Visible-light-enabled aerobic oxidative Csp3-H functionalization of glycine derivatives using an organic photocatalyst: Access to substituted quinoline-2-carboxylates

Article abstract of DOI:10.1039/d0ob01837f

A practical visible-light-induced aerobic oxidative dehydrogenative coupling reaction of glycine derivatives with olefins has been developed to efficiently synthesize quinoline-2-carboxylates. This metal-free process proceeds smoothly under mild condition

Full text of DOI:10.1039/d0ob01837f

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DOI: 10.1039/D0OB01837F
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Visible light-enabled aerobic oxidative Csp3−H functionalization of
glycine derivatives using an organic photocatalyst: access to
substituted quinoline-2-carboxylates
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Jingxin Wang, Liqi Li, Ying Guo, Shengyu Li, Shutao Wang, Ying Li and Yuan Zhang*
www.rsc.org/
A practical visible light-induced aerobic oxidative dehydrogenative coupling reaction of glycine derivatives with olefins has
been developed to efficiently synthesize quinoline-2-carboxylates. This metal-free process proceeds smoothly under mild
conditions and exhibits good tolerance of functional groups. Given the low cost of catalyst and feedstock materials, the mild
reaction conditions as well as the absence of hazardous byproducts, this protocol should find broad applications in the
synthesis of quinoline-2-carboxylate derivatives.
Introduction
The direct oxidative cross-dehydrogenative coupling (CDC) of two
The quinoline-2-carboxylate (Q2C) moiety constitutes the core
structure of numerous natural products1 and pharmaceutically
active molecules (Fig. 1), which typically exhibit a variety of
biological activities, such as anti-inflammatory, antibacterial,
anti-HIV, and anticancer activities.2-4 Moreover, the simple Q2C
structure motif also serves as the crucial intermediate for the
synthesis of Quinox ligands, which have been widely used in
Csp3−H bonds, which avoids the tedious prefunctionalization
procedures, has long been considered as one of the most
straightforward and atom-economical synthetic protocol for the
construction of C−C bonds.7-11 In particular, the direct cross-
dehydrogenative coupling of glycine derivatives with divers
nucleophiles has been applied as an effective strategy for the
12-15
synthesis of α-amino acid derivatives
and azo-heterocyclic
metal-catalyzed transformations.5, Therefore, the need for
6
compounds.16-18 In 2011, Mancheno et al. reported the first example
of oxidative dehydrogenative coupling of glycine derivatives with
olefins for the synthesis of quinoline-2-carboxylates, employing a
FeCl3/TEMPO oxoammonium salt catalytic system.19, 20 Inspired by
this elegant work, subsequently, the group of Jia21-23, Huo14, 24-26, Liu27,
step-economic and green synthetic routes to quinoline-2-
carboxylates is of great interest for organic and medicinal
chemists.
and Feng29 independently explored various kinds of catalytic
28
systems for this effective transformation. Despite the remarkable
advances that have been made in this process, however, most of the
reactions typically involved the use of stoichiometric amount of
oxidants, and some of them were carried out at relative harsh
reaction conditions. Therefore, from environmental and practical
standpoints, it would be highly desirable to develop new sustainable
and green catalytic versions for this type of reaction.
In this context, photoredox catalysis 30-32 has recently become an
attractive protocol to initiate the CDC reaction.33-54 However, to date,
most of these studies have focused on the α-Csp3–H functionalization
of tertiary amines,33-38 whereas the α-Csp3–H functionalization of
secondary amines (i.e. glycine derivatives) still remains far behind.39-
Fig.
carboxylates.
1 Representative bioactive compounds containing quinoline-2-
46
Our group has a longstanding interest in the visible light-induced
CDC reactions for the Csp3-H functionalization of glycine
derivatives.47-54 Recently, we have presented a visible light-induced
aerobic oxidative dehydrogenative coupling/aromatization tandem
reaction of glycine esters with alkenes.47 This method provides rapid
synthesis of substituted quinoline-2-carboxylates under very mild
conditions. However, the practical application of this reaction is still
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and
Chemical Engineering, Lanzhou University, 222 Tianshui South Road, Lanzhou
730000, P. R. China. E-mail: zhangyuan@lzu.edu.cn.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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used. d Under the irradiation of a 23 W blue LED strip. e 20 mol% HClO4 was
restricted by the use of toxic and expensive ruthenium-based
complex as photocatalyst. Therefore, from environmentally friendly
and cost effective point of view, the use of less toxic and inexpensive
used. 2.0 mL CH3CN was used. 3.0 mL CH3CN was used.ViewReAartcictiloenOnwlinaes
f
g
h
DOI: 10.1039/D0OB01837F
carried out under Ar. i Reaction was carried out in the dark.
