Coproduct promoted povarov reaction: Synthesis of substituted quinolines from methyl ketones, arylamines, and α-ketoesters

Article abstract of DOI:10.1021/acs.joc.5b00785

A highly efficient I₂-catalyzed Povarov-type reaction of methyl ketones, arylamines, and α-ketoesters is developed. This reaction utilizes a catalytic amount of HI coproduct as a promoter for the synthesis of substituted quinolones. This simple procedure represents an interesting new form of reactivity for the Povarov reaction with good functional group compatibility.

Full text of DOI:10.1021/acs.joc.5b00785

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Note
Coproduct Promoted Povarov Reaction: Synthesis of Substituted
Quinolines from Methyl Ketones, Arylamines, and #-Ketoesters
Qinghe Gao, Shan Liu, Xia Wu, Jingjing Zhang, and Anxin Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00785 • Publication Date (Web): 14 May 2015
Downloaded from http://pubs.acs.org on May 16, 2015
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Coproduct Promoted Povarov Reaction: Synthesis of
Substituted Quinolines from Methyl Ketones,
Arylamines, and α-Ketoesters
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Qinghe Gao,† Shan Liu,† Xia Wu,† Jingjing Zhang,† and Anxin Wu*,†
† Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry,
Central China Normal University, Wuhan 430079, P. R. China
E-mail: †chwuax@mail.ccnu.edu.cn
Table of Contents Graphic
ABSTRACT: A highly efficient I2-catalyzed Povarov-type reaction of methyl ketones,
arylamines, and α-ketoesters is developed. This reaction utilizes a catalytic amount of
HI coproduct as a promoter for the synthesis of substituted quinolones. This simple
procedure represents an interesting new form of reactivity for the Povarov reaction
with good functional group compatibility.
The concept of an ideal synthesis is to bring together readily available fragments in
a convergent manner using only carbon–hydrogen bond couplings to forge the
requisite carbon–carbon and carbon–heteroatom bonds of the target compound.1 In
pursuit of ideal syntheses, great attention is currently being given to domino, one-pot,
and multicomponent reactions that allow the direct synthesis of complex molecules
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from simple substrates in a highly efficient manner.2 Nevertheless, many reactions
still suffer from issues, such as the simultaneous production of large amounts of
byproducts with the desired product.3 Recently, domino reactions have been designed
to directly utilize a generated byproduct as a catalyst/co-catalyst for a subsequent
reaction.4 In 2008, Alaimo et al. first reported that the InCl3 byproduct produced from
a reduction step is internally recycled to catalyze a subsequent cycloaddition reaction.
The reaction used two equivalents of indium powder as the reducing agent and five
equivalents of an aldehyde to achieve a high overall yield.4a Subsequently, Tian and
co-workers described an indirect method for utilization of the byproduct of TMSCl
hydrolysis to construct protected β-amino esters/ketones. Water was used as a
hydrolyzing agent to decompose the TMSCl and yield the secondary byproduct HCl
that serves as an active catalyst for the following two steps.4b The byproduct catalyzed
strategy has also proven successful for the assembly of saturated ketones scaffolds.
This involves Ph3PO generated from a Wittig reaction, being used as a catalyst for a
following step.4c Despite these promising results, the byproduct catalyzed strategy is a
young and relatively unexplored area of synthesis. Herein, we report our progress
towards the direct synthesis of substituted quinolines using a coproduct promoted
Povarov reaction in the absence of external additives.
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Quinolines occur widely in natural products and are broadly used in medicinal
chemistry, particularly as antiviral, anticancer, antituberculosis, and antimalarial
agents.5 Consequently, much attention has been paid to develop more efficient and
convenient strategies for the synthesis of substituted quinolines, through either
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construction or modification of quinoline rings. The Povarov reaction has become one
of the most attractive protocols for quinoline preparation.6 However, the substrate
scope of these reactions is limited to preformed aldimines or aldehydes, and Povarov
reaction that involve ketones are rare.7 The Mancheño and Wang groups,
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independently and systematically developed
a
versatile dehydrogenative
Povarov/oxidation tandem reaction of α-amino carbonyl compounds (Scheme 1a).8
Both Ji and Tamariz demonstrated an interesting route for the synthesis of
1,2-Dihydroquinolines from an arylamine and two of the same enolizable ketone
(Scheme 1b).9 We reported in 2014 the first example of formal [3 + 2 + 1]
cycloaddition via the oxidative Csp3−H bonds of the methyl ketone, providing a
series of quinoline derivatives (Scheme 1c).10 However, to the best of our
knowledge, no example of an I2-catalyzed Povarov-type reaction of arylamine with
two different kinds of ketones is reported (Scheme 1d), wherein the catalytic amount
of HI coproduct serves as promoter to accelerate the quinoline synthesis.
