Visible-Light-Induced Decarboxylation Coupling/Intramolecular Cyclization: A One-Pot Synthesis for 4-Aryl-2-quinolinone Derivatives

Article abstract of DOI:10.1021/acs.joc.7b02979

A visible-light-induced decarboxylation coupling/intramolecular cyclization is reported. The one-pot synthesis system provides mild, efficient, and atom economical access to the synthesis of 4-aryl-2-quinolinone derivatives. It is notable that the necessa

Full text of DOI:10.1021/acs.joc.7b02979

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Article
Visible-light-induced Decarboxylation Coupling/Intramolecular
Cyclization# A One-Pot Synthesis for 4-aryl-2-quinolinone Derivatives
Chenglong Wang, Jingyi Qiao, Xiaochong Liu, He Song, Zhizhong Sun, and Wenyi Chu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02979 • Publication Date (Web): 11 Jan 2018
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The Journal of Organic Chemistry
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Visible-light-induced
Decarboxylation
Coupling/Intramolecular
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Cyclization： A One-Pot Synthesis for 4-aryl-2-quinolinone Derivatives
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Chenglong Wang, Jingyi Qiao, Xiaochong Liu, He Song, Zhizhong Sun, and Wenyi
Chu*
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School of Chemistry and Materials Science, Heilongjiang University, Harbin 150080,
P. R. China;
Key Laboratory of Chemical Engineering Process & Technology for Highꢀefficiency
Conversion, College of Heilongjiang Province, Harbin 150080, P. R. China.
*Eꢀmail: wenyichu@hlju.edu.cn
ABSTRACT: A visibleꢀlightꢀinduced decarboxylation coupling /intramolecular
cyclization is reported. The oneꢀpot synthesis system provides mild, efficient and
atom economical access to the synthesis of 4ꢀarylꢀ2ꢀquinolinone derivatives. It is
notable that the necessary oxidant in the traditional decarboxylation coupling is
replaced by the visibleꢀlightꢀirradiation in this paper. In addition, the HBV inhibitor is
synthesized by the oneꢀpot synthesis system in an atom economical manner.
INTRODUCTION:
Among the known heterocyclic compounds, 2ꢀquinolinones are a significant
class of privileged heterocycles with a variety of biological activities including
antibiotic, anticancer, antiviral and antihypersensitivity.1 In particular, the
4ꢀarylꢀ2ꢀquinolinone derivatives have attracted increasing interest in the synthesis of
natural products, medicinal compounds and the application in clinical trials (Scheme
1).2ꢀ3 Although various routes were so far reported about the synthesis of
2ꢀquinolinone
structural
motifs,
there
are
very
few
reports
on
transitionꢀmetalꢀcatalyzed approaches, which would be a more efficient and practical
strategy.4
In recent years, transitionꢀmetalꢀcatalyzed decarboxylation coupling have
gradually become an effective method to construct C–C bond because these reactions
avoided expensive organometallic reagents and toxic metal salt wastes.5 Particularly,
the carboxylic acids as the raw materials are easily available and inexpensive.
Furthermore, the decarboxylation coupling reactions caused by the catalyzed
carboxylic acids have high selectivity and tolerance of functional groups. Since Myers
et al. and Goossen et al.6 reported Pdꢀcatalyzed decarboxylation coupling, a series of
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relevant studies were carried out. Kim and coꢀworkers7 reported a Pdꢀcatalyzed
decarboxylation acylation of oꢀmethyl ketoximes, phenylꢀacetamides and oꢀphenyl
carbonates. Tan,8 Wang,9 Zhang10 and Lang11 respectively described the
decarboxylation acylation of oximes, azoxybenzenes, 2ꢀaryloxypyridines and
benzofurans/ benzothiophenes in the presence of palladium catalyst. Recently, our
research group reported the Pdꢀcatalyzed decarboxylation acylation of
Nꢀacetylꢀ1,2,3,4ꢀtetrahydroquinolines.12 In addition, visibleꢀlightꢀinduced catalytic
system has served as an increasingly significant role in the design and development of
a variety of radical reactions under observably mild reaction conditions.13 From the
above, the combination of transitionꢀmetal catalysis mode with visibleꢀlightꢀinduced
catalytic system was tried in this work.
On the other hand, the rapid construction of complicated compounds through
multiple bondꢀforming reactions in a single step, the soꢀcalled oneꢀpot process, is a
powerful tool.14 Such process can improve the reaction efficiency, reduce the cost of
energy and produce fewer wastes. Therefore, it would be attractive from the
viewpoint of environmentally friendly development and economical synthetic
methods. From the above, we designed an efficient and environmentꢀfriendly route
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for the oneꢀpot synthesis of 4ꢀarylꢀ2ꢀquinolinone derivatives through
visibleꢀlightꢀinduced decarboxylation coupling /intramolecular cyclization.
a
Scheme 1. Selected 4ꢀarylꢀ2ꢀquinolinones with Biological Activities
RESULT AND DISCUSSION
The
reaction
conditions
of
visibleꢀlightꢀinduced
decarboxylation
reaction of
coupling/intramolecular cyclization were investigated by
a
Nꢀacetylꢀ1,2,3,4ꢀtetrahydroquinoline 1a and αꢀoxophenylacetic acid 2a, the
experimental results were summarized in Table 1. An initial idea was tried toward
decarboxylation coupling approach. The substrate 1a (1.0 equiv.) was treated with 2a
(1.5 equiv.) in the presence of Pd(OAc)2 (10 mol %) in 1,2ꢀdichloroethane (2 mL) at
room temperature under the 25W Blue LED. To our delight, the above mentioned
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Table 1. Optimization of Reaction Conditiona
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Entry
Catalyst (mol %)
Lightb
Oxidant
Solvent
Temp(℃)
Base (equiv.)
Yieldc (%)
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1
Pd(OAc)2（10）
Pd(OAc)2（10）
Pd(OAc)2（10）
Pd(OAc)2（10）
Pd(OAc)2（10）
Pd(OAc)2（10）
Pd(OAc)2（10）
Pd(OAc)2（10）
Pd(OAc)2（10）
Pd(OAc)2（10）
Pd(OAc)2（10）
Pd(OAc)2（10）
Pd(OAc)2（10）
Pd(OAc)2（5）
Pd(PPh3)4（10）
Rh2(OAc)4（10）
IrCl3（10）
Y
Y
Y
Y
Y
Y
Y
N
N
N
N
N
N
Y
Y
Y
Y
Y
Y
N
Y
Y
̶
DCE
Dioxane
Diglyme
Toluene
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
80
80
80
80
60
40
20
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
DBU(5)
DBU(5)
DBU(5)
DBU(5)
DBU(5)
DBU(5)
DBU(5)
DBU(5)
DBU(5)
DBU(5)
DBU(5)
DBU(5)
DBU(5)
DBU(5)
DBU(5)
DBU(5)
DBU(5)
DBU(5)
DBU(5)
DBU(5)
K2CO3(5)
KOH(5)
88
20
27
32
70
53
37
̶
2
̶
3
̶
4
̶
5
̶
6
̶
7
̶
8
̶
9
(NH4)2S2O8
44
36
33
20
17
40
32
21
̶
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19
20
21
K2S2O8
mꢀCPBA
Ag2CO3
Cu(OAc)2
̶
̶
̶
̶
RuCl3（10）
̶
̶
Pd(TFA)2 (10)
̶
53
80
trace
trace
Pd(TFA)2 (10)
(NH4)2S2O8
Pd(OAc)2（10）
Pd(OAc)2（10）
̶
̶
22
a
1a (0.2 mmol), 2a (0.3 mmol), catalyst, 2 mL of solvent, 25W Blue LED, after 10 hours, the reaction
b
completed (monitored by TLC), then add base (5.0 equiv.), after 5 hours, the reaction completed. Y =
with the 25W Blue LED, N = in the dark. c Isolated yield by flash column chromatography.
