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A Pummerer Reaction-Enabled Modular Synthesis of Alkyl

Quinoline-3-carboxylates and 3‑Arylquinolines from Amino Acids
Jin-Tian Ma, Ting Chen, Bo-Cheng Tang, Xiang-Long Chen, Zhi-Cheng Yu, You Zhou, Shi-Yi Zhuang,
Yan-Dong Wu, Jia-Chen Xiang,* and An-Xin Wu*
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ABSTRACT: Concise synthesis of functionalized quinolines has

received continuous research attention owing to the biological
importance and synthetic potential of bicyclic N-heterocycles.
However, synthetic routes to the 2,4-unsubstituted alkyl quinoline-
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3-carboxylate scaffold, which is an important motif in drug design,

remain surprisingly limited, with modular protocols that proceed
from readily available materials being even more so. We herein
report an acidic I2−DMSO system that converts readily available aspartates and anilines into alkyl quinoline-3-carboxylate. This
method can be extended to a straightforward synthesis of 3-arylquinolines by simply replacing the aspartates with phenylalanines.
Mechanistic studies revealed that DMSO was activated by HI via a Pummerer reaction to provide the C1 synthon, while the amino
acid catabolized to the C2 synthon through I2-mediated Strecker degradation. A formal [3 + 2 + 1] annulation of these two
concurrently generated synthons with aniline was responsible for the selective formation of the quinoline core. The synthetic utility
of this protocol was illustrated by the efficient synthesis of human 5-HT4 receptor ligand. Moreover, an unprecedented
chemoselective synthesis of 2-deuterated, 3-substituted quinoline, featuring this reaction, has been established.

■ INTRODUCTION
Quinolines are some of the most basic yet highly valuable
hyde, act as a C1 unit for the cyclization. However, a relative
expensive catalytic system, i.e., (Rh(cod)Cl]2 + dppm), is
nitrogen-containing heterocycles.1 As well as established indispensable to realize this elegant conversion.8
named reactions,2 numerous methodologies have been Recently, our group reported one example of alkyl quinoline-
continuously developed for the synthesis of these potentially 3-carboxylate synthesis using aniline, aspartate, and glycine as
bioactive compounds.3 The 2,4-unsubstituted alkyl quinoline- the substrates (Scheme 1e).9a Notwithstanding the successful
execution of such amino-acid cross-dimerization, in which
3-carboxylate motif is a special quinoline skeleton found in
aspartate and glycine act as a C2 and C1 synthon, respectively,
many drug candidates, including anti-inflammatory4a and anti-
there are three issues with this system need to be addressed.
Alzheimer’s drugs.4b Although this skeleton seems structurally
First, the yield of the alkyl quinoline-3-carboxylate in this
simple, synthetic access to alkyl quinoline-3-carboxylate has
transformation is 42% and the separation process is difficult.
been rarely reported (Scheme 1). A classical two-step Gould−
This is attributed to the formation of the pyridine byproduct,
Jacobs route has been used to synthesize the quinoline core,
which is competitively generated by heterotrimerization of the
followed by another two-step deoxygenation procedure to
amino acids.9b Second, using glycine as the C1 unit results in
furnish the target (Scheme 1a).5 Alternatively, Baylis−Hillman
poor atom economy for the entire process. Finally, we can only
adducts have been used as the cyclization precursors to achieve
provide one synthetic example in this work; thus, the
alkyl quinoline-3-carboxylate by at least three overall steps
practicability of the protocol needs to be further established.
(Scheme 1b).6 Compared with the above stepwise synthesis, a
On the basis of these considerations, we are seeking other C1
one-step modular synthesis strategy holds significant advan-
synthons to develop this modular synthesis.
tages, since each module can be varied independently, thus
The Pummerer reaction, which was revealed in the first
increasing the diversity of products. A limited modular
decade of the 20th century, has become a powerful synthetic
synthesis of alkyl quinoline-3-carboxylate involves using o-
aldehyde aniline with 3,3-dimethoxy methyl propionate or
methyl propiolate (Scheme 1c).7 However, this strategy Received: December 19, 2022
requires preprepared substrates and has a limited substrate Published: February 23, 2023
scope. Balaraman et al. used aniline, CO surrogates, and
methyl propiolate to produce the quinoline through a metal-
catalyzed three-component reaction (Scheme 1d). CO
surrogates, e.g., 3 atm of carbon monoxide or paraformalde-

© 2023 American Chemical Society https://doi.org/10.1021/acs.joc.2c03034

3760 J. Org. Chem. 2023, 88, 3760−3771
The Journal of Organic Chemistry pubs.acs.org/joc Article

Scheme 1. Representative Stepwise Synthesis and Modular Synthesis of Alkyl Quinoline-3-carboxylate

tool for the total synthesis of natural products and the Based on our continuous research interests in using DMSO
construction of heterocycles.10 Mechanistically, the Pummerer as a versatile synthon in heterocyclic synthesis in I2−DMSO
reaction involves the activation of a sulfoxide oxygen and systems,17 we reasoned that we could use the Pummerer
converts it into a good leaving group, thus providing a reaction to activate DMSO into a highly reactive C1 synthon
thionium ion intermediate. This heteroatom-stabilized carbo- providing access to alkyl quinoline-3-carboxylate. We antici-
pated that such C1 and C2 synthons, which derive from
cation is an excellent electrophile, which accepts nucleophilic DMSO and aspartate ester, respectively, could be generated
addition to generate an α-substituted sulfide. Usually, the independently and integrate into a quinoline ring convergently
reaction does not stop at this stage since the sulfide may also when specific activation reagents and conditions are finely
act as a leaving group to participate in a sequential domino chosen. We were also keen to study whether this new strategy
process. In recent years, DMSO, a special sulfoxide species, has could further extend our previous synthesis of such not-easy-
been widely used as a C1 synthon in intermolecular reactions accessible heterocycles.
which rely on Pummerer-based chemistry.11−15 Using the
methyl group of DMSO to assemble heterocycles, such as
benzothiazoles,11 pyridines,12 and quinolines,13 as well as for
■ RESULTS AND DISCUSSION
Our research initiated with optimization of the reaction
the formylation14 and methylation of heterocycles,15 is well conditions between the aspartate ester with p-toluidine in the
established. Different types of activation reagents, e.g., acid presence of I2 and DMSO (Table 1). Four additives which
were capable of triggering Pummerer reaction, e.g. Ac2O, TFA,
anhydrides, Bronsted and Lewis acids, peroxides, hypervalent
K2S2O8, NH4OAc, were first investigated respectively. Results
iodine reagents, and NH4OAc, have been used to trigger such showed that target product 3b could be formed in some cases
transformations (Scheme 2).11−16 with moderate yield, indicating the successful execution of our
design (entries 1−4). Notably, when no additive was added to
Scheme 2. Conventional Reagents for Triggering the the reaction conditions, 3b could also be obtained in 45% yield
Pummerer Reaction (entry 5). We anticipated that the HI, which was the product
of I2-mediated Strecker degradation of amino acid, might be
the key to promote the Pummerer reaction. Indeed, when
using HI as the additive, the yield of 3b climbed to 58% (entry
6). After screening the most suitable dose of I2 and HI, we
found that a higher temperature could further improve the
yield (entries 7−12). The optimized conditions were settled as
follows: 1.5 equiv of I2, 2.0 equiv of HI at 140 °C reacting in
DMSO for 10 h (entry 10).
With the optimized conditions in hand, we turned to
investigate the substrate compatibility of this transformation
(Scheme 3). Frist, Aspartate derivatives bearing different ester
groups were tested, resulting in generally good yields of the
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The Journal of Organic Chemistry pubs.acs.org/joc Article

Table 1. Optimization of the Reaction Conditionsa transformations were still feasible in 10 mmol scale despite
the decline of yields.
The facile synthesis of alkyl quinoline-3-carboxylate
provided us with a new opportunity for its synthetic
application. For example, it was convenient to synthesize
drug candidate 3-amidoquinoline from alkyl quinoline-3-
entry I2 (x equiv) Additive (y equiv) Temp (°C) yield 3b (%) carboxylate. Furthermore, starting from 3ab, a lead structure
1 1.5 Ac2O (2.0) 100 trace of human 5-HT4 receptor ligand which is tedious to access can
2 1.5 TFA (2.0) 100 37 be prepared in overall 4 steps5b (Scheme 4).
3 1.5 K2S2O8 (2.0) 100 trace The current methodology provides a new strategy to prepare
4 1.5 NH4OAc (2.0) 100 25 2-deuterated quinoline derivatives. Isotopic labeling of nitro-
5 1.5 None 100 45 gen-containing heterocycles is an important research topic
6 1.5 HI (2.0) 100 58 holding significance in drug design and structure−activity
7 2.0 HI (2.0) 100 56 relationship study.20 However, reports of the preparation of
8 − HI (2.0) 100 19 deuterated quinolines are limited especially in a highly
9 0.1 HI (2.0) 100 22 chemoselective manner.21 Indeed, Guo et al. reported that,
10 1.5 HI (2.0) 140 68 under basic and high temperature conditions, H−D exchange
11 1.5 HI (0.5) 140 53 which was triggered by DMSO-d6 would occur in the 2/4/8
12 1.5 HI (3.0) 140 64 positions of quinolines with partial deuteriation and poor
a
General conditions: 1b (1.0 mmol), 2a (1.0 mmol), I2, additive, selectivity, displaying imprecise deuteriation outcomes
DMSO (3.0 mL, c 0.17 M) were added to a pressure vessel and stirred (Scheme 5a).19a Under present acidic conditions in the
for 10 h. Isolated yields. presence of DMSO-d6, the H/D scrambling was successfully
suppressed, resulting in a completely recovery of starting
desired products (3a−3c). On the one hand, a series of aniline materials (Scheme 5b). Taking advantage of this selectivity, we
derivatives with an electron-withdrawing group on the arene used DMSO-d6 as an isotopic source to achieve 2-deuterated,
part, such as halogen and ester, could successfully complete the 3-substituted quinoline 5a with excellent isotopic incorpo-
conversion in useful yields (3d−3j). On the other hand, aniline ration in an acceptable yield (Scheme 5c).
derivatives bearing electron-donating groups, such as −OMe, Several control experiments have been conducted to further
−OBn, −SMe, and −Ph could also convert into the desired support the mechanistic assumption. When phenylacetalde-
product in moderate yields (3k−3n). Furthermore, polysub- hyde was submitted to the reaction to replace phenylalanine,
stituted aniline was a good candidate in this transformation the desired 3-arylquinoline 4a was obtained in 57% yield
resulting in alkyl quinoline-3-carboxylate smoothly. 1-Naph- indicating that the Strecker degradation of amino acids to give
thylamine, 2-naphthylamine, and 3-aminodibenzofuran were the corresponding aldehyde as the key intermediate did occur
also tolerated in the transformation, affording interesting as we anticipated (Scheme 6a). Under the standard conditions
planar skeletons (3u−3w). We also encountered some failed otherwise in the absence of I2 or HI, using phenylalanine or
attempts. Asparagine and aspartic acid were unfortunately not phenylacetaldehyde could not afford 4a illustrating the
suitable for this reaction. Employing leucine or alanine as necessity of each component in the conditions (Scheme 6b,
substrates resulted failures which may be attributed to their 6c). In addition, since (6-methyl-3-phenylquinolin-2-yl)-
inactive β-positions. (phenyl)methanone 6a was a reasonable byproduct generated
To our delight, when phenylalanine was submitted to the from aniline assisted dimerization of phenylalanines, the
reaction conditions to replace aspartate, 3-arylquinoline was debenzylation process of 6a to afford 4a was also considered
obtained as the product. 2,4-Unsubstituted 3-arylquinolines are as a competitive pathway. Finally, an experimental result of no
also a type of interesting monosubstituted quinoline skeletons conversion was detected by directly submitting 6a to the
which have been used as platelet-derived growth factor reaction conditions, thus negating the above-mentioned
(PDGF) receptor tyrosine kinase inhibitors.18 [3 + 1 + 1 + scenario (Scheme 6d).
1] annulation,19a reaction of anilines with styrene oxide,19b and Taking these experimental results and existing literature into
copper-catalyzed transformation of anilines with phenyl- consideration,11−15,22 a possible mechanism was proposed, as
acetaldehyde19c are typical existing modular synthetic strat- shown in Scheme 7. Based on a classical Pummerer reaction,
egies for construction of this compound. New synthetic DMSO is activated by hydroiodic acid to generate the
approaches, especially for modular synthesis using readily corresponding sulfonium ylide B, which undergoes a base-
available starting materials toward this skeleton, are still of promoted elimination to afford thionium ion C/C′. This
significant interest. Based on our achieved method, we electrophilic species reacts with aniline to form intermediate D.
expected to further investigate the range of substrates, and Then, attack of the sulfur atom in D to the thionium ion C
the results are as follows. Anilines with both electron-donating provides sulfonium E, which transforms into the imine
groups (such as alkyl, alkoxy or aryl groups on the para intermediate F upon losing one molecule of bis(methylthio)-
position of aniline) and electron-withdrawing groups (such as methane. Cooperatively, amino acid 1 transforms into the
halogen, trifluoromethoxy) were all good reaction substrate corresponding aldehyde intermediate 8a by I2-mediated
candidates. Polysubstituted aniline could also transform into Strecker degradation.23 In the presence of acid, the aniline
the desired products in medium to good yields. Various readily reacts with 8a to generate electron-rich olefin 9a′, which is
available phenylalanines bearing different substituents on the capable of triggering a Povarov reaction with azadiene F. The
aromatic ring transformed into the target products successfully, resulted cycloadduct intermediate G undergoes an elimina-
showing the good tolerance and generality of our reaction. The tion/aromatization process under heating and oxidative
gram-scale experiments of 3b and 4a showed that the conditions to afford 3-substituted quinoline. It is worth
3762 https://doi.org/10.1021/acs.joc.2c03034
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The Journal of Organic Chemistry pubs.acs.org/joc Article