Scheme 1. Povarov Reactions Involving Ketones
Initially, we optimized the procedure for the preparation of quinolines from
phenylglyoxal (1ac) with p-toluidine (2a) and ethyl pyruvate (3a). There are also few
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reports dealing with the use of α-oxo aldehydes as one of the partners in Povarov
reaction.11 Rewardingly, the reaction proceeded smoothly over 1 h using 1.0 equiv of
I2 at 100 °C in DMSO to afford the Povarov cycloaddition product (4a) in 90% yield
as a single regioisomer (Table 1, entry 1). The structure of this compound was
unambiguously confirmed by X-ray crystallography analysis (Supporting Information,
Figure S1). A control experiment was conducted without I2, which gave the product in
low yields of 24% (Table 1, entry 5). It is well known that protic acids can also
catalyze the Povarov-type reaction involving α-ketoesters. Considering the role of I2
in the reaction, it is possible that trace amounts of HI, generated during the reaction,
might be the actual catalyst for this process. Thus, some control experiments were
performed using different amounts of HI (Table 1, entries 12−14). It can be seen that
HI at 1 mol% was sufficient to catalyze the model reaction giving the product in a
good yield at 110 °C after 1 h. Therefore, we considered the possibility of preparing
4a via a byproduct catalyzed strategy by combining aromatic ketones with I2, where
HI is generated as a coproduct in the iodination and Kornblum oxidation steps.12 After
many screening experiments, we found that heating acetophenone (1a) in the presence
of I2 (50 mol %) at 130 °C for 40 min, then adding p-toluidine (2a) and ethyl pyruvate
(3a) at 130 °C for another 1 h yielded the desired product in good yield (88%).
Table 1. Optimization of the Reaction Conditionsa
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entry
catalyst
I2 (100 %)
I2 (50 %)
temp (°C) yieldb (%)
1
2
100
100
90
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I2 (30 %)
I2 (10 %)
100
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100
rt
50
70
88
88
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36
64
66
87
91
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78
91
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I2 (50 %)
I2 (50 %)
I2 (50 %)
I2 (50 %)
I2 (50 %)
I2 (50 %)
HI (1%)
HI (5%)
HI (10%)
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aReaction conditions: 1ac (0.5 mmol), 2a (0.5 mmol), 3a (0.75 mmol), DMSO (2
mL). Isolated yields.
The efficient formation of the desired product prompted us to study the reaction
scope further. The reaction demonstrated good tolerance of different aromatic ketone
units (Scheme 2). Aryl methyl ketones bearing electron-neutral (e.g., 4-H),
electron-rich (e.g., 4-Me, 4-OMe, 3,4-OCH2O), and electron-deficient (e.g., 4-NO2,
3-NO2) phenyl rings were successfully converted to the corresponding products in
moderate to good yields (67−89%; 4a−f). Furthermore, the optimized conditions were
mild enough to be compatible with a broad range of halogenated (e.g., 4-Cl, 4-Br)
substrates (42−76%; 4g−h), which allow the possibility of further functionalization.
2-Naphthyl methyl ketone also provided the expected product (4i) in 87% yield.
Furthermore, the optimized conditions could be applied to various heteroaryl ketones,
including thienyl, furanyl, and benzofuryl methyl ketones, which gave the
corresponding products in moderate to good yields (61−83%; 4j−l).
Scheme 2. Scope of Methyl Ketonesa
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aIsolated yield
The scope and generality of the coproduct promoted Povarov reaction were tested
with respect to various aromatic amines, and the desired products were obtained in
satisfactory yields (Scheme 3). Interestingly, in the absence of any aniline substituent
the quinoline product 4m was isolated in good yield, which is different from research
by our group and others.11,12a,12d Both electron-rich and electron-deficient anilines
could be smoothly converted to the desired products (56−94%; 4n−q). In general,
aromatic amines containing electron-rich groups showed better activities than those
bearing electron-withdrawing groups. Notably, substrates bearing halogen substituents
were well tolerated with the corresponding halo-substituted products being isolated in
reasonable yields (48−68%; 4r−t). 1-Naphthylamine and 2-naphthylamine were
suitable for this protocol and gave 4u and 4v in 78% and 85% yields, respectively.
Furthermore, Methyl pyruvate was also a good substrate for the reaction. However,
the yield decreased if the ester functional group was then changed to another electron
withdrawing group such as a phenyl (34%; 4x), ketone (0%; 4y) and carboxyl (0%;
4z), indicating that ester substitution is optimal. It may be noted that the ester group
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can be transformed easily into other groups such as carboxyl or amide groups. We
also performed the reaction on a gram scale and were pleased to find that the
quinolone product 4a was obtained in 84% yield (Scheme 4).
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Scheme 3. Scope of Anilines and α-ketoestersa
aIsolated yield
Scheme 4. Scaled up for The Gram-Scale
With the scope of the method established, the reaction mechanism was considered.
