Visible-Light-Mediated Oxidative Cyclization of 2-Aminobenzyl Alcohols and Secondary Alcohols Enabled by an Organic Photocatalyst

Article abstract of DOI:10.1021/acs.joc.1c01386

This paper describes a visible-light-mediated oxidative cyclization of 2-aminobenzyl alcohols and secondary alcohols to produce quinolines at room temperature. This photocatalytic method employed anthraquinone as an organic small-molecule catalyst and DMSO as an oxidant. According to this present procedure, a series of quinolines were prepared in satisfactory yields.

Full text of DOI:10.1021/acs.joc.1c01386

pubs.acs.org/joc
Article
Visible-Light-Mediated Oxidative Cyclization of 2‑Aminobenzyl
Alcohols and Secondary Alcohols Enabled by an Organic
Photocatalyst
Jing-xiu Xu, Nan-lian Pan, Jia-xi Chen, and Jin-wu Zhao*
Cite This: J. Org. Chem. 2021, 86, 10747−10754
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: This paper describes a visible-light-mediated
oxidative cyclization of 2-aminobenzyl alcohols and secondary
alcohols to produce quinolines at room temperature. This
photocatalytic method employed anthraquinone as an organic
small-molecule catalyst and DMSO as an oxidant. According to this
present procedure, a series of quinolines were prepared in satisfactory yields.
unique catalysts, although they could provide alternative
approaches to quinoline scaffolds. Therefore, it is highly
desirable to develop a green and practical process for the
synthesis of quinolines.
In recent years, visible-light-mediated photocatalysis has
emerged as a powerful tool to devise novel organic
transformations under mild reaction conditions.12 Compared
to their transition metal counterparts, organic photocatalysts
offer advantages such as simple work-up, low toxicity, and
special reactivity.13 Herein, we wish to report a metal-free
process for the synthesis of quinolines from 2-aminobenzyl
alcohols and secondary alcohols at room temperature enabled
by an organic photocatalyst (Scheme 1).
INTRODUCTION
■
Quinolines represent an important class of nitrogen-containing
heterocycles, which are widely present as key moieties in a
variety of natural products, pharmaceuticals, agrochemicals,
dyestuffs, and materials.1 Moreover, this class of compounds is
also used as an N-donor ligand toward metallic ions and
valuable intermediates in organic synthesis.2 Especially in
medicinal chemistry, quinoline is identified as a privileged
scaffold in terms of its promising biological activities such as
anticancer, anti-HIV, anti-Alzheimer’s, antiviral, antibacterial,
antifungal, anti-inflammatory, or antiplatelet aggregation, and
the potency of quinoline pharmacophore has been validated by
representative clinical drugs such as cinchophen, quinine,
pitavastatin, camptothecin, and so on.3
The high importance of quinolines urges chemists all over
the world to develop procedures for the synthesis of quinoline
derivatives.4 Traditional routes to quinoline frameworks
include Skraup, Doebner−von Miller, Conrad−Limpach,
Ptzinger, and Friedlander syntheses.5 Although the Friedlander
reaction is considered as one of the most direct access to
quinoline skeletons, it possesses a significant disadvantage
owing to the use of unstable 2-aminobenzaldehydes.6 There-
fore, the indirect Friedlander quinoline synthesis is sub-
sequently developed.7 The indirect protocols were first
achieved through the oxidative cyclization of ketones with 2-
aminobenzyl alcohols instead of 2-aminobenzaldehydes, using
a ketone,8 molecular oxygen, or air as an oxidant.9 Recently,
dehydrogenation strategies were developed under the catalysis
of different complexes of metals such as Ru, Ir, Ni, Co, Mn,
and so on.10 These strategies worked without oxidizing
reagents, and some of them could apply to secondary alcohols,
which are considered as suitable alternatives to ketones
because they are easier to handle and store, cheaper, and
more environmentally friendly.11 However, these reported
procedures suffer from drawbacks such as high reaction
temperature, long reaction period, and/or the requirement of
Scheme 1. Visible-Light-Mediated Oxidative Cyclization of
Secondary Alcohols and 2-Aminobenzyl Alcohols
RESULTS AND DISCUSSION
■
In our previous study, we developed a mild protocol for the
synthesis of quinolines through an N-heterocyclic carbene
copper-catalyzed reaction of 2-aminobenzyl alcohols and aryl
ketones using DMSO as an oxidant at room temperature.14
When 1-phenylethan-1-ol was subjected to this reaction, the
Received: June 11, 2021
Published: July 23, 2021
https://doi.org/10.1021/acs.joc.1c01386
J. Org. Chem. 2021, 86, 10747−10754
© 2021 American Chemical Society
10747

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a
Table 1. Optimization of Reaction Conditions
b
entry
PC
oxidant (equiv)
base
solvent
yield (%)
1
2
3
4
5
6
7
8
Rose Bengal
Eosin Y
[Acr-Mes]+ClO4
O2
O2
O2
O2
O2
O2
O2
air
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
NaOH
t-BuONa
t-BuOK
Cs2CO3
NaOH
NaOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
toluene
toluene
dioxane
CH3CN
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
0
0
17
0
15
0
90
90
90
30
36
14
28
0
95
93
90
0
−
thioxanthenone
9-fluorenone
CF3SO2Na
AQ
AQ
AQ
AQ
AQ
AQ
AQ
AQ
AQ
AQ
AQ
AQ
AQ
c
9
10
11
12
13
14
15
16
17
18
O2
DMSO (20)
DMSO (20)
DMSO (20)
DMSO (20)
d
19
20
0
0
a
Reaction conditions: 1a (0.35 mmol), 2a (0.35 mmol), base (2.0 equiv), catalyst (3 mol %), and oxidant (indicated amount) in 1 mL of solvent
b
under the irradiation at 450−460 nm using a 25 W LED lamp at room temperature (cooling by air) for 6 h. GC yield using phenanthrene as an
internal standard. The reaction was purged by nitrogen. The reaction was carried out in the darkness.
c
d
corresponding quinoline could also be obtained. However,
other alcohols performed unacceptably poorly. We decided to
carry out further optimization. With the advantages of
photocatalysis in mind, we turned our attention to the
influence of visible light on the oxidative cyclization of 2-
aminobenzyl alcohol (1a) and 1-phenylethan-1-ol (2a) (Table
1). Given that the indirect Friedlander reaction generally
involves the oxidation of alcohols, we first examined the
photocatalysts that were reportedly employed for this class of
oxidative transformations (entries 1−6), including Rose
With optimal reaction conditions in hand, we explored the
scope and limitations of this reaction (Table 2). A series of
secondary alcohols were first subjected to the oxidative
annulation with 2-aminobenzyl alcohol. 1-Phenylethan-1-ol
possessing a substituent at the para-position of the phenyl ring
was able to undergo this cyclization reaction smoothly,
delivering the target heterocyclic compounds in moderate to
excellent yields (3aa−3aj). Especially, strong electron-donating
alkoxyl and strong electron-withdrawing trifluoromethyl were
well tolerated (3ae and 3aj). 1-Phenylethan-1-ol with a
substituent at the meta-position of the phenyl ring and those
with a substituent at the ortho-position (3ak−3am; 3an−3aq)
could also go across this visible-light-induced oxidative
cyclization reaction, although they provided the corresponding
quinoline products in lower yields, by a yield order of para >
meta > ortho (3ab vs 3ak vs 3an, 3ae vs 3al vs 3ao, and 3aj vs
3aq). These experimental results revealed that steric hindrance
of the group on the phenyl ring of 1-phenylethan-1-ol had an
influence on this transformation. As demonstrated in Table 2,
1-(benzo[d][1,3]dioxol-5-yl)ethan-1-ol and 1-(3,4-
dichlorophenyl)ethan-1-ol were also suitable substrates for
the reaction of photocatalytic quinoline synthesis (3ar−3as).
