Synthesis of (E)-3-Styrylquinolin-4(1H)-ones in Water by Ohmic Heating: a Comparison with Other Methodologies

Article abstract of DOI:10.1002/ejoc.201600150

Ohmic heating offers a very efficient way to perform organic reactions in aqueous media. Potentially bioactive (E)-3-styrylquinolin-4(1H)-ones were synthesized by the Heck reaction of 3-iodo-1-methylquinolin-4(1H)-one with styrenes in water and with ohmic heating. Pd(OAc)₂was used as catalyst, and tetrabutylammonium bromide was used as phase-transfer catalyst in the presence of an inorganic base. Comparison with other established procedures highlight the benefits of this new methodology.

Full text of DOI:10.1002/ejoc.201600150

DOI: 10.1002/ejoc.201600150
Full Paper
Ohmic Heating
Synthesis of (E)-3-Styrylquinolin-4(1H)-ones in Water by Ohmic
Heating: a Comparison with Other Methodologies
Joana Pinto,[a] Vera L. M. Silva*[a] Luis M. N. B. F. Santos,[b] and Artur M. S. Silva*[a]
Abstract: Ohmic heating offers a very efficient way to perform tetrabutylammonium bromide was used as phase-transfer cata-
organic reactions in aqueous media. Potentially bioactive (E)-3-
styrylquinolin-4(1H)-ones were synthesized by the Heck reac-
tion of 3-iodo-1-methylquinolin-4(1H)-one with styrenes in wa-
ter and with ohmic heating. Pd(OAc)2 was used as catalyst, and
lyst in the presence of an inorganic base. Comparison with
other established procedures highlight the benefits of this new
methodology.
Introduction
cost,[6] and it is also known to enhance the rates and to affect
the selectivity of a wide variety of organic reactions.[7]
One of the current priorities in organic chemistry is the devel-
opment of efficient synthetic routes and heating processes that
lead to target compounds and at the same time reduce or elim-
inate the use of toxic organic solvents in these synthetic proce-
dures.
We have demonstrated that ΩH can be used to heat reaction
mixtures and that it is a competitive alternative to classical
heating (CH) and to microwave (MW) irradiation methods.[2–5]
To date, several different types of organic reactions have been
performed by using ΩH, which include nucleophilic substitu-
tion reactions, N-alkylation of amines, Diels–Alder reactions, se-
quential Knoevenagel and hetero-Diels–Alder reactions, in-
dium-promoted dehalogenations, and reductive elimination re-
actions.[2,3,5] Recently, we reported an efficient protocol for the
synthesis of 3-arylquinolin-4(1H)-ones by using ΩH that in-
volves the Suzuki–Miyaura cross-coupling reaction of 3-iodo-1-
methylquinolin-4(1H)-one (1) with several arylboronic acids in
water under phase-transfer catalysis (PTC) conditions.[4] Now we
aim to study the Heck reaction of the same scaffold 1 with
several substituted styrenes 2a–2j with ΩH to prepare a library
of complex (E)-1-methyl-3-styrylquinolin-4(1H)-ones (3a–3j).
Quinolin-4(1H)-one is a common scaffold found in natural
products and is considered as a privileged structure, especially
for anti-infective medicines.[8] However, when conveniently
functionalized these compounds have potential use as antitu-
mor[9] and antiviral[9d] agents, and as CB2 receptor agonists.[10]
In particular, (E)-3-styrylquinolin-4(1H)-ones 3, which are analo-
gous to 3-arylquinolin-4(1H)-ones and aza analogues of (E)-3-
styryl-4H-chromen-4-ones, are important compounds the bio-
logical potential of which remains unexplored (Figure 1). The
structural similarity of (E)-3-styrylquinolin-4(1H)-ones with (E)-3-
styryl-4H-chromen-4-ones (Figure 1), which show antifungal
and antibacterial activity,[11] highlights the biological potential
of these quinolone derivatives.
Ohmic heating (ΩH) is a highly energy-efficient heating
process in which heat is generated directly within the reaction
medium itself (which behaves as an electrical ohmic heater). An
AC electrical current of tunable high frequency passes through
a conductive reaction medium so that heat is generated in situ,
which removes the heat-transfer step from the surroundings to
the reaction medium by means of temperature gradients or hot
surfaces.[1,2] Thus, heating is less dependent on the heat trans-
fer to the medium, which results in a fast rate of heating that
allows fast, volumetric and uniform heating (temperature ho-
mogeneity), and increased the dynamics of charged species in
solution, which leads to shorter reaction times and increased
yields.[2–5] In some cases better reaction selectivities were ob-
served.[3] ΩH differs from other heating techniques by the pres-
ence of electrodes in contact with the reaction mixture that
allow the use of a variable frequency and waveform; in general
a sinusoidal waveform is selected.[2]
A combination of ΩH and water as solvent provides great
opportunities for sustainable chemistry. Water is non-toxic, non-
flammable, has a large heat capacity, is easily available at low
[a] Department of Chemistry & QOPNA, University of Aveiro,
3810-193 Aveiro, Portugal
E-mail: jfpinto@ua.pt
verasilva@ua.pt
To date, only two methods for the synthesis of (E)-3-styryl-
quinolin-4(1H)-ones have been reported in the literature. One
method is the Wittig reaction of 4-chloroquinoline and 1-substi-
tuted 4-quinolone-3-carbaldehydes with benzylic ylides.[12] (Z)-
1-Methyl- and (Z)-1-tosyl-3-styrylquinolin-4(1H)-ones were ob-
tained with high diastereoselectivity (38–72 %), relative to the
isomeric (E)-1-methyl- and (E)-1-tosyl-3-styrylquinolin-4(1H)-
artur.silva@ua.pt
https://sites.google.com/site/artursilvaua/
[b] Centro de Investigação em Química, Departamento de Química
e Bioquímica, Faculdade de Ciências, Universidade do Porto
Rua Campo Alegre 687, 4169-007 Porto, Portugal
E-mail: lbsantos@fc.up.pt
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600150.
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One of the most attractive protocols developed for an aque-
ous Heck reaction uses water as solvent in the presence of a
proper phase-transfer agent. This protocol was employed by Xia
and co-workers that used polyethylene glycol (PEG; both as a
polymeric support and PTC) in the coupling of PEG-supported
4-iodobenzoate with styrene and acrylic acid by using Pd(OAc)2
(5 mol-%) and Na2CO3 in water at 60 °C for 1–4 h.[18] The ex-
pected products were obtained after resin cleavage in 94 and
76 % yield, respectively.
MW heating proved to be a very efficient way to couple a
series of aryl iodides with styrene, methyl acrylate, and acrylic
acid, in the presence of Pd(PPh3)2Cl2 (5 mol-%) as catalyst, to-
gether with tetrabutylammonium bromide (TBAB) and K2CO3 in
water.[19] After 10 min of MW irradiation (at 375 W) under ar-
gon, the (E) diastereomers of the alkenes were exclusively ob-
tained in high yields (86–93 %).
Cai and co-workers described the Heck arylation reaction of
acrylonitrile with a variety of aryl iodides, which bore both elec-
tron-donating and electron-withdrawing substituents, in water,
that led to corresponding (E)-cinnamonitriles in good yields.[20]
Similarly, the Heck arylation of n-butyl acrylate and acrylamide
with aryl iodides afforded (E)-cinnamates and (E)-cinnamamides
in good yields.[21] By using Amberlite IRA-400 (basic) as base
and PTC, good results were obtained in the stereoselective Heck
reaction of bromobenzene, p-iodotoluene and p-iodoanisole
with a variety of olefins.[22] Inspired by these findings we aim
to develop a more efficient protocol for the ΩH-assisted Mizor-
oki–Heck reaction of 3-iodo-1-methylquinolin-4(1H)-one (1)
with styrenes 2a–2j.