Acetophenone (1a) was reacted with I2 in DMSO at 130 °C to give phenylglyoxal
(1ab) and the corresponding hydrated species (1ac) in quantitative yield (Scheme 5a).
When the acetophenone substrate was replaced with α-iodo acetophenone (1aa),
which was identified as a probable precursor of α-ketoaldehyde (1ab), the desired
product 4a was obtained in good yields, both with I2 (50 mol %) and without (Scheme
5b). When the reaction of 1ac with ethyl pyruvate (3a) was performed under the
standard conditions, the product 6 was not detected (Scheme 5c), suggesting that this
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reaction mechanism might be different from that of the modified Doebner-von Miller
reaction. When C-acylimine (5p) was tested in the presence of HI, the desired product
4p was formed in excellent yield. However, the Povarov adduct was isolated in poor
yield when the reaction was conducted in the absence of HI (Scheme 5d), indicating
that the catalytic amount of HI generated as a coproduct from the upstream iodination
and Kornblum oxidation process may be responsible for the Povarov process.
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Scheme 5. Control Experiments
On the basis of our findings and previous reports,13 a possible mechanism can be
proposed using acetophenone (1a), p-toluidine (2a), and ethyl pyruvate (3a) as the
substrates (Scheme 6). The initial elimination of HI from 1a by I2 generates α-iodo
ketone in situ, which is converted into phenylglyoxal and releases HI after the
following Kornblum oxidation. The reaction of p-toluidine (2a) with the aldehyde
group of 1ab then gives the C-acylimine 5a, Next, the enolate quickly formed from
the tautomerization of ketoester reacted with the activated C-acyl imine ion 5a′ in the
presence of HI, which was formed as a coproduct from the upstream iodination and
Kornblum oxidation process, to afford intermediate A. Subsequently the electron-rich
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benzene ring can add to the keto group to form intermediate B. Finally, B undergoes
sequential dehydration and oxidative aromatization reactions to give the desired 4a.
Scheme 6. Possible Mechanism
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In summary, we have developed a coproduct promoted Povarov reaction for the
synthesis of substituted quinolines from methyl ketones, arylamines, and α-ketoesters.
HI is generated in situ from the iodination and Kornblum oxidation steps served as a
promoter for the following Povarov step, without the need for any additives. This
reaction presents an interesting new form of reactivity for the Povarov reaction with
good functional group compatibility.
Experimental Section
General Information. IR spectra were recorded as KBr pellets with absorption in
1
13
cm–1. H NMR and C NMR spectra were recorded in CDCl3 or DMSO-d6. HRMS
were obtained on a 7.0T FTMS equipped with ESI.
General procedure for the synthesis of 4 (4a as an example). A sealed tube was
charged with acetophenone (1a) (60 mg, 0.5 mmol), iodine (63.5 mg, 50 mol%) at
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room temperature, and then dried solvent DMSO (2 mL) was added. The resulting
mixture was stirred at 130 °C, after disappearance of the reactant (monitored by TLC),
then added p-toluidine (2a) (53.5 mg, 0.5 mmol) and ethyl pyruvate (3a) (87 mg, 0.75
mmol) at 130 °C for another 1 h. After the reaction completed, and added 50mL water
to the mixture, then extracted with EtOAc 3 times. The extract was washed with
Na2S2O3 solution, dried over anhydrous Na2SO4 and evaporation. The residue was
purified by column chromatography on silica gel (eluent: petroleum ether/EtOAc) to
afford 4a.
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ethyl 2-benzoyl-6-methylquinoline-4-carboxylate (4a): Light yellow solid; 140.3 mg
(yield 88%); mp 111–113 °C; IR (KBr): 1719, 1654, 1595, 1341, 1234 cm–1; 1H NMR
(600 MHz, DMSO-d6): δ (ppm) 8.45 (s, 1H), 8.38 (s, 1H), 8.13 (d, J = 7.2 Hz, 2H),
8.04 (d, J = 9.0 Hz, 1H), 7.73 (t, J = 7.2 Hz, 2H), 7.59 (t, J = 7.8 Hz, 2H), 4.49 (q, J =
7.2 Hz, 2H), 2.57 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, DMSO-d6) δ
(ppm) 192.4, 165.2, 152.8, 145.5, 140.6, 135.6, 135.2, 133.2, 132.9, 130.9, 130.3,
128.2, 124.9, 123.9, 121.1, 61.9, 21.82, 14.0; HRMS (ESI): m/z [M + H]+ calcd for
C20H18NO3: 320.1281; found: 320.1280.
ethyl 6-methyl-2-(4-methylbenzoyl)quinoline-4-carboxylate (4b): Yellow solid;
144.8 mg (yield 87%); mp 104–107 °C; IR (KBr): 1723, 1659, 1608, 1343, 1237 cm–1;
1H NMR (600 MHz, CDCl3): δ (ppm) 8.63 (s, 1H), 8.56 (s, 1H), 8.18–8.11 (m, 3H),
7.65 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 7.8 Hz, 2H), 4.53 (q, J = 7.2 Hz, 2H), 2.61 (s,
13
3H), 2.45 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) δ (ppm)
192.6, 166.0, 153.4, 146.3, 144.0, 140.5, 135.3, 133.3, 132.5, 131.5, 130.7, 128.9,
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125.8, 124.3, 122.0, 61.9, 22.3, 21.7, 14.3; HRMS (ESI): m/z [M + Na]+ calcd for
C21H19NNaO3: 356.1257; found: 356.1256.