combination resulted in 2aa with full transformation after 10 hours. Then DBU
(1,8ꢀdiazabicyclo[5.4.0]undecꢀ7ꢀene) (5.0 equiv.) was added and the reaction process
continued to proceed in 80 °C. After 5 hours, 3a with 88% yield was obtained (Table
1, entry 1). For comparison with reported procedures, some organic solvents were
tested, but the use of dioxane (20%), diglyme (27%) and toluene (32%) resulted in
lower yields (Table 1, entries 2-4). For the temperature, the yields decreased from 88%
to 37% when the temperature varied from 80 °C to 20 °C, respectively (Table 1,
entries 5-7). It was notable that there was no product detected in the dark (Table 1,
entry 8). The oxidant was screened in the dark. When (NH4)2S2O8 (44%), K2S2O8
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(36%), mꢀchloroperbenzoic acid (mꢀCPBA) (33%), Ag2CO3 (20%) and Cu(OAc)2
(17%) served as the oxidant, the yields varied from 44% to 17%, respectively (Table
1, entries 9-13). This showed that the oxidants also had favorable effect for the
reaction, but the 25W Blue LED had better effect for the reaction. When the amount
of Pd(OAc)2 decreased from 10 mol% to 5 mol%, the yield decreased to 40% (Table 1,
entry 14). About the catalysts, Pd(PPh3)4 (32%) and Rh2(OAc)4 (21%) could catalyze
the reaction with inferior yields (Table 1, entries 15-16). Other catalysts, such as
IrCl3 (0%) and RuCl3 (0%) in lieu of Pd(OAc)2 were found to give no target product
(Table 1, entries 17-18). It was notable that Pd(TFA)2 (53%) was found to support the
reaction with lower yield compared with Pd(OAc)2(Table 1, entry 19). The reason
was probably that Pd(TFA)2 was unstable under the 25W Blue LED. In addition, on
the basis of our previous work,[12] Pd(TFA)2 was tested with oxidant (NH4)2S2O8 in
the dark, the yield can achieve 80% (Table 1, entry 20). Although the previous work
also offered good yield, but the improved method in this work that oxidant was
replaced by 25W blue LED reduced the cost of reaction and provided better
environmental protection. For intramolecular cyclization, the inorganic base such as
K2CO3 and KOH gave trace of desired product (Table 1, entries 21-22). Compared
with the frequentlyꢀused inorganic bases in aldol condensation, the DBU avoided
metalꢀsalt wastes and was treated harmlessly. In addition, the probable generated ionic
liquid by the combination of DCE and DBU may accelerate the reaction by increasing
the solubility of substrates.15 The concrete work is going on in our group.
To explore the substrate scope of the protocol, the above optimized condition
was further applied to a variety of Nꢀacetylꢀ1,2,3,4ꢀtetrahydroquinolines 1aꢀ1l. As
shown in Table 2, the Nꢀacetylꢀ1,2,3,4ꢀtetrahydroquinoline 1a without substituent
group afforded the product 3a in 88% yield. Compound 3b with substituent ꢀBr at the
5ꢀposition of aromatic ring was obtained with 78% yield. However, compound 3c
with acetamido at the 5ꢀposition of aromatic ring was not obtained.
Nꢀacetylꢀ1,2,3,4ꢀtetrahydroquinolines 1dꢀ1i with electronꢀrich and electronꢀdeficient
substituents (ꢀCF3, ꢀOMe, ꢀF, ꢀCl, ꢀBr and ꢀMe) at the 6ꢀposition of aromatic ring
supported the reaction and afforded the desired products 3dꢀ3i in high yields
(75%ꢀ88%). The electronꢀdonating groups (ꢀOMe, 88%) (ꢀMe, 87%) were more
beneficial to the reaction compared with electronꢀwithdrawing groups (ꢀCF3, ꢀF, ꢀCl,
ꢀBr) (75%ꢀ80%). About Nꢀacetylꢀ1,2,3,4ꢀtetrahydroquinolines 1j and 1k with
substituent –NO2 and ꢀCF3 at the 7ꢀposition of aromatic ring, no corresponding
product 3j and 3k could be observed. For the substrates 1j and 1k, a receivable reason
was proposed that the strong electronꢀwithdrawing effect of –NO2 and ꢀCF3 and large
steric hindrance at the 7ꢀposition of aromatic ring restrained the process of reaction
seriously. In addition, Compound 3l with substituent ꢀMe at the 2ꢀposition of
tetrahydroquinoline ring was obtained with excellent yield (89%).
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Table 2. Scope of Nꢀacetylꢀ1,2,3,4ꢀtetrahydroquinolinesa,b
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a Conditions: 1a-l (0.2 mmol), 2a (0.3 mmol), Pd(OAc)2 (10 mol%), 2 mL of DCE, 25W Blue LED, after
the reaction completed (monitored by TLC), then add DBU (5.0 equiv.) until the reaction was completed.
b Isolated yield by flash column chromatography.
To further explore the substrate scope and limitations of this process, a
broad range of αꢀoxophenylacetic acids were also screened. As shown in Table
3
, αꢀoxophenylacetic acid with both electronꢀrich and electronꢀdeficient groups
gave the expected products in good yields (80%ꢀ92%), for example, ꢀMeꢀ 3m
ꢀNO2ꢀ 3n ꢀMeꢀ 3q ꢀMeOꢀ 3r and ꢀNO2ꢀ 3u groups. But the
electronꢀdonating groups 3m 3q, 3r (92%, 91%, 87%) provided superior yields
m
,
m
,
p
,
p
p
,
compared with electronꢀwithdrawing groups 3n and 3u (80%, 81%). This
transformation also proved good tolerance toward the halogen groups to give
yields 80%ꢀ86%, including
αꢀoxophenylacetic acid with substituent groups (ꢀMe, ꢀF and ꢀBr) in the
2ꢀposition of aromatic ring gave the desired product 3v 3w and 3x in decreased
mꢀFꢀ 3o, mꢀBrꢀ 3p, pꢀFꢀ 3s and pꢀClꢀ 3t. However,
,
yields (75%ꢀ79%) because of the stericꢀhindrance effect. It's worth noting that
there was no product 3y detected when a strong electronꢀwithdrawing group
ꢀNO2 was in the 2ꢀposition of the aromatic ring of αꢀoxophenylacetic acid. The
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Table 3. Scope of α ꢀ oxoarylacetic Acidsa,b
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a Conditions: 1a (0.2 mmol), 2b-t (0.3 mmol), Pd(OAc)2 (10 mol%), 2 mL of DCE, 25W Blue LED, after
the reaction completed (monitored by TLC), then add DBU (5.0 equiv.) until the reaction was completed.
b Isolated yield by flash column chromatography.
reason was probably that the electronꢀwithdrawing ability and stericꢀhindrance
effect of ꢀNO2 was stronger notably than ꢀF and –Br, so the product 3v was not
generated. Moreover, αꢀoxophenylacetic acid 2o and 2p with the naphthyl
moiety also participated in the process with good yields (89% and 88%). In
addition, heterocyclic oxoacetic acids 2ꢀthienylglyoxylic acid and
3ꢀindoleglyoxylic acid were tested and resulted in no products 3zb and 3zc. It
was
noteworthy
that
aliphatic
ketoꢀacids
pyruvic
acid
and
3,3ꢀdimethylꢀ2ꢀoxobutyric acid gave no products 3zd and 3ze
.
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Scheme 2. Application of the Protocol to the Synthesis of HBV Inhibitor
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To further demonstrate the synthetic utility of this protocol, we applied it
to the synthesis of the HBV inhibitor (in Scheme 2). 4ꢀchloroacetanilide and 2a
were selected to the optimized reaction conditions to obtain the HBV inhibitor
with 85% yield. Compared with the previous methods,16 this protocol has the
advantages of readily available starting materials, superior atom economy and
the reduction of wastes.
Although the reaction mechanism is unclear at this stage, a tentative
mechanism to rationalize this transformation is illustrated on the basis of
previous reports17 in Scheme 3. Firstly, the active palladium catalyst reacts
with 1a by chelationꢀdirected CꢀH activation to generate intermediate
Meanwhile, the benzoyl radical is obtained by a decarboxylation of 2a by
visible light irradiation. Subsequently, undergoes oxidative addition with
to give intermediate . Subsequently, the intermediate 2aa, which has been
isolated to obtain (Spectroscopic data is in the following page), is obtained by
the reductive elimination of and Pd(II) catalyst continue to participate the
A.
B
A
B
C
C
next catalytic cycle. Then the compound 2aa is converted to the target
compound 3a by the aldol condensation in the presence of DBU.
To gather further insight about the reaction mechanism, the reaction
between 1a and 2a was performed in the presence of 2,2,6,6ꢀtetramethylꢀ
piperidinꢀ1ꢀylꢀoxyl (TEMPO) as a radical scavenger (Scheme 4). Under this
condition, 2,2,6,6ꢀtetramethylꢀpiperidino benzoate
4 was isolated in 81% yield
(Spectroscopic data is in the following page) and the desired acylated product
2aa was not detected. This suggested the radical nature of the decarboxylation
coupling. In addition, 2,2,6,6ꢀtetramethylꢀpiperidino benzoate
4 was detected
with trace of yield and acylated product 2aa was not detected when the whole
reaction system was in the dark. This suggested that the benzoyl radical was
forming from the corresponding ketoꢀacid by light irradiation.