Figure 1. Structures of (E)-3-styrylquinolin-4(1H)-ones, 3-arylquinolin-4(1H)-
ones, and (E)-3-styryl-4H-chromen-4-ones.
ones (4–24 %), from the reaction of 1-methyl- and 1-tosylquin-
olin-4(1H)-one-3-carbaldehyde with benzylic ylides, whereas
(E)-3-styrylquinolin-4(1H)-ones were obtained in very good
yield (85–99 %) as the sole product from the Wittig reaction of
4-chloroquinoline-3-carbaldehyde with benzylic ylides followed
by acid hydrolysis.[12] The other method allows the synthesis of
(E)-3-styrylquinolin-4(1H)-ones in a direct way, and involves the
Mizoroki–Heck cross-coupling reaction of (E)-3-iodo-1-substi-
tuted quinolin-4(1H)-ones with styrenes to afford (E)-3-styryl-
quinolin-4(1H)-ones in moderate to good yields (55–65 %) after
prolonged reaction times (5 h). In some cases, traces of
branched regioisomer 1-methyl-3-(1-phenylethenyl)quinolin-
4(1H)-ones were obtained as a by-product, which are a result
of coupling at the α-position of the styrene moiety.[13] Silva and
co-workers studied several reaction conditions[13] and the effect
of MW heating for this reaction, which led to the shortening of
the reaction time from 5 to 1.5 h, although the yields of the
product were disappointingly low (30–48 %).[13]
Results and Discussion
The Mizoroki–Heck reaction is a highly versatile Pd0-medi-
ated carbon–carbon bond-forming reaction method used
widely in the synthesis of natural products, fine chemicals, phar-
maceuticals, polymers, and in materials science.[14] Due to its
importance, it is highly desirable to develop milder and simpler
procedures for this reaction. The pioneering work of Beletskaya
and co-workers in 1989[15] showed that the Pd-catalyzed cou-
pling reaction of aryl halides with acrylic acid and acrylonitrile
in the presence of base (NaHCO3 or K2CO3) in water at 80–
100 °C provided an efficient method for the synthesis of substi-
tuted cinnamic acids and cinnamonitriles in high yields. Instead,
the reactions could be carried out faster and at a lower temper-
ature (50–60 °C) with KOAc as base.[15] Since then, the transi-
tion-metal-catalyzed Heck reaction in aqueous solvents has
been developed by applying three major protocols: (a) without
phosphane ligands by using transition-metal salts in water or
aqueous organic solvents; (b) aqueous phosphane-assisted
methods by using hydrophilic phosphane ligands in aqueous
organic solvents; and (c) recyclable phase-separation methods
by using heterogeneous systems in which the catalyst is within
Optimizing Conditions
The combination of water as solvent with ΩH has proved to be
efficient for several types of reactions that include the Suzuki–
Miyaura cross-coupling reaction.[2–4] By aiming to develop a
more efficient protocol for the Mizoroki–Heck reaction of 3-
iodo-1-methylquinolin-4(1H)-one (1) with styrenes 2a–2j, to
prepare potentially bioactive quinolin-4(1H)-ones, Silva and co-
workers performed the reaction of quinolin-4(1H)-one 1 with
styrene 2a (the model reaction) in water in an ΩH reactor with
316 stainless steel based electrodes with Pd(OAc)2 as catalyst,
tetrabutylammonium bromide (TBAB) as PTC, and K2CO3 as
base. 3-Iodo-1-methylquinolin-4(1H)-one (1) was synthesized by
applying the methodology already published.[4] As reported,
preparation of the analogous C-3-brominated derivative of 1 is
more complicated, because the reaction is not regioselective
and affords a complex mixture of products. It is also known
that iodinated substrates are more reactive in Heck reactions
than the corresponding brominated derivatives.
The use of ligand-free Pd catalysts in combination with tetra-
the aqueous phase, and the stock of substrates is within the alkylammonium salts (Jeffery conditions) is of particular rele-
hydrophobic organic phase that also receives the products of vance to this work.[23] Under these reaction conditions,
the reaction. Other protocols that involve the use of super- Pd(OAc)2 is reduced in situ to Pd0 (the alkene may act as the
heated or subcritical water have also been reported but, in gen- reducing agent), which initiates the catalytic cycle by oxidative
eral, show poor selectivity.[16,17]
addition to the aryl iodide.[23] The probable mechanism for the
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Table 1. Optimization of the Heck cross-coupling reaction of 3-iodo-1-methylquinolin-4(1H)-one (1) with styrene 2a and the effect of heating method on
reaction yield.
Entry
Heating method
Styrene [mol-equiv.]
Pd(OAc)2 [mol-equiv.]
Time [min]
Yield of 3a [%][a]
Yield of 4a [%]
1
2
3
4
5
6
7
ΩH
ΩH
ΩH
ΩH
ΩH
MW
CH
5
5
3
5
5
5
5
0.005
0.05
0.05
0.05
0.05
0.05
0.05
30
30
45
54
68
–
10[b]
37[c]
53
–
–
15
60[d]
30
80
–
traces
–
57[e]
16[f]
240
[a] Isolated yields. [b] Yield calculated by NMR spectroscopy. [c] Starting material 1 (33 %) was recovered. [d] Reaction time was 15 + 15 + 30 min. [e] Micro-
wave-assisted reaction was carried out in a circular single-mode cavity instrument (300 W max. magnetron power output). Reaction was carried out in a
closed vessel (10 mL) filled with the reaction mixture (4 mL) and closed with a cap. The temperature measurements were recorded by means of an infrared
sensor, which monitors and controls the temperature conditions of the reaction vessel located in the instrument cavity. Medium stirring speed was used. [f] A
round-bottom flask was immersed in an oil bath at 100 °C; starting material 1 (73 %) was recovered.
reduction of PdII to Pd0 involves intramolecular nucleophilic at- to 1 h) product 3a was obtained in 80 % yield (Table 1, Entry 5).
tack of acetate onto the alkene (styrene or butyl acrylate) coor- With MW heating (E)-3-styrylquinolin-4(1H)-one 3a was ob-
dinated to PdII, followed by a ꢀ-hydride elimination to give tained in 57 % yield after 30 min. Thus, we can conclude that
HPdOAc and subsequent formation of Pd0 in the presence of for the same reaction time (30 min) the reaction yield obtained
base (K2CO3).[24] In the presence of TBAB (or other R4N+X– salts) by ΩH (68 %) was slightly better than that obtained under MW
thermolytic decomposition of Pd(OAc)2 occurs at 100–130 °C, heating conditions (57 %; Table 1, Entries 2 and 6). For classical
and cleavage of the Pd–OAc bond generates Bu4N+Br–-stabi- heating, a poor yield of 3a (16 %) was obtained after 4 h, and
lized Pd0 nanoparticles. One of the key advantages of these 73 % of starting material 1 was recovered (Table 1, Entry 7).
nanoparticles is that they are catalytically active in much lower These results demonstrate that ΩH is the most efficient heating
amounts than molecular Pd catalysts, owing to the large surface method for this reaction.
area of the particles (ratio of atoms that remain at the surface).