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ethyl 2-(4-methoxybenzoyl)-6-methylquinoline-4-carboxylate (4c): White solid; 129
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o
1
mg (yield 74%); mp 129–131 C; IR (KBr): 1715, 1655, 1597, 1247 cm–1; H NMR
(600 MHz, CDCl3): δ (ppm) 8.62 (s, 1H), 8.55 (s, 1H), 8.30 (d, J = 9.0 Hz, 2H), 8.13
(d, J = 8.4 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 4.53 (q, J = 7.2
13
Hz, 2H), 3.90 (s, 3H), 2.61 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H); C NMR (100 MHz,
CDCl3) δ (ppm) 191.3, 165.9, 163.7, 153.8, 146.2, 140.4, 135.3, 133.8, 132.4, 130.5,
128.6, 125.7, 124.3, 122.1, 113.5, 61.9, 55.4, 22.2, 14.2; HRMS (ESI): m/z [M + Na]+
calcd for C21H19NNaO4: 372.1206; found: 372.1206.
ethyl 2-(benzo[d][1,3]dioxole-5-carbonyl)-6-methylquinoline-4-carboxylate (4d):
o
Yellow solid; 161.5 mg (yield 89%); mp 165–168 C; IR (KBr): 1716, 1639, 1599,
1489, 1441, 1250 cm–1; H NMR (600 MHz, CDCl3): δ (ppm) 8.62 (s, 1H), 8.53 (s,
1
1H), 8.13 (d, J = 9.0 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.78 (s, 1H), 7.65 (d, J = 9.0
Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.07 (s, 2H), 4.53 (q, J = 6.6 Hz, 2H), 2.61 (s, 3H),
13
1.49 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) δ (ppm) 190.8, 165.9, 153.6,
152.0, 147.7, 146.1, 140.5, 135.4, 132.5, 130.6, 130.2, 128.5, 125.7, 124.3, 122.1,
110.8, 107.8, 101.8, 61.9, 22.3, 14.2; HRMS (ESI): m/z [M + H]+ calcd for
C21H18NO5: 364.1180; found: 364.1186.
ethyl 6-methyl-2-(4-nitrobenzoyl)quinoline-4-carboxylate (4e): Light yellow solid;
121.9 mg (yield 67%); mp 174–176 oC; IR (KBr): 1728, 1673, 1620, 1518, 1348 cm–1;
1H NMR (600 MHz, CDCl3): δ (ppm) 8.67 (s, 1H), 8.64 (s, 1H), 8.41 (d, J = 8.4 Hz,
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2H), 8.35 (d, J = 8.4 Hz, 2H), 8.09 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 4.55
(q, J = 7.2 Hz, 2H), 2.63 (s, 3H), 1.51 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ (ppm) 191.2, 165.7, 151.6, 149.9, 146.3, 141.6, 141.2, 135.8, 132.9, 132.2, 130.7,
126.2, 124.5, 123.0, 121.7, 62.1, 22.4, 14.3; HRMS (ESI): m/z [M + Na]+ calcd for
C20H16N2NaO5: 387.0951; found: 387.0951.
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ethyl 6-methyl-2-(3-nitrobenzoyl)quinoline-4-carboxylate (4f): Light yellow solid;
125.6 mg (yield 69%); mp 145–146 oC; IR (KBr): 1720, 1659, 1611, 1529, 1349 cm–1;
1H NMR (600 MHz, CDCl3): δ (ppm) 9.24 (s, 1H), 8.68 (s, 1H), 8.64 (s, 1H), 8.61 (d,
J = 7.2 Hz, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 9.0 Hz, 1H), 7.72 (t, J = 7.8 Hz,
1H), 7.68 (d, J = 8.4 Hz, 1H), 4.55 (q, J = 7.2 Hz, 2H), 2.63 (s, 3H), 1.52 (t, J = 7.2
13
Hz, 3H); C NMR (100 MHz, CDCl3) δ (ppm) 190.0, 165.7, 151.6, 147.9, 146.3,
141.5, 137.3, 136.8, 135.8, 132.9, 130.8, 129.2, 127.0, 126.6, 126.2, 124.5, 121.7,
62.1, 22.4, 14.3; HRMS (ESI): m/z [M + Na]+ calcd for C20H16N2NaO5: 387.0951;
found: 387.0959.
