; Pinto,
D. C. G. A.; Cavaleiro, J. A. S.; Patonay, T. Synlett 2004,
2717. (d) Gomes, A.; Fernandes, E.; Silva, A. M. S.; Santos,
C. M. M.; Pinto, D. C. G. A.; Cavaleiro, J. A. S.; Lima, J. L.
F. C. Bioorg. Med. Chem. 2007, 15, 6027. (e) Marinho, J.;
Pedro, M.; Pinto, D. C. G. A.; Silva, A. M. S.; Cavaleiro,
J. A. S.; Sunkel, C. E.; Nascimento, M. S. J. Biochem.
Pharmacol. 2008, 75, 826.
(10) Physical Data of (E)-2¢-(4-Methoxycinnamoyl-
amino)acetophenone(3b): mp 106–109 °C. 1H NMR
(300.13 MHz, CDCl3): d = 2.68 (s, 3 H, 2-Me), 2.83 (s, 3 H,
4¢¢-OMe), 6.49 (d, 1 H, J = 15.6 Hz, H-a), 6.91 (d, 2 H, J =
8.9 Hz, H-3¢¢, H-5¢¢), 7.11 (ddd, 1 H, J = 8.0, 7.6, 1.2 Hz, H-
5¢), 7.51–7.60 (m, 3 H, H-4¢, H-2¢¢, H-6¢¢), 7.70 (d, 1 H, J =
15.6 Hz, H-b), 7.91 (dd, 1 H, J = 8.0, 1.6 Hz, H-6¢), 8.91 (dd,
1 H, J = 8.5, 1.2 Hz, H-3¢), 11.98 (s, 1 H, NH). 13C NMR
(75.47 MHz, CDCl3): d = 28.6 (2-Me), 55.3 (4¢¢-OMe),
114.2 (C-3¢¢, C-5¢¢), 119.5 (C-a), 120.8 (C-3¢), 121.6 (C-1¢),
122.2 (C-5¢), 127.3 (C-1¢¢), 129.6 (C-2¢¢, C-6¢¢), 131.7 (C-6¢),
135.1 (C-4¢), 141.4 (C-2¢), 141.8 (C-b), 161.1 (C-4¢¢), 165.2
(C=O), 202.9 (C-1). MS (ESI, +): m/z = 296 (100) [M + H]+,
318 (52) [M + Na]+, 591 (6) [2 × M + H]+, 613 (32) [2 × M
+ Na]+. Anal. Calcd for C18H17NO3 (295.332): C, 73.20; H,
5.80; N, 4.74. Found: C, 72.90; H, 5.96; N, 4.92.
(11) (a) Hadjeri, M.; Pellier, E. L.; Beney, C.; Deka, N.; Lawson,
M. A.; Dumontet, C.; Boumendjel, A. J. Med. Chem. 2004,
47, 4964. (b) Beney, C.; Hadjeri, M.; Mariotte, A. M.
Tetrahedron Lett. 2000, 41, 7037. (c) Gao, H.; Kawabata, J.
Bioorg. Med. Chem. 2005, 13, 1661.
(12) Optimized Experimental Procedure; Classical Heating
Conditions: Potassium tert-butoxide (101.6 mg, 0.91 mmol)
was added to a solution of the appropriate (E)-2¢-cinna-
moylaminoacetophenones 3a–c (0.75 mmol) in anhyd THF
(60 mL). The mixture was heated at 80 °C with stirring,
under a N2 atmosphere for 4 h. After that period the mixture
was poured into H2O and ice and acidified at pH 5 with a
20% solution of HCl. The obtained solid was filtered and
recrystallized from CH2Cl2–light petroleum to give (E)-2-
styryl-4-quinolones 4a–c in good yields (4a, 91%; 4b, 82%;
4c, 74%).
