An economical synthesis of substituted quinoline-2-carboxylates through the potassium persulfate-mediated cross-dehydrogenative coupling of N-aryl glycine derivatives with olefins

Article abstract of DOI:10.1039/c5ob02216a

A practical and economical K₂S₂O₈-mediated oxidative cross-dehydrogenative coupling of N-aryl glycine derivatives with olefins has been established, affording structurally diverse quinoline-2-carboxylates in good to high e

Full text of DOI:10.1039/c5ob02216a

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Biomolecular Chemistry
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An economical synthesis of substituted quinoline-
2-carboxylates through the potassium persulfate-
mediated cross-dehydrogenative coupling of
N-aryl glycine derivatives with olefins†
Cite this: DOI: 10.1039/c5ob02216a
Guoliang Liu,‡c Jiarui Qian,‡a Jing Hua,d Feng Cai,*e Xia Li*c and Lei Liu*a,b
A practical and economical K2S2O8-mediated oxidative cross-dehydrogenative coupling of N-aryl glycine
derivatives with olefins has been established, affording structurally diverse quinoline-2-carboxylates in
good to high efficiency. The low cost, negligible toxicity, and ease of handling of K2S2O8 combined with
the absence of hazardous byproducts and the easy workup consisting of simple filtration are attractive
based on economic and environmental factors.
Received 27th October 2015,
Accepted 29th November 2015
DOI: 10.1039/c5ob02216a
www.rsc.org/obc
Introduction
Quinoline-2-carboxylate (Q2C) derivatives are present in a
number of biologically active natural products and synthetic
pharmaceuticals possessing diverse activities including anti-
bacterial, anticancer, anti-HIV, anti-inflammatory, and anti-
tuberculosis activities.1,2 For example, Q2C A is an inhibitor
against the vesicular glutamate transport (VGLUT) protein
(Fig. 1).2a Q2C B is a potent 5-hydroxytryptamine antagonist.1e
Q2C C is a potent lead compound for inhibiting the binding of
Insulin-like Growth Factor (IGF) to IGF-binding proteins.1f
Besides their importance in life sciences, Q2C derivatives can
also act as functional molecules in other research fields.3 For
instance, Q2C D was found to be a promising biocompatible
fluorescent tag.3b The simple Q2C E is the real intermediate
for the synthesis of quinox ligands which have been widely
employed in asymmetric catalysis.3c
Fig. 1 Representative Q2C derivatives.
an effective alternative to conventional protocols for the syn-
thesis of complex molecules.5 The CDC reactions involving
α-amino acid derivatives as substrates have received consider-
able attention.6 In 2011, the Mancheño group developed an
elegant method to prepare substituted Q2C derivatives through
CDC of N-aryl glycine esters with styrenes mediated by FeCl3
and TEMPO oxoammonium salt (T+BF4−).7 Jia and Wang dis-
closed that the same reaction can be promoted in the presence
of catalytic InCl3 and tris(4-bromophenyl)aminium hexachlor-
oantimonate (TBPA+•) employing molecular oxygen as the term-
inal oxidant.8 Both systems afforded substituted Q2Cs in high
Due to the importance of Q2Cs in modern pharmacology
and organic synthesis, significant efforts have been devoted to
their synthesis.4 Recently, the direct cross-dehydrogenative
coupling (CDC) of readily accessible substrates has emerged as
aSchool of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
E-mail: leiliu@sdu.edu.cn
bKey Lab for Colloid and Interface Chemistry of Education Ministry, School of
Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China
cSchool of Ocean, Shandong University, Weihai 264209, China.
E-mail: xiali@sdu.edu.cn
efficiency. However, the oxidation systems are still not ideal
−
dKey Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources from an economic viewpoint. T+BF4 is not commercially avail-
(Guangxi Normal University), Ministry of Education of China, Guilin 541004, China
eNational Glycoengineering Research Center, Shandong University, Jinan 250012,
able, and the preparation requires extra effort. In the latter case,
while molecular oxygen is an ideal terminal oxidant, TBPA+•,
China. E-mail: feng.cai@live.com
†Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ob02216a
the precursor of the real oxidant, is rather expensive, with a cost
of $9226 per mol according to 2014–2015 Aldrich catalog even if
‡These authors contributed equally to this work.
