An experimental NMR and computational study of 4-quinolones and related compounds

Article abstract of DOI:10.1007/s00706-011-0473-y

We report the synthesis and structural study of eight compounds, either quinolin-4(1H)-ones or quinolines. Tautomerism as well as (E) → (Z) and rotational isomerism were studied both experimentally (¹H and ¹³C NMR) and theoretically [B3LYP/6-311++G(d,p)]. Springer-Verlag 2011.

Full text of DOI:10.1007/s00706-011-0473-y

Monatsh Chem (2011) 142:731–742
DOI 10.1007/s00706-011-0473-y
ORIGINAL PAPER
An experimental NMR and computational study of 4-quinolones
and related compounds
•
Raquel S. G. R. Seixas Artur M. S. Silva
•
•
Ibon Alkorta Jose Elguero
´
Received: 6 November 2010 / Accepted: 20 February 2011 / Published online: 22 March 2011
Ó Springer-Verlag 2011
Abstract We report the synthesis and structural study of
eight compounds, either quinolin-4(1H)-ones or quinolines.
Tautomerism as well as (E) ? (Z) and rotational isomer-
ism were studied both experimentally (1H and 13C NMR)
and theoretically [B3LYP/6-311??G(d,p)].
factor receptor (EGFR) tyrosine kinase, and cytotoxic
activity against human cancer cell lines [12–16].
We have devoted three papers to these compounds, where
abundant bibliography can be found. In the first of these, we
reported synthesis of 1,4-dihydro-4-oxoquinoline-3-carbal-
dehyde (1, Fig. 1) and its use as a scaffold for preparation of a
library of drug-like compounds [17]. In the second paper,
1,4-dihydro-1-methyl-4-oxoquinoline-3-carbaldehyde (2) and
ethyl 3-formyl-1,4-dihydro-4-oxoquinoline-1(4H)-carboxyl-
ate (3) were prepared and used as dienophiles in Diels–Alder
reactions [18]. Finally, in the last of these papers, all the above
compounds were described [19]. These compounds were
prepared from the perspective of pharmacological applica-
tion, and their nuclear magnetic resonance (NMR) properties
were not discussed.
Keywords Thermal diastereomerization ꢀ
Quinolin-4(1H)-ones ꢀ Tautomerism ꢀ DFT calculations ꢀ
GIAO ꢀ NMR spectroscopy
Introduction
4-Quinolones are a large group of heterocycles that play an
important role in the development of new drugs [1]. They
can be found in a variety of natural products, mainly from
plants of the Rutaceae family [2–8], but the majority are of
synthetic origin. The most studied property of 4-quinolones
is their broad spectrum of antibiotic activity, including as
second-line drugs for treatment of tuberculosis [9–11].
3-Styryl-4-quinolones are structurally similar to 3-aryl-4-
quinolones, being the aza-analogs of 3-styryl-4-chromones.
3-Aryl-4-quinolones or azoisoflavones have shown inhibi-
tory effects against P-glycoprotein and epidermal growth
1
The aim of the present paper is to report H and 13C
NMR data of compounds 1–8 (Fig. 1), to discuss their
tautomerism and isomerism, and report calculations of their
properties (energies and NMR).
Results and discussion
Chemistry
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-011-0473-y) contains supplementary
material, which is available to authorized users.
1,4-Dihydro-4-oxoquinoline-3-carbaldehyde (1) was obtained
through a Vilsmeier reaction of 20-aminoacetophenone,
followed by acidic hydrolysis of the resultant 4-chloro-
quinoline-3-carbaldehyde (9) [5]. Methylation of 1 gave 1,4-
dihydro-1-methyl-4-oxoquinoline-3-carbaldehyde (2), while
carboxyethylation and tosylation afforded ethyl 3-formyl-1,4-
dihydro-4-oxoquinoline-1(4H)-carboxylate (3) and 1,4-dihy-
dro-4-oxo-1-tosylquinoline-3-carbaldehyde (4), respectively
(Scheme 1, vide experimental part) [18, 19]. The most
R. S. G. R. Seixas ꢀ A. M. S. Silva (&)
Chemistry Department and QOPNA, University of Aveiro,
3810-193 Aveiro, Portugal
e-mail: artur.silva@ua.pt
I. Alkorta ꢀ J. Elguero
´
Instituto de Quımica Medica, CSIC, Juan de la Cierva 3,
28006 Madrid, Spain
´
123

732
R. S. G. R. Seixas et al.
H
N
CH3
N
SO2C6H4CH3
CO2Et
N
N
CHO
CHO
CHO
CHO
O
1
O
2
O
4
O
3
H
N
CH3
N
SO2C6H4CH3
N
N
O
Cl
O
O
5
6
7
8
Fig. 1 Structures of quinolin-4(1H)-ones 1-7 and quinoline 8
CH3
N
H
N
N
(ii)
(iii)
(i)
CHO
CHO
CHO
NH2
O
Cl
O
O
1
9
2
(v)
(iv)
SO2C6H4CH3
N
CO2Et
N
(i) POCl3, DMF, 4 h, 60 °C
(ii) HCO2H (aq., 54%), 2 h, 50 °C
(iii) CH3I, PS-TBD, THF, 2 h, 40 °C
(iv) ClCO2Et, K2CO3, Acetone, 0.5 h, rt
(v) p-Toluenesulfonyl chloride,
K2CO3, Acetone, 3 h, rt
CHO
CHO
O
4
O
3
Scheme 1
important NMR features of these compounds are the signals
due to the resonance of the formyl group (dH = 10.37–
10.46 ppm, dC = 186.3–186.5 ppm) and C-4 carbonyl group
(dC = 172.2–173.3 ppm). Some of these chemical shifts are
not self-evident, which is one of the reasons we carried out
theoretical calculations.
36%, (Z)-8 55%, Scheme 3] [19]. Hydrolysis of the dia-
stereomeric mixture (Z)-8, (E)-8 with 40% aqueous formic
acid at 120 °C for 24 h led to the formation of (E)-3-sty-
rylquinolin-4(1H)-one (5) in 93% yield. However,
controlling the reaction at 18 h reaction time, we found a
mixture of (Z)- and (E)-3-styrylquinolin-4(1H)-ones (Z)-5,
(E)-5 in a proportion of 9:78%. This seems to indicate that
we are in the presence of a (Z) ? (E) thermal isomeriza-
tion, since all the transformation was carried out in the
absence of light.