In conclusion, we have established two successful meth-
odologies to perform the synthesis of (E)-N-methyl-2-
styryl-4-quinolones in good yields. Both methods start
with the synthesis of suitable (E)-2¢-cinnamoylamino-
acetophenones 3a–d from 2¢-aminoacetophenone (1) and
cinnamic acid derivatives 2a–d. In the first one, 3a–c
were cyclized into (E)-2-styryl-4-quinolones 4a–c by al-
kaline medium and then methylated to afford 5a–c in
good yields. Both reactions have been performed under
classical heating conditions and MW irradiation; the
yields obtained in both procedures were similar but the
transformations were faster under microwave irradiation.
In the second method 3a–c were methylated and in situ
cyclized under classical heating conditions or under MW
irradiation to afford 5a–c. The beneficial effect of using
microwave irradiation as the source of energy was the
shortening of the reaction time but the methodology was
applied with success only in the synthesis of the nonsub-
stituted (E)-N-methyl-2-styryl-4-quinolone (5a). (E)-N-
methyl-2-(4-nitrostyryl)-4-quinolone (5d) has only been
obtained in a moderate yield by a slightly modified second
synthetic method.
Acknowledgment
Thanks are due to the University of Aveiro, the FCT and the
FEDER for funding the Organic Chemistry Research Unit and the
Project POCI/QUI/58835/2004. Andreia I. S. Almeida and Vera L.
M. Silva also thank the FCT for a research project (POCI/QUI/
58835/2004) and a postdoctoral grant (SFRH/BPD/27098/2006).
(13) Ding, D.; Li, X.; Wang, X.; Du, Y.; Shen, J. Tetrahedron
Lett. 2006, 47, 6997.
References and Notes
(14) Optimized Experimental Procedure; Microwave
Irradiation: NaOH (263.2 mg, 6.55 mmol) was added to a
solution of the appropriate (E)-2¢-cinnamoylamino-aceto-
phenones 3a–d (1.31 mmol) in t-BuOH (10 mL). The
mixture was irradiated in a high-pressure vessel in an Ethos
SYNTH microwave instrument (Milestone Inc.) during 18
min (8 min to reach 120 °C and 10 min at 120 °C). After that
period the mixture was poured over H2O and ice and was
acidified at pH 5 with a 20% solution of HCl. The precipitate
was filtered and recrystallized from CH2Cl2–light petroleum
to give (E)-2-styryl-4-quinolones 4a–d in good yields (4a,
79%; 4b, 78%; 4c, 83%; 4d, 25%).
(1) (a) Mitscher, L. A. Chem. Rev. 2005, 105, 559. (b) Alós,
J.-I. Enferm. Infecc. Microbiol. Clin. 2003, 21, 261.
(c) Oliphant, C. M.; Green, G. M. Am. Fam. Physician 2002,
65, 455.
(2) Li, L.; Wang, H.-K.; Kuo, S.-C.; Wu, T.-S.; Mauger, A.; Lin,
C. M.; Hamel, E.; Lee, K.-H. J. Med. Chem. 1994, 37, 3400.
(3) Chen, Y.-C.; Lu, P.-H.; Pan, S.-L.; Teng, C.-M.; Kuo, S.-C.;
Lin, T.-P.; Ho, Y.-F.; Huang, Y.-C.; Guh, J.-H. Biochem.
Pharmacol. 2007, 74, 10.
(4) Huang, L.-J.; Hsieh, M.-C.; Teng, C.-M.; Lee, K.-H.; Kuo,
S.-C. Bioorg. Med. Chem. 1998, 6, 1657.
(5) Xia, Y.; Yang, Z.-Y.; Xia, P.; Bastow, K. F.; Nakanishi, Y.;
Nampoothiri, P.; Hamel, E.; Brossi, A.; Lee, K.-H. Bioorg.
Med. Chem. Lett. 2003, 13, 2891.
