Regioselective synthesis of 3-bromoquinoline derivatives and diastereoselective synthesis of tetrahydroquinolines via acid-promoted rearrangement of arylmethyl azides

Article abstract of DOI:10.1021/acs.joc.5b00375

Regioselective synthesis of 3-bromoquinoline derivatives was achieved via a formal [4 + 2]-cycloaddition between N-aryliminium ion, generated from arylmethyl azides, and 1-bromoalkynes. This method could also be applied to other quinoline derivatives using appropriate alkynes. Moreover, the current strategy could be utilized for the diastereoselective synthesis of tetrahydroquinoline derivatives employing alkenyl substrates in good to excellent yields.

Full text of DOI:10.1021/acs.joc.5b00375

Article
pubs.acs.org/joc
Regioselective Synthesis of 3‑Bromoquinoline Derivatives and
Diastereoselective Synthesis of Tetrahydroquinolines via Acid-
Promoted Rearrangement of Arylmethyl Azides
Jumreang Tummatorn,*,†,‡ Piyapratch Poonsilp,‡ Phongprapan Nimnual,† Jindaporn Janprasit,†
Charnsak Thongsornkleeb,†,‡ and Somsak Ruchirawat†,‡
†Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand
‡Program on Chemical Biology, Chulabhorn Graduate Institute, Center of Excellence on Environmental Health and Toxicology
(EHT), Ministry of Education, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand
S
* Supporting Information
ABSTRACT: Regioselective synthesis of 3-bromoquinoline derivatives
was achieved via a formal [4 + 2]-cycloaddition between N-aryliminium
ion, generated from arylmethyl azides, and 1-bromoalkynes. This
method could also be applied to other quinoline derivatives using
appropriate alkynes. Moreover, the current strategy could be utilized for
the diastereoselective synthesis of tetrahydroquinoline derivatives
employing alkenyl substrates in good to excellent yields.
preparing such quinoline system relies on the electrophilic
cyclization of alkynylaniline11 and alkynylaryl azide12 derivatives
(Scheme 1). However, the former methodology is well suited
for the preparation of 3-iodoquinolines using electrophilic ICl
and I2, while electrophilic cyclization using molecular Br2
INTRODUCTION
■
Quinoline derivatives are one of the most prevalent core
structures in bioactive compounds, both in natural products
and synthetic compounds.1 Nowadays, the investigation of
biological activity of novel quinoline derivatives has continued
to be of interest to many pharmaceutical companies. A number
of quinoline derivatives have been clinically used as antifungal,2
antibacterial,3 antiprotozoal,4 antimalarial,5 as well as anticancer
drugs.6 A variety of synthetic methods have been reported for
the preparation of quinoline derivatives.7 Among these
synthetic methods, aniline and ortho-functionalized aniline
derivatives are well-established precursors which could react
with several substrates to provide libraries of quinoline
analogues. However, the structurally diverse quinoline com-
pounds have been obtained by different synthetic approaches.
There are limitations for each strategy, such as lengthy
synthetic steps, difficulty in preparing starting materials and
high reaction temperatures. Therefore, the development of a
new synthetic method to enable the synthesis of diverse
quinoline frameworks is still a challenging task. This included
the development of a new synthetic method for preparing
halogen-containing quinolines because the halogen atom could
enhance the biological activity in many cases8 and could also be
used for further functionalization in preparing other complex
molecules.9 Several methods for the synthesis of haloquinoline
have been revealed, including the direct halogenation which
always suffers from poor regioselectivity and over halogen-
ation,10 but only few methods for the regioselective synthesis of
3-haloquinolines are known. A dependable method for
Scheme 1. Previous Reported Methods
Received: February 17, 2015
© XXXX American Chemical Society
A
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Scheme 2. Our Proposed Synthetic Methodology
provided a complex mixture or low yields of the 3-
bromoquinoline products.11
Table 1. Optimization Conditions for the Synthesis of 3-
Bromoquinoline Compound
Recently, we presented the utility of benzylic azides in
generating N-aryliminium ion13 in situ under acidic conditions
at ambient temperature. This iminium ion could be trapped by
a variety of nucleophiles intermolecularly to furnish N-
arylmethylarene, polycyclic alkaloid14 and 2,4-unsubstitued
quinoline compounds,15 as well as intramolecularly to form
phenanthridine compounds.16 We found the reaction pro-
ceeded through a formal [4 + 2] cycloaddition by a stepwise
process as demonstrated in our previous work. For example in
the regioselective synthesis of quinoline-3-carboxylates, when
ethyl-3-ethoxyacrylate was used as the nucleophile to trap with
N-aryliminium ion intermediates, the reaction generated the
oxocarbenium ion intermediate before further cyclization
intramolecularly to give the products.15 Therefore, we envision
that haloacetylenes could serve as another class of two-atom
component in a formal [4 + 2] cycloaddition with N-
aryliminium ion intermediate to produce stable 2-halovinyl
cation intermediates which would lead to the regioselective
annulation to provide 3-haloquinoline as the final products.
Moreover, we also aim to expand the scope of our methodology
for the incorporation of other functional groups at 3-position
such as a carbonyl moiety, an aryl and an alkyl group.
Moreover, we have also applied our methodology for a
diastereoselective synthesis of tetrahydroquinoline derivatives17
as shown in Scheme 2.
1a
2a
temp.
time
(h)
yield
a
entry (equiv) (equiv)
solvent
DCM
(°C)
(%)
1
2
3
4
5
6
7
8
1.0
1.0
2.0
1.0
1.0
1.0
1.0
1.0
1.2
2.0
1.0
2.0
2.0
2.0
2.0
2.0
rt
rt
rt
rt
rt
0
18
18
18
18
18
18
5
58
68
24
72
49
69
63
63
DCM
DCM
DCE
Toluene
DCE
b
DCE
rt
rt
DCE, one pot
18
a
b
Isolated yield. The reaction was carried out at 0 °C for 1 h before
allowing to warm to room temperature for overnight.
room temperature for overnight. Unfortunately, the reaction
gave a lower yield of the desired product (entry 6). Reducing
the reaction time, the yield of the quinoline product could not
be improved (entry 7). Moreover, we attempted the reaction in
one-pot fashion by adding DDQ after the reaction was stirred
for overnight. Unfortunately, we were unsuccessful in
improving the yield of the corresponding product. On the
basis of our results, we therefore adopted 1.0 equiv of
arylmethyl azide, 2.0 equiv of haloacetylene and 1.2 equiv of
TfOH in DCE in the first step and 1.0 equiv of DDQ in EtOAc
in the second step as our optimal combination to further study
the scope of the reaction.
With the optimal conditions in hand, we then applied these
optimal conditions to a variety of arylmethyl azide substrates to
verify the generality of the method (Table 2). The reactions
proceeded readily when electronically neutral substrates, benzyl
azide (1a) and o-tolylmethyl azide (1b), were employed to give
the desired quinolines in 72% and 61% yields, respectively. 4-
tert-Butylbenzyl azide (1c) could also provide the quinoline
product 3c in moderate yield (57%, entry 3). In the case of 2-
naphthylmethyl azide (1d), the desired quinoline product was
obtained in low yield (16%, entry 4), presumably because the
steric hindrance of the 2-naphthyl iminium ion affected the
annulation step thus providing a complex mixture instead.
Arylmethyl azide with mildly electron-withdrawing group, p-
phenyl substituent (1e) furnished the corresponding 3-
bromoquinoline in good yield (75%, entry 5). Moreover, the
effects of halogen-substituent of arylmethyl azides were
explored (entries 6−14). The reaction of o-chloro- and p-
RESULTS AND DISCUSSION
■
We initially investigated the synthesis of 3-bromoquinoline
using benzyl azide (1a)15 and bromophenyl acetylene (2a)18 as
the screening substrates. TfOH was employed to promote the
rearrangement of benzyl azide in the first step, followed by the
reaction with bromophenylacetylene to afford dihydroquinoline
crude product which was then subjected to a well-established
oxidizing conditions using 1.0 equiv of DDQ in EtOAc, in the
second step. Several conditions have been investigated
including equivalents of starting materials, TfOH, solvents,
temperature and time as shown in Table 1. Using 1.0 equiv of
1a and 1.2 equiv of 2a could provide the desired product with
excellent regioselectivity as anticipated in 58% yield, while the
higher yield (68%) was obtained when 2.0 equiv of compound
2a was employed (entry 2). Switching the numbers of
equivalent between compounds 1a and 2a dramatically
decreased the yield of the desired product (24%, entry 3).