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only 10 mol% of TBPA+• is employed. In 2014, Huo reported an A variety of different metal salt additives (10 mol%) were
elegant auto-oxidative coupling system to prepare the Q2C explored to improve the reaction efficiency (entries 2–14,
derivatives using air as the sole oxidant.9 However, only moder- Table 1). While several additives including CuOAc, Mg(OTf)2,
ate reaction efficiency was obtained. Such issues led to a search and Yb(OTf)3 inhibited the reaction, other salts like CuBr2,
for an economical and efficient oxidation system for the CDC CuCl, CuBr, and LiOTf13 proved to be beneficial for improving
reaction affording substituted Q2C derivatives.
the efficiency, with CuBr affording the best yields (entry 9,
Persulfate has long been known to oxidize hydrocarbons Table 1). The reaction was found to be highly dependent on
initiated by a single electron transfer process.10,11 The oxidant the solvent choice, and CH3CN was identified as the optimal
is inexpensive, less toxic, and easily handled. The price of candidate (entries 9 and 15–19). Other types of persulfates
persulfates like K2S2O8 is only $39 per mol according to including K2S2O8 and (NH4)2S2O8 were next investigated, and
2014–2015 Aldrich catalog, and the byproduct can be easily the former proved to be the best oxidant (entries 16, 20 and
removed with a simple filtration over Celite or by washing with 21). Either elevating or lowering the reaction temperature
H2O.10 Therefore, the synthesis of substituted Q2Cs through resulted in inferior yields (entries 20, 22 and 23). Reaction
the persulfate mediated CDC of glycine derivatives with olefins under an Ar atmosphere resulted in a slight loss of the
would be attractive based on economic and environmental efficiency (entries 20 and 24, Table 1).
factors.12
With the optimized reaction conditions in hand, the scope
of olefin components was first examined (Scheme 1). A wide
range of electronically varied styrenes with different substi-
tution patterns participated in the oxidative CDC reactions
with glycine ester 1a, affording diverse Q2C derivatives 3a–3f
in good to high efficiency (Scheme 1). The reaction efficiency
was found to be not sensitive to the electronic substituent
effect on the aryl rings except for the styrene bearing strong
electron-withdrawing substituent like 2g. Bromo and chloro
substituents were compatible with the oxidation system, which
will be beneficial for further diversification. 1,2-Disubstituted
olefin 2h was also a competent component, providing 2,3,4-tri-
substituted Q2C 3h in excellent regioselectivity with an alkene
installed at the 4-position for further manipulation. Aliphatic
olefin 2i also participated in the CDC reaction, albeit moderate
yield (46%) was obtained.
Results and discussion
Initially, the CDC of glycine ester 1a with styrene (2a) was
chosen as a model reaction for optimization (Table 1). When
1 equiv. of Na2S2O8 was employed as the oxidant, the desired
quinoline 3a was observed in 9% yield (entry 1, Table 1).
Table 1 Reaction condition optimizationa
Oxidant
(1.0 equiv.)
Additive
(10 mol%)
Yieldb
(%)
Entry
Solvent
1
2
3
4
5
6
7
8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
K2S2O8
—
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CHCl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
CH2Cl2
CH3CN
THF
Toluene
EtOAc
CH3CN
CH3CN
CH3CN
CH3CN
9
43
25
31
<5
16
40
58
67
30
<5
<5
26
20
41
80
57
33
46
83
62
78
62
80
CuBr2
Cu3(PO4)2
Cu(OTf)2
CuOAc
CuOTf·C6H6
Cu(MeCN)4PF6
CuCl
CuBr
LiOTf
Mg(OTf)2
Yb(OTf)3
FeCl3
FeCl2
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
9
10
11
12
13
14
15
16
17
18
19
20
21
22c
23d
24e
(NH4)2S2O8
K2S2O8
K2S2O8
CuBr
CuBr
CuBr
K2S2O8
CH3CN
a General conditions: 1a (0.1 mmol), 2a (0.2 mmol), oxidant
(0.1 mmol), additive (0.01 mmol), solvent (1.0 mL) under air at 40 °C
for 16 h, unless stated otherwise. b Isolated yield. c Reaction at 60 °C.
d Reaction at room temperature. e Reaction under Ar.
Scheme 1 The scope of olefin components. aReaction at 60 °C.
