Synthesis and cyclisation studies of (E)-2-aryl-1-methyl-3-styrylquinolin-4(1H)-ones

Article abstract of DOI:10.1016/j.tet.2015.07.058

The synthesis of (E)-2-aryl-1-methyl-3-styrylquinolin-4(1H)-ones, through the Heck reaction of 2-aryl-3-iodo-1-methyl-quinolin-4(1H)-ones with styrene is described. 2-Aryl-3-iodo-1-methyl-2-quinolin-4(1H)-ones can be obtained efficiently in a two-step tra

Full text of DOI:10.1016/j.tet.2015.07.058

Tetrahedron xxx (2015) 1e5
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Synthesis and cyclisation studies of (E)-2-aryl-1-methyl-3-
styrylquinolin-4(1H)-ones
*
*
Djenisa H.A. Rocha, Diana C.G.A. Pinto , Artur M.S. Silva
Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of (E)-2-aryl-1-methyl-3-styrylquinolin-4(1H)-ones, through the Heck reaction of 2-aryl-3-
iodo-1-methyl-quinolin-4(1H)-ones with styrene is described. 2-Aryl-3-iodo-1-methyl-2-quinolin-
4(1H)-ones can be obtained efficiently in a two-step transformation, methylation followed by in situ
cyclization of N-(2-acetylphenyl)benzamides into 2-aryl-1-methylquinolin-4(1H)-ones, which un-
derwent selective 3-iodination with iodine and a catalytic amount of Can. Cyclisation studies of (E)-2-
aryl-1-methyl-3-styrylquinolin-4(1H)-ones under high temperature or photoinduced electrocyclisation
lead to 4-aryl-2-phenylfuro[3,2-c]quinolines and 12-methyl-5-phenylbenzo[c]acridin-7(12H)-ones.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 16 May 2015
Received in revised form 18 July 2015
Accepted 21 July 2015
Available online xxx
Keywords:
(E)-2-Aryl-1-methyl-3-styrylquinolin-
4(1H)-ones
Benzo[c]acridin-7(12H)-ones
4-Arylfuro[3,2-c]quinolones
Heck reaction
N-methylation
1. Introduction
reported. In most of the cases good yields (above 70%) for the final
step are reported, but their procedures involve several steps so the
The nucleus quinolin-4(1H)-one is a well-known nitrogen het-
erocycle due to its occurrence in a wide range of biological active
molecules, namely natural compounds1 or commercially available
synthetic drugs. Although active derivatives are known for more
than fifty years, the synthesis and biological assessments are still
a hot topic.2 For example, in 2010 Mphahlele3 reviewed several
synthetic methodologies towards 2-arylquinolin-4(1H)-ones, and
also described some natural derivatives widely distributed in the
Rutaceae family. The interest in these compounds arises mostly
from their broad spectrum as antimicrobial agents. Some are al-
ready in the market and other are potential pharmaceuticals acting
as promising antitumor agents.4 One particular biological assess-
ment showed that 2-arylquinolin-4(1H)-ones can inhibit bacterial
DNA-gyrase and mammalian topoisomerase II enzymes, which
indicates their potential as antibacterial and antitumor agents,
respectively.5
overall yield, which is not reported, should be lower. However, Lee
et al.6a reported an overall yield of 39%e68% of a 6-step sequence.
All the same, other methodologies, with higher yields and fewer
steps are desired.
We showed that quinolin-4(1H)-ones bearing groups such as 2-
and 3-styryl can be obtained with efficient methodologies.8 Con-
tinuing our research in this area, we report the stereoselective
synthesis of (E)-2-aryl-1-methyl-3-styrylquinolin-4(1H)-ones, as
well as their transformation into 4-aryl-2-phenylfuro[3,2-c]
quinolones.
2. Results and discussion
In connection with our previous interest in the synthesis of new
3-styrylquinolin-4(1H)-ones8 and 3-styrylflavones9 we envisaged
the synthesis of new 2-aryl-3-styrylquinolin-4(1H)-ones through
the Heck reaction of 2-aryl-3-iodoquinolin-4(1H)-ones 3 and sty-
rene (Scheme 1). Having previously studied the synthesis of 3-iodo-
2-styrylquinolin-4(1H)-ones,8d we chose to apply the same meth-
odology to obtain the desired 2-aryl-3-iodoquinolin-4(1H)-ones 3.
