Ohmic heating-assisted synthesis of 3-arylquinolin-4(1h)-ones by a reusable and ligand-free Suzuki-Miyaura reaction in water

Article abstract of DOI:10.1021/acs.joc.5b00793

Potential bioactive 3-arylquinolin-4(lH)-ones were synthesized under ohmic heating using an efficient, reusable, and ligand-free protocol developed for the Suzuki-Miyaura coupling of l-substituted-3-iodoquinolin-4(lH)-ones with several boronic acids in water using Pd(OAc)₂ as a catalyst and tetrabutylammonium bromide (TBAB) as the phase transfer catalyst. Good substrate generality, ease of execution, short reaction time, and practicability make this method exploitable for the generation of libraries of B ring-substituted 3-arylquinolin-4(lH)-ones. After a simple workup, the Pd/catalyst-H₂O-TBAB system could be reused for at least seven cycles without significant loss of activity.

Full text of DOI:10.1021/acs.joc.5b00793

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Article
Ohmic heating assisted synthesis of 3-arylquinolin-4(1H)-ones
by a reusable and ligand-free Suzuki-Miyaura reaction in water
Joana Pinto, Vera Lucia Marques Silva, Ana M. G. Silva, Luis M. N. B. F. Santos, and Artur M. S. Silva
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 02 Jun 2015
Downloaded from http://pubs.acs.org on June 5, 2015
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Ohmic heating assisted synthesis of 3-arylquinolin-4(1H)-ones by a reusable and ligand-
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free Suzuki-Miyaura reaction in water
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Joana Pinto,† Vera L. M. Silva,*† Ana M. G. Silva,‡ Luís M. N. B. F. Santos§ and Artur M.
S. Silva*†
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†Department of Chemistry & QOPNA, University of Aveiro, 3810ꢀ193 Aveiro, Portugal.
‡UCIBIO/REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências,
Universidade do Porto, 4169ꢀ007 Porto, Portugal.
§Centro de Investigação em Química, Departamento de Química e Bioquímica, Faculdade
de Ciências da Universidade do Porto, Rua Campo Alegre 687, 4169ꢀ007 Porto, Portugal.
*Email for Vera L. M. Silva: verasilva@ua.pt. *Email for Artur M. S. Silva:
artur.silva@ua.pt.
Abstract
Potential bioactive 3ꢀarylquinolinꢀ4(1
using an efficient, reusable and ligandꢀfree protocol developed for the SuzukiꢀMiyaura
coupling of 1ꢀsubstitutedꢀ3ꢀiodoquinolinꢀ4(1 )ꢀones with several boronic acids in water
H)ꢀones were synthesised under ohmic heating
H
using Pd(OAc)2 as catalyst and TBAB as phase transfer catalyst. Good substrate
generality, ease of execution, short reaction time and practicability make this method
exploitable for the generation of libraries of B ring substituted 3ꢀarylquinolinꢀ4(1H)ꢀones.
After a simple workup, Pd/catalystꢀH2OꢀTBAB system could be reused for at least seven
cycles without significant loss in activity.
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Introduction
Ohmic heating is an advanced thermal processing method where the reaction mixture or the
medium, which serves as an electrical resistor, is heated by passing electricity through it
(electrodes are in contact with the reaction medium).1 The heating occurs in the form of
internal energy transformation (from electric to thermal) within the reaction, being water the
ideal green solvent to be used. In the ohmic heating methodology the thermal energy
generation is due to the motion of the charged species in solution as result of the high
frequency (25 kHz) AC electric current. The thermal energy transfer occurs mostly between
the electrodes plates cross session region and the surroundings.1 Thus, electrical energy is
dissipated into heat with high efficiency, which results in a high speed heating rate allowing
rapid and uniform heating (temperature homogeneity), leading to shorter reaction times and
increased reaction yields. In a previous publication we presented ohmic heating as a new
efficient process for organic synthesis in water and we described our reactor (Portuguese
Patent 105908).1 Now using this technology we prepared a library of 3ꢀarylquinolinꢀ4(1H)ꢀ
ones for further biological evaluation.
Quinolinꢀ4(1H)ꢀone is a common scaffold found in natural products and is considered as a
privileged structure, especially for antiꢀinfective medicines.2 Recently, the groups of Kyle,
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Manestsch and Riscoe demonstrated that 3ꢀsubstituted quinolinꢀ4(1H)ꢀones display
antimalarial activity at low to single digit nanomolar concentrations3 while Kuo and coꢀ
workers discovered that 3ꢀphenylquinolinꢀ4(1H)ꢀone has an excellent inhibitory effect against
AAꢀinduced platelet aggregation, superior to that of indomethacin and aspirin, which are
wellꢀknown for their potent antiplatelet activity.4 Other 3ꢀarylquinolinꢀ4(1H)ꢀones
demonstrated good activity as antiꢀinflammatory agents.5 3ꢀChlorophenylꢀ5,7ꢀ
dihydroxyquinolinꢀ4(1H)ꢀone and 3ꢀchlorophenylꢀ5ꢀhydroxyꢀ7ꢀmethoxyquinolinꢀ4(1H)ꢀone,
close analogues of the natural isoflavone genistein, possess potent EGFR tyrosine kinase
inhibition activity.6 Therefore an increasing interest in the synthesis of this kind of quinolinꢀ
4(1H)ꢀones has been observed. To optimize its pharmacological properties a considerable
number of modifications have been made on the benzenoid ring (Cꢀ5 to Cꢀ8 positions) of the
quinolinꢀ4(1H)ꢀone moiety, but the modifications on the pyridinone ring (Cꢀ2 to Cꢀ4) are still
less common.
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The ConradꢀLimpach cyclization is the most used protocol for the preparation of 2ꢀ or 2,3ꢀ
substituted quinolinꢀ4(1H)ꢀones involving 2ꢀsubstitutedꢀβꢀketoesters and anilines as starting
materials.7 Other reported methods to prepare 3ꢀsubstitutedꢀquinolinꢀ4(1H)ꢀones involve the
cyclization
of
2ꢀarylꢀ3ꢀarylaminoꢀ4,4,4ꢀtrifluoroꢀ2ꢀbutenenitriles
hydrates
with
polyphosphoric acid,8 the reverse Vilsmeier reaction of Nꢀmethylformanilide (MFA) with
amides in POCl3 followed by alkaline workup,9 or ring closure of an appropriate ketone under
modified VilsmeierꢀHaack conditions (POCl3, DMF) to give directly the 3ꢀsubstituted
quinolone in moderate yield.6c However, these methods commonly generate the desired
quinolinꢀ4(1H)ꢀones in poor yields requiring difficult purification procedures.
In the context of our recent studies on the application of ohmic heating in organic
synthesis,1 and connected with our ongoing research in the synthesis and transformation of
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quinolinꢀ4(1H)ꢀones,10 we describe here a protocol for the synthesis of 3ꢀarylquinolinꢀ4(1H)ꢀ
ones via SuzukiꢀMiyaura cross coupling reaction of Nꢀsubstituted 3ꢀiodoquinolinꢀ4(1H)ꢀones
with commercially available boronic acids using ohmic heating in water under phase transfer
catalysis conditions.
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SuzukiꢀMiyaura reaction has received much attention, chiefly due to its great versatility in
the formation of C−C bonds.11 The importance of this reaction has been documented by
awarding the 2010 Nobel Prize in Chemistry to Professor Akira Suzuki.12 The reaction is
generally green, relatively easy to carry out, normally gives good yields and selectivities
without much synthetic effort and is being increasingly applied in the synthesis of
pharmaceuticals, natural products and advanced functional materials.13 Developing aqueous
systems for the SuzukiꢀMiyaura reactions has become also very attractive and is one of the
latest challenges for modern chemists.14ꢀ16 On the other hand the use of organoboron
compounds is also compatible with aqueous reaction conditions since they are generally
thermally stable and inert to water and oxygen.15
Now we report a ligandꢀfree protocol for SuzukiꢀMiyaura reaction under ohmic heating
using water as solvent and tetrabutylammonium bromide (TBAB) as additive.