CONCLUSION
In conclusion, we reported a visibleꢀlightꢀinduced decarboxylation
coupling/intramolecular cyclization sequence, leading to a mild, efficient and
atom economical oneꢀpot access for the construction of 4ꢀarylꢀ2ꢀquinolinones.
Sequential chemical transformations without the isolation of each intermediate
serve as a practical procedure improve the reaction efficiency, produce less
waste, and require less energy. Besides, the reaction also tolerates various
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functional groups with excellent yields. In addition, the protocol could be used
for the synthesis of HBV inhibitor in excellent yield. Exploration of the
substrate scope and reaction mechanism will be further investigated in the
future.
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Scheme 3. Postulated Reaction Mechanism
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Scheme 4. Investigation on the Reaction Mechanism in the Presence of TEMPO
O
O
TEMPO, (2.0 equiv.)
N
OH
+
N
+
N
O
Ac
O
Pd(OAc)2 10mol%
25W blue LED
DCE, rt, 10h
O
Ac
1a
2a
4, 81%
2aa, not detected
O
TEMPO, (2.0 equiv.)
O
O
N
OH
+
N
+
N
Ac
O
Pd(OAc)2 10mol%
In The Dark
O
Ac
1a
2a
DCE, rt, 10h
4, trace
2aa, not detected
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EXPERIMENTAL SECTION
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General information: Unless otherwise noted, all commercial materials and
solvents were used without further purification. The compounds only with CAS
1
registry numbers were purchased. H NMR and 13C NMR spectra were recorded on a
1
9
Bruker DRX 400 MHz and 100 MHz spectrometer in CDCl3 or DMSO. Data for H
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NMR are reported as follows: chemical shift (δ ppm), multiplicity, integration, and
coupling constant (Hz). Data for 13C NMR are reported in terms of chemical shift (δ
ppm). The following abbreviations were used to describe peak splitting patterns when
appropriate: s = singlet, d = doublet, t = triplet, m = multiplet. Highꢀresolution mass
spectra (HRMS) were recorded on Agilent 1100 LC/MSD Trap VL mass
spectrometer. Elemental analyses (C, H, N) were performed on a Fisons EA110CHN.
Melting points were measured by Shang Guang WRR melting point apparatus.
Infrared spectroscopy (IR) was measured by SPꢀ100 Fourier transform infrared
spectroscopy. TLC was performed using commercially prepared 100ꢀ400 mesh silica
gel plates (GF254), and visualization was effected at 254 nm. All the other chemicals
were purchased from Energy Chemical. Commercial reagents were used without
further purification.
General Procedure for the Preparation of Starting Materials 1: To a
solution of 1,2,3,4ꢀtetrahydroquinolines (0.3 mmol, 1.0 equiv.) in DCM (10 mL) at
0 °C, acetyl chloride or acetic anhydride (0.6 mmol, 2 equiv.) was added dropwise.
After stirring for 1 h at room temperature, the solvent was evaporated under reduced
pressure. The residue was taken up with ethyl acetate (10 ml) and washed with 1 N
HCl (3 × 5 mL) and brine (2 × 5 mL). The organic layer was dried (Na2SO4) and
concentrated in vacuo to give 1.
NꢀAcetylꢀ1,2,3,4ꢀtetrahydroquinoline (1a): 47.31 mg of 1a (90%). 1H NMR (400
MHz, Chloroformꢀd): δ 7.16 (m, 4H, arom), 3.81 (t, J = 6.0 Hz, 2H), 2.73 (t, J = 6.0
Hz, 2H), 2.24 (s, 3H), 1.97 (q, J = 6.0 Hz, 2H). (Spectroscopic data in agreement with
literature[1] in Supporting Information)
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NꢀAcetylꢀ5ꢀbromoꢀ1,2,3,4ꢀtetrahydroquinoline (1b): 66.72 mg of 1b (87%). H
NMR (400 MHz, Chloroformꢀd) δ 7.51 (dd, J = 7.5, 2.1 Hz, 1H), 7.34 (dd, J = 7.6, 2.0
Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 4.47 (t, J = 5.1 Hz, 2H), 2.89 (t, J = 6.0 Hz, 2H),
2.15 – 2.05 (m, 2H), 2.04 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 170.5, 144.1,
128.9, 128.5, 127.8, 126.4, 117.6, 42.8, 26.6, 23.1, 22.4.
NꢀAcetylꢀ5ꢀacetamidoꢀ1,2,3,4ꢀtetrahydroquinoline (1c): 59.85 mg of 1c (86%).
1H NMR (400 MHz, Chloroformꢀd) δ 8.24 (s, 1H), 7.30 (d, J = 15.8 Hz, 1H), 7.20 –
6.88 (m, 2H), 3.71 (s, 2H), 2.59 (t, J = 6.5 Hz, 2H), 2.17 (d, J = 21.9 Hz, 6H), 1.92 –
1.85 (m, 2H). 13C NMR (100 MHz, Chloroformꢀd) δ 170.5, 169.0, 141.8, 138.4, 129.0,
120.3, 113.8, 112.7, 42.8, 25.4, 23.4, 23.1, 22.4.
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NꢀAcetylꢀ6ꢀtrifluoromethylꢀ1,2,3,4ꢀtetrahydroquinoline (1d): 62.75 mg of 1d
(86%). 1H NMR (400 MHz, Chloroformꢀd) δ 7.54 – 7.38 (m, 3H), 3.80 (t, J = 6.3 Hz,
2H), 2.80 (t, J = 6.4 Hz, 2H), 2.27 (s, 3H), 2.00 (p, J = 6.4 Hz, 2H). 13C NMR (100
MHz, Chloroformꢀd) δ 170.2, 125.73 (d , J = 4 Hz), 125.72 (d, J = 11 Hz), 125.5,
124.8, 123.27 (d, J = 11 Hz), 123.26 (d, J = 4 Hz), 122.8, 27.2, 23.8, 23.5.
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NꢀAcetylꢀ6ꢀmethoxyꢀ1,2,3,4ꢀtetrahydroquinoline (1e): 98% (purity), CAS
Registry Number : 1136ꢀ78ꢀ3.
NꢀAcetylꢀ6ꢀfluoroꢀ1,2,3,4ꢀtetrahydroquinoline (1f): 98% (purity), CAS Registry
Number : 1786347ꢀ77ꢀ0.
NꢀAcetylꢀ6ꢀchloroꢀ1,2,3,4ꢀtetrahydroquinoline (1g): 98% (purity), CAS Registry
Number : 1368960ꢀ10ꢀ4.
NꢀAcetylꢀ6ꢀbromoꢀ1,2,3,4ꢀtetrahydroquinoline (1h): 98% (purity), CAS Registry
Number : 22190ꢀ40ꢀ5.
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NꢀAcetylꢀ6ꢀmethylꢀ1,2,3,4ꢀtetrahydroquinoline (1i): 51.14 mg of 1i (90%). H
NMR (400 MHz, Chloroformꢀd) δ 7.02 – 6.94 (m, 3H), 3.77 (t, J = 6.2 Hz, 2H), 2.68
(t, J = 6.4 Hz, 2H), 2.31 (s, 3H), 2.21 (s, 3H), 1.94 (p, J = 6.7 Hz, 2H). 13C NMR (100
MHz, Chloroformꢀd) δ 170.1, 138.6, 129.9, 128.3, 126.9, 123.3, 118.0, 42.8, 27.0,
24.2, 21.0, 20.4.
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NꢀAcetylꢀ7ꢀnitroꢀ1,2,3,4ꢀtetrahydroquinoline (1j): 60.83 mg of 1j (92%). H
NMR (400 MHz, Chloroformꢀd) δ 8.43 (d, J = 2.0 Hz, 1H), 7.89 (dd, J = 7.5, 2.0 Hz,
1H), 7.23 (dt, J = 7.4, 1.0 Hz, 1H), 3.84 (t, J = 5.2 Hz, 2H), 2.84 (td, J = 6.0, 1.1 Hz,
2H), 2.09 (s, 3H), 2.03 – 2.01 (m, 2H). (Spectroscopic data in agreement with
literature[6] in Supporting Information)
NꢀAcetylꢀ7ꢀtrifluoromethylꢀ1,2,3,4ꢀtetrahydroquinoline (1k): 65.67 mg of 1k
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(90%). H NMR (400 MHz, Chloroformꢀd) δ 7.60ꢀ7.43 (m, 1H), 7.41ꢀ7.15 (m, 2H),
4.45 (t, J = 5.7 Hz, 2H), 2.84 (td, J = 5.6, 1.0 Hz, 2H), 2.10 (p, J = 5.7 Hz, 2H), 2.05
(s, 3H). (Spectroscopic data in agreement with literature[2] in Supporting Information)
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NꢀAcetylꢀ2ꢀmethylꢀ1,2,3,4ꢀtetrahydroquinoline (1l): 51.71 mg of 1l (91%). H
NMR (400 MHz, Chloroformꢀd) δ 7.24 – 7.04 (m, 4H), 4.83 (s, 1H), 2.61 (dt, J = 14.7,
4.7 Hz, 1H), 2.51 (td, J = 13.5, 11.6, 4.6 Hz, 1H), 2.35 (td, J = 12.7, 4.9 Hz, 1H), 2.14
(s, 3H), 1.34 (s, 1H), 1.12 (d, J = 6.5 Hz, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ
170.3, 129.5, 129.3, 127.5, 126.4, 126.1, 125.8, 48.6, 32.9, 32.7, 23.3, 20.5.