organic dyes as photocatalysts, is undoubtedly
a promising
Table 2 Scope of the olefin component
alternative protocol. In this regard, very recently, we have
successfully demonstrated the effective synthesis of several azo-
heterocyclic compounds through metal-free visible light induced α-
Csp3–H functionalization of glycine derivatives.48-51 Herein, we report
a
metal-free visible light-induced oxidative dehydrogenative
coupling/aromatization tandem reaction of glycine esters and
unactivated alkenes. In comparison with previous work, the crucial
innvoation of this protocol is the avoidance of the use of toxic and
expensive transition metal catalyst, which means greener and cost-
effective.
Results and discussion
Our initial reaction screening focused on the photocatalyzed
coupling reaction of glycine ester 1a and styrene 2a with a variety of
organic-dyes and BF3∙Et2O under the irradiation of a 3 W blue LED
lamp (Table 1, for details, see the ESI†). To our delight, the reaction
proceeded smoothly with Rhodamine 6G (Rh-6G) as the
photocatalyst and afforded the desired product 3a in 11% yield
(Table 1, entry 1). Encouraged by this result, we then screened
different acids to improve the yield (Table 1, entries 4–6). Gratifyingly,
3a could be obtained in 60% yield when 15 mol% of HClO4 was
employed (Table 1, entry 6). When a 23 W blue LED strip was used as
the light source, the yield of 3a was improved to 68% (Table 1, entry
7). The product yield could be further improved to 75% in a lower
concentration (Table 1, entry 9). We also used green LEDs as light
source (Table S3, entry 6), however, no improvement of the
efficiency was afforded (51% yield). In addition, trace oxanilate
byproduct from 1a was observed in this reaction. Finally, control
experiments indicated that photocatalyst, acid, air and visible light
are all essential for this reaction (Table 1, entries 11–14).
Reaction conditions: 1a (0.1 mmol), 2 (0.5 mmol), Rh-6G (5 mol%), HClO4 (15
mol%), CH3CN (2.0 mL), 23 W blue LED light irradiation in air at rt. Yield of the
isolated product.
Having established the optimized reaction conditions, we next
explored the scope of this photocatalytic aerobic oxidative coupling
reaction. Firstly, a variety of alkenes were investigated. As shown in
Table 2, the reaction of substituted styrenes 2 bearing either
electron-donating or electron-withdrawing groups at the para- and
meta-positions of the phenyl ring proceeded smoothly with 1a to
afford the desired coupling products in 48–84% yields (3b–3g). The
use of disubstituted alkene as the substrates gave similar results (3h).
In addition, besides styrenes, aliphatic alkene is also a suitable
substrate for this tandem reaction (3i). Specifically, potentially
reactive chloro- and bromo- substituents are well tolerated with this
mild catalytic system (3e–3g), which afford handles for further
modifications.
Table 1 Optimization of the reaction conditionsa
Entry
1
2
Photocatalyst
Rh-6G
Rose Bengal
Methylene blue
Rh-6G
Rh-6G
Rh-6G
Rh-6G
Rh-6G
Rh-6G
Rh-6G
—
Rh-6G
Rh-6G
Rh-6G
Acid
Yield (%)b
11
10
—
33
53
60
68
64
75
71
19
—
trace
32
BF3·Et2O
BF3·Et2O
BF3·Et2O
TsOH
3
4
5c
TfOH
6c
HClO4
HClO4
HClO4
HClO4
HClO4
HClO4
—
The scope of this reaction in terms of the glycine ester partner was
7c,d
also investigated (Table 3).