Results and discussion
Synthesis of 3ꢀiodoquinolinꢀ4(1H)ꢀones used in the SuzukiꢀMiyaura cross coupling
reaction
The 1ꢀsubstitutedꢀ3ꢀiodoquinolinꢀ4(1
H)ꢀones 4 and 6 were synthesised following the
strategy depicted in Scheme 1. Following the published protocols10b,c for the synthesis of
quinolinꢀ4(1
H
)ꢀone
3
, first we performed the reaction of 2’ꢀaminoacetophenone
1
with
was
methyl formate in the presence of sodium at 40ºC, and the quinolinꢀ4(1H)ꢀone 2
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obtained with an improved yield of 75%. Next Cꢀ3 iodination was carried out using
molecular iodine in dry THF in the presence of sodium carbonate at room temperature
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affording compound
3 in excellent yield (91%). Cꢀ3 bromination was also attempted with
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pyridinium tribromide (1 equiv) in AcOH at room temperature; however the reaction was
not regioselective affording a complex mixture of products. Therefore we chose to use
the iodinated compound in this work, since 3ꢀiodoquinolinꢀ4(1
H)ꢀones proved to be more
reactive (I > Br) in the SuzukiꢀMiyaura crossꢀcoupling reaction.17
Methylation of quinolinꢀ4(1
triazabicyclo[4.4.0]decꢀ5ꢀene polystyrene) in dry THF afforded
Alternatively compound was obtained in excellent yield (98%) by methylation with
methyl iodide in dry THF using sodium hydride (NaH) as base at room temperature. Both
methods selectively afforded the desired ꢀmethylated quinolinꢀ4(1 )ꢀone in very good
isolated yields without isolation of the corresponding isomer 4ꢀmethoxyquinoline . The
alkylation of , to introduce the 1ꢀpentyl group, was performed in the ohmic heating
H)ꢀone
3
with methyl iodide and PSꢀTBD (1,5,7ꢀ
4
in 87% yield.
4
N
H
4
5
3
reactor, in water under phase transfer conditions, using TBAB as catalyst, pentyl iodide
as alkylating agent and potassium carbonate as base, at 100ºC for 30 minutes. After that
period 3ꢀiodoꢀ1ꢀpentylquinolinꢀ4(1
H)ꢀone
6 was isolated in 62% yield together with the
isomer 3ꢀiodoꢀ4ꢀpentyloxyquinoline
7
in 17% isolated yield.
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Scheme 1. Synthesis of 3-iodoquinolin-4(1H)-ones 4 and 6 used in the Suzuki-Miyaura
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cross coupling reaction
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In 2011, Corelli and coꢀworkers17b reported the synthesis of 3ꢀphenylquinolinꢀ4(1
H)ꢀ
one 9a through the reaction of 3ꢀiodoꢀ1ꢀmethylquinolinꢀ4(1 )ꢀone with phenylboronic
H
4
acid 8a (1.2 equiv) using Pd(OAc)2 as catalyst (10 mol%), PPh3 as ligand (30 mol%), in
the presence of Na2CO3 (2.0 M in H2O) (2.5 equiv), in DME/EtOH (1.5:1), under
microwave irradiation at 70ºC for 5 minutes. The 3ꢀphenylquinolinꢀ4(1
H)ꢀone 9a was
obtained in 75% isolated yield. Based on this protocol, we performed the reaction of
4
with phenylboronic acid 8a (1.5 equiv) in water at 100ºC using sodium carbonate (1.0
equiv) as base and Pd(OAc)2 (5 mol%) as catalyst under ohmic heating using TBAB (0.1
equiv) as phase transfer catalyst (PTC). PTC has long been recognized as a versatile
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methodology for organic synthesis in industry, academia and in process chemistry and is
particularly suitable when substrates are insoluble in the reaction medium as is the case of
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1ꢀsubstitutedꢀ3ꢀiodoquinolinꢀ4(1
H)ꢀones 4 . Under these conditions 3ꢀ
and 6 18
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phenylquinolinꢀ4(1 )ꢀone 9a was obtained in 75% isolated yield after 30 minutes
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reaction time (Table 1, entry 1).
An extensive optimization of the reaction parameters led us to study: i) the effect of
using the PTC (TBAB addition), ii) the effect of Pd catalyst addition, and iii) the reaction
time. The base, solvent and the temperature used remain unchanged. Using the model
reaction depicted in Table 1, our initial investigations focused on the study of the effect
of the PTC (Table 1, entries 1 and 2). Lower yield (61%) was obtained without the
addition of PTC (TBAB), demonstrating that TBAB played an important role in the
efficiency of this ligandꢀfree protocol in water. The product 9a was isolated in very good
yield (80%) when the reaction was performed without addition of Pd(OAc)2 under ohmic
heating (Table 1, entry 3), but no product was found when the reaction was performed
under classical heating conditions without Pd(OAc)2 (Table 1, entry 4). This result
highlights that some contamination of the reaction media with palladium catalyst
probably comes from the electrodes (made of 316 stainless steel) used in ohmic heating,
in the first assay, and that such a small quantity of palladium seems to be sufficient to
give the coupling product in very good yield. Indeed when we performed the reaction
under classical heating conditions with the same electrodes immersed in the reaction
medium, the product 9a was obtained in 60% yield after 5.5 h (Table 1, entry 5). In order
to clarify the effect of the electrodes in the reaction outcome we performed again the
reaction under ohmic heating without addition of Pd(OAc)2 using two new electrodes
which were not in contact with palladium catalyst. In this case no product 9a was isolated
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after 90 minutes of reaction time (Table 1, entry 6). The same result was obtained when
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the reaction was performed without addition of both catalysts
(Table 1, entry 7), as expected.
[TBAB and Pd(OAc)2]
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Finally we found that the optimal conditions for the reaction required the presence of
Pd(OAc)2 (5 mol%), Na2CO3 (1.0 equiv) and TBAB (0.1 equiv) as PTC, at 100ºC for 15
minutes, leading to the formation of the product 9a in very good isolated yield (86%)
(Table 1, entry 8). When compared to the yield reported by Corelli and coꢀworkers for
the synthesis of 3ꢀphenylquinolinꢀ4(1H)ꢀone 9a (yield 75%) our method led to a better
yield (86%). No ligand was required, less amount of catalyst and base were used in the
reaction which proceeds using exclusively water as solvent.
Based on the previous results we suspected that the high heating rate in the beginning
of the reaction may be crucial for the higher yields found under ohmic heating although
some “electrochemical effects” that may be involved in the deposition and the
solubilisation of Pdꢀcatalyst cannot be excluded.
In order to clarify this idea we performed the reaction under classical heating using the
optimal conditions found (Table 1, entry 8) with electrodes immersed in the reaction
without passing electric current. The reaction was monitored by TLC and after 240
minutes of reaction time the coupling product 9a was isolated in 70% yield (Table 1,
entry 9). Then we repeat the reaction without addition of Pd(OAc)2 with the electrodes
from the previous experiment immersed in the reaction medium to find if there was Pdꢀ
catalyst deposited in the electrodes to efficiently catalyse the reaction. After 240 minutes
the reaction product 9a was isolated in 4% yield (Table 1, entry 10). These results
highlight that deposition of Pdꢀcatalyst in the electrodes under classical conditions is not
as efficient as under ohmic heating.
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Table 1 Optimization of Suzuki-Miyaura cross-coupling reaction of 3-iodo-1-
methylquinolin-4(1H)-one 4 with phenylboronic acid 8a, under classical heating (CH)
and ohmic heating (ꢀH).
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Entry
Heating
Method
TBAB
(molar equiv)
Pd(OAc)2
(molar equiv)
Time
(min.)
Yield 9a
(%)a
75
0.1
ꢀꢀꢀ
0.05
0.05
ꢀꢀꢀ
ꢀꢀꢀ
ꢀꢀꢀ
ꢀꢀꢀ
ꢀꢀꢀ
0.05
0.05
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30
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330
90
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15
240
240
1
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3
ꢀH
ꢀH
ꢀH
CH
CH
ꢀH
ꢀH
ꢀH
CH
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0.1
0.1
0.1
0.1
ꢀꢀꢀ
0.1
0.1
0.1
80
ꢀꢀꢀb
60
4
5c
6d
7d
8
ꢀꢀꢀb
ꢀꢀꢀ b
86
70
4
9
10e
CH
b
ꢀꢀꢀ
aIsolated yields. Formation of 9a was not observed. The used electrodes of entry 3 were
c
d
immersed in the reaction medium without passing electrical current. New electrodes which
were not in contact with Pdꢀcatalyst were used. eThe same electrodes of entry 9 were used and
Pd(OAc)2 was not added in this experiment.