Wittig reaction of N-substituted quinolone-3-carbalde-
hydes 2 and 4 with benzylidenetriphenylphosphorane,
obtained from the reaction of benzyltriphenylphosphonium
chloride with a molar equivalent of NaH in freshly dried
Tetrahydrofuran (THF), led to the formation of a diaste-
reomeric mixture of (Z)- and (E)-1-substituted-3-
styrylquinolin-4(1H)-ones (Z)-6, (Z)-7 and (E)-6, (E)-7 in
good yields [R = CH3, (E)-6 8%, (Z)-6 70%; R = tosyl,
(E)-7 6%, (Z)-7 46%; Scheme 2] [19]. The (Z)-isomer was
the more abundant, as expected from the reaction of a
semistabilized ylide with sterically crowded carbonyl
compounds [20–23].
The assignment of the stereochemistry of styrylquin-
olines described above was based on the coupling
3
constant of the styryl olefinic protons, being Jtrans
&
3
16 Hz and Jcis & 12 Hz, and also on the nuclear
Overhauser effect (NOE) cross peaks observed in the
NOE spectroscopy (NOESY) spectra of some of these
compounds (Fig. 2).
Wittig reaction of 4-chloroquinoline-3-carbaldehyde (9)
with benzylidenetriphenylphosphorane led to the formation
of a diastereomeric mixture of (Z)- and (E)-4-chloro-3-
styrylquinolines (E)-8, (Z)-8 in good yields [(E)-8
Experimental NMR data
The chemical shifts are reported in Tables 1 and 2. Note in
the case of the styryl derivatives 5–8 the possible existence
123

An experimental NMR and computational study
733
R
N
R
N
(i)
NaH
O
(i)
(Z )-6, (Z )-7
+
+
CHO
H2C
R
HC
PPh3X
PPh3
10
O
2,4
N
2,6: R = CH3
4,7:
R = Ts
(i) dry THF, reflux, N2
O
(E )-6, (E )-7
Scheme 2
N
N
H
N
+
CHO
(i)
Cl
(Z )-
(ii)
8
Cl
HC
+
N
PPh3
10
O
9
5
(i) dry THF, reflux, N2
(ii) HCO2H (aq. 40%)
Cl
(E )-
8
Scheme 3
of an (E)/(Z) isomerism (Scheme 4 and analogously for 8)
as well as a anti/syn rotation about the C3–Ca bond mainly
for the (E)-isomers, although NOESY experiments (Fig. 2)
show that there is a weak interaction between H2 and Ha
for the (Z)-isomers. Furthermore, in the case of 5 (R = H),
the possible existence of hydroxy forms (b) must be con-
sidered (see ‘‘Discussion’’ on tautomerism).
tautomer is observed but in the gas phase (mass spectrometry
and theoretical calculations) both tautomers are present.
Our B3LYP/6-311??G(d,p) energy calculations for
compound 1 afford for 1 (C=O) -590.64828 hartree and for
1b (OH) -590.65243 hartree; i.e., the OH tautomer is the
more stable by 10.9 kJ mol-1. In the case of 5 the situation is
reversed (Table 3) and the oxo tautomers are the more stable
by 25.8 kJ mol-1. We ascribe the difference of about
37 kJ mol-1 to an intramolecular hydrogen bond (IMHB) in
the case of 1b (Scheme 5). This kind of stabilization was
known for 4-hydroxyquinolines bearing an ester group at
position 3 [24].
Theoretical calculations
Tautomerism
NH-quinolones 1 and 5 present oxo/hydroxy (b) tautomer-
ism (see Scheme 5 for 1); its position was not well known
in 1976 [24]. In the 2006 update, the situation remained
confused [25]. 2-Substituted 4-quinolones showed
predominance of 4-hydroxy tautomers (b) in dimethyl
sulfoxide (DMSO)-d6 solution and of 4-oxo ones in CDCl3/
CD3OD [26]. According to Mphahlele and coworkers, the
3-bromoderivatives exist bothin solutionandinthesolidstate
as the oxo tautomers [27]. Subsequently, these latter authors
discussed the case of 2-aryl-4-quinolones [28]: in solution
(NMR in DMSO-d6) and in the solid state only the 4-oxo
Rotational isomerism
We have carried out B3LYP/6-311??G(d,p) calculations
on the structures 5–8. When trying to calculate the crowded
syn-(Z)-conformations in the case of compounds 5 and 6,
we obtained the anti-(Z)-ones (Scheme 4). This result is
not inconsistent with the NOESY experiments (Fig. 2)
because, even if these isomers are not stable, the anti-(Z)/
syn-(Z) rotation about the C3-Ca bond puts the H2 and Ha
protons in close proximity [29, 30].
123

734
R. S. G. R. Seixas et al.
H
N
H
N
2
3
2
H
H
H
H
β
2'
α
H
α
H
3
6'
O
H
O
H
H
6'
β
anti-(E )-
H
5
2'
syn-(E )-
5
CH3
CH3
CH3
CH3
H2-H2'
weak
2'
2
2
2
2
N
H
N
H
N
H
H
N
H
6'
H
H
H
β
β
2'
α
α
H
H
H
3
3
H
3
H
3
α
H
α
6'
O
O
O
H
O
H
H
6'
β
β
2'
anti-(Z )-
6
anti-(E )-
6
H
2'
H
6'
syn-(E )-
6
syn-(Z )-
6
H2-H2'
weak
2'
2
2
2
N
H
N
H
N
2
H
H
N
H
6'
H
H
H
β
β
2'
α
α
H
H
H
3
H
3
H
α
α
3
3
Cl
6'
Cl
H
Cl
Cl
H
H
β
H
β
6'
2'
anti-(Z )-
8
H
2'
H
6'
anti-(E )-8
syn-(E )-
syn-(Z )-
8
8
Fig. 2 Main NOE cross peaks observed in the NOESY spectra of (E)-5, (E)-6, (Z)-6, (E)-8, and (Z)-8
Table 1 1H NMR chemical shifts (ppm) of compounds 1–8 [2–4, 6–8 in CDCl3 and 1, 5 in dimethyl sulfoxide (DMSO)-d6]
R
R
8
8
8
8a
4a
N
1
8a
4a
8a
4a
N
1
2
2
3
N
1
7
6
7
6
7
6
H
2
H
β
β
α
4
α
4
4
3
i
3
5
CHO
i
5
5
p
H
Cl
o
p
H
O
o
O
m
m
Comp.