A variety of electron-donating
8d,e
9c,d,f
10c,d,g
11c,d,f
12c,d,f
13c,d,f,h
14c,d,f,i
substituents at the benzene rings are well tolerated under these mild
reaction conditions, affording the corresponding quinoline-2-
carboxylates (3a, 3j-3m) in 53% to 75% yields. Notably, bromo-
substituent was also tolerated using this mild protocol (3n). We also
performed the reaction with glycine ester bearing strong electron-
withdrawing group (ester), however, only trace product could be
observed. The reaction is also amenable to a range of ester
HClO4
HClO4
a
Unless otherwise noted, all reactions were run under the following
conditions: 1a (0.1 mmol), 2a (0.5 mmol), photocatalyst (5 mol%), acid (10
mol%), CH3CN (1.0 mL), 3 W blue LED light irradiation under air at room substrates, such as methyl ester, isopropyl ester, phenyl ester, benzyl
b
c
temperature. Yields of isolated products are given. 15 mol% of acid was
2 | J. Name., 2012, 00, 1-3
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ester, and allyl ester, affording the corresponding products 3o-3s quinoline fused lactone 3u with 40% yield in one steVpiew(SAcrhtieclme Oenl1in)e.
DOI: 10.1039/D0OB01837F
with 50-70% yield. Specifically, in addition to glycine esters, a glycine This reaction may open a new avenue for the rapid construction of
derived dipeptide can also be utilized in this transformation (3t).
quinoline fused lactone skeletons, which are widely spread in natural
products. Furthermore, to evaluate the synthetic utility of this
protocol, a gram scale reaction of 1a (5 mmol) and 2a was conducted
We then turned our focus toward the intramolecular variant of
Table 3 Scope of the glycine ester component
Scheme 3 Control Experiments.
(Scheme 2). The target product 3a was obtained in 72% yield.
The interaction between 1a and Rh-6G was studied by
photoluminescence investigations (for details, see Fig. S2†). The
fluorescence intensity of Rh-6G was quenched obviously upon the
addition of 1a with a rate constant of 35.11 L mol−1, which should be
attributed to the formation of the radical anion of Rh-6G via
photoinduced electron transfer. We further performed electron
paramagnetic resonance (EPR) studies to detect the active species of
oxygen in this photocatalytic reaction (for details, see Fig. S3†). When
the solution of 1a, Rh-6G and 5,5-dimethyl-1-pyrroline-N-oxide
(DMPO) in air-saturated CH3CN was irradiated with blue LED, a signal
Reaction conditions: 1 (0.1 mmol), 2a (0.5 mmol), Rh-6G (5 mol%), HClO4 (15
mol%), CH3CN (2.0 mL), 23 W blue LED light irradiation in air at rt. Yield of the
isolated product.
-∙
of the trapping radical of O2 was captured (Fig. S3a†). By contrast,
only very weak EPR signal could be detected when 2,2,6,6-
tetramethylpiperidine (TEMP), an 1O2 scavenger, was used as a probe
in the same air-saturated CH3CN solution (Fig. S3b†). These results
illustrate that O2-∙ generated from O2 is the main active species in this
photocatalytic oxidative reaction.
Scheme 1 Visible light-mediated intramolecular reaction of glycine ester 1u.
We also conducted several control experiments to provide insights
into the reaction mechanisms of this transformation (Scheme 3).
Upon irradiation of 1a with blue LEDs under the standard conditions,
the imine intermediate 4a was isolated in 22% yield, which reacted
readily with 2a under the standard conditions, giving 3a in 59% yield;
however, in the absence of photocatalyst and light, no 3a was
obtained. These control reactions revealed that the cyclization could
not happen spontaneously along with possible spontaneous
autooxidation, and imine 4a should be the key intermediate of this
reaction.
Scheme 2 Large scale synthesis of 3a.
On the basis of these control experiments and the precedent
literatures,47 a plausible mechanism for this photocatalytic oxidative
dehydrogenative coupling/aromatization tandem reaction was
this visible light-induced reaction. To our delight, the intramolecular
reaction occurred smoothly under our standard conditions, giving
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proposed (Scheme 4). Firstly, the excited state of Rh-6G (Rh-6G*, To a solution of N-arylglycine ester 1a (20.9 mg, 0.1 mVmieowl,A1rticeleqO) nalninde
Eox1/2=1.29 V vs. SCE)55 would readily accept a single electron from 1a Rhodamine 6G (2.4 mg, 0.005 mmol, 5 mol%) in dry CH3CN (2.0 mL,
DOI: 10.1039/D0OB01837F
(0.74 V vs. SCE)37 to produce the radical cation A and [Rh-6G]‒. Rh- 0.05 M) were added HClO4 (the HClO4 used in this study was
6G may be regenerated by the oxidation of O2; meanwhile, an active purchased as neat; 1.5 mg, 0.015 mmol, 15 mol%) and styrene 2a
∙‒
species O2 is formed during this process, which may abstract an (52.1 mg, 57.3 μL, 0.5 mmol, 5 eq). The mixed solution was irradiated
electron and two protons from A to generate the imine intermediate with blue LED (3 W in optimization, 23 W in scope) under air
4a. 4a subsequently forms the active iminium intermediate B under atmosphere at room temperature. After completion of the reaction
the action of acid. Finally, trapping of B with 2a would form the as monitored by TLC, the solvent was removed under vacuo, and the
tetrahydroquinoline C, which may be further dehydrogenated via residue was separated by silica gel column chromatography (with
photocatalysis to afford 3a. Alternatively, an α-amino radical is also petroleum ether/EtOAc = 8/1 as eluent) to afford the product 3a.