Scheme 3. Scopes of General Substratesa

a
General conditions: 1 (1.0 mmol), 2 (1.0 mmol), I2 (1.5 equiv), HI (2.0 equiv), DMSO (3.0 mL, c 0.17 M) were added to a pressure vessel and
stirred at 140 °C for 10 h. isolated yields.

mentioning that 9a′ can also react with thionium ion C to give
10 and then intermediate 11 through fragmentation. However,
■ CONCLUSION
In summary, we have developed a facile construction of alkyl
because of the E configuration of the imine double bond, the quinoline-3-carboxylate and 3-arylquinolines from aspartates
intramolecular cyclization/aromatization process is not favored and phenylalanines, respectively. The wide compatibility of this
to take place. Indeed, according to our deuteriation experi- newly developed transformation was illustrated using a variety
ments, we did not find any deuteriation in the C4 position. of substrates, affording functionalized quinolines in generally
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Scheme 4. Synthetic Applications of Current Methodology mechanism, a 2-deuterated, 3-substituted quinoline, which is
difficult to access, was prepared with high chemoselectivity by
simply using DMSO-d6 as isotopic sources. We anticipate that
this work will provide a new blueprint for the synthesis of 3-
substituted quinolines and an updated example for direct
heteroaromatization of amino acids.

■ EXPERIMENTAL SECTION
General Procedure. A flame-dried pressure sealed tube was
charged with aspartate ester (1b) (1.0 mmol, 223.0 mg) or
phenylalanine (1a′) (1.0 mmol, 165.0 mg), p-toluidine (2a) (1.0
mmol 107.0 mg), I2 (1.5 mmol 381.0 mg), HI (2.0 mmol), and
DMSO (3.0 mL, c 0.17 M) at 140 °C (heating block) for 10 h until
almost complete conversion of the substrates by TLC analysis. When
Scheme 5. Precise Preparation of 2-Deuterated, 3- the reaction is completed, the reaction was quenched by slow addition
Substituted Quinoline of saturated sodium thiosulfate, water, and ethyl acetate. The mixture
was then poured into a separating funnel. After the phases were
separated, the aqueous phase was extracted three times with ethyl
acetate. The combined organic layers were washed with brine, dried
over anhydrous Na2SO4, and concentrated by rotary evaporation. The
crude product can be separated by silica gel column chromatography
to obtain the dichlorination product 3b (188.4 mg, 68% yield) or 4a
(190.6 mg, 87% yield). General procedure for 10 mmol scale synthesis
of 3b and 4a: A flame-dried pressure sealed tube was charged with
aspartate ester (1b) (10.0 mmol, 2.23 g) or phenylalanine (1a′) (10.0
mmol, 1.65 g), p-toluidine (2a) (10.0 mmol 1.07 g), I2 (15.0 mmol
3.81 g), HI (20.0 mmol), and DMSO (30.0 mL, c 0.17 M) at 140 °C
(heating block) for 10 h until almost completed conversion of the
substrates by TLC analysis. When the reaction is completed, the
reaction was quenched by slow addition of saturated sodium
thiosulfate, water, and ethyl acetate. The mixture was then poured
into a separating funnel. After the phases were separated, the aqueous
phase was extracted three times with ethyl acetate. The combined
organic layers were washed with brine, dried over anhydrous Na2SO4,
and concentrated by rotary evaporation. The crude product can be
separated by silica gel column chromatography to obtain the
dichlorination product 3b (1.163 g, 42% yield) or 4a (1.467 g, 67%
yield).
Tabulated Data for Products. Methyl 6-Methylquinoline-3-
carboxylate (3a).24a Yield 63%; 126.6 mg; yellow solid; mp 117−119
°C; column chromatography, silica gel, Rf = 0.28 (petroleum ether/
Scheme 6. Control Experiments ethyl acetate = 12:1) 1H NMR (400 MHz, CDCl3) δ 9.38 (s, 1H),
8.76 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 10.8 Hz, 2H), 4.02
(s, 3H), 2.57 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 166.0,
149.1, 148.4, 138.1, 137.5, 134.2, 129.1, 127.8, 126.8, 122.9, 52.4,
21.6. HRMS (ESI) m/z calcd for C12H12NO2+ (M+H)+ 202.0863,
found 202.0860.
Benzyl 6-Methylquinoline-3-carboxylate (3b). Yield 68%; 188.4
mg; yellow solid; mp 120−122 °C; column chromatography, silica
gel, Rf = 0.28 (petroleum ether/ethyl acetate = 12:1) 1H NMR (400
MHz, CDCl3) δ 9.42 (d, J = 2.0 Hz, 1H), 8.79 (s, 1H), 8.07 (d, J =
8.4 Hz, 1H), 7.67 (d, J = 9.2 Hz, 2H), 7.50 (d, J = 7.2 Hz, 2H), 7.46−
7.36 (m, 3H), 5.46 (s, 2H), 2.56 (s, 3H). 13C {1H} NMR (100 MHz,
CDCl3) δ 165.3, 149.0, 148.3, 138.4, 137.6, 135.6, 134.4, 128.9, 128.7,
128.5, 128.3, 127.8, 126.9, 122.9, 67.1, 21.6. HRMS (ESI) m/z calcd
for C18H16NO2+ (M+H)+ 278.1176, found 278.1172.
Cyclohexyl 6-Methylquinoline-3-carboxylate (3c). Yield 63%;
169.5 mg; yellow solid; mp 115−117 °C; column chromatography,
silica gel, Rf = 0.26 (petroleum ether/ethyl acetate = 12:1) 1H NMR
(400 MHz, CDCl3) δ 9.40 (s, 1H), 8.80 (s, 1H), 8.13 (d, J = 8.8 Hz,
1H), 7.73 (s, 1H), 7.69 (d, J = 8.8 Hz, 1H), 5.16−5.08 (m, 1H), 2.58
good yields. Mechanistically, an acidic I2−DMSO system (s, 3H), 1.99 (d, J = 4.0 Hz, 2H), 1.83 (dd, J = 9.6, 3.6 Hz, 2H), 1.66
(d, J = 10.0 Hz, 2H), 1.48 (dd, J = 10.0, 3.2 Hz, 2H), 1.25 (s, 2H).
activates the amino acid by Strecker degradation, giving the 13
C {1H} NMR (100 MHz, CDCl3) δ 164.6, 148.7, 147.4, 138.6,
corresponding aldehyde species as a C2 synthon, and the C1 137.8, 134.5, 128.4, 127.8, 127.0, 123.8, 74.0, 31.6, 29.7, 25.4, 23.7,
synthon is provided from DMSO through a Pummerer 21.6. HRMS (ESI) m/z calcd for C17H20NO2+ (M+H)+ 270.1489,
reaction. By assembly of these in situ generated C1 and C2 found 270.1486.
synthons with aniline, the quinoline core is forged by formal [3 Benzyl 6-Fluoroquinoline-3-carboxylate (3d). Yield 62%; 174.2
+ 2 + 1] annulation. Benefiting from this well-studied mg; yellow solid; mp 122−124 °C; column chromatography, silica

3764 https://doi.org/10.1021/acs.joc.2c03034
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Scheme 7. Probable Mechanism