Our experimental results suggested that secondary ethanols
substituted by heteroaryl, such as pyridyl, thienyl, benzothien-
yl, and furyl, exhibited good reactivities and furnished the
expected heterocycles in 70−93% yields (3at−3ax). Among
them, 2-(pyridin-2-yl)quinoline (3at) was obtained with a
yield of 70% on the gram scale, which reflects the potential
application of this photochemical protocol in the preparation
of N-polydentate ligands. Regarding nonmethyl secondary
benzylic alcohols, cyclic 1,2,3,4-tetrahydronaphthalen-1-ol was
17
Bengal,15 Eosin Y,16 [Mes-Acr]+ClO4 , thioxanthenone,18
−
9-fluorenone,19 and sodium trifluoromethanesulfinate.20
−
Among them, [Mes-Acr]+ClO4 and 9-fluorenone showed
activity under our reaction conditions (entries 3 and 5). To
our delight, in the presence of 3 mol % of anthraquinone
(AQ), the desired heterocyclic compound was obtained in 90%
yield (entry 7). Our experimental results showed that this
reaction proceeded smoothly in a test tube open to air, even
under the atmosphere of nitrogen (entries 8 and 9). These
findings revealed that DMSO played the role of an oxidizing
agent and a reaction medium. Common solvents were then
screened. When this reaction was carried out in toluene using
DMSO or oxygen as an oxidant, 3aa was formed in a lower
yield (entries 10 and 11). Other solvents examined were all not
able to provide better yields compared with DMSO (entries
12−14). A variety of bases were finally investigated. The
screening results indicated that NaOH performed better than
other bases (entries 15−18). Additionally, when 1a and 2a
were stirred in the darkness or in the absence of AQ under the
irradiation, no 3aa was detected with the recovery of starting
materials (entries 19 and 20).
10748
https://doi.org/10.1021/acs.joc.1c01386
J. Org. Chem. 2021, 86, 10747−10754

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a b
,
a b
,
Table 2. Substrate Scope of Secondary Alcohols
Table 3. Substrate Scope of Secondary Alcohols
a
Standard condition: 1 (0.35 mmol), 2a (0.35 mmol), NaOH (28.0
mg) and AQ (2.2 mg) in 1 mL DMSO under the irradiation at 450−
460 nm using a 25 W LED lamp at room temperature (cooling by air)
b
for 6 h. Isolated yield.
Scheme 2. Control Experiments
a
Standard condition: 1a (0.35 mmol), 2 (0.35 mmol), NaOH (28.0
mg) and AQ (2.2 mg) in 1 mL DMSO under the irradiation at 450-
460 nm using a 25 W LED lamp at room temperature (cooling by air)
b
c
for 6 h. Isolated yield. Yield on a 10 mmol scale.
efficiently transformed into 5, 6-dihydrobenzo[c]acridine with
an excellent yield (3ay), while those with a long-chain
substituent produced the desired quinolines in lower yields
(3az and 3azz).
A variety of 2-aminobenzyl alcohols were then investigated,
and the results are summarized in Table 3. 2-Aminobenzyl
alcohols with substituents on the aromatic ring were all able to
go through the oxidative cyclization with 1-phenylethan-1-ol,
affording the desired quinoline skeletons in good to excellent
yields (Table 3, 3ba−3ga). Our experimental results indicated
that (3-aminonaphthalen-2-yl)methanol was an excellent
coupling partner for 2a (3ha). Unexpectedly, (2-
aminophenyl)(phenyl)methanol afforded a higher yield than
1-(2-aminophenyl)ethan-1-ol (3ia−3ja), for the possible
reason that the conjugative effect of phenyl benefited the
oxidation of the benzylic hydroxyl group under photocatalysis
in contrast to other cyclization reactions of 2-aminobenzyl
alcohols and secondary alcohols. Moreover, this visible-light-
induced reaction tolerated (2-aminopyridin-3-yl)methanol,
providing 2-phenyl-1,8-naphthyridine in 78% yield (3ka).
To gain more mechanistic insight into the visible-light-
promoted reaction between secondary alcohols and 2-amino-
benzyl alcohols, some control experiments were carried out
(Scheme 2). Acetophenone was formed in 16% yield when 1-
phenylethan-1-ol went through this reaction in the absence of
2-amimobenzyl alcohol under the standard conditions
(abbreviated as SC) (EQ 1). Irradiating 2a in 1 mL of
DMSO at 450−460 nm provided acetophenone in 55% yield
(EQ 2). 3aa was generated in 99% yield by reacting
acetophenone and 2-aminobenzyl alcohol under the photo-
10749
https://doi.org/10.1021/acs.joc.1c01386
J. Org. Chem. 2021, 86, 10747−10754

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
chemical reaction conditions (EQ 3). Treating 2-amino-
benzaldehyde with 2a or acetophenone led to the formation
of 3aa in 53, 70% yield, respectively (EQ 4 and EQ 5). These
results revealed that 2-aminobenzaldehyde and acetophenone
were the reaction intermediates and the quinoline skeleton was
formed through their Friedlander condensation. When 2.5
equiv of TEMPO or butylated hydroxytoluene was added to
the reaction of 1a and 2a under the SCs, trace amounts of 3aa
were detected by GC−MS (EQ 6 and EQ 7). These results
suggested that this reaction was greatly inhibited by a radical
scavenger, and this visible-light-induced oxidative cyclization
reaction might take place through a free-radical pathway. When
the reaction of 1a and 2a was conducted under an argon
atmosphere in 1 mL of toluene containing 4 equiv of dibenzyl
sulfoxide. Trace amounts of benzyl sulfide were detected by
GC along with 3aa in 44% yield, and no dibenzyl sulfoxide was
detected (EQ 8), which revealed that sulfoxide presumably
functioned as an oxidant and was reduced to thioether in the
photochemical transformation.
EXPERIMENTAL SECTION
■
General Information. All reagents were of analytical grade and
obtained from commercial suppliers and used without further
1
purification. H and 13C{1H} NMR spectra were obtained with a
Bruker AVANCE III HD 400 at 400 and 100 MHz, respectively, using
CDCl3 as the solvent with tetramethylsilane as an internal standard at
room temperature. High-resolution mass spectra were obtained with
an Agilent 6545 Q-TOF LC/MS system using electrospray ionization.
GC−MS was performed using a Thermo Trace DSQ. Column
chromatography was performed using silica gel (200−300 mesh). A
25 W LED light source was assembled from 450−460 nm 2835 LED
beads with a peak wavelength of 455 nm without the use of any filter
(Planck ShenZhen Opto-Electronic Technology Co.,Ltd).
Typical Procedure for the Synthesis of Product 3. To a
quartz test tube (25 mL), AQ (2.2 mg, 0.00105 mmol), secondary
alcohol 1 (0.3 mmol), 2-aminobenzylic alcohol 2 (0.3 mmol), NaOH
(24.0 mg, 2.0 equiv), and 1 mL of DMSO were added. The reaction
mixture was stirred at room temperature under the irradiation at
450−460 nm (25 W LED, distance = 8−10 cm, cooling by air) for 6
h. After this, the reaction was quenched by the addition of 10 mL of
water, and the aqueous solution was extracted with ethyl acetate (3 ×
10 mL). The combined extract was dried with anhydrous MgSO4 and
evaporated under vacuum. The residue was purified by a silica gel-
packed flash chromatography column with petroleum ether/ethyl
acetate (10:1) as the eluent to afford the desired products.
On the basis of above experimental results and previous
reports,21 a possible reaction mechanism was proposed
(Scheme 3). The photocatalyst AQ first absorbs photons to
Scheme 3. Possible Reaction Mechanism
Gram Scale Synthesis. To a quartz test tube (50 mL), AQ (62.5
mg, 0.3 mmol), 1-(pyridin-2-yl)ethan-1-ol (2 t) (1.23 g, 10 mmol), 2-
aminobenzylic alcohol (1a) (1.23 g, 10 mmol), NaOH (0.80 g, 20
mmol), and 25 mL of DMSO were added. The reaction mixture was
stirred at room temperature under the irradiation at 450−460 nm (25
W LED × 3, distance = 8 cm, cooling by air) for 6 h. After this, the
reaction mixture was transferred to a separating funnel and diluted
with ethyl acetate (100 mL); the organic phase was washed three
times with water, dried over MgSO4, and concentrated. The crude
product was purified by a silica gel-packed flash chromatography
column with petroleum ether/ethyl acetate (5:1) as the eluent to give
3at (1.44 g, 70% yield).