ethyl 2-(4-chlorobenzoyl)-6-methylquinoline-4-carboxylate (4g): Light yellow solid;
134.1 (yield 76%); mp 147–148 oC; IR (KBr): 1727, 1664, 1662, 1593, 1345 cm–1; 1H
NMR (600 MHz, CDCl3): 8.63 (s, 1H), 8.60 (s, 1H), 8.23 (d, J = 8.4 Hz, 2H), 8.11 (d,
J = 8.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H), 4.54 (q, J = 7.2 Hz,
13
2H), 2.62 (s, 3H), 1.50 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) δ (ppm)
191.5, 165.8, 152.7, 146.2, 140.9, 139.6, 135.6, 134.3, 132.9, 132.7, 130.7, 128.4,
126.0, 124.4, 121.9, 62.0, 22.3, 14.3; HRMS (ESI): m/z [M + H]+ calcd for
C20H17ClNO3: 354.0892; found: 354.0894.
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ethyl 2-(4-bromobenzoyl)-6-methylquinoline-4-carboxylate (4h): Light yellow solid;
83.6 mg (yield 42%); mp 148–150 oC; IR (KBr): 1727, 1666, 1622, 1588, 1246 cm–1;
1H NMR (600 MHz, CDCl3): δ (ppm) 8.63 (s, 1H), 8.60 (s, 1H), 8.15 (d, J = 8.4 Hz,
2H), 8.12 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 8.4 Hz, 3H), 4.54 (d, J = 7.2 Hz, 2H), 2.63
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(s, 3H), 1.50 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) δ (ppm) 191.6, 165.8,
152.5, 146.2, 140.9, 135.5, 134.6, 132.9, 132.6, 131.4, 130.6, 128.3, 125.9, 124.4,
121.8, 61.9, 22.3, 14.2; HRMS (ESI): m/z [M + H]+ calcd for C20H17BrNO3: 398.0386;
found: 398.0386.
ethyl 2-(2-naphthoyl)-6-methylquinoline-4-carboxylate (4i): Yellow solid; 160.5 mg
(yield 87%); mp 138–140 oC; IR (KBr): 1717, 1649, 1623, 1356, 1264 cm–1; 1H NMR
(600 MHz, CDCl3): δ (ppm) 8.83 (s, 1H), 8.65 (s, 1H), 8.63 (s, 1H), 8.27–8.24 (m,
1H), 8.15 (d, J = 8.4 Hz, 1H), 7.97–7.93 (m, 2H), 7.89 (d, J = 8.4 Hz, 1H), 7.65 (d, J
= 8.4 Hz, 1H), 7.62–7.58 (m, 1H), 7.55–7.51 (m, 1H), 4.54 (q, J = 7.2 Hz, 2H), 2.62
13
(s, 3H), 1.49 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) δ (ppm) 192.8, 165.9,
153.3, 146.3, 140.6, 135.5, 135.4, 134.0, 133.2, 132.5, 132.3, 130.7, 129.8, 128.5,
127.9, 127.6, 126.5, 126.3, 125.8, 124.3, 122.0, 61.9, 22.3, 14.2; HRMS (ESI): m/z
[M + H]+ calcd for C24H20NO3: 370.1438; found: 370.1438.
ethyl 6-methyl-2-(thiophene-2-carbonyl)quinoline-4-carboxylate (4j): Yellow solid;
118.6 mg (yield 73%); mp 128–130 oC; IR (KBr): 1726, 1641 1503, 1412, 1360 cm–1;
1H NMR (600 MHz, CDCl3): δ (ppm) 8.68 (s, 1H), 8.61 (s, 1H), 8.50 (d, J = 3.6 Hz,
1H), 8.20 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 4.8 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.22
(t, J = 4.2 Hz, 1H), 4.52 (q, J = 7.2 Hz, 2H), 2.60 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H); 13C
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NMR (100 MHz, CDCl3) δ (ppm) 182.7, 165.8, 151.8, 146.2, 140.9, 139.3, 136.8,
135.3, 132.6, 130.3, 127.5, 126.2, 124.4, 121.0, 120.9, 61.9, 22.3, 14.2; HRMS (ESI):
m/z [M + H]+ calcd for C18H16NO3S: 326.0845; found: 326.0850.