likely to be generated from radical cation A, which may directly react Ethyl 6-methoxy-4-phenylquinoline-2-carboxylate (3a).47
with alkenes. In addition, excited state Rh-6G may act as a triplet Purified by flash column chromatography (silica gel, petroleum
energy transfer catalyst to oxygen, producing 1O2 which could ether/EtOAc = 8/1 as eluent). White solid, 23.1 mg, 75% yield.
undergo alternative product forming pathways (hydrogen atom 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 9.3 Hz, 1H), 8.10 (s, 1H),
transfer followed by electron transfer processes).56
7.61 – 7.47 (m, 5H), 7.44 (dd, J = 9.3, 2.8 Hz, 1H), 7.22 (d, J = 2.7
Hz, 1H), 4.56 (q, J = 7.1 Hz, 2H), 3.81 (s, 3H), 1.49 (t, J = 7.1 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 165.6, 159.5, 148.0, 145.4,
144.3, 137.9, 132.7, 129.3, 129.2, 128.8, 128.6, 122.8, 121.8,
103.3, 62.1, 55.5, 14.4.
Ethyl
6-methoxy-4-(4-methoxyphenyl)quinoline-2-
carboxylate (3b).47 Purified by flash column chromatography
(silica gel, petroleum ether/EtOAc = 8/1 as eluent). White solid,
20.9 mg, 62% yield. 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 9.3
Hz, 1H), 8.08 (s, 1H), 7.50 (d, J = 8.7 Hz, 2H), 7.43 (dd, J = 9.2, 2.8
Hz, 1H), 7.27 (d, J = 3.2 Hz, 1H), 7.09 (d, J = 8.7 Hz, 2H), 4.55 (q,
J = 7.1 Hz, 2H), 3.92 (s, 3H), 3.83 (s, 3H), 1.49 (t, J = 7.1 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 165.9, 160.1, 159.6, 148.0, 145.5,
144.6, 132.9, 130.8, 130.3, 129.5, 122.9, 121.9, 114.4, 103.5,
62.3, 55.7, 55.6, 14.6.
Ethyl
4-(3,5-dimethoxyphenyl)-6-methoxyquinoline-2-
carboxylate (3c).47 Purified by flash column chromatography
(silica gel, petroleum ether/EtOAc = 8/1 as eluent). White solid,
25.3 mg, 69% yield. 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 9.3
Hz, 1H), 8.10 (s, 1H), 7.43 (dd, J = 9.3, 2.8 Hz, 1H), 7.28 (d, J = 3.5
Hz, 1H), 6.67 (d, J = 2.3 Hz, 2H), 6.61−6,59 (m, 1H), 4.55 (q, J =
Scheme 4 Proposed Mechanism.
7.1 Hz, 2H), 3.85 (s, 6H), 3.83 (s, 3H), 1.49 (t, J = 7.1 Hz, 3H); 13
C
NMR (101 MHz, CDCl3) δ 165.6, 161.0, 159.5, 147.9, 145.3,
144.3, 139.8, 132.7, 129.1, 122.8, 121.5, 107.4, 103.3, 100.6,
62.1, 55.6, 55.5, 14.4.
Conclusions
In summary, we have disclosed a metal-free visible light-mediated
oxidative dehydrogenative coupling/aromatization tandem reaction
of glycine esters and unactivated alkenes employing an organic-
dye/acid catalytic system, which provides a straightforward access to
diverse quinoline-2-carboxylates. This mild and efficient protocol
tolerates a range of functional groups. Given the cheap catalysts and
starting materials, as well as the mild and operationally simple
reaction conditions, this reaction should find broad applications in
the synthesis of quinoline-2-carboxylates. Further research towards
the application of this protocol for the synthesis of pharmaceutically
active molecules is underway in our laboratory.