In order to compare the three heating methods, the model reaction was performed
under classical heating (oil bath), microwave and ohmic heating and the results are
presented in Table 2.
These results show that for a reaction time of 15 minutes ohmic heating was the most
efficient heating method leading to the highest yield of 9a (Table 2, entry 1). There is a
significant difference between the yields obtained under ohmic heating and under the
other heating methods. It is important to note that, the reaction under microwave heating
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gave lower yield, even when the reaction time is prolonged to 30 minutes (Table 2,
entries 2 and 3). Our suspicion is that under ohmic heating the high heating rates in the
beginning, may enhance the reduction of Pd(II) to Pd(0) which is the species involved in
the catalytic cycle of the Suzuki reaction. Moreover it is very likely that the used ironꢀ
containing electrodes will readily reduce aqueous solutions of Pd(OAc)2 to the pure metal
Pd(0). The deposition mechanism under the ohmic heating process itself may enforce this
phenomenon.
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Table 2 The effect of the heating method on the cross-coupling of 3-iodo-1-
methylquinolin-4(1H
)-one 4 with phenylboronic acid 8aa
Yield 9ab(%)
Entry
Heating method
Time (min.)
1c
2d
3d
4
15
15
30
15
86
35e
76
4f
ꢀ
H
MW
MW
CH
aReaction conditions: 3ꢀiodoꢀ1ꢀmethylquinolinꢀ4(1
H)ꢀone
4
(0.28 mmol),
phenylboronic acid 8a (1.5 equiv), Pd(OAc)2 (5 mol%), Na2CO3 (1 equiv) and TBAB
b
c
(0.1 equiv), H2O (4 mL), 100ºC. Isolated yield. Model reaction for comparison.
dReactions were performed in a singleꢀmode microwave reactor under openꢀvessel
conditions (temperature was measured using an IR sensor). e62% of Starting material
was recovered. fThe round bottom flask was immersed into an oil bath at 100ºC.
According to the literature the SuzukiꢀMiyaura coupling reactions can be catalysed by
unusual low Pdꢀloading.19 De Vries and Reetz have shown that the Heck reaction can be
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run with the addition of what they term “homeopathic” quantities of palladium catalysts
(ideally 0.01ꢀ0.1 mol%), but they have found that when using very low metal
concentrations the rate of reaction is too slow to be practical.19aꢀc De Vries and coworkers
have also shown that the use of unusually low Pdꢀloading in the Suzuki reaction on aryl
bromides is also possible.19d
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Inspired in these findings we decided to study the effect of the palladium amount in
the model reaction yield in order to find the lower threshold of synthetically viable Pdꢀ
catalyst concentration. The results obtained (Table 3) showed that for the ideally
homeopathic quantities the reaction occurs with a very low yield even after a prolonged
reaction time (Table 3, entries 2 and 3). However when using 0.5 mol% of Pdꢀcatalyst the
yield increased to 73% (Table 3, entry 4) and similar yields were obtained using 1, 3 and
5 mol% of catalyst (Table 3, entries 5ꢀ7). When using 5 mol% of catalyst the coupling
product was obtained in 86% isolated yield after only 15 minutes showing that the
increase of palladium concentration led to shorter reaction time.
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Table 3 The effect of the amount of Pd(OAc)2 on the cross-coupling reaction of 3-
5
6
7
8
iodo-1-methylquinolin-4(1
heating.a
H)-one 4 with phenylboronic acid (8a) using ohmic
9
10
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Entry
Pd(OAc)2
(molar equiv)
---
Time (min.)
Yield 9a (%)b
1
2
---c
90
120
120
30
0.0001
0.001
0.005
0.01
6
11
3
73
4
30
74
5
0.03
30
80
6
0.05
30
75
7
8d
0.05
15
86
aReaction conditions: 3ꢀiodoꢀ1ꢀmethylquinolinꢀ4(1
acid 8a (1.5 equiv), Na2CO3 (1 equiv) and TBAB (0.1 equiv), H2O (4 mL), 100ºC.
bIsolated yield. cNo product was isolated. dModel reaction for comparison.
H)ꢀone (0.28 mmol), phenylboronic
Since tetraalkylammonium halides are known to induce the formation and stabilization
of nanoꢀsized transition metal colloids,20 we investigated the formation of Pdꢀcolloids
under the optimized reaction conditions. A solution of Pd(OAc)2 (0.014 mmol), TBAB
(0.028 mmol) as a stabilizer and the phenylboronic acid 8a (0.42 mmol) in water (4 mL)
was heated at reflux under ohmic heating. Once reached the reflux, the solution colour
becomes dark brown, suggesting the formation of nanoꢀsized Pdꢀcolloids. The heating
was continued for 10 minutes and the resulting mixture was monitored by UVꢀVis
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spectroscopy. The UVꢀVis spectra obtained (see Figure S45 in Supplementary
Information) also suggests the formation of nanoꢀsized Pdꢀcolloids as can be inferred
from the observation of a small band in the nearꢀUV. According to Creighton and
coworkers21 for small particles of most of the dꢀblock metals the absorption in the UVꢀ
Vis range is continuous across the range, but in the case of colloidal Pd this absorption
has some structure, giving broad or at least partly resolved absorption bands in the nearꢀ
UV. However, in our case, these colloidal Pd particles might be very unstable under the
experimental conditions used, leading to the formation of a dark precipitate at the end of
the reaction. Similar observations were made by ElꢀSayed and coworkers22 and by
Herrmann and coworkers23 for coupling reactions using palladium colloid as catalyst,
suggesting that the instability of the colloid might be due to the use of high temperatures.
In our case, it is very likely that the refluxing conditions used under ohmic heating leads
to the Pd metal precipitation. Therefore it is not Pd(OAc)2 that can be recycled but Pd(0).
The high temperature and the presence of TBAB will initially lead to the formation of Pd
colloids which then are deposited as thin film or Pd black on the electrodes thus
explaining how the Pd on the electrodes (especially in the presence of TBAB) can
catalyse the reaction so efficiently. According to the literature,24 if a colloidal solution of
Pdꢀnanoparticles is formed in this reaction, a process of this kind should not belong to the
traditional area of homogeneous catalysis, instead it should be more closely related to
heterogeneous catalysis.
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Scope and limitations of substrates
With a viable coupling procedure in hand, attention was turned to generalize the process,
and the substrate scope of the coupling reaction was studied in detail by varying the
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substituents in the boronic acid coupling partner. To highlight the usefulness and
flexibility of this protocol we employed boronic acids containing electronꢀwithdrawing
and electron donating substituents as well as sterically hindered boronic acids. All
reactions were performed in water (4 mL) using Pd(OAc)2 (5 mol%) as catalyst and
TBAB as additive (0.1 equiv), in the presence of a base at 100ºC under ohmic heating
conditions and the results are summarized in Table 4. Analysing the results, we
concluded that the reaction is sensitive to the electronic effects of the boronic acid
substituents. The yield of the reaction is higher for boronic acids bearing electron
donating groups (EDG) (9b, R4 = OCH3 and 9c, R4 = OH, 83%) and for the neutral
substituent (9a, R4 = H, 86% and 9m, R4 = H, 90%) (Table 4, entries 1ꢀ3 and 13), and
lower with those having electron withdrawing groups (EWG) (9e, R4 = CHO, 67% and
9f, R4 = NO2, 36%) (Table 4, entries 5 and 6), considering substitution at paraꢀposition.
In the case of derivative 9f another product, the 3ꢀ(4ꢀaminophenyl)ꢀ1ꢀmethylquinolinꢀ
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4(1H)ꢀone 11 was isolated in 13% yield due to the reduction of the nitro group.
