FeCl3-promoted formation of C-C bonds: Synthesis of substituted quinolines from imines and electron-deficient alkynes

Article abstract of DOI:10.1016/j.tet.2014.05.051

An efficient method for the synthesis of substituted quinolines is described. By FeCl₃-promoted C-C bond formation, 2,3-disubstituted and 2,3,4-trisubstituted quinolines were successfully synthesized from the reaction between imines and electron-deficient alkynes in good yields. The reaction can also be performed in a sequential three-component manner by using aromatic amines and aromatic aldehydes instead of the corresponding imines.

Full text of DOI:10.1016/j.tet.2014.05.051

Accepted Manuscript
FeCl -Promoted Formation of C-C Bonds: Synthesis of substituted Quinolines from
3
Imines and Electron-deficient Alkynes
Yu-feng Li , Zheng-guang Wu , Jie Shi , Yi Pan , Hong-zhong Bu , Hong-fei Ma , Jia-
chao Gu , Hao Huang , Yao-zhu Wang , Lin Wu
PII:
S0040-4020(14)00731-5
10.1016/j.tet.2014.05.051
TET 25600
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 March 2014
Revised Date: 7 May 2014
Accepted Date: 15 May 2014
Please cite this article as: Li Y-f, Wu Z-g, Shi J, Pan Y, Bu H-z, Ma H-f, Gu J-c, Huang H, Wang Y-z,
Wu L, FeCl -Promoted Formation of C-C Bonds: Synthesis of substituted Quinolines from Imines and
3
Electron-deficient Alkynes, Tetrahedron (2014), doi: 10.1016/j.tet.2014.05.051.
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FeCl3-promoted formation of C-C bonds:
synthesis of substituted quinolines from
imines and electron-deficient alkynes
,
Yu-feng Li, a, Zheng-guang Wu, a Jie Shi, a Yi Pan, b Hong-zhong Bu, a Hong-fei Ma, a Jiao-chao Gu, a Hao
Huang, a Yao-zhu Wang, a Lin Wu a
a College of Sciences, Nanjing University of Technology, Nanjing 211816, PR China
b School of Chemistry and Chemical Engineering, Nanjing University, 210093, PR China

1
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Tetrahedron
journal homepage: www.elsevier.com
FeCl3-Promoted Formation of C-C Bonds: Synthesis of substituted Quinolines from
Imines and Electron-deficient Alkynes
Yu-feng Li, a, Zheng-guang Wu, a Jie Shi, a Yi Pan, b, Hong-zhong Bu, a Hong-fei Ma, a Jia-chao Gu, a
Hao Huang, a Yao-zhu Wang, a Lin Wu a
a College of Sciences, Nanjing University of Technology, Nanjing 211816, PR China
b School of Chemistry and Chemical Engineering, Nanjing University, 210093, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient method for the synthesis of substituted quinolines is described. By FeCl3-promoted
C-C bond formation, 2,3-disubstituted and 2,3,4-trisubstituted quinolines were successfully
synthesized from the reaction between imines and electron-deficient alkynes in good yields. The
reaction can also be performed in a sequential three-component manner by using aromatic
amines and aromatic aldehydes instead of the corresponding imines.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved
.
C-C bond formation
Iron trichloride
Quinolines
Electron-deficient alkynes
1. Introduction
product was isolated by chromatograph method, and was
confirmed as 3a according to NMR analysis (Scheme 1, eq. 2).
As the structure of 3a is considered, it is distinct to Fan’s results8
with regard to the position of substituent (Scheme 1, eq. 1),
which also indicates a different mechanism involved in.
To our knowledge, substituted quinolines are useful units
associated with various biologically active substances.10
Recently, an attractive route to this framework was based on
Fan’s investigation, but wherein, electron deficient alkynes were
not mentioned for unknown reasons. Thus, we herein describe
FeCl3-promoted C-C bond formation for the synthesis of 2,3-
substitueted quinolines starting from electron-deficient alkynes
and imines.