H2
H5
H6
H7
H8
CHO
Ha
Hb
Ho
Hm
Hp
1
8.49
8.31
9.03
9.27
8.30
7.77
7.48
8.80
8.42
9.20
8.57
8.22
8.54
8.47
8.43
8.21
8.55
8.54
8.42
8.40
8.29
8.29
7.48
7.53
7.53
7.47
7.36
7.42
7.41
7.41
7.39
7.64
7.65
7.77
7.78
7.75
7.66
7.66
7.67
7.67
7.58
7.56
7.74
7.74
7.68
7.50
8.61
8.21
7.58
7.41
7.35
8.21
8.09
8.11
8.04
10.20
–
–
–
–
–
–
–
–
2
10.42
–
–
–
–
3
10.44
–
–
–
–
4
10.46
–
–
–
–
(E)-5
(E)-6
(Z)-6
(E)-7
(Z)-7
(E)-8
(Z)-8
–
–
–
–
–
–
–
7.22
7.17
6.79
7.20
6.72
7.65
6.80
7.80
7.65
6.65
7.68
6.87
7.34
6.96
7.51
7.54
7.35
7.58
7.32
7.65
7.18
7.36
7.34
7.26
7.38
7.32
7.42
7.18
7.22
7.22
7.22
7.28
7.32
7.34
7.18
NR 2 (CH3, 3.93); 3 (CH2, 4.61; CH3, 1.54); 4 (Ho, 7.83, Hm, 7.38, CH3, 2.43); (E)-6 (CH3, 3.88); (Z)-6 (CH3, 3.56); (E)-7 (tosyl: Ho, 7.78, Hm,
7.32, CH3, 2.40); (Z)-7 (tosyl: Ho, 7.46, Hm, 7.26, CH3, 2.40)
123

An experimental NMR and computational study
735
Table 2 13C NMR chemical shifts (ppm) of compounds 1–8 [2–4, 6-8 in CDCl3 and 1, 5 in dimethyl sulfoxide (DMSO)-d6]
Comp.
C2
C3
C4
C4a
C5
C6
C7
C8
C8a
CHO
1
143.3
146.7
142.4
141.8
138.9
142.0
142.0
134.8
136.9
148.1
151.2
116.3
117.1
118.0
118.2
116.8
118.5
118.5
120.9
120.1
129.6
129.4
176.3
177.0
177.4
177.0
175.3
176.2
176.2
177.2
177.8
139.5
140.7
127.8
129.3
127.9
128.0
125.4
126.7
126.7a
126.2
125.8
126.4
126.4
125.5a
127.3
126.6
127.5
125.5
127.4
127.4
127.6
127.4
124.5
124.0a
125.3a
125.9
126.8
126.9
123.5
123.9
123.9
125.7
125.5
128.0
127.7
133.1
133.3
133.8
133.6
131.5
131.9
131.9
132.4
132.4
129.8
129.9
119.5
116.2
120.2
118.6
118.4
115.2
115.2
118.1
118.0
129.6
129.6
139.4
140.2
137.9
136.4
138.6
139.3
139.3
135.9
136.2
147.6
147.4
188.8
2
189.3
3
189.1
4
188.7
(E)-5
(E)-6
(Z)-6
(E)-7
(Z)-7
(E)-8
(Z)-8
–
–
–
–
–
–
–
Comp.
Ca
Cb
Ci
Co
Cm
Cp
(E)-5
(E)-6
(Z)-6
(E)-7
(Z)-7
(E)-8
(Z)-8
124.1
126.6
128.3
129.0
131.2
132.3
133.2
134.0
138.5
138.2
137.6
137.4
137.1
136.5
135.9
125.8
126.3
128.6
126.6
128.8a
127.0
128.9
128.8
128.6
128.4
128.7
128.7a
128.8
128.6
126.8
127.1
126.9
127.8
127.1
128.7
128.0
122.6
123.7a
121.2
123.0
122.4
124.1a
Comp.
(NR)
2
CH3
41.6 (CH3)
3
CO2Et
Tosyl
CH3
150.8 (C=O), 66.2 (CH2), 14.1 (CH3)
4
132.9 (Ci), 127.9 (Co), 130.6 (Cm), 147.3 (Cp), 21.8 (CH3)
41.0 (CH3)
(E)-6
(Z)-6
(E)-7
(Z)-7
CH3
40.6 (CH3)
Tosyl
Tosyl
133.7 (Ci), 127.5 (Co), 130.4 (Cm), 146.4 (Cp), 21.7 (CH3)
133.6 (Ci), 127.6 (Co), 130.2 (Cm), 146.2 (Cp), 21.7 (CH3)
a
For a given compound, the assignment of these signals can be permuted
d1H ¼ 31:0 ꢁ 0:97r1H
The (Z)-isomers are always the less stable, but between the
(E)-ones there is an inversion between quinolones 5, 6, and 7
[syn-(E) more stable than anti-(E)] and 4-chloroquinolines 8
[anti-(E) more stable than syn-(E)]. We assign this difference
to a C–HꢀꢀꢀO=C IMHB in the syn-(E)-3-styrylquinolin-4(1H)-
d13C ¼ 175:7 ꢁ 0:963r13C
The r and d values can be found in the Supplementary
Material.
ones (Fig. 3). The lower stability of the (Z)-isomers (between
16 and 21 kJ mol-1) agrees with our previous comment about
the (Z) ? (E) thermal isomerization.