The homogeneous/heterogeneous character of the catalysis is
still under debate, but probably it should be more closely re-
Scope and Limitations of Substrates
lated to heterogeneous catalysis.[23]
De Vries and Reetz have shown that the Heck reaction can Having found the optimal reaction conditions, attention was
be run with the addition of what they term “homeopathic” turned to generalizing the process, and the substrate scope of
quantities of palladium catalysts (ideally, 0.01–0.1 mol-%), but the coupling reaction was studied in detail by varying the sub-
at very low metal concentrations the rate of reaction is too slow stituents in the styrene coupling partner. To highlight the use-
to be practical.[25] Nevertheless, in a first attempt the reaction fulness and flexibility of this protocol, we employed styrenes
of 3-iodo-1-methylquinolin-4(1H)-one (1) with styrene 2a was that contained electron-withdrawing and electron-donating
performed with a low amount of Pd catalyst (0.5 mol-%) and substituents as well as α-substituted styrenes. All reactions were
afforded expected (E)-3-styrylquinolin-4(1H)-one 3a in 54 % performed in water (4 mL) with Pd(OAc)2 (5 mol-%) as catalyst,
yield after 30 min (Table 1, Entry 1). Based on our previous and TBAB as PTC (0.1 equiv.) in the presence of K2CO3
results in the study of the Suzuki–Miyaura reaction,[4] we per- (1.0 equiv.) as base, at 100 °C in ΩH. The results are summarized
formed the reaction of quinolin-4(1H)-one 1 with styrene 2a in Table 2 and Scheme 1. Reactions were monitored by TLC.
with Pd catalyst (5 mol-%). After 30 min, product 3a was ob- The yields were moderate to good and, relative to conventional
tained in 68 % yield, and another product, branched 1-methyl- methodologies reported in the literature,[13] the reaction works
3-(1-phenylethenyl)quinolin-4(1H)-one (4a), was obtained in efficiently without the use of a phosphane ligand, which is
10 % yield (Table 1, Entry 2). Styrene polymerizes easily, so we known to act as a reducing agent of PdII to give catalytically
decided to use 5 equiv. to ensure complete consumption of active Pd0 species prior to the Heck catalytic cycle that often
starting material 1. This seems to be the ideal amount, because acts as a stabilizing ligand to prevent the formation of Pd black.
with 3 equiv. of styrene product 3a was obtained in 37 % yield, As demonstrated in our previous work[4] and observed in this
and 33 % of starting material was recovered (Table 1, Entry 3). work, under ΩH the high heating rates at the beginning (see
A shorter reaction time (15 min) led to a decrease in yield of Supporting Information, Figure S48) may enhance the reduc-
3a to 53 % (Table 1, Entry 4). For prolonged reaction times (up tion of PdII to Pd0, which is the species involved in the catalytic
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Table 2. Synthesis of (E)-3-styrylquinolin-4(1H)-ones 3a–3j by a Heck cross-coupling reaction of 3-iodo-1-methylquinolin-4(1H)-one (1) with styrenes 2a–2j by
ohmic heating. Reaction scope and yields.
Entry
Compound
R1
R2
Styrene [equiv.]
Reaction time [min]
Yield of 3 [%][a,b]
Yield of 4 [%][c]
Recovered 1 [%][a]
1[d]
2[d]
3
4
5
6
7
8
9
10
11
12
13
14
15
a
a
b
b
c
H
H
H
H
H
H
H
H
H
H
H
H
H
NO2
OCH3
H
H
OCH3
OCH3
Cl
Cl
Br
Br
F
5
5
2.5
5
2.5
5
5
5
2.5
5
5
2.5
5
30
60
30
30
30
30
30
60
30
30
30
30
30
30
68
80
6
10
–
–
21
–
–
–
–
–
–
–
–
57
–
55
–
33
–
41
24
51
63
96
47
47
78
36
19
96
38
c
d
d
e
e
f
g
g
h
i
–
F
48
22
–
NO2
CO2CH3
CO2CH3
H
–
–
12
–
48[c]
–
5
5
OCH3
60 (30 + 30)
20[a]
–
[a] Isolated yields. [b] Reaction conditions: 3-iodo-1-methylquinolin-4(1H)-one (1; 1.0 equiv.) was treated with appropriate styrene 2a–2j (2.5 or 5.0 equiv.),
Pd(OAc)2 (0.05 equiv.), TBAB (0.1 equiv.), and K2CO3 (1.0 equiv.) in H2O (4.0 mL) at 100 °C by ohmic heating. [c] Yields calculated by NMR spectroscopy.
[d] Model reactions for analysis.
cycle of the Heck reaction. Moreover, the presence of TBAB, literature.[26] It is known that EDGs considerably lower the reac-
which is known to induce the formation and stabilization of Pd tion rate, so higher temperatures and longer reaction times are
nanoparticles, will initially lead to the formation of Pd colloids, often required to achieve good yields of Heck product. Another
which are then deposited as thin films or Pd black on the elec- important aspect is the influence of EDGs (3b, R2 = OCH3; 3i,
trodes.
R1 = R2 = OCH3; Table 2, Entries 4 and 15) and neutral substitu-
ents (3a, R2 = H; Table 2, Entry 1), which favors formation of
branched product 4, which results from coupling at the α-posi-
tion of the styrene. With regards to substitution at the meta
position of the styrene, only compound 3h is shown, which was
obtained in very good yield (96 %; Table 2, Entry 14) as ex-
pected. Compound 3i, which is a disubstituted compound, was
obtained in low yield (38 %), and the branched regioisomer was
formed in 20 % yield because of two EDGs at the meta and
para positions (Table 2, Entry 15). The reaction with sterically
more hindered styrene 2j afforded product 3j in 38 % yield
(Scheme 1). Thus, the yield of the Heck reaction, under the
experimental conditions adopted in this work, is clearly de-
pendent on substituent electron-withdrawing strength and
steric hindrance factors; however, these are not the only factors
that affect the reaction outcome and selectivity. Competing
coupling reactions at the α-position of the styrene moiety and
isomerization of the (E) diastereomer to the (Z) diastereomer
(which in some cases was extensive, such as for compound 3j)
make the purification processes and the isolation of the pure
(E) diastereomer difficult. This photochemical (E) → (Z) isomeri-
zation was also observed for compound 3d in solution. After
8 d in deuterated dimethyl sulfoxide (DMSO) at room tempera-
Scheme 1. Heck reaction of 3-iodo-1-methylquinolin-4(1H)-one (1) with α-
substituted styrene 2j.
By analyzing the results presented in Table 2, we conclude
that the reaction is sensitive to the electronic and steric effects
of the styrene substituents. In general, the yield of the reaction
is higher for styrenes that bear electron-withdrawing groups
(EWG) and for neutral substituents (3a, R2 = H, 68 and 80 %; 3c,
R2 = Cl, 51 %; 3d, R2 = Br, 63 % and 96 %; 3e, R2 = F, 47 %; 3f,
R4 = NO2, 78 %; Table 2, Entries 1, 2 and 5–11) and lower for
styrenes that have electron-donating groups (EDG; 3b, R2
=
OCH3, 41 %; Table 2, Entries 3 and 4) if substitution at the para
position of the styrene moiety is considered. When 2.5 equiv. of
styrene 2g was used, 36 % of product 3g was obtained (Table 2,
Entry 12). In the presence of a higher excess of styrene 2g
(5 equiv.) the yield of 3g decreased (19 %), and the formation ture, 40 % of (E) diastereomer was converted into the (Z) dia-
of regioisomer 4g (12 %) was observed (Table 2, Entry 13). Our stereomer (see Supporting Information, Figures S39–S41 and
results are in good agreement with the results reported in the S42–S47).