Ethyl 6-methoxy-4-(p-tolyl)quinoline-2-carboxylate (3d).57
Purified by flash column chromatography (silica gel, petroleum
ether/EtOAc = 4/1 as eluent). White solid, 27.1 mg, 84% yield.
1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 9.3 Hz, 1H), 8.08 (s, 1H),
7.47 – 7.29 (m, 5H), 7.24 (d, J = 2.8 Hz, 1H), 4.55 (q, J = 7.2 Hz,
2H), 3.82 (s, 3H), 2.48 (s, 3H), 1.48 (t, J = 7.1 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 165.7, 159.4, 148.1, 145.4, 144.3, 138.6,
134.9, 132.7, 129.5, 129.2, 122.7, 121.7, 103.4, 62.1, 55.5, 21.3,
14.4.
Ethyl 4-(4-chlorophenyl)-6-methoxyquinoline-2-carboxylate
(3e).47 Purified by flash column chromatography (silica gel,
petroleum ether/EtOAc = 8/1 as eluent). White solid, 19.5 mg,
1
57% yield. H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 9.3 Hz, 1H),
Experimental
General procedure for the metal-free visible light-induced
oxidative dehydrogenative coupling/aromatization tandem
reaction of glycine esters and alkenes
8.07 (s, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 7.44
(dd, J = 9.3, 2.8 Hz, 1H), 7.13 (d, J = 2.7 Hz, 1H), 4.55 (q, J = 7.1
Hz, 2H), 3.82 (s, 3H), 1.48 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 165.7, 159.8, 146.8, 145.3, 144.3, 136.3, 134.8, 132.8,
130.6, 129.0, 128.9, 122.9, 121.7, 102.9, 62.1, 55.5, 14.4.
4 | J. Name., 2012, 00, 1-3
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Ethyl 4-(3-chlorophenyl)-6-methoxyquinoline-2-carboxylate Ethyl 6-ethyl-4-phenylquinoline-2-carboxylate (3l). Purified by
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(3f).47 Purified by flash column chromatography (silica gel, flash column chromatography (siliDcaOI: 10g.e10l,39/Dp0eOtrBo0l1e8u3m7F
petroleum ether/EtOAc = 4/1 as eluent). White solid, 16.4 mg, ether/EtOAc = 8/1 as eluent). White solid, 16.8 mg, 55% yield.
1
48% yield. H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 9.3 Hz, 1H), 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 8.7 Hz, 1H), 8.11 (s, 1H),
8.05 (s, 1H), 7.58 (m, 1H), 7.48 – 7.37 (m, 4H), 7.13 (d, J = 2.8 Hz, 7.73 (s, 1H), 7.67 (dd, J = 8.7, 1.8 Hz, 1H), 7.59 – 7.50 (m, 5H),
1H), 4.55 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 1.48 (t, J = 7.1 Hz, 3H); 4.57 (q, J = 7.1 Hz, 2H), 2.79 (q, J = 7.6 Hz, 2H), 1.49 (t, J = 7.1 Hz,
13C NMR (101 MHz, CDCl3) δ 165.4, 159.7, 146.3, 145.3, 3H), 1.27 (t, J = 7.6 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ 165.7,
144.3,139.6, 134.8, 132.8, 130.0, 129.3, 128.8, 128.7, 127.5, 149.1, 147.0, 145.1, 137.8, 131.2, 131.1, 129.6, 128.7, 128.6,
122.9, 121.7, 102.9, 62.1, 55.5, 14.4.
127.8, 123.2, 121.4, 62.2, 29.3, 15.4, 14.4. HRMS (ESI):
Ethyl 4-(4-bromophenyl)-6-methoxyquinoline-2-carboxylate calculated [C20H19NO2+H]+: 306.1489, found: 306.1487.
(3g).57 Purified by flash column chromatography (silica gel, Ethyl 6-hydroxy-4-phenylquinoline-2-carboxylate (3m).47
petroleum ether/EtOAc = 4/1 as eluent). White solid, 22.9 mg, Purified by flash column chromatography (silica gel, petroleum
1
59% yield. H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 9.3 Hz, 1H), ether/EtOAc = 8/1 as eluent). White solid, 17.0 mg, 58% yield.