Regarding to the substitution at metaꢀposition, higher yields were obtained for derivative
9g (R3 = OCH3, 86%) in comparison with 9h (R3 = CHO, 64%), when using K3PO4 as
base for 5 minutes reaction time (Table 4, entries 7 and 8). Actually, the greater reactivity
and higher reaction yields associated to EDGꢀsubstituted boronic acids were observed
before in the synthesis of arylnaphthalenes by SuzukiꢀMiyaura crossꢀcoupling reaction
using a mixture of H2O:DMF as solvent.25 Our reaction conditions are similar since DMF
is a solvent with bulk properties similar to those of water (high dielectric constant and
high ability to stabilize ionic species).26 The yield of the SuzukiꢀMiyaura reaction in the
experimental conditions adopted in this work clearly have some dependency with the
substituent electron donor strength, and with steric hindrance factors, however these are
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not the only factors affecting the reaction outcome. Solubility aspects and competing
undesirable side reactions may also play a role in defining the trend observed. For
example, in the synthesis of the dimethylamino derivative 9d, the strongest EDG, [R4 =
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N(CH3)2,
methylaminophenyl)quinolinꢀ4(1
starting material was recovered (Table 4, entry 4). This is an indication that the yield of
1ꢀmethylꢀ3ꢀ(4ꢀdimethylaminophenyl)quinolinꢀ4(1 )ꢀone 9d may be lowered by the
40%],
another
reaction
product,
the
1ꢀmethylꢀ3ꢀ(4ꢀ
H
)ꢀone 10 was isolated in 10% yield and 12.5% of
H
presence of a significant sideꢀreaction, what could explain the deviation from the trend
observed for EDG substituted compounds. In addition there are usually three pathways in
SuzukiꢀMiyaura crossꢀcoupling reaction: the main Suzuki reaction, and two important
side reactions: homocoupling, and hydrolytic deboronation of the boronic acid. These
side reactions were occasionally observed in this work, mainly when boronic acids
presented EWG substituents.
Concerning to the SuzukiꢀMiyaura reaction mechanism, these observations are
consistent with the idea that increased nucleophilicity increases the transmetalation rate.27
Reported pKa values indicate that boronic acids bearing EWGs (such as R4 = 4ꢀCHO and
4ꢀNO2) are by far the strongest acids and the ones substituted with EDGs (R4 = OCH3 and
CH3) the weakest and that orthoꢀsubstituted phenylboronic acids are generally less
acidic.15c,28 As the main role of the base in the Suzuki reaction mechanism under these
conditions is to increase the reactivity of the boronic acid toward the Pdꢀhalide complex27
different bases, weak (Cs2CO3, K3PO4) or strong (NaOH), and amounts were tested for
boronic acids containing EWGs. Water soluble inorganic bases such as K3PO4, Na2CO3,
K2CO3, and NaOH have been successfully used in efficient ligandꢀfree catalytic systems.
In fact, when Cs2CO3 and K3PO4 were used in the reaction of
4 with phenylboronic acid
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8j (R3 = CHO, R4 = OCH3) the yield of the product 9j was slightly better (42% and 49%,
respectively) than when Na2CO3 was used (30%). In order to improve the yields of 9j we
also tried NaOH and Na2CO3 in DMF/H2O as solvent but these conditions led to lower
reaction yields (29% and 24%, respectively).
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In some cases the reaction was faster or the yields were slightly better in the presence of
K3PO4 as base, however previous studies on the role of the base in the SuzukiꢀMiyaura
reaction showed that a few bases favour the reactivity of the boronic acids with lower
reactivity (more acid).27
The reaction with the borate ester (pinacol) 8k (R3 = CH3, R4 = OH, R5 = CH3)
afforded the coupling product 9k in very low yield (20%) (Table 4, entry 11) while no
reaction product was obtained in the case of 2,6ꢀdimethylphenylboronic acid 8l (R2 =
CH3, R6 = CH3) (Table 4, entry 12). This result is not surprising since it is wellꢀknown
that orthoꢀsubstituted phenylboronic acids were found to be generally less reactive than
the other isomers probably due to steric hindrance.29 However, when the reaction occurs
with these steric hindered boronic acids generally lead to lower Suzuki reaction yields.
The yields as well as coupling rates can be improved by using stronger bases like NaOH
or Ba(OH)2. However it is known that more extensive deboronation, which is expected to
be favoured in highly basic media and for orthoꢀsubstituted boronic acids, tends to
occur.15a,c,30 This was the main reason why we did not try a stronger base in the reaction
of 3ꢀiodoꢀ1ꢀmethylquinolinꢀ4(1
substitution of the Nꢀmethyl group by the
moiety did not affect the reaction yield being the corresponding product 9m obtained in
excellent yield (90%) (Table 4, entry 13).
H)ꢀone
4
with 2,6ꢀdimethylphenylboronic acid 8l. The
N
ꢀpentyl group in the quinolinꢀ4(1 )ꢀone
H
6
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Table 4 Synthesis of 3-arylquinolin-4(1H)-ones 9a-k,m by Suzuki-Miyaura cross-
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6
coupling reaction of 4 and 6 with arylboronic acids 8a-l: reaction scope and yieldsa
7
8
9
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Boronic
acid
Time
Base
Yield
Entry Compound
Product
9 (%)b
(min.) (molar equiv)
1c
15
15
Na2CO3/ 1.0
Na2CO3/ 1.0
86
83
9a
2
9b
15
Na2CO3/ 1.0
Na2CO3/ 1.0
83
3
9c
B(OH)2
40 +
10d
30
4
5
9d
9e
N(CH3)2
15
15
Na2CO3/ 1.0
K3PO4/ 1.0
67
66
36 +
13e
14
5
10
Na2CO3/ 1.0
K3PO4/ 1.0
6
7
9f
30
5
Na2CO3/ 1.0
K3PO4/ 1.0
39
86
9g
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9
Na2CO3/
1.0
K3PO4/ 1.5
15
5
69
64
8
9
9h
9i
15
15
5
Na2CO3/ 1.0
K3PO4/ 1.0
K3PO4/ 1.0
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37
61f
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15
Na2CO3/ 1.0
NaOH/ 1.0
Na2CO3/ 1.0
in DMF/H2O
Cs2CO3/1.0
K3PO4/ 1.0
30
29
24
10
11
9j
15
15
42
49
Na2CO3/
1.0
15
20
9k
No
reaction
30
30
K3PO4 / 1.5
12
13
9l
Na2CO3/
1.0
90
9m
aReaction conditions: For entries 1ꢀ12, 3ꢀiodoꢀ1ꢀmethylquinolinꢀ4(1H)ꢀone 4 (80.0 mg, 0.28
mmol), aryl boronic acid 8a-l (0.42 mmol), base (see Table 4, for amount and base used),
TBAB (9.02 mg, 0.028 mmol), Pd(OAc)2 (3.15 mg, 0.014 mmol), H2O (4 mL), 100 ºC. For
entry 13, 3ꢀiodoꢀ1ꢀpentylquinolinꢀ4(1H)ꢀone 6 (60.0 mg, 0.18 mmol), phenylboronic acid 8a
(32.92 mg, 0.27 mmol), Na2CO3 (19.07 mg, 0.18 mmol), TBAB (5.80 mg, 0.018 mmol),
b
Pd(OAc)2 (2.02 mg, 9x10ꢀ3 mmol), H2O (4 mL), 100 ºC. Isolated yield. cModel reaction for
comparison. d1ꢀMethylꢀ3ꢀ(4ꢀmethylaminophenyl)quinolinꢀ4(1
H
)ꢀone 10 was isolated as
)ꢀone 11 was isolated as a
e
a byꢀproduct. 3ꢀ(4ꢀAminophenyl)ꢀ1ꢀmethylquinolinꢀ4(1
byꢀproduct; the yield was calculated from the NMR mixture with 9f. fUnreacted starting
H
material was recovered (9.4%).
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Reusability of the catalysts
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The possible reduction of the amount of palladium catalyst to 0.5 mol%, as shown
previously for the model reaction (Table 3, entry 4), that could also be catalysed by
surfaceꢀdeposits of Pd on the electrodes, led us to explore the possibility to reuse the
catalyst. Moreover environmental and economic concerns (Pd is an expensive metal
catalyst) corroborate this study. So, initially the reusability of the Pdꢀcatalyst was
investigated using as model reaction the Suzuki coupling of 3ꢀiodoꢀ1ꢀmethylquinolinꢀ
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4(1H)ꢀone 4 with phenylboronic acid 8a in the presence of Pd(OAc)2, Na2CO3 and TBAB
at 100ºC for 15 minutes using water as solvent. After the first cycle the reaction mixture
was removed from the reactor which was then charged with all the reactants in each run,
except Pd(OAc)2, which was not added in the following runs. The results were shown in
figure 1.