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To broaden the scope of this new methodology we studied phosphane ligand, organic solvent, and Et3N as a base) in terms
the coupling of (E)-3-iodo-1-methylquinolin-4(1H)-one (1) with of global yield, but higher amounts of branched regioisomers
butyl acrylate (5). The reaction was performed in water (4 mL) were observed in the first case. In addition, significantly shorter
with Pd(OAc)2 (5 mol-%) as catalyst and TBAB as PTC (0.1 equiv.) reaction times were needed with ΩH. This methodology ena-
in the presence of K2CO3 (1.0 equiv.) as base at 100 °C by ΩH bles the preparation of (E)-3-styrylquinolin-4(1H)-ones in one
(Scheme 2). In the first attempt, acrylate (2.0 equiv.) was added, step, which is more straightforward than the Wittig reaction of
and coupling product 6 was obtained in moderate isolated 1-substituted 4-quinolone-3-carbaldehydes or of the 4-chloro-
yield (52 %) after 45 min. Two other attempts were made to quinoline-3-carbaldehyde with benzylic ylides followed by acid
increase the reaction yield by prolonging the reaction time hydrolysis.[12] Moreover the ΩH-assisted Heck reaction was per-
(60 min) and by increasing the amount of butyl acrylate (5; formed in water, whereas dry organic solvents, anhydrous con-
4.0 equiv.), but in both cases the yields of 6 were lower than ditions (nitrogen or argon), and longer reaction times (1–3 h for
52 %. For the first attempt the yield was 50 %, and for the sec- ylide formation plus 0.75–21 h after addition of the carbonyl
ond attempt 31 % of 6 and 41 % of starting material were re- compound) are required for the Wittig reaction. The addition
covered.
of the carbonyl compound in the Wittig reaction should be
performed as soon as the ylide has been formed, otherwise
the reaction may be ineffective. For the Wittig reaction with 4-
chloroquinoline-3-carbaldehyde a further hydrolysis step (24 h)
is required to convert the diastereomeric mixture of (Z)- and
(E)-4-chloro-3-styrylquinoline derivatives into the correspond-
ing unprotected (E)-3-styrylquinolin-4(1H)-ones.
Scheme 2. Heck cross-coupling reaction of 3-iodo-1-methylquinolin-4(1H)-
one (1) with butyl acrylate (5).
Nuclear Magnetic Resonance
Analysis with Conventional Methodologies
All the synthesized compounds were characterized by NMR
spectroscopy. The main features in the 1H NMR spectra that
confirm the formation of expected (E)-3-styrylquinolin-4(1H)-
ones 3a–3j (Figure 2) are the signals that result from resonance
of the vinylic protons, α-H and ꢀ-H, which appear as doublets
at δHα = 7.04–7.43 ppm and δHꢀ = 7.64–7.94 ppm with large
coupling constants (J ≈ 16.0 Hz), which indicates (E) configura-
tion. In the case of branched regioisomers 4a, 4b, 4g, and 4i
(Figure 2) the signals of these protons also appear as doublets
(δH = 5.28–5.60 ppm) but with small coupling constants (J =
1.7–1.8 Hz), which indicates geminal coupling. Typical signals
for compounds 3a–3j are: (i) the resonance of the 2-H proton,
the signal of which appears as a singlet at high frequency val-
When analyzing the methodology developed here for the Heck
reaction of (E)-3-iodo-1-methylquinolin-4(1H)-one (1) with sty-
renes 2a–2j with other methodologies reported in the literature
(Table 3), we found several advantages to our method, such as:
(i) the use of water instead of toxic and more expensive organic
solvents; (ii) the use of a low-cost and stable Pd catalysts with
no need of additional ligands (some ligands are sensitive, toxic,
expensive, and make purification procedures more compli-
cated); and (iii) higher yields and shorter reaction times. More-
over, ΩH proved to give superior results relative to those ob-
tained under MW irradiation with respect to reaction time and
yield.
Table 3 presents the results obtained by using the new meth- ues (δH = 8.18–8.52 ppm), that results from deshielding effects
odology developed and methodologies reported in the litera- of the heterocyclic nitrogen atom (inductive effect) and of the
ture.[13] New (E)-3-styrylquinolin-4(1H)-one derivatives 3c, 3d, carbonyl group (mesomeric effect); (ii) the resonance of the 5-
3f, 3g, 3i, and 3j synthesized in this work were not included in H proton, which appears as a double doublet or as a doublet
Table 3. In general, the reactions performed in the ΩH reactor at high frequency values (δH = 8.23–8.32 ppm), that results from
gave results similar to those obtained under classical heating the mesomeric and anisotropic deshielding effects of the carb-
conditions and with conventional methodology (Pd catalyst, onyl group; and (iii) the singlet in the aliphatic region of the
Table 3. Analysis of the results obtained by using the new methodology developed with those already reported in the literature that use more conventional
Heck cross-coupling reaction conditions.
Compound
Ohmic heating[a]
Reaction time [min]
Classical heating[13][b]
Microwave heating[13][c]
R1
R2
Yield [%]
Reaction time [h]
Yield [%]
Reaction time [h]
Yield [%]
H
H
H
H
NO2
H
H
OCH3
F
30
60
30
30
30
68 (3a); 10 (4a)
80 (3a); – (4a)
41 (3b); 21 (4b)
47 (3e); 21 (4e)
96 (3h); – (4h)
5
55 (3a); 14 (4a)[d]
1.5
40 (3a); – (4a)
5
5
5
59 (3b); – (4b)[e]
56 (3e); traces (4e)[e]
65 (3h); – (4h)[d]
1.5
1.5
1.5
36 (3b); traces (4b)
48 (3e); – (4e)
45 (3h); – (4h)
H
[a] Reaction conditions: 3-iodo-1-methylquinolin-4(1H)-one (1; 1.0 equiv.) was treated with appropriate styrene 2a, 2b, 2e, or 2h (5.0 equiv.), Pd(OAc)2
(0.05 equiv.), TBAB (0.1 equiv.) and K2CO3 (1.0 equiv.) in H2O (4.0 mL) at 100 °C for 30–60 min. [b] Reaction conditions: 3-iodo-1-methylquinolin-4(1H)-one (1;
1.0 equiv.) was treated with appropriate styrene 2a, 2b, 2e, or 2h (5.0 equiv.), appropriate Pd catalyst (0.05 equiv.), Ph3P (0.1 equiv.), and Et3N (1.0 equiv.) in
N-methyl-2-pyrrolidone (3.0 mL) at 100 °C for 5 h. [c] Reaction conditions: the same conditions as in [b] but performed in a closed vessel under MW irradiation
(2 min ramp to reach 100 °C and 1.5 h hold at 100 °C). [d] Pd(PPh3)4 as catalyst. [e] PdCl2 as catalyst.
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spectra that results from resonance of the methyl group (δH
=
give different 3-substituted quinolin-4(1H)-ones. This methodol-
3.91–3.94 ppm). Typical signals in the 13C NMR spectra of 3a– ogy is of interest, because it is environmentally friendly, be-
3j result from resonance of the N-methyl group (δC = 40.3– cause of the use of water as a solvent, and there is no need for
40.7 ppm) and of the carbonyl group (δC = 174.6–175.2 ppm). costly and toxic phosphine ligands. Yields, which were depend-
For compounds 3d and 3j the presence of the (Z) diastereomer ent on the styrene substitution pattern, were moderate to good
was easily identified by the appearance of some signals in du- and in most cases better than those obtained by conventional
plicate but at lower frequency values than those typical of the procedures that used organic solvents. Ohmic heating proved
(E) diastereomer; namely the signals from resonances of the N- to be more efficient than conventional and microwave heating.
methyl group, 2-H, and 5-H. For compound 3d it was also possi- Good substrate generality, ease of execution, short reaction
ble to observe the signals from resonance of α-H and ꢀ-H pro- time, and practicability make this method suitable for the gen-
tons with a coupling constant of 3JHα,Hꢀ ≈ 12 Hz, which is typical eration of libraries of 3-styrylquinolin-4(1H)-ones.
of (Z) configuration (see the Supporting Information for further
details).