8.06 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.0 Hz, 3H), 7.13 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.11 (d, J = 9.2 Hz,
(s, 1H), 4.58-4.53 (m, 2H), 3.83 (s, 3H), 1.49 (t, J = 7.1 Hz, 3H); 1H), 7.87 (s, 1H), 7.61 – 7.54 (m, 5H), 7.43 (dd, J = 9.1, 2.7 Hz,
13C NMR (101 MHz, CDCl3) δ 165.5, 159.7, 146.7, 145.4, 144.3, 1H), 7.16 (d, J = 2.7 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.37 (t, J =
136.8, 132.9, 132.1, 130.9, 128.9, 123.1, 123.0, 121.7, 102.9, 7.1 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 165.0, 158.0, 146.6,
102.8, 62.2, 55.6, 14.4.
Ethyl 2-methoxy-7,8-dihydrobenzo[k]phenanthridine-6- 120.8, 105.9, 61.3, 14.3.
carboxylate (3h).47 Purified by flash column chromatography Ethyl
6-bromo-4-phenylquinoline-2-carboxylate
144.2, 142.8, 137.4, 132.3, 129.2, 128.9, 128.8, 128.7, 123.2,
(3n).47
(silica gel, petroleum ether/EtOAc = 8/1 as eluent). Pale yellow Purified by flash column chromatography (silica gel, petroleum
solid, 14.7 mg, 44% yield. 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J ether/EtOAc = 4/1–2/1 as eluent). White solid, 19.6 mg, 55%
= 9.2 Hz, 1H), 8.00 – 7.94 (m, 1H), 7.78 (d, J = 2.7 Hz, 1H), 7.44- yield. 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 9.0 Hz, 1H), 8.15 (s,
7.36 (m, 4H), 4.53 (q, J = 7.1 Hz, 2H), 3.92 (s, 3H), 3.15 – 3.06 (m, 1H), 8.11 (d, J = 2.1 Hz, 1H), 7.86 (dd, J = 9.0, 2.2 Hz, 1H), 7.63 –
2H), 2.87 – 2.79 (m, 2H), 1.48 (t, J = 7.1 Hz, 3H); 13C NMR (101 7.49 (m, 5H), 4.57 (q, J = 7.1 Hz, 2H), 1.49 (t, J = 7.1 Hz, 3H); 13
C
MHz, CDCl3) δ 167.1, 159.4, 146.8, 143.6, 140.5, 140.4, 132.5, NMR (101 MHz, CDCl3) δ 165.4, 149.2, 148.3, 147.0, 137.1,
132.2, 130.7, 129.1, 128.6, 128.3, 126.5, 126.5, 121.7, 103.6, 133.9, 133.0, 129.7, 129.3, 129.1, 128.1, 123.5, 122.3, 62.6, 14.6.
62.2, 55.7, 29.0, 25.9, 14.5.
Ethyl (E)-6-methoxy-4-(prop-1-en-1-yl)quinoline-2- Purified by flash column chromatography (silica gel, petroleum
Methyl 6-methoxy-4-phenylquinoline-2-carboxylate (3o).47
carboxylate (3i).47 Purified by flash column chromatography ether/EtOAc = 8/1–4/1 as eluent). White solid, 20.5 mg, 70%
(silica gel, petroleum ether/EtOAc = 8/1 as eluent). Pale White yield. 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 9.3 Hz, 1H), 8.12
solid, 14.7 mg, 50% yield. 1H NMR (400 MHz, CDCl3) δ 8.18 (t, J (s, 1H), 7.60 – 7.47 (m, 5H), 7.44 (dd, J = 9.3, 2.8 Hz, 1H), 7.23 (d,
= 4.6 Hz, 2H), 7.41 (dd, J = 9.3, 2.7 Hz, 1H), 7.31 – 7.28 (m, 1H), J = 2.7 Hz, 1H), 4.08 (s, 3H), 3.81 (s, 3H); 13C NMR (101 MHz,
7.02 (d, J = 15.6 Hz, 1H), 6.68 – 6.56 (m, 1H), 4.55 (q, J = 7.1 Hz, CDCl3) δ 166.2, 159.6, 148.1, 145.0, 144.3, 137.8, 132.6, 129.3,
2H), 3.99 (s, 3H), 2.07 (dd, J = 6.7, 1.8 Hz, 3H), 1.49 (t, J = 7.1 Hz, 129.3, 128.8, 128.7, 122.9, 121.9, 103.3, 55.5, 53.1.