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Scheme 3 The mechanistic study.
Fig. 2 A proposed mechanism for the oxidative CDC reaction.
Scheme 2 The scope of N-aryl glycine derivatives. aReaction at 60 °C.
the N-aryl imine
5 might be the intermediate for the
The scope of glycine derivatives was next investigated subsequent nucleophilic addition process by 2a and the final
(Scheme 2). The electronic substituent effect on the aniline aromatization step.14 According to the literature, Cu(I) could
fragment was first studied. A variety of anilines 1 bearing elec- promote the decomposition of the persulfate to generate the
tron-donating and -withdrawing substituents joined in the SO4 radical anion together with the formation of Cu(II) under
CDC reaction with 2a smoothly afforded the corresponding thermal conditions.10,11 Two pathways have been postulated
Q2C products 4a–4e in good yields (Scheme 2). No reaction for the generation of the imine 5 from 1a. The first pathway
was observed for aniline 1f bearing a strong electron-withdraw- proceeds through an initial hydrogen atom abstraction from
ing CF3 moiety. The carboxylic fragment was next explored. 1a to the SO4 radical anion giving free radical 6, which then
Besides the ethyl ester 1a, other commonly encountered alkyl undergoes one electron oxidation by Cu(II) to afford intermedi-
esters including methyl 1g, isopropyl 1h, tert-butyl 1i, isobutyl ate 5. Alternatively, an initial electron transfer from 1a to the
1j, benzyl 1k, and allyl moieties 1m as well as aryl ester 1l also SO4 radical anion provides the radical cation 7, which then
proved to be suitable components for the oxidative CDC reac- proceeds through a proton abstraction followed by a second
tion with 2a, affording Q2C 4g–4m in good yields. N-Phenyl- electron transfer to generate intermediate 5. In the presence of
glycine amides were also tolerated in the economical oxidation Cu(II), 5 reacts with styrene 2a to afford intermediate 8 that
system (4n–4p).
was further oxidized and aromatized to quinoline 3a.
While the mechanism is not yet fully understood, radical
intermediates should be involved in the reaction since 1 equiv.
of TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl free radical)
completely blocked the transformation. During the course of
the reaction of 1a with 2a, a considerable amount of an inter-
mediate was detected by TLC analysis, which was identified as
imine 5. Therefore, a control experiment was conducted by
subjecting 5 to the standard reaction conditions (Scheme 3).
The reaction gave a comparable result to that starting from 1a,
indicating that 5 might be involved in the reaction.
Conclusions
In summary, a practical and economical K2S2O8-mediated oxi-
dation system for the CDC reaction of a variety of N-aryl
glycine derivatives with olefins has been established, affording
structurally diverse Q2Cs in good to high efficiency. The low
cost, negligible toxicity, and ease of handling of K2S2O8 com-
bined with the absence of hazardous byproducts and the easy
workup consisting of simple filtration are attractive.
A tentative mechanism for the CDC reaction of glycine ester
(1a) with styrene (2a) is proposed in Fig. 2. We envisioned that
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1148, 1109, 1010, 848, 822, 790 cm−1; HRMS (EI) m/z calcd for
C19H16BrNO2 [M + H]+ 370.0437, found 370.0445.
Experimental
Proton (1H NMR) and carbon (13C NMR) nuclear magnetic
(E)-Ethyl 6-methyl-3-phenyl-4-styrylquinoline-2-carboxylate
resonance spectra were recorded at 300, 400, or 600 MHz and (3h). 1H NMR (300 MHz, CDCl3) δ 8.16 (d, J = 8.6 Hz, 1H), 8.07
75, 100, or 151 MHz, respectively. The chemical shifts are (s, 1H), 7.62 (dd, J = 8.6, 1.8 Hz, 1H), 7.50–7.28 (m, 10H), 7.08
given in parts per million (ppm) on the delta (δ) scale. The (d, J = 16.7 Hz, 1H), 6.78 (d, J = 16.7 Hz, 1H), 4.13 (q, J = 7.1
solvent peak was used as a reference value for 1H NMR: Hz, 2H), 2.58 (s, 3H), 1.01 (t, J = 7.1 Hz, 3H). The data are con-
CDCl3 = 7.27 ppm, for 13C NMR: CDCl3 = 77.23 ppm. Analytical sistent with the known literature.8
TLC was performed on precoated silica gel GF254 plates.