2-Phenylquinoline (3aa)10c Purified by column chromatography on
silica gel (petroleum ether/ethyl acetate = 10:1) as a white solid (64.7
mg, 90%), mp 83−84 °C. 1H NMR (400 MHz, CDCl3) δ 8.24−8.17
(m, 4H), 7.89 (d, J = 8.6 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.74 (t, J
= 7.7 Hz, 1H), 7.57−7.53 (m, 3H), 7.48 (t, J = 7.3 Hz, 1H). 13C{1H}
NMR (101 MHz, CDCl3) δ 157.3, 148.2, 139.6, 136.8, 129.7, 129.7,
129.3, 128.8, 127.6, 127.4, 127.2, 126.3, 119.0.
2-(p-Tolyl)quinoline (3ab)10c Purified by column chromatography
on silica gel (petroleum ether/ethyl acetate = 10:1) as a white solid
(69.8 mg, 91%), mp 98−99 °C. 1H NMR (400 MHz, CDCl3) δ 8.19
(dd, J = 8.5, 1.1 Hz, 1H), 8.16−8.05 (m, 3H), 7.82 (d, J = 8.6 Hz,
1H), 7.78 (dd, J = 8.1, 1.5 Hz, 1H), 7.71 (ddd, J = 8.4, 6.9, 1.5 Hz,
1H), 7.49 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H),
2.43 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 157.4, 148.4,
139.4, 137.0, 136.7, 129.7, 129.6, 129.6, 127.5, 127.5, 127.2, 126.1,
118.9, 21.4.
reach its excited state and abstracts a hydrogen atom from the
benzylic position of 1a or 2a through the hydrogen atom
transfer (HAT) process, furnishing a benzylic radical
intermediate A or A′. Subsequently, another HAT process
occurs, and the hydrogen atom of benzylic hydroxyl of the
radical intermediate is abstracted to produce 2-amino-
benzaldehyde B or acetophenone B′. The generated AQH is
oxidized back to AQ by DMSO, which is reduced to dimethyl
sulfide along with a molecule of water. Finally, 2-amino-
benzaldehyde B and acetophenone B′ react through Fried-
lander condensation to yield final product 3aa.
2-(4-Isobutylphenyl)quinoline (3ac)new Purified by column chroma-
tography on silica gel (petroleum ether/ethyl acetate = 10:1) as a
1
white solid (77.8 mg, 85%), mp 58−59 °C. H NMR (400 MHz,
CDCl3) δ 8.25 (d, J = 8.5 Hz, 1H), 8.18 (d, J = 8.6 Hz, 1H), 8.14 (d, J
= 8.1 Hz, 2H), 7.92−7.72 (m, 3H), 7.58−7.44 (m, 1H), 7.36 (d, J =
8.0 Hz, 2H), 2.61 (d, J = 7.2 Hz, 2H), 1.99 (dt, J = 13.5, 6.8 Hz, 1H),
1.01 (d, J = 6.7 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 157.4,
148.3, 143.2, 137.1, 136.6, 129.6, 129.6, 127.4, 127.3, 127.1, 126.1,
118.9, 45.2, 30.2, 22.4. HRMS calcd for C19H19N [M + H]+:
262.1590. Found: 262.1579.
CONCLUSIONS
■
In conclusion, we have developed a visible-light-mediated
process for the oxidative cyclization of secondary alcohols and
2-aminobenzyl alcohols to prepare quinolines at room
temperature enabled by an organic photocatalyst. This
photochemical strategy employed DMSO as an oxidant and
readily available AQ as an organophotocatalyst, avoiding the
requirement of high reaction temperature and special metal-
based catalysts. The oxidation of alcohols to aldehydes or
ketones under the photocatalysis using AQ as a photosensitizer
is underway in our lab.
2-([1,1′-Biphenyl]-4-yl)quinoline (3ad)4c Purified by column
chromatography on silica gel (petroleum ether/ethyl acetate =
1
10:1) as a white solid (91.6 mg, 93%), mp 85−86 °C. H NMR
(400 MHz, CDCl3) δ 8.33−8.21 (m, 4H), 7.95 (d, J = 8.6 Hz, 1H),
7.87 (dd, J = 8.2, 1.4 Hz, 1H), 7.83−7.68 (m, 5H), 7.61−7.47 (m,
3H), 7.45−7.37 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 156.8,
10750
https://doi.org/10.1021/acs.joc.1c01386
J. Org. Chem. 2021, 86, 10747−10754

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
148.2, 142.1, 140.5, 138.3, 136.9, 129.7, 129.6, 128.8, 128.0, 127.6,
127.5, 127.4, 127.2, 127.1, 126.3, 118.9.
CDCl3) δ 8.21−8.13 (m, 2H), 7.95−7.86 (m, 2H), 7.79 (d, J = 8.6
Hz, 2H), 7.72 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H), 7.56−7.40 (m, 2H),
7.14 (tdd, J = 8.4, 2.7, 1.0 Hz, 1H). 13C{1H} NMR (101 MHz,
CDCl3) δ 163.4 (d, J = 243.9 Hz), 155.8 (d, J = 2.6 Hz), 148.2, 141.9
(d, J = 7.3 Hz), 137.1, 130.3 (d, J = 8.0 Hz), 129.9, 129.8, 127.5,
127.4, 126.7, 123.1 (d, J = 2.9 Hz), 118.7, 116.2 (d, J = 21.1 Hz),
114.5 (d, J = 23.0 Hz).
2-(4-Methoxyphenyl)quinoline (3ae)10c Purified by column chro-
matography on silica gel (petroleum ether/ethyl acetate = 10:1) as a
white solid (71.6 mg, 87%), 129−130 °C. 1H NMR (400 MHz,
CDCl3) δ 8.25−8.14 (m, 4H), 7.90−7.80 (m, 2H), 7.74 (ddd, J = 8.4,
6.9, 1.5 Hz, 1H), 7.53 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.11−7.04 (m,
2H), 3.91 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.9, 156.8,
136.8, 129.7, 129.3, 128.9, 127.4, 126.9, 126.0, 118.5, 114.2, 53.9.
2-(4-(Trifluoromethoxy)phenyl)quinoline (3af)new Purified by col-
umn chromatography on silica gel (petroleum ether/ethyl acetate =
10:1) as a white solid (72.9 mg, 72%), mp 98−99 °C. 1H NMR (400
MHz, CDCl3) δ 8.20 (t, J = 9.2 Hz, 3H), 8.12 (d, J = 8.5 Hz, 1H),
7.82−7.71 (m, 3H), 7.54 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.41−7.35
(m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 155.6, 150.1 (q, J =
1.8 Hz), 148.2, 138.1, 136.9, 129.8, 129.7, 129.7, 129.0, 127.4, 127.2,
126.5, 121.0, 120.6 (q, J = 255.9 Hz), 118.4. HRMS calcd for
C16H10F3NO [M + H]+: 290.0787. Found: 290.0796.
2-(o-Tolyl)quinoline (3an)10c Purified by column chromatography
on silica gel (petroleum ether/ethyl acetate = 10:1) as a white solid
(57.6 mg, 75%), 68−69 °C. 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J
= 8.5 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.87 (dd, J = 8.2, 1.6 Hz,
1H), 7.78 (ddd, J = 8.5, 6.9, 1.6 Hz, 1H), 7.63−7.52 (m, 3H), 7.44−
7.32 (m, 3H), 2.49 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
160.3, 147.9, 140.7, 136.1, 136.0, 130.9, 129.7, 129.6, 129.6, 128.5,
127.5, 126.7, 126.4, 126.0, 122.4, 20.4.