N-(2-Acetylaryl)benzamides 1aec were obtained in excellent
yields from the commercially available 20-aminoacetophenone and
benzoyl chlorides. The cyclization into 2-arylquinolin-4(1H)-ones
2aec was not as easy as described in the literature.3 It was neces-
sary to study the reaction conditions, several combinations of
Due to the described biological properties, the research on new
and efficient methodologies to obtain 2-arylquinolin-4(1H)-ones is
still essential. Recently efficient routes using benzoic acid de-
rivatives6 or 2-aminobenzylic alcohol,7 as starting materials were
* Corresponding authors. Tel.: þ351 234 401 407; fax: þ351 234 370 084
(D.C.G.A.P.); tel.: þ351 234 370 714; fax: þ351 234 370 084 (A.M.S.S.); e-mail
addresses: diana@ua.pt (D.C.G.A. Pinto), artur.silva@ua.pt (A.M.S. Silva).
http://dx.doi.org/10.1016/j.tet.2015.07.058
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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2
D.H.A. Rocha et al. / Tetrahedron xxx (2015) 1e5
Previous fruitful results with 2-styrylquinolin-4(1H)-ones8d
prompted us to envisage another route involving the synthesis of
2-aryl-3-iodo-1-methylquinolin-4(1H)-ones (Scheme 2). The
7
synthesis of this type of compounds was previously reported3 but
using a different approach and again there is no reference to the
nitro derivative nor to overall yields. Our methodology involves the
synthesis of 2-aryl-1-methylquinolin-4(1H)-ones 4aec followed by
its iodination with iodine in the presence of CAN as catalyst. First
we study the synthesis of 2-aryl-1-methylquinolin-4(1H)-ones 4
following two synthetic strategies, the N-methylation of 2-
arylquinolin-4(1H)-ones 2 or the N-methylation and in situ cycli-
zation of N-(2-acetylaryl)benzamides 1. For compounds 4a and 4b
both routes produced the desired product as the major one and
a by-product was also obtained (compounds 5 or 6 the structure of
which were confirmed by NMR spectroscopy) (Scheme 2). In the
case of compound 4c only the methylation and in situ cyclization of
N-(2-acetylaryl)benzamide 1c can be used (overall yield of 56%, 6%
with the other method).
Scheme 1. Proposal for the synthesis of 2-aryl-3-styrylquinolin-4(1H)-ones.
solvents (THF and t-BuOH),y bases (NaH and t-BuOK),y temperature
(from 30 ꢀC to 80 ꢀC and also MW irradiation) and different re-
actions times were tested in order to obtain the products in good
yields. The best reaction conditions found for derivative 2a (t-BuOK
as base and THF as solvent) were not appropriate for the other
derivatives. For instance for derivative 2b t-BuOH was the best
solvent and for derivative 2c NaH was the best base. The next step
was the iodination under our previously reported conditions8d
,
which allowed the synthesis of the desired 2-aryl-3-iodoquinolin-
4(1H)-ones 3aec in good yields (Scheme 1). It should be emphas-
ised that as far as we are aware the synthesis of both 2-(4-
nitrophenyl)quinolin-4(1H)-one 2c and 3-iodo-2-(4-nitrophenyl)
quinolin-4(1H)-one 3c are being reported for the first time, the
overall yields (2c, 46% and 3c, 28%) are not extraordinary but the
presence of such an electron withdrawing group usually causes
some difficulties. The synthesis of the other derivatives 2a,b and
3a,b was previously reported3 but the overall yields were not in-
dicated and in our conditions were moderate (2a, 48%; 2b, 62%; 3a,
34% and 3b, 56%).
Scheme 2. Synthesis of 2-aryl-3-iodo-1-methylquinolin-4(1H)-ones 7.
In addition to the characteristic signals of the 2-arylquinolin-
4(1H)-one skeleton, the 1H NMR spectrum of 2-aryl-1-
methylquinolin-4(1H)-ones
4,
3.61e3.65 ppm due to the N-methyl protons and a signal at
37.3e37.4 ppm in the 13C NMR spectrum due to the methyl carbon
present
a
singlet
at
d
The characterization of these compounds was mainly done with
NMR experiments; most care was taken with the nitro substituted
derivatives due to their novelty. The most important features in the
1H and 13C NMR spectra of N-(2-acetylaryl)benzamides 1aec are
d
resonance.