HRMS was carried out on an Orbitrap analyzer.
Ethyl 4-cyclohexyl-6-methylquinoline-2-carboxylate (3i). 1H
NMR (300 MHz, CDCl3) δ 8.21 (d, J = 8.6 Hz, 1H), 8.06 (s, 1H),
7.86 (s, 1H), 7.58 (dd, J = 8.7, 1.7 Hz, 1H), 4.56 (q, J = 7.1 Hz,
2H), 3.42–3.27 (m, 1H), 2.60 (s, 3H), 2.07–1.83 (m, 5H),
General procedure for the CDC reaction
In a 10 mL sealed tube, to the solution of 1a (0.1 mmol, 1.72–1.54 (m, 5H), 1.50 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz,
1.0 equiv.) and 2a (0.2 mmol, 2.0 equiv.) in CH3CN (1.0 mL) CDCl3) δ 166.2, 154.2, 147.4, 146.7, 138.4, 131.9, 131.6, 128.1,
were added CuBr (0.01 mmol, 10 mol%) and K2S2O8 121.9, 117.7, 62.2, 39.2, 33.6, 27.0, 26.4, 22.4, 14.6; IR νmax
(0.1 mmol, 1.0 equiv.). The resulting solution was stirred at 3061, 2923, 2851, 1715, 1583, 1506, 1446, 1369, 1342, 1264,
40 °C for 16–24 h, before the reaction mixture was filtered 1211, 1146, 1024, 946, 899, 825, 793 cm−1; HRMS (EI) m/z
through a Celite pad. The mixture was evaporated under calcd for C19H23NO2 [M + H]+ 298.1802, found 298.1803.
vacuum and the residue was purified by flash chromatography
using ethyl acetate/petroleum ether (10 : 90) as the eluent to
afford 3a.
Characterization data for the products in Scheme 2
Ethyl 4-phenylquinoline-2-carboxylate
(400 MHz, CDCl3) δ 8.39 (d, J = 8.5 Hz, 1H), 8.14 (s, 1H), 7.98
(4a). 1H NMR
Characterization data for the products in Scheme 1
Ethyl 6-methyl-4-phenylquinoline-2-carboxylate (3a). 1H (d, J = 8.5 Hz, 1H), 7.80 (t, J = 7.7 Hz, 1H), 7.67–7.47 (m, 6H),
NMR (600 MHz, CDCl3) δ 8.28 (d, J = 8.7 Hz, 1H), 8.11 (s, 1H), 4.58 (q, J = 7.1 Hz, 2H), 1.50 (t, J = 7.1 Hz, 3H); 13C NMR
7.71 (s, 1H), 7.63 (dd, J = 8.7, 1.8 Hz, 1H), 7.60–7.47 (m, 5H), (101 MHz, CDCl3) δ 165.7, 150.0, 148.4, 148.1, 137.8, 131.4,
4.57 (q, J = 7.1 Hz, 2H), 2.50 (s, 3H), 1.50 (t, J = 7.1 Hz, 3H). 130.2, 129.8, 128.9, 128.9, 128.8, 128.0, 125.9, 121.5, 62.5, 14.6.