2-(2-Methoxyphenyl)quinoline (3ao)11d Purified by column chro-
matography on silica gel (petroleum ether/ethyl acetate = 10:1) as a
1
white solid (59.3 mg, 72%), mp 52−53 °C. H NMR (400 MHz,
2-(4-Bromophenyl)quinoline (3ag)10c Purified by column chroma-
tography on silica gel (petroleum ether/ethyl acetate = 10:1) as a
white solid (85.5 mg, 86%), mp 120−121 °C 1H NMR (400 MHz,
CDCl3) δ 8.22−8.14 (m, 2H), 8.09−8.02 (m, 2H), 7.81 (d, J = 8.5
Hz, 2H), 7.73 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.67−7.62 (m, 2H),
7.53 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H). 13C{1H} NMR (101 MHz,
CDCl3) δ 156.0, 148.2, 138.4, 137.0, 131.9, 129.9, 129.7, 129.1, 127.5,
127.2, 126.5, 123.9, 118.5.
CDCl3) δ 8.16 (dd, J = 16.8, 8.5 Hz, 2H), 7.92−7.80 (m, 3H), 7.71
(td, J = 7.6, 6.9, 1.6 Hz, 1H), 7.57−7.49 (m, 1H), 7.47−7.38 (m, 1H),
7.14 (t, J = 7.5 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 3.87 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 157.2, 157.1, 148.2, 135.0,
131.4, 130.3, 129.7, 129.6, 129.1, 127.3, 127.0, 126.1, 123.4, 121.2,
111.4, 55.6.
2-(2-Fluorophenyl)quinoline (3ap)4c Purified by column chroma-
tography on silica gel (petroleum ether/ethyl acetate = 10:1) as a
2-(4-Chlorophenyl)quinoline (3ah)10c Purified by column chroma-
tography on silica gel (petroleum ether/ethyl acetate = 10:1) as a
1
white solid (68.0 mg, 87%), mp 85−86 °C. H NMR (400 MHz,
CDCl3) δ 8.25 (d, J = 8.5 Hz, 1H), 8.17 (dd, J = 9.4, 6.8 Hz, 2H),
7.90 (dd, J = 8.6, 2.7 Hz, 1H), 7.81 (dt, J = 8.5, 2.1 Hz, 1H), 7.75
(ddd, J = 8.5, 6.8, 1.6 Hz, 1H), 7.54 (dd, J = 8.3, 7.0 Hz, 1H), 7.43
(dtd, J = 7.4, 5.2, 2.4 Hz, 1H), 7.34 (td, J = 7.6, 1.4 Hz, 1H), 7.23
(ddd, J = 11.2, 8.1, 1.5 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ
160.8, (d, J = 248.0 Hz), 154.0 (d, J = 2.0 Hz), 148.3, 136.1, 131.6 (d,
J = 3.0 Hz), 130.8 (d, J = 8.4 Hz), 129.7, 129.6, 127.9 (d, J = 11.7
Hz), 127.5, 127.2, 126.6, 124.7 (d, J = 3.6 Hz), 122.4 (d, J = 8.0 Hz),
116.2 (d, J = 22.6 Hz).
1
white solid (73.0 mg, 87%), mp 111−112 °C. H NMR (400 MHz,
CDCl3) δ 8.23−8.09 (m, 4H), 7.84−7.71 (m, 3H), 7.59−7.47 (m,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 155.8, 148.1, 137.9, 136.9,
135.5, 129.8, 129.6, 129.0, 128.8, 127.5, 127.2, 126.5, 118.4.
2-(4-Fluorophenyl)quinoline (3ai)10c Purified by column chroma-
tography on silica gel (petroleum ether/ethyl acetate = 10:1) as a
1
white solid (71.8 mg, 92%), mp 100−101 °C H NMR (400 MHz,
CDCl3) δ 8.22−8.09 (m, 4H), 7.79 (td, J = 5.5, 2.8 Hz, 2H), 7.72
(ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.51 (ddd, J = 8.0, 6.8, 1.1 Hz, 1H),
7.24−7.15 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 163.8 (d, J
= 247.2 Hz), 156.2, 148.2, 136.9, 135.8 (d, J = 3.3 Hz), 129.8, 129.7,
129.4 (d, J = 8.4 Hz), 127.5, 127.1, 126.4, 118.6, 115.8 (d, J = 21.5
Hz).
2-(2-(Trifluoromethyl)phenyl)quinoline (3aq)10c Purified by column
chromatography on silica gel (petroleum ether/ethyl acetate = 10:1)
as a white solid (66.0 mg, 69%), mp 77−78 °C. 1H NMR (400 MHz,
CDCl3) δ 8.22 (t, J = 7.6 Hz, 2H), 7.89 (d, J = 8.2 Hz, 1H), 7.83 (d, J
= 8.0 Hz, 1H), 7.78 (t, J = 7.7 Hz, 1H), 7.73−7.53 (m, 5H). 13C{1H}
NMR (101 MHz, CDCl3) δ 158.0, 147.6, 140.2 (q, J = 1.4 Hz), 136.0,
131.7, 131.5, 129.9, 129.6, 128.5, 128.5, 127.5, 127.0, 126.8, 126.4 (q,
J = 5.1 Hz), 124.1 (q, J = 272.3 Hz), 121.9 (q, J = 2.2 Hz).
2-(Benzo[d][1,3]dioxol-5-yl)quinoline (3ar)4d Purified by column
chromatography on silica gel (petroleum ether/ethyl acetate = 10:1)
2-(4-(Trifluoromethyl)phenyl)quinoline (3aj)10c Purified by column
chromatography on silica gel (petroleum ether/ethyl acetate = 10:1)
1
as a white solid (85.1 mg, 89%), mp 144−145 °C. H NMR (400
MHz, CDCl3) δ 8.31−8.26 (m, 2H), 8.26−8.22 (m, 1H), 8.21 (dt, J =
8.6, 0.9 Hz, 1H), 7.90−7.81 (m, 2H), 7.81−7.71 (m, 3H), 7.57 (ddd,
J = 8.1, 6.9, 1.2 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 155.6,
148.2, 142.9, 137.2, 131.1 (q, J = 32.4 Hz), 130.1, 129.8, 127.9, 127.6,
127.5, 126.9, 125.8 (q, J = 3.7 Hz), 124.2 (q, J = 270.5 Hz), 118.8.
2-(m-Tolyl)quinoline (3ak)4c Purified by column chromatography
on silica gel (petroleum ether/ethyl acetate = 10:1) as a white solid
(63.7 mg, 83%), 59−60 °C. 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J
= 8.7 Hz, 1H), 8.18 (d, J = 8.6 Hz, 1H), 8.09 (d, J = 2.3 Hz, 1H), 7.99
(d, J = 7.8 Hz, 1H), 7.89−7.74 (m, 3H), 7.54 (ddd, J = 8.2, 6.9, 1.2
Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 2.53 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 157.5, 148.2, 139.6, 138.5,
136.7, 130.1, 129.7, 129.6, 128.7, 128.3, 127.5, 127.2, 126.2, 124.7,
119.1, 21.6.
1
as a white solid (74.2 mg, 85%), mp 105−106 °C. H NMR (400
MHz, CDCl3) δ 8.18 (d, J = 8.5 Hz, 1H), 8.10 (d, J = 8.6 Hz, 1H),
7.81−7.65 (m, 5H), 7.50 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 6.96 (d, J =
8.1 Hz, 1H), 6.02 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ
156.5, 148.8, 148.4, 148.1, 136.6, 134.0, 129.6, 129.5, 127.4, 126.9,
126.0, 121.7, 118.5, 108.4, 107.9, 101.3.
2-(3,4-Dichlorophenyl)quinoline (3as)4d Purified by column chro-
matography on silica gel (petroleum ether/ethyl acetate = 10:1) as a
1
white solid (73.9 mg, 77%), mp 116−117 °C. H NMR (400 MHz,
CDCl3) δ 8.25 (d, J = 2.1 Hz, 1H), 8.12 (dd, J = 8.7, 4.6 Hz, 2H),
7.91 (dd, J = 8.4, 2.2 Hz, 1H), 7.80−7.67 (m, 3H), 7.54−7.47 (m,
2H). 13C{1H} NMR (101 MHz, CDCl3) δ 154.5, 148.1, 139.4, 137.1,
133.5, 133.1, 130.7, 130.0, 129.7, 129.4, 127.5, 127.4, 126.8, 126.5,
118.2.