100
80
60
40
20
0
1
2
3
4
5
6
Recycle Number
Figure 1. The reusability of Pdꢀcatalyst in the SuzukiꢀMiyaura coupling reaction of 3ꢀiodoꢀ1ꢀ
methylquinolinꢀ4(1H)ꢀone 4 with phenylboronic acid 8a.
It was clear that the Pdꢀcatalyst could be reused for at least six times without significant loss
in activity. In the first cycle the yield was lower than the expected (49%) probably due to the
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loss of some product that remained adsorbed in the electrodes even after washing them
abundantly with water. As we presume that some catalyst can also remain on the electrodes
surface we do not clean them with organic solvents or by scraping. In the following cycles the
yields were very good (68%, 79% 74%, 74% and 71%) and the starting material was
completely consumed until the sixth cycle. When the last cycle was finished, the TLC of the
reaction mixture showed some starting material, evidencing that consumption was not
complete after 15 minutes probably due to the decrease of the catalyst efficiency or decrease
of its amount in the reaction medium.
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Then we decided to investigate the reusability of the reaction medium, more precisely of the
mixture H2OꢀTBABꢀPd/catalyst, thus envisioning the possibility of recovering both catalysts
and also the solvent, aiming to achieve a more economic synthetic process and promoting the
reduction of waste that will exist for further treatment at the end of the synthetic process. The
results obtained are presented in figure 2. Once again it was clear that H2OꢀTBABꢀPd/catalyst
catalytic system could be reused at least seven times without loss of activity. In the last cycle
we performed the reaction without adding base to the mixture and complete consumption of
starting material occurred. The ohmic heating data showed an increase in the current intensity
and heating rate for the last 3 assays (See Figure S46 of Supplementary Information). These
data indicate an increase in the medium conductivity thus suggesting higher concentrations of
reactants mainly of those that can contribute to increase the medium conductivity such as the
base and boronic acid which were added in each experiment. So it seems that the increase in
the concentration of these reactants may be due to the recovery of some amounts of base and
acid when reusing the reaction medium.
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1
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7
Recycle number
Figure 2 The reusability of H2OꢀTBABꢀPdꢀcatalyst in the Suzuki coupling reaction of 3ꢀiodoꢀ
1ꢀmethylquinolinꢀ4(1H)ꢀone (4) with phenylboronic acid (8a).
The yield was determined at the end of the seventh cycle applying the equation (1) where
m is the mass of product obtained for each reaction from 1 to 7 cycles and m’ is the
theoretical mass of product expected for the same cycles. Curiously the global yield obtained
was 86% the same yield we obtained when we performed the reaction during 15 minutes for
the first time (see Table 1, entry 8).
% global yield = [(m1+m2+m3+m4+m5+m6+m7)/7]/[(m'1+m'2+m'3+m'4+m'5+m'6+m'7)/7] x100
(Equation 1)
Conclusion
From the standpoint of generating diversity, this protocol allows the rapid preparation of a
multitude of 3ꢀarylquinolinꢀ4(1H)ꢀone analogues, given the large number of commercially
available boronic acids. The use of ohmic heating represents a significant improvement over
existing synthetic approaches. The high heating rates achieved in the beginning of the reaction
and the local energy generation seems to be crucial for the reaction efficiency and enhance the
deposition of Pdꢀcatalyst in the surface of the electrodes, allowing the reuse of the catalyst for
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at least six catalytic cycles without significant loss of activity. It was found that using the
ohmic heating reactor the reaction occurs successfully in water in a shorter time, in good to
excellent yields, using ligandꢀfree conditions. Moreover we have shown that the reaction can
be run using 0.5 mol% of Pd(OAc)2 which is a very low Pd catalyst amount when compared
to the 10 mol% used by Corelli and coworkers. Good substrate generality, ease of execution,
practicability, and the possibility of reusing the catalysts and the solvent make this synthetic
methodology exploitable for the generation of libraries of potentially bioactive 3ꢀarylquinolinꢀ
4(1H)ꢀones, with environmental and economic benefits.
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Experimental section
All reactions were carried out in air without any protection of inert gases. 3ꢀIodoꢀ1ꢀ
metilquinolinꢀ4(1H)ꢀone 4 was prepared following the method reported in literature10b,31 or
using methyl iodide and NaH in dry THF being necessary in the latter case the use of a
nitrogen atmosphere. Boronic acids, bases and TBAB were purchased and used without
further purification. Preparative thinꢀlayer chromatography was carried out with silica gel (60
DGF254) plates. Melting points were determined on a melting point apparatus and are
uncorrected. NMR spectra were recorded on 300 or 500 [300.13 MHz (1H), 75.47 MHz (13C)
or 500.13 MHz (1H), 125.77 MHz (13C)] NMR spectrometers with TMS as internal reference
and with CDCl3 or DMSOꢀd6 as solvent. Chemical shifts (δ) are quoted in ppm relative to
13
TMS. Coupling constants (J) are quoted in Hz. Unequivocal C assignments were made on
the basis of 2D gHSQC (1H/13C) and gHMBC (delays for one bond and longꢀrange JC/H
couplings were optimized for 145 and 7 Hz, respectively) experiments. Mass spectra (EI, 70
eV) were measured. Positiveꢀion ESI mass spectra were acquired using nitrogen as nebulizer
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gas and argon as collision gas. The needle voltage was set at 3000 V, with the ion source at 80
ºC and desolvation temperature at 150 ºC. Cone voltage was 35 V]. High resolution mass
spectra (EIꢀHRMS, 70 eV) were also measured. For experiments carried out under ohmic
heating, the 10 mL reactor was filled with the reaction mixture, closed and the mixture was
heated to reflux. For 4 mL of reaction mixture the length of electrodes immersed in the
reaction medium was 9 mm, the distance between the electrodes was 10 mm. Temperature
measurement was done using a type J glass sheathed thermocouple located inside the reactor.
Medium magnetic stirring speed (740 rpm) was used in all the experiments carried out in the
ohmic heating reactor. For the experiments carried out in conventional heating (oil bath)
under reflux conditions, the same reaction vessel used in the ohmic heating reactor was filled
with the reaction mixture and was immersed into the oil bath at 100 ºC. Medium magnetic
stirring speed (740 rpm) was used. Microwaveꢀassisted reactions were carried out in a circular
singleꢀmode cavity instrument (300 W max magnetron power output). Reactions were carried
out in an openꢀvessel using a 50 mL roundꢀbottom flask filled with the reaction mixture and
equipped with a condensator. The temperature measurement was done through 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. The
conditions used for the experiments performed in classical heating were also described in
tables 1 and 2 and those used in MW heating experiments were described in table 2.
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General procedure for the synthesis of 3-iodo-1-pentylquinolin-4(1H)-one (6). The 10 mL
ohmic heating reactor1 was charged with 3ꢀiodoquinolinꢀ4(1H)ꢀone 3 (125.2 mg, 0.44 mmol),
pentyl iodide (0.14 mL, 1.07 mmol), potassium carbonate (127.8 mg, 0.92 mmol), TBAB
(15.2 mg, 0.047 mmol) and H2O (4 mL). The mixture was heated at reflux for 30 minutes.
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After cooling to room temperature the aqueous mixture was extracted with ethyl acetate (4 x
10 mL) and the combined organic layer was dried with anhydrous sodium sulfate and
concentrated under reduced pressure. The obtained mixture was purified by thin layer
chromatography (TLC) using ethyl acetate: hexane (3:2). Two products were isolated: 3ꢀiodoꢀ
1ꢀpentylquinolinꢀ4(1H)ꢀone 6 as the main product (62%) and 3ꢀiodoꢀ4ꢀpentyloxyquinoline 7
as minor product (17%).