Experimental Section
General: All reactions were carried out in air without any protection
of inert gases. 3-Iodo-1-methylquinolin-4(1H)-one (1) was prepared
according to a method reported in the literature by using methyl
iodide and NaH in dry tetrahydrofuran (THF),[4] which required the
use of a nitrogen as inert gas in this case. Styrenes, bases, and TBAB
were purchased and used without further purification. Preparative
thin-layer chromatography was carried out with silica gel (60
DGF254) plates. Melting points were determined with a Büchi B-545
melting point apparatus. NMR spectra were recorded with 300 or
500 MHz [300.13 MHz (1H), 75.47 MHz (13C), or 500.13 MHz (1H),
125.77 MHz (13C)] NMR spectrometers with tetramethylsilane as the
internal reference and with [D6]DMSO as the solvent. Chemical
shifts (δ) are quoted relative to TMS. Unequivocal 13C assignments
were made on the basis of 2D gHSQC (1H/13C) and gHMBC (delays
for one-bond and long-range JC/H couplings were optimized for 145
and 7 Hz, respectively) experiments. Positive-ion ESI mass spectra
and high-resolution mass spectra were performed with an LTQ Orbi-
Figure 2. Structures and numbering systems of the compounds characterized
by NMR spectroscopy.
trap XL mass spectrometer (Thermo Fischer Scientific, Bremen, Ger-
many) controlled by LTQ Tune Plus 2.5.5 and Xcalibur 2.1.0. The
capillary voltage of the electrospray ionization (ESI) was set to
3100 V. The capillary temperature was 275 °C. The sheath gas flow
rate (nitrogen) was set to 5 (arbitrary unit as provided by the soft-
ware settings). The capillary voltage was 36 V and the tube lens
voltage 110 V. For experiments carried out with ohmic heating, the
1
The most typical signals in the H and 13C NMR spectra of
acrylate 6: (i) result from the resonance of protons and carbon
atoms of the butyl group; and (ii) result from resonance of the
N-methyl group (δH = 3.91 ppm and δC = 40.7 ppm) in the
aliphatic region of the spectra. Typically, signals that arise from 10 mL reactor was filled with the reaction mixture and closed, and
the mixture was heated to reflux. For 4 mL of reaction mixture, the
length of the electrodes immersed in the reaction medium was
9 mm, and the distance between the electrodes was 10 mm. Tem-
perature measurements were performed with a type J glass-
sheathed thermocouple located inside the reactor. Medium mag-
netic stirring speed (740 rpm) was used in all of the experiments
carried out in the ohmic heating reactor. For the experiments car-
ried out by using conventional heating (oil bath) under reflux condi-
tions, a round-bottom flask filled with 4 mL of the reaction mixture
was immersed in an oil bath at 100 °C. A medium magnetic stirring
the resonance of the vinylic protons, which appear as doublets
at δHα = 7.57 ppm (δCα = 140.0 ppm) and δHꢀ = 7.16 ppm
(δCꢀ = 115.4 ppm) with large coupling constants (J = 15.8 Hz),
indicate (E) configuration. α-H is more deshielded than ꢀ-H be-
cause of the mesomeric effect of the carbonyl group of the
ester moiety; the resonance of the 2-H proton, which appears
as a singlet at δH = 8.63 ppm (δC = 148.6 ppm), and the reso-
nance of the 5-H proton, which appears as a double doublet at
δH = 8.28 ppm (δC = 126.0 ppm), are also typical signals of
compound 6. Other characteristic signals in the 13C NMR spec- speed (740 rpm) was used. Microwave-assisted reactions were car-
ried out in a CEM Discovery SP circular single-mode cavity instru-
ment (300 W max. magnetron power output) from CEM Corpora-
tion. Reactions were performed at 100 °C with a closed 10 mL vessel
filled with 4 mL of the reaction mixture and closed with a cap.
Temperature measurements were recorded by using an infrared
sensor, which monitors and controls the temperature conditions of
the reaction vessel located in the instrument cavity. Medium stirring
speed was used in the experiments performed.
trum arise from the resonance of the carbonyl groups of the
quinolone at δC = 174.9 ppm and of the ester group at δC
=
167.5 ppm.
Conclusions
The Heck reaction provides a direct route to synthesize poten-
tially bioactive 3-styrylquinolin-4(1H)-ones from appropriate
styrenes and 3-iodo-1-methylquinolin-4(1H)-one as shown in
General Procedure for the Heck Cross-Coupling Reaction of 3-
Iodo-1-methylquinolin-4(1H)-one 1 with Styrenes 2a–2j: The
this work. Acrylates can also be used as coupling partners to ohmic heating reactor (10 mL) was charged with 3-iodo-1-methyl-
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quinolin-4(1H)-one (1; 80.0 mg, 0.28 mmol), appropriate styrene 2a–
(
79Br, 100) [M + H]+, 342 (81Br, 98) [M + H]+, 362 (79Br, 12) [M + Na]+,
2j (0.7 mmol or 1.4 mmol; see Table 2), K2CO3 (29.1 mg, 0.28 mmol), 364 (81Br, 10) [M + Na]+. HRMS (ESI+): calcd. for C18H1579BrNO [M +
TBAB (9.02 mg, 0.028 mmol), Pd(OAc)2 (3.15 mg, 0.014 mmol), and
H2O (4 mL). The reaction mixture was heated to reflux and stirred
for the period described in Table 2. Then, the aqueous mixture was
extracted with ethyl acetate (4 × 10 mL), and the combined organic
layers were dried with anhydrous sodium sulfate and concentrated
under reduced pressure. (E)-3-Styrylquinolin-4(1H)-ones 3a–3j were
isolated as the main products after TLC (ethyl acetate/hexane, 3:2).
H]+ 340.0337; found 340.0331; calcd. for C18H1581BrNO [M + H]+
342.0337; found 342.0305.
(E)-3-[2-(4-Fluorophenyl)vinyl]-1-methylquinolin-4(1H)-one
(3e): Yellow solid (36.8 mg, 47 %). M.p. 164–165 °C. 1H NMR
(500.13 MHz, [D6]DMSO): δH = 3.92 (s, 3 H, NCH3), 7.12 (d, J =
16.4 Hz, 1 H, α-H), 7.19 (t, J = 8.8 Hz, 2 H, 3′,5′-H), 7.45 (ddd, J =
8.0, 6.9, 1.1 Hz, 1 H, 6-H), 7.54 (dd, J = 8.8, 5.6 Hz, 2 H, 2′,6′-H), 7.73
(d, J = 16.4 Hz, 1 H, ꢀ-H), 7.71–7.73 (m, 1 H, 8-H), 7.77 (ddd, J = 8.5,
6.9, 1.4 Hz, 1 H, 7-H), 8.30 (dd, J = 8.0, 1.4 Hz, 1 H, 5-H), 8.41 (s, 1
H, 2-H) ppm. 13C NMR (125.77 MHz, [D6]DMSO): δC = 40.5 (NCH3),
115.5 (C-3′,5′, J = 21.4 Hz), 116.6 (C-3), 116.9 (C-8), 123.5 (C-α), 123.8
(C-6), 125.6 (C-ꢀ), 126.0 (C-5), 126.2 (C-4a), 127.6 (C-2′,6′, J = 7.6 Hz),
131.9 (C-7), 134.8 (C-1′), 139.3 (C-8a), 144.3 (C-2), 161.3 (C-4′, J =
242.7 Hz), 174.7 (C-4) ppm. MS (ESI+): m/z (%) = 280 (100) [M + H]+,
302 (18) [M + Na]+, 318 (2) [M + K]+. HRMS (ESI+): calcd. for
(E)-1-Methyl-3-(2-phenylvinyl)quinolin-4(1H)-one (3a): Pale yel-
low solid (58.5 mg, 80 %). M.p. 117–118 °C. 1H NMR (300.13 MHz,
[D6]DMSO): δH = 3.91 (s, 3 H, NCH3), 7.18 (d, J = 16.3 Hz, 1 H, α-H),
7.20–7.29 (m, 1 H, 4′-H), 7.35 (d, J = 7.5 Hz, 2 H, 3′,5′-H), 7.44 (ddd,
J = 8.1, 6.7, 1.4 Hz, 1 H, 6-H), 7.50 (d, J = 7.5 Hz, 2 H, 2′,6′-H), 7.69
(d, J = 8.6 Hz, 1 H, 8-H), 7.73 (d, J = 16.3 Hz, 1 H, ꢀ-H), 7.75 (ddd,
J = 8.6, 6.7, 1.5 Hz, 1 H, 7-H), 8.30 (dd, J = 8.1, 1.5 Hz, 1 H, 5-H), 8.43
(s, 1 H, 2-H) ppm. 13C NMR (75.47 MHz, [D6]DMSO): δC = 40.4 (NCH3),
116.7 (C-3), 116.8 (C-8), 123.4 (C-α), 123.7 (C-6), 125.8 (C-2′,6′), 126.0
(C-5), 126.1 (C-4a), 126.6 (C-4′), 126.9 (C-ꢀ), 128.8 (C-3′,5′), 131.8 (C-
7), 138.2 (C-1′), 139.2 (C-8a), 144.2 (C-2), 174.6 (C-4) ppm. MS (ESI+):
m/z (%) = 262 (100) [(M + H)+]. HRMS (ESI+): calcd. for C18H16NO [M
+ H]+ 262.1232; found 262.1224.