The demand for clean, efficient, and selective processes has
prompted the great development of metal-based reaction
promoters in organic synthesis.1 However, majority of catalysts
are derived from rare metals, and reasonably, their application is
restricted due to their toxicity and prohibitive prices. In contrast,
iron, which is abundant on earth and easily recyclable, becomes
increasingly attractive for its environment friendly nature and
promising efficiency comparable with other transition metals in
many fields2 such as C-H oxidation,3 cycloaddition,4 C-H
activation5 and Fe-porphyrins chemistry.6 Nevertheless, only a
few of literatures described Fe-mediated C-C formation including
mainly FeCl3-catalyzed alkenylation of arenes,7 FeCl3-promoted
cyclization of imines with electron-rich alkynes,8 Fe-catalyzed
addition of tert-butylisonitrile to unreactive arenes.9 So,
broadening iron-promoted reactions is significative in synthetic
chemistry.
Ph
N
FeCl3(15 mol %)
(eq. 1)
Fan's work
Ph
N
N
During our previous work on the reaction between imines and
methyl propionate, we found that FeCl3 is not a suitable catalyst
for propargylamine intermediates synthesis. However, when the
mixture of N-phenylbenzaldimine (1a), methyl propionate (2a),
and a catalytic loading of FeCl3 (10 mol %) in dichloroethane
was heated (80 °C) in atmosphere for a prolonged time (10 h), a
COOMe 2a
1a
FeCl3(10 mol %)
(eq. 2)
COOMe
3a
Scheme 1. The comparison between electron-deficient and electron-rich
new product was detected according to TLC analysis. Thus the
alkyne reacts with imine.
———
Corresponding author. Tel.: +0-086-025-58139483; fax: +0-086-025-58139483; e-mail: yufengli@njut.edu.cn
Corresponding author. Tel.: +0-086-025-83592846; fax: +0-086-025-83592846; e-mail: yipan@nju.edu.cn

2
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2. Results and Discussion
= H);
2a
At the outset, we explored reaction between imine (1a) and
80 °C, 5 h
3c
methyl propiolate (2a) with CuCl, CuCl2, ZnCl2, PdCl2, and
FeCl3 respectively in a 10 mol % loading. When the mixture of
1a and 2a was treated in 1,2-dichoroethane (DCE,) at 80 °C in
the presence of CuCl, a propargylamine-type adduct was
obtained as we had described.11 Using CuCl2, ZnCl2, and PdCl2
instead of CuCl, no reaction took place according to TLC
analysis (Table 1, entries 2-4). However, when the reaction was
performed in the presence of FeCl3, 3a was isolated in a yield of
61% after heated for 10 h (Table 1, entry 5). From the theoretical
view, we assumed that oxygen is necessary for this
transformation. So the reaction condition was optimized with
blowing air into the system, and the reaction time was shortened
to 5 h affording 3a in 82% yield (Table 1, entry 6). When ethanol,
N,N-dimethylformamide was checked as the solvent, 3a’s yields
were quite lowered. When FeCl2 was used as the catalyst instead
of FeCl3, the reaction proceeded also smoothly but the yield 3a of
was little decreased (75%) (Table 1, entry 7).
1d (R1 = 3-t-Bu, R2
t-Bu
N
4
90
73
69
80
82
75
87
= H);
2a
COOMe
COOMe
COOMe
80 °C, 5 h
3d
1e (R1 = 4-Cl, R2 =
5
N
H);
2a
Cl
80 °C, 8 h
3e
1f (R1 = 4-F, R2 =
6
N
H);
2a
F
80 °C, 8 h
3f
1g (R1 = H, R2 = 4-
Table 1
7
N
The conditions screening for synthesis of quinoline from imine and methyl
propiolate
CH3);
2a
COOMe
3g
80 °C, 4.5 h
Ph
COOMe
N
Conditions
OMe
N
1h (R1 = H, R2 = 4-
Ph
COOMe
8
N
N
3a
1a
2a
OMe);
2a
Entry
Catalyst
CuCl
Conditions
3a, Yielda (%)
COOMe
80 °C, 5 h
3h
1
2
10 mol %, DCE, 80 °C, 10 h
10 mol %, DCE, 80 °C, 10 h
0
0
Cl
CuCl2
1i (R1 = H, R2 = 4-
9
Cl);
3
ZnCl2
PdCl2
FeCl3
FeCl3
FeCl2
10 mol %, DCE, 80 °C, 10 h
10 mol %, DCE, 80 °C, 10 h
10 mol %, DCE, 80 °C, 10 h
10 mol %, DCE, 80 °C, 5 h
10 mol %, DCE, 80 °C, 5 h
0
2a
4
0
COOMe
80 °C, 6 h
3i
5
61
82
75
6b
7b
OMe
1j (R1 = 4-Me, R2 =
4-OMe);
10
N
2a
a Isolate yield of 3a.