2-(3-Methoxyphenyl)quinoline (3al)11d Purified by column chroma-
tography on silica gel (petroleum ether/ethyl acetate = 10:1) as a
1
2-(Pyridin-2-yl)quinoline (3at)11c Purified by column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate = 5:1) as a white
solid (56.3 mg, 78%), mp 96−97 °C. 1H NMR (400 MHz, CDCl3) δ
8.71 (ddd, J = 4.7, 1.9, 0.9 Hz, 1H), 8.63 (dt, J = 8.0, 1.1 Hz, 1H),
8.55 (d, J = 8.6 Hz, 1H), 8.23 (dd, J = 8.6, 0.8 Hz, 1H), 8.17 (dq, J =
8.6, 0.9 Hz, 1H), 7.87−7.77 (m, 2H), 7.70 (ddd, J = 8.4, 6.9, 1.5 Hz,
1H), 7.50 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.30 (ddd, J = 7.5, 4.8, 1.2
Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 156.3, 156.1, 149.1,
147.9, 136.8, 136.7, 129.8, 129.5, 128.2, 127.6, 126.7, 123.9, 121.8,
118.9.
white solid (65.9 mg, 80%), mp 69−70 °C. H NMR (400 MHz,
CDCl3) δ 8.25 (d, J = 8.5 Hz, 1H), 8.11 (dd, J = 8.7, 2.8 Hz, 1H),
7.85 (q, J = 2.0 Hz, 1H), 7.80 (dd, J = 8.6, 2.0 Hz, 1H), 7.78−7.69
(m, 3H), 7.52−7.40 (m, 2H), 7.07−7.01 (m, 1H), 3.90 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 160.3, 157.1, 148.3, 141.2,
136.8, 129.9, 129.8, 129.8, 127.6, 127.4, 126.4, 120.1, 119.1, 115.4,
112.9, 55.4.
2-(3-Fluorophenyl)quinoline (3am)4c Purified by column chroma-
tography on silica gel (petroleum ether/ethyl acetate = 10:1) as a
1
white solid (71.1 mg, 91%), mp 91−92 °C. H NMR (400 MHz,
10751
https://doi.org/10.1021/acs.joc.1c01386
J. Org. Chem. 2021, 86, 10747−10754

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
2-(Thiophen-3-yl)quinoline (3au)4c Purified by column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate = 10:1) as a white
solid (67.3 mg, 91%), mp 133−134 °C. 1H NMR (400 MHz, CDCl3)
δ 8.06 (t, J = 7.7 Hz, 2H), 7.97 (d, J = 2.7 Hz, 1H), 7.82 (d, J = 4.9
Hz, 1H), 7.67 (dq, J = 14.7, 7.9 Hz, 3H), 7.42 (t, J = 7.4 Hz, 1H),
7.36 (dd, J = 5.0, 2.7 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ
153.3, 148.3, 142.7, 136.8, 129.8, 129.5, 127.6, 127.2, 127.0, 126.5,
126.2, 124.8, 119.2.
CDCl3) δ 8.10 (ddd, J = 18.3, 9.6, 4.7 Hz, 4H), 7.83 (dd, J = 8.6, 2.6
Hz, 1H), 7.52 (t, J = 7.7 Hz, 2H), 7.42 (dd, J = 25.0, 8.4 Hz, 2H),
7.09 (s, 1H), 3.94 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
157.6, 155.0, 144.3, 139.7, 135.4, 131.1, 128.9, 128.7, 128.0, 127.2,
122.2, 119.2, 104.9, 55.5.
6-Fluoro-2-phenylquinoline (3da)4c Purified by column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate = 10:1) as a white
solid (64.1 mg, 82%), mp 95−96 °C. 1H NMR (400 MHz, CDCl3) δ
8.17 (tt, J = 7.3, 3.1 Hz, 4H), 7.89 (dd, J = 8.6, 2.7 Hz, 1H), 7.59−
7.39 (m, 5H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.4 (d, J =
247.9 Hz), 154.1, 145.4, 139.3, 136.1 (d, J = 5.2 Hz), 132.2 (d, J = 9.1
Hz), 129.4, 128.9, 127.8, 127.7 (d, J = 9.6 Hz), 127.5, 119.85 (d, J =
26.8 Hz), 110.47 (d, J = 21.6 Hz).
2-(Thiophen-2-yl)quinoline (3av)10c Purified by column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate = 10:1) as a white
solid (66.6 mg, 90%), mp 115−116 °C. 1H NMR (400 MHz, CDCl3)
δ 8.17 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.76−7.69 (m,
4H), 7.48 (t, J = 7.2 Hz, 2H), 7.17 (dd, J = 5.0, 3.7 Hz, 1H). 13C{1H}
NMR (101 MHz, CDCl3) δ 152.3, 148.1, 145.4, 136.6, 129.8, 129.2,
128.6, 128.1, 127.5, 127.2, 126.1, 125.9, 117.6.
6-Chloro-2-phenylquinoline (3ea)4c Purified by column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate = 10:1) as a white
solid (67.1 mg, 80%), mp 114−115 °C. 1H NMR (400 MHz, CDCl3)
δ 8.17−8.10 (m, 2H), 8.07 (d, J = 9.0 Hz, 1H), 7.94 (dd, J = 8.7, 0.8
Hz, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.61 (dd,
J = 9.0, 2.4 Hz, 1H), 7.55−7.43 (m, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 157.4, 146.7, 139.2, 135.8, 131.9, 131.4, 130.6, 129.7, 129.0,
127.7, 127.6, 126.2, 119.7.
2-(Benzo[b]thiophen-2-yl)quinoline (3aw)22a Purified by column
chromatography on silica gel (petroleum ether/ethyl acetate = 10:1)
1
as a light yellow solid (85.1 mg, 93%), mp 106−107 °C. H NMR
(400 MHz, CDCl3) δ 8.18 (t, J = 7.7 Hz, 2H), 7.99 (s, 1H), 7.92 (d, J
= 8.3 Hz, 2H), 7.88−7.83 (m, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.75
(ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.60−7.49 (m, 1H), 7.47−7.36 (m,
2H), 13C{1H} NMR (101 MHz, CDCl3) δ 152.2, 148.0, 145.3, 141.1,
140.4, 136.6, 129.9, 129.4, 127.5, 127.4, 126.5, 125.3, 124.5, 124.3,
122.6, 122.5, 117.8.
7-Bromo-2-phenylquinoline (3fa)22b Purified by column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate = 10:1) as a white
solid (82.5 mg, 83%), mp 132−133 °C. 1H NMR (400 MHz, CDCl3)
δ 8.37 (d, J = 1.9 Hz, 1H), 8.21−8.12 (m, 3H), 7.89 (d, J = 8.6 Hz,
1H), 7.69 (d, J = 8.6 Hz, 1H), 7.61 (dd, J = 8.6, 1.9 Hz, 1H), 7.57−
7.47 (m, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 158.2, 148.9,
139.2, 136.7, 132.1, 129.8, 129.7, 128.9, 128.7, 127.6, 125.8, 123.7,
119.3.
2-(Furan-2-yl)quinoline (3ax)10c Purified by column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate = 10:1) as a light
1
brown solid (47.8 mg, 70%), mp 96−97 °C. H NMR (400 MHz,
CDCl3) δ 8.14 (dd, J = 16.3, 8.6 Hz, 2H), 7.85−7.67 (m, 3H), 7.63
(d, J = 1.8 Hz, 1H), 7.48 (td, J = 7.4, 6.8, 1.2 Hz, 1H), 7.23 (d, J = 3.5
Hz, 1H), 6.58 (dd, J = 3.4, 1.8 Hz, 1H). 13C{1H} NMR (101 MHz,
CDCl3) δ 153.6, 148.9, 148.0, 144.0, 136.6, 129.8, 129.3, 127.5, 127.1,
126.1, 117.4, 112.2, 110.1.