gel, Rf = 0.28 (petroleum ether/ethyl acetate = 12:1) 1H NMR (400 HRMS (ESI) m/z calcd for C17H13INO2+ (M+H)+ 389.9985, found
MHz, CDCl3) δ 9.44 (s, 1H), 8.81 (s, 1H), 8.17 (dd, J = 9.2, 5.2 Hz, 389.9983.
1H), 7.62−7.57 (m, 1H), 7.55−7.48 (m, 3H), 7.45−7.37 (m, 3H), 3-Benzyl 6-Methyl Quinoline-3,6-dicarboxylate (3h). Yield 53%;
5.46 (s, 2H). 13C {1H} NMR (100 MHz, CDCl3) δ 164.9, 160.8 (d, J 170.1 mg; yellow solid; mp 130−132 °C; column chromatography,
= 249.0 Hz, 1JCF), 149.4 (d, J = 3.0 Hz, 4JCF), 147.0, 138.1 (d, J = 5.0 silica gel, Rf = 0.25 (petroleum ether/ethyl acetate = 10:1) 1H NMR
Hz, 4JCF), 135.4, 132.0 (d, J = 9.0 Hz, 3JCF), 128.7, 128.6, 128.4, 127.5 (400 MHz, CDCl3) δ 9.56 (s, 1H), 8.96 (s, 1H), 8.69 (s, 1H), 8.41
(d, J = 10.0 Hz, 3JCF), 123.6, 122.2 (d, J = 28.0 Hz, 2JCF), 111.9 (d, J = (d, J = 8.8 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 7.2 Hz, 2H),
26.0 Hz, 2JCF), 67.3. 19F NMR (376 MHz, CDCl3) δ −111.55. HRMS 7.47−7.34 (m, 3H), 5.47 (s, 2H), 4.01 (s, 3H).13C {1H} NMR (100
(ESI) m/z calcd for C17H13FNO2+ (M+H)+ 282.0925, found MHz, CDCl3) δ 166.1, 164.8, 152.1, 151.5, 140.0, 135.3, 132.1, 131.3,
282.0919. 129.8, 129.0, 128.7, 128.6, 128.4, 126.0, 123.7, 67.4, 52.6. HRMS
Benzyl 6-Chloroquinoline-3-carboxylate (3e). Yield 59%; 175.3 (ESI) m/z calcd for C19H16NO4+ (M+H)+ 322.1074, found 322.1066
mg; yellow solid; mp 121−123 °C; column chromatography, silica 3-Benzyl 6-Ethyl Quinoline-3,6-dicarboxylate (3i). Yield 55%;
gel, Rf = 0.27 (petroleum ether/ethyl acetate = 12:1) 1H NMR (400 184.3 mg; yellow solid; mp 101−103 °C; column chromatography,
MHz, CDCl3) δ 9.47 (d, J = 1.6 Hz, 1H), 8.79 (s, 1H), 8.12 (d, J = silica gel, Rf = 0.25 (petroleum ether/ethyl acetate = 10:1) 1H NMR
9.2 Hz, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.77 (dd, J = 9.2, 2.4 Hz, 1H), (400 MHz, CDCl3) δ 9.56 (s, 1H), 8.97 (s, 1H), 8.70 (s, 1H), 8.42
7.50 (d, J = 6.8 Hz, 2H), 7.47−7.35 (m, 3H), 5.46 (s, 2H). 13C {1H} (d, J = 7.6 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.50 (s, 2H), 7.43 (d, J =
NMR (100 MHz, CDCl3) δ 164.8, 150.1, 148.1, 137.9, 135.3, 133.4, 7.6 Hz, 3H), 5.47 (s, 2H), 4.47 (d, J = 6.8 Hz, 2H), 1.46 (s, 3H). 13C
132.8, 131.0, 128.7, 128.6, 128.4, 127.6, 127.5, 123.8, 67.4. HRMS {1H} NMR (100 MHz, CDCl3) δ 165.6, 164.8, 152.1, 151.5, 140.0,
(ESI) m/z calcd for C17H13ClNO2+ (M+H)+ 298.0629, found 135.3, 132.0, 131.4, 129.8, 129.4, 128.7, 128.6, 128.5, 126.0, 123.7,
298.0629. 67.4, 61.6, 14.3. HRMS (ESI) m/z calcd for C20H18NO4+ (M+H)+
Benzyl 6-Bromoquinoline-3-carboxylate (3f). Yield 51%; 184.8 336.1230, found 336.1224.
mg; yellow solid; mp 123−125 °C; column chromatography, silica Benzyl 6-(Trifluoromethoxy)quinoline-3-carboxylate (3j). Yield
gel, Rf = 0.27 (petroleum ether/ethyl acetate = 12:1) 1H NMR (400 52%; 180.5 mg; yellow solid; mp 98−100 °C; column chromatog-
MHz, CDCl3) δ 9.48 (d, J = 1.6 Hz, 1H), 8.77 (s, 1H), 8.06 (dd, J = raphy, silica gel, Rf = 0.23 (petroleum ether/ethyl acetate = 10:1) 1H
23.6, 5.2 Hz, 2H), 7.89 (dd, J = 9.2, 2.0 Hz, 1H), 7.50 (d, J = 6.8 Hz, NMR (400 MHz, CDCl3) δ 9.50 (s, 1H), 8.86 (s, 1H), 8.21 (d, J =
2H), 7.46−7.38 (m, 3H), 5.46 (s, 2H). 13C {1H} NMR (100 MHz, 8.0 Hz, 1H), 7.79−7.65 (m, 2H), 7.54−7.37 (m, 5H), 5.47 (s, 2H).
13
CDCl3) δ 164.8, 150.4, 148.4, 137.7, 135.4, 135.3, 131.2, 130.9, 128.7, C {1H} NMR (100 MHz, CDCl3) δ 164.8, 150.5, 148.0, 147.5,
128.6, 128.4, 127.9, 123.7, 121.4, 67.4. HRMS (ESI) m/z calcd for 138.5, 135.3, 131.8, 128.7, 128.6, 128.5, 127.0, 125.8, 123.8, 120.4 (q,
C17H13BrNO2+ (M+H)+ 342.0124, found 342.0017. J = 257.0 Hz, 1JCF), 118.6, 67.4. 19F NMR (376 MHz, CDCl3) δ
Benzyl 6-Iodoquinoline-3-carboxylate (3g). Yield 49%; 190.6 mg; −57.84. HRMS (ESI) m/z calcd for C18H13F3NO3+ (M+H)+
yellow solid; mp 125−127 °C; column chromatography, silica gel, Rf 348.0842, found 348.0836.
= 0.27 (petroleum ether/ethyl acetate = 12:1) 1H NMR (400 MHz, Benzyl 6-Methoxyquinoline-3-carboxylate (3k). Yield 64%; 187.5
CDCl3) δ 9.47 (d, J = 1.6 Hz, 1H), 8.75 (d, J = 1.6 Hz, 1H), 8.32 (d, J mg; yellow solid; mp 119−121 °C; column chromatography, silica
= 1.6 Hz, 1H), 8.06 (dd, J = 8.8, 2.0 Hz, 1H), 7.89 (d, J = 8.8 Hz, gel, Rf = 0.26 (petroleum ether/ethyl acetate = 10:1) 1H NMR (400
1H), 7.49 (d, J = 6.8 Hz, 2H), 7.42 (dd, J = 12.4, 5.2 Hz, 3H), 5.46 (s, MHz, CDCl3) δ 9.34 (d, J = 1.6 Hz, 1H), 8.77 (s, 1H), 8.07 (d, J =
2H). 13C {1H} NMR (100 MHz, CDCl3) δ 164.8, 150.5, 148.7, 140.5, 9.2 Hz, 1H), 7.48 (dd, J = 12.8, 4.8 Hz, 3H), 7.45−7.37 (m, 3H), 7.16
137.7, 137.5, 135.4, 131.0, 128.7, 128.6, 128.4, 123.5, 93.1, 67.4. (d, J = 2.8 Hz, 1H), 5.45 (s, 2H), 3.94 (s, 3H). 13C {1H} NMR (100

3765 https://doi.org/10.1021/acs.joc.2c03034
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The Journal of Organic Chemistry pubs.acs.org/joc Article