COOMe
3j
80 °C, 5 h
b Air was blowed into the system.
Table 2
1a;
N
Scope of the reaction of imines 1 with alkynes 2a
11
81
2b (R3 = COOEt, R4
= H)
R2
COOEt
R3(EWG)
N
N
FeCl3(10 mol %)
dichloroethane
80 °C, 5 h
R2
3k
R3
R1
R1
R4
R4
3
1
2
Substrates,
Conditions
Table 2 (continued)
Entry
1
Product
Yieldb (%)
1a (R1 = H, R2 = H);
2a (R3 = COOMe,
R4 = H)
N
82
86
COOMe
80 °C, 5 h
3a
1b (R1 = 4-Me, R2 =
2
3
N
H);
2a
COOMe
COOMe
80 °C, 4 h
3b
1c (R1 = 4-MeO, R2
N
81
MeO

3
To have a penetrating insight into the behavior of the
ACCEPTED MANUSCRIPT
Substrates,
Conditions
Entry
12
Product
Yieldb (%)
catalyst, 2a and FeCl3 were refluxed in DCE in the absence of 1a,
and the interaction was detectable from TLC analysis. While in
absence of 2a, the interaction between 1a and FeCl3 was not
detected. Based on the experimental results in combination with
literatures,7,13 a plausible mechanism was depicted in Scheme 2.
The first step is the formation of an alkenyl cation 4 by the FeCl3
as Lewis acid attacking alkynoate. Subsequently, an electrophilic
aromatic substitution occurs between the alkenyl cation 4 and 1a
to produce an intermediate 5, which belongs to a Friedel-Crafts-
type process. Then 5 is activated by proton to elevate carbon
eletropositivity of imine 6, which intrigues the cyclization to
generate 7 with leaving of FeCl3 under the help of chloride ion.
In this course, we deem that the forming of the intermediate 5
and the subsequent cyclization experience a cooperative process
since we did not detect 5 in the reaction mixture. The oxidation
of 7 with FeCl3 subsequently gives 3a as well as FeCl2.
Oxidation of FeCl2 with oxygen provides FeCl3 to fulfill a
catalytic cycle.
1a;
78
2c (R3 = COOMe,
R4 = COOMe)
80 °C, 7 h
N
COOMe
3l
COOMe
1a;
2d (R3 = H, R4 =
Ph)
13
84
80 °C, 6 h
3m
a
Reaction conditions: imine 1 (5 mmol), alkyne 2 (5 mmol), FeCl3 (0.5
mmol), and dichloroethane (25 mL) at 80 °C with the air blowing into the
system.
b
N
Isolated yield after purification by silica gel chromatography.
N
Ph
COOMe
Then, various N-arylbenzaldimines were prepared according
to the literature method12 and checked for the transformation. As
shown in Table 2, imines 1a-1j showed good reactivity with
methyl propionate in spite of the electron effect of substituent on
them (Table 2, entries 1-10). For example, imine 1b, 1c, and 1d,
all bearing electron-donating groups on the amine moiety,
reacted smoothly with 2a affording high yields of 3b, 3c and 3d,
respectively (Table 2, entries 2-4). The halogen substituent either
on the amine moiety or aldehyde moiety was also well
compatible with the reaction (Table 2, entries 5-6, 9).
Nevertheless, the nitro group exhibited severe suppression on the
reaction. It’s depressing that aliphatic aldimines which derived
from aniline and paraformaldehyde or other aliphatic aldehydes
exhibited worse selectivity giving inseparable mixtures. 3e’s fine
crystal was cultivated from its dichloromethane-methanol
solution and the analysis result was shown as Figure 1.
3a
FeCl3
H
N
FeCl2
HCl
O2
Ph
COOMe
COOMe
2a
FeCl3
FeCl3
7
Cl-
COOMe
H
N
Ph
H
COOMe
4
+
FeCl2
6
FeCl2 Cl-
N
Ph
N
Ph
H+
1a
COOMe
H+
FeCl2
5
Scheme 2. Plausible mechanism for FeCl3-catalyzed reaction of imines and
electron-deficient alkynes
Alternatively, a typical three-component manner for the
transformation was explored starting with benzaldehyde, aniline
and 2a in the presence of FeCl3. When the condensation between
benzaldehyde and aniline completed, the catalyst and 2a were
added to the in-situ mixture and then corresponding quinoline (3a)
was acquired in a good yield. This sequential manner is useful for
directed assembly of 2,3-substituted quinolines from aldehydes,
aromatic amines and electron-deficient alkynes.