Compounds 4 having been obtained, the next step was their
iodination and 2-aryl-3-iodo-1-methylquinolin-4(1H)-ones 7aec
were obtained in excellent yields (above 90%). In this study we
proved that the route involving steps (iv) and (v) (Scheme 2), not
only has less steps but also gives better overall yields (61%).
Having the 2-aryl-3-iodo-1-methylquinolin-4(1H)-ones 7aec
the next step was their reaction with styrene under Heck reaction
conditions and using MW irradiation as source of energy to shorten
the reaction time. This methodology proved to be efficient to syn-
thesise (E)-2-aryl-1-methyl-3-styrylquinolin-4(1H)-ones 8aec
(Scheme 3).
Our interest in the synthesis of benzoacridone derivatives star-
ted with the synthesis of benzo[b]acridin-12(7H)-ones.11 So, in or-
der to assess the value of (E)-2-aryl-1-methyl-3-styrylquinolin-
4(1H)-ones 8 as synthon for preparation of new benzo[c]acridin-
7(12H)-ones, their electrocyclisation was studied (Scheme 3). To
begin we used the established methodology that was efficient for
the synthesis of O-analogues, benzo[c]xanthones, through the
photoinduced electrocyclisation of 3-styrylflavones.9a The first
conclusions of this study are: i) the reactivity of these aza-
the resonances of 2-CH3 protons (
12.7e12.9 ppm), C-1 ( w203 ppm) and the amide carbonyl carbon
164e166 ppm). In the case of 2-arylquinolin-4(1H)-ones 2aec it
can be highlight the resonances of proton H-3 ( 6.3e6.5 ppm), NH
proton 11.6e12.0 ppm), C-3 107e109 ppm) and C-4
w177 ppm). Finally, 2-aryl-3-iodoquinolin-4(1H)-ones 3aec
present the characteristic resonances of NH proton
12.2e12.5 ppm), C-3 ( w86 ppm) and C-4 ( w174 ppm).
The next consisted in the use of our previous optimal conditions
to obtain 2-aryl-3-styrylflavones9 hoping to synthesise 2-aryl-3-
styrylquinolin-4(1H)-ones.8b However, since all the attempts were
unfruitful, even using MW as source of energy did not improve the
results and only the (E)-2-phenyl-3-styrylquinolin-4(1H)-one was
identified as a minor product in one of our attempts,10 a different
approach was hypothesised.
dw2.7 ppm), NH proton (d
d
(
d
d
(
d
(d
(d
(
d
d
d
y
We use the abbreviation t-Bu¼C(CH3)3 for the t-butyl group.
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D.H.A. Rocha et al. / Tetrahedron xxx (2015) 1e5
3
Scheme 4. Proposal mechanism for the synthesis of 4-aryl-2-phenylfuro[3,2-c]quin-
olines 11.
protons H-
a
and H-
b
confirms the (E) configuration; ii) the chem-
w8 ppm) is typical of an intramolecular
ical shift of proton H-
b (d
hydrogen bond with the carbonyl oxygen8c (Fig. 1a); iii) the NOE
Scheme 3. Synthesis and transformation of (E)-2-aryl-1-methyl-3-styrylquinolin-
4(1H)-ones 8.
effect between H-
a
and H-20,60 observed in the NOESY spectra
(Fig. 1a).
analogues is much lower due to the fact that more than one week
was necessary to obtain the desired 12-methyl-5-phenylbenzo[c]
acridin-7(12H)-ones 9 and their yields were not very good; ii) with
the nitro derivative 8c the transformation did not occur. If we take
into account the mechanism proposed for the O-analogues elec-
trocyclisation9a it makes sense that the nitro group do not favour
the transformation; iii) again the analysis of the expected mecha-
nism9a also explains the lower yield in the case of derivative 8b, the
methoxy group although an electron donating group also favours
the ortho/para substitution and in this case it should occur at the
meta; iv)
a by-product, (Z)-2-aryl-1-methyl-3-styrylquinolin-
Fig. 1. Important NMR features.