The effect of solvent was also investigated (entries 4−5) and
DCE was found to be the most effective solvent. We next tried
to perform the reaction at 0 °C for 1 h before allowing to stir at
B
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Table 2. Scope of Arylmethyl Azide Substrates
a
b
c
Isolated yield. Condition A. Condition B.
chlorophenylmethyl azides (entries 6 and 8) also proceeded
well under these conditions and furnished the desired products
in good yields (65% and 62%, respectively), whereas m-
chlorophenylmethyl azide (entry 7) afforded the separable
regioisomeric products (3g-1 and 3g-2) in lower combined
yields (44%). These were presumably due to the inductive
effect of the chlorine atom which decreased the nucleophilicity
of the carbon atoms toward the cyclization. Surprisingly,
compound 3g-2, obtained via the cyclization at slightly more
steric position, was obtained in higher yield than compound 3g-
1. The higher yields of the corresponding quinolines were
obtained when various bromoarylmethyl azides (entries 9−11)
were employed in this transformation. In addition, m-
fluorophenylmethyl azide (1l) could provide the desired
products 3l-1 and 3l-2 in 38% combined yields. Comparing
to entry 7, the higher inductive effect of the fluorine atom could
decrease the nucleophilicity of the aromatic nucleophile more
than the chlorine atom, providing the quinoline products in
lower yields (entry 12). p-Fluorophenylmethyl azide (1m) was
capable of converting to the corresponding 3-bromoquinoline
C
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product in good yield (entry 13). However, the product yields
dramatically dropped when increasing the electron-withdrawing
effect of substituents on the arylmethyl azide substrates such as
2,3-difluoro, p-trifluoromethyl, p-trifluoromethoxy and p-nitro
groups (entries 14−17). The unsuccessful results might
possibly be caused by the difficulty of the electron-deficient
aniline species to cyclize onto the vinyl carbocation
intermediate, thus affording low yields of the quinoline
products. In these cases, we observed the corresponding aniline
derivatives as the results of hydrolysis of the iminium ions as
well as complex mixtures of other unidentifiable products. In
addition, the reaction of arylmethyl azide bearing electron-
donating group 2-chloro-3,4-dimethoxybenzyl azide (1r) was
also unsuccessful, leading to a complex mixture and no desired
product was observed. Presumably, the arylmethyl azide
substrates containing electron-donating groups, especially the
methoxy group, provided the corresponding dihydroquinoline
which may have undergone decomposition under the DDQ
oxidation conditions. To avoid this decomposition, I2-
promoted oxidation16 (condition B) was applied instead
which could provide the desired product 3r in 26% yield.
These latter oxidation conditions could be applied to several
prior cases (entries 3, 5, 13 and 17) to afford products in higher
yields than DDQ oxidation while longer reaction time was
needed.
Table 3. Scope of Alkyne Substrates
Diverse alkynyl nucleophiles were next examined (Table 3)
to probe the scope of the methodology in the preparation of
various quinoline analogues. In these experiments, we selected
p-bromobenzyl azide (1k) as the substrate for this purpose and
used iodine oxidation to avoid the decomposition of some
electron-rich intermediates. Various substituted bromoacety-
lene compounds were applied under these conditions (entries
1−3). 1-Bromo-1-hexyne (2b) provided the desired product in
low yield (19%, entry 1). The higher yields were obtained when
the substituent groups of bromoacetylenes could better stabilize
the carbocation intermediates as demonstrated in entry 10 of
Table 1 and entries 2 and 3 of Table 3. Bromoethynylanisole
(2c) could give the more stable vinyl cation intermediate than
bromoethynyl-4-fluoro-benzene (2d), thus providing the
corresponding product in higher yields. Moreover, this method
could be applied to synthesize 3-chloro- and 3-iodoquinolines
by using chloro-18 and iodophenylacetylene19 as nucleophiles
(entries 5−6), providing 3-chloroquinoline 4e and 3-
iodoquinoline 4f in 55% and 46% yields, respectively. These
results illustrated that the bulkiness of iodine atom may affect
lower yield of the quinoline product. Besides the halopheny-
lacetylenes, this method was also compatible with methyl-3-
phenylpropiolate (2g) for preparing quinoline-3-carboxylate in
good yield (entry 7). Diphenylacethylene was then applied to
these conditions to give the desired quinoline in 42% yied. This
method could also be used to conveniently prepare quinolines
in moderate yields starting from arylmethyl azide and terminal
alkynes such as phenylacetylene (2i, entry 8) and 4-
ethynylanisole (2j, entry 9). Surprisingly, the electron rich
alkyne 2j provided the desired product in lower yield,
presumably because it could not tolerate well under the
reaction conditions, leading to the decomposition of the
starting material. An additional advantage of using this method
for the synthesis of quinolines is the obliteration of the use of
toxic metal catalyst, thus providing metal-free final products.11b
Having established the strategy for the synthesis of quinoline
compounds using arylmethyl azide and alkyne precursors, we
continued to further expand the scope of this method for
a
Isolated yields.
preparing tetrahydroquinoline scaffolds. The synthesis also
involved with nucleophilic addition to the iminium ion
intermediates with alkenyl nucleophiles. We found the reaction
required less amounts of the alkenes (1.2 equiv) in the reaction
due to their higher stability than the alkynes under the reaction
conditions. Moreover we also discovered that DCM could be
used as the optimal solvent for this process. Initially, chalcone
derivatives were first employed to evaluate the ability of our
method (entries 1−5, Table 4). When the chalcone derivatives
D
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Table 4. Scope of Alkene Substrates
a
b
Isolated yields. Azide 2j was employed.
E
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Scheme 3. Proposed Mechanism
containing electron donating groups on aromatic ring (5a−5c)
were employed as the nucleophiles, all of tetrahydroquinoline
products were obtained as single antidiastereomers in good
yields (entries 1−3). Interestingly, chloro-substituted chalcone
5d could provide tetrahydroquinoline 6d in 24% yield, while
chalcone 5e failed to give the desired product 6e, and starting
material 5e was recovered. These results indicated that chlorine
atom could increase the nucleophilicity of the α,β-unsaturated
ketone to facilitate the nucleophilic addition to the iminium ion
intermediate. Moreover, both α,β-unsaturated ketone and ester
were also applicable under these conditions to furnish the
corresponding products in good yields (entries 6−8). Next, a
series of styrene derivatives (entries 9−11) was also
investigated using these conditions. The reaction of trans-
methylstyrene 5i provided the desired product 6i in good yield
with excellent regio- and diastereoselectivity. It is important to
note that cinnamyl bromide 5j could also tolerate under the
employed conditions and offered tetrahydroquinoline 6j in high
yield as a single regioisomeric product. In addition, nitrostyrene
5k was found to perform well under the reaction conditions,
giving the corresponding product 6k in good yield. In all
alkenes, only anti-isomeric products were obtained. To further
understand the stereochemical outcome including the reaction
mechanism, both trans- and cis-stilbenes (5l and 5m) were
employed in this study. The reaction of trans-stilbene gave
tetrahydroquinoline product 6l as a single antidiastereomer in
good yield, whereas cis-stilbene provided both syn- and anti-
tetrahydroquinoline products (6m and 6l, respectively) in 1:1
ratio in moderate combined yield (entries 12−13). These
results indicated that the reaction mechanism involved with the
formation of the benzylic carbocation intermediate. Therefore,
the stability of carbocation intermediate played an important
role in the stereochemical outcome of the desired product. In
case of trans-stilbene (5l), the transient carbocation inter-
mediate already attained the more stable conformation B which
readily cyclized to give only the anti-isomeric product.