(15) Physical Data of (E)-2-(4-Methoxystyryl)-4-quinolone
(4b): mp 222–223 °C. 1H NMR (300.13 MHz, DMSO-d6):
d = 3.81 (s, 3 H, 4¢-OMe), 6.32 (s, 1 H, H-3), 6.95–7.05 (m,
Synlett 2008, No. 17, 2593–2596 © Thieme Stuttgart · New York

2596
A. I. S. Almeida et al.
LETTER
3 H, H-a, H-3¢, H-5¢), 7.27–7.32 (m, 1 H, H-6), 7.59–7.66
(m, 5 H, H-7, H-8, H-b, H-2¢, H-6¢), 8.05 (d, 1 H, J = 8.1 Hz,
H-5), 11.52 (s, 1 H, NH). 13C NMR (75.47 MHz, DMSO-d6):
d = 55.3 (4¢-OMe), 106.9 (C-3), 114.5 (C-3¢, C-5¢), 118.2 (C-
8), 119.6 (C-a), 122.9 (C-6), 124.7 (C-5), 125.1 (C-10),
128.2 (C-1¢), 128.9 (C-2¢, C-6¢), 131.8 (C-7), 134.6 (C-b),
140.2 (C-9), 147.4 (C-2), 160.2 (C-4¢), 176.9 (C-4). MS
(ESI, +): m/z 278 (100) [M + H]+, 577 (4) [2 × M + Na]+.
Anal. Calcd for C18H15NO2 (277.317): C, 73.20; H, 5.80; N,
4.74. Found: C, 72.90; H, 5.96; N, 4.92.
(20) Physical Data of (E)-1,3-Dimethyl-2-styryl-4-quinolone
(7a): 1H NMR (300.13 MHz, CDCl3): d = 2.22 (s, 3 H, 3-
Me), 3.81 (s, 3 H, NMe), 6.77 (d, 1 H, J = 16.6 Hz, H-a), 6.98
(d, 1 H, J = 16.6 Hz, H-b), 7.26–7.49 (m, 6 H, H-2¢, H-3¢,
H-4¢, H-5¢, H-6¢, H-6), 7.56 (dd, 1 H, J = 7.4, 1.0 Hz, H-8),
7.65 (ddd, 1 H, J = 7.4, 7.9, 1.5 Hz, H-7), 8.51 (dd, 1 H, J =
7.9, 1.5 Hz, H-5). MS (ESI, +): m/z = 276 (100) [M + H]+.
(21) Optimized Experimental Procedure: NaH (68.0 mg, 2.84
mmol) was added to a solution of the appropriate (E)-2¢-
cinnamoylaminoacetophenone 3a–c (1.89 mmol) in anhyd
THF (20 mL). The mixture was stirred at r.t. for 30 min and
then an excess of MeI (0.18 mL, 2.84 mmol) was added. The
reaction mixture was stirred at r.t. for a period of time (see
Table 3) and then an excess of NaH (45.3 mg, 1.89 mmol)
was added. After 24 h, the reaction was poured into H2O, ice
and Et3N (39 mL, 2.84 mmol) and acidified with HCl to pH
6. The yellow solid obtained was filtered and taken in
CHCl3. The organic layer was extracted with EtOAc (3 ×
100 mL), dried with anhyd Na2SO4 and concentrated. The
crude product was purified by preparative TLC using a 3:2-
mixture of EtOAc–light petroleum as eluent. The desired
(E)-1-methyl-2-styryl-4-quinolones 5a–c were obtained as
the main component and corresponded to the spot with lower
Rf value (5a, 68%; 5b, 66%; 5c, 86%) and compound 7a–c
were obtained as the spot with high Rf value (7a, traces; 7b,
2%; 7c, 4%). In some cases some starting material and traces
of the (E)-2¢-(N-cinnamoyl-N-methylamino)acetophenones
8a–c were recovered.
(16) Hadjeri, M.; Mariotte, A. M.; Boumendjel, A. Chem. Pharm.
Bull. 2001, 49, 1352.
(17) Ko, T.-C.; Hour, M.-J.; Lien, J.-C.; Teng, C.-M.; Lee, K.-H.;
Kuo, S.-C.; Huang, L.-J. Bioorg. Med. Chem. Lett. 2001, 11,
279.