4(1H)-one 10 is obtained in the case of the unsubstituted derivative
8a (Scheme 3). This result indicates that a syn-(E) to syn-(Z) isom-
erization is favoured under the reaction conditions and the elec-
trocyclisation would be favoured if
isomerization occurs.
The most typical signals in the 1H and 13C NMR spectra of 12-
methyl-5-phenylbenzo[c]acridin-7(12H)-ones 9 are: i) the singlet
a syn-(E) to anti-(E)
due to proton H-6 at
proton H-8 at w8.6 ppm, the most deshielded protons owed to the
anisotropic and mesomeric effects of the carbonyl group; ii) the
singlet due to the N-methyl protons at w4.2 ppm and the re-
spective carbon signal at 45.0 ppm; iii) the signal due to carbon C-
7 at w178 ppm. The HMBC correlations observed in the spectra
dw8.4 ppm and the double doublet due to
d
Considering that acridones can be obtained through thermal
cyclisation8d a solution of (E)-2-aryl-1-methyl-3-styrylquinolin-
4(1H)-ones 8 was heated to reflux in 1,2,4-trichlorobenzene with
a catalytic amount of iodine for several days. The result was not the
expected one as new 4-aryl-2-phenylfuro[3,2-c]quinolines 11 were
obtained instead of the desired 12-methyl-5-phenylbenzo[c]acri-
din-7(12H)-ones 9 (Scheme 3). This type of furo[3,2-c]quinolone
derivatives were previously obtained from quinolin-4(1H)-
ones.8d,12 As far as we are aware, this is the first report of the
synthesis of such derivatives from N-methylated quinolin-4(1H)-
ones. We suspect that first an electrophilic addition of iodine oc-
curs, followed by demethylation and hydroiodic acid elimination
(Scheme 4). To confirm this hypothesis, we tested the reaction
using an equimolar amount of iodine and, after two days, the furo
[3,2-c]quinolone derivatives 11 were obtained in good to very good
yields (above 70%).
d
d
d
(Fig. 1b) not only confirmed the depicted structure but also allowed
the assignment of all protons and carbons resonance.
The most typical signals in 1H and 13C NMR spectra of 4-aryl-2-
phenylfuro[3,2-c]quinolines 11 are: i) the singlet due to proton H-3
at
carbon resonance; ii) the doublets due to protons H-6 at
w8.3 ppm and H-9 at w8.4 ppm, the most deshielded protons
dw7.4 ppm and the signal at d 101e102 ppm due to the C-3
d
d
owing to the through-space magnetic deshielding effect of the
heterocyclic nitrogen and oxygen atoms, respectively; iii) the signal
due to carbon C-9b at
d w156e157 ppm. The HMBC correlations
observed in the spectra (Fig. 1c) not only confirmed the depicted
structure but also allowed the assignment of all protons and car-
bons resonance.
The new (E)-2-aryl-1-methyl-3-styrylquinolin-4(1H)-ones
were fully characterized and in addition to the signals of the 2-aryl-
8
1-methylquinolin-4(1H)-one moiety, it can be observed the pres-
ence of an extra aromatic ring and the vinylic system, H-
at 6.23e6.47 ppm, H- doublet at 8.15e8.22 ppm, C-
122.2e123.9 ppm and C- at 130.7e132.4 ppm.
The syn-(E) stereochemistry depicted in Scheme 3 was con-
firmed by: i) the vinylic coupling constant (Jw16 Hz) between
a
doublet
3. Conclusions
d
b
b
d
a
at
d
d
New (E)-2-aryl-1-methyl-3-styrylquinolin-4(1H)-ones 8 were
prepared in good to excellent yields by the Heck reaction of 2-aryl-
3-iodo-1-methylquinolin-4(1H)-ones 7 with styrene. Novel 4-aryl-
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4
D.H.A. Rocha et al. / Tetrahedron xxx (2015) 1e5
2-phenylfuro[3,2-c]quinolines 11 were obtained in excellent yields
by an intramolecular cyclization of (E)-2-aryl-1-methyl-3-
styrylquinolin-4(1H)-ones 8.