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3-Iodo-1-pentylquinolin-4(1H)-one (6). 62% Yield (93.0 mg), yellow solid, m.p 117.3–
117.6 ºC. 1H NMR (300.13 MHz, DMSOꢀd6): δH = 0.84 (t, J = 6.8 Hz, 3 H, CH3,), 1.13ꢀ 1.33
(m, 2 H, Hꢀ3’, 4’), 1.67ꢀ1.76 (m, 1 H, Hꢀ2’), 4.29 (t, J = 7.4 Hz, 1 H, Hꢀ1’), 7.42ꢀ7.47 (m, 1
H, Hꢀ6), 7.74ꢀ7.80 (m, 2 H, Hꢀ7,8), 8.20 (d, J = 7.9 Hz, 1 H, Hꢀ5), 8.66 (s, 1 H, Hꢀ2) ppm. 13C
NMR (125.77 MHz, DMSOꢀd6): δC = 13.9 (Cꢀ5’), 21.8 (Cꢀ4’), 28.0 (Cꢀ3’), 28.3 (Cꢀ2’), 52.0
(Cꢀ1’), 80.4 (Cꢀ3), 117.0 (Cꢀ8), 123.3 (Cꢀ4a), 124.3 (Cꢀ6), 126.4 (Cꢀ5), 132.3 (Cꢀ7), 139.0 (Cꢀ
8a), 149.0 (Cꢀ2), 172.7 (Cꢀ4) ppm. MS (EI) m/z (%): 341 (M+., 74), 285 (6), 284 [(MꢀC4H9)+,
100], 271 (10), 158 (6), 144 (10). HRMS (EI) m/z calcd for C14H16NOI (M)+.: 341.0277,
found: 341.0275.
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3-Iodo-4-pentyloxyquinoline (7). 17% Yield (25.5 mg), dark yellow oil. H NMR (300.13
MHz, DMSOꢀd6): δH = 0.93 (t, J = 7.2 Hz, 3 H, CH3), 1.34ꢀ1.59 (m, 2 H, Hꢀ3’,4’), 1.92
(quintet, J = 6.6 Hz, 1 H, Hꢀ2’), 4.14 (t, J = 6.6 Hz, 1 H, Hꢀ1’), 7.67 (ddd, J = 8.3, 6.9, 1.1 Hz,
1 H, Hꢀ6), 7.82 (ddd, J = 8.3, 6.9, 1.3 Hz, 1 H, Hꢀ7), 8.04 (d, J = 8.3 Hz, 1 H, Hꢀ8), 8.08 (dd,
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J = 8.3, 1.3 Hz, 1 H, Hꢀ5), 9.06 (s, 1 H, Hꢀ2) ppm. C NMR (125.77 MHz, DMSOꢀd6): δC =
14.0 (Cꢀ5’), 22.0 (Cꢀ4’), 27.7 (Cꢀ3’), 29.5 (Cꢀ2’), 74.9 (Cꢀ1’), 86.1 (Cꢀ3), 121.8 (Cꢀ5), 124.4
(Cꢀ4a), 127.4 (Cꢀ6), 129.2 (Cꢀ8), 130.4 (Cꢀ7), 149.0 (Cꢀ8a), 157.6 (Cꢀ2), 162.6 (Cꢀ4) ppm.
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MS (EI) m/z (%): 341 (M+˙, 85), 285 (11), 284 [(MꢀC4H9)+, 100], 255 (4), 236 (5), 214 [(Mꢀ
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I)+, 4], 144 (8). HRMS (EI) m/z calcd for (C14H16NOI) (M)+˙: 341.0277, found: 341.0279.
General procedure for the Suzuki-Miyaura cross-coupling reaction of 3-iodo-1-
metilquinolin-4(1H)-one (4) with arylboronic acids (8a-l). The 10 mL ohmic heating
reactor was charged with 3ꢀiodoꢀ1ꢀmethylquinolinꢀ4(1H)ꢀone 4 (80.0 mg, 0.28 mmol), the
appropriate aryl boronic acid 8a-l (0.42 mmol), base (see table 2, for amount and base used),
TBAB (9.02 mg, 0.028 mmol), Pd(OAc)2 (3.15 mg, 0.014 mmol) and H2O (4 mL). The
mixture was heated at reflux with stirring for the period described in table 2. Then the
aqueous mixture was extracted with ethyl acetate (4 x 10 mL) and the combined organic layer
was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The
products 9a-k were isolated after TLC using ethyl acetate: hexane (3:2) as eluent.
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1-Methyl-3-phenylquinolin-4(1H)-one (9a). 86% Yield (56.6 mg), white solid, m.p. 119.8 ꢀ
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120.2 ºC. H NMR (300.13 MHz, CDCl3): δH = 3.83 (s, 3 H, NCH3), 7.26ꢀ7.43 (m, 5 H, Hꢀ
6,8,4’,3’,5’), 7.64ꢀ7.70 (m, 3 H, Hꢀ7,2’,6’), 7.68 (s, 1 H, Hꢀ2), 8.56 (dd, J = 8.3, 1.6 Hz, 1 H,
Hꢀ5) ppm. 13C NMR (75.47 MHz, CDCl3): δC = 40.9 (NCH3), 114.9 (Cꢀ8), 121.9 (Cꢀ3), 123.9
(Cꢀ6), 126.9 (Cꢀ4’), 127.1 (Cꢀ4a), 127.5 (Cꢀ5), 128.2 (Cꢀ3’,5’), 128.8 (Cꢀ2’,6’), 132.0 (Cꢀ7),
135.3 (Cꢀ1’), 139.8 (Cꢀ8a), 142.6 (Cꢀ2), 175.8 (Cꢀ4) ppm. MS (EI) m/z (%): 235 (M+˙, 41),
234 [(MꢀH)+, 100], 165 (6), 145 (10). HRMS (EI) m/z calcd for (C16H13NO) (M)+˙: 235.0997,
found: 235.0995.
3-(4-Methoxyphenyl)-1-methylquinolin-4(1H)-one (9b). 83% Yield (61.6 mg), white solid,
m.p. 154.8ꢀ155.3 ºC. 1H NMR (300.13 MHz, DMSOꢀd6): δH = 3.78 (s, 3 H, OCH3), 3.90 (s, 3
H, NCH3), 6.96 (d, J = 8.9 Hz, 2 H, Hꢀ3’,5’), 7.42 (ddd, J = 8.0, 6.9, 1.0 Hz, 1 H, Hꢀ6), 7.66ꢀ
7.68 (m, 1 H, Hꢀ8), 7.68 (d, J = 8.9 Hz, 2 H, Hꢀ2’,6’), 7.74 (ddd, J = 9.3, 6.9, 1.5 Hz, 1 H, Hꢀ
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7), 8.24 (s, 1 H, Hꢀ2), 8.30 (dd, J = 8.0, 1.5 Hz, 1 H, Hꢀ5) ppm. 13C NMR (125.77 MHz,
DMSOꢀd6): δC = 40.0 (NCH3), 55.0 (OCH3), 113.3 (Cꢀ3’,5’), 116.5 (Cꢀ8), 119.4 (Cꢀ3), 123.3
(Cꢀ6), 126.1 (Cꢀ5), 126.5 (Cꢀ4a), 128.1 (Cꢀ1’), 129.4 (Cꢀ2’,6’), 131.8 (Cꢀ7), 139.7 (Cꢀ8a),
143.3 (Cꢀ2), 158.0 (Cꢀ4’), 174.3 (Cꢀ4) ppm. MS (EI) m/z (%): 265 (M+˙, 100), 264 [(MꢀH)+,
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71], 251 (6), 250 [(MꢀCH3)+, 36], 249 (8), 235 (4), 222 (19). HRMS (EI) m/z calcd for
(C17H15NO2) (M)+˙: 265.1103, found: 265.1101.