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General Procedure for the Preparation of Starting Materials 2: In a dry,
singleꢀneck, 25ꢀmL, roundꢀbottom flask equipped with a stir bar and flushed with
nitrogen, acetophenones (1 mmol, 1 equiv.) and selenium dioxide (SeO2, 1.5 mmol,
1.5 equiv.) were added followed by anhydrous pyridine (10 mL). The reaction
mixture was heated in an oil bath to 110 °C for 1 h, and then the bath temperature was
reduced to 90°C. The mixture was stirred at this temperature (90 °C) for an additional
4 h, and progress of the reaction was monitored by TLC. After completion of the
reaction, as determined by TLC, the solution containing precipitated selenium was
filtered using a Buckner funnel, and the residue was washed with ethyl acetate (50
mL). The combined filtrate was treated with 1N HCl (20 mL), the organic layer was
separated, and the aqueous layer was extracted with ethyl acetate (3 × 50 mL). The
organic layers were combined and treated with 1N NaOH (50 mL), and the aqueous
layer was separated. The organic layer was extracted with water (25 mL) and the
combined aqueous layers were acidified using 1N HCl to about pH 1.5. The mixture
was extracted with ethyl acetate (3 × 50 mL), and the combined organic layers were
dried (anhydrous Na2SO4) and concentrated on a rotary evaporator (Bath temperature:
40–45°C). The benzoylformic acid products 2 were obtained by silicaꢀgel column
chromatography using ethyl acetate=hexane (ratio: 9:1) as solvent system for elution.
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Benzoylformic acid (2a): 79.57 mg of 2a (53%). 1H NMR (400 MHz,
Chloroformꢀd) δ 7.55 (2H, t, J = 7.6 Hz), 7.72 (1H, t, J = 7.6 Hz), 8.33 (2H, d, J = 7.6
Hz), 9.50 (1H, brs). (Spectroscopic data in agreement with literature[3] in Supporting
Information)
3ꢀMethylbenzoylformic acid (2b): 88.65 mg of 2b (54%).1H NMR (400 MHz,
Chloroformꢀd) δ 7.42 (1H, dt, J = 8.0 Hz, J = 2.4 Hz), 7.54 (1H, dt, J = 8.0 Hz, J =
5.2 Hz), 8.01 (1H, dt, J = 9.2 Hz, J = 2.4 Hz), 8.15 (1H, dd, J = 8.0 Hz, J = 2.4 Hz),
9.76 (1H, brs). (Spectroscopic data in agreement with literature[3] in Supporting
Information)
3ꢀNitrobenzoylformic acid (2c): 97% (purity), CAS Registry Number :
6330ꢀ40ꢀ1.
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3ꢀFluorobenzoylformic acid (2d): 87.42 mg of 2d (52%). H NMR (400 MHz,
Chloroformꢀd) δ 7.42 (1H, dt, J = 8.0 Hz, J = 2.4 Hz), 7.54 (1H, dt, J = 8.0 Hz, J =
5.2 Hz), 8.01 (1H, dt, J = 9.2 Hz, J = 2.4 Hz), 8.15 (1H, dd, J = 8.0 Hz, J = 2.4 Hz),
9.76 (1H, brs). (Spectroscopic data in agreement with literature[3] in Supporting
Information)
3ꢀBromobenzoylformic acid (2e): 97% (purity), CAS Registry Number :
7194ꢀ78ꢀ7.
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4ꢀMethylbenzoylformic acid (2f): 91.93 mg of 2f (56%). 1H NMR (400 MHz,
Chloroformꢀd) δ 8.98 (brs, 1H), 8.23 (d, J = 7.6 Hz, 2H), 7.33 (d, J = 7.6 Hz, 2H),
2.46 (s, 3H). (Spectroscopic data in agreement with literature[4] in Supporting
Information)
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4ꢀMethoxylbenzoylformic acid (2g): 102.69 mg of 2g (57%). 1H NMR (400 MHz,
Chloroformꢀd) δ 9.93 (brs, 1H), 8.33 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H),
3.90 (s, 3H). (Spectroscopic data in agreement with literature[4] in Supporting
Information)
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4ꢀFluorobenzoylformic acid (2h): 89.10 mg of 2h (53%). H NMR (400 MHz,
Chloroformꢀd) δ 9.66 (brs, 1H), 8.40–8.37 (m, 2H), 7.23–7.19 (m, 2H).
(Spectroscopic data in agreement with literature[4] in Supporting Information)
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4ꢀChlorobenzoylformic acid (2i): 99.67 mg of 2i (54%). H NMR (400 MHz,
Chloroformꢀd) δ 9.85 (brs, 1H), 8.27 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H).
(Spectroscopic data in agreement with literature[4] in Supporting Information)
4ꢀNitrobenzoylformic acid (2j): 113.18 mg of 2j (58%). 1H NMR (400 MHz,
Chloroformꢀd) δ 8.55 (d, 2H, J = 9.1 Hz), 8.40 (d, 2H, J = 9.1 Hz), 5.36 (brs, 1H).
(Spectroscopic data in agreement with literature[5] in Supporting Information)
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2ꢀMethylbenzoylformic acid (2k): 87.00 mg of 2k (53%). H NMR (400 MHz,
Chloroformꢀd) δ 11.02 (brs, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H),
7.33–7.29 (m, 2H), 2.59 (s, 3H). (Spectroscopic data in agreement with literature[5] in
Supporting Information)
2ꢀFluorobenzoylformic acid (2l): 97% (purity), CAS Registry Number :
79477ꢀ86ꢀ4.
2ꢀBromobenzoylformic acid (2m): 97% (purity), CAS Registry Number :
26767ꢀ16ꢀ8.
2ꢀNitrobenzoylformic acid (2n): 97% (purity), CAS Registry Number : 610ꢀ33ꢀ3.
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1ꢀNaphthylglyoxylic acid (2o): 122.12 mg of 2o (61%). H NMR (400 MHz,
Chloroformꢀd) δ 10.03 (brs, 1H), 8.92 (d, J = 8.4 Hz, 1H), 8.37 (d, J = 7.2 Hz, 1H),
8.14 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.72ꢀ7.55 (m, 3H). (Spectroscopic
data in agreement with literature[4] in Supporting Information)
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2ꢀNaphthylglyoxylic acid (2p): 126.12 mg of 2p (63%). 1H NMR (400 MHz,
Chloroformꢀd) δ 9.97 (brs, 1H), 9.02 (s, 1H), 8.16 (dd, J = 8.8, 1.6 Hz, 1H), 8.00 (d, J
= 8.0 Hz, 1H), 7.92–7.86 (m, 2H), 7.69–7.56 (m, 2H). (Spectroscopic data in
agreement with literature[4] in Supporting Information)
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2ꢀThiopheneglyoxylic acid (2q): 97% (purity), CAS Registry Number :
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3ꢀIndoleglyoxylic acid (2r): 97% (purity), CAS Registry Number : 1477ꢀ49ꢀ2.
Pyruvic acid (2s): 97% (purity), CAS Registry Number : 127ꢀ17ꢀ3.
3,3ꢀDimethylꢀ2ꢀoxobutyric acid (2t): 97% (purity), CAS Registry Number :
815ꢀ17ꢀ8.
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1ꢀ(8ꢀBenzoylꢀ3,4ꢀdihydroquinolinꢀ1(2H)ꢀyl)ethanꢀ1ꢀone (2aa): H NMR (400
MHz, DMSOꢀd6) δ 7.62–7.56 (m, 3H), 7.47 (dd, J = 8.8, 6.8 Hz, 3H), 7.43–7.37 (m,
1H),7.22 (d, J = 1.4 Hz, 1H), 3.54 (t, J = 6.4 Hz, 2H), 2.78 (t, J = 6.6 Hz, 2H), 1.96 (t,
J = 6.5 Hz, 2H), 1.69 (s, 3H). (Spectroscopic data in agreement with literature[2] in
Supporting Information)
General Procedure for the Preparation of Starting Materials 3: Add
Nꢀacetylꢀ1,2,3,4ꢀtetrahydroquinolines (0.2 mmol, 1.0 equiv.), benzoylformic acid (0.3
mmol, 1.5 equiv.), Pd(OAc)2 (0.02 mmol, 10 mol%) and DCE (2 mL) to the vial, the
resulting mixture was stirred under 25W blue LED at room temperature for 10 h.