First, we will discuss the case of the 3-formyl deriva-
tives 1–4. By interpolation of the experimental 13C NMR
chemical shifts (Table 2) of compound 1 (obtained in
DMSO-d6) we have calculated that it is a mixture of 75%
oxo 1 and 25% hydroxy 1b tautomers. If we exclude the
signal of the ipso carbon of the tosyl derivative 4 we obtain
Eq. (2):
Theoretical calculations of chemical shifts
1
We have calculated the H and 13C absolute shieldings
(r, ppm) using the Gauge Including Atomic Orbitals
(GIAO) approximation on the minimum geometries
obtained at the 6-311??G(d,p) level. These r values were
transformed into chemical shifts (d, ppm) using two
empirical equations we have previously established
[31, 32]:
d13Cexp: ¼ ð1:007 ꢂ 0:002Þd13Ccalcd:
n ¼ 48; R2 ¼ 1:000:
;
ð1Þ
The 75% of oxo tautomer 1 in DMSO-d6 agrees with
Mphahlele’s results [27, 28]. We assign the inversion of the
123

736
R. S. G. R. Seixas et al.
E-isomer
Z-isomer
R
N
R
N
N
O
H
H
R = H
H
H
O
H
O
H
H
anti-(Z )
anti-(E)
anti-(E)-5b
R
N
R
N
N
O
R = H
H
H
H
H
O
O
H
5, R = H
H
H
6
, R = CH3
7, R = tosyl
syn-(E)-
syn-(E)
5b
syn-(Z )
Scheme 4
H
N
N
N
O
H
CHO
CHO
O
O
OH
H
1
1b
Scheme 5
populations between the gas phase (the OH tautomer 1b
more stable by about 11 kJ mol-1) and the DMSO solution
(75% oxo 1 and 25% hydroxy 1b) to the fact that the IMHB
of 1b present in the gas phase (Scheme 5) breaks in this
solvent.
The 1H NMR chemical shifts (Table 1) are less suited to
discuss the tautomerism of 1, however the regression is
slightly better using the averaged 75/25 mixture (Eq. 3)
than considering the four compounds to be oxo tautomers
(Eq. 2).
5, 6, and 7. Then, by interpolation we obtain the following
results:
ðEÞ-5 45%anti-55%syn
ðEÞ-6 33%anti-67%syn
ðEÞ-7 55%anti-45%syn
ðEÞ-8 50%anti-50%syn
To compare the experimental 13C NMR chemical shifts
with the calculated ones, we simplified the problem of
anti-/syn-isomerism by considering that, in all cases, the
mixture is 50%/50%, obtaining the plot shown in Fig. 4
[dexp. = (1.002 0.002)dCalcd., n = 118, R2 = 1.000].
We have already signaled that carbon atoms bearing
chlorine or sulfur substituents are not well reproduced at
the used computational level [33, 34]. The contribution of
these substituents can be estimated at -(6.7 2.1) ppm
for the SO2 group on the Cipso carbon and at
-(8.3 1.5) ppm for the chlorine atom on C4.
d1Hexp: ¼ ð1:010ꢂ 0:006Þd1Hcalcd:; n ¼ 30; R2 ¼ 0:9989;
ð2Þ
d1Hexp: ¼ ð1:008 ꢂ 0:005Þd1Hcalcd:; n ¼ 30; R2 ¼ 0:9992
ð3Þ
Now we will examine the case of the 3-styryl-
derivatives 5–8. For compound 5 there exist oxo and
hydroxyl tautomers. For the (E)-isomer, that corresponds to
four structures: 5 oxo anti-(E), 5 oxo syn-(E), 5b hydroxy
anti-(E), and 5b hydroxy syn-(E). We have assumed,
according to the calculations, that all are oxo tautomers
We have carried out a similar study concerning 1H NMR
chemical shifts assuming that there are equal amounts of
anti- and syn-rotational isomers (Fig. 5).
123

An experimental NMR and computational study
737
Table 3 Energies and dipole moments calculated at the B3LYP/6-
311??G(d,p) computational level
Comp.
Etotal (hartree)
Dipole (D)
Erel (kJ mol-1
)
5
anti-(E)
syn-(E)
anti-(Z)
5b
-785.82349
-785.82488
-785.81752
5.97
6.00
5.97
4.0
0.0
19.3
anti-(E)
syn-(E)
6
-785.81503
-785.81464
2.57
2.71
25.8
26.9
anti-(E)
syn-(E)
anti-(Z)
7
-825.13905
-825.14058
-825.13316
6.48
6.53
6.43
4.0
0.0
19.5
anti-(E)
syn-(E)
anti-(Z)
8
-1604.87919
-1604.88012
-1604.87193
5.78
6.20
5.93
2.4
0.0
21.5
Fig. 4 Plot of experimental versus calculated 13C NMR chemical
shifts
anti-(E)
syn-(E)
anti-(Z)
-1170.18742
-1170.18354
-1170.18116
0.93
1.12
0.58
0.0
10.2
16.4
Fig. 3 Intramolecular hydrogen
bond of syn-(E)-3-
styrylquinolin-4(1H)-one (5)
H
N
syn-(E)-5
H
O
H
IMHB
AIM analysis of intramolecular interactions
We decided to study the situations corresponding to 1b
(Scheme 5), anti-(E)-5 (Scheme 4 and Fig. 3), and syn-(E)-5
(Scheme 4) using the atoms in molecules (AIM) method-
ology (Fig. 6). The analysis of the electron density in these
molecules shows the presence of several types of intra-
molecular interactions such as HꢀꢀꢀH, CHꢀꢀꢀO, and OHꢀꢀꢀO.
The presence of these interactions is associated to bond
critical points (bcp), and due to the topological nature of
these compounds to a ring critical point (rcp). The strength
of these interactions can be qualitatively assigned based on
the distance of the bcp and the rcp. The proximity of bcp
and rcp (HꢀꢀꢀH contacts) indicates that small perturbations
in the system can result in the disappearance of both crit-
ical points, which corresponds to weak interactions. In
contrast, the OHꢀꢀꢀO contacts represent distant positions of
the bcp and rcp and can be associated to stronger
interactions.
Fig. 5 Plot of experimental versus calculated 1H NMR chemical
shifts. The trendline corresponds to dExp. = (1.001 0.003)dCalcd.
,
n = 102, R2 = 0.999. The two worse points are labeled
Conclusions
1,4-Dihydro-4-oxoquinoline-3-carbaldehyde (1) was obtained
from 20-aminoacetophenone and used as synthon for
123

738
R. S. G. R. Seixas et al.
Fig. 6 Main intramolecular
interactions present in 1b,
anti-(E)-5, and syn-(E)-5
obtained by AIM
preparation of other 1-substituted 1,4-dihydro-4-oxoqui-
noline-3-carbaldehydes and 3-styrylquinolin-4(1H)-ones.