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ethyl 2-(furan-2-carbonyl)-6-methylquinoline-4-carboxylate (4k): Yellow solid;
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94.2 mg (yield 61%); mp 140–142 C; IR (KBr): 1727, 1650, 1466, 1270 cm–1; H
NMR (600 MHz, CDCl3): δ (ppm) 8.69 (s, 1H), 8.62 (s, 1H), 8.29 (d, J = 3.6 Hz, 1H),
8.16 (d, J = 8.4 Hz, 1H), 7.80 (s, 1H), 7.70–7.65 (m, 1H), 6.70–6.66 (m, 1H), 4.53 (q,
J = 7.2 Hz, 2H), 2.62 (s, 3H), 1.50 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 178.4, 165.9, 151.9, 150.9, 147.9, 146.5, 140.9, 135.3, 132.6, 130.6, 126.2,
124.8, 124.5, 121.0, 112.5, 61.9, 22.3, 14.2; HRMS (ESI): m/z [M + H]+ calcd for
C18H16NO4: 310.1074; found: 310.1075.
ethyl 2-(benzofuran-2-carbonyl)-6-methylquinoline-4-carboxylate (4l): Yellow solid;
o
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149 mg (yield 83%); mp 164–166 C; IR (KBr): 1729, 1644, 1536, 1275 cm–1; H
NMR (400 MHz, CDCl3): δ (ppm) 8.70 (s, 1H), 8.65 (s, 1H), 8.61 (s, 1H), 8.21 (d, J =
8.4 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.74–7.66 (m, 2H), 7.50 (t, J = 7.8 Hz, 1H),
7.33 (t, J = 7.4 Hz, 1H), 4.53 (q, J = 7.2 Hz, 2H), 2.61 (s, 3H), 1.50 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ (ppm) 180.1, 165.8, 155.8, 151.8, 150.7, 146.5, 141.1,
135.4, 132.7, 130.7, 128.7, 127.5, 126.3, 124.5, 123.8, 123.8, 121.0, 120.7, 112.4,
62.0, 22.3, 14.3; HRMS (ESI): m/z [M + H]+ calcd for C22H18NO4: 360.1230; found:
360.1236.
ethyl 2-benzoylquinoline-4-carboxylate (4m): Yellow solid; 123.5 mg (yield 81%);
mp 84–86 oC; IR (KBr): 1731, 1670, 1256 cm–1; 1H NMR (600 MHz, CDCl3): δ (ppm)
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8.86 (d, J = 8.4 Hz, 1H), 8.62 (s, 1H), 8.25 (d, J = 8.4 Hz, 3H), 7.85–7.80 (m, 1H),
7.76 (t, J = 7.8 Hz, 1H), 7.66–7.62 (m, 1H), 7.53 (t, J = 7.8 Hz, 2H), 4.54 (q, J = 6.6
Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 192.9, 165.8,
154.1, 147.6, 136.4, 135.8, 133.2, 131.4, 131.0, 130.2, 130.0, 128.2, 125.8, 125.6,
121.9, 62.0, 14.3; HRMS (ESI): m/z [M + Na]+ calcd for C19H15NNaO3: 328.0944;
found: 328.0946.
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ethyl 2-benzoyl-6-isopropylquinoline-4-carboxylate (4n): Brown oil; 163 mg (yield
94%); IR (KBr): 1725, 1663, 1343, 1237 cm–1; 1H NMR (600 MHz, CDCl3): δ (ppm)
8.71 (s, 1H), 8.62 (s, 1H), 8.24 (d, J = 7.8 Hz, 2H), 8.18 (d, J = 9.0 Hz, 1H),
7.75–7.72 (m, 1H), 7.64–7.59 (m, 1H), 7.53–7.48 (m, 2H), 4.54 (q, J = 7.2 Hz, 2H),
3.21–3.14 (m, 1H), 1.50 (t, J = 7.2 Hz, 3H), 1.38 (d, J = 7.2 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ (ppm) 192.9, 165.9, 153.1, 151.1, 146.5, 135.8, 135.5, 133.0, 131.3,
130.8, 130.0, 128.0, 125.9, 121.9, 121.8, 61.8, 34.6, 23.6, 14.2; HRMS (ESI): m/z [M
+ H]+ calcd for C22H22NO3: 348.1594; found: 348.1593.
ethyl 2-benzoyl-7,8-dimethylquinoline-4-carboxylate (4o): White solid; 149.8 mg
o
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(yield 90%); mp 87–89 C; IR (KBr): 1721, 1667, 1242 cm–1; H NMR (600 MHz,
CDCl3): δ (ppm) 8.59 (s, 1H), 8.55 (d, J = 8.4 Hz, 1H), 8.31 (d, J = 7.8 Hz, 2H),
7.64–7.59 (m, 1H), 7.55–7.49 (m, 3H), 4.51 (q, J = 7.2 Hz, 2H), 2.69 (s, 3H), 2.50 (s,
13
3H), 1.48 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) δ (ppm) 192.8, 166.1,
152.1, 146.5, 138.2, 136.3(3), 136.2(9), 136.2(2), 132.9, 132.7, 131.5, 127.8, 124.2,
122.1, 120.4, 61.8, 20.5, 14.2, 13.8; HRMS (ESI): m/z [M + H]+ calcd for C21H20NO3:
334.1438; found: 334.1441.