After the reaction completed (monitored by TLC), then added DBU (1 mmol, 5 equiv.)
to the vial at 80 °C for another 5 h. After the reaction completed (monitored by TLC),
added 10 mL water to the mixture, then extracted with DCM 3 times (3 × 20 mL).
The extract was dried over anhydrous Na2SO4. Removal of the solvent under reduced
pressure gave a crude product. The crude product was purified by column
chromatography on silica gel (petroleum ether/EtOAc = 10:1) to yield the desired
product 3.
1ꢀPhenylꢀ6,7ꢀdihydropyrido[3,2,1ꢀij]quinolinꢀ3(5H)ꢀone (3a): (45.98 mg, 0.176 mmol, 88%).
Light yellow solid (88%). Mp. 116 – 118 °C. H NMR (400 MHz, Chloroformꢀd) δ
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7.40 (ddd, J = 33.7, 24.9, 6.4 Hz, 7H), 7.06 (s, 1H), 6.66 (s, 1H), 4.26 (s, 2H), 3.03 (s,
2H), 2.16 (s, 2H). 13C NMR (100 MHz, Chloroformꢀd) δ 161.7, 151.1, 137.6, 137.1,
130.2, 129.0, 128.7, 128.6, 125.8, 125.2, 121.6, 121.0, 120.5, 42.6, 28.2, 20.8. HRMS
(EI) calcd for C18H15NO (M+): 261.1154. Found: 261.1143. Elemental analysis.calcd
for C18H15NO: C, 82.73; H, 5.79; N, 5.36. Found: C, 82.76; H, 5.81; N, 5.34. IR (KBr
disc): v= 1642, 1583 cmꢀ1.
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8ꢀBromoꢀ1ꢀphenylꢀ6,7ꢀdihydropyrido[3,2,1ꢀij]quinolinꢀ3(5H)ꢀone(3b): (53.07 mg, 0.156 mmol,
78%). Yellow solid (78%). Mp. 108 – 110 °C. H NMR (400 MHz, Chloroformꢀd) δ
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7.48 (d, J = 6.6 Hz, 2H), 7.44 – 7.36 (m, 3H), 7.32 (d, J = 7.1 Hz, 1H), 7.05 (t, J = 7.7
Hz, 1H), 6.66 (s, 1H), 4.35 – 4.17 (m, 2H), 3.03 (t, J = 6.1 Hz, 2H), 2.16 (p, J = 6.1
Hz, 2H). 13C NMR (100 MHz, Chloroformꢀd) δ 161.7, 151.0, 137.6, 137.1, 130.2,
129.0, 128.7, 128.6, 125.8, 125.2, 121.6, 121.0, 120.5, 42.6, 28.1, 20.8. HRMS (EI)
calcd for C18H14BrNO (M+): 339.0259. Found: 339.0250. Elemental analysis.calcd
for C18H14BrNO: C, 63.55; H, 4.15; N, 4.12. Found: C, 63.54; H, 4.15; N, 4.12. IR
(KBr disc): v= 1643, 1583 cmꢀ1.
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1ꢀPhenylꢀ9ꢀ(trifluoromethyl)ꢀ6,7ꢀdihydropyrido[3,2,1ꢀij]quinolinꢀ3(5H)ꢀone (3d): (41.90 mg,
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0.150 mmol, 75%). White solid (75%). Mp. 101 – 103 °C. H NMR (400 MHz,
Chloroformꢀd) δ 7.65 (s, 1H), 7.57 – 7.49 (m, 4H), 7.40 (dd, J = 7.1, 2.4 Hz, 2H), 6.73
(s, 1H), 4.31 – 4.23 (m, 2H), 3.08 (t, J = 6.2 Hz, 2H), 2.19 (p, J = 6.1 Hz, 2H). 13C
NMR (100 MHz, Chloroformꢀd) δ 161.6, 150.9, 139.3, 136.6, 134.4, 129.2, 129.0,
128.9, 126.3, 126.1, 123.1, 122.3, 120.1, 100.1, 42.7, 28.2, 20.5. HRMS (EI) calcd for
C19H14F3NO (M+): 329.1027. Found: 329.1018. Elemental analysis.calcd for
C19H14F3NO: C, 69.30; H, 4.28; N, 4.25. Found: C, 69.27; H, 4.27; N, 4.29. IR (KBr
disc): v= 1652, 1590 cmꢀ1.
9ꢀMethoxyꢀ1ꢀphenylꢀ6,7ꢀdihydropyrido[3,2,1ꢀij]quinolinꢀ3(5H)ꢀone(3e): (49.17 mg, 0.176
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mmol, 88%). Light yellow solid (88%). Mp. 153 – 155 °C. H NMR (400 MHz,
DMSOꢀd6) δ 7.54 (q, J = 6.2 Hz, 3H), 7.47 (d, J = 7.1 Hz, 2H), 7.17 – 7.09 (m, 1H),
6.71 (d, J = 2.1 Hz, 1H), 6.48 (s, 1H), 4.12 – 4.04 (m, 2H), 3.65 (s, 3H), 2.98 (t, J =
5.8 Hz, 2H), 2.02 (q, J = 11.7, 8.4 Hz, 2H). 13C NMR (100 MHz, DMSOꢀd6) δ 159.5,
153.3, 149.5, 136.9, 131.2, 128.7, 128.7, 128.6, 127.1, 120.8, 120.0, 118.0, 107.4,
55.2, 41.7, 27.3, 20.2. HRMS (EI) calcd for C19H17NO2 (M+): 291.1259. Found:
291.1251. Elemental analysis.calcd for C19H17NO2: C, 78.33; H, 5.88; N, 4.81. Found:
C, 78.32; H, 5.87; N, 4.83. IR (KBr disc): v= 1646, 1585 cmꢀ1.
9ꢀFluoroꢀ1ꢀphenylꢀ6,7ꢀdihydropyrido[3,2,1ꢀij]quinolinꢀ3(5H)ꢀone(3f): (43.02 mg, 0.154 mmol,
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77%). White solid (77%). Mp. 108 – 110 °C. H NMR (400 MHz, Chloroformꢀd) δ
7.48 (d, J = 6.9 Hz, 2H), 7.44 – 7.36 (m, 3H), 7.32 (d, J = 7.2 Hz, 1H), 7.05 (t, J = 7.7
Hz, 1H), 6.66 (s, 1H), 4.30 – 4.22 (m, 2H), 3.03 (t, J = 6.2 Hz, 2H), 2.16 (p, J = 6.1
Hz, 2H). 13C NMR (100 MHz, Chloroformꢀd) δ 161.7, 151.1, 137.6, 137.1, 130.1,
129.0, 128.7, 128.6, 125.8, 125.2, 121.6, 121.0, 120.5, 42.6, 28.2, 20.8. HRMS (EI)
calcd for C18H14FNO (M+): 279.1059. Found: 279.1048. Elemental analysis.calcd for
C18H14FNO: C, 77.40; H, 5.05; N, 5.01. Found: C, 77.42; H, 5.02; N, 4.99. IR (KBr
disc): v= 1642, 1583 cmꢀ1.
9ꢀChloroꢀ1ꢀphenylꢀ6,7ꢀdihydropyrido[3,2,1ꢀij]quinolinꢀ3(5H)ꢀone(3g): (43.58 mg, 0.156 mmol,
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78%). Yellow solid (78%). Mp. 110 – 112 °C. H NMR (400 MHz, Chloroformꢀd) δ
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7.48 (d, J = 6.9 Hz, 2H), 7.43 – 7.35 (m, 3H), 7.32 (d, J = 7.2 Hz, 1H), 7.05 (t, J = 7.7
Hz, 1H), 6.66 (s, 1H), 4.31 – 4.22 (m, 2H), 3.03 (t, J = 6.2 Hz, 2H), 2.15 (p, J = 6.1
Hz, 2H). 13C NMR (100 MHz, Chloroformꢀd) δ 161.6, 151.0, 137.6, 137.1, 130.1,
129.0, 128.7, 128.6, 125.8, 125.2, 121.6, 121.0, 120.5, 42.6, 28.1, 20.8. HRMS (EI)
calcd for C18H14ClNO (M+): 295.0764. Found: 295.0769. Elemental analysis.calcd
for C18H14ClNO: C, 73.10; H, 4.77; N, 4.74. Found: C, 73.12; H, 4.78; N,4.70. IR
(KBr disc): v= 1642, 1583 cmꢀ1.