3-(4-Hydroxyphenyl)-1-methylquinolin-4(1H)-one (9c). 83% Yield (58.4 mg), white solid,
m.p. 295.9ꢀ296.8 ºC. 1H NMR (300.13 MHz, DMSOꢀd6): δH = 3.88 (s, 3 H, NCH3), 6.79 (d, J
= 7.4 Hz, 2 H, Hꢀ3’,5’), 7.40 (ddd, J = 8.0, 6.8, 0.9 Hz, 1 H, Hꢀ6), 7.53 (d, J = 7.4 Hz, 2 H, Hꢀ
2’,6’), 7.66 (d, J = 8.5 Hz, 1 H, Hꢀ8), 7.73 (ddd, J = 8.5, 6.8, 1.5 Hz, 1 H, Hꢀ7), 8.18 (s, 1 H,
Hꢀ2), 8.28 (dd, J = 8.0, 1.5 Hz, 1 H, Hꢀ5), 9.53 (br s, 1 H, OH) ppm. 13C NMR (75.47 MHz,
DMSOꢀd6): δC = 40.3 (NCH3), 115.2 (Cꢀ3’,5’), 116.7 (Cꢀ8), 119.8 (Cꢀ3), 123.6 (Cꢀ6), 126.2
(Cꢀ5), 126.5 (Cꢀ4a, 1’), 129.4 (Cꢀ2’,6’), 132.1 (Cꢀ7), 139.8 (Cꢀ8a), 143.3 (Cꢀ2), 156.7 (Cꢀ4’),
174.4 (Cꢀ4) ppm. MS (EI) m/z (%): 251 (M+˙, 66), 250 [(MꢀH)+, 100], 235 (6), 208 (7), 185
(7), 120 (7). HRMS (EI) m/z calcd for (C16H13NO2) (M)+˙: 251.0946, found: 251.0942.
1-Methyl-3-[4-(dimethylamino)phenyl]quinolin-4(1H)-one (9d). 40% Yield (31.2 mg),
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yellow solid, m.p. 188.8ꢀ189.4 ºC. H NMR (300.13 MHz, DMSOꢀd6): δH = 2.91 [s, 6 H,
N(CH3)2], 3.90 (s, 3 H, NCH3), 6.76 (d, J = 8.8 Hz, 2 H, Hꢀ3’,5’), 7.40 (ddd, J = 8.0, 6.8, 0.9
Hz, 1 H, Hꢀ6), 7.60 (d, J = 8.8 Hz, 2 H, Hꢀ2’,6’), 7.67 (d, J = 8.4 Hz, 1 H, Hꢀ8), 7.74 (ddd, J =
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8.4, 6.8, 1.4 Hz, 1 H, Hꢀ7), 8.20 (s, 1 H, Hꢀ2), 8.29 (dd, J = 8.0, 1.4 Hz, 1 H, Hꢀ5) ppm. C
NMR (75.47 MHz, DMSOꢀd6): δC = 40.2 (NCH3), 40.3 [N(CH3)2], 112.0 (Cꢀ3’,5’), 116.5 (Cꢀ
8), 120.1 (Cꢀ3), 123.2 (Cꢀ6), 123.7 (Cꢀ1’), 126.2 (Cꢀ5), 126.4 (Cꢀ4a), 129.0 (Cꢀ2’,6’), 131.7
(Cꢀ7), 139.7 (Cꢀ8a), 142.7 (Cꢀ2), 149.3 (Cꢀ4’), 174.4 (Cꢀ4) ppm. MS (EI) m/z (%): 278 (M+˙,
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100), 277 [(MꢀH)+, 58], 264 (16), 263 (35), 261 (18). HRMS (EI) m/z calcd for (C18H18N2O)
(M)+˙: 278.1419, found: 278.1416.
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1-Methyl-3-[4-(methylamino)phenyl]quinolin-4(1H)-one (10). 10% Yield, pale yellow
residue. 1H NMR (300.13 MHz, CDCl3): δH = 2.87 (s, 3 H, NHCH3), 3.84 (s, 3 H, NCH3),
6.77 (d, J = 8.7 Hz, 2 H, Hꢀ3’,5’), 7.37ꢀ7.42 (m, 2 H, Hꢀ6,8), 7.53 (d, J = 8.7 Hz, 2 H, Hꢀ
2’,6’), 7.66 (m, 1 H, Hꢀ7), 7.66 (s, 1 H, Hꢀ2), 8.56 (dd, J = 8.2, 1.7 Hz, 1 H, Hꢀ5) ppm. MS
(EI) m/z (%): 264 (M+˙, 100), 263 [(MꢀH)+, 56], 249 [(MꢀCH3)+, 21], 248 (7), 234 [(Mꢀ
NHCH3)+, 12]. HRMS (EI) m/z calcd for (C17H16N2O) (M)+˙: 264.1263, found: 264.1262.
3-(4-Formylphenyl)-1-methylquinolin-4(1H)-one (9e).32 61% Yield (44.9 mg), white solid,
m.p. 212.0 ꢀ 212.5 ºC. 1H NMR (500.13 MHz, DMSOꢀd6): δH = 3.95 (s, 3H, NCH3), 7.48 (dt,
J = 7.6, 0.8 Hz, 1 H, Hꢀ6), 7.73 (d, J = 8.4 Hz, 1 H, Hꢀ8), 7.80 (ddd, J = 8.4, 7.6, 1.5 Hz, 1 H,
Hꢀ7), 7.93 (d, J = 6.9 Hz, 2 H, Hꢀ2’,6’), 8.06 (d, J = 6.9 Hz, 2H, Hꢀ3’,5’), 8.33 (dd, J = 7.6,
1.5 Hz, 1 H, Hꢀ5), 8.50 (s, 1 H, Hꢀ2), 10.01 (s, 1 H, CHO) ppm. 13C NMR (125.77 MHz,
DMSOꢀd6): δC = 40.3 (NCH3), 116.8 (Cꢀ8), 117.9 (Cꢀ3), 124.0 (Cꢀ6), 126.2 (Cꢀ5), 126.7 (Cꢀ
4a), 128.4 (Cꢀ3’,5’), 129.2 (Cꢀ2’,6’), 132.3 (Cꢀ7), 134.2 (Cꢀ1’), 139.8 (Cꢀ8a), 142.3 (Cꢀ4’),
145.0 (Cꢀ2), 174.1 (Cꢀ4), 192.6 (CHO) ppm. MS (EI) m/z (%): 263 (M+˙, 58), 262 [(MꢀH)+,
100], 257 (4), 234 (11), 233 (3), 190 (5), 164 (4). HRMS (EI) m/z calcd for (C17H13NO2)
(M)+˙: 263.0946, found: 263.0946.
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1-Methyl-3-(4-nitrophenyl)quinolin-4(1H)-one (9f). 36% Yield (28.2 mg), yellow solid,
m.p. 242.2 ꢀ 244.3 ºC. 1H NMR (300.13 MHz, DMSOꢀd6): δH = 3.97 (s, 3 H, NCH3), 7.51
(ddd, J = 8.0, 6.8, 1.1 Hz, 1 H, Hꢀ6), 7.76 (dd, J = 8.2, 1.1 Hz, 1 H, Hꢀ8), 7.83 (ddd, J = 8.2,
6.8, 1.6 Hz, 1 H, Hꢀ7), 8.14 (d, J = 8.9 Hz, 2 H, Hꢀ2’,6’), 8.28 (d, J = 8.9 Hz, 2 H, Hꢀ3’,5’),
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8.34 (dd, J = 8.0, 1.6 Hz, 1 H, Hꢀ5), 8.59 (s, 1 H, Hꢀ2) ppm. C NMR (75.47 MHz, DMSOꢀ
d6): δC = 40.6 (NCH3), 116.8 (Cꢀ3), 117.0 (Cꢀ8), 123.2 (Cꢀ3’,5’), 124.3 (Cꢀ6), 126.2 (Cꢀ5),
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126.8 (Cꢀ4a), 128.7 (Cꢀ2’,6’), 132.5 (Cꢀ7), 139.8 (Cꢀ8a), 143.2 (Cꢀ1’), 145.48 (Cꢀ4’), 145.51
(Cꢀ2), 174.0 (Cꢀ4) ppm. MS (EI) m/z (%): 280 (M+˙, 66), 279 [(MꢀH)+, 100], 250 (85), 249
(91), 234 (35), 233 (33), 190 (17). HRMS (EI) m/z calcd for (C16H12N2O3) (M)+˙: 280.0848,
found: 280.0846.