MHz, CDCl3) δ 165.3, 158.3, 147.5, 145.9, 137.6, 135.6, 130.6, 128.7, HRMS (ESI) m/z calcd for C18H16NO2+ (M+H)+ 278.1176, found
128.5, 128.4, 128.0, 125.0, 123.2, 106.0, 67.2, 55.6. HRMS (ESI) m/z 278.1172.
calcd for C18H16NO3+ (M+H)+ 294.1125, found 294.1120. Benzyl 6,7-Dimethylquinoline-3-carboxylate (3s). Yield 54%;
Benzyl 6-(Benzyloxy)quinoline-3-carboxylate (3l). Yield 58%; 214 157.2 mg; yellow solid; mp 114−116 °C; column chromatography,
mg; yellow solid; mp 135−137 °C; column chromatography, silica silica gel, Rf = 0.28 (petroleum ether/ethyl acetate = 12:1) 1H NMR
gel, Rf = 0.26 (petroleum ether/ethyl acetate = 10:1) 1H NMR (400 (400 MHz, CDCl3) δ 9.39 (s, 1H), 8.75 (s, 1H), 7.92 (s, 1H), 7.64 (s,
MHz, CDCl3) δ 9.34 (d, J = 1.2 Hz, 1H), 8.73 (s, 1H), 8.07 (d, J = 1H), 7.50 (d, J = 7.2 Hz, 2H), 7.46−7.36 (m, 3H), 5.44 (s, 2H), 2.48
9.2 Hz, 1H), 7.56 (dd, J = 9.2, 2.4 Hz, 1H), 7.52−7.47 (m, 4H), (d, J = 17.2 Hz, 6H). 13C {1H} NMR (100 MHz, CDCl3) δ 165.4,
7.45−7.36 (m, 6H), 7.23 (d, J = 2.4 Hz, 1H), 5.45 (s, 2H), 5.20 (s, 149.1, 148.9, 142.9, 137.9, 137.6, 135.7, 128.7, 128.4, 128.3, 128.1,
2H). 13C {1H} NMR (100 MHz, CDCl3) δ 165.4, 157.3, 147.8, 146.1, 125.4, 122.1, 67.0, 20.7, 20.0. HRMS (ESI) m/z calcd for
137.5, 136.0, 135.6, 130.9, 128.73, 128.69, 128.5, 128.4, 128.3, 127.9, C19H18NO2+ (M+H)+ 292.1332, found 292.1327.
127.5, 125.2, 123.1, 107.3, 70.3, 67.1. HRMS (ESI) m/z calcd for Benzyl 5,7-Dimethylquinoline-3-carboxylate (3t). Yield 55%;
C24H20NO3+ (M+H)+ 370.1438, found 370.1434. 160.1 mg; yellow solid; mp 113−115 °C; column chromatography,
Benzyl 6-(Methylthio)quinoline-3-carboxylate (3m). Yield 51%; silica gel, Rf = 0.28 (petroleum ether/ethyl acetate = 12:1) 1H NMR
157.6 mg; yellow solid; mp 128−130 °C; column chromatography, (400 MHz, CDCl3) δ 9.43 (s, 1H), 8.97 (s, 1H), 7.78 (s, 1H), 7.51
silica gel, Rf = 0.28 (petroleum ether/ethyl acetate = 10:1) 1H NMR (d, J = 7.2 Hz, 2H), 7.44−7.37 (m, 3H), 7.28 (s, 1H), 5.47 (s, 2H),
(400 MHz, CDCl3) δ 9.39 (s, 1H), 8.75 (s, 1H), 8.04 (d, J = 8.8 Hz, 2.70 (s, 3H), 2.54 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ
1H), 7.68 (dd, J = 8.8, 1.6 Hz, 1H), 7.58 (s, 1H), 7.50 (d, J = 7.2 Hz, 165.6, 150.5, 149.6, 142.5, 135.8, 135.7, 135.2, 130.3, 128.7, 128.4,
2H), 7.46−7.38 (m, 3H), 5.45 (s, 2H), 2.60 (s, 3H). 13C {1H} NMR 128.3, 126.6, 124.4, 121.6, 67.0, 22.1, 18.6. HRMS (ESI) m/z calcd
(100 MHz, CDCl3) δ 165.1, 149.0, 147.9, 139.1, 137.4, 135.5, 131.2, for C19H18NO2+ (M+H)+ 292.1332, found 292.1326.
129.4, 128.7, 128.5, 128.4, 127.4, 123.4, 122.7, 67.2, 15.4. HRMS Benzyl Benzo[h]quinoline-3-carboxylate (3u). Yield 52%; 161.8
(ESI) m/z calcd for C18H16NO2S+ (M+H)+ 310.0896, found mg; yellow solid; mp 139−141 °C; column chromatography, silica
310.0893. gel, Rf = 0.27 (petroleum ether/ethyl acetate = 12:1) 1H NMR (400
Benzyl 6-Phenylquinoline-3-carboxylate (3n). Yield 58%; 196.6 MHz, CDCl3) δ 9.59 (d, J = 1.6 Hz, 1H), 9.37−9.27 (m, 1H), 8.84
mg; yellow solid; mp 125−127 °C; column chromatography, silica (d, J = 1.6 Hz, 1H), 7.95−7.91 (m, 1H), 7.87 (d, J = 8.8 Hz, 1H),
gel, Rf = 0.3 (petroleum ether/ethyl acetate = 12:1) 1H NMR (400 7.80−7.73 (m, 3H), 7.52 (d, J = 7.2 Hz, 2H), 7.41 (dt, J = 20.4, 7.2
MHz, CDCl3) δ 9.48 (d, J = 2.0 Hz, 1H), 8.91 (s, 1H), 8.23 (d, J = Hz, 3H), 5.48 (s, 2H). 13C {1H} NMR (100 MHz, CDCl3) δ 165.4,
9.2 Hz, 1H), 8.12−8.07 (m, 2H), 7.71 (d, J = 7.6 Hz, 2H), 7.51 (dd, J 149.0, 137.9, 135.7, 134.5, 131.0, 129.3, 128.74, 128.70, 128.5, 128.3,
= 9.6, 5.2 Hz, 4H), 7.46−7.38 (m, 4H), 5.47 (s, 2H). 13C {1H} NMR 127.9, 127.5, 125.5, 125.22, 125.16, 123.6, 67.1. HRMS (ESI) m/z
(100 MHz, CDCl3) δ 165.2, 150.0, 149.2, 140.3, 139.7, 139.0, 135.5, calcd for C21H16NO2+ (M+H)+ 314.1176, found 314.1171.
131.7, 129.9, 129.1, 128.7, 128.5, 128.4, 128.1, 127.4, 127.0, 126.6, Benzyl Benzo[g]quinoline-3-carboxylate (3v). Yield 52%; 161.8
123.3, 67.2. HRMS (ESI) m/z calcd for C23H18NO2+ (M+H)+ mg; yellow solid; mp 136−138 °C; column chromatography, silica
340.1332, found 340.1327. gel, Rf = 0.27 (petroleum ether/ethyl acetate = 12:1) 1H NMR (400
Benzyl [1,3]Dioxolo[4,5-g]quinoline-7-carboxylate (3o). Yield MHz, CDCl3) δ 9.57 (s, 1H), 9.51 (d, J = 1.6 Hz, 1H), 8.66 (d, J =
56%; 172.0 mg; yellow solid; mp 124−126 °C; column chromatog- 8.0 Hz, 1H), 8.03 (dd, J = 24.4, 9.2 Hz, 2H), 7.94 (d, J = 7.6 Hz, 1H),
raphy, silica gel, Rf = 0.27 (petroleum ether/ethyl acetate = 8:1) 1H 7.70 (dd, J = 14.4, 7.2 Hz, 2H), 7.53 (d, J = 7.2 Hz, 2H), 7.43 (d, J =
NMR (400 MHz, CDCl3) δ 9.27 (d, J = 1.6 Hz, 1H), 8.62 (s, 1H), 7.6 Hz, 2H), 7.36 (s, 1H), 5.50 (s, 2H). 13C {1H} NMR (100 MHz,
7.49 (d, J = 7.2 Hz, 2H), 7.45−7.36 (m, 4H), 7.11 (s, 1H), 6.14 (s, CDCl3) δ 165.4, 150.4, 149.7, 135.6, 133.5, 132.9, 131.7, 129.6, 128.8,
2H), 5.43 (s, 2H). 13C {1H} NMR (100 MHz, CDCl3) δ 165.4, 152.7, 128.7, 128.5, 128.4, 127.9, 127.8, 127.6, 126.9, 124.4, 122.8, 67.2.
148.8, 148.5, 148.1, 137.0, 135.6, 128.6, 128.4, 128.3, 123.9, 121.3, HRMS (ESI) m/z calcd for C21H16NO2+ (M+H)+ 314.1176, found
105.9, 103.6, 102.2, 67.0. HRMS (ESI) m/z calcd for C18H14NO4+ 314.1169.
(M+H)+ 308.0917, found 308.0912. Benzyl Benzofuro[3,2-g]quinoline-3-carboxylate (3w). Yield
Benzyl 2,3-Dihydro-[1,4]dioxino[2,3-g]quinoline-8-carboxylate 48%; 169.5 mg; yellow solid; mp 143−145 °C; column chromatog-
(3p). Yield 54%; 173.4 mg; yellow solid; mp 120−122 °C; column raphy, silica gel, Rf = 0.28 (petroleum ether/ethyl acetate = 10:1) 1H
chromatography, silica gel, Rf = 0.27 (petroleum ether/ethyl acetate = NMR (400 MHz, CDCl3) δ 9.52 (s, 1H), 9.39 (s, 1H), 8.30 (d, J =
8:1) 1H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H), 8.62 (s, 1H), 7.55 8.8 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.72
(s, 1H), 7.48 (d, J = 7.2 Hz, 2H), 7.42 (d, J = 6.8 Hz, 2H), 7.40−7.32 (d, J = 8.4 Hz, 1H), 7.54 (t, J = 6.4 Hz, 3H), 7.47−7.40 (m, 4H), 5.50
(m, 2H), 5.42 (s, 2H), 4.38 (d, J = 4.8 Hz, 2H), 4.35 (d, J = 5.2 Hz, (s, 2H). 13C {1H} NMR (100 MHz, CDCl3) δ 165.0, 156.6, 151.3,
2H). 13C {1H} NMR (100 MHz, CDCl3) δ 165.4, 148.8, 148.4, 146.4, 149.7, 149.2, 135.5, 132.0, 128.7, 128.6, 128.5, 127.1, 124.5, 124.3,
144.8, 137.1, 135.6, 128.6, 128.3, 128.2, 122.6, 121.1, 114.1, 113.0, 124.0, 123.6, 122.9, 120.6, 120.5, 115.4, 112.0, 67.3. HRMS (ESI) m/
66.8, 64.4, 64.1. HRMS (ESI) m/z calcd for C19H16NO4+ (M+H)+ z calcd for C23H16NO3+ (M+H)+ 354.1125, found 354.1122.
322.1074, found 322.1068. Methyl 6-Methoxyquinoline-3-carboxylate (3ab).24b Yield 65%;
Benzyl 2,2-Difluoro-[1,3]dioxolo[4,5-g]quinoline-7-carboxylate 141.1 mg; yellow solid; mp 120−122 °C; column chromatography,
(3q). Yield 51%; 175.0 mg; yellow solid; mp 125−127 °C; column silica gel, Rf = 0.27 (petroleum ether/ethyl acetate = 8:1) 1H NMR
chromatography, silica gel, Rf = 0.25 (petroleum ether/ethyl acetate = (400 MHz, CDCl3) δ 9.30 (s, 1H), 8.75 (s, 1H), 8.06 (d, J = 9.2 Hz,
8:1) 1H NMR (400 MHz, CDCl3) δ 9.42 (s, 1H), 8.80 (s, 1H), 7.74 1H), 7.48 (dd, J = 9.2, 2.4 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 4.01 (s,
(s, 1H), 7.50 (d, J = 6.8 Hz, 2H), 7.47−7.38 (m, 4H), 5.45 (s, 2H). 3H), 3.96 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 166.0, 158.3,
13
C {1H} NMR (100 MHz, CDCl3) δ 164.8, 149.5, 147.9, 147.5, 147.4, 145.9, 137.4, 130.7, 128.0, 124.9, 123.2, 106.0, 55.6, 52.5.
143.9, 138.1, 136.0, 135.3, 131.4 (t, J = 257.0 Hz, 1JCF), 128.7, 128.6, HRMS (ESI) m/z calcd for C12H12NO3+ (M+H)+ 218.0812, found
128.5, 128.4, 124.0, 122.7, 108.1, 106.0, 67.3. 19F NMR (376 MHz, 218.0807.
CDCl3) δ −50.84. HRMS (ESI) m/z calcd for C18H12F2NO4+ (M 6-Methyl-3-phenylquinoline (4a).19b Yield 87%; 190.6 mg; yellow
+H)+ 344.0729, found 344.0723. solid; mp 97−99 °C; column chromatography, silica gel, Rf = 0.25
Benzyl 7-Methylquinoline-3-carboxylate (3r). Yield 61%; 169.0 (petroleum ether/ethyl acetate = 12:1) 1H NMR (400 MHz, CDCl3)
mg; yellow solid; mp 111−113 °C; column chromatography, silica δ 9.11 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H),
gel, Rf = 0.28 (petroleum ether/ethyl acetate = 12:1) 1H NMR (400 7.71−7.68 (m, 2H), 7.62 (s, 1H), 7.55−7.49 (m, 3H), 7.43 (dd, J =
MHz, CDCl3) δ 9.45 (s, 1H), 8.82 (s, 1H), 7.94 (s, 1H), 7.82 (d, J = 11.6, 4.4 Hz, 1H), 2.54 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ
8.4 Hz, 1H), 7.51−7.39 (m, 6H), 5.45 (s, 2H), 2.60 (s, 3H). 13C {1H} 148.9, 145.9, 138.0, 136.8, 133.7, 132.6, 131.7, 129.1, 128.8, 128.00,
NMR (100 MHz, CDCl3) δ 165.4, 150.1, 142.9, 138.6, 135.6, 129.8, 127.96, 127.3, 126.8, 21.6. HRMS (ESI) m/z calcd for C16H14N+ (M
128.73, 128.69, 128.48, 128.46, 128.4, 128.3, 124.8, 122.1, 67.1, 22.2. +H)+ 220.1121, found 220.1117.

3766 https://doi.org/10.1021/acs.joc.2c03034
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The Journal of Organic Chemistry pubs.acs.org/joc Article