C
18H15FNO [M + H]+ 280.1138; found 280.1129.
(E)-1-Methyl-3-[2-(4-nitrophenyl)vinyl]quinolin-4(1H)-one (3f):
Orange solid (66.9 mg, 78 %). M.p. 227–228 °C. 1 H NMR
(500.13 MHz, [D6]DMSO): δH = 3.94 (s, 3 H, NCH3), 7.43 (d, J =
16.5 Hz, 1 H, α-H), 7.49 (ddd, J = 7.7, 7.1, 1.0 Hz, 1 H, 6-H), 7.75 (d,
J = 8.8 Hz, 2 H, 2′,6′-H), 7.75 (d, J = 8.6 Hz, 1 H, 8-H), 7.80 (ddd, J =
8.6, 7.1, 1.5 Hz, 1 H, 7-H), 7.94 (d, J = 16.5 Hz, 1 H, ꢀ-H), 8.22 (d, J =
8.8 Hz, 2 H, 3′,5′-H), 8.32 (dd, J = 7.7, 1.5 Hz, 1 H, 5-H), 8.52 (s, 1 H,
2-H) ppm. 13C NMR (125.77 MHz, [D6]DMSO): δC = 40.7 (NCH3), 115.9
(C-3), 117.1 (C-8), 124.20 and 124.22 (C-6, C-3′,5′), 124.4 (C-ꢀ), 126.0
(C-5), 126.3 (C-4a), 126.4 (C-2′,6′), 128.9 (C-α), 132.2 (C-7), 139.2 (C-
8a), 145.5 (C-4′), 145.6 (C-1′), 146.1 (C-2), 174.8 (C-4) ppm. MS (ESI+):
m/z (%) = 307 (100) [M + H]+, 329 (12) [M + Na]+. HRMS (ESI+): calcd.
for C18H15N2O3 [M + H]+ 307.1083; found 307.1076.
(E)-3-[2-(4-Methoxyphenyl)vinyl]-1-methylquinolin-4(1H)-one
(3b): Pale yellow solid (33.4 mg, 41 %). M.p. 123–125 °C. 1H NMR
(500.13 MHz, [D6]DMSO): δH = 3.78 (s, 3 H, OCH3), 3.92 (s, 3 H, NCH3),
6.95 (d, J = 8.8 Hz, 2 H, 3′,5′-H), 7.04 (d, J = 16.4 Hz, 1 H, α-H), 7.42–
7.45 (m, 1 H, 6-H), 7.44 (d, J = 8.8 Hz, 2 H, 2′,6′-H), 7.65 (d, J =
16.4 Hz, 1 H, ꢀ-H), 7.70 (d, J = 8.4 Hz, 1 H, 8-H), 7.76 (ddd, J = 8.4,
6.9, 1.5 Hz, 1 H, 7-H), 8.29 (dd, J = 8.1, 1.5 Hz, 1 H, 5-H), 8.39 (s, 1
H, 2-H) ppm. 13C NMR (125.77 MHz, [D6]DMSO): δC = 40.4 (NCH3),
55.1 (OCH3), 114.2 (C-3′,5′), 116.8 (C-8), 117.1 (C-3), 121.1 (C-α), 123.6
(C-6), 125.0 (C-5), 126.1 (C-4a), 126.4 (C-ꢀ), 127.0 (C-2′,6′), 130.8 (C-
1′), 131.7 (C-7), 139.2 (C-8a), 143.6 (C-2), 158.5 (C-4′), 174.6 (C-4)
ppm. MS (ESI+): m/z (%) = 292 (100) [M + H]+, 330 (2) [M + K]+.
HRMS (ESI+): calcd. for C19H18NO2 [M + H]+ 292.1338; found
292.1327.
Methyl (E)-4-[2-(1-Methyl-4-oxo-1,4-dihydroquinolin-3-
yl)vinyl]benzoate (3g): White solid (32.2 mg, 36 %). M.p. 110–
111 °C. 1H NMR (500.13 MHz, [D6]DMSO): δH = 2.28 (s, 3 H, CO2CH3),
3.93 (s, 3 H, NCH3), 7.13 (d, J = 8.6 Hz, 2 H, 3′,5′-H), 7.15 (d, J =
16.4 Hz, 1 H, α-H), 7.46 (dt, J = 7.7, 1.0 Hz, 1 H, 6-H), 7.53 (d, J =
8.6 Hz, 2 H, 2′,6′-H), 7.72 (d, J = 7.7 Hz, 1 H, 8-H), 7.74 (d, J = 16.4 Hz,
1 H, ꢀ-H), 7.76–7.81 (m, 1 H, 7-H), 8.30 (dd, J = 7.7, 1.4 Hz, 1 H, 5-
(E)-3-[2-(4-Chlorophenyl)vinyl]-1-methylquinolin-4(1H)-one
(3c): Yellow solid (42.2 mg, 51 %). M.p. 174–175 °C. 1H NMR
(300.13 MHz, [D6]DMSO): δH = 3.92 (s, 3 H, NCH3), 7.18 (d, J =
16.4 Hz, 1 H, α-H), 7.42 (d, J = 8.6 Hz, 2 H, 3′,5′-H), 7.46 (ddd, J =
8.1, 6.7, 1.5 Hz, 1 H, 6-H), 7.52 (d, J = 8.6 Hz, 2 H, 2′,6′-H), 7.72 (d,
J = 7.6 Hz, 1 H, 8-H), 7.74 (d, J = 16.4 Hz, 1 H, ꢀ-H), 7.76 (ddd, J =
7.6, 6.7, 1.5 Hz, 1 H, 7-H), 8.30 (dd, J = 8.1, 1.5 Hz, 1 H, 5-H), 8.43 (s,
1 H, 2-H) ppm. 13C NMR (75.47 MHz, [D6]DMSO): δC = 40.5 (NCH3),
116.4 (C-3), 116.8 (C-8), 123.8 (C-6), 124.5 (C-α), 125.3 (C-ꢀ), 125.9
(C-5), 126.1 (C-4a), 127.3 (C-2′,6′), 128.7 (C-3′,5′), 131.0 (C-4′), 131.9
(C-7), 137.2 (C-1′), 139.2 (C-8a), 144.6 (C-2), 174.6 (C-4) ppm. MS
(ESI+): m/z (%) = 296 (35Cl, 100) [M + H]+, 298 (37Cl, 32) [M + H]+,
318 (35Cl, 6) [M + Na]+, 334 (35Cl, 8) [M + K]+. HRMS (ESI+): calcd. for
C18H1535ClNO [M + H]+ 296.0842; found 296.0835; calcd. for
C18H1537ClNO [M + H]+ 298.0842; found 298.0801.