3. Conclusion
Figure 1. X-ray crystal structure for 3e.
In summary, we have developed an eco-friendly method for
the synthesis of functionalized quinolines from amines,
aldehydes and electron-deficient alkynes. The efficiency and
functional-group tolerance of this transformation have been fully
demonstrated by synthesizing a series of substituted quinolines.
Moreover, the FeCl3-promoted C-C bond formation makes
alkynes particularly attractive for synthetic chemistry. Further
study in alkyne chemistry is ongoing in our laboratory.
Other alkynes were then examined for their possible adaption
in pursuing for molecular diversity. Propargyl benzoate, 3-Butyn-
2-one, 2-propyn-1-amine, trimethyl silyl acetylene (TMSA),
ethyl propiolate, dimethyl acetylenedicarboxylate (DMAD) and
phenylacetylene were respectively tested for this transformation.
Propargyl benzoate, 3-Butyn-2-one, 2-propyn-1-amine and
TMSA showed lowered reactivity and gave no desired products.
Both DMAD and ethyl propiolate reacted smoothly with the
corresponding imines giving good yields of quinolines (Table 2,
entries 11-12). As a comparative experiment, phenylacetylene
was adopted for this transformation resulting in accordingly the
formation of 2,4-diphenyl quinoline (Table 2, entry 13).
4. Experimental section
4.1. General
All the reagents were purchased from commercial suppliers,
and were used without further purification. The 1H NMR and 13
C
NMR spectra were performed with a Varian Unity Plus

4
Tetrahedron
ACCEPTED MANUSCRIPT
spectrometer in CDCl3 using TMS as internal standard.
methyl 6-chloro-2-phenylquinoline-3-carboxylate (3e), a pale
Chemical shifts are expressed in parts per million (δ) using
yellow solid, mp: 91.1 - 95.0 °C, 73% yield. 1H NMR (400
MHz, CDCl3): δ = 8.52 (s, 1H), 8.10 (d, J = 9.0 Hz, 1H), 7.86 (d,
J = 2.2 Hz, 1H), 7.72 (dd, J = 9.0, 2.3 Hz, 1H), 7.65 - 7.60 (m,
2H), 7.50 - 7.44 (m, 3H), 3.74 (s, 3H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 168.1, 158.2, 146.8, 140.1, 138.1, 133.0, 132.5,
131.2, 128.9, 128.6, 128.3, 126.7, 126.4, 126.0, 52.6 ppm.
HRMS (EI+) 297.0557 (cal. For C17H12ClNO2 297.0555).
1
residual solvent protons as internal standards (δ 7.26 for H, δ
77.0 for 13C). Coupling constants (J) are reported in Hertz (Hz).
Splitting patterns are designated as s (singlet), d (doublet), t
(triplet), m (multiplet). Melting points were measured on
microscopic melting point apparatus.
4.2. Representative procedures for the synthesis of quinoline
3a
methyl 6-fluoro-2-phenylquinoline-3-carboxylate (3f), a pale
yellow solid, mp: 91.0 - 94.2 °C, 69% yield. 1H NMR (400 MHz,
CDCl3): δ = 8.57 (s, 1H), 8.18 (dd, J = 9.2, 5.2 Hz, 1H), 7.63 (dd,
J = 7.8, 1.6 Hz, 2H), 7.59 - 7.54 (m, 1H), 7.52 (dd, J = 8.5, 2.8
Hz, 1H), 7.49 - 7.44 (m, 3H), 3.74 (s, 3H) ppm. 13C NMR (101
MHz, CDCl3): δ = 168.2, 159.6, 157.3, 145.6, 140.2, 138.3,
132.2, 128.8, 128.5, 128.3, 126.5, 125.9, 122.0, 121.7, 111.0,
52.5 ppm. HRMS (EI+) 281.0852 (cal. For C17H12FNO2
281.0850).