However, in cis-stilbene (5m), the less stable conformer of
carbocation intermediate (conformer A), initially formed and
underwent the cyclization directly to form the syn-isomeric
product, or underwent a bond rotation to give the more stable
conformation of the carbocation intermediate (conformer B)
which led to the anti-product as shown in Scheme 3.
confirm the regiochemical outcome. In using stilbene 5o,
containing the electron-deficient nitro group, the reaction failed
to give the corresponding product with nearly 60% of
compound 5o recovered. Trisubstituted stilbene 5p was
subjected to the usual conditions to evaluate the steric effect
of the stilbene substrate. The results showed that stilbene 5p
underwent the isomerization of the double bond before
trapping with the iminium ion to provide the corresponding
product in moderate yield.
CONCLUSIONS
■
In conclusion, we have successfully developed the regioselective
synthesis of 3-haloquinoline compounds via a formal [4 + 2]
cycloaddition of N-aryliminium ions, generated in situ from the
benzylic azide rearrangement, and haloacetylene analogues.
Besides 3-bromo-, 3-chloro-, and 3-iodoquinolines, this method
could be used for the construction of 3-alkyl-, 3-aryl-, 3-
carbonyl as well as 3-unsubstituted quinoline compounds
starting from appropriate nucleophilic alkyne derivatives.
Moreover, our method could be used to prepare tetrahy-
droquinolines with high regio- and diastereoselectivity using
nucleophilic alkenes. The method is highlighted from the
readily available starting materials and tolerance of a variety of
substituents under reaction conditions. Moreover, the corre-
sponding quinoline products could be obtained under metal-
free conditions, constituting a green chemistry approach for the
synthesis of quinoline derivatives in modest to high yields.
EXPERIMENTAL SECTION
■
General Procedure. The commercial grade chemicals were used
without further purification, unless otherwise specified. All solvents
used were purified by the solvent purification system. The oven-dried
glassware (110 °C at least for 2 h) was used for all reactions. Crude
reaction mixtures were concentrated under reduced pressure by
removing organic solvent with the rotary evaporator. Column
chromatography was performed using silica gel 60 (particle size
0.06−0.2 mm; 70−230 mesh ASTM). Analytical thin layer
chromatography (TLC) was performed with silica gel 60 F254
aluminum sheets. The nuclear magnetic resonance (NMR) spectra
were recorded in deuterochloroform (CDCl3) with 300 and 600 MHz
1
spectrometers. Chemical shifts for H NMR and 13C NMR spectra
were reported in part per million (ppm, δ), relative to
tetramethylsilane (TMS) as the internal reference. Coupling constants
(J) were reported in hertz (Hz). Infrared spectra were measured using
FT-IR spectrometer and were reported in cm−1. High resolution mass
spectra (HRMS) were obtained using time-of-flight (TOF).
General Procedure for the Synthesis of Quinolines (3a−3r,
4b−4j). The arylmethyl azides (1.0 equiv) were placed in a round
bottle flask and added with dry dichloroethane (DCE, 0.14 mmol/mL)
under argon. TfOH (1.0 equiv) was subsequently added into a
solution and the mixture was stirred for 5 min at room temperature
before haloacetylenes (2.0 equiv) were added. The reaction was stirred
In addition, the nucleophilic addition of unsymmetrical
stilbene 5n to the iminium ion intermediate generated from
azide 1a was also examined (entry 14) and was found to afford
the desired quinoline 6n-1 as a single regioisomeric product.
To determine the regioselectivity of the product, stilbene 5n
was reacted with N-aryliminium ion generated from azide 1j,
resulting in quinoline 6n-2 as a single regioisomeric product,
which was subjected to an NOE difference experiment to
F
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for overnight and was then quenched with saturated sodium
bicarbonate (NaHCO3). The reaction mixture was extracted with
EtOAc, and the combined organic layers were washed with brine, dried
over Na2SO4, filtered and concentrated under reduced pressure. For
oxidation, the crude products were oxidized by either one of the
following methods.
Method A: The crude product was dissolved in EtOAc (0.08 mmol/
mL) and added with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) (2.5 equiv). The reaction mixture was stirred for 5 min and
concentrated to give a crude product which was purified by silica gel
column chromatography using hexane to 4:1 hexane/EtOAc.
Method B: The crude product was dissolved in THF (0.08 mmol/
mL) and added with I2 (2.5 equiv) The reaction mixture was stirred at
room temperature for 2 h and quenched with saturated Na2S2O3. The
mixture was extracted with EtOAc, dried over Na2SO4, concentrated
and purified with silica gel column chromatography using hexane to
4:1 hexane/EtOAc to give the desired product.
1.2 Hz), 7.58−7.53 (m, 3H), 7.44 (d, 1H, J = 9.0 Hz), 7.40 (dd, 1H, J
= 8.4, 1.8 Hz), 7.31−7.30 (m, 2H); 13C NMR (150 MHz, CDCl3) δ
153.0, 147.9, 147.2, 136.3, 135.6, 129.2, 128.9, 128.7, 128.6, 28.5,
127.7, 127.3, 118.7; HRMS (ESI-TOF) calcd for C15H10BrClN (Br-
79) (Cl-35) (M + H+) 317.9680, found 317.9672.
3-Bromo-5-chloro-4-phenylquinoline (3g-2). Yield 79.9 mg (31%,
yellow solid); mp 78−79 °C. IR (neat): νmax 1601, 1480, 697 cm−1; 1H
NMR (300 MHz, CDCl3) δ 9.06 (s, 1H), 8.10 (dd, 1H, J = 7.8, 1.8
Hz), 7.63−7.54 (m, 2H), 7.48−7.45 (m, 3H), 7.24−7.21 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 152.2, 148.5, 146.7, 139.5, 130.8, 130.5,
129.9, 129.1, 129.0, 128.3, 128.0, 125.9, 122.3; HRMS (ESI-TOF)
calcd for C15H10BrClN (Br-79) (Cl-35) (M + H+) 317.9680, found
317.9677.
3-Bromo-6-chloro-4-phenylquinoline (3h). Yield 135.8 mg (62%,
yellow solid); mp 156−157 °C. IR (neat): νmax 3048, 2319, 1603,
1
1483, 1105, 826, 704 cm−1; H NMR (300 MHz, CDCl3) δ 9.03 (s,
1H), 8.06 (d, 1H, J = 9 Hz), 7.66−7.56 (m, 4H), 7.45 (s, 1H), 7.31−
7.26 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 152.2, 146.9, 145.3,
136.0, 133.6, 131.2, 130.4, 129.5, 129.2, 129.0, 128.8, 125.1, 119.6;
HRMS (ESI-TOF) calcd for C15H10BrClN (Br-79) (Cl-35) (M + H+)
317.9680, found 317.9678.
3-Bromo-4-phenylquinoline (3a). Yield 84.3 mg (72%, yellow
solid); mp 99−101 °C. IR (neat): νmax 1569, 1489, 1102, 763, 699
1
cm−1; H NMR (300 MHz, CDCl3) δ 9.05 (s, 1H), 8.13 (d, 1H, J =
8.4 Hz), 7.71 (t, 1H, J = 7.2 Hz), 7.53−7.42 (m, 5H), 7.33−7.26 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 152.0, 147.6, 146.8, 136.7, 129.6,
129.4, 129.3, 128.8, 128.6, 128.5, 127.5, 126.3, 118.4; HRMS (ESI-
TOF) calcd for C15H11BrN (Br-79) (M + H+) 284.0069, found
284.0063.
3,8-Dibromo-4-phenylquinoline (3i). Yield 67.5 mg (74%, yellow
solid); mp 122−123 °C. IR (neat): νmax 2922, 2852, 1475, 1113, 982,
755, 700 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.16 (s, 1H), 8.05 (dd,
1H, J = 7.5, 1.2 Hz), 7.60−7.45 (m, 5H), 7.32−7.26 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 152.7, 148.1, 144.0, 136.4, 133.2, 130.1,
129.2, 128.8, 128.6, 127.8, 126.3, 124.9, 119.7; HRMS (ESI-TOF)
calcd for C15H10Br2N (Br-79) (M + H+) 361.9175, found 361.9181.