6-Ethyl-3-phenylquinoline (4b).19b Yield 83%; 193.5 mg; yellow 6-Fluoro-3-phenylquinoline (4i).19b Yield 79%; 176.2 mg; yellow
solid; mp 101−103 °C; column chromatography, silica gel, Rf = 0.25 solid; mp 124−126 °C; column chromatography, silica gel, Rf = 0.25
(petroleum ether/ethyl acetate = 12:1) 1H NMR (400 MHz, CDCl3) (petroleum ether/ethyl acetate = 12:1) 1H NMR (400 MHz, CDCl3)
δ 9.12 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 8.8 δ 9.15 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.15 (dd, J =
Hz, 1H), 7.70 (d, J = 7.6 Hz, 2H), 7.64 (s, 1H), 7.60−7.56 (m, 1H), 10.0, 5.2 Hz, 1H), 7.74−7.69 (m, 2H), 7.57−7.45 (m, 5H). 13C {1H}
7.52 (t, J = 7.6 Hz, 2H), 7.43 (t, J = 7.6 Hz, 1H), 2.85 (q, J = 7.6 Hz, NMR (100 MHz, CDCl3) δ 160.8 (d, J = 247.0 Hz, 1JCF), 149.2 (d, J
2H), 1.35 (t, J = 7.6 Hz, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ = 2.0 Hz, 4JCF), 144.3, 137.4, 134.6, 132.7 (d, J = 6.0 Hz, 4JCF), 131.6
149.0, 146.1, 143.1, 138.0, 133.7, 132.8, 130.7, 129.1, 128.9, 128.1, (d, J = 9.0 Hz, 3JCF), 129.2, 128.8 (d, J = 9.0 Hz, 3JCF), 128.4, 127.5,
128.0, 127.4, 125.5, 28.9, 15.3. HRMS (ESI) m/z calcd for C17H16N+ 119.7 (d, J = 26.0 Hz, 2JCF), 110.9 (d, J = 22.0 Hz, 2JCF).19F NMR
(M+H)+ 234.1277, found 234.1276. (376 MHz, CDCl3) δ −112.68. HRMS (ESI) m/z calcd for
6-Isopropyl-3-phenylquinoline (4c).19c Yield 82%; 202.7 mg; C15H11FN+ (M+H)+ 224.0870, found 224.0867.
yellow solid; mp 102−104 °C; column chromatography, silica gel, 6-Chloro-3-phenylquinoline (4j).19c Yield 71%; 169.7 mg; yellow
Rf = 0.25 (petroleum ether/ethyl acetate = 12:1) 1H NMR (400 solid; mp 123−125 °C; column chromatography, silica gel, Rf = 0.24
MHz, CDCl3) δ 9.12 (d, J = 2.4 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), (petroleum ether/ethyl acetate = 12:1) 1H NMR (400 MHz, CDCl3)
8.07 (d, J = 8.8 Hz, 1H), 7.72−7.68 (m, 2H), 7.67−7.60 (m, 2H), δ 9.18 (s, 1H), 8.24 (s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 2.0
7.51 (t, J = 7.6 Hz, 2H), 7.41 (dd, J = 10.8, 4.4 Hz, 1H), 3.11 (dt, J = Hz, 1H), 7.74−7.65 (m, 3H), 7.56 (d, J = 7.6 Hz, 2H), 7.47 (t, J = 7.2
14.0, 6.8 Hz, 1H), 1.36 (d, J = 6.8 Hz, 6H). 13C {1H} NMR (100 Hz, 1H). 13C {1H} NMR (100 MHz, CDCl3) δ 149.9, 137.2, 134.8,
MHz, CDCl3) δ 149.0, 147.6, 146.2, 138.0, 133.7, 132.9, 129.3, 129.1, 132.9, 132.5, 130.6, 130.5, 129.3, 128.7, 128.5, 127.5, 126.6. HRMS
129.0, 128.0, 127.9, 127.3, 124.0, 34.1, 23.8. HRMS (ESI) m/z calcd (ESI) m/z calcd for C15H11ClN + (M+H)+ 240.0575, found 240.0574.
for C18H18N+ (M+H)+ 248.1434, found 248.1435. 6-Bromo-3-phenylquinoline (4k).19c Yield 63%; 178.3 mg; yellow
6-(tert-Butyl)-3-phenylquinolinee (4d).19c Yield 71%; 185.4 mg; solid; mp 129−131 °C; column chromatography, silica gel, Rf = 0.24
yellow oil; column chromatography, silica gel, Rf = 0.25 (petroleum (petroleum ether/ethyl acetate = 12:1) 1H NMR (400 MHz, CDCl3)
ether/ethyl acetate = 12:1) 1H NMR (400 MHz, CDCl3) δ 9.12 (d, J δ 9.18 (s, 1H), 8.23 (s, 1H), 8.07−8.00 (m, 2H), 7.79 (dd, J = 8.8, 1.6
= 2.4 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.81 Hz, 1H), 7.70 (d, J = 7.6 Hz, 2H), 7.54 (t, J = 7.6 Hz, 2H), 7.47 (d, J
(dd, J = 11.2, 2.4 Hz, 2H), 7.73−7.68 (m, 2H), 7.51 (t, J = 7.6 Hz, = 7.2 Hz, 1H). 13C {1H} NMR (100 MHz, CDCl3) δ 150.0, 145.5,
2H), 7.42 (t, J = 7.6 Hz, 1H), 1.44 (s, 9H). 13C {1H} NMR (100 137.2, 134.7, 133.0, 132.4, 130.7, 129.9, 129.3, 129.2, 128.5, 127.4,
MHz, CDCl3) δ 149.8, 149.2, 145.8, 138.1, 133.7, 133.3, 129.1, 128.6, 121.1. HRMS (ESI) m/z calcd for C15H11BrN + (M+H)+ 284.0069,
128.4, 127.9, 127.7, 127.3, 122.9, 34.9, 31.1. HRMS (ESI) m/z calcd found 284.0071.
for C19H20N+ (M+H)+ 262.1590, found 262.1589. 6-Iodo-3-phenylquinoline (4l). Yield 55%; 182.0 mg; yellow solid;
6-Methoxy-3-phenylquinoline (4e).19c Yield 82%; 192.8 mg; mp 132−134 °C; column chromatography, silica gel, Rf = 0.24
yellow solid; mp 119−121 °C; column chromatography, silica gel, (petroleum ether/ethyl acetate = 12:1) 1H NMR (400 MHz, CDCl3)
Rf = 0.23 (petroleum ether/ethyl acetate = 10:1) 1H NMR (400 δ 9.18 (d, J = 2.4 Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H), 8.16 (d, J = 8.4
MHz, CDCl3) δ 9.02 (d, J = 2.4 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.77−7.69 (m, 3H), 7.62−7.57 (m,
8.03 (d, J = 9.2 Hz, 1H), 7.71−7.67 (m, 2H), 7.51 (t, J = 7.6 Hz, 2H), 1H), 7.53 (t, J = 7.6 Hz, 2H), 7.46 (d, J = 7.6 Hz, 1H). 13C {1H}
7.42 (t, J = 7.6 Hz, 1H), 7.36 (dd, J = 9.2, 2.8 Hz, 1H), 7.11 (d, J = NMR (100 MHz, CDCl3) δ 149.7, 147.0, 137.8, 133.9, 133.6, 129.6,
2.8 Hz, 1H), 3.93 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 129.2, 129.0, 128.2, 128.08, 128.05, 127.5, 127.2. HRMS (ESI) m/z
158.1, 147.3, 143.4, 138.0, 134.0, 132.1, 130.5, 129.1, 129.0, 128.0, calcd for C15H11IN + (M+H)+ 331.9931, found 331.9929.
127.3, 122.2, 105.2, 55.5. HRMS (ESI) m/z calcd for C16H14NO+ (M 3-Phenyl-6-(trifluoromethoxy)quinoline (4m).19c Yield 78%;
+H)+ 236.1070, found 236.1069. 225.5 mg; yellow solid; mp 120−122 °C; column chromatography,
6-Ethoxy-3-phenylquinoline (4f).24c Yield 81%; 201.8 mg; yellow silica gel, Rf = 0.24 (petroleum ether/ethyl acetate = 10:1) 1H NMR
solid; mp 124−126 °C; column chromatography, silica gel, Rf = 0.23 (400 MHz, CDCl3) δ 9.20 (d, J = 2.0 Hz, 1H), 8.29 (d, J = 2.0 Hz,
(petroleum ether/ethyl acetate = 10:1) 1H NMR (400 MHz, CDCl3) 1H), 8.18 (d, J = 9.2 Hz, 1H), 7.71 (d, J = 6.8 Hz, 3H), 7.55 (dd, J =
δ 9.01 (d, J = 2.0 Hz, 1H), 8.17 (s, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.70 16.4, 8.4 Hz, 3H), 7.46 (t, J = 7.2 Hz, 1H). 13C {1H} NMR (100
(d, J = 7.6 Hz, 2H), 7.51 (t, J = 7.6 Hz, 2H), 7.42 (t, J = 7.2 Hz, 1H), MHz, CDCl3) δ 150.4, 147.35, 147.33, 145.5, 137.3, 134.8, 132.9,
7.36 (dd, J = 9.2, 2.8 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 4.16 (q, J = 131.5, 129.3, 128.5, 128.3, 127.5, 123.4, 120.5 (q, J = 256.0 Hz, 1JCF),
7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H). 13C {1H} NMR (100 MHz, 117.9. 19F NMR (376 MHz, CDCl3) δ −57.75. HRMS (ESI) m/z
CDCl3) δ 157.4, 147.3, 143.4, 138.1, 134.0, 132.1, 130.5, 129.1, 128.0, calcd for C16H11F3NO+ (M+H)+ 290.0787, found 290.0786.
127.4, 122.5, 106.0, 63.8, 14.7. HRMS (ESI) m/z calcd for Ethyl 3-Phenylquinoline-6-carboxylate (4n).24d Yield 59%; 163.5
C17H16NO+ (M+H)+ 250.1226, found 250.1225. mg; yellow solid; mp 96−98 °C; column chromatography, silica gel,
6-Isopropoxy-3-phenylquinoline(4g). Yield 75%; 197.3 mg; Rf = 0.23 (petroleum ether/ethyl acetate = 10:1) 1H NMR (400
yellow solid; mp 123−125 °C; column chromatography, silica gel, MHz, CDCl3) δ 9.27 (d, J = 2.0 Hz, 1H), 8.67 (s, 1H), 8.41 (d, J =
Rf = 0.23 (petroleum ether/ethyl acetate = 10:1) 1H NMR (400 2.0 Hz, 1H), 8.32 (dd, J = 8.8, 1.6 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H),
MHz, CDCl3) δ 9.01 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 7.2 Hz, 2H), 7.55 (t, J = 7.6 Hz, 2H), 7.47 (t, J = 7.2 Hz,
8.03 (d, J = 9.2 Hz, 1H), 7.69 (d, J = 7.6 Hz, 2H), 7.51 (t, J = 7.6 Hz, 1H), 4.47 (q, J = 7.2 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H). 13C {1H}
2H), 7.42 (t, J = 7.6 Hz, 1H), 7.35 (dd, J = 9.2, 2.8 Hz, 1H), 7.13 (d, J NMR (100 MHz, CDCl3) δ 166.1, 152.0, 149.0, 137.3, 134.6, 134.3,
= 2.8 Hz, 1H), 4.71 (dt, J = 12.0, 6.0 Hz, 1H), 1.42 (d, J = 6.0 Hz, 131.1, 129.5, 129.3, 128.9, 128.4, 127.4, 127.2, 61.4, 14.4. HRMS
6H). 13C {1H} NMR (100 MHz, CDCl3) δ 156.3, 147.2, 143.2, 138.0, (ESI) m/z calcd for C18H16NO2+ (M+H)+ 278.1176, found 278.1173.
133.9, 132.0, 130.5, 129.1, 129.0, 127.9, 127.3, 123.1, 107.5, 70.1, 5,7-Dimethyl-3-phenylquinoline (4o).19c Yield 75%; 174.8 mg;
21.9. HRMS (ESI) m/z calcd for C18H18NO+ (M+H)+ 264.1383, yellow solid; mp 101−103 °C; column chromatography, silica gel, Rf
found 264.1382. = 0.26 (petroleum ether/ethyl acetate = 12:1) 1H NMR (400 MHz,
3,6-Diphenylquinoline (4h).13e Yield 71%; 199.8 mg; yellow solid; CDCl3) δ 9.12 (d, J = 2.0 Hz, 1H), 8.36 (d, J = 2.0 Hz, 1H), 7.76 (s,
mp 119−121 °C; column chromatography, silica gel, Rf = 0.28 1H), 7.73−7.67 (m, 2H), 7.51 (t, J = 7.6 Hz, 2H), 7.45−7.38 (m,
(petroleum ether/ethyl acetate = 12:1) 1H NMR (400 MHz, CDCl3) 1H), 7.23 (d, J = 9.6 Hz, 1H), 2.67 (s, 3H), 2.52 (s, 3H). 13C {1H}
δ 9.18 (d, J = 2.0 Hz, 1H), 8.36 (s, 1H), 8.21 (d, J = 8.8 Hz, 1H), 8.07 NMR (100 MHz, CDCl3) δ 149.2, 147.8, 139.2, 138.3, 134.3, 132.6,
(d, J = 1.6 Hz, 1H), 7.99 (dd, J = 8.8, 2.0 Hz, 1H), 7.74 (d, J = 7.6 Hz, 129.8, 129.6, 129.1, 127.8, 127.4, 126.3, 125.3, 21.8, 18.5. HRMS
4H), 7.53 (dt, J = 11.2, 7.6 Hz, 4H), 7.44 (dd, J = 14.0, 7.2 Hz, 2H). (ESI) m/z calcd for C17H16N+ (M+H)+ 234.1277, found 234.1276.
13
C {1H} NMR (100 MHz, CDCl3) δ 149.9, 146.7, 140.3, 139.8, 5,6,7-Trimethyl-3-phenylquinoline (4p). Yield 67%; 165.6 mg;
137.8, 134.2, 133.4, 129.6, 129.2, 129.0, 128.23, 128.16, 127.8, 127.5, yellow solid; mp 105−107 °C; column chromatography, silica gel, Rf
127.4, 125.7. HRMS (ESI) m/z calcd for C21H16N+ (M+H)+ = 0.26 (petroleum ether/ethyl acetate = 12:1) 1H NMR (400 MHz,
282.1277, found 282.1273. CDCl3) δ 9.07 (d, J = 2.0 Hz, 1H), 8.44 (d, J = 1.6 Hz, 1H), 7.80 (s,