4.2.1 Procedure A: synthesizing 3a from imine 1a and methyl
propiolate 2a
To a mixture of imine 1a (5.0 mmol), methyl propiolate (2a,
5.0 mmol) in DCE (25 mL) was added FeCl3 (0.5 mmol). With
blowing air slowly in, the mixture was heated at 80 °C till the
reaction completed. After cooled to room temperature, the
mixture was filtered and the filtrate was evaporated in vacuo. The
residue was purified by flash chromatography on silica gel to
give desired 3a (82% yield, calculated from 2a).
methyl 2-(p-tolyl)quinoline-3-carboxylate (3g), a deep yellow
solid, mp: 90.2 - 95.0 °C, 80% yield. 1H NMR (400 MHz,
CDCl3): δ = 8.54 (s, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.82 (d, J =
8.1 Hz, 1H), 7.72 (t, J = 7.3 Hz, 1H), 7.51 - 7.45 (m, 3H), 7.20
(d, J = 7.8 Hz, 2H), 3.69 (s, 3H), 2.34 (s, 3H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 168.6, 158.0, 148.5, 139.1, 138.6, 137.7,
131.5, 129.6, 128.9, 128.5, 128.2, 127.1, 125.7, 125.1, 52.4, 21.4
ppm. HRMS (EI+) 277.1103 (cal. For C18H15NO2 277.1105).
4.2.2 Procedure B: synthesizing 3a from aniline, benzaldehyde
and 2a in a sequential three-component manner
A mixture of aniline (5.0 mmol), benzaldehyde (5.0 mmol) in
DCE (25 mL) was refluxed for about 8 h. Methyl propiolate (2a,
5.0 mmol) and FeCl3 (0.5 mmol) were added, and the mixture
was further treated as Procedure A giving 3a (78% yield,
calculated from 2a).
methyl 2-(4-methoxyphenyl)quinoline-3-carboxylate (3h), a
yellow solid, mp: 92.1 - 95.7 °C, 82% yield. 1H NMR (400 MHz,
CDCl3): δ = 8.58 (s, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.87 (d, J =
8.1 Hz, 1H), 7.80 - 7.75 (m, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.55
(t, J = 7.5 Hz, 1H), 7.00 (d, J = 8.7 Hz, 2H), 3.85 (s, 3H), 3.77 (s,
3H) ppm. 13C NMR (101 MHz, CDCl3): δ = 168.7, 160.3, 157.4,
148.5, 139.1, 132.9, 131.5, 130.1, 129.4, 128.2, 127.0, 125.6,
125.0, 113.8, 55.3, 52.5 ppm. HRMS (EI+) 293.1052 (cal. For
C18H15NO3 293.1050).
4.3 Characterization
methyl 2-phenylquinoline-3-carboxylate (3a),
a
yellow
1
viscous liquid, 82% yield. H NMR (400 MHz, CDCl3): δ = 8.65
(s, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.93 - 7.89 (m, 1H), 7.81 (ddd,
J = 8.4, 6.9, 1.4 Hz, 1H), 7.66 - 7.62 (m, 2H), 7.59 (ddd, J = 8.1,
7.0, 1.1 Hz, 1H), 7.50 - 7.43 (m, 3H), 3.74 (s, 3H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 168.4, 158.1, 148.5, 140.6, 139.2, 131.6,
129.6, 128.7, 128.6, 128.2, 127.3, 125.8, 125.1, 52.4 ppm.
HRMS (EI+) 263.0946 (cal. For C17H13NO2 263.0940).
methyl 2-(4-chlorophenyl)quinoline-3-carboxylate (3i):
a
1
maize-yellow solid, mp: 111.2 - 114.4 °C, 75% yield. H NMR
(400 MHz, CDCl3): δ = 8.67 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H),
7.91 (d, J = 8.1 Hz, 1H), 7.85 - 7.79 (m, 1H), 7.63 - 7.56 (m, 3H),
7.46 - 7.43 (m, 2H), 3.77 (s, 3H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 168.0, 156.9, 148.5, 139.6, 139.1, 134.9, 131.9,
130.0, 129.5, 128.4, 128.3, 127.5, 125.9, 124.6, 52.5 ppm.