(m, 5H, H-200,300,400,500,600), 7.49 (t, 1H, H-6, J 7.5 Hz), 7.50 (d, 1H, H-8, J
8.1 Hz), 7.62 (d, 2H, H-20,60, J 8.6 Hz), 7.72 (t, 1H, H-7, J 7.5 Hz), 8.15
(d,1H, H-
8.1 Hz) ppm. 13C NMR (75.47 MHz, CDCl3):
8), 117.7 (C-3), 122.2 (C-
), 124.2 (C-6), 124.5 (C-30,50), 126.1 (C-
200,600), 126.5 (C-4a), 127.2 (C-5), 127.3(C-400), 128.5 (C-300,500), 130.6
b
, J 16.0 Hz), 8.47 (d, 2H, H-30,50, J 8.6 Hz), 8.60 (d,1H, H-5, J
2-Aryl-3-iodo-1-methylquinolin-4(1H)-ones 7 were obtained in
fair to excellent yields in a straightforward methodology through
only three steps: synthesis of N-(2-acetylaryl)benzamides 1 fol-
lowed by their methylation and in situ cyclization, and finally se-
lective iodination at C-3. To the best of our knowledge the synthesis
of 2-arylquinolin-4(1H)-ones bearing nitro groups (4c and 7c) are
scarcely reported in the literature and our methodology allowed
the synthesis in good yields of several new nitro derivatives.
d 37.9 (NCH3), 115.6 (C-
a
(C-20,60), 132.4 (C- ), 132.43 (C-7), 138.5 (C-100), 140.1 (C-8a), 141.4
b
(C-10), 148.3 (C-40), 149.8 (C-2), 176.4 (C-4) ppm. ESIþ-MS m/z (%):
383.1 [MþH]þ (100). Anal. Calcd for C24H18N2O3: C, 75.38%; H,
4.74%; N, 7.33%. Found: C, 75.13%; H, 4.89%; N, 7.34%.
4.3. General procedure for the synthesis of 4-aryl-2-
phenylfuro[3,2-c]quinolines 11aec
4. Experimental section
4.1. General information
A
mixture of the appropriate (E)-2-aryl-1-methyl-3-
styrylquinolin-4(1H)-one 8aec (0.05 mmol) and an equimolar
amount of iodine (12.7 mg) in 1,2,4-trichlorobenzene (3 mL) was
stirred under reflux during 2 days. After that period, the reaction
mixture was poured into a silica gel column and eluted with light
petroleum to remove the excess of iodine and the 1,2,4-
trichlorobenzene. Upon changing the eluent to dichloromethane
and then to a mixture of dichloromethane/ethyl acetate (9:1)
compounds 11aec, 2,4-diarylfuro[3,2-c]quinolines, were obtained
in good to very good yields [11a 16 mg (92%), 11b 13 mg (72%), 11c
15 mg (80%)].
Melting points were determined on a BUCHI Melting point B-
545 apparatus and are uncorrected. 1H and 13C NMR spectra were
recorded on Bruker Avance III 300, Avance III HD 500, and Bruker
Avance III HD 700 [300.13 MHz (1H), 75.47 MHz (13C); 500.13 MHz
(1H), 125.76 MHz (13C); 700.13 MHz (1H), 176,05 MHz (13C)] spec-
trometers with TMS as internal reference and with CDCl3 or DMSO-
d6 as solvent. Chemical shifts (d) are reported in parts per million
values and coupling constants (J) in Hertz. Unequivocal 1H assign-
ments were made using 2D NOESY experiments (mixing time of
800 ms), while 13C assignments were made on the basis of 2D
gHSQC (1H/13C) and gHMBC (delays for one bond and long-range JC/
4.3.1. Spectral data of a selected compound, 4-(4-Methoxyphenyl)-2-
phenylfuro[3,2-c]quinoline (11b). 1H NMR (300.13 MHz, CDCl3):
couplings were optimized for 145 and 7 Hz, respectively) exper-
H
iments. Positive-ion ESI mass spectra were acquired using a Q-TOF
2 instrument [Nitrogen was used as nebulizer gas and argon as
collision gas. The needle voltage was set at 3000 V, with the ion
source at 80 ꢀC and desolvation temperature at 150 ꢀC. Cone voltage
was 35 V]. High resolution mass spectra (HRMS-ESIþ) were mea-
sure in a microTOF (focus) mass spectrometer. Ions were generated
using an Apolloll (ESI) source. Ionization was achieved by electro-
spray, using a voltage of 4500 V applied to the needle and a counter
voltage between 100 and 150 V applied to the capillary. Elemental
analyses were obtained with LECO 932 CHNS analyser. Preparative
thin layer chromatography was carried out with Silica gel 60 GF254
(Merck KGaA) and column chromatography using Silica gel
0.060e0.020 mm 60A (Acros Organics). All other chemicals and
solvents were obtained from commercial sources and used as re-
ceived or dried using standard procedures.