3H); 13C NMR (101 MHz, CDCl3) δ 165.9, 159.1, 145.5, 144.1, Isopropyl 6-methoxy-4-phenylquinoline-2-carboxylate (3p).47
143.2, 133.7, 132.8, 128.4, 125.6, 122.6, 117.7, 101.1, 62.0, 55.6, Purified by flash column chromatography (silica gel, petroleum
19.2, 14.4.
Ethyl 6-ethoxy-4-phenylquinoline-2-carboxylate
ether/EtOAc = 8/1–4/1 as eluent). Pale yellow solid, 16.1 mg, 50%
(3j).23b yield. 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 9.3 Hz, 1H), 8.05
Purified by flash column chromatography (silica gel, petroleum (s, 1H), 7.57-7.50 (m, 5H), 7.43 (dd, J = 9.3, 2.8 Hz, 1H), 7.20 (d,
ether/EtOAc = 8/1 as eluent). White solid, 17.0 mg, 53% yield. J = 2.8 Hz, 1H), 5.44-5.35 (m, 1H), 3.81 (s, 3H), 1.46 (d, J = 6.3 Hz,
1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 9.3 Hz, 1H), 8.09 (s, 1H), 6H); 13C NMR (101 MHz, CDCl3) δ 165.0, 159.4, 147.9, 145.7,
7.61 – 7.47 (m, 5H), 7.43 (dd, J = 9.3, 2.7 Hz, 1H), 7.20 (d, J = 2.7 144.4, 138.0, 132.9, 129.4, 129.1, 128.8, 128.6, 122.7, 121.8,
Hz, 1H), 4.56 (q, J = 7.1 Hz, 2H), 4.01 (q, J = 7.0 Hz, 2H), 1.49 (t, J 103.2, 69.7, 55.5, 22.0.
= 7.1 Hz, 3H), 1.42 (t, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) Phenyl 6-methoxy-4-phenylquinoline-2-carboxylate (3q).47
δ 165.9, 159.1, 148.1, 144.4, 138.2, 132.9, 129.5, 129.4, 128.9, Purified by flash column chromatography (silica gel, petroleum
128.8, 123.2, 122.0, 104.2, 64.0, 62.3, 14.8, 14.6.
Ethyl 6-methyl-4-phenylquinoline-2-carboxylate
ether/EtOAc = 8/1 as eluent). Pale yellow solid, 22.1 mg, 62%
1
(3k).47 yield. H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 9.3 Hz, 1H),
Purified by flash column chromatography (silica gel, petroleum 8.08 (s, 1H), 7.69 – 7.57 (m, 6H), 7.51 (dd, J = 8.8, 7.1 Hz, 2H),
ether/EtOAc = 8/1 as eluent). White solid, 17.7 mg, 61% yield. 7.35 (d, J = 7.9 Hz, 3H), 7.26 (d, J = 2.9 Hz, 1H), 3.81 (s, 3H); 13
C
1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.7 Hz, 1H), 8.11 (s, 1H), NMR (101 MHz, DMSO-d6) δ 163.7, 159.6, 150.8, 147.5, 143.8,
7.71 (s, 1H), 7.63 (dd, J = 8.7, 1.9 Hz, 1H), 7.60 – 7.48 (m, 5H), 137.0, 132.4, 129.8, 129.4, 129.13, 129.07, 128.6, 126.3, 123.3,
4.57 (q, J = 7.1 Hz, 2H), 2.50 (s, 3H), 1.49 (t, J = 7.1 Hz, 3H); 13
C
122.0, 121.8, 103.3, 55.6.
NMR (101 MHz, CDCl3) δ 165.6, 148.9, 146.82, 146.75, 139.0, Benzyl 6-methoxy-4-phenylquinoline-2-carboxylate (3r).47
137.7, 132.3, 130.9, 129.5, 128.62, 128.56, 127.8, 124.3, 121.4, Purified by flash column chromatography (silica gel, petroleum
62.2, 22.0, 14.4.
ether/EtOAc = 8/1–4/1 as eluent). Pale yellow solid, 21.0 mg, 57%
yield. 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 9.3 Hz, 1H), 8.08
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4
Y.-F. Zhu, X.-C. Wang, P. Connors, K. Wilcoxen, Y.VGieawoA,rRtic.leGOronlsinse,
(s, 1H), 7.56 – 7.50 (m, 7H), 7.44 (dd, J = 9.3, 2.8 Hz, 1H), 7.40 –
7.30 (m, 3H), 7.21 (d, J = 2.8 Hz, 1H), 5.53 (s, 2H), 3.81 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 165.4, 159.6, 148.0, 145.0, 144.4,
137.9, 135.8, 132.8, 129.3, 129.2, 128.8, 128.7, 128.6, 128.6,
128.4, 122.9, 121.9, 103.2, 67.6, 55.6.