1H and 13C NMR data and theoretical calculations on these
compounds showed that those having an unsubstituted
heterocyclic nitrogen can exist as a mixture of tautomers;
1,4-dihydro-4-oxoquinoline-3-carbaldehyde mainly exists
as the hydroxyl tautomer in the gas phase and as oxo
tautomer in DMSO solution, while in the case of 3-sty-
rylquinolinone the oxo tautomer is the more stable in both
situations. DFT calculations on (E) ? (Z) and rotational
isomerism of 3-styrylquinolin-4(1H)-ones and of 4-chloro-
3-styrylquinoline showed that the cis isomers (Z) are
always less stable. For the trans isomers, syn-(E) is more
stable than anti-(E) in the case of 3-styrylquinolin-4(1H)-
ones, due to an IMHB between Hb and the carbonyl group,
while in the case of 4-chloro-3-styrylquinoline the con-
verse applies.
acquired using a Q-TOF 2 instrument, diluting 1 mm3 of
the sample chloroform solution (*10-5 M) in 200 mm3
0.1% trifluoroacetic acid/methanol solution. Nitrogen was
used as nebulizer gas and argon as collision gas. The
needle voltage was set at 3,000 V, with the ion source at
80 °C and desolvation temperature at 150 °C. Cone voltage
was 35 V. High-resolution mass spectra (HRMS-ESI?)
were performed on a microTOF (focus) mass spectrometer
[HRMS were in good agreement ( 0.5 ppm) with the
calculated values]. Ions were generated using an ApolloII
(ESI) source. Ionization was achieved by electrospray,
using a voltage of 4,500 V applied to the needle, and a
countervoltage between 100 and 150 V applied to the
capillary. Electron ionization and the corresponding high-
resolution mass spectra (HREI-MS) were obtained on an
Autospec Micromass spectrometer. Elemental analyses
were obtained with a LECO 932 CHN analyzer (University
of Aveiro), and the results were in good agreement
( 0.4%) with the calculated values. Preparative thin-layer
chromatography was carried out with Riedel silica gel 60
DGF254, and column chromatography using Merck silica
gel 60, 70–230 mesh.
Experimental
Melting points were determined on a Bu¨chi melting point
B-540 apparatus. NMR spectra were recorded on Bruker
1
Avance 300 (300.13 MHz for H and 75.47 MHz for 13C)
1,4-Dihydro-4-oxoquinoline-3-carbaldehyde (1)
and Bruker Avance 500 (500.13 MHz for 1H and
125.76 MHz for 13C) spectrometers, with CDCl3 as sol-
vent. Chemical shifts (d) are reported as ppm values and
coupling constants (J) in Hz. The internal standard was
tetramethylsilane (TMS). 1H assignments were made using
two-dimensional (2D) and NOESY (mixing time 800 ms)
experiments, while 13C assignments were made using 2D
gradient-assisted heteronuclear single-quantum correlation
(gHSQC) and gradient-assisted heteronuclear multiple
bond correlation (gHMBC) (long-range C/H coupling
constants were optimized to 7 Hz) experiments. Positive-
ion electrospray ionization (ESI) mass spectra were
To 50 cm3 dry Dimethylformamide (DMF), POCl3
(246.8 mmol) was added dropwise at 0 °C, and the mixture
was stirred for 15 min under nitrogen at room temperature.
Then, 5 cm3 20-aminoacetophenone (41.1 mmol) was
added dropwise, and the mixture was heated for 4 h at
60 °C. After addition of 200 g ice and 200 cm3 water, the
solution was neutralized with NaHCO3, and the formed
solid was filtered. The solid was dissolved in 400 cm3
CHCl3 and washed with 3 9 400 cm3 water. After evap-
oration of the solvent, the resulting solid was purified by
column chromatography using CH2Cl2 as eluent and
crystallized from a mixture of ethyl acetate and hexane to
123

An experimental NMR and computational study
739
afford 4-chloroquinoline-3-carbaldehyde 9 as a white solid
(3.938 g; 50%). A suspension of 3.324 g 9 (17.3 mmol) in
40 cm3 54% aqueous formic acid was heated at 50 °C for
2 h. The resulting suspension was frozen for 2 h, and
the formed solid was filtered off and washed with water.
Pure 1,4-dihydro-4-oxoquinoline-3-carbaldehyde was
collected as a white solid without purification or crystalli-
zation (2.856 g, 97%). M.p.: [278 °C (dec.); 1H NMR
(300.13 MHz, DMSO-d6): d = 7.48 (ddd, 1H, J = 1.3, 7.0,
8.1 Hz, H-6), 7.68 (d, 1H, J = 8.1 Hz, H-8), 7.77 (ddd, 1H,
J = 1.3, 7.0, 8.1 Hz, H-7), 8.22 (1H, dd, J = 1.3, 8.1 Hz,
H-5), 8.49 (s, 1H, H-2), 10.20 (s, 1H, 3-CHO) ppm; 13C
NMR (75.47 MHz, DMSO-d6): d = 116.3 (C-3), 119.5
(C-8), 125.3 and 125.5 (C-5 and C-6), 127.8 (C-4a), 133.1
(C-7), 139.4 (C-8a), 143.3 (C-2), 176.3 (C-4), 188.8
(3-CHO) ppm; EI-MS (70 eV): m/z (%) = 173 (M?, 100),
172 (55), 116 (15), 89 (24).
9.03 (s, 1H, H-2), 10.44 (s, 1H, 3-CHO) ppm; 13C NMR
(125.76 MHz, CDCl3): d = 14.1 (N-CO2CH2CH3), 66.2
(N-CO2CH2CH3), 118.0 (C-3), 120.2 (C-8), 126.6 (C-5),
126.8 (C-6), 127.9 (C-4a), 133.8 (C-7), 137.9 (C-8a), 142.4
(C-2), 150.8 (N-COOCH2CH3), 177.4 (C-4), 189.1
(3-CHO) ppm; ESI?-MS: m/z (%) = 246 (12) [M ? H]?,
268 (100) [M ? Na]?, 284 (5) [M ? K]?.