H), 8.43 (s, 1 H, 2-H) ppm. 13C NMR (125.77 MHz, [D6]DMSO): δC
=
20.9 (CO2CH3) 40.5 (NCH3), 116.6 (C-3), 116.9 (C-8), 122.2 (C-3′,5′),
123.7 (C-α), 123.8 (C-6), 124.4 (C-4a), 125.7 (C-ꢀ), 126.0 (C-5), 126.6
(C-2′,6′), 131.9 (C-7), 135.9 (C-1′), 139.3 (C-8a), 144.4 (C-2), 149.3 (C-
4′), 169.3 (CO2CH3), 174.6 (C-4) ppm. MS (ESI+): m/z (%) = 320 (100)
[M + H]+, 342 (8) [M + Na]+, 358 (3) [M + K]+. HRMS (ESI+): calcd.
for C20H18NO3 [M + H]+ 320.1287; found 320.1277.
(E)-1-Methyl-3-[2-(3-nitrophenyl)vinyl]quinolin-4(1H)-one (3h):
Dark yellow solid (82.3 mg, 96 %). M.p. 220–221 °C. 1H NMR
(300.13 MHz, [D6]DMSO): δH = 3.93 (s, 3 H, NCH3), 7.36 (d, J =
16.2 Hz, 1 H, α-H), 7.48 (ddd, J = 8.0, 6.7, 1.4 Hz, 1 H, 6-H), 7.65 (t,
J = 8.0 Hz, 1 H, 5′-H), 7.73 (dd, J = 8.5, 1.4 Hz, 1 H, 8-H), 7.79 (ddd,
J = 8.5, 6.7, 1.6 Hz, 1 H, 7-H), 7.94 (d, J = 8.0 Hz, 1 H, 6′-H), 7.94 (d,
J = 16.2 Hz, 1 H, ꢀ-H), 8.06 (ddd, J = 8.0, 2.1, 0.8 Hz, 1 H, 4′-H), 8.32
(d, J = 2.1 Hz, 1 H, 2′-H), 8.32 (dd, J = 8.0, 1.6 Hz, 1 H, 5-H), 8.50 (s,
1 H, 2-H) ppm. 13C NMR (75.47 MHz, [D6]DMSO): δC = 40.6 (NCH3),
115.9 (C-3), 116.9 (C-8), 116.6 (C-3), 119.4 (C-2′), 121.1 (C-4′), 124.3
(C-6), 126.0 (C-ꢀ), 126.3 (C-5), 126.8 (C-4a), 126.9 (C-α), 130.3 (C-5′),
132.0 (C-7), 132.2 (C-6), 139.2 (C-8a), 140.3 (C-1′), 145.6 (C-2), 148.4
(C-3′), 174.7 (C-4) ppm. MS (ESI+): m/z (%) = 307 (100) [M + H]+, 329
(16) [M + Na]+. HRMS (ESI+): calcd. for C18H15N2O3 [M + H]+
307.1083; found 307.1073.
(E)-3-[2-(4-Bromophenyl)vinyl]-1-methylquinolin-4(1H)-one
(3d): White solid (91.4 mg, 96 %). M.p. 186–188 °C. 1H NMR
(500.13 MHz, [D6]DMSO): δH = 3.92 (s, 3 H, NCH3), 7.20 (d, J =
16.2 Hz, 1 H, α-H), 7.44–7.47 (m, 1 H, 6-H), 7.46 (d, J = 8.5 Hz, 2 H,
2′,6′-H), 7.55 (d, J = 8.5 Hz, 2 H, 3′,5′-H), 7.72 (d, J = 16.2 Hz, 1 H, ꢀ-
H), 7.73 (d, J = 6.9 Hz, 1 H, 8-H), 7.77 (ddd, J = 8.5, 6.9, 1.4 Hz, 1 H,
7-H), 8.30 (dd, J = 8.0, 1.4 Hz, 1 H, 5-H), 8.43 (s, 1 H, 2-H) ppm. 13C
NMR (125.77 MHz, [D6]DMSO): δC = 40.5 (NCH3), 116.4 (C-3), 116.9
(C-8), 119.6 (C-4′), 123.8 (C-6), 124.6 (C-α), 125.4 (C-ꢀ), 126.0 (C-5),
126.2 (C-4a), 127.7 (C-2′,6′), 131.6 (C-3′,5′), 131.9 (C-7), 137.6 (C-1′),
(E)-3-[2-(3,4-Dimethoxyphenyl)vinyl]-1-methylquinolin-4(1H)-
139.2 (C-8a), 144.7 (C-2), 174.6 (C-4) ppm. MS (ESI+): m/z (%) = 340 one (3i): Yellow solid (34.2 mg, 38 %). M.p. 175–176 °C. 1H NMR
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(300.13 MHz, [D6]DMSO): δH = 3.76 (s, 4′-OCH3), 3.82 (s, 3′-OCH3),
3.91 (s, 3 H, NCH3), 6.94 (d, J = 8.4 Hz, 1 H, 5′-H), 7.00 (dd, J = 8.4,
1.7 Hz, 1 H, 6′-H), 7.05 (d, J = 16.4 Hz, 1 H, α-H), 7.12 (d, J = 1.7 Hz, (300.13 MHz, [D6]DMSO): δH
Butyl (E)-3-(1-Methyl-4-oxo-1,4-dihydroquinolin-3-yl)acrylate
(6): White solid (31.2 mg, 52 %). M.p. 139–140 °C. 1H NMR
= 0.92 (t, J = 7.4 Hz, 3 H,
1 H, 2′-H), 7.43 (ddd, J = 8.0, 6.7, 1.3 Hz, 1 H, 6-H), 7.66 (d, J =
16.4 Hz, 1 H, ꢀ-H), 7.68 (d, J = 8.1 Hz, 1 H, 8-H), 7.74 (ddd, J = 8.1,
6.7, 1.5 Hz, 1 H, 7-H), 8.30 (dd, J = 8.0, 1.5 Hz, 1 H, 5-H), 8.38 (s, 1
-OCH2CH2CH2CH3), 1.38 (m, 2 H, OCH2CH2CH2CH3), 1.62 (m, 2 H,
OCH2CH2CH2CH3), 3.91 (s, 3 H, NCH3), 4.12 (t, J = 6.9 Hz, 2 H,
OCH2CH2CH2CH3), 7.16 (d, J = 15.8 Hz, 1 H, ꢀ-H), 7.50 (ddd, J = 8.0,
H, 2-H) ppm. 13C NMR (75.47 MHz, [D6]DMSO): δC = 40.4 (NCH3), 6.8, 1.2 Hz, 1 H, 6-H), 7.57 (d, J = 15.8 Hz, 1 H, α-H), 7.74 (dd, J =
55.4 (4′-OCH3), 55.5 (3′-OCH3), 108.5 (C-2′), 111.9 (C-5′), 116.8 (C-8), 8.2 Hz, 1 H, 8-H), 7.81 (ddd, J = 8.2, 6.8, 1.6 Hz, 1 H, 7-H), 8.28 (dd,
117.1 (C-3), 119.0 (C-6′), 121.3 (C-α), 123.6 (C-6), 125.9 (C-5), 126.1 J = 8.0, 1.6 Hz, 1 H, 5-H), 8.63 (s, 1 H, 2-H) ppm. 13C NMR (75.47 MHz,
(C-4a), 126.9 (C-ꢀ), 131.2 (C-1′), 131.7 (C-7), 139.2 (C-8a), 143.7 (C-2),
[D6]DMSO): δC = 13.6 (OCH2CH2CH2CH3), 18.8 (OCH2CH2CH2CH3),
148.2 (C-4′), 149.0 (C-3′), 174.7 (C-4) ppm. MS (ESI+): m/z (%) = 322 40.7 (NCH3), 63.3 (OCH2CH2CH2CH3), 113.8 (C-3), 115.4 (C-ꢀ), 117.2
(100) [M + H]+, 344 (6) [M + Na]+, 360 (1) [M + K]+. HRMS (ESI+):
calcd. for C20H20NO3 [M + H]+ 322.1443; found 322.1431.