HRMS (EI+) 297.0557 (cal. For C17H12ClNO2 297.0556).
methyl 6-methyl-2-phenylquinoline-3-carboxylate (3b),
a
maize-yellow solid, mp: 69.0 - 72.3 °C, 86% yield. 1H NMR (400
MHz, CDCl3): δ = 8.51 (s, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.64 -
7.61 (m, 2H), 7.58 (d, J = 7.2 Hz, 2H), 7.47 - 7.40 (m, 3H), 3.70
(s, 3H), 2.49 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ =
168.5, 157.1, 147.1, 140.7, 138.5, 137.3, 134.0, 129.2, 128.6,
128.5, 128.2, 127.0, 125.8, 125.0, 52.4, 21.6 ppm. HRMS (EI+)
277.1103 (cal. For C18H15NO2 277.1105).
methyl 2-(4-methoxyphenyl)-6-methylquinoline-3-carboxylate
(3j), a yellowish-brown solid, mp: 85.2 - 91.4 °C, 87% yield. H
1
NMR (400 MHz, CDCl3): δ = 8.43 (s, 1H), 7.97 (d, J = 8.4 Hz,
1H), 7.58 - 7.50 (m, 4H), 6.92 (d, J = 8.6 Hz, 2H), 3.79 (s, 3H),
3.70 (s, 3H), 2.48 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ =
168.9, 160.1, 156.6, 147.1, 138.4, 137.0, 133.9, 133.1, 130.0,
129.1, 126.9, 125.7, 125.0, 113.7, 55.3, 52.4, 21.6 ppm. HRMS
(EI+) 307.1208 (cal. For C19H17NO3 307.1204).
methyl 6-methoxy-2-phenylquinoline-3-carboxylate (3c), a
deep yellow solid, mp: 102.3 -104.4 °C, 81% yield. H NMR
1
(400 MHz, CDCl3): δ = 8.53 (s, 1H), 8.07 (d, J = 9.2 Hz, 1H),
7.63 - 7.59 (m, 2H), 7.49 - 7.42 (m, 4H), 7.15 (d, J = 2.8 Hz, 1H),
3.95 (s, 3H), 3.73 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ =
168.6, 158.3, 155.6, 144.7, 140.7, 137.8, 131.0, 128.5, 128.4,
128.2, 126.9, 125.3, 124.5, 105.3, 55.7, 52.4 ppm. HRMS (EI+)
293.1052 (cal. For C18H15NO3 293.1053).
ethyl 2-phenylquinoline-3-carboxylate (3k), a pale yellow
1
viscous liquid, 81% yield. H NMR (300 MHz, CDCl3): δ = 8.65
(s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.80 (t,
J = 7.7 Hz, 1H), 7.68 - 7.62 (m, 2H), 7.58 (t, J = 7.5 Hz, 1H),
7.51 - 7.43 (m, 3H), 4.25 - 4.15 (m, 2H), 1.08 (td, J = 7.1, 1.6 Hz,
3H) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.8, 158.0, 148.3,
140.7, 138.9, 131.4, 129.4, 128.5, 128.4, 128.1, 128.0, 127.1,
125.7, 125.4, 61.4, 13.6 ppm. HRMS (EI+) 277.1103 (cal. For
C18H15NO2 277.1100).
methyl 7-(tert-butyl)-2-phenylquinoline-3-carboxylate (3d), a
yellow solid, mp: 100.1 - 103.4 °C, 90% yield. H NMR (400
1
MHz, CDCl3): δ = 8.63 (s, 1H), 8.18 - 8.14 (m, 1H), 7.85 (d, J =
8.6 Hz, 1H), 7.69 (dd, J = 8.6, 1.9 Hz, 1H), 7.62 (dt, J = 8.3, 2.1
Hz, 2H), 7.50 - 7.42 (m, 3H), 3.73 (s, 3H), 1.44 (s, 9H) ppm. 13
C
NMR (101 MHz, CDCl3): δ = 168.4, 158.2, 155.4, 148.7, 140.9,
138.8, 128.5, 128.5, 128.2, 127.7, 126.3, 125.0, 124.3, 123.8,
52.3, 35.5, 31.1 ppm. HRMS (EI+) 319.1572 (cal. For
C21H21NO2 319.1572).
dimethyl 2-phenylquinoline-3,4-dicarboxylate (3l), a kelly
1
viscous liquid, 78% yield. H NMR (500 MHz, CDCl3): δ = 8.21
(d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.81 (t, J = 7.6 Hz,

5
1H), 7.68 (d, J = 7.0 Hz, 2H), 7.63 (t, J = 7.6 Hz, 1H), 7.51 - 7.43
ACCEPTED MANUSCRIPT
(m, 3H), 4.04 (s, 3H), 3.70 (s, 3H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 167.5, 166.1, 156.2, 147.9, 139.4, 138.7, 131.0,
129.6, 128.6, 128.0, 128.0, 127.8, 126.9, 124.9, 122.6, 52.7, 52.3
ppm. HRMS (EI+) 321.1001 (cal. For C19H15NO4 321