1,4-Dihydro-4-oxo-1-(4-toluolsulfonyl)quinoline-3-carbal-
dehyde (4)
To a suspension of 200.9 mg 1,4-dihydro-4-oxoquinoline-
3-carbaldehyde (1.16 mmol) in 20 cm3 acetone, 320.6 mg
anhydrous potassium carbonate (2.32 mmol) was added,
and the mixture was stirred at room temperature
for 30 min. p-Toluenesulfonyl chloride (331.7 mg,
1.74 mmol) was then added, and the mixture was stirred
at room temperature for 3 h. After that time, the potassium
carbonate was filtered off, washed with 2 9 20 cm3
acetone, and the filtrate was concentrated. The residue
was purified by silica gel chromatography, first using
CH2Cl2 as eluent (to remove the excess of p-toluenesul-
fonyl 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 petroleum
to give 1,4-dihydro-4-oxo-1-(4-toluolsulfonyl)quinoline-3-
carbaldehyde as a white solid (376.4 mg, 99%). M.p.:
170–172 °C; 1H NMR (300.13 MHz, CDCl3): d = 2.43
(s, 3H, 40-CH3), 7.38 (d, 2H, J = 8.4 Hz, H-30,50), 7.47
(dd, 1H, J = 7.4, 7.7 Hz, H-6), 7.66 (ddd, 1H, J = 1.7,
7.4, 8.8 Hz, H-7), 7.83 (d, 2H, J = 8.4 Hz, H-20,60), 8.21
(d, 1H, J = 8.8 Hz, H-8), 8.43 (dd, 1H, J = 1.7, 7.7 Hz,
H-5), 9.27 (s, 1H, H-2), 10.46 (s, 1H, 3-CHO) ppm; 13C
NMR (75.47 MHz, CDCl3): d = 21.8 (40-CH3), 118.2
(C-3), 118.6 (C-8), 126.8 (C-6), 127.4 (C-5), 127.9
(C-2’,6’), 128.0 (C-4a), 130.6 (C-3’,5’), 132.9 (C-1’),
133.6 (C-7), 136.4 (C-8a), 141.8 (C-2), 147.3 (C-4’), 177.0
(C-4), 188.7 (3-CHO) ppm; ESI?-MS: m/z (%) = 328 (39)
[M ? H]?, 350 (100) [M ? Na]?.
1,4-Dihydro-1-methyl-4-oxoquinoline-3-carbaldehyde
(2)
To a suspension of1,4-dihydro-4-oxoquinoline-3-carbaldehyde
(4.0 mmol) and polystyrene-bound 1,5,7-triazabicyclo
[4.4.0]dec-5-ene (PS-TBD, 10 mmol) in 300 cm3 dry
THF, 2.49 cm3 iodomethane (40 mmol) was added. The
reaction mixture was heated at 40 °C for 2 h. Ice (100 g),
100 cm3 water, and a small amount of triethylamine (10 cm3)
were added to the reaction mixture, and the pH adjusted to 7
with dilute hydrochloric acid. PS-TBD was filtered off, and
the filtrate was extracted with 3 9 150 cm3 chloroform. The
solvent was evaporated to dryness, and the residue was
crystallized from ethanol to afford 1,4-dihydro-1-methyl-4-
oxoquinoline-3-carbaldehyde as white needles (726.3 mg,
97%). M.p.: 212–213 °C (Ref. [35]: 210 °C).
Ethyl 3-formyl-4-oxoquinoline-1(4H)-carboxylate (3)
Anhydrous potassium carbonate (8.10 mmol, 1.12 g) was
added to a suspension of 701.3 mg 1,4-dihydro-4-oxoqui-
noline-3-carbaldehyde (4.05 mmol) in 50 cm3 acetone, and
the mixture was stirred at room temperature for 30 min.
Then, 581 mm3 ethyl chloroformate (6.08 mmol) was
added, and the mixture was stirred at room temperature
for another 30 min. After this period, the potassium
carbonate was filtered off and washed with 2 9 50 cm3
acetone, and the filtrate was concentrated. Water (50 cm3)
was added, and the aqueous mixture was extracted with
3 9 50 cm3 chloroform. After evaporation of the solvent,
pure ethyl 3-formyl-4-oxoquinoline-1(4H)-carboxylate was
obtained as a yellowish solid without purification or
crystallization (953.4 mg, 96%). M.p.: 93–94 °C; 1H
NMR (300.13 MHz, CDCl3): d = 1.54 (t, 3H, J = 7.1
Hz, N–CO2CH2CH3), 4.61 (q, 2H, J = 7.1 Hz, N-CO2
CH2CH3), 7.53 (ddd, 1H, J = 0.7, 7.2, 7.9 Hz, H-6), 7.75
(ddd, 1H, J = 1.7, 7.2, 8.8 Hz, H-7), 8.47 (dd, 1H,
J = 1.7, 7.9 Hz, H-5), 8.61 (d, 1H, J = 8.8 Hz, H-8),
General procedure for the synthesis of 3-styrylquinolin-
4(1H)-ones (E)-6, (Z)-6, (E)-7, and (Z)-7
and 4-chloro-3-styrylquinolines (E)-8 and (Z)-8
A
mixture of 37 mg sodium hydride (1.56 mmol)
and 606.6 mg benzyltriphenylphosphonium chloride
(1.56 mmol) in 20 cm3 dry refluxing THF was stirred for
3 h. The appearance of an orange color and the disap-
pearance of the suspension of the phosphonium salt
indicated ylide formation. Subsequently, the appropriate
3-carbaldehyde 2, 4 or 9 (0.52 mmol) was added, and
reflux was continued for 3 h (2), 4 h (4) or 45 min (9).
After cooling to room temperature, the reaction mixture
was poured onto 20 g ice and 20 cm3 water, and the pH
123

740
R. S. G. R. Seixas et al.
light petroleum-ethyl acetate (4:1). Once again the com-
ponent of higher Rf value was identified as (E)-3-styryl-1-
(4-toluolsulfonyl)quinolin-4(1H)-one (E)-7 and the other
one as the (Z)-3-styryl-1-(4-toluolsulfonyl)quinolin-4(1H)-
one (Z)-7.
was adjusted to 5 with dilute hydrochloric acid. In the case
of precipitation, the solid was filtered off, washed with
3 9 50 cm3 water, dissolved in 50 cm3 CHCl3, and
washed with 2 9 50 cm3 water, and the organic solvent
evaporated to dryness. If no solid precipitated, the organic
layer was extracted with 3 9 50 cm3 CHCl3 and the sol-
vent was evaporated to dryness. In all cases the residues
were dissolved in CH2Cl2.