These data are consistent with the reported literature values.8
Ethyl 4-(4-methoxyphenyl)-6-methylquinoline-2-carboxylate
The data are consistent with the known literature.8
Ethyl 6-methoxy-4-phenylquinoline-2-carboxylate (4b). 1H
(3b). 1H NMR (300 MHz, CDCl3) δ 8.26 (d, J = 8.7 Hz, 1H), 8.08 NMR (300 MHz, CDCl3) δ 8.28 (d, J = 9.3 Hz, 1H), 8.10 (s, 1H),
(s, 1H), 7.76 (s, 1H), 7.66–7.55 (m, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.66–7.48 (m, 5H), 7.44 (dd, J = 9.3, 2.8 Hz, 1H), 7.22 (d, J =
7.09 (d, J = 8.8 Hz, 2H), 4.57 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 2.8 Hz, 1H), 4.56 (q, J = 7.1 Hz, 2H), 3.81 (s, 3H), 1.49 (t, J =
2.51 (s, 3H), 1.50 (t, J = 7.1 Hz, 3H). These data are consistent 7.1 Hz, 3H). The data are consistent with the known
with the reported literature values.8
literature.8
Ethyl 6-methyl-4-p-tolylquinoline-2-carboxylate (3c). 1H
Ethyl 5,7-dimethyl-4-phenylquinoline-2-carboxylate (4c). 1H
NMR (300 MHz, CDCl3) δ 8.27 (d, J = 8.7 Hz, 1H), 8.09 (s, 1H), NMR (300 MHz, CDCl3) δ 8.06 (s, 1H), 7.93 (s, 1H), 7.52–7.41
7.74 (s, 1H), 7.67–7.58 (m, 1H), 7.49–7.33 (m, 4H), 4.56 (q, J = (m, 3H), 7.39–7.31 (m, 2H), 7.23 (s, 1H), 4.55 (q, J = 7.1 Hz,
7.1 Hz, 2H), 2.58–2.43 (m, 6H), 1.49 (t, J = 7.1 Hz, 3H). The 2H), 2.53 (s, 3H), 2.01 (s, 3H), 1.48 (t, J = 7.1 Hz, 3H). The data
data are consistent with the known literature.8
Ethyl 4-(4-tert-butylphenyl)-6-methylquinoline-2-carboxylate
are consistent with the known literature.8
Ethyl 6-bromo-4-phenylquinoline-2-carboxylate (4d). 1H
(3d). 1H NMR (300 MHz, CDCl3) δ 8.27 (d, J = 8.7 Hz, 1H), 8.10 NMR (300 MHz, CDCl3) δ 8.25 (d, J = 9.0 Hz, 1H), 8.15 (s, 1H),
(s, 1H), 7.79 (s, 1H), 7.68–7.55 (m, 3H), 7.55–7.42 (m, 2H), 4.56 8.11 (d, J = 2.1 Hz, 1H), 7.93–7.82 (m, 1H), 7.66–7.46 (m, 5H),
(q, J = 7.1 Hz, 2H), 2.52 (s, 3H), 1.49 (t, J = 7.1 Hz, 3H), 1.43 (s, 4.58 (q, J = 7.1 Hz, 2H), 1.50 (t, J = 7.1 Hz, 3H). The data are
9H). The data are consistent with the known literature.8
Ethyl 4-(4-chlorophenyl)-6-methylquinoline-2-carboxylate
consistent with the known literature.8
Ethyl 6-chloro-4-phenylquinoline-2-carboxylate (4e). 1H
(3e). 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J = 9.2 Hz, 1H), 8.07 NMR (300 MHz, CDCl3) δ 8.33 (d, J = 9.0 Hz, 1H), 8.16 (s, 1H),
(s, 1H), 7.64 (d, J = 6.9 Hz, 2H), 7.60–7.42 (m, 4H), 4.57 (q, J = 7.94 (d, J = 2.3 Hz, 1H), 7.86–7.72 (m, 1H), 7.72–7.42 (m, 5H),
7.1 Hz, 2H), 2.51 (s, 3H), 1.50 (t, J = 7.1 Hz, 3H). The data are 4.58 (q, J = 7.1 Hz, 2H), 1.50 (t, J = 7.1 Hz, 3H). The data are
consistent with the known literature.8
Ethyl 4-(4-bromophenyl)-6-methylquinoline-2-carboxylate
consistent with the known literature.8
Methyl 6-methyl-4-phenylquinoline-2-carboxylate (4g). 1H
(3f). 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J = 9.2 Hz, 1H), 8.07 NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.7 Hz, 1H), 8.13 (s, 1H),
(s, 1H), 7.78–7.59 (m, 4H), 7.47–7.35 (m, 2H), 4.57 (q, J = 7.73 (s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.60–7.50 (m, 5H), 4.09 (s,
7.1 Hz, 2H), 2.51 (s, 3H), 1.50 (t, J = 7.1 Hz, 3H); 13C NMR 3H), 2.51 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 166.4, 149.3,
(75 MHz, CDCl3) δ 165.7, 147.8, 147.2, 147.1, 139.5, 136.9, 147.0, 146.8, 139.3, 137.9, 132.7, 131.0, 129.8, 128.9, 128.9,
132.7, 132.1, 131.4, 131.3, 127.7, 124.5, 123.3, 121.5, 62.5, 22.3, 128.1, 124.7, 121.7, 53.4, 22.2; IR νmax 3055, 2955, 1731, 1620,
14.6; IR νmax 2921, 2851, 1711, 1593, 1488, 1378, 1250, 1205, 1571, 1492, 1433, 1281, 1231, 1152, 1114, 1002, 830, 760,
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705 cm−1; HRMS (EI) m/z calcd for C18H15NO2 [M + H]+ 119.4, 66.9, 22.2; IR νmax 3059, 2921, 1709, 1581, 1486, 1445,
278.1176, found 278.1177.