d
3.93 (s, 3H, 40-OCH3), 7.14 (d, 2H, H-30,50, J 8.7 Hz), 7.39 (s,1H, H-3),
7.38e7.43 (m, 1H, H-400), 7.48e7.53 (m, 2H, H-300,500), 7.62 (br dd, 1H,
H-8, J 7.0 and 8.0 Hz), 7.71 (br dd, 1H, H-7, J 7.0 and 8.0 Hz),
7.96e7.99 (m, 2H, H-200,600), 8.09 (d, 2H, H-20,60, J 8.7 Hz), 8.25 (d,1H,
H-6, J 8.0 Hz), 8,37 (d, 1H, H-9, J 8.0 Hz) ppm. 13C NMR (75.47 MHz,
CDCl3):
d
55.5 (40-OCH3), 101.7 (C-3), 114.3 (C-30,50), 116.1 (C-9a),
119.9 (C-9), 120.1 (C-3a), 124.9 (C-200,600), 126.3 (C-8), 128.4 (C-7),
128.9 (C-400), 129.0 (C-300,500), 129.7 (C-6), 129.9 (C-10), 130.2 (C-
20,60), 132.2 (C-100), 145.7 (C-5a), 153.2 (C-4), 156.1 (C-2), 156.2 (C-
9b), 160.7 (C-40) ppm. ESIþ-MS m/z (%): 352.1 [MþH]þ (100). EI-
HRMS: calcd for (C24H17NO2) 351.1259; found 351.1257.
Acknowledgements
Thanks are due to FCT/MEC for the financial support to the
QOPNA research Unit (FCT UID/QUI/00062/2013), through national
founds and where applicable co-financed by the FEDER, within the
PT2020 Partnership Agreement, and also to the Portuguese NMR
Network. D.H.A. Rocha also thanks FCT for her PhD grant (SFRH/BD/
68991/2010).
4.2. General procedure for the synthesis of (E)-2-aryl-1-
methyl-3-styrylquinolin-4(1H)-ones 8aec
A mixture of the appropriate 2-aryl-3-iodo-1-methylquinolin-
4-(1H)-one 7aec (0.10 mmol), Ph3P (3 mg, 0.010 mmol), Et3N
(13.9
m
L, 0.10 mmol), tetrakis(triphenylphosphine)palladium(0)
Supplementary data
(5.8 mg, 0.005 mmol) and styrene (48.4
mL, 0.42 mmol) in NMP
(7 mL) was heated under microwave irradiation in an Ethos SYNTH
microwave (Milestone Inc.) [2 min at 500 W until 100 ꢀC and hold at
100 ꢀC for 30 min] After that period, the reaction mixture was
poured into ice (20 g) and water (40 mL) and extracted with diethyl
ether (3ꢁ10 mL). The organic layer was washed with water
(3ꢁ30 mL), dried over anhydrous sodium sulfate and evaporated.
The residue was purified by thin layer chromatography using
a (6:4) mixture of dichloromethane/light petroleum as eluent. (E)-
2-Aryl-1-methyl-3-styrylquinolin-4(1H)-ones 8aec were obtained
in good to very good yields [8a 29 mg (85%), 8b 21 mg (57%), 8c
27 mg (70%)].
Supplementary data (Detailed experimental procedures, char-
acterization data for all products and representative 1H, 13C NMR
spectra.) related to this article can be found at http://dx.doi.org/
10.1016/j.tet.2015.07.058.