3,7-Dibromo-8-methyl-4-phenylquinoline (3j). Yield 116.8 mg
(66%, yellow solid); mp 113−114 °C. IR (neat): νmax 2922, 1268,
3-Bromo-8-methyl-4-phenylquinoline (3b). Yield 72.7 mg (61%,
yellow solid); mp 72−74 °C. IR (neat): νmax 3058, 2921, 2339, 1483,
1
1142, 761, 699 cm−1; H NMR (300 MHz, CDCl3) δ 9.07 (s, 1H),
7.58−7.51 (m, 4H), 7.34−7.29 (m, 4H), 2.84 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 150.6, 147.6, 145.9, 137.4, 137.2, 129.6, 129.3, 128.9,
128.4, 127.2, 124.4, 118.5, 18.2; HRMS (ESI-TOF) calcd for
C16H13BrN (Br-79) (M + H+) 298.0226, found 298.0228.
1
1126, 901, 762, 706 cm−1; H NMR (300 MHz, CDCl3) δ 9.04 (s,
1H), 7.57−7.51 (m, 4H), 7.30−7.25 (m, 2H), 7.18 (d, 1H, J = 9.0
Hz), 2.94 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 151.4, 147.7, 146.2,
137.3, 136.6, 131.5, 129.2, 128.7, 128.5, 127.8, 125.9, 124.8, 118.7,
17.8; HRMS (ESI-TOF) calcd for C16H12Br2N (Br-79) (M + H+)
375.9331, found 375.9318.
3,6-Dibromo-4-phenylquinoline (3k). Yield 102.0 mg (80%, yellow
solid); mp 160−161 °C. IR (neat): νmax 3049, 2324, 1599, 1480, 1103,
824, 704 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.05 (s, 1H), 7.99 (d,
1H, J = 8.7 Hz), 7.78 (dd, 1H, J = 9, 2.1 Hz), 7.63−7.52 (m, 4H),
7.34−7.26 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 152.4, 146.8,
145.5, 136.0, 133.0, 131.3, 130.0, 129.2, 129.0, 128.8, 128.3, 121.9,
119.6; HRMS (ESI-TOF) calcd for C15H10Br2N (Br-79) (M + H+)
361.9175, found 361.9180.
3-Bromo-7-fluoro-4-phenylquinoline (3l-1). Yield 33.2 mg (13%,
yellow solid); mp 100−101 °C. IR (neat): νmax 1621, 1485, 1191, 761
cm−1; 1H NMR (300 MHz, CDCl3) δ 9.05 (s, 1H), 7.76 (dd, 1H, J =
9.7, 2.5 Hz), 7.60−7.48 (m, 4H), 7.35−7.29 (m, 2H), 7.27−7.20 (m,
1H); 13C NMR (75 MHz, CDCl3) δ 162.9 (d, JCF = 250 Hz), 153.1,
147.88 (d, JCF = 12 Hz), 147.87, 136.5, 129.2, 128.8, 128.7 (d, JCF = 9
Hz), 128.6, 125.94 (d, JCF = 3 Hz), 125.87, 117.9 (d, JCF = 25 Hz),
113.2 (d, JCF = 20 Hz); HRMS (ESI-TOF) calcd for C15H10BrFN (Br-
79) (M + H+) 301.9975, found 301.9975.
3-Bromo-6-(tert-butyl)-4-phenylquinoline (3c). Condition A: Yield
102.2 mg (57%). Condition B: Yield 154.6 mg (69%, yellow solid);
mp 101−102 °C. IR (neat): νmax 3058, 2963, 2319, 1493, 1109, 701
cm−1; 1H NMR (300 MHz, CDCl3) δ 8.99 (s, 1H), 8.07 (d, 1H, J = 9
Hz), 7.81 (dd, 1H, J = 8.7, 2.1 Hz), 7.59−7.49 (m, 3H), 7.41 (d, 1H, J
= 2.1 Hz), 7.33 (dd, 2H, J = 7.8, 1.5 Hz), 1.26 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 151.2, 150.5, 147.5, 145.3, 136.8, 129.3, 129.0, 128.6,
128.44, 128.35, 121.2, 118.4, 35.0, 31.0; HRMS (ESI-TOF) calcd for
C19H19BrN (Br-79) (M + H+) 340.0695, found 340.0683.
2-Bromo-1-phenylbenzo[f ]quinoline (3d). Yield 25.4 mg (16%,
yellow solid); mp 176−178 °C. IR (neat): νmax 3046, 2370, 1953,
1484, 1440, 1122, 834, 754 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.12
(s, 1H), 8.00 (app s, 2H), 7.87 (dd, 1H, J = 8.1, 1.2 Hz), 7.62−7.57
(m, 3H), 7.50−7.45 (m, 1H), 7.40 (d, 1H, J = 8.7 Hz), 7.33−7.26 (m,
2H), 7.14 (ddd, 1H, J = 8.4, 6.9, 1.5 Hz); 13C NMR (75 MHz, CDCl3)
δ 150.8, 148.3, 147.4, 141.3, 133.3, 131.9, 129.6, 129.5, 128.8, 128.6,
128.6, 128.3, 128.1, 127.1, 126.1, 125.8, 121.7; HRMS (ESI-TOF)
calcd for C19H13BrN (Br-79) (M + H+) 334.0226, found 334.0223.
3-Bromo-4,6-diphenylquinoline (3e). Condition A: Yield 138.9 mg
(75%). Condition B: Yield 159.7 mg (83%, yellow solid); mp 145−
146 °C. IR (neat): νmax 3357, 2922, 1954, 1485, 1104, 761, 698 cm−1;
1H NMR (300 MHz, CDCl3) δ 9.05 (s, 1H), 8.22 (d, 1H, J = 9 Hz),
7.98 (dd, 1H, J = 9, 3 Hz), 7.66 (s, 1H), 7.61−7.51 (m, 5H), 7.45−
7.33 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 151.7, 147.9, 146.1,
140.4, 140.1, 136.6, 129.9, 129.3, 129.0, 128.9, 128.7, 128.6, 127.9,
127.4, 124.0, 118.9; HRMS (ESI-TOF) calcd for C21H15BrN (Br-79)
(M + H+) 360.0382, found 360.0386.
3-Bromo-5-fluoro-4-phenylquinoline (3l-2). Yield 62.8 mg (25%,
yellow solid); mp 75−76 °C. IR (neat): νmax 1623, 1567, 1460, 756
1
cm−1; H NMR (300 MHz, CDCl3) δ 9.08 (s, 1H), 8.00 (d, 1H, J =
8.4 Hz), 7.68 (ddd, 1H, J = 8.0, 8.0, 5.4 Hz), 7.54−7.51 (m, 3H),
7.31−7.26 (m, 2H), 7.16 (ddd, 1H, J = 11.9, 7.8, 1.0 Hz); 13C NMR
(75 MHz, CDCl3) δ 157.5 (d, JCF = 258 Hz), 152.7 (d, JCF = 1 Hz),
148.2, 144.6 (d, JCF = 5 Hz), 139.2 (d, JCF = 3 Hz), 129.3 (d, JCF = 9
Hz), 128.1, 128.0, 127.9 (d, JCF = 3 Hz), 126.0 (d, JCF = 4 Hz), 120.7,
119.1 (d, JCF = 9 Hz), 112.8 (d, JCF = 22 Hz); HRMS (ESI-TOF)
calcd for C15H10BrFN (Br-79) (M + H+) 301.9975, found 301.9981.
3-Bromo-6-fluoro-4-phenylquinoline (3m). Condition A: Yield
182.8 mg (61%). Condition B: Yield 154.9 mg (76%, yellow solid);
mp 65−66 °C. IR (neat): νmax 3058, 1622, 1490, 1192, 831, 736, 699
3-Bromo-8-chloro-4-phenylquinoline (3f). Yield 85.6 mg (65%,
yellow solid); mp 140−146 °C. IR (neat): νmax 3061, 3023, 1682,
1
1478, 1116, 757 cm−1; H NMR (300 MHz, CDCl3) δ 9.17 (s, 1H),
7.84 (dd, 1H, J = 6.9, 1.5 Hz), 7.57−7.55 (m, 3H), 7.45−7.26 (m,
4H); 13C NMR (75 MHz, CDCl3) δ 152.4, 148.1, 143.1, 136.3, 133.7,
130.1, 129.6, 129.1, 128.8, 128.6, 127.3, 125.5, 119.6; HRMS (ESI-
TOF) calcd for C15H10BrClN (Br-79) (Cl-35) (M + H+) 317.9680,
found 317.9686.