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9ꢀBromoꢀ1ꢀphenylꢀ6,7ꢀdihydropyrido[3,2,1ꢀij]quinolinꢀ3(5H)ꢀone(3h): (44.70 mg, 0.160 mmol,
80%). Light yellow solid (80%). Mp. 115 – 117 °C. 1H NMR (400 MHz,
Chloroformꢀd) δ 7.48 (d, J = 6.5 Hz, 2H), 7.44 – 7.36 (m, 3H), 7.32 (d, J = 7.2 Hz,
1H), 7.05 (t, J = 7.7 Hz, 1H), 6.66 (s, 1H), 4.35 – 4.19 (m, 2H), 3.03 (t, J = 6.0 Hz,
2H), 2.16 (p, J = 6.1 Hz, 2H). 13C NMR (100 MHz, Chloroformꢀd) δ 161.6, 151.0,
137.6, 137.1, 130.1, 129.0, 128.7, 128.6, 125.8, 125.2, 121.6, 121.0, 120.5, 42.6, 28.2,
20.8. HRMS (EI) calcd for C18H14BrNO (M+): 339.0259. Found: 339.0257.
Elemental analysis.calcd for C18H14BrNO: C, 63.55; H, 4.15; N, 4.12. Found: C,
63.54; H, 4.16; N, 4.12. IR (KBr disc): v= 1642, 1583 cmꢀ1.
9ꢀMethylꢀ1ꢀphenylꢀ6,7ꢀdihydropyrido[3,2,1ꢀij]quinolinꢀ3(5H)ꢀone(3i):(48.10mg,0.174mmol,87%).
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Light yellow solid (87%). Mp. 145 – 147 °C. H NMR (400 MHz, Chloroformꢀd) δ
7.53 – 7.45 (m, 3H), 7.40 (dd, J = 7.4, 2.0 Hz, 2H), 7.18 – 7.12 (m, 2H), 6.63 (s, 1H),
4.28 – 4.20 (m, 2H), 2.99 (t, J = 6.2 Hz, 2H), 2.28 (s, 3H), 2.14 (p, J = 6.1 Hz, 2H).
13C NMR (100 MHz, Chloroformꢀd) δ 161.5, 150.8, 137.8, 135.1, 131.5, 131.1, 129.0,
128.6, 128.6, 125.3, 125.1, 121.1, 120.4, 50.3, 42.5, 28.1, 20.9. HRMS (EI) calcd for
C19H17NO (M+): 275.1310. Found: 275.1313. Elemental analysis.calcd for C19H17NO:
C, 82.88; H, 6.22; N, 5.09. Found: C, 82.89; H, 6.21; N, 5.09. IR (KBr disc): v= 1643,
1582 cmꢀ1.
3ꢀMethylꢀ7ꢀphenylꢀ2,3ꢀdihydroꢀ1H,5Hꢀpyrido[3,2,1ꢀij]quinolinꢀ5ꢀone (3l): (49.21 mg, 0.178 mmol,
89%).Light yellow solid (89%). Mp. 116 – 118 °C. 1H NMR (400 MHz, Chloroformꢀd)
δ 7.48 (q, J = 5.2 Hz, 3H), 7.43 – 7.32 (m, 4H), 7.06 (t, J = 7.7 Hz, 1H), 6.65 (s, 1H),
5.42 – 5.31 (m, 1H), 3.30 – 3.17 (m, 1H), 2.92 (d, J = 18.2 Hz, 1H), 2.15 – 2.02 (m,
2H), 1.38 (d, J = 6.6 Hz, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 161.1, 151.0,
137.7, 136.3, 130.5, 129.0, 128.6, 128.6, 125.9, 124.4, 121.4, 121.4, 120.8, 46.0, 25.9,
23.1, 18.2. HRMS (EI) calcd for C19H17NO (M+): 275.1310. Found: 275.1312.
Elemental analysis.calcd for C19H17NO: C, 82.88; H, 6.22; N, 5.09. Found: C, 82.88;
H, 6.21; N, 5.10. IR (KBr disc): v= 1644, 1582 cmꢀ1.
1ꢀ(mꢀtolyl)ꢀ6,7ꢀdihydropyrido[3,2,1ꢀij]quinolinꢀ3(5H)ꢀone (3m): (51.40 mg, 0.184 mmol,
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92%). White solid (92%). Mp. 126 – 128 °C. H NMR (400 MHz, Chloroformꢀd) δ
7.44 – 7.27 (m, 4H), 7.21 (d, J = 8.6 Hz, 2H), 7.06 (t, J = 7.7 Hz, 1H), 6.65 (s, 1H),
4.32 – 4.21 (m, 2H), 3.03 (t, J = 6.1 Hz, 2H), 2.43 (s, 3H), 2.16 (p, J = 6.0 Hz, 2H).
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13C NMR (100 MHz, Chloroformꢀd) δ 161.7, 151.3, 138.4, 137.5, 137.1, 130.1, 129.7,
129.4, 128.5, 126.1, 125.9, 125.2, 121.6, 120.9, 120.6, 42.6, 28.2, 21.6, 20.8. HRMS
(EI) calcd for C19H17NO (M+): 275.1310. Found: 275.1301. Elemental analysis.calcd
for C19H17NO: C, 82.88; H, 6.22; N, 5.09. Found: C, 82.86; H, 6.23; N, 5.10. IR (KBr
disc): v= 1644, 1582 cmꢀ1.
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1ꢀ(3ꢀnitrophenyl)ꢀ6,7ꢀdihydropyrido[3,2,1ꢀij]quinolinꢀ3(5H)ꢀone (3n): (44.70 mg, 0.160 mmol,
80%). Yellow solid (80%). Mp. 121 – 123 °C. H NMR (400 MHz, Chloroformꢀd) δ
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8.40 – 8.27 (m, 2H), 7.79 – 7.65 (m, 2H), 7.37 (d, J = 7.1 Hz, 1H), 7.22 (d, J = 7.7 Hz,
1H), 7.09 (t, J = 7.7 Hz, 1H), 6.68 (s, 1H), 4.34 – 4.21 (m, 2H), 3.05 (t, J = 6.1 Hz,
2H), 2.18 (p, J = 6.0 Hz, 2H). 13C NMR (100 MHz, Chloroformꢀd) δ 161.2, 148.4,
139.2, 137.2, 135.0, 130.7, 129.9, 125.7, 125.0, 124.1, 123.7, 122.1, 121.7, 119.7,
42.7, 28.1, 20.7. HRMS (EI) calcd for C18H14N2O3 (M+): 306.1004. Found: 306.1021.
Elemental analysis.calcd for C18H14N2O3: C, 70.58; H, 4.61; N, 9.15; Found: C, 70.59;
H, 4.62; N, 9.13; IR (KBr disc): v= 1648, 1587 cmꢀ1.
1ꢀ(3ꢀfluorophenyl)ꢀ6,7ꢀdihydropyrido[3,2,1ꢀij]quinolinꢀ3(5H)ꢀone(3o): (47.49 mg, 0.170 mmol,
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85%). Yellow solid (85%). Mp.101 – 103 °C. H NMR (400 MHz, Chloroformꢀd) δ
7.46 (td, J = 7.9, 5.9 Hz, 1H), 7.34 (d, J = 7.9 Hz, 2H), 7.22 – 7.11 (m, 3H), 7.07 (t, J
= 7.7 Hz, 1H), 6.65 (s, 1H), 4.31 – 4.21 (m, 2H), 3.04 (t, J = 6.2 Hz, 2H), 2.16 (p, J =
6.1 Hz, 2H). 13C NMR (100 MHz, Chloroformꢀd) δ 164.0, 155.6 (d, J = 1183 Hz),
139.7 (d, J = 7 Hz), 137.2, 130.375 (d, J = 8 Hz), 130.368, 125.5, 125.4, 124.8(d, J =
3 Hz), 121.8, 121.2, 120.1, 116.2 (d, J = 22 Hz), 115.8, 115.6, 42.6, 28.1, 20.8.
HRMS (EI) calcd for C18H14FNO (M+): 279.1059. Found: 279.1032. Elemental
analysis.calcd for C18H14FNO: C, 77.40; H, 5.05; N, 5.01. Found: C, 77.41; H, 5.04;
N, 5.01. IR (KBr disc): v= 1644, 1583 cmꢀ1.