(E)-3-Styryl-1-(4-toluolsulfonyl)quinolin-4(1H)-one
((E)-7)
1
White solid (12.5 mg, 6%); m.p.: 190–194 °C (dec.); H
1-Methyl-3-styrylquinolin-4(1H)-ones (6)
NMR (300.13 MHz, CDCl3): d = 2.40 (s, 3H, 400-CH3),
7.20 (d, 1H, J = 16.4 Hz, H-a), 7.26–7.30 (m, 1H, H-40),
7.32 (d, 2H, J = 8.2 Hz, H-300,500), 7.38 (t, 2H, J = 7.3 Hz,
H-30,50), 7.38–7.43 (m, 1H, H-6), 7.58 (ddd, 1H, J = 1.7,
7.1, 8.8 Hz, H-7), 7.58 (d, 2H, J = 7.3 Hz, H-20,60), 7.68
(d, 1H, J = 16.4 Hz, H-b), 7.78 (d, 2H, J = 8.2 Hz,
H-200,600), 8.21 (d, 1H, J = 8.8 Hz, H-8), 8.42 (dd, 1H,
J = 1.7, 8.0 Hz, H-5), 8.80 (s, 1H, H-2) ppm; 13C NMR
(75.47 MHz, CDCl3): d = 21.7 (400-CH3), 118.1 (C-8),
120.9 (C-3), 121.2 (C-a), 125.7 (C-6), 126.2 (C-4a), 126.6
(C-200,60), 127.5 (C-200,600), 127.6 (C-5), 127.8 (C-40), 128.7
(C-3 ,50), 130.4 (C-300,500), 131.2 (C-b), 132.4 (C-7), 133.7
(C-100), 134.8 (C-2), 135.9 (C-8a), 137.4 (C-1’), 146.4
(C-400), 177.2 (C-4) ppm; ESI?-MS: m/z (%) = 402 (100)
[M ? H]?.
For the reaction of 1,4-dihydro-1-methyl-4-oxoquinoline-3-
carbaldehyde, the residue was purified by silica gel column
chromatography with a mixture of CH2Cl2-ethyl acetate
(4:1). The component with the higher Rf value was identified
as (E)-1-methyl-3-styrylquinolin-4(1H)-one (E)-6, with
the slower eluting component being (Z)-1-methyl-3-styr-
ylquinolin-4(1H)-one (Z)-6. These compounds were
recrystallized from a mixture of CH2Cl2-light petroleum.
(E)-1-Methyl-3-styrylquinolin-4(1H)-one ((E)-6)
1
White solid (10.9 mg, 8%); m.p.: 136–138 °C; H NMR
(300.13 MHz, CDCl3): d = 3.88 (s, 3H, N-CH3), 7.17 (d,
1H, J = 16.3 Hz, H-a), 7.22 (tt, 1H, J = 1.3, 7.3 Hz,
H-40), 7.34 (t, 2H, J = 7.3 Hz, H-30,50), 7.41 (d, 1H,
J = 7.9 Hz, H-8), 7.42 (ddd, 1H, J = 1.1, 7.4, 8.2 Hz,
H-6), 7.54 (d, 2H, J = 7.3 Hz, H-20,60), 7.65 (d, 1H,
J = 16.3 Hz, H-b), 7.67 (ddd, 1H, J = 1.6, 7.4, 7.9 Hz,
H-7), 7.77 (s, 1H, H-2), 8.55 (dd, 1H, J = 1.6, 8.2 Hz,
H-5) ppm; 13C NMR (75.47 MHz, CDCl3): d = 41.0
(N-CH3), 115.2 (C-8), 118.5 (C-3), 122.6 (C-a), 123.9
(C-6), 126.3 (C-20,60), 126.7 (C-4a), 127.1 (C-40), 127.4
(C-5), 128.3 (C-b), 128.6 (C-30,50), 131.9 (C-7), 138.2
(C-10), 139.3 (C-8a), 142.0 (C-2), 176.2 (C-4) ppm;
ESI?-MS: m/z (%) = 262 (100) [M ? H]?, 523 (11)
[2 M ? H]?.
(Z)-3-Styryl-1-(4-toluolsulfonyl)quinolin-4(1H)-one
((Z)-7)
Yellow oil (96.0 mg, 46%); 1H NMR (300.13 MHz,
CDCl3): d = 2.40 (s, 3H, 400-CH3), 6.72 (dd, 1H,
J = 1.0, 12.0 Hz, H-a), 6.87 (d, 1H, J = 12.0 Hz, H-b),
7.26 (d, 2H, J = 8.3 Hz, H-300,500), 7.30–7.35 (m, 5H,
H-20,60, H-30,50, H-40), 7.39 (ddd, 1H, J = 0.8, 7.2, 8.1 Hz,
H-6), 7.46 (d, 2H, J = 8.3 Hz, H-200,600), 7.56 (ddd, 1H,
J = 1.7, 7.2, 8.7 Hz, H-7), 8.09 (d, 1H, J = 8.7 Hz, H-8),
8.40 (dd, 1H, J = 1.7, 8.1 Hz, H-5), 8.42 (d, 1H,
J = 1.0 Hz, H-2) ppm; 13C NMR (75.47 MHz, CDCl3):
d = 21.7 (400-CH3), 118.0 (C-8), 120.1 (C-3), 123.0 (C-a),
125.5 (C-6), 125.8 (C-4a), 127.1 (C-40), 127.4 (C-5), 127.6
(C-200,600), 128.7 and 128.8 (C-20,60 and C-30,50), 130.2
(C-300,500), 132.3 (C-b), 132.4 (C-7), 133.6 (C-100), 136.2
(C-8a), 136.9 (C-2), 137.1 (C-1’), 146.2 (C-400), 177.8
(C-4) ppm; ESI?-MS: m/z (%) = 402 (100) [M ? H]?,
424 (6) [M ? Na]?.