1369, 1278, 1114, 946, 896, 817, 757, 697 cm−1; HRMS (EI) m/z
Isopropyl 6-methyl-4-phenylquinoline-2-carboxylate (4h). 1H calcd for C20H17NO2 [M + H]+ 304.1332, found 304.1335.
NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.7 Hz, 1H), 8.05 (s, 1H), N,6-Dimethyl-4-phenylquinoline-2-carboxamide
(4n). 1H
7.69 (s, 1H), 7.62 (dd, J = 8.7, 1.4 Hz, 1H), 7.60–7.49 (m, 5H), NMR (300 MHz, CDCl3) δ 8.37–8.16 (m, 2H), 8.07 (d, J = 8.6 Hz,
5.45–5.37 (m, 1H), 2.50 (s, 3H), 1.48 (s, 3H), 1.46 (s, 3H); 13C 1H), 7.74 (s, 1H), 7.68–7.44 (m, 6H), 3.13 (d, J = 5.1 Hz, 3H),
NMR (101 MHz, CDCl3) δ 165.2, 149.0, 147.5, 147.2, 139.0, 2.50 (s, 3H). The data are consistent with the known
138.2, 132.4, 131.2, 129.8, 128.9, 128.8, 128.0, 124.5, 121.5, literature.8
70.0, 22.2, 22.1; IR νmax 2978, 2923, 1707, 1623, 1493, 1373,
1251, 1206, 1104, 1031, 843, 820, 792 cm−1; HRMS (EI) m/z NMR (400 MHz, CDCl3) δ 8.28 (d, J = 4.1 Hz, 1H), 8.22 (s, 1H),
calcd for C20H19NO2 [M + H]+ 306.1489, found 306.1493.
8.04 (d, J = 8.6 Hz, 1H), 7.76 (s, 1H), 7.59 (dd, J = 8.6, 1.6 Hz,
N,6-Dimethyl-4-(p-tolyl)quinoline-2-carboxamide
(4o). 1H
tert-Butyl 6-methyl-4-phenylquinoline-2-carboxylate (4i). 1H 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 7.9 Hz, 2H), 3.12 (d, J =
NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.6 Hz, 1H), 7.99 (s, 1H), 5.1 Hz, 3H), 2.56–2.43 (m, 6H); 13C NMR (75 MHz, CDCl3)
7.68 (s, 1H), 7.65–7.45 (m, 6H), 2.50 (s, 3H), 1.69 (s, 9H); 13C δ 165.6, 149.5, 148.8, 146.0, 138.6, 138.1, 135.2, 132.3, 129.9,
NMR (101 MHz, CDCl3) δ 164.6, 148.9, 148.3, 147.1, 138.9, 129.7, 129.51, 128.0, 125.0, 119.3, 26.4, 22.2, 21.5; IR νmax
138.3, 132.3, 131.3, 129.8, 128.8, 128.7, 127.8, 124.5, 121.4, 3323, 2918, 2851, 1671, 1655, 1555, 1499, 1393, 1370, 1254,
82.7, 28.4, 22.2; IR νmax 2978, 2922, 2853, 1777, 1714, 1620, 1134, 1023, 904, 829 cm−1; HRMS (EI) m/z calcd for C19H18N2O
1518, 1366, 1147, 1107, 899, 820, 751 cm−1; HRMS (EI) m/z [M + H]+ 291.1492, found 291.1494.
calcd for C21H21NO2 [M + H]+ 320.1645, found 320.1644.