(C-8), 124.6 (C-6), 126.0 (C-5), 126.5 (C-4a), 132.5 (C-7), 139.3 (C-8a),
140.0 (C-α), 148. 6 (C-2), 167.5 (C=O ester), 174.9 (C-4) ppm. MS
(ESI+): m/z (%) = 286 (100) [M + H]+, 308 (38) [M + Na]+, 324 (7) [M
+ K]+. HRMS (ESI+): calcd. for C17H20NO3 [M + H]+ 286.1443; found
286.1437.
(E)-3-[1-(3,4-Dimethoxyphenyl)vinyl]-1-methylquinolin-4(1H)-
one (4i): Yellow residue (18.0 mg, 20 %). 1H NMR (300.13 MHz,
[D6]DMSO): δH = 3.72 (s, 3 H, 4′′-OCH3), 3.74 (s, 3 H, 3′′-OCH3), 3.87
(s, 3 H, NCH3), 5.41 (d, J = 1.7 Hz, 1 H, 2′-H), 5.55 (d, J = 1.7 Hz, 1 H,
2′-H), 6.77 (dd, J = 8.3, 2.0 Hz, 1 H, 6′′-H), 6.86 (d, J = 8.3 Hz, 1 H,
5′′-H), 6.98 (d, J = 2.0 Hz, 1 H, 2′′-H), 7.41 (ddd, J = 8.0, 6.8, 1.1 Hz,
1 H, 6-H), 7.69 (d, J = 8.1 Hz, 1 H, 8-H), 7.77 (ddd, J = 8.1, 6.8, 1.5 Hz,
1 H, 7-H), 8.00 (s, 1 H, 2-H), 8.18 (dd, J = 8.0, 1.5 Hz, 1 H, 5-H) ppm.
13C NMR (75.47 MHz, [D6]DMSO): δC = 40.3 (NCH3), 55.5 (2 × OCH3),
110.2 (C-2′′), 111.3 (C-5′′), 114.2 (C-2′), 116.7 (C-8), 119.3 (C-6′′), 121.3
(C-3), 123.4 (C-6), 126.0 (C-5), 126.3 (C-4a), 131.9 (C-7), 133.4 (C-1′′),
140.2 (C-8a), 144.2 (C-2), 144.4 (C-1′), 148.4 (C-4′′), 148.5 (C-3′′), 174.4
(C-4) ppm. MS (ESI+): m/z (%) = 322 (77) [M + H]+, 344 (100) [M +
Na]+. HRMS (ESI+): calcd. for C20H20NO3 [M + H]+ 322.1434; found
322.1434.
Acknowledgments
Thanks are due to the University of Aveiro and the FCT/Minis-
tério da Educação e Ciência (MEC) for financial support, to the
QOPNA research project (FCT UID/QUI/00062/2013) through na-
tional funds and as applicable co-financed by the FEDER within
the PT2020 Partnership Agreement, and also to the Portuguese
NMR Network. V. L. M. S. thanks the project New Strategies
Applied to Neuropathological Disorders (CENTRO-07-ST24-
FEDER-002034), cofounded by QREN, “Mais Centro-Programa
Operacional Regional do Centro” and the EU, FEDER for her
assistant research position and FCT for her post-doctoral grant
(SFRH/BPD/108807/2015). J. P. thanks FCT for her Ph.D. grant
(SFRH/BD/77807/2011).
(E)-1-Methyl-3-(1-phenylprop-1-en-2-yl)quinolin-4(1H)-one (3j):
Yellow solid (29.3 mg, 38 %). M.p. 184–186 °C. 1H NMR (300.13 MHz,
[D6]DMSO), signals of the (E) isomer: δH = 2.233 (s, 3 H, 1′-CH3), 3.93
(s, 3 H, NCH3), 6.83 (s, 1 H, 3′-H), 7.25–7.33 (m, 1 H, 4′′-H), 7.38 (d,
J = 7.4 Hz, 2 H, 3′′,5′′-H), 7.48 (ddd, J = 7.9, 6.7, 1.1 Hz, 1 H, 6-H),
7.54 (d, J = 7.4 Hz, 2 H, 2′′,6′′-H), 7.70 (d, J = 8.4 Hz, 1 H, 8-H), 7.78
(ddd, J = 8.4, 6.7, 1.4 Hz, 1 H, 7-H), 8.18 (s, 1 H, 2-H), 8.25 (dd, J =
7.9, 1.4 Hz, 1 H, 5-H); signals of the (Z) isomer: δH = 2.229 (s, 3 H,
1′-CH3), 3.87 (s, 3 H, NCH3), 6.829 (s, 1 H, 3′-H), 7.20–7.25 (m, 1 H,
4′′-H), 7.37–7.40 (m, 2 H, 3′′,5′′-H), 7.39 (m, 1 H, 6-H), 7.53–7.56 (m,
2 H, 2′′,6′′-H), 7.69–7.80 (m, 2 H, 7,8-H), 8.21(dd, J = 7.9, 1.4 Hz, 1 H,
5-H), 8.65 (s, 1 H, 2-H) ppm. 13C NMR (75.47 MHz, [D6]DMSO), signals
of the (E) isomer: δC = 17.4 (C-1′), 25.1 (C-2′), 40.3 (NCH3), 116.8 (C-
8), 117.8 (C-4a), 121.2 (C-3′), 123.5 (C-6) 125.6 (C-2′′,6′′), 125.8 (C-5),
127.0 (C-4′′), 128.4 (C-3′′,5′′), 131.9 (C-7), 139.8 (C-8a), 143.3 (C-1′′),
144.0 (C-2), 175.2 (C-4); signals of the (Z) isomer: δC = 17.4 (C-1′),
26.3 (C-2′), 40.3 (NCH3), 117.0 (C-8), 117.8 (C-4a), 121.2 (C-3′), 124.4
(C-6) 125.6 (C-2′′,6′′), 126.11 (C-5), 127.9 (C-4′′), 128.6 (C-3′′,5′′), 132.2
(C-7), 139.8 (C-8a), 143.3 (C-1′′), 149.5 (C-2), 175.2 (C-4) ppm. MS
(ESI+): m/z (%) = 276 (100) [M + H]+, 298 (10) [M + Na]+. HRMS
(ESI+): calcd. for C19H18NO [M + H]+ 276.1388; found 276.1379.
Keywords: Ohmic heating · C-C coupling · Palladium ·
Phase-transfer catalysis · Quinolones · Synthetic methods
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Published Online: May 23, 2016
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