(Z)-1-Methyl-3-styrylquinolin-4(1H)-one ((Z)-6)
1
White solid (95.1 mg, 70%); m.p.: 121–123 °C; H NMR
(300.13 MHz, CDCl3): d = 3.56 (s, 3H, N-CH3), 6.65
(d, 1H, J = 12.2 Hz, H-b), 6.79 (d, 1H, J = 12.2 Hz, H-a),
7.19–7.24 (m, 1H, H-40), 7.24–7.29 (m, 2H, H-30,50),
7.33–7.37 (m, 3H, H-8, H-20,60), 7.41 (ddd, 1H, J = 1.8,
7.7, 8.2 Hz, H-6), 7.48 (s, 1H, H-2), 7.67 (ddd, 1H,
J = 1.5, 7.7, 8.6 Hz, H-7), 8.54 (dd, 1H, J = 1.5, 8.2 Hz,
H-5) ppm; 13C NMR (75.47 MHz, CDCl3): d = 40.6
(N-CH3), 115.3 (C-8), 117.8 (C-3), 123.7 and 123.8 (C-6
and C-a), 126.5 (C-4a), 126.9 (C-40), 127.2 (C-5), 128.4
(C-30,50), 128.6 (C-20,60), 129.0 (C-b), 131.9 (C-7), 137.6
(C-10), 139.7 (C-8a), 143.0 (C-2), 176.8 (C-4) ppm; ESI?-
MS: m/z (%) = 262 (100) [M ? H]?, 284 (8) [M ? Na]?.
4-Chloro-3-styrylquinolines (8)
For the reaction of 4-chloroquinoline-3-carbaldehyde,
the residue was purified by silica gel chromatography,
eluting with a mixture of light petroleum:ethyl acetate
(7:1). The component of higher Rf value was identified
as (Z)-4-chloro-3-styrylquinoline (Z)-8 and the second as
(E)-4-chloro-3-styrylquinoline (E)-8. These compounds
were recrystallized from a mixture of CH2Cl2-light
petroleum.
3-Styryl-1-(4-toluolsulfonyl)quinolin-4(1H)-ones (7)
For the reaction of 1,4-dihydro-4-oxo-1-(4-toluolsulfo-
nyl)quinoline-3-carbaldehyde, the residue was purified by
preparative thin-layer chromatography with a mixture of
123

An experimental NMR and computational study
741
the Project POCI/QUI/58835/2004 and the Portuguese National NMR
Network (RNRMN). R.S.G.R.S. also thanks FCT for her PhD Grant
(SFRH/BD/30734/2006). We thank the Ministerio de Ciencia e
(E)-4-Chloro-3-styrylquinoline ((E)-8)
1
White solid (49.7 mg, 36%); m.p.: 153–154 °C; H NMR
(300.13 MHz, CDCl3): d = 7.31–7.37 (m, 1H, H-40), 7.34
(d, 1H, J = 16.6 Hz, H-b), 7.40–7.45 (m, 2H, H-30,50),
7.62–7.67 (m, 3H, H-20, H-60, H-6), 7.65 (d, 1H,
J = 16.6 Hz, H-a), 7.74 (dt, 1H, J = 1.2, 7.9 Hz, H-7),
8.11 (d, 1H, J = 7.9 Hz, H-8), 8.29 (d, 1H, J = 8.2 Hz,
H-5), 9.20 (br s, 1H, H-2) ppm; 13C NMR (75.47 MHz,
CDCl3): d = 122.4 (C-a), 124.5 (C-5), 126.4 (C-4a), 127.0
(C-20,60), 128.0 (C-6), 128.7 (C-40), 128.8 (C-30,50), 129.6
(C-3 and C-8), 129.8 (C-7), 133.2 (C-b), 136.5 (C-10),
139.5 (C-4), 147.6 (C-8a), 148.1 (C-2) ppm; ESI?-MS:
m/z (%) = 266 (100) [M ? H]?.
´
Innovacion (project no. CTQ2009-13129-C02-02), the Spanish MEC
(CTQ2007-62113), and the Comunidad Autonoma de Madrid (project
´
MADRISOLAR2, ref. S2009/PPQ-1533) for continuing support.
Thanks are given to the CTI (CSIC) for an allocation of computer
time.
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(Z)-4-Chloro-3-styrylquinoline ((Z)-8)
White solid (76.0 mg, 55%); m.p.: 55–57 °C; 1H NMR
(300.13 MHz, CDCl3): d = 6.80 (d, 1H, J = 12.1 Hz,
H-a), 6.96 (d, 1H, J = 12.1 Hz, H-b), 7.14–7.22 (m, 5H,
H-2’, H-30, H-40, H-50, H-60), 7.65 (ddd, 1H, J = 1.2, 7.0,
8.2 Hz, H-6), 7.74 (ddd, 1H, J = 1.5, 7.0, 8.3 Hz, H-7),
8.04 (d, 1H, J = 8.3 Hz, H-8), 8.29 (d, 1H, J = 8.2 Hz,
H-5), 8.57 (s, 1H, H-2) ppm; 13C NMR (75.47 MHz,
CDCl3): d = 124.0 and 124.1 (C-5 and C-a), 126.4 (C-4a),
127.7 (C-6), 128.0 (C-40), 128.6 (C-30,50), 128.9 (C-20,60),
129.4 (C-3), 129.6 (C-8), 129.9 (C-7), 134.0 (C-b), 135.9
(C-10), 140.7 (C-4), 147.4 (C-8a), 151.2 (C-2) ppm; ESI?-
MS: m/z (%) = 266 (100) [M ? H]?.
(E)-3-Styrylquinolin-4(1H)-one (5)
A suspension of a mixture of 50.5 mg (Z)- and (E)-4-
chloro-3-styrylquinoline (0.19 mmol) in 6 cm3 40% aque-
ous formic acid was refluxed for 24 h. The resulting
suspension was cooled in ice for 30 min, the pH adjusted to
5 with Na2CO3, and the precipitate formed was filtered off
and washed with water. Pure (E)-3-styrylquinolin-4(1H)-
one was collected as a white solid without the need for
further purification (43.7 mg, 93%). M.p.: 284–287 °C
(Ref. [36]: 269–270 °C).
Computational details
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FCT, and FEDER for funding the Organic Chemistry Research Unit,
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123