4-(4-Chlorophenyl)-N,6-dimethylquinoline-2-carboxamide
Isobutyl 6-methyl-4-phenylquinoline-2-carboxylate (4j). 1H (4p). 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 4.4 Hz, 1H), 8.20
NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.7 Hz, 1H), 8.07 (s, 1H), (s, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.66 (s, 1H), 7.61 (dd, J = 8.6,
7.70 (s, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.61–7.48 (m, 5H), 4.29 (d, 1.7 Hz, 1H), 7.55–7.51 (m, 2H), 7.50–7.44 (m, 2H), 3.12 (d, J =
J = 6.9 Hz, 2H), 2.50 (s, 3H), 2.26–2.12 (m, 1H), 1.06 (d, J = 6.7 5.1 Hz, 3H), 2.51 (s, 3H); 13C NMR (75 MHz, CDCl3) δ = 165.4,
Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 165.7, 149.1, 147.2, 148.8, 148.1, 145.9, 138.6, 136.7, 135.9, 132.5, 131.1, 130.0,
147.2, 139.1, 138.1, 132.5, 131.2, 129.8, 128.9, 128.8, 128.0, 129.1, 127.7, 124.5, 119.3, 26.5, 22.2; IR νmax 3329, 2919, 2850,
124.6, 121.5, 72.2, 28.1, 22.2, 19.4; IR νmax 3057, 2962, 2873, 1659, 1603, 1533, 1487, 1393, 1252, 1133, 1091, 1016, 904, 843,
1736, 1616, 1578, 1483, 1464, 1275, 1224, 1104, 997, 893, 826, 824, 754 cm−1; HRMS (EI) m/z calcd for C18H15ClN2O [M + H]+
766, 700 cm−1; HRMS (EI) m/z calcd for C21H21NO2 [M + H]+ 311.0946, found 311.0951.
320.1645, found 320.1644.
Benzyl 6-methyl-4-phenylquinoline-2-carboxylate (4k). 1H
NMR (400 MHz, CDCl3) δ 8.29 (d, J = 8.7 Hz, 1H), 8.09 (s, 1H),
7.70 (s, 1H), 7.63 (dd, J = 8.7, 1.7 Hz, 1H), 7.60–7.46 (m, 7H),
Acknowledgements
7.43–7.32 (m, 3H), 5.55 (s, 2H), 2.50 (s, 3H); 13C NMR This work was supported by the National Science Foundation
(101 MHz, CDCl3) δ 165.6, 149.2, 147.1, 146.9, 139.3, 138.0, of China (No. 21202093 and 21472112), the Program for New
136.0, 132.6, 131.2, 129.8, 128.9, 128.8, 128.6, 128.1, 124.6, Century Excellent Talents in University (No. NCET-13-0346),
121.7, 67.8, 22.2; IR νmax 3026, 2971, 1738, 1709, 1588, 1546, the Shandong Science Fund for Distinguished Young Scholars
1456, 1389, 1352, 1246, 1144, 1108, 989, 896, 825, 751 cm−1
HRMS (EI) m/z calcd for C24H19NO2 [M + H]+ 354.1489, found University (No. 2014JC005 and 2015JC035), and the Key Labo-
;
(JQ201404), the Fundamental Research Funds of Shandong
354.1490.
ratory for the Chemistry and Molecular Engineering of Medi-
Phenyl 6-methyl-4-phenylquinoline-2-carboxylate (4l). 1H cinal Resources (Guangxi Normal University), Ministry of
NMR (400 MHz, CDCl3) δ 8.34 (d, J = 8.7 Hz, 1H), 8.24 (s, 1H), Education of China (CHEMR2014-B11).
7.76 (s, 1H), 7.68 (dd, J = 8.7, 1.7 Hz, 1H), 7.64–7.52 (m, 5H),
7.51–7.41 (m, 2H), 7.40–7.30 (m, 3H), 2.53 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 164.5, 151.4, 149.4, 147.2, 146.3, 139.7,
137.9, 132.8, 131.2, 129.8, 129.7, 128.9, 128.3, 126.3, 124.7,
Notes and references
122.1, 122.0, 22.3; IR νmax 2971, 2920, 2220, 1729, 1590, 1496,
1357, 1231, 1186, 1088, 987, 918, 817, 792, 722 cm−1; HRMS
(EI) m/z calcd for C23H17NO2 [M + H]+ 340.1332, found
340.1334.
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7.72 (s, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.60–7.49 (m, 5H),
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