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1H), 7.75−7.67 (m, 2H), 7.51 (t, J = 7.6 Hz, 2H), 7.42 (t, J = 7.6 Hz, {1H} NMR (100 MHz, CDCl3) δ 148.4, 146.0, 137.1, 136.9, 132.6,
1H), 2.64 (s, 3H), 2.51 (s, 3H), 2.40 (s, 3H). 13C {1H} NMR (100 132.5, 132.3, 132.0, 128.9, 128.8, 127.9, 126.8, 122.4, 21.6. HRMS
MHz, CDCl3) δ 148.3, 146.1, 139.5, 138.7, 134.4, 132.6, 131.2, 129.7, (ESI) m/z calcd for C16H13BrN + (M+H)+ 298.0226, found 298.0223.
129.1, 127.7, 127.4, 126.9, 125.9, 21.8, 16.3, 14.6. HRMS (ESI) m/z 3-(2-Fluorophenyl)-6-methoxyquinoline (4x).24f Yield 79%; 200.1
calcd for C18H18N+ (M+H)+ 248.1434, found 248.1432. mg; yellow solid; mp 122−124 °C; column chromatography, silica
6-Fluoro-7-methoxy-3-phenylquinoline (4q). Yield 75%; 189.8 gel, Rf = 0.24 (petroleum ether/ethyl acetate = 10:1) 1H NMR (400
mg; yellow solid; mp 133−135 °C; column chromatography, silica MHz, CDCl3) δ 8.95 (s, 1H), 8.23 (s, 1H), 8.04 (d, J = 9.2 Hz, 1H),
gel, Rf = 0.22 (petroleum ether/ethyl acetate = 10:1) 1H NMR (400 7.56 (t, J = 7.6 Hz, 1H), 7.43−7.37 (m, 2H), 7.29 (t, J = 7.6 Hz, 1H),
MHz, CDCl3) δ 9.08 (s, 1H), 8.19 (s, 1H), 7.68 (d, J = 7.6 Hz, 2H), 7.26−7.19 (m, 1H), 7.13 (d, J = 2.8 Hz, 1H), 3.95 (s, 3H). 13C {1H}
7.50 (ddd, J = 27.6, 16.0, 7.6 Hz, 5H), 4.06 (s, 3H). 13C {1H} NMR NMR (100 MHz, CDCl3) δ 160.0 (d, J = 247.0 Hz, 1JCF), 158.1,
(100 MHz, CDCl3) δ 152.7 (d, J = 251.0 Hz, 1JCF), 150.8 (d, J = 14.0 148.2 (d, J = 3.0 Hz, 4JCF), 143.4, 134.4 (d, J = 3.0 Hz, 4JCF), 130.7 (d,
Hz, 2JCF) 149.0 (d, J = 3.0 Hz, 4JCF), 145.2, 137.6, 132.7, 132.5 (d, J = J = 3.0 Hz, 4JCF), 130.6, 129.9 (d, J = 8.0 Hz, 3JCF) 129.1, 128.8, 125.9
5.0 Hz, 3JCF), 129.2, 128.0, 127.2, 122.8 (d, J = 9.0 Hz, 3JCF), 111.5 (d, (d, J = 14.0 Hz, 2JCF), 124.7 (d, J = 4.0 Hz, 3JCF), 122.6, 116.3 (d, J =
J = 19.0 Hz, 2JCF), 109.5 (d, J = 3.0 Hz, 4JCF), 56.2. 19F NMR (376 23.0 Hz, 2JCF), 105.3, 55.6. 19F NMR (376 MHz, CDCl3) δ −117.58.
MHz, CDCl3) δ −131.82. HRMS (ESI) m/z calcd for C16H13FNO+ HRMS (ESI) m/z calcd for C16H13FNO+ (M+H)+ 254.0976, found
(M+H)+ 254.0976, found 254.0972. 254.0974.
2,2-Difluoro-7-phenyl-[1,3]dioxolo[4,5-g]quinoline (4r). Yield 3-(3-Fluorophenyl)-6-methoxyquinoline (4y). Yield 77%; 194.9
73%; 208.1 mg; yellow solid; mp 122−124 °C; column chromatog- mg; yellow solid; mp 125−127 °C; column chromatography, silica
raphy, silica gel, Rf = 0.2 (petroleum ether/ethyl acetate = 8:1) 1H gel, Rf = 0.24 (petroleum ether/ethyl acetate = 10:1) 1H NMR (400
NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 8.27 (s, 1H), 7.76−7.66 (m, MHz, CDCl3) δ 9.00 (d, J = 2.0 Hz, 1H), 8.20 (s, 1H), 8.03 (d, J =
3H), 7.54 (t, J = 7.6 Hz, 2H), 7.50−7.40 (m, 2H). 13C {1H} NMR 9.2 Hz, 1H), 7.48 (d, J = 5.6 Hz, 2H), 7.45−7.36 (m, 2H), 7.19−7.09
(100 MHz, CDCl3) δ 149.1, 145.9, 144.8, 143.8, 137.3, 133.7, 133.0, (m, 2H), 3.96 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 163.3
131.5 (t, J = 255.0 Hz, 1JCF), 129.3, 128.3, 127.4, 125.2, 107.8, 105.1. (d, J = 246.0 Hz, 1JCF), 158.2, 147.0, 143.8, 140.3 (d, J = 7.0 Hz, 3JCF),
19
F NMR (376 MHz, CDCl3) δ −51.12. HRMS (ESI) m/z calcd for 132.9 (d, J = 2.0 Hz, 4JCF), 132.3, 130.7, 130.68 (d, J = 8.0 Hz, 3JCF),
C16H10F2NO2+ (M+H)+ 286.0674, found 286.0670. 129.0, 123.1 (d, J = 3.0 Hz, 4JCF), 122.6, 114.9 (d, J = 19.0 Hz, 2JCF),
6-Methyl-3-(p-tolyl)quinoline (4s).19c Yield 82%; 191.2 mg; yellow 114.3 (d, J = 22.0 Hz, 2JCF), 105.3, 55.6. 19F NMR (376 MHz,
solid; mp 100−102 °C; column chromatography, silica gel, Rf = 0.28 CDCl3) δ −112.08. HRMS (ESI) m/z calcd for C16H13FNO + (M
(petroleum ether/ethyl acetate = 12:1) 1H NMR (400 MHz, CDCl3) +H)+ 254.0976, found 254.0974.
δ 9.10 (s, 1H), 8.19 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.65−7.58 (m, 3-(3-Bromophenyl)-6-methylquinoline (4z).24e Yield 64%; 190.1
3H), 7.54 (d, J = 8.8 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 2.56 (s, 3H), mg; yellow solid; mp 129−131 °C; column chromatography, silica
2.44 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 149.0, 145.8, gel, Rf = 0.25 (petroleum ether/ethyl acetate = 12:1) 1H NMR (400
138.0, 136.8, 135.2, 133.8, 132.3, 131.6, 129.9, 128.8, 128.2, 127.3, MHz, CDCl3) δ 9.08 (s, 1H), 8.28 (s, 1H), 8.13 (d, J = 8.8 Hz, 1H),
126.8, 21.7, 21.2. HRMS (ESI) m/z calcd for C17H16N+ (M+H)+ 7.85 (s, 1H), 7.68 (s, 1H), 7.65−7.56 (m, 3H), 7.41 (t, J = 8.0 Hz,
234.1277, found 234.1275. 1H), 2.59 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 147.6, 139.6,
3-(4-(Benzyloxy)phenyl)-6-methylquinoline (4t). Yield 71%; 230.9 137.8, 133.9, 132.8, 132.5, 131.2, 130.7, 130.4, 128.1, 128.0, 126.9,
mg; yellow solid; mp 113−115 °C; column chromatography, silica 126.0, 123.3, 21.7. HRMS (ESI) m/z calcd for C16H13BrN+ (M+H)+
gel, Rf = 0.26 (petroleum ether/ethyl acetate = 10:1) 1H NMR (400 298.0226, found 298.0221.
MHz, CDCl3) δ 9.08 (d, J = 2.0 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 6-Methyl-3-(naphthalen-2-yl)quinoline (4aa).24e Yield 77%;
8.02 (d, J = 8.8 Hz, 1H), 7.68−7.61 (m, 3H), 7.54 (d, J = 8.8 Hz, 207.2 mg; yellow solid; mp 130−132 °C; column chromatography,
1H), 7.47 (d, J = 7.2 Hz, 2H), 7.41 (t, J = 7.6 Hz, 2H), 7.35 (t, J = 7.2 silica gel, Rf = 0.28 (petroleum ether/ethyl acetate = 12:1) 1H NMR
Hz, 1H), 7.13 (d, J = 8.8 Hz, 2H), 5.15 (s, 2H), 2.55 (s, 3H). 13C (400 MHz, CDCl3) δ 9.25 (s, 1H), 8.36 (s, 1H), 8.17 (s, 1H), 8.08
{1H} NMR (100 MHz, CDCl3) δ 158.9, 148.7, 145.4, 136.9, 136.7, (d, J = 8.8 Hz, 1H), 8.03−7.89 (m, 3H), 7.84 (dd, J = 8.4, 1.6 Hz,
133.4, 132.0, 131.5, 130.6, 128.7, 128.6, 128.5, 128.2, 128.1, 127.5, 1H), 7.68 (s, 1H), 7.63−7.49 (m, 3H), 2.58 (s, 3H). 13C {1H} NMR
126.7, 115.5, 70.1, 21.6. HRMS (ESI) m/z calcd for C23H20NO+ (M (100 MHz, CDCl3) δ 148.9, 145.6, 137.1, 135.2, 133.8, 133.6, 133.1,
+H)+ 326.1539, found 326.1537. 132.8, 131.9, 129.0, 128.6, 128.3, 128.1, 127.7, 126.8, 126.7, 126.5,
3-(4-Fluorophenyl)-6-methylquinoline (4u).24e Yield 76%; 180.2 126.4, 125.2, 21.7. HRMS (ESI) m/z calcd for C20H16N+ (M+H)+
mg; yellow solid; mp 117−119 °C; column chromatography, silica 270.1277, found 270.1274.
gel, Rf = 0.25 (petroleum ether/ethyl acetate = 12:1) 1H NMR (400 2-Deuterated-6-methyl-3-phenylquinoline (5a).13e Yield 53%;
MHz, CDCl3) δ 9.05 (s, 1H), 8.14 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 116.6 mg; yellow solid; mp 98−100 °C; column chromatography,
7.68−7.60 (m, 3H), 7.55 (d, J = 8.8 Hz, 1H), 7.20 (t, J = 8.4 Hz, 2H), silica gel, Rf = 0.25 (petroleum ether/ethyl acetate = 12:1) 1H NMR
2.55 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 162.8 (d, J = (400 MHz, CDCl3) δ 9.12 (s, 0.08H), 8.25 (s, 1H), 8.07 (d, J = 8.8
246.0 Hz, 1JCF), 148.7, 145.9, 137.0, 134.2 (d, J = 3.0 Hz, 4JCF), 132.8, Hz, 1H), 7.71 (d, J = 7.2 Hz, 2H), 7.66 (s, 1H), 7.59−7.51 (m, 3H),
132.4, 131.8, 129.1, 129.0 (d, J = 8.0 Hz, 3JCF), 127.9, 126.7, 116.1 (d, 7.45 (d, J = 7.6 Hz, 1H), 2.57 (s, 3H). HRMS (ESI) m/z calcd for
J = 22.0 Hz, 2JCF), 21.6. 19F NMR (376 MHz, CDCl3) δ −114.24. C16H13DN+ (M+H)+ 221.1184, found 221.1178. 13C {1H} NMR
HRMS (ESI) m/z calcd for C16H13FN+ (M+H)+ 238.1027, found (100 MHz, CDCl3) δ 145.7, 137.9, 137.0, 133.7, 132.8, 131.8, 130.2,
238.1024. 129.2, 128.7, 128.08, 128.05, 127.4, 126.8, 21.6.
3-(4-Chlorophenyl)-6-methylquinoline (4v).24e Yield 71%; 179.7
mg; yellow solid; mp 118−120 °C; column chromatography, silica
gel, Rf = 0.25 (petroleum ether/ethyl acetate = 12:1) 1H NMR (400
MHz, CDCl3) δ 9.04 (s, 1H), 8.14 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H),
■ ASSOCIATED CONTENT
Data Availability Statement
7.62−7.57 (m, 3H), 7.54 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.0 Hz,
2H), 2.54 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 148.5, 146.0, The data underlying this study are available in the published
137.0, 136.4, 134.2, 132.51, 132.48, 131.9, 129.3, 128.8, 128.5, 127.9, article and its Supporting Information.
126.7, 21.6. HRMS (ESI) m/z calcd for C16H13ClN+ (M+H)+ *
sı Supporting Information
254.0731, found 254.0763.
3-(4-Bromophenyl)-6-methylquinoline (4w).24e Yield 62%; 184.2 The Supporting Information is available free of charge at
mg; yellow solid; mp 124−126 °C; column chromatography, silica https://pubs.acs.org/doi/10.1021/acs.joc.2c03034.
gel, Rf = 0.25 (petroleum ether/ethyl acetate = 12:1) 1H NMR (400
Experimental procedures and spectral data for all new
MHz, CDCl3) δ 9.05 (s, 1H), 8.17 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H),
7.63 (d, J = 8.8 Hz, 3H), 7.55 (d, J = 8.0 Hz, 3H), 2.55 (s, 3H). 13C compounds (PDF)