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3-(4-Aminophenyl)-1-methylquinolin-4(1H)-one (11): All the data of this compound were
taken from a mixture of 11 with the expected reaction product 9f (See SI): 13% Yield (9.1
mg), 1H NMR (300.13 MHz, CDCl3): δH = 3.09 (s, 3 H, NCH3), 6.99 (d, J = 9.2 Hz, 2 H, Hꢀ
3’,5’), 7.46ꢀ7.54 (m, 2 H, Hꢀ6; Hꢀ8), 7.74ꢀ7ꢀ80 (m, 1 H, Hꢀ7), 8.12 (d, J = 9.2 Hz, 2 H, Hꢀ
2’,6’), 8.17 (s, 1 H, Hꢀ2), 8.48 (dd, J = 8.1, 1.5 Hz, 1 H, Hꢀ5) ppm. MS (EI) m/z (%): 250
(M+˙, 100), 249 [(MꢀH)+, 100], 235 [(MꢀCH3)+, 14], 234 [(MꢀNH2)+, 22], 233 (13), 207 (13).
HRMS (EI) m/z calcd for (C16H14N2O) (M)+˙: 250.1106, found: 250.1105.
3-(3-Methoxyphenyl)-1-methylquinolin-4(1H)-one (9g). 86% Yield (63.9 mg), white solid,
m.p. 209.4ꢀ210.3 ºC. 1H NMR (300.13 MHz, DMSOꢀd6): δH = 3.80 (s, 3 H, NCH3), 3.92 (s, 3
H, OCH3), 6.87 (m, 1 H, Hꢀ4’), 7.31ꢀ7.34 (m, 1 H, Hꢀ5’,6’), 7.38ꢀ7.39 (m, 1 H, Hꢀ2’), 7.45
(ddd, J = 7.9, 6.9, 1.1 Hz, 1 H, Hꢀ6), 7.69 (dd, J = 8.2, 1.1 Hz, 1 H, Hꢀ8), 7.77 (ddd, J = 8.2,
6.9, 1.6 Hz, 1 H, Hꢀ7), 8.32 (dd, J = 7.9, 1.6 Hz, 1 H, Hꢀ5), 8.33 (s, 1 H, Hꢀ2) ppm. 13C NMR
(75.47 MHz, DMSOꢀd6): δC = 40.3 (NCH3), 55.0 (OCH3), 112.0 (Cꢀ4’), 114.1 (Cꢀ2’), 116.6
(Cꢀ8), 119.3 (Cꢀ3), 120.7 (Cꢀ6’), 123.6 (Cꢀ6), 126.2 (Cꢀ5), 126.7 (Cꢀ4a), 128.9 (Cꢀ5’), 132.0
(Cꢀ7), 137.2 (Cꢀ1’), 139.8 (Cꢀ8a), 144.1 (Cꢀ2), 159.0 (Cꢀ3’), 174.2 (Cꢀ4) ppm. MS (ESI) m/z
(%): 553 [(2M+Na)+, 10], 288 [(M+Na)+, 15], 266 [(M+H)+, 100]. HRMS (EI) m/z calcd for
(C17H15NO2) (M)+˙: 265.1103, found: 265.1102.
3-(3-Formylphenyl)-1-methylquinolin-4(1H)-one (9h).32 69% Yield (50.8 mg), white solid,
m.p. 166.1ꢀ167.1 ºC. 1H NMR (300.13 MHz, DMSOꢀd6): δH = 3.94 (s, 3 H, NCH3), 7.47 (ddd,
J = 8.0, 6.8, 1.2 Hz, 1 H, Hꢀ6), 7.63 (t, J = 7.8 Hz, 1 H, Hꢀ5’), 7.72 (dd, J = 7.6, 1.2 Hz, 1 H,
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Hꢀ8), 7.78 (dd, J = 7.8, 1.5 Hz, 1 H, Hꢀ4’), 7.82 (ddd, J = 7.6, 6.8, 1.5 Hz, 1 H, Hꢀ7), 8.10 (dt,
J = 7.8, 1.5 Hz, 1 H, Hꢀ6’), 8.31 (dd, J = 8.0, 1.5 Hz, 1 H, Hꢀ5), 8.34 (br s, 1 H, Hꢀ2’), 8.45 (s,
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1 H, Hꢀ2), 10.06 (s, 1H, CHO) ppm. C NMR (75.47 MHz, DMSOꢀd6): δC = 40.3 (NCH3),
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116.8 (Cꢀ8), 118.2 (Cꢀ3), 123.9 (Cꢀ6), 126.2 (Cꢀ5), 126.7 (Cꢀ4a), 127.6 (Cꢀ4’), 128.8 (Cꢀ5’),
129.4 (Cꢀ2’), 132.2 (Cꢀ7), 134.3 (Cꢀ6’), 136.1 (Cꢀ3’), 136.8 (Cꢀ1’), 139.9 (Cꢀ8a), 144.4 (Cꢀ2),
174.2 (Cꢀ4), 193.4 (CHO) ppm. MS (EI) m/z (%): 263 (M+˙, 52), 262 [(MꢀH)+, 100], 234 [(Mꢀ
CHO)+, 15], 190 (6), 165 (6). HRMS (EI) m/z calcd for (C17H13NO2) (M)+˙: 263.0946, found:
263.0943.
3-(3,4-Dimetoxyphenyl)-1-methylquinolin-4(1H)-one (9i). 61% Yield (50.4 mg), pale
yellow solid, m.p. 158.2ꢀ159.3 ºC. 1H NMR (300.13 MHz, DMSOꢀd6): δH = 3.78 (s, 3 H, 4’ꢀ
OCH3), 3.80 (s, 3 H, 3’ꢀOCH3), 3.92 (s, 3 H, NCH3), 6.98 (d, J = 8.4 Hz, 1 H, Hꢀ5’), 7.30 (dd,
J = 8.4, 2.0 Hz, 1 H, Hꢀ6’), 7.42 (d, J = 2.0 Hz, 1 H, Hꢀ2’), 7.43 (ddd, J = 8.0, 6.8, 1.1 Hz, 1
H, Hꢀ6), 7.69 (dd, J = 8.4, 1.1 Hz, 1 H, Hꢀ8), 7.76 (ddd, J = 8.4, 6.8, 1.6 Hz, 1 H, Hꢀ7), 8.28
(s, 1 H, Hꢀ2), 8.31 (dd, J = 8.0, 1.6 Hz, 1 H, Hꢀ5) ppm. 13C NMR (75.47 MHz, DMSOꢀd6): δC
= 40.3 (NCH3), 55.54 and 55.57 (2 x OCH3), 111.5 (Cꢀ5’), 112.4 (Cꢀ2’), 116.6 (Cꢀ8), 119.4
(Cꢀ1’), 120.6 (Cꢀ6’), 123.4 (Cꢀ6), 126.2 (Cꢀ5), 126.6 (Cꢀ3), 128.5 (Cꢀ4a), 131.9 (Cꢀ7), 139.7
(Cꢀ8a), 143.5 (Cꢀ2), 147.7 (Cꢀ4’), 148.1 (Cꢀ3’), 174.3 (Cꢀ4) ppm. MS (EI) m/z (%): 295 (M+˙,
100), 294 [(MꢀH)+, 22], 280 [(MꢀCH3)+, 57], 274 (65), 259 (35), 249 (22), 209 (24), 208 (18).
HRMS (EI) m/z calcd for (C18H17NO3) (M)+˙: 295.1208, found: 295.1208.
3-(3-Formyl-4-methoxyphenyl)-1-methylquinolin-4(1H)-one (9j).32 49% Yield (40.2 mg),
pale yellow solid, m.p. 241.5ꢀ242.3 ºC. 1H NMR (300.13 MHz, DMSOꢀd6): δH = 3.93 (s, 3 H,
NCH3), 3.96 (s, 3 H, OCH3), 7.29 (d, J = 6.9 Hz, 1 H, Hꢀ5’), 7.45 (ddd, J = 8.1, 6.8, 1.2 Hz, 1
H, Hꢀ6), 7.71 (dd, J = 8.2, 1.2 Hz, 1 H, Hꢀ8), 7.79 (ddd, J = 8.2, 6.8, 1.5 Hz, 1 H, Hꢀ7), 8.07
(d, J = 2.4 Hz, 1 H, Hꢀ2’), 8.10 (dd, J = 6.9, 2.4 Hz, 1 H, Hꢀ6’), 8.31 (dd, J = 8.1, 1.5 Hz, 1 H,
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