(18) Optimized Experimental Procedure: NaH (5.0 mg, 0.20
mmol) was added to a stirred suspension of the appropriate
(E)-2-styryl-4-quinolone 4a–c (0.20 mmol) in anhyd THF
(25 mL) and the reaction mixture was stirred at r.t. for 30
min. After that period an excess of MeI (0.25 mL, 4.04
mmol) was added and the reaction mixture was stirred for 5
h. Then, it was poured over H2O, ice and Et3N (56.3 mL,
4.04 mmol) and acidified with HCl to pH 6. The obtained
yellow solid was filtered, dissolved in CHCl3 and purified by
preparative TLC using a 3:1-mixture of CH2Cl2–acetone as
eluent. Two very close spots were collected, and the one
with the lower Rf value was identified as (E)-1-methyl-2-
styryl-4-quinolones 5a–c (5a, 55%; 5b, 53%; 5c, 47%)
whereas that with the higher Rf value was identified as (E)-
4-methoxy-2-styrylquinolines 6a–c (6a, 16%; 6b, 17%; 6c,
18%). During the reaction time and workup the reaction
mixture had to be protected from the light, otherwise the (E)-
1-methyl-2-styryl-4-quinolones 5a–c could isomerize into
the Z-isomers.
Physical Data of (E)-1-Methyl-2-styryl-4-quinolone (5a):
mp 182–183 °C. 1H NMR (300.13 MHz, CDCl3): d = 3.83
(s, 3 H, NMe), 6.54 (s, 1 H, H-3), 7.09 (d, 1 H, J = 15.8 Hz,
H-a), 7.20 (d, 1 H, J = 15.8 Hz, H-b), 7.38–7.46 (m, 4 H,
H-3¢, H-5¢, H-4¢, H-6), 7.51–7.56 (m, 3 H, H-2¢, H-6¢, H-8),
7.70 (dd, 1 H, J = 7.8, 1.6 Hz, H-7), 8.47 (dd, 1 H, J = 8.0,
1.6 Hz, H-5). 13C NMR (75.47 MHz, CDCl3): d = 35.7
(NMe), 109.7 (C-3), 115.4 (C-8), 121.7 (C-a), 123.5 (C-6),
126.7 (C-5), 126.9 (C-10), 127.3 (C-2¢, C-6¢), 129.0 (C-3¢,
C-5¢), 129.5 (C-4¢), 132.3 (C-7), 135.4 (C-1¢), 138.0 (C-b),
141.7 (C-9), 151.8 (C-2), 178.0 (C-4). MS (ESI, +): m/z =
262 (100) [M + H]+. Anal. Calcd for C18H15NO (261.318): C,
82.73; H, 5.79; N, 5.36. Found: C, 82.61; H, 5.90; N, 5.15.
(19) Physical Data of (E)-4-Methoxy-2-(4-methoxy-
styryl)quinoline (6b): mp 134–135 °C. 1H NMR (300.13
MHz, CDCl3): d = 3.85 (s, 3 H, 4¢-OMe), 4.12 (s, 3 H, 4-
OMe), 6.94 (d, 2 H, J = 8.8 Hz, H-3¢, H-5¢), 6.98 (s, 1 H,
H-3), 7.24 (d, 1 H, J = 15.2 Hz, H-a), 7.45 (dt, 1 H, J = 7.7,
1.1 Hz, H-6), 7.58–7.66 (m, 3 H, H-b, H-2¢, H-6¢), 7.68 (ddd,
1 H, J = 8.0, 7.7, 1.4 Hz, H-7), 8.00 (d, 1 H, J = 8.0 Hz,
H-8), 8.14 (dd, 1 H, J = 7.7, 1.4 Hz, H-5). 13C NMR (75.47
MHz, CDCl3): d = 55.3 (4¢-OMe), 55.6 (4-OMe), 97.6 (C-3),
114.2 (C-3¢, C-5¢), 120.6 (C-10), 121.6 (C-5), 125.1 (C-6),
127.3 (C-a), 128.5 (C-8), 128.6 (C-2¢, C-6¢), 128.2 (C-1¢),
130.7 (C-7), 133.7 (C-b), 149.0 (C-9), 157.4 (C-2), 160.1 (C-
4¢), 162.4 (C-4). HRMS (ESI, +): m/z calcd for C19H18NO2:
292.1332; found: 292.1322.