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ethyl 2-benzoyl-6-methoxyquinoline-4-carboxylate (4p): Light yellow solid; 144 mg
(yield 86%); mp 98–100 oC; IR (KBr): 1712, 1668, 1618, 1477, 1250 cm–1; 1H NMR
(600 MHz, CDCl3): δ (ppm) 8.69 (s, 1H), 8.33–8.30 (m, 1H), 8.24 (d, J = 7.8 Hz, 2H),
8.11 (d, J = 9.0 Hz, 1H), 7.64–7.60 (m, 1H), 7.64–7.49 (t, 2H), 7.46–7.42 (m, 1H),
4.52 (q, J = 7.2 Hz, 2H), 4.00 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 192.7, 165.9, 160.8, 151.3, 143.9, 136.0, 133.5, 132.9, 132.5, 131.3,
128.0, 127.7, 123.4, 122.7, 103.1, 61.8, 55.6, 14.2; HRMS (ESI): m/z [M + H]+ calcd
for C20H18NO4: 336.1230; found: 336.1232.
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diethyl 2-benzoylquinoline-4,6-dicarboxylate (4q): Light yellow solid; 105.5 mg
(yield 56%); mp 118–121 oC; IR (KBr): 1714, 1657, 1596, 1284, 1234 cm–1; 1H NMR
(600 MHz, CDCl3): δ (ppm) 9.60–9.58 (m, 1H), 8.65 (s, 1H), 8.44–8.40 (m, 1H), 8.29
(d, J = 9.0 Hz, 1H), 8.24 (d, J = 7.8 Hz, 2H), 7.69–7.64 (m, 1H), 7.55 (t, J = 7.8 Hz,
2H), 4.58 (q, J = 7.2 Hz, 2H), 4.50 (q, J = 6.6 Hz, 2H), 1.53 (t, J = 7.2 Hz, 3H), 1.48 (t,
13
J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) δ (ppm) 192.6, 165.9, 165.3, 155.9,
149.2, 137.7, 135.4, 133.5, 131.4, 131.3, 131.2, 129.8, 128.4, 128.3, 125.0, 122.6,
62.4, 61.7, 14.4, 14.3; HRMS (ESI): m/z [M + H]+ calcd for C22H20NO5: 378.1336;
found: 378.1339.
ethyl 2-benzoyl-6-chloroquinoline-4-carboxylate (4r): Yellow solid; 115.2 mg
(yield 68%); mp 108–110 oC; IR (KBr): 1718, 1657, 1597, 1449, 1342, 1239 cm–1; 1H
NMR (600 MHz, CDCl3): δ (ppm) 8.96 (s, 1H), 8.66 (s, 1H), 8.22 (d, J = 8.4 Hz, 2H),
8.18 (d, J = 9.0 Hz, 1H), 7.78–7.74 (m, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.55–7.51 (m,
2H), 4.54 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
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(ppm) 192.5, 165.2, 154.2, 146.0, 136.5, 135.6, 135.2, 133.3, 132.4, 131.3, 128.2,
126.4, 124.8, 122.9 (x 2), 62.3, 14.3; HRMS (ESI): m/z [M + H]+ calcd for
C19H15ClNO3: 340.0735; found: 340.0741.
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ethyl 2-benzoyl-6-bromoquinoline-4-carboxylate (4s): Brown solid; 115 mg (yield
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60%); mp 94–96 C; IR (KBr): 1725, 1667, 1596, 1446, 1238 cm–1; H NMR (600
MHz, CDCl3): δ (ppm) 9.15–9.11 (m, 1H), 8.65 (s, 1H), 8.22 (d, J = 7.8 Hz, 2H), 8.10
(d, J = 9.0 Hz, 1H), 7.92–7.88 (m, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.56–7.51 (m, 2H),
13
4.54 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) δ
(ppm) 192.5, 165.2, 154.3, 146.2, 135.5, 135.1, 134.0, 133.3, 132.4, 131.3, 128.2,
128.1, 126.8, 125.1, 122.9, 62.3, 14.3; HRMS (ESI): m/z [M + H]+ calcd for
C19H15BrNO3: 384.0230; found: 384.0237.
ethyl 2-benzoyl-6-iodoquinoline-4-carboxylate (4t): Yellow solid; 103.4 mg (yield
48%); mp 113–114 oC; IR (KBr): 1723, 1668, 1594, 1443, 1342, 1235 cm–1; 1H NMR
(600 MHz, CDCl3): δ (ppm) 9.36–9.34 (m, 1H), 8.63 (s, 1H), 8.22 (d, J = 7.2 Hz, 2H),
8.10–8.06 (m, 1H), 7.94 (d, J = 9.0 Hz, 1H), 7.68–7.63 (m, 1H), 7.53 (t, J = 7.8 Hz,
2H), 4.54 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 192.5, 165.3, 154.6, 146.6, 139.3, 135.7, 134.9, 134.8, 133.3, 132.3, 131.4,
128.3, 127.2, 122.8, 97.5, 62.3, 14.3; HRMS (ESI): m/z [M + H]+ calcd for
C19H15INO3: 432.0091; found: 432.0091.