6,8-Dibromo-2-phenylquinoline (3ga)22b Purified by column chro-
matography on silica gel (petroleum ether/ethyl acetate = 10:1) as a
1
5,6-Dihydrobenzo[c]acridine (3ay)10c Purified by column chroma-
tography on silica gel (petroleum ether/ethyl acetate = 10:1) as a
white solid (96.6 mg, 76%), mp 139−140 °C. H NMR (400 MHz,
CDCl3) δ 8.26−8.19 (m, 2H), 8.06 (d, J = 2.1 Hz, 1H), 7.89 (d, J =
8.7 Hz, 1H), 7.82−7.71 (m, 2H), 7.57−7.43 (m, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 157.4, 143.6, 138.2, 136.1, 135.8, 130.0, 129.2,
128.9, 128.7, 127.5, 126.5, 119.7, 119.2.
1
white solid (74.5 mg, 92%), mp 68−69 °C. H NMR (400 MHz,
CDCl3) δ 8.57 (d, J = 7.7 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.85 (s,
1H), 7.69 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.42 (dt, J =
11.9, 7.5 Hz, 2H), 7.34 (t, J = 7.3 Hz, 1H), 7.28−7.19 (m, 1H), 3.07
(dd, J = 8.3, 5.5 Hz, 2H), 2.96 (dd, J = 8.4, 5.5 Hz, 2H). 13C{1H}
NMR (101 MHz, CDCl3) δ 153.4, 147.6, 139.5, 134.7, 133.8, 130.6,
129.7, 129.4, 128.7, 128.0, 127.9, 127.4, 127.0, 126.1, 126.1, 28.9,
28.4.
2-Phenylbenzo[g]quinoline (3ha)22c Purified by column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate = 10:1) as a white
solid (84.0 mg, 94%), mp 88−89 °C. 1H NMR (400 MHz, CDCl3) δ
9.01 (d, J = 8.7 Hz, 1H), 8.64 (d, J = 8.2 Hz, 1H), 8.22 (d, J = 7.6 Hz,
2H), 8.10 (d, J = 9.1 Hz, 1H), 8.02 (t, J = 8.3 Hz, 2H), 7.95 (d, J = 7.8
Hz, 1H), 7.68 (dt, J = 22.3, 7.3 Hz, 2H), 7.55 (t, J = 7.5 Hz, 2H), 7.48
(t, J = 7.3 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 156.9,
148.2, 139.4, 131.7, 131.6, 131.1, 129.7, 129.3, 128.9, 128.8, 128.6,
127.5, 127.2, 127.1, 124.2, 122.7, 118.8.
3-Methyl-2-phenylquinoline (3az)4d Purified by column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate = 10:1) as a white
solid (57.7 mg, 75%), mp 43−44 °C. 1H NMR (400 MHz, CDCl3) δ
8.14 (d, J = 8.4 Hz, 1H), 7.99 (s, 1H), 7.76 (dd, J = 8.0, 1.4 Hz, 1H),
7.65 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.60−7.57 (m, 2H), 7.52−7.39
(m, 4H), 2.44 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.5,
146.5, 140.8, 136.9, 129.3, 129.2, 128.9, 128.9, 128.4, 128.3, 127.6,
126.8, 126.5, 20.7.
4-Methyl-2-phenylquinoline (3ia)4c Purified by column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate = 10:1) as a white
solid (62.2 mg, 81%), mp 70−71 °C. 1H NMR (400 MHz, CDCl3) δ
8.26 (d, J = 8.4 Hz, 1H), 8.24−8.18 (m, 2H), 7.98 (dd, J = 8.3, 1.5
Hz, 1H), 7.75 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.71 (d, J = 1.5 Hz,
1H), 7.61−7.46 (m, 4H), 2.73 (d, J = 2.1 Hz, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 156.9, 148.0, 144.8, 139.7, 130.2, 129.3, 129.2,
128.7, 127.5, 127.2, 126.0, 123.6, 119.6, 18.9.
2-Phenyl-3-propylquinoline (3azz)11d Purified by column chroma-
tography on silica gel (petroleum ether/ethyl acetate = 10:1) as a
white solid (49.3 mg, 47%), mp 39−41 °C.1H NMR (400 MHz,
CDCl3) δ 8.18 (d, J = 8.5 Hz, 1H), 8.07 (s, 1H), 7.84 (dd, J = 8.2, 1.5
Hz, 1H), 7.70 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.63−7.45 (m, 6H),
2.84−2.75 (m, 2H), 1.61 (h, J = 7.4 Hz, 2H), 0.90 (t, J = 7.4 Hz,
3H).13C{1H} NMR (101 MHz, CDCl3) δ 160.7, 146.2, 140.8, 135.8,
133.8, 129.1, 128.8, 128.7, 128.2, 128.0, 127.6, 126.9, 126.4, 34.8,
23.6, 13.8.
2,4-Diphenylquinoline (3ja)4c Purified by column chromatography
on silica gel (petroleum ether/ethyl acetate = 10:1) as a white solid
1
(89.6 mg, 91%), mp 116−117 °C. H NMR (400 MHz, CDCl3) δ
8.36 (dd, J = 8.4, 1.2 Hz, 1H), 8.31−8.25 (m, 2H), 7.97 (dd, J = 8.4,
1.4 Hz, 1H), 7.89 (s, 1H), 7.79 (ddd, J = 8.4, 6.7, 1.5 Hz, 1H), 7.66−
7.48 (m, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 156.8, 149.2,
148.8, 139.6, 138.4, 130.1, 129.6, 129.6, 129.4, 128.9, 128.6, 128.4,
127.6, 126.4, 125.8, 125.6, 119.3.
6-Methyl-2-phenylquinoline (3ba)4c Purified by column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate = 10:1) as a white
solid (69.8 mg, 91%), mp 80−81 °C. 1H NMR (400 MHz, CDCl3) δ
8.24−8.18 (m, 2H), 8.15 (d, J = 8.5 Hz, 1H), 8.09−8.04 (m, 1H),
7.81 (d, J = 8.6 Hz, 1H), 7.59 (t, J = 1.8 Hz, 1H), 7.57−7.53 (m, 3H),
7.53−7.46 (m, 1H), 2.55 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 156.5, 147.0, 139.9, 136.1, 136.1, 132.0, 129.5, 129.2, 128.9, 127.5,
127.3, 126.4, 119.0, 21.7.
2-Phenyl-1,8-naphthyridine (3ka)4d Purified by column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate = 2:1) as a light
1
brown solid (52.0 mg, 72%), 120−121 58−59 °C. H NMR (400
MHz, CDCl3) δ 9.09 (d, J = 4.1 Hz, 1H), 8.32−8.26 (m, 2H), 8.20−
8.09 (m, 2H), 7.94 (d, J = 8.5 Hz, 1H), 7.54−7.36 (m, 4H). 13C{1H}
NMR (101 MHz, CDCl3) δ 160.1, 156.0, 153.7, 138.4, 137.7, 136.7,
130.0, 128.7, 127.8, 121.7, 121.6, 119.6.
6-Methoxy-2-phenylquinoline (3ca)4c Purified by column chroma-
tography on silica gel (petroleum ether/ethyl acetate = 10:1) as a
1
white solid (76.6 mg, 93%), mp 121−122 °C H NMR (400 MHz,
10752
https://doi.org/10.1021/acs.joc.1c01386
J. Org. Chem. 2021, 86, 10747−10754

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(b) Kouznetsov, V.; Mendez, L.; Gomez, C. Recent Progress in the
Synthesis of Quinolines. Curr. Org. Chem. 2005, 9, 141−161.
(c) Batista, V. F.; Pinto, D. C. G. A.; Silva, A. M. S. Synthesis of
Quinolines: A Green Perspective. ACS Sustainable Chem. Eng. 2016,
4, 4064−4078.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01386.