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nitrophenyl)-3-styrylquinolin-4(1H)-one (8c). 1H NMR (300.13 MHz,
CDCl3):
d
3.49 (s, 3H, NCH3), 6.23 (d, 1H, H-
a
, J 16.0 Hz), 7.13e7.24
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D.H.A. Rocha et al. / Tetrahedron xxx (2015) 1e5
5
4. e.g., (a) Hadjeri, M.; Peiller, E.-L.; Beney, C.; Deka, N.; Lawson, M. A.; Dumontet,
C.; Boumendjel, A. J. Med. Chem. 2004, 47, 4964e4970; (b) Huang, S.-M.; Cheng,
Y.-Y.; Chen, M.-H.; Huang, C.-H.; Huang, L.-J.; Hsu, M.-H.; Kuo, S.-C.; Lee, K.-H.
Bioorg. Med. Chem. Lett. 2013, 23, 699e701; (c) Cheng, Y.-Y.; Liu, C.-Y.; Tsai, M.-T.;
Lin, H.-Y.; Yang, J.-S.; Wu, T.-S.; Kuo, S.-C.; Huang, L.-J.; Lee, K.-H. Bioorg. Med.
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9. (a) Rocha, D. H. A.; Pinto, D. C. G. A.; Silva, A. M. S.; Cavaleiro, J. A. S.; Patonay, T.
Synlett 2012, 559e564; (b) Rocha, D. H. A.; Pinto, D. C. G. A.; Silva, A. M. S.
Synlett 2013, 2683e2686.
10. (E)-2-Phenyl-3-styrylquinolin-4(1H)-one: Mp 245e247 ꢀC, yellow solid. 1H
NMR (300.13 MHz, CDCl3):
200,300,400,500,600), 7.34 (br dd, 1H, H-6, J 7.0 and 8.1 Hz), 7.46e7.49 (m, 3H, H-8, H-
20,60), 7.52e7.61 (m, 4H, H-7, H-30,40,50), 8.11 (d, 1H, H-
, J 16.2 Hz), 8.39 (d, 1H,
H-5, J 8.1 Hz), 9.23 (s, 1H, NH) ppm. 13C NMR (75.47 MHz, CDCl3):
116.0 (C-3),
117.3 (C-8), 122.5 (C-
), 123.9 (C-6), 125.3 (C-4a), 126.2 (C-300,500), 126.6 (C-5),
126.8 (C-400), 128.4 (C-200,600), 128.9 (C-20,60), 129.2 (C-30,50), 130.0 (C-40), 131.4
d 6.78 (d, 1H, H-a, J 16.2 Hz), 7.10e7.24 (m, 5H, H-
5. Sui, Z.; Nguyen, V. N.; Altom, J.; Fernandez, J.; Hilliard, J. J.; Bernstein, J. I.;
Barrett, J. F.; Ohemeng, K. A. Eur. J. Med. Chem. 1999, 34, 381e387.
6. (a) Song, Y. J.; Choi, J. S.; Lee, J. I. Bull. Korean Chem. Soc. 2013, 34, 3117e3120; (b)
Dhiman, R.; Sharma, S.; Singh, G.; Nepali, K.; Bedi, P. M. S. Arch. Pharm. Chem.
Life Sci. 2013, 346, 7e16.
b
d
a
(C-b
), 131.8 (C-7), 135.1 (C-10), 138.1 (C-8a), 139.1 (C-100), 149.2 (C-2), 177.6 (C-4)
7. Seppanen, O.; Muuronen, M.; Helaja, J. Eur. J. Org. Chem. 2014, 4044e4052.
ppm. ESIþ-MS m/z (%): 324.1 [MþH]þ (100).
€
8. (a) Almeida, A. I. S.; Silva, V. L. M.; Silva, A. M. S.; Pinto, D. C. G. A.; Cavaleiro, J.
A. S. Synlett 2008, 2593e2596; (b) Almeida, A. I. S.; Silva, A. M. S.; Cavaleiro, J.
A. S. Synlett 2010, 462e466; (c) Seixas, R. S. G. R.; Silva, A. M. S.; Alkorta, I.;
Elguero, J. Monatsh. Chem. 2011, 142, 731e742; (d) Silva, V. L. M.; Silva, A. M. S.
Tetrahedron 2014, 70, 5310e5320.
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3193e3197.
12. Venkataraman, S.; Barange, D. K.; Pal, M. Tetrahedron Lett. 2006, 47, 7317e7322.
Please cite this article in press as: Rocha, D. H.A.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.07.058