N. Strack, T. Gross, J. R. McCarthy, Q. Xie, N. Ling and C. Chen,
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5
6
7
Allyl
6-methoxy-4-phenylquinoline-2-carboxylate
(
3s).47
Purified by flash column chromatography (silica gel, petroleum
ether/EtOAc = 8/1 as eluent). White solid, 16.6 mg, 52% yield.
1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 9.3 Hz, 1H), 8.11 (s, 1H),
7.59-7.50 (m, 5H), 7.44 (dd, J = 9.3, 2.8 Hz, 1H), 7.22 (d, J = 2.8
Hz, 1H), 6.18 – 6.07 (m, 1H), 5.47 (dd, J = 17.2, 1.5 Hz, 1H), 5.33
(d, J = 10.4, 1H), 4.99 (d, J = 5.8 Hz, 2H), 3.81 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 165.5, 159.8, 148.2, 145.2, 144.6, 138.0,
132.9, 132.1, 129.5, 129.4, 129.0, 128.8, 123.1, 122.1, 119.4,
103.4, 66.9, 55.7.
8
9
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Ethyl
(
(6-methoxy-4-phenylquinoline-2-carbonyl)glycinate
3t).47 Purified by flash column chromatography (silica gel,
petroleum ether/EtOAc = 8/1 as eluent). White solid, 13.1 mg,
36% yield. H NMR (400 MHz, CDCl3) δ 8.69 (t, J = 5.7 Hz, 1H),
1
8.19 (s, 1H), 8.09 (d, J = 9.2 Hz, 1H), 7.56 – 7.48 (m, 5H), 7.43 (dd,
J = 9.3, 2.8 Hz, 1H), 7.24 (d, J = 2.8 Hz, 1H), 4.33 (t, J = 5.9 Hz,
2H), 4.28 (q, J = 7.1Hz, 2H), 3.81 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 170.1, 165.3, 159.3, 148.5, 146.6,
143.4, 138.2, 131.9, 129.6, 129.3, 128.9, 128.8, 122.9, 119.7,
103.6, 61.7, 55.7, 41.7, 14.4.
17
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7-Methyl-9-phenylfuro[3,4-b]quinolin-3(1H)-one
(
3u).21
Purified by flash column chromatography (silica gel, petroleum
ether/EtOAc = 4/1 as eluent). Pale yellow solid, 11.0 mg, 40%
yield. 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 8.7 Hz, 1H), 7.69
(dd, J = 8.7, 1.6 Hz, 1H), 7.66 – 7.52 (m, 4H), 7.45 (dd, J = 7.8, 1.5
Hz, 2H), 5.37 (s, 2H), 2.52 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
167.9, 148.3, 142.3, 141.8, 139.0, 132.7, 132.1, 131.5, 130.0,
128.4, 128.3, 127.8, 126.9, 123.3, 66.8, 21.1.
25 C. D. Huo, H. S. Xie, M. X. Wu, X. D. Jia, X. C. Wang, F. J. Chen
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357, 3648-3654.
Conflicts of interest
There are no conflicts to declare.
27 G. Liu, J. Qian, J. Hua, F. Cai, X. Li and L. Liu, Org. Biomol. Chem.,
2016, 14, 1147-1152.
28 Z. Xie, J. Jia, X. Liu and L. Liu, Adv. Synth. Catal., 2016, 358, 919-
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29 M. Ni, Y. Zhang, T. Gong and B. Feng, Adv. Synth. Catal., 2017,
359, 824-831.
30 J. Xuan and W. J. Xiao, Angew. Chem., Int. Ed., 2012, 51, 6828-
6838.
Acknowledgements
We gratefully acknowledge the National Natural Science Foundation
of China (Nos. 22071092, 21572092 and 21772079) and Natural
Science Foundation of Gansu Province (18JR4RA003) for financial
support.
31
C. K. Prier, D. A. Rankic and D. W. MacMillan, Chem. Rev., 2013,
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