■
sı
(6) Marco-Contelles, J.; Pérez-Mayoral, E.; Samadi, A.; Carreiras, M.
Details on the experimental procedure and character-
ization data of all compounds (PDF)
̈
D. C.; Soriano, E. Recent Advances in the Friedlander Reaction.
Chem. Rev. 2009, 109, 2652−2671.
(7) (a) Li, H.-J.; Wang, C.-C.; Zhu, S.; Dai, C.-Y.; Wu, Y.-C.
Ruthenium(II)-Catalyzed Hydrogen Transfer/Annulation Cascade
Processes between Alcohols and 2-Nitrobenzaldehydes. Adv. Synth.
Catal. 2015, 357, 583−588. (b) Xie, F.; Zhang, M.; Chen, M.; Lv, W.;
Jiang, H. Convenient Synthesis of Quinolines from alpha-2-Nitroaryl
Alcohols and Alcohols via a Ruthenium-catalyzed Hydrogen Transfer
Strategy. ChemCatChem 2015, 7, 349−353. (c) Rubio-Presa, R.;
Suárez-Pantiga, S.; Pedrosa, M. R.; Sanz, R. Molybdenum-Catalyzed
AUTHOR INFORMATION
Corresponding Author
Jin-wu Zhao − School of Pharmacy, Guangdong Medical
University, Dongguan 523808, China; orcid.org/0000-
0002-0434-4711; Email: jwzhao@gdmu.edu.cn
■
Authors
̈
Sustainable Friedlander Synthesis of Quinolines. Adv. Synth. Catal.
2018, 360, 2216−2220.
Jing-xiu Xu − School of Pharmacy, Guangdong Medical
University, Dongguan 523808, China
(8) (a) Porcheddu, A.; Chelucci, G. Base-Mediated Transition-
Metal-Free Dehydrative C-C and C-N Bond-Forming Reactions from
Alcohols. Chem. Rec. 2019, 19, 2398−2435. (b) Cho, C. S.; Kim, B.
T.; Kim, T. J.; Shim, S. C. Ruthenium-catalysed Oxidative Cyclisation
of 2-Aminobenzyl Alcohol with Ketones: Modified Friedlaender
Quinoline Synthesis. Chem. Commun. 2001, 2576−2577. (c) Martínez,
Nan-lian Pan − School of Pharmacy, Guangdong Medical
University, Dongguan 523808, China
Jia-xi Chen − School of Pharmacy, Guangdong Medical
University, Dongguan 523808, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01386
̈
R.; Ramón, D. J.; Yus, M. Transition-Metal-Free Indirect Friedlander
Synthesis of Quinolines from Alcohols. J. Org. Chem. 2008, 73, 9778−
9780. (d) Zhu, Y.; Cai, C. An N-heterocyclic Carbene-catalyzed
Notes
̈
Approach to the Indirect Friedlander Quinoline Synthesis. RSC Adv.
The authors declare no competing financial interest.
2014, 4, 52911−52914. (e) Rahul, P.; Nitha, P. R.; Omanakuttan, V.
K.; Babu, S. A.; Sasikumar, P.; Praveen, V. K.; Hopf, H.; John, J.
ACKNOWLEDGMENTS
■
̈
Superbase-Mediated Indirect Friedlander Reaction: A Transition
The authors thank Discipline Construction Project of
Guangdong Medical University (4SG21004G) for financial
support.
Metal-Free Oxidative Annulation Toward Functionalized Quinolines.
Eur. J. Org. Chem. 2020, 2020, 3081−3089.
(9) (a) Yao, S.; Zhou, K.; Wang, J.; Cao, H.; Yu, L.; Wu, J.; Qiu, P.;
Xu, Q. Synthesis of 2-Substituted Quinazolines by CsOH-mediated
Direct Aerobic Oxidative Cyclocondensation of 2-Aminoarylmetha-
nols with Nitriles in Air. Green Chem. 2017, 19, 2945−2951.
(b) Chen, B. W. J.; Chng, L. L.; Yang, J.; Wei, Y.; Yang, J.; Ying, J. Y.
Palladium-Based Nanocatalyst for One-Pot Synthesis of Polysub-
stituted Quinolines. ChemCatChem 2013, 5, 277−283. (c) Cho, C. S.;
Ren, W. X.; Yoon, N. S. A Recyclable Copper Catalysis in Modified
REFERENCES
■
(1) (a) Prajapati, S. M.; Patel, K. D.; Vekariya, R. H.; Panchal, S. N.;
Patel, H. D. Recent Advances in the Synthesis of Quinolines: A
Review. RSC Adv. 2014, 4, 24463−24476. (b) Shang, X.-F.; Morris-
Natschke, S. L.; Yang, G.-Z.; Liu, Y.-Q.; Guo, X.; Xu, X.-S.; Goto, M.;
Li, J.-C.; Zhang, J.-Y.; Lee, K.-H. Biologically Active Quinoline and
Quinazoline Alkaloids Part II. Med. Res. Rev. 2018, 38, 1614−1660.
(2) Romero, E. A.; Chen, G.; Gembicky, M.; Jazzar, R.; Yu, J.-Q.;
Bertrand, G. Understanding the Activity and Enantioselectivity of
Acetyl-Protected Aminoethyl Quinoline Ligands in Palladium-
Catalyzed beta-C(sp(3))-H Bond Arylation Reactions. J. Am. Chem.
Soc. 2019, 141, 16726−16733.
̈
Friedlander Quinoline Synthesis. J. Mol. Catal. A: Chem. 2009, 299,
117−120.
(10) (a) Chelucci, G.; Porcheddu, A. Synthesis of Quinolines via a
Metal-Catalyzed Dehydrogenative N- Heterocyclization. Chem. Rec.
2017, 17, 200−216. (b) Li, H.; Guo, H.; Fang, Z.; Aida, T. M.; Smith,
R. L. Cycloamination Strategies for Renewable N-heterocycles. Green
Chem. 2020, 22, 582−611. (c) Lan, X.; Ye, Z.; Huang, M.; Liu, J.; Liu,
Y.; Ke, Z. Nonbifunctional Outer-Sphere Strategy Achieved Highly
Active α-Alkylation of Ketones with Alcohols by N-Heterocyclic
Carbene Manganese (NHC-Mn). Org. Lett. 2019, 21, 8065−8070.
(11) (a) Maji, M.; Chakrabarti, K.; Panja, D.; Kundu, S. Sustainable
synthesis of N-heterocycles in water using alcohols following the
double dehydrogenation strategy. J. Catal. 2019, 373, 93−102.
(b) Wei, D.; Dorcet, V.; Darcel, C.; Sortais, J.-B. Synthesis of
Quinolines Through Acceptorless Dehydrogenative Coupling Cata-
lyzed by Rhenium PN(H)P Complexes. ChemSusChem 2019, 12,
3078−3082. (c) Hu, W.; Zhang, Y.; Zhu, H.; Ye, D.; Wang, D.
Unsymmetrical Triazolyl-naphthyridinyl-pyridine Bridged Highly
Active Copper Complexes Supported on Reduced Graphene Oxide
and Their Application in Water. Green Chem. 2019, 21, 5345−5351.
(d) Guo, B.; Yu, T.-Q.; Li, H.-X.; Zhang, S.-Q.; Braunstein, P.; Young,
D. J.; Li, H.-Y.; Lang, J.-P. Phosphine Ligand-Free Ruthenium
Complexes as Efficient Catalysts for the Synthesis of Quinolines and
Pyridines by Acceptorless Dehydrogenative Coupling Reactions.
ChemCatChem 2019, 11, 2500−2510.
(3) (a) Musiol, R. An Overview of Quinoline as a Privileged Scaffold
in Cancer Drug Discovery. Expert Opin. Drug Discovery 2017, 12,
583−597. (b) Solomon, V. R.; Lee, H. Quinoline as a Privileged
Scaffold in Cancer Drug Discovery. Curr. Med. Chem. 2011, 18,
1488−1508.