3768 https://doi.org/10.1021/acs.joc.2c03034
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The Journal of Organic Chemistry pubs.acs.org/joc Article

Accession Codes
CCDC 2227221 contains the supplementary crystallographic
■ REFERENCES
(1) (a) Bergstrom, F. W. Heterocyclic Nitrogen Compounds. Part
data for this paper. These data can be obtained free of charge IIA. Hexacyclic Compounds: Pyridine, Quinoline, and Isoquinoline.
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing Chem. Rev. 1944, 35, 77−277. (b) Claret, P. A.; Osborne, A. G. In The
data_request@ccdc.cam.ac.uk, or by contacting The Cam- Chemistry of Heterocyclic Compounds, Quinolines; Jones, G., Ed.;
JohnWiley and Sons: Chichester, 1982; Vol. 32, Part 2, p 31.
bridge Crystallographic Data Centre, 12 Union Road, DOI: 10.1002/9780470187036.ch1. (c) Balasubramanian, M.; Keay,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033. J. G. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees,
C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 5,
■ AUTHOR INFORMATION
Corresponding Authors
Chapter 5.06, pp 245−300. DOI: 10.1016/B978-008096518-5.00109-
X. (d) Michael, J. P. Quinoline, Quinazoline and Acridonealkaloids.
Nat. Prod. Rep. 2008, 25, 166−187. (e) Afzal, O.; Kumar, S.; Haider,
Jia-Chen Xiang − School of Chemistry and Chemical M. R.; Ali, M. R.; Kumar, R.; Jaggi, M.; Bawa, S. A Review on
Engineering, Southeast University, Nanjing 211189, China; Anticancer Potential of Bioactive Heterocycle Quinoline. Eur. J. Med.
orcid.org/0000-0003-2422-6103; Email: xiangjiachen@ Chem. 2015, 97, 871−910.
seu.edu.cn (2) (a) Madapa, S.; Tusi, Z.; Batra, S. Advances in the Syntheses of
Quinoline and Quinoline-Annulated Ring Systems. Curr. Org. Chem.
An-Xin Wu − Key Laboratory of Pesticide & Chemical 2008, 12, 1116−1183. (b) Marco-Contelles, J.; Pérez-Mayoral, E.;
Biology, Ministry of Education, College of Chemistry, Central Samadi, A.; Carreiras, M. D. C.; Soriano, E. Recent Advances in the
China Normal University, Wuhan 430079, P. R. China; Friedländer Reaction. Chem. Rev. 2009, 109, 2652−2671 and
orcid.org/0000-0001-7673-210X; Email: chwuax@ references therein. (c) Barluenga, J.; Rodríguez, F.; Fañanás, F.
mail.ccnu.edu.cn Recent Advances in the Synthesis of Indole and Quinoline Derivatives
Through Cascade Reactions. Chem.�Asian J. 2009, 4, 1036−1048.
Authors (d) Kouznetsov, V.; Mendez, L.; Gomez, C. Recent Progress in the
Jin-Tian Ma − Key Laboratory of Pesticide & Chemical Synthesis of Quinolines. Curr. Org. Chem. 2005, 9, 141−161.
Biology, Ministry of Education, College of Chemistry, Central (3) For selected recent studies for a review, see: (a) Prajapati, S. M.;
China Normal University, Wuhan 430079, P. R. China Patel, K. D.; Vekariya, R. H.; Panchal, S. N.; Patel, H. D. Recent
Ting Chen − Key Laboratory of Pesticide & Chemical Biology, Advances in the Synthesis of Quinolines: a Review. RSC Adv. 2014, 4,
24463−24476. (b) Xu, X.; Yang, Y.; Zhang, X.; Yi, W. Direct
Ministry of Education, College of Chemistry, Central China Synthesis of Quinolines via Co(III)-Catalyzed and DMSO-Involved
Normal University, Wuhan 430079, P. R. China C−H Activation/Cyclization of Anilines with Alkynes. Org. Lett.
Bo-Cheng Tang − Key Laboratory of Pesticide & Chemical 2018, 20, 566−569. (c) Su, L. L.; Zheng, Y. W.; Wang, W. G.; Chen,
Biology, Ministry of Education, College of Chemistry, Central B.; Wei, X. Z.; Wu, L. Z.; Tung, C. H. Photocatalytic Synthesis of
China Normal University, Wuhan 430079, P. R. China Quinolines via Povarov Reaction Under Oxidant-Free Conditions.
Xiang-Long Chen − Key Laboratory of Pesticide & Chemical Org. Lett. 2022, 24, 1180−1185. (d) Nan, J.; Yin, J.; Gong, X.; Hu, Y.;
Biology, Ministry of Education, College of Chemistry, Central Ma, Y. Rhodium-Catalyzed C−H Annulation of Free Anilines with
China Normal University, Wuhan 430079, P. R. China Vinylene Carbonate as a Bifunctional Synthon. Org. Lett. 2021, 23,
Zhi-Cheng Yu − Key Laboratory of Pesticide & Chemical 8910−8915. (e) Cen, J.; Li, J.; Zhang, Y.; Zhu, Z.; Yang, S.; Jiang, H.
Biology, Ministry of Education, College of Chemistry, Central Direct Assembly of 4-Substituted Quinolines with Vinyl Azides as a
Dual Synthon via C�C and C-N Bond Cleavage. Org. Lett. 2018, 20,
China Normal University, Wuhan 430079, P. R. China 4434−4438. (f) Kumar, G. S.; Singh, D.; Kumar, M.; Kapur, M.
You Zhou − Key Laboratory of Pesticide & Chemical Biology, Palladium-Catalyzed Aerobic Oxidative Coupling of Allylic Alcohols
Ministry of Education, College of Chemistry, Central China with Anilines in the Synthesis of Nitrogen Heterocycles. J. Org. Chem.
Normal University, Wuhan 430079, P. R. China 2018, 83, 3941−3951. (g) Li, M.; Dong, X.; Zhang, N.; Jérôme, F.;
Shi-Yi Zhuang − Key Laboratory of Pesticide & Chemical Gu, Y. Eco-efficient Synthesis of 2-quinaldic Acids from Furfural.
Biology, Ministry of Education, College of Chemistry, Central Green Chem. 2019, 21, 4650−4655. (h) Zhao, P.; Wu, X.; Zhou, Y.;
China Normal University, Wuhan 430079, P. R. China Geng, X.; Wang, C.; Wu, Y. D.; Wu, A. X. Direct Synthesis of 2,3-
Yan-Dong Wu − Key Laboratory of Pesticide & Chemical Diaroyl Quinolines and Pyridazino[4,5-b]quinolines via an I2-
Biology, Ministry of Education, College of Chemistry, Central Promoted One-Pot Multicomponent Reaction. Org. Lett. 2019, 21,
China Normal University, Wuhan 430079, P. R. China; 2708−2711.
(4) Bioactive studies: (a) Deaton, D. N.; et al. The Discovery of
orcid.org/0000-0003-0589-7155 Quinoline-3-carboxamides as Hematopoietic Prostaglandin D Syn-
Complete contact information is available at: thase (H-PGDS) Inhibitors. Bioorg. Med. Chem. 2019, 27, 1456−
https://pubs.acs.org/10.1021/acs.joc.2c03034 1478. (b) Ţ înţaş, M. L.; Gembus, V.; Alix, F.; Barré, A.; Coadou, G.;
Truong, L.; Sebban, M.; Papamicaël, C.; Oulyadi, H.; Levacher, V.
Notes Rational Design of Carbamate-based Dual Binding Site and Central
AChE Inhibitors by a “biooxidisable” Prodrug Approach: Synthesis, In
The authors declare no competing financial interest. vitro Evaluation and Docking Studies. Eur. J. Med. Chem. 2018, 155,
171−182.
■ ACKNOWLEDGMENTS
This work was supported by the National Natural Science
(5) (a) Lutz, R. E.; Ohnmacht, C. J.; Davis, F. Antimalarials. 5..
alpha.-Dibutylaminomethyl- and. alpha.-(2-piperidyl)-3-quinolineme-
thanols. J. Med. Chem. 1971, 14, 17−24. (b) Hanna-Elias, A.;
Foundation of China (Grant nos. 21971080, 22171098, and Manallack, D. T.; Berque-Bestel, I.; Irving, H. R.; Coupar, I. M.;
21971079). This work was also supported by “The Iskander, M. N. Synthesis of Quinoline Derivatives as 5-HT4
Fundamental Research Funds for the Central Universities Receptor Ligands. Aust. J. Chem. 2009, 62, 150.
(6) (a) Wang, W. X.; Zhang, Q. Z.; Zhang, T. Q.; Li, Z. S.; Zhang,
(2242022R42009)” and 111 Project B17019 and Jiangsu W.; Yu, W. N-Bromosuccinimide-Mediated Radical Cyclization of 3-
Provincial Natural Science Foundation of China Arylallyl Azides: Synthesis of 3-Substituted Quinolines. Adv. Synth.
(BK20210202). Catal. 2015, 357, 221−226. (b) Han, E. G.; Kim, H. J.; Lee, K. J.

3769 https://doi.org/10.1021/acs.joc.2c03034
J. Org. Chem. 2023, 88, 3760−3771
The Journal of Organic Chemistry pubs.acs.org/joc Article