(22) (a) Loupy, A. Microwaves in Organic Synthesis; Wiley-
VCH: Weinheim, 2002. (b) Kappe, C. O. Angew. Chem. Int.
Ed. 2004, 43, 6250. (c) Kappe, C. O.; Dallinger, D. Nat.
Rev. Drug Discov. 2006, 5, 51.
(23) Physical Data of (E)-2¢-[N-Methyl-N-(4-nitrocinna-
moyl)amino]acetophenone (8d): mp 165–166 °C. 1H NMR
(300.13 MHz, CDCl3): d = 2.48 (s, 3 H, 2-Me), 3.38 (s, 3 H,
NMe), 6.28 (d, 1 H, J = 15.5 Hz, H-a), 7.32 (dd, 1 H, J = 7.9,
1.1 Hz, H-6¢), 7.41 (d, 2 H, J = 8.8 Hz, H-2¢¢, H-6¢¢), 7.54
(ddd, 1 H, J = 7.4, 7.5, 1.1 Hz, H-4¢), 7.64 (ddd, 1 H, J = 7.4,
7.9, 1.5 Hz, H-5¢), 7.70 (d, 1 H, J = 15.5 Hz, H-b), 7.79 (dd,
1 H, J = 7.5, 1.5 Hz, H-3¢), 8.14 (d, 2 H, J = 8.8 Hz, H-3¢¢,
H-5¢¢). 13C NMR (75.47 MHz, CDCl3): d = 29.4 (2-Me), 37.8
(NMe), 122.1 (C-a), 124.0 (C-3¢¢, C-5¢¢), 128.4 (C-2¢¢, C-6¢¢),
128.5 (C-1¢), 128.8 (C-4¢), 129.5 (C-6¢), 130.0 (C-3¢), 133.2
(C-5¢), 139.7 (C-b), 141.1 (C-1¢¢), 141.2 (C-2¢), 144.5 (C-
4¢¢), 165.0 (C=O), 199.1 (C-1). HRMS (ESI, +): m/z calcd
for C18H17N2O4: 325.1183; found: 325.1174.
(24) Physical Data (E)-1-Methyl-2-(4-nitrostyryl)-4-
quinolone (5d): 1H NMR (300.13 MHz, CH3OD): d = 3.86
(s, 3 H, NMe), 6.54 (s, 1 H, H-3), 7.24 (AB, 1 H, J = 16.0 Hz,
H-a), 7.24 (AB, 1 H, J = 16.0 Hz, H-b), 7.43 (ddd, 1 H, J =
7.8, 7.3, 0.7 Hz, H-6), 7.55 (d, 1 H, J = 8.5 Hz, H-8), 7.70 (d,
2 H, J = 8.8 Hz, H-2¢, H-6¢), 7.70–7.76 (m, 1 H, H-7), 8.30
(d, 2 H, J = 8.8 Hz, H-3¢, H-5¢), 8.48 (dd, 1 H, J = 7.8, 1.5
Hz, H-5). 13C NMR (75.47 MHz, CH3OD): d = 35.9 (NMe),
110.2 (C-3), 115.4 (C-8), 123.8 (C-6), 124.3 (C-3¢, C-5¢),
126.2 (C-a), 126.8 (C-5), 126.9 (C-10), 127.9 (C-2¢, C-6¢),
132.6 (C-7), 135.3 (C-b), 141.5 (C-1¢), 141.7 (C-9), 147.8
(C-4¢), 150.5 (C-2), 178.1 (C-4). HRMS (ESI, +): m/z calcd
for C18H15N2O3: 307.1083; found: 307.1073.
Synlett 2008, No. 17, 2593–2596 © Thieme Stuttgart · New York

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