1
cm−1; H NMR (300 MHz, CDCl3) δ 9.01 (s, 1H), 8.16−8.11 (m,
3-Bromo-7-chloro-4-phenylquinoline (3g-1). Yield 33.2 mg (13%,
1H), 7.59−7.53 (m, 3H), 7.51−7.44 (m, 1H), 7.32−7.30 (m, 2H),
7.10 (dd, 1H, J = 9.9, 2.7 Hz); 13C NMR (75 MHz, CDCl3) δ 161.0
(d, JCF = 248 Hz), 151.1 (d, JCF = 3 Hz), 147.3 (d, JCF = 5 Hz), 143.8,
white solid); mp 80−81 °C. IR (neat): νmax 1598, 1478, 1070, 888
1
cm−1; H NMR (600 MHz, CDCl3) δ 9.06 (s, 1H), 8.14 (d, 1H, J =
G
DOI: 10.1021/acs.joc.5b00375
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
136.2, 132.0 (d, JCF = 9 Hz), 129.7 (d, JCF = 10 Hz), 129.1, 128.9,
128.7, 119.7 (d, JCF = 26 Hz), 119.4, 109.8 (d, JCF = 24 Hz); HRMS
(ESI-TOF) calcd for C15H10BrFN (Br-79) (M + H+) 301.9975, found
301.9983.
J
CF = 22 Hz); HRMS (ESI-TOF) calcd for C15H9Br2FN (Br-79) (M +
H+) 379.9080, found 379.9097.
6-Bromo-3-chloro-4-phenylquinoline (4e). Yield 107.9 mg (55%,
yellow solid); mp 106−107 °C. IR (neat): νmax 3058, 2929, 1726,
1
3-Bromo-7,8-difluoro-4-phenylquinoline (3n). Yield 78.0 mg
1482, 1112, 828, 699 cm−1; H NMR (300 MHz, CDCl3) δ 8.93 (s,
(36%, white solid); mp 142−143 °C. IR (neat): νmax 2927, 1634,
1H), 8.00 (d, 1H, J = 9.0 Hz), 7.77 (dd, 1H, J = 8.7, 2.1 Hz), 7.65 (d,
1H, J = 2.1 Hz), 7.60−7.54 (m, 3H), 7.35−7.32 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 150.4, 145.2, 144.3, 134.0, 132.8, 131.3, 129.4,
129.0, 128.8, 128.3, 128.1, 121.9; HRMS (ESI-TOF) calcd for
C15H10BrClN (Br-79) (Cl-35) (M + H)+ 317.9680, found 317.9681.
6-Bromo-3-iodo-4-phenylquinoline (4f). Yield 100.0 mg (46%,
yellow solid); mp 183−184 °C. IR (neat): νmax 2923, 1732, 1481,
1
1475, 1386, 1288, 822 cm−1; H NMR (300 MHz, CDCl3) δ 9.10 (s,
1H), 7.59−7.55 (m, 3H), 7.37−7.24 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ 153.2, 149.2 (dd, JCF = 250, 11 Hz), 147.8 (t, JCF = 8 Hz),
144.7 (dd, JCF = 256, 12 Hz), 138.3 (dd, JCF = 9, 4 Hz), 135.9, 129.1,
129.0, 128.7, 126.5, 122.2 (dd, JCF = 8, 6 Hz), 119.0 (d, JCF = 3 Hz),
118.2 (d, JCF = 21 Hz); HRMS calcd for C15H9BrF2N (Br-79) (M +
H+) 319.9881, found 319.9872.
1
1068, 966, 703 cm−1; H NMR (300 MHz, CDCl3) δ 9.25 (s, 1H),
3-Bromo-4-phenyl-6-(trifluoromethyl)quinolone (3o). Yield 108.5
mg (40%, white solid); mp 107−108 °C. IR (neat): νmax 1308, 1126,
1065, 835 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.16 (s, 1H), 8.25 (d,
1H, J = 8.7 Hz), 7.89 (dd, 1H, J = 9.0, 2.1 Hz), 7.80 (d, 1H, J = 0.6
Hz), 7.61−7.57 (m, 3H), 7.34−7.31 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 154.1, 148.6, 147.8, 135.7, 130.9, 129.4 (q, JCF = 33 Hz),
129.22, 129.18, 128.9, 128.0, 125.2 (q, JCF = 3 Hz), 124.2 (q, JCF = 4
Hz), 123.7 (q, JCF = 271 Hz), 119.9; HRMS (ESI-TOF) calcd for
C16H10BrF3N (Br-79) (M + H+) 351.9943, found 351.9944.
3-Bromo-4-phenyl-6-(trifluoromethoxy)quinolone (3p). Yield
97.0 mg (48%, yellow solid); mp 168−169 °C. IR (neat): vmax 2927,
7.99 (d, 1H, J = 9.0 Hz), 7.79 (dd, 1H, J = 9.0, 2.4 Hz), 7.62−7.56 (m,
4H), 7.28−7.25 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 157.0, 151.4,
145.7, 139.6, 133.2, 131.2, 129.8, 129.0, 128.9, 128.8, 128.7, 121.6,
97.5; HRMS (ESI-TOF) calcd for C15H10BrIN (M + H) (Br-79)
409.9036, found 409.9049.
+
Methyl 6-Bromo-4-phenylquinoline-3-carboxylate (4g). Yield
118.1 mg (60%, yellow solid); mp 170−172 °C. IR (neat): νmax
3750, 3057, 1729, 1220, 1125, 759 cm−1; 1H NMR (300 MHz,
CDCl3) δ 9.32 (s, 1H), 8.05 (d, 1H, J = 9.0 Hz), 7.85 (dd, 1H, J = 9.0,
2.1 Hz), 7.73 (d, 1H, J = 2.1 Hz), 7.54−7.52 (m, 3H), 7.30−7.26 (m,
2H), 3.68 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.45, 150.2,
149.1, 147.8, 135.5, 134.5, 131.3, 129.5, 128.7, 128.6, 128.5, 128.3,
123.7, 121.7, 52.3; HRMS (ESI-TOF) calcd for C17H13BrNO2 (M +
1
1490, 1249, 1216, 1165, 1098, 833, 759, 699 cm−1; H NMR (300
MHz, CDCl3) δ 9.07 (s, 1H), 8.17 (d, 1H, J = 9.3 Hz), 7.60−7.56 (m,
4H), 7.33−7.31 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 152.5, 147.7
(q, JCF = 1.8 Hz), 147.5, 145.1, 135.9, 131.9, 129.2, 129.1, 129.0, 128.8,
123.3, 120.4 (q, JCF = 257 Hz), 119.7, 116.8; HRMS (ESI-TOF) calcd
for C16H10BrF3NO (Br-79) (M + H+) 367.9892, found 367.9895.
3-Bromo-6-nitro-4-phenylquinoline (3q). Condition A: Yield 32.7
mg (21%). Condition B: Yield 80.0 mg (40%, yellow solid); mp 159−
+
H) (Br-79) 342.0124, found 342.0128.
6-Bromo-3,4-diphenylquinoline (4h). Yield 100.9 mg (42%, yellow
solid); mp 220−221 °C. IR (neat): νmax 3058, 2370, 1893, 1481, 1063,
700 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.99 (s, 1H), 8.05 (d, 1H, J
= 8.4 Hz), 7.80 (d, 2H, J = 15.3 Hz), 7.36−7.16 (m, 10H); 13C NMR
(75 MHz, CDCl3) δ 152.2, 146.1, 144.6, 137.6, 135.5, 133.9, 132.6,
131.3, 130.4, 130.0, 128.6, 128.5, 128.4, 128.1, 128.0, 127.3, 121.1;
HRMS (ESI-TOF) calcd for C21H15BrN (M + H+) (Br-79) 360.0382,
found 360.0392.
1
160 °C. IR (neat): νmax 3357, 2922, 2853, 1529, 1347, 744 cm−1; H
NMR (300 MHz, CDCl3) δ 9.21 (s, 1H), 8.49−8.44 (m, 2H), 8.27 (d,
1H, J = 9.0 Hz), 7.64−7.60 (m, 3H), 7.36−7.33 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 155.4, 149.5, 148.8, 146.2, 135.1, 131.6, 129.5,
129.1, 129.0, 127.9, 123.1, 122.9, 120.6; HRMS (ESI-TOF) calcd for
C15H10BrN2O2 (Br-79) (M + H+) 328.9920, found 328.9898.