(4) (a) Li, L.-H.; Niu, Z.-J.; Liang, Y.-M. Organocatalyzed Synthesis
of Functionalized Quinolines. Chem. − Asian J. 2020, 15, 231−241.
(b) Bains, A. K.; Ankit, Y.; Adhikari, D. Bioinspired Radical-Mediated
Transition-Metal-Free Synthesis of N-Heterocycles under Visible
Light. ChemSusChem 2021, 14, 324−329. (c) Xu, T.; Shao, Y.; Dai,
L.; Yu, S.; Cheng, T.; Chen, J. Pd-Catalyzed Tandem Reaction of 2-
Aminostyryl Nitriles with Arylboronic Acids: Synthesis of 2-
Arylquinolines. J. Org. Chem. 2019, 84, 13604−13614. (d) Xi, L.-Y.;
Zhang, R.-Y.; Zhang, L.; Chen, S.-Y.; Yu, X.-Q. An Efficient Synthesis
of Quinolines via Copper-catalyzed C−N Cleavage. Org. Biomol.
Chem. 2015, 13, 3924−3930. (e) Xie, F.; Zhang, M.; Chen, M.; Lv,
W.; Jiang, H. Convenient Synthesis of Quinolines from α-2-Nitroaryl
Alcohols and Alcohols via a Ruthenium-catalyzed Hydrogen Transfer
Strategy. ChemCatChem 2015, 7, 349−353.
(12) (a) Marzo, L.; Pagire, S. K.; Reiser, O.; König, B. Visible-Light
Photocatalysis: Does It Make a Difference in Organic Synthesis?
Angew. Chem. Int. Ed. Engl. 2018, 57, 10034−10072. (b) Chen, J.-R.;
(5) (a) Weyesa, A.; Mulugeta, E. Recent Advances in the Synthesis
of Biologically and Pharmaceutically Active Quinoline and Its
Analogues: A Review. RSC Adv. 2020, 10, 20784−20793.
10753
https://doi.org/10.1021/acs.joc.1c01386
J. Org. Chem. 2021, 86, 10747−10754

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Hu, X.-Q.; Lu, L.-Q.; Xiao, W.-J. Exploration of Visible-Light
Photocatalysis in Heterocycle Synthesis and Functionalization:
Reaction Design and Beyond. Acc. Chem. Res. 2016, 49, 1911−
1923. (c) Strieth-Kalthoff, F.; Glorius, F. Triplet Energy Transfer
Photocatalysis: Unlocking the Next Level. Chem 2020, 6, 1888−1903.
(13) (a) Sideri, I. K.; Voutyritsa, E.; Kokotos, C. G. Photo-
organocatalysis, Small Organic Molecules and Light in the Service of
Organic Synthesis: The Awakening of a Sleeping Giant. Org. Biomol.
Chem. 2018, 16, 4596−4614. (b) Romero, N. A.; Nicewicz, D. A.
Organic Photoredox Catalysis. Chem. Rev. 2016, 116, 10075−10166.
(14) Xu, J.; Chen, Q.; Luo, Z.; Tang, X.; Zhao, J. N-Heterocyclic
Carbene Copper Catalyzed Quinoline Synthesis from 2-Aminobenzyl
Alcohols and Ketones Using DMSO as an Oxidant at Room
Temperature. RSC Adv. 2019, 9, 28764−28767.
(15) Sheriff Shah, S.; Pradeep Singh, N. D. Pseudohalide Assisted
Aerobic Oxidation of Alcohols in the Presence of Visible-Light.
Tetrahedron Lett. 2018, 59, 247−251.
(16) Xia, Q.; Shi, Z.; Yuan, J.; Bian, Q.; Xu, Y.; Liu, B.; Huang, Y.;
Yang, X.; Xu, H. Visible-Light-Enabled Selective Oxidation of Primary
Alcohols through Hydrogen-Atom Transfer and its Application in the
Synthesis of Quinazolinones. Asian J. Org. Chem. 2019, 8, 1933−1941.
(17) Pramanik, M.; Choudhuri, K.; Mathuri, A.; Mal, P.
Dithioacetalization or Thioetherification of Benzyl Alcohols Using
9-Mesityl-10-methylacridinium Perchlorate Photocatalyst. Chem.
Commun. 2020, 56, 10211−10214.
(18) Nikitas, N. F.; Tzaras, D. I.; Triandafillidi, I.; Kokotos, C. G.
Photochemical Oxidation of Benzylic Primary and Secondary
Alcohols Utilizing Air as the Oxidant. Green Chem. 2020, 22, 471−
477.
(19) (a) Schilling, W.; Riemer, D.; Zhang, Y.; Hatami, N.; Das, S.
Metal-Free Catalyst for Visible-Light-Induced Oxidation of Unac-
tivated Alcohols Using Air/Oxygen as an Oxidant. ACS Catal. 2018,
8, 5425−5430. (b) Zhang, Y.; Schilling, W.; Riemer, D.; Das, S.
Metal-free Photocatalysts for the Oxidation of Non-activated Alcohols
and the Oxygenation of Tertiary Amines Performed in Air or Oxygen.
Nat. Protoc. 2020, 15, 822−839.
(20) Zhu, X.; Liu, C.; Liu, Y.; Yang, H.; Fu, H. A Sodium
Trifluoromethanesulfinate-mediated Photocatalytic Strategy for Aero-
bic Oxidation of Alcohols. Chem. Commun. 2020, 56, 12443−12446.
(21) (a) Cervantes-González, J.; Vosburg, D. A.; Mora-Rodriguez, S.
E.; Vázquez, M. A.; Zepeda, L. G.; Villegas Gómez, C.; Lagunas-
Rivera, S. Anthraquinones: Versatile Organic Photocatalysts. Chem-
CatChem 2020, 12, 3811−3827. (b) Capaldo, L.; Ravelli, D.
Hydrogen Atom Transfer (HAT): A Versatile Strategy for Substrate
Activation in Photocatalyzed Organic Synthesis. Eur. J. Org. Chem.
2017, 2017, 2056−2071. (c) Li, J.; Yu, J.; Xiong, W.; Tang, H.; Hu,
M.; Wu, W.; Jiang, H. A Palladium-catalyzed Oxidative Amino-
carbonylation Reaction of Alkynone O-methyloximes with Amines
and CO in PEG-400. Green Chem. 2020, 22, 465−470. (d) Zha, G.-F.;
Fang, W.-Y.; Leng, J.; Qin, H.-L. A Simple, Mild and General
Oxidation of Alcohols to Aldehydes or Ketones by SO2F2/K2CO3
Using DMSO as Solvent and Oxidant. Adv. Synth. Catal. 2019, 361,
2262−2267. (e) Xia, Z.-H.; Gao, Z.-H.; Dai, L.; Ye, S. Visible-Light-
Promoted Oxo-difluoroalkylation of Alkenes with DMSO as the
Oxidant. J. Org. Chem. 2019, 84, 7388−7394.
(22) (a) Ouyang, J.-S.; Li, Y.-F.; Huang, F.-D.; Lu, D.-D.; Liu, F.-S.
The Highly Efficient Suzuki−Miyaura Cross-Coupling of (Hetero)-
aryl Chlorides and (Hetero)arylboronic Acids Catalyzed by “Bulky-
yet-Flexible” Palladium−PEPPSI Complexes in Air. ChemCatChem
2018, 10, 371−375. (b) Lee, S. Y.; Cheon, C.-H. On-Water Synthesis
of 2-Substituted Quinolines from 2-Aminochalcones Using Benzyl-
amine as the Nucleophilic Catalyst. J. Org. Chem. 2018, 83, 13036−
13044. (c) Li, C.; Li, J.; An, Y.; Peng, J.; Wu, W.; Jiang, H. Palladium-
Catalyzed Allylic C−H Oxidative Annulation for Assembly of
Functionalized 2-Substituted Quinoline Derivatives. J. Org. Chem.
2016, 81, 12189−12196.
10754
https://doi.org/10.1021/acs.joc.1c01386
J. Org. Chem. 2021, 86, 10747−10754