Quinolines from Morita-Baylis-Hillman Acetates of 2-azidobenzalde- (14) Fei, H.; Yu, J.; Jiang, Y.; Guo, H.; Cheng, J. The Ammonium-
hydes. Tetrahedron 2009, 65, 9616−9625. (c) O’Dell, D. K.; Nicholas, promoted Formylation of Indoles by DMSO and H2O. Org. Biomol.
K. M. Synthesis of 3-Substituted Quinolines via Transition-Metal- Chem. 2013, 11, 7092−7095.
Catalyzed Reductive Cyclization of o-Nitro Baylis-Hillman Acetates. J. (15) Jiang, X.; Wang, C.; Wei, Y.; Xue, D.; Liu, Z.; Xiao, J. A General
Org. Chem. 2003, 68, 6427−6430. (d) Batchu, H.; Bhattacharyya, S.; Method for N-Methylation of Amines and Nitro Compounds with
Batra, S. Iodine-Mediated Intramolecular Electrophilic Aromatic Dimethylsulfoxide. Chem.�Eur. J. 2014, 20, 58−63.
Cyclization in Allylamines: A General Route to Synthesis of (16) (a) Zhang, X.; Zhou, Z.; Xu, H.; Xu, X.; Yu, X.; Yi, W. Cobalt-
Quinolines, Pyrazolo[4,3-b]pyridines, and Thieno[3,2-b]pyridines. Catalyzed Allylation of Amides with Styrenes Using DMSO as Both
Org. Lett. 2012, 14, 6330−6333. (e) Kim, J. N.; Lee, H. J.; Lee, K. the Solvent and the A-Methylene Source. Org. Lett. 2019, 21, 7248−
Y.; Kim, H. S. Synthesis of 3-quinolinecarboxylic Acid Esters from the 7253. (b) Padwa, A.; Waterson, A. Synthesis of Nitrogen Heterocycles
Baylis−Hillman Adducts of 2-halobenzaldehyde N-tosylimines. Using the Intramolecular Pummerer Reaction. Curr. Org. Chem. 2000,
Tetrahedron Lett. 2001, 42, 3737−3740. (f) Kim, J. N.; Chung, Y. 4, 175−203. (c) Kumari, S.; Shakoor, S. M. A.; Markad, D.; Mandal,
M.; Im, Y. J. Synthesis of Quinolines from the Baylis−Hillman S. K.; Sakhuja, R. NH4OAcPromoted Cascade Approach towards
Acetates via the Oxidative Cyclization of Sulfonamidyl Radical as the Aberrant Synthesis of Chromene-Fused Quinolinones. Eur. J. Org.
Key Step. Tetrahedron Lett. 2002, 43, 6209−6211. (g) Murru, S.; Chem. 2019, 2019, 705−714. (d) Feldman, K. S.; Nuriye, A. Y.
McGough, B.; Srivastava, R. S. Synthesis of Substituted Quinolines via Extending Pummerer Reaction Chemistry: Application to the
Allylic Amination and Intramolecular Heck-coupling. Org. Biomol. Assembly of the Pentacyclic Core of Dibromopalau’amine. Org.
Chem. 2014, 12, 9133−9138. Lett. 2010, 12, 4532−4535.
(7) (a) Venkatesan, H.; Hocutt, F. M.; Jones, T. K.; Rabinowitz, M. (17) (a) Xu, C.; Jiang, S. F.; Wen, X. H.; Zhang, Q.; Zhou, Z. W.;
H. A One-Step Synthesis of 2,4-Unsubstituted Quinoline-3-carboxylic Wu, Y. D.; Jia, F. C.; Wu, A. X. Dimethyl Sulfoxide Serves as a Dual
Acid Esters from o-Nitrobenzaldehydes. J. Org. Chem. 2010, 75, Synthon: Construction of 5-Methyl Pyrimidine Derivatives via Four
3488−3491. (b) Cai, H.; Xia, L.; Lee, Y. R.; Shim, J. J.; Kim, S. H. Component Oxidative Annulation. Adv. Synth. Catal. 2018, 360,
Construction of Diverse and Functionalized 2H-Chromenes by 2267−2271. (b) Zheng, K.; Zhuang, S.; Shu, W.; Wu, Y.; Yang, C.;
Organocatalytic Multicomponent Reactions. Eur. J. Org. Chem. Wu, A. Molecular Iodine-mediated Formal [2 + 1+1 + 1]
2015, 2015, 5212−5220. Cycloaddition Access to Pyrrolo[2,1-a]isoquinolines with DMSO as
(8) Midya, S. P.; Sahoo, M. K.; Landge, V. G.; Rajamohanan, P. R.; the Methylene Source. Chem. Commun. 2018, 54, 11897−11900.
Balaraman, E. Reversed Reactivity of Anilines with Alkynes in the (c) Zhao, P.; Yu, X. X.; Zhou, Y.; Geng, X.; Wang, C.; Huang, C.; Wu,
Rhodium-catalysed C−H Activation/carbonylation Tandem. Nat. Y. D.; Zhu, Y. P.; Wu, A. X. Splitting Methyl Ketones into Two Parts:
Commun. 2015, 6, 8591. Synthesis of 4(3H)-Quinazolinones via Consecutive Cyclization/
(9) (a) Xiang, J. C.; Wang, Z. X.; Cheng, Y.; Xia, S. Q.; Wang, M.;
Ring-Opening Reaction. Org. Lett. 2020, 22, 7103−7107. (d) Ma, J.
Tang, B. C.; Wu, Y. D.; Wu, A. X. Divergent Synthesis of
T.; Wang, L. S.; Chai, Z.; Chen, X. F.; Tang, B. C.; Chen, X. L.; He,
Functionalized Quinolines from Aniline and Two Distinct Amino
C.; Wu, Y. D.; Wu, A. X. Access to 2-arylquinazolines via Catabolism/
Acids. J. Org. Chem. 2017, 82, 9210−9216. (b) Xiang, J. C.; Cheng,
reconstruction of Amino Acids with the Insertion of Dimethyl
Y.; Wang, Z. X.; Ma, J. T.; Wang, M.; Tang, B. C.; Wu, Y. D.; Wu, A.
Sulfoxide. Chem. Commun. 2021, 57, 5414−5417.
X. Oxidative Trimerization of Amino Acids: Selective Synthesis of
(18) Maguire, M. P.; Sheets, K. R.; McVety, K.; Spada, A. P.;
2,3,5-Trisubstituted Pyridines. Org. Lett. 2017, 19, 2997−3000.
Zilberstein, A. A New Series of PDGF Receptor Tyrosine Kinase
(10) (a) Feldman, K. S. Modern Pummerer-type Reactions.
Inhibitors: 3-Substituted Quinoline Derivatives. J. Med. Chem. 1994,
Tetrahedron 2006, 62, 5003−5034 and references cited therein.
37, 2129−2137.
(b) Pummerer, R. Ü ber Phenyl-sulfoxyessigsäure. Ber. Dtsch. Chem.
(19) (a) Yang, T.; Li, H.; Nie, Z.; Su, M. D.; Luo, W. P.; Liu, Q.;
Ges. 1909, 42, 2282−2291. (c) Smith, L.; Coote, S.; Sneddon, H.;
Guo, C. C. [3 + 1 + 1 + 1] Annulation to the Pyridine Structure in
Procter, D. Beyond the Pummerer Reaction: Recent Developments in
Thionium Ion Chemistry. Angew. Chem., Int. Ed. 2010, 49, 5832− Quinoline Molecules Based on DMSO as a Nonadjacent Dual-
5844. Methine Synthon: Simple Synthesis of 3-Arylquinolines from
(11) Zhu, X.; Zhang, F.; Kuang, D.; Deng, G.; Yang, Y.; Yu, J.; Liang, Arylaldehydes, Arylamines, and DMSO. J. Org. Chem. 2022, 87,
Y. K2S as Sulfur Source and DMSO as Carbon Source for the 2797−2808. (b) Zhang, Y.; Wang, M.; Li, P.; Wang, L. Iron-
Synthesis of 2-Unsubstituted Benzothiazoles. Org. Lett. 2020, 22, Promoted Tandem Reaction of Anilines with Styrene Oxides via C−C
3789−3793. Cleavage for the Synthesis of Quinolines. Org. Lett. 2012, 14, 2206−
(12) Wu, X.; Zhang, J.; Liu, S.; Gao, Q.; Wu, A. An Efficient 2209. (c) Yan, R.; Liu, X.; Pan, C.; Zhou, X.; Li, X.; Kang, X.; Huang,
Synthesis of Polysubstituted Pyridines via Csp3-H Oxidation and C-S G. Aerobic Synthesis of Substituted Quinoline from Aldehyde and
Cleavage of Dimethyl Sulfoxide. Adv. Synth. Catal. 2016, 358, 218− Aniline: Copper-Catalyzed Intermolecular C−H Active and C−C
225. Formative Cyclization. Org. Lett. 2013, 15, 4876−4879.
(13) DMSO participated synthesis: (a) Phanindrudu, M.; Wakade, (20) (a) Atzrodt, J.; Derdau, V.; Kerr, W. J.; Reid, M. Deuterium-
S. B.; Tiwari, D. K.; Likhar, P. R.; Tiwari, D. K. Transition-Metal-Free and Tritium-Labelled Compounds: Applications in the Life Sciences.
Approach for the Synthesis of 4-Aryl-quinolines from Alkynes and Angew. Chem., Int. Ed. 2018, 57, 1758−1784. (b) A., Limbach, H.-H,
Anilines. J. Org. Chem. 2018, 83, 9137−9143. (b) Yuan, J.; Yu, J. T.; Eds. Isotope Effects in Chemistry and Biology; Kohen; CRC Press: Boca
Jiang, Y.; Cheng, J. Carbon Annulation of Ortho-vinylanilines with Raton, FL, 2006; pp 1−1019. (c) Schmidt, C. First Deuterated Drug
Dimethyl Sulfoxide to Access 4-aryl Quinolines. Org. Biomol. Chem. Approved. Nat. Biotechnol. 2017, 35, 493−494 and references cited
2017, 15, 1334−1337. (c) Jadhav, S. D.; Singh, A. Oxidative therein.
Annulations Involving DMSO and Formamide: K2S2O8 Mediated (21) (a) Boix, C.; Poliakoff, M. Efficient H-D Exchange of Aromatic
Syntheses of Quinolines and Pyrimidines. Org. Lett. 2017, 19, 5673− Compounds in Near-critical D2O Catalysed by a Polymer-supported
5676. (d) Liu, Y.; Hu, Y.; Cao, Z.; Zhan, X.; Luo, W.; Liu, Q.; Guo, C. Sulphonic Acid. Tetrahedron Lett. 1999, 40, 4433−4436. (b) Li, C.;
Copper-Catalyzed Aerobic Oxidative Cyclization of Anilines, Aryl Wang, H.; Liu, L.; Sun, R.; Wang, X.; Zhou, M. D.; Li, L. Base-
Methyl Ketones and DMSO: Efficient Assembly of 2-Arylquinolines. Catalyzed Intramolecular Self-Cyclization of o-Alkenylaryl Isocya-
Adv. Synth. Catal. 2018, 360, 2691−2695. (e) Zhang, P.; Yang, Y.; nides: Access to 4-Cyano-3-arylquinolines. Chemistry Select 2022, 7,
Chen, Z.; Xu, Z.; Xu, X.; Zhou, Z.; Yu, X.; Yi, W. Cobalt(III)- e202103829. (c) Ferlin, F.; Zangarelli, A.; Lilli, S.; Santoro, S.;
Catalyzed, DMSO-Involved, and TFA-Controlled Regioselective C− Vaccaro, L. Waste-minimized Synthesis of C2 Functionalized
H Functionalization of Anilines with Alkynes for Specific Assembly of Quinolines Exploiting Iron-catalysed C-H Activation. Green Chem.
3-Arylquinolines. Adv. Synth. Catal. 2019, 361, 3002−3007. 2021, 23, 490−495.

3770 https://doi.org/10.1021/acs.joc.2c03034
J. Org. Chem. 2023, 88, 3760−3771
The Journal of Organic Chemistry pubs.acs.org/joc Article

(22) Forrest, T. P.; Dauphinee, G. A.; Miles, W. F. On the

Mechanism of the Doebner−Miller Reaction. Can. J. Chem. 1969, 47,
2121−2122.
(23) Schonberg, A.; Moubacher, R. The Strecker Degradation of α-
Amino Acids. Chem. Rev. 1952, 50, 261−277.
(24) (a) Xiang, J. C.; Wang, Z. X.; Cheng, Y.; Xia, S. Q.; Wang, M.;
Tang, B. C.; Wu, Y. D.; Wu, A. X. Divergent Synthesis of
Functionalized Quinolines from Aniline and Two Distinct Amino
Acids. J. Org. Chem. 2017, 82, 9210−9216. (b) Kim, H. J.; Jeong, E.
M.; Lee, K. J. Using Morita-Baylis-Hillman Acetates of 2-
azidobenzaldehydes for the Synthesis of 2-alkoxy-3-cyanomethylqui-
nolines and Alkyl Quinoline-3-carboxylates. J. Heterocyclic Chem.
2011, 48, 965−972. (c) Sharghi, H.; Aberi, M.; Khataminejad, M.;
Shiri, P. Solvent-free and Room Temperature Synthesis of 3-
arylquinolines from Different Anilines and Styrene Oxide in the
Presence of Al2O3/MeSO3H. Beilstein J. Org. Chem. 2017, 13, 1977−
1981. (d) Gu, Y.; Wu, F.; Yang, J. Oxidative [3 + 3] Annulation of
Atropaldehyde Acetals with 1,3-Bisnucleophiles: An Efficient Method
of Constructing Six-Membered Aromatic Rings, Including Salicylates
and Carbazoles. Adv. Synth. Catal. 2018, 360, 2727−2741. (e) Gattu,
R.; Mondal, S.; Ali, S.; Khan, A. T. Iodine Monobromide Catalysed
Regioselective Synthesis of 3-arylquinolines from α-aminoacetophe-
nones and trans-β-nitrostyrenes. Org. Biomol. Chem. 2019, 17, 347−
353. (f) Dherange, B. D.; Kelly, P. Q.; Liles, J. P.; Sigman, M. S.;
Levin, M. D. Carbon Atom Insertion into Pyrroles and Indoles
Promoted by Chlorodiazirines. J. Am. Chem. Soc. 2021, 143, 11337−
11344.

3771 https://doi.org/10.1021/acs.joc.2c03034
J. Org. Chem. 2023, 88, 3760−3771