3-Bromo-8-chloro-6,7-dimethoxy-4-phenylquinoline (3r). Yield
75.9 mg (36%, yellow solid); mp 163−164 °C. IR (neat): νmax
3352, 2920, 2334, 1481, 1042, 707 cm−1; 1H NMR (300 MHz,
CDCl3) δ 9.01 (s, 1H), 7.60−7.50 (m, 3H), 7.32−7.27 (m, 2H), 6.68
(s, 1H), 4.00 (s, 3H), 3.73 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
153.4, 150.1, 149.0, 146.4, 140.0, 136.7, 129.0, 128.8, 128.7, 126.8,
126.2, 118.9, 103.4, 60.9, 55.8; HRMS (ESI-TOF) calcd for
C17H14BrClNO2 (Br-79) (Cl-35) (M + H+) 377.9891, found
377.9884.
3,6-Dibromo-4-butylquinoline (4b). Yield 35.1 mg (19%, dark
brown liquid); IR (neat): νmax 2957, 2927, 2859, 1726, 1487, 1073,
827 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.89 (s, 1H), 8.15 (d, 1H, J
= 2.1 Hz), 7.94 (d, 1H, J = 9.0 Hz), 7.77 (dd, 1H, J = 8.7, 2.1 Hz), 3.17
(t, 2H, J = 8.0 Hz), 1.70−1.51 (m, 4H), 1.02 (t, 3H, J = 7.2 Hz); 13C
NMR (75 MHz, CDCl3) δ 152.5, 146.5, 145.6, 132.6, 132.0, 129.5,
126.2, 121.7, 120.5, 31.6, 31.2, 23.0, 13.8; HRMS (ESI-TOF) calcd for
C13H14Br2N (Br-79) (M + H+) 341.9488, found 341.9504.
6-Bromo-4-phenylquinoline (4i). Yield 88.8 mg (65%, brown
solid); mp 76−77 °C. IR (neat): νmax 3057, 1919, 1583, 1486, 1350,
1
845, 700 cm−1; H NMR (300 MHz, CDCl3) δ 8.93 (d, 1H, J = 4.5
Hz), 8.05 (d, 1H, J = 2.1 Hz), 8.03 (s, 1H), 7.78 (dd, 1H, J = 9.0, 2.1
Hz), 7.58−7.45 (m, 5H), 7.34 (d, 1H, J = 4.5 Hz); 13C NMR (75
MHz, CDCl3) δ 150.2, 147.7, 147.2, 137.2, 132.8, 131.6, 129.4, 128.8,
128.7, 127.94, 127.92, 122.0, 120.8; HRMS (ESI-TOF) calcd for
+
C15H11BrN (M + H) (Br-79) 284.0069, found 284.0057.
6-Bromo-4-(4-methoxyphenyl)quinoline (4j). Yield 79.0 mg (56%,
yellow solid); mp 110−113 °C. IR (neat): νmax 2957, 1731, 1609,
1489, 1248, 830 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.90 (d, 1H, J =
4.5 Hz), 8.09 (d, 1H, J = 2.4 Hz), 8.02 (d, 1H, J = 9.0 Hz), 7.76 (dd,
1H, J = 9.0, 2.4 Hz), 7.43- 7.40 (m, 2H), 7.31 (d, 1H, J = 4.5 Hz),
7.08−7.05 (m, 2H), 3.89 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
160.0, 150.2, 147.3, 147.2, 132.6, 131.5, 130.6, 129.4, 128.1, 128.0,
121.9, 120.7, 114.2, 55.3; HRMS (ESI-TOF) calcd for C16H13BrNO
+
(M + H) (Br-79) 314.0175, found 314.0180.
General Procedure for the Synthesis of Quinolines (6a−6d,
6f−6p). The arylmethyl azides (1.0 equiv) were placed in a round
bottle flask and added with dry dichloroethane (DCM, 0.14 mmol/
mL) under argon. TfOH (1.2 equiv) was subsequently added into a
solution and the mixture was stirred for 5 min at room temperature
before alkene substrates (1.2 equiv) were added. The reaction was
stirred for overnight and was then quenched with saturated sodium
bicarbonate (NaHCO3). The reaction mixture was extracted with
EtOAc, and the combined organic layers were washed with brine, dried
over Na2SO4, filtered and concentrated under reduced pressure. The
crude products were purified by silica gel column chromatography.
(4-(4-Methoxyphenyl)-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)-
methanone (6a). Yield 113 mg (68%, light yellow solid); mp 157−
158 °C; IR (neat): νmax 3399, 3053, 2933, 2835, 1676, 1607, 1508,
1241, 1177, 1033, 829, 750, 701 cm−1; 1H NMR (300 MHz, CDCl3) δ
7.78−7.75 (m, 2H), 7.51−7.45 (m, 1H), 7.38−7.33 (m, 2H), 7.12−
7.07 (m, 2H), 7.01 (td, 1H, J = 7.8, 0.9 Hz), 6.76−6.72 (m, 3H),
6.62−6.57 (m, 2H), 4.57 (d, 1H, J = 9.3 Hz), 4.08−4.00 (m, 2H),
3,6-Dibromo-4-(4-methoxyphenyl)quinoline (4c). Yield 156.1 mg
(76%, yellow solid); mp 113−114 °C. IR (neat): νmax 1610, 1513,
1
1481, 1248 cm−1; H NMR (300 MHz, CDCl3) δ 9.02 (s, 1H), 7.97
(d, 1H, J = 9.0 Hz), 7.76 (dd, 1H, J = 8.7, 2.1 Hz), 7.69 (d, 1H, J = 2.1
Hz), 7.26−7.22 (m, 2H), 7.11−7.07 (m, 2H), 3.92 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 159.9, 152.4, 146.6, 145.5, 132.9, 131.3, 130.6,
130.2, 128.5, 128.1, 121.8, 120.0, 114.2, 55.3; HRMS (ESI-TOF) calcd
for C16H12Br2NO (Br-79) (M + H+) 391.9280, found 391.9292.
3,6-Dibromo-4-(4-fluorophenyl)quinoline (4d). Yield 116.6 mg
(54%, yellow solid); mp 178−179 °C. IR (neat): νmax 3073, 1603,
1508, 1481, 1222, 840, 826 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.04
(s, 1H), 8.00 (d, 1H, J = 9.0 Hz), 7.79 (dd, 1H, J = 9.0, 2.1 Hz), 7.61
(d, 1H, J = 2.4 Hz), 7.33−7.25 (m, 4H); 13C NMR (75 MHz, CDCl3)
δ 162.9 (d, JCF = 248 Hz), 152.3, 145.7, 145.4, 133.0, 131.8 (d, JCF = 4
Hz), 131.4, 131.1(d, JCF = 8 Hz), 129.8, 128.0, 122.0, 119.7, 116.0 (d,
H
DOI: 10.1021/acs.joc.5b00375
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The Journal of Organic Chemistry
Article
1
3.71(s, 3H), 3.48−3.40 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
201.2, 158.2, 144.0, 136.7, 136.6, 133.3, 130.4, 130.1, 128.5, 128.1,
127.0, 124.6, 117.9, 114.4, 113.8, 55.2, 48.8, 45.0, 44.3; HRMS (ESI-
TOF) calcd for C23H22NO2 (M + H)+ 344.1645, found 344.1643.
(4-(2-Chloro-3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroquinolin-3-
yl)(phenyl)methanone (6b). Yield 140 mg (70%, yellow solid); mp
72−73 °C; IR (neat): νmax 3397, 2939, 2830, 1681, 1487, 1271, 1039,
1492,1452, 1317, 1266 cm−1; H NMR (300 MHz, CDCl3) δ 7.31−
7.20 (m, 3H), 7.13−7.11 (m, 2H), 6.97 (td, 1H, J = 6.0, 3.0 Hz),
6.63−6.60 (m, 1H), 6.54−6.49 (m, 2H), 3.64 (d, 1H, J = 9.0 Hz), 3.28
(dd, 1H, J = 12.0, 6.0 Hz), 3.01 (dd, 1H, J = 12.0, 9.0 Hz), 2.19−2.09
(m, 1H), 0.92 (d, 3H, J = 6.0 Hz) ; 13C NMR (75 MHz, CDCl3) δ
145.7, 144.6, 130.7, 129.2, 128.2, 126.9, 126.2, 123.9, 117.1, 113.9,
51.2, 47.0, 34.9, 18.0; HRMS (ESI-TOF) calcd for C16H18N (M + H)+
224.1434, found 224.1432.
1
750 cm−1; H NMR (300 MHz, CDCl3) δ 7.81 (dd, 2H, J = 7.2, 1.2
Hz), 7.50−7.46 (m, 1H), 7.38−7.33 (m, 2H), 6.99 (td, 1H, J = 8.1, 0.9
Hz), 6.75−6.53 (m, 5H), 3.94 (d, 1H, J = 4.2 Hz), 4.14−3.98 (m, 1H),
3.80 (s, 3H), 3.77 (s, 3H), 3.48−3.37 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 200.6, 152.1, 143.9, 136.3, 132.8, 129.9, 128.4, 128.2, 128.1,
127.0, 126.2, 122.6, 118.0, 114.4, 110.3, 60.4, 55.9, 45.9, 42.7; HRMS
(ESI-TOF) calcd for C24H22ClNNaO3 (M + Na)+ (Cl-35) 430.1180,
found 430.1187.
(4-Methoxyphenyl)(4-(4-methoxyphenyl)-1,2,3,4-tetrahydroqui-
nolin-3-yl)methanone (6c). Yield 129 mg (75%, light yellow solid),
mp 139−140 °C; IR (neat): νmax 3394, 2837, 1664, 1598, 1508, 1252,
1168, 1029, 828, 749 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.80−7.75
(m, 2H), 7.12−7.07 (m, 2H), 7.03−6.98 (m, 1H), 6.85−6.80 (m, 2H),
6.76−6.70 (m, 3H), 6.61−6.56 (m, 2H), 4.55 (d, 1H, J = 9.3 Hz),
4.08−3.97 (m, 2H), 3.81 (s, 3H), 3.71 (s, 3H), 3.44 (d, 2H, J = 6.6
Hz); 13C NMR (75 MHz, CDCl3) δ 199.5, 163.4, 158.1, 144.0, 136.2,
130.4, 130.3, 130.0, 129.6, 126.9, 124.8, 117.7, 114.3, 113.7, 113.6,
55.3, 55.0, 48.2, 45.1, 44.5; HRMS (ESI-TOF) calcd for
C24H23NNaO3 (M + Na)+ 396.1570, found 396.1573.
3-(Bromomethyl)-4-phenyl-1,2,3,4-tetrahydroquinoline (6j). Yield
223.1 mg (77%, white crystals): mp 95−96 °C; IR (neat): νmax 3414,
2919, 1605, 1492, 1316, 746, 700 cm−1; 1H NMR (300 MHz, CDCl3)
δ 7.24−7.11 (m, 3H), 7.03 (dd, 2H, J = 8.4, 1.5 Hz), 6.94 (td, 1H, J =
7.8, 1.2 Hz), 6.66 (d, 1H, J = 7.2 Hz), 6.51 (t, 2H, J = 7.2 Hz), 3.99 (d,
1H, J = 6.0 Hz), 3.76 (br s, 1H), 3.37 (dd, 1H, J = 10.2, 5.1 Hz), 3.32−
3.25 (m, 2H), 3.20 (dd, 1H, J = 11.7, 6.3 Hz), 2.32−2.22 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 145.2, 143.9, 131.2, 128.9, 128.5, 127.5,
126.5, 121.5, 117.8, 114.2, 46.9, 42.2, 42.1, 36.0; HRMS (ESI-TOF)
calcd for C16H17BrN (Br-79) (M + H)+ 302.0539, found 302.0537.
4-(4-Methoxyphenyl)-3-nitro-1,2,3,4-tetrahydroquinoline (6k).
Yield 117 mg (77%, yellow solid); mp 106−107 °C; IR (neat): νmax
1
3412, 2837, 1607, 1544, 1509, 1248, 1030, 830, 750 cm−1; H NMR
(300 MHz, CDCl3) δ 7.10−7.06 (m, 3H), 6.88−6.80 (m, 3H), 6.70−
6.60 (m, 2H), 4.86−4.79 (m, 2H), 4.00 (br s, 1H), 3.88−3.81 (m,
1H), 3.79 (s, 3H), 3.63 (dd, 1H, J = 12.0, 2.7 Hz); 13C NMR (75
MHz, CDCl3) δ 159.0, 142.7, 133.4, 130.5, 129.9, 127.9, 120.3, 118.7,
114.7, 114.3, 85.3, 55.3, 45.8, 42.4; HRMS (ESI-TOF) calcd for
C16H17N2O3 (M + H)+ 285.1234, found 285.1231.
3,4-Diphenyl-1,2,3,4-tetrahydroquinoline (6l). Yield 101.6 mg
(71%, reddish-orange solid): mp 98−99 °C; IR (neat): νmax 3409,
1495, 1452 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.21−7.07 (m, 6H),
7.05−6.97 (m, 5H), 6.69 (d, 1H, J = 6.0 Hz), 6.59−6.53 (m, 2H), 4.24
(d, 1H, J = 9.0 Hz), 3.47−3.38 (m, 2H), 3.23 (td, 1H, J = 9.0, 3.0 Hz);
13C NMR (75 MHz, CDCl3) δ 145.0, 144.7, 142.7, 130.7, 129.1, 128.2,
(4-(4-Chlorophenyl)-1,2,3,4-tetrahydroquinolin-3-yl)(4-
methoxyphenyl)methanone (6d). Yield 43 mg (24%, yellow oil); IR
(neat): νmax 3393, 2935, 2839, 1165, 1599, 1489, 1259, 1169, 750
1
cm−1; H NMR (300 MHz, CDCl3) 7.79−7.75 (m, 2H), 7.18−7.10
(m, 5H), 7.04−6.99 (m, 1H), 6.86−6.81 (m, 2H), 6.66−6.56 (m, 3H),
4.60 (d, 1H, J = 9.6 Hz) 3.99 (d, 1H, J = 9.3, 4.2 Hz), 3.81 (s, 3H),
3.48−3.36 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 199.0, 163.6,
144.0, 142.8, 132.2, 130.5, 130.4, 130.3, 129.3, 128.5, 127.2, 124.0,
117.9, 114.5, 113.8, 55.4, 48.2, 45.2, 44.6; HRMS (ESI-TOF) calcd for
C23H20ClNNaO2 (M + Na)+ (Cl-35) 400.1075, found 400.1076.
1-(4-(4-Methoxyphenyl)-1,2,3,4-tetrahydroquinolin-3-yl)-2,2-di-
methylpropan-1-one (6f). Yield 108.3 mg (72%, yellow crystal): mp
124−126 °C; IR (neat): νmax 3398, 1695, 1608, 1586, 1509, 1240.
1176 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.05−6.96 (m, 3H), 6.80−
6.76 (m, 2H), 6.69−6.67 (m, 1H), 6.58−6.54 (m, 2H), 4.40 (d, 1H, J
= 12.0 Hz), 3.77 (s, 3H), 3.54 (td, 1H, J = 21.0, 3.0 Hz), 3.35−3.19
(m, 2H), 0.80 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 216.0, 158.4,
143.9, 135.8, 130.5, 130.3, 126.9, 125.2, 117.7, 114.2, 113.7, 55.2, 48.9,
46.1, 45.8, 44.8, 25.4; HRMS (ESI-TOF) calcd for C21H25NNaO2 (M
+ Na)+ 346.1778, found 346.1775.
128.0, 127.7, 127.0, 126.4, 126.1, 124.7, 117.4, 114.2, 50.1, 47.4, 46.9;
HRMS (ESI-TOF) calcd for C21H20N (M + H)+ 286.1590, found
286.1582.
3,4-Diphenyl-1,2,3,4-tetrahydroquinoline (6m). Yield 76.1 mg
(28%, white solid): mp 155−156 °C; IR (neat): νmax 3415, 2889,
1606, 1493, 669 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.18−7.00 (m,
7H), 6.90 (d, 1H, J = 7.5 Hz), 6.72 (dd, 2H, J = 5.4, 1.8 Hz), 6.64−
6.57 (m, 4H), 4.25 (d, 1H, J = 4.5 Hz), 3.85 (br s, 1H), 3.66 (dd, 1H, J
= 11.7, 11.7 Hz), 3.50 (dt, 1H, J = 12.3, 3.6 Hz), 3.28 (dd, 1H, J =
11.1, 2.1 Hz); 13C NMR (75 MHz, CDCl3) δ 143.5, 142.1, 141.1,
130.5, 130.2, 128.0, 127.8, 127.5, 127.1, 126.4, 126.0, 123.7, 117.0,
113.9, 49.9, 42.9, 40.9; HRMS (ESI-TOF) calcd for C21H20N (M +
H)+ 286.1590, found 286.1600.
Ethyl 4-(4-Methoxyphenyl)-1,2,3,4-tetrahydroquinoline-3-car-
boxylate (6g). Yield 119 mg (81%, yellow oil); IR (neat): νmax
3404, 2980, 2836, 2308, 1727, 1608, 1509, 1247, 1176, 1034, 829,
4-(4-Methoxyphenyl)-3-phenyl-1,2,3,4-tetrahydroquinoline (6n-
1). Yield 260.1 mg (93%, white solid); mp 106−107 °C; IR (neat):
1
νmax 3410, 2908, 1496, 1244, 1034, 699 cm−1; H NMR (300 MHz,
1
749 cm−1; H NMR (300 MHz, CDCl3) δ 7.07−7.05 (m, 2H), 6.99
CDCl3) δ 7.24−7.11 (m, 3H), 7.05−6.99 (m, 3H), 6.90 (d, 2H, J = 8.7
Hz), 6.70 (app d, 3H, J = 8.4 Hz), 6.60−6.54 (m, 2H), 4.19 (d, 1H, J =
9.0 Hz), 4.08 (br s, 1H), 3.72 (s, 3H), 3.52−3.40 (m, 2H), 3.24−3.16
(m, 1H); 13C NMR (75 MHz, CDCl3) δ 157.9, 144.8, 142.9, 137.1,
130.7, 130.0, 128.3, 127.8, 127.1, 126.4, 125.1, 117.5, 114.3, 113.5,
55.1, 49.3, 47.5, 47.1; HRMS (ESI-TOF) calcd for C22H22NO (M +
H)+ 316.1696, found 316.1698.
(td, 1H, J = 7.2, 0.9 Hz), 6.83−6.80 (m, 2H), 6.70 (d, 1H, J = 7.5 Hz),
6.58−6.51 (m, 2H), 4.38 (d, 1H, J = 8.4 Hz), 4.01 (qd, 2H, J = 7.2, 1.2
Hz), 3.76 (s, 3H), 3.53−3.37 (m, 2H), 2.95 (td, 1H, J = 8.1, 3.6 Hz),
1.07 (t, 3H, J = 7.2 H); 13C NMR (75 MHz, CDCl3) δ 173.1, 158.2,
143.8, 136.0, 130.1, 129.9, 127.1, 123.0, 117.4, 114.1, 113.6, 60.4, 55.1,
46.8, 44.8, 42.2, 13.9; HRMS (ESI-TOF) calcd for C19H21NNaO3 (M
+ Na)+ 334.1414, found 334.1414.
6-Bromo-4-(4-methoxyphenyl)-3-phenyl-1,2,3,4-tetrahydroqui-
Ethyl 4-(3,4-Dimethoxyphenyl)-1,2,3,4-tetrahydroquinoline-3-
noline (6n-2). Yield 223.0 mg (84%, white solid); mp 87−88 °C; IR
1
(neat): νmax 3414, 2952, 1493, 1247, 1033, 670 cm−1; H NMR (300
carboxylate (6h). Yield 127.1 mg (82%, white solids): mp 125−127
1
°C; IR (neat): νmax 3399, 1726, 1513, 1464, 1250, 1026 cm−1; H
MHz, CDCl3) δ 7.23−7.14 (m, 3H), 7.09 (dd, 1H, J = 8.4, 2.1 Hz),
7.04−7.01 (m, 2H), 6.90−6.86 (m, 2H), 6.81 (dd, 1H, J = 2.1, 0.6
Hz), 6.74−6.70 (m, 2H), 6.46 (d, 1H, J = 8.4 Hz), 4.13 (d, 1H, J = 8.7
Hz), 4.12 (br s, 1H), 3.74 (s, 3H), 3.44−3.42 (m, 2H), 3.19−3.12 (m,
1H); 13C NMR (75 MHz, CDCl3) δ 158.0, 143.7, 142.4, 136.3, 133.0,
129.91, 129.87, 128.3, 127.7, 126.9, 126.5, 115.7, 113.7, 108.9, 55.1,
49.0, 46.8, 46.6; HRMS (ESI-TOF) calcd for C22H21BrNO (Br-79)
(M + H)+ 394.0801, found 394.0802.
NMR (300 MHz, CDCl3) δ 7.01 (td, 1H, J = 6.0, 0.9 Hz), 6.80−6.77
(m, 1H), 6.72−6.78 (m, 3H), 6.60−6.55 (m, 2H), 4.38 (d, 1H, J = 9.0
Hz), 4.10−3.98 (m, 3H), 3.86 (s, 3H), 3.81 (s, 3H), 3.56−3.41 (m,
2H), 2.99 (td, 1H, J = 9.0, 3.0 Hz), 1.09 (t, 3H, J = 7.2 Hz); 13C NMR
(75 MHz, CDCl3) δ 173.1, 148.8, 147.7, 143.8, 136.4, 130.2, 127.2,
122.9, 121.4, 117.5, 114.2, 111.9, 110.3, 60.5, 55.80, 55.76, 46.9, 45.3,
42.5, 14.0; HRMS (ESI-TOF) calcd for C20H24NO4 (M + H)+
342.1700, found 342.1703.
4-Benzyl-4-phenyl-1,2,3,4-tetrahydroquinoline (6p). Yield 83.2
3-Methyl-4-phenyl-1,2,3,4-tetrahydroquinoline (6i). Yield 98.6 mg
(70%, white crystals): mp 84−85 °C; IR (neat): νmax 3412, 1605,
mg (55%, white solid): mp 121−122 °C; IR (neat): νmax 1678,
1
1596, 1573, 1511, 1256, 1076 cm−1; H NMR (300 MHz, CDCl3) δ
I
DOI: 10.1021/acs.joc.5b00375
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
7.39 (dd, 1H, J = 9.0, 3.0 Hz), 7.26−7.03 (m, 9H), 6.93−6.90 (m,
2H), 6.77−6.71 (m, 1H), 6.48 (dd, 1H, J = 9.0, 3.0 Hz), 3.47 (d, 1H, J
= 12.0 Hz), 3.42 (d, 1H, J = 12.0 Hz), 3.05−2.88 (m, 2H), 2.22 (dt,
1H, J = 12.0, 6.0 Hz), 2.13−2.03 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 148.3, 145.2, 138.2, 131.1, 129.4, 128.0, 127.9, 127.6, 127.4,
126.1, 125.8, 125.1, 116.3, 114.7, 47.5, 45.0, 38.2, 33.3; HRMS (ESI-
TOF) calcd for C22H22N (M + H)+ 300.1747, found 300.1737.
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ASSOCIATED CONTENT
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S
* Supporting Information
́
(10) (a) Lokhov, R. E.; Gigolaeva, N. D.; Gusalova, E. G.; Avezov, M.
1H and 13C NMR spectra of all prepared products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: jumreang@cri.or.th
■
Notes
The authors declare no competing financial interest.
(13) (a) Pearson, W. H.; Fang, W.-K. Israel J. Chem. 1997, 37−39.
(b) Desai, P.; Schildknegt, K.; Agrios, K. A.; Mossman, C.; Milligan, G.
ACKNOWLEDGMENTS
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L.; Aube, J. J. Am. Chem. Soc. 2000, 122, 7226−7232. (c) Song, Z.;
This research work was supported in part by grants from
Chulabhorn Research Institute, Mahidol University, Thailand
Research Fund (TRG558008), and the Center of Excellence on
Environmental Health and Toxicology, Science & Technology
Postgraduate Education and Research Development Office
(PERDO), Ministry of Education.
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