1ꢀ(3ꢀbromophenyl)ꢀ6,7ꢀdihydropyrido[3,2,1ꢀij]quinolinꢀ3(5H)ꢀone(3p): (48.05 mg, 0.172 mmol,
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86%). White solid (86%). Mp. 169 – 171 °C. H NMR (400 MHz, Chloroformꢀd) δ
7.61 (dt, J = 7.2, 2.0 Hz, 1H), 7.59 – 7.53 (m, 1H), 7.35 (p, J = 9.1, 8.4 Hz, 4H), 7.12
– 7.05 (m, 1H), 6.64 (s, 1H), 4.30 – 4.22 (m, 2H), 3.04 (t, J = 6.2 Hz, 2H), 2.16 (p, J =
6.1 Hz, 2H). 13C NMR (100 MHz, Chloroformꢀd) δ 161.4, 149.4, 139.6, 137.1, 131.9,
131.8, 130.4, 130.3, 127.7, 125.5, 125.4, 122.7, 121.8, 121.3, 120.1, 42.6, 28.1, 20.8.
HRMS (EI) calcd for C18H14BrNO (M+): 339.0259. Found: 339.0245. Elemental
analysis.calcd for C18H14BrNO: C, 63.55; H, 4.15; N, 4.12. Found: C, 63.57; H, 4.13;
N, 4.12. IR (KBr disc): v= 1643, 1582 cmꢀ1.
1ꢀ(pꢀtolyl)ꢀ6,7ꢀdihydropyrido[3,2,1ꢀij]quinolinꢀ3(5H)ꢀone(3q): (50.84 mg, 0.182 mmol, 91%).
Gray solid (91%). Mp. 103 – 104 °C. 1H NMR (400 MHz, Chloroformꢀd) δ 7.41 (d, J
= 7.2 Hz, 1H), 7.34 – 7.27 (m, 5H), 7.08 – 7.02 (m, 1H), 6.65 (s, 1H), 4.29 – 4.21 (m,
2H), 3.03 (t, J = 6.2 Hz, 2H), 2.44 (s, 3H), 2.16 (q, J = 6.1, 5.7 Hz, 2H). 13C NMR
(100 MHz, Chloroformꢀd) δ 161.7, 151.1, 138.6, 137.1, 134.7, 130.1, 129.3, 129.0,
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125.8, 125.2, 121.5, 120.9, 120.6, 42.6, 28.2, 21.4, 20.8. HRMS (EI) calcd for
C19H17NO (M+): 275.1310. Found: 275.1317. Elemental analysis.calcd for C19H17NO:
C, 82.88; H, 6.22; N, 5.09. Found: C, 82.89; H, 6.25; N, 5.05. IR (KBr disc): v= 1650,
1584cmꢀ1.
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1ꢀ(4ꢀmethoxyphenyl)ꢀ6,7ꢀdihydropyrido[3,2,1ꢀij]quinolinꢀ3(5H)ꢀone (3r):(48.61 mg, 0.174
mmol, 87%). Light yellow solid (87%). Mp. 103 – 105 °C. H NMR (400 MHz,
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Chloroformꢀd) δ 7.44 (d, J = 8.0 Hz, 1H), 7.39 – 7.34 (m, 2H), 7.31 (d, J = 6.7 Hz,
1H), 7.08 – 7.00 (m, 3H), 6.64 (s, 1H), 4.28 – 4.22 (m, 2H), 3.88 (s, 3H), 3.03 (t, J =
6.1 Hz, 2H), 2.15 (p, J = 6.1 Hz, 2H). 13C NMR (100 MHz, Chloroformꢀd) δ 161.8,
160.0, 150.8, 137.1, 130.3, 130.1, 129.9, 125.8, 125.2, 121.5, 120.8, 120.7, 114.1,
55.5, 42.6, 28.2, 20.8. HRMS (EI) calcd for C19H17NO2 (M+): 291.1259. Found:
291.1237. Elemental analysis.calcd for C19H17NO2: C, 78.33; H, 5.88; N, 4.81. Found:
C, 78.35; H, 5.84; N, 4.83. IR (KBr disc): v= 1644, 1586 cmꢀ1.
1ꢀ(4ꢀfluorophenyl)ꢀ6,7ꢀdihydropyrido[3,2,1ꢀij]quinolinꢀ3(5H)ꢀone(3s): (44.70 mg, 0.160 mmol,
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80%). White solid (80%). Mp. 118 – 120 °C. H NMR (400 MHz, Chloroformꢀd) δ
7.42 – 7.37 (m, 2H), 7.34 (d, J = 7.8 Hz, 2H), 7.22 – 7.15 (m, 2H), 7.07 (t, J = 7.7 Hz,
1H), 6.64 (s, 1H), 4.29 – 4.22 (m, 2H), 3.04 (t, J = 6.2 Hz, 2H), 2.16 (p, J = 6.1 Hz,
2H). 13C NMR (100 MHz, Chloroformꢀd) δ 161.5, 150.0, 137.1, 133.5, 132.2 (d, J =
259 Hz), 130.8, 130.8, 130.3, 125.5, 125.3, 121.7, 121.2, 120.4, 115.9, 115.6, 42.6,
28.1, 20.8. HRMS (EI) calcd for C18H14FNO (M+): 279.1059. Found: 279.1051.
Elemental analysis.calcd for C18H14FNO: C, 77.40; H, 5.05; N, 5.01. Found: C, 77.42;
H, 5.03; N, 5.02. IR (KBr disc): v= 1642, 1582 cmꢀ1.
1ꢀ(4ꢀchlorophenyl)ꢀ6,7ꢀdihydropyrido[3,2,1ꢀij]quinolinꢀ3(5H)ꢀone(3t): (46.37 mg, 0.166 mmol,
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83%). Gray solid (83%). Mp. 145 – 147 °C. H NMR (400 MHz, Chloroformꢀd) δ
7.50 – 7.43 (m, 2H), 7.39 – 7.29 (m, 4H), 7.10 – 7.03 (m, 1H), 6.63 (s, 1H), 4.28 –
4.21 (m, 2H), 3.03 (t, J = 6.2 Hz, 2H), 2.16 (p, J = 6.4 Hz, 2H). 13C NMR (100 MHz,
Chloroformꢀd) δ 161.5, 149.8, 136.0, 134.9, 134.9, 130.4, 130.4, 129.0, 125.5, 125.4,
121.7, 121.2, 120.2, 42.6, 28.1, 20.8. HRMS (EI) calcd for C18H14ClNO (M+):
295.0764. Found: 295.0742. Elemental analysis.calcd for C18H14ClNO: C, 73.10; H,
4.77; N, 4.74. Found: C, 73.12; H, 4.79; N, 4.70. IR (KBr disc): v= 1649, 1583 cmꢀ1.
1ꢀ(4ꢀnitrophenyl)ꢀ6,7ꢀdihydropyrido[3,2,1ꢀij]quinolinꢀ3(5H)ꢀone (3u): (44.70 mg, 0.160 mmol,
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80%). Yellow solid (80%). Mp. 173 – 175 °C. H NMR (400 MHz, Chloroformꢀd) δ
8.37 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 7.1 Hz, 1H), 7.21 (d, J
= 7.8 Hz, 1H), 7.09 (t, J = 7.7 Hz, 1H), 6.67 (s, 1H), 4.31 – 4.22 (m, 2H), 3.05 (t, J =
6.2 Hz, 2H), 2.17 (p, J = 6.1 Hz, 2H). 13C NMR (100 MHz, Chloroformꢀd) δ 161.1,
148.7, 148.2, 144.1, 137.2, 130.7, 130.1, 125.6, 125.1, 124.0, 122.0, 121.5, 119.5,
42.7, 28.1, 20.7. HRMS (EI) calcd for C18H14N2O3 (M+): 306.1004. Found: 306.1029.
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Elemental analysis. calcd for C18H14N2O3: C, 70.58; H, 4.61; N, 9.15. Found: C, 70.59;
H, 4.63; N, 9.12. IR (KBr disc): v= 1652, 1587 cmꢀ1.
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1ꢀ(oꢀtolyl)ꢀ6,7ꢀdihydropyrido[3,2,1ꢀij]quinolinꢀ3(5H)ꢀone(3v): (43.58 mg, 0.156 mmol, 78%).