ethyl 2-benzoylbenzo[h]quinoline-4-carboxylate (4u): Yellow solid; 138.4 mg
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(yield 78%); mp 96–98 C; IR (KBr): 1721, 1666, 1599, 1369, 1341, 1236 cm–1; H
NMR (600 MHz, CDCl3): δ (ppm) 9.13 (d, J = 7.8 Hz, 1H), 8.77 (s, 1H), 8.72 (d, J =
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9.6 Hz, 1H), 8.33 (d, J = 7.8 Hz, 2H), 8.01 (d, J = 9.0 Hz, 1H), 7.94 (d, J = 7.8 Hz,
1H), 7.77–7.66 (m, 3H), 7.58 (t, J = 7.8 Hz, 2H), 4.56 (q, J = 7.2 Hz, 2H), 1.52 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 192.9, 166.1, 152.1, 146.1,
136.2(9), 136.2(7), 133.3, 132.9, 131.6, 131.5, 129.0, 128.1, 127.8, 125.2, 125.1(1),
125.0(7), 122.5, 122.4, 122.2, 62.13, 14.30; HRMS (ESI): m/z [M + H]+ calcd for
C23H18NO3: 356.1281; found: 356.1288.
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ethyl 3-benzoylbenzo[f]quinoline-1-carboxylate (4v): Yellow solid; 150.8 mg (yield
85%); mp 120–122 oC; IR (KBr): 1737, 1658, 1596, 1372, 1330, 1262 cm–1; 1H NMR
(600 MHz, CDCl3): δ (ppm) 8.32 (d, J = 8.4 Hz, 1H), 8.30 (s, 1H), 8.26 (d, J = 7.8 Hz,
2H), 8.07–8.00 (m, 2H), 7.94 (d, J = 8.4 Hz, 1H), 7.71–7.64 (m, 1H), 7.65–7.59 (m,
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2H), 7.51 (t, J = 7.8 Hz, 2H), 4.60 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H); C
NMR (100 MHz, CDCl3) δ (ppm) 192.4, 169.8, 153.1, 147.8, 139.3, 135.7, 133.2,
133.0, 132.3, 131.3, 128.9, 128.4(3), 128.3(5), 128.0, 127.5, 126.8, 126.2, 122.5,
120.5, 62.6, 13.8; HRMS (ESI): m/z [M + H]+ calcd for C23H18NO3: 356.1281; found:
356.1281.
methyl 2-benzoyl-6-methylquinoline-4-carboxylate (4w): Light yellow solid; 135.7
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mg (yield 89%); mp 100–102 C; IR (KBr): 1728, 1663, 1579, 1352, 1241 cm–1; H
NMR (600 MHz, CDCl3): δ (ppm) 8.63 (s, 1H), 8.60 (s, 1H), 8.24 (d, J = 7.8 Hz, 2H),
8.13 (d, J = 8.4 Hz, 1H), 7.68–7.61 (m, 2H), 7.54–7.49 (m, 2H), 4.06 (s, 3H), 2.62 (s,
13
3H); C NMR (100 MHz, CDCl3) δ (ppm) 192.9, 166.3, 153.1, 146.3, 140.8, 135.9,
135.0, 133.1, 132.6, 131.4, 130.7, 128.1, 125.8, 124.3, 122.1, 52.7, 22.3; HRMS (ESI):
m/z [M + Na]+ calcd for C19H15NNaO3: 328.0944; found: 328.0945.
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(6-methyl-4-phenylquinolin-2-yl)(phenyl)methanone (4x)11: Light yellow solid; 54.9
6
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o
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mg (yield 34%); mp 125–128 C; IR (KBr): 1653, 1442, 1357, 1248 cm–1; H NMR
(600 MHz, CDCl3): δ (ppm) 8.26 (d, J = 7.8 Hz, 2H), 8.16 (d, J = 8.4 Hz, 1H), 8.02 (s,
1H), 7.75 (s, 1H), 7.62 (d, J = 7.8 Hz, 2H), 7.58–7.55 (m, 4H), 7.52 (t, J = 7.2 Hz,
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13
3H), 2.51 (s, 3H); C NMR (100 MHz, CDCl3) δ (ppm) 193.9, 153.4, 148.8, 145.9,
138.8, 137.9, 136.3, 132.9, 132.2, 131.4, 130.6, 129.5, 128.6, 128.5, 128.1, 127.4,
124.5, 121.1, 22.0; HRMS (ESI): m/z [M + H]+ calcd for C23H18NO: 324.1383; found:
324.1384.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (Grant
21272085, 21472056).
Supporting Information
1H and 13C NMR spectra of compounds 4. This material is available free of charge via
the Internet at http://pubs.acs.org.
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