Yellow solid (78%). Mp. 65 – 67 °C. H NMR (400 MHz, DMSOꢀd6) δ 7.40 (d, J =
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7.2 Hz, 3H), 7.33 (t, J = 7.2 Hz, 1H), 7.19 (d, J = 7.4 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H),
6.83 (d, J = 7.9 Hz, 1H), 6.42 (s, 1H), 4.12 (t, J = 7.1 Hz, 2H), 2.99 (t, J = 5.9 Hz, 2H),
2.05 (s, 5H). 13C NMR (100 MHz, DMSOꢀd6) δ 160.1, 150.0, 136.5, 136.4, 135.1,
130.1, 130.1, 128.7, 128.5, 126.0, 125.2, 124.6, 121.5, 120.3, 119.5, 41.8, 27.0, 20.1,
19.3. HRMS (EI) calcd for C19H17NO (M+): 275.1310. Found: 275.1323. Elemental
analysis.calcd for C19H17NO: C, 82.88; H, 6.22; N, 5.09. Found: C, 82.89; H, 6.21; N,
5.08. IR (KBr disc): v= 1651, 1586 cmꢀ1.
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1ꢀ(2ꢀfluorophenyl)ꢀ6,7ꢀdihydropyrido[3,2,1ꢀij]quinolinꢀ3(5H)ꢀone(3w): (41.90 mg, 0.150 mmol,
75%). Light yellow solid (75%). Mp. 130 – 131 °C. 1H NMR (400 MHz, DMSOꢀd6) δ
7.63 – 7.56 (m, 1H), 7.50 – 7.36 (m, 4H), 7.11 (t, J = 7.6 Hz, 1H), 7.03 (d, J = 8.2 Hz,
1H), 6.58 (s, 1H), 4.19 – 4.06 (m, 2H), 2.99 (t, J = 5.7 Hz, 2H), 2.12 – 2.02 (m, 2H).
13C NMR (100 MHz, DMSOꢀd6) δ 159.8, 158.7 (d, J = 244 Hz), 144.6, 136.3, 131.1
(d, J = 8 Hz), 131.0 (d, J = 3 Hz), 130.3, 125.3, 124.9 (d, J = 3 Hz), 124.5, 124.2 (d, J
= 16 Hz), 121.6, 121.5, 119.0, 115.8 (d, J = 22 Hz), 41.9, 27.0, 20.0. HRMS (EI)
calcd for C18H14FNO (M+): 279.1059. Found: 279.1051. Elemental analysis.calcd for
C18H14FNO: C, 77.40; H, 5.05; N, 5.01. Found: C, 77.42; H, 5.02; N, 5.02. IR (KBr
disc): v= 1650, 1587 cmꢀ1.
1ꢀ(2ꢀbromophenyl)ꢀ6,7ꢀdihydropyrido[3,2,1ꢀij]quinolinꢀ3(5H)ꢀone(3x): (44.14 mg, 0.158 mmol,
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79%). Yellow solid (79%). Mp. 67 – 69 °C. H NMR (400 MHz, Chloroformꢀd) δ
7.70 (d, J = 7.5 Hz, 1H), 7.43 (t, J = 7.4 Hz, 1H), 7.37 – 7.27 (m, 3H), 7.12 – 6.90 (m,
2H), 6.62 (s, 1H), 4.27 (t, J = 5.8 Hz, 2H), 3.03 (t, J = 5.3 Hz, 2H), 2.18 (dt, J = 12.2,
5.9 Hz, 2H). 13C NMR (100 MHz, Chloroformꢀd) δ 161.5, 150.0, 138.3, 136.8, 133.1,
130.8, 130.2, 130.1, 127.6, 125.5, 125.2, 122.8, 121.7, 121.7, 120.0, 42.6, 28.0, 20.8.
HRMS (EI) calcd for C18H14BrNO (M+): 339.0259. Found: 339.0267. Elemental
analysis.calcd for C18H14BrNO: C, 63.55; H, 4.15; N, 4.12. Found: C, 63.57; H, 4.13;
N, 4.11. IR (KBr disc): v= 1648, 1584 cmꢀ1.
1ꢀ(naphthalenꢀ1ꢀyl)ꢀ6,7ꢀdihydropyrido[3,2,1ꢀij]quinolinꢀ3(5H)ꢀone(3z):(49.72 mg, 0.178 mmol,
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89%). Gray solid (89%). Mp. 131 – 133 °C H NMR (400 MHz, Chloroformꢀd) δ
7.94 (dd, J = 11.2, 8.4 Hz, 2H), 7.60 – 7.52 (m, 2H), 7.52 – 7.47 (m, 1H), 7.42 (dd, J
= 7.0, 1.0 Hz, 1H), 7.36 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.29 (t, J = 4.4 Hz, 1H), 6.90
(d, J = 4.6 Hz, 2H), 6.77 (s, 1H), 4.39 – 4.26 (m, 2H), 3.06 (t, J = 6.2 Hz, 2H), 2.21 (p,
J = 7.2, 6.3 Hz, 2H). 13C NMR (100 MHz, Chloroformꢀd) δ 161.7, 150.0, 136.8, 135.2,
133.5, 131.7, 130.2, 129.0, 128.4, 126.9, 126.6, 126.3, 126.2, 126.0, 125.5, 125.1,
122.4, 121.7, 121.5, 42.6, 28.1, 20.9. HRMS (EI) calcd for C22H17NO (M+): 311.1310.
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Found: 311.1334. Elemental analysis.calcd for C22H17NO: C, 84.86; H, 5.50; N, 4.50.
Found: C, 84.88; H, 5.51; N, 4.48. IR (KBr disc): v= 1655, 1584 cmꢀ1.
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1ꢀ(naphthalenꢀ2ꢀyl)ꢀ6,7ꢀdihydropyrido[3,2,1ꢀij]quinolinꢀ3(5H)ꢀone (3za): (49.17 mg, 0.176
mmol, 88%). Yellow solid (88%). Mp. 201 – 203 °C. H NMR (400 MHz,
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Chloroformꢀd) δ 8.00 – 7.86 (m, 4H), 7.61 – 7.49 (m, 3H), 7.42 (d, J = 7.9 Hz, 1H),
7.34 (d, J = 7.0 Hz, 1H), 7.05 (t, J = 7.7 Hz, 1H), 6.76 (s, 1H), 4.35 – 4.23 (m, 2H),
3.05 (t, J = 6.1 Hz, 2H), 2.19 (dd, J = 11.2, 5.2 Hz, 2H). 13C NMR (100 MHz,
Chloroformꢀd) δ 161.7, 151.1, 137.2, 135.1, 133.3, 133.3, 130.2, 128.4, 128.3, 128.2,
127.9, 126.8, 126.8, 126.8, 125.9, 125.3, 121.7, 121.4, 120.6, 42.6, 28.2, 20.9. HRMS
(EI) calcd for C22H17NO (M+): 311.1310. Found: 311.1334. Elemental analysis. calcd
for C22H17NO: C, 84.86; H, 5.50; N, 4.50. Found: C, 84.87; H, 5.51; N, 4.48. IR (KBr
disc): v= 1642, 1584 cmꢀ1.
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HBV inhibitor: (46.53 mg, 0.170 mmol, 85%). 1H NMR (400 MHz,
Chloroformꢀd) δ 12.90 (s, 1H), 7.54 (t, J = 5.3 Hz, 4H), 7.49 (s, 2H), 7.48 – 7.43 (m,
2H), 6.72 (s, 1H). CAS Registry Number : 30169ꢀ33ꢀ6.
Mechanistic studies: Add Nꢀacetylꢀ1,2,3,4ꢀtetrahydroquinolines (0.2 mmol, 1.0
equiv.), benzoylformic acid (0.3 mmol, 1.5 equiv.), Pd(OAc)2 (0.02 mmol, 10 mol%),
TEMPO (0.4 mmol, 2.0 equiv.) and DCE (2 mL) to the vial, the resulting mixture was
stirred under 25W blue LED at room temperature for 10 h. After the reaction was
completed, it was cooled to room temperature and quenched with water and extracted
with ethyl acetate and then dried with Na2SO4. The organic phase was concentrated
under reduced pressure to yield the crude product, which was further purified by flash
chromatography on silica gel (eluant: petroleum ether/ethyl acetate = 15:1, V/V) to
provide the 2,2,6,6ꢀtetramethylpiperidino benzoate 4 in 81% yield.
1
2,2,6,6ꢀtetramethylpiperidino benzoate: H NMR (400 MHz, Chloroformꢀd) δ
8.11 – 8.05 (m, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 1.84 – 1.69 (m,
3H), 1.59 (d, J = 12.5 Hz, 2H), 1.49 – 1.42 (m, 1H), 1.28 (s, 6H), 1.12 (s, 6H). 13C
NMR (100 MHz, Chloroformꢀd) δ 166.5, 133.0, 129.9, 129.7, 128.6, 60.6, 39.2, 32.1,
21.0, 17.2.
ASSOCIATED CONTENT
Supporting Information
Copies of 1H and 13C NMR spectra of all products.
AUTHOR INFORMATION
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Corresponding Author
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*Eꢀmail: wenyichu@hlju.edu.cn
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by Fund of Natural Science Foundation of Heilongjiang
Province of China (No. B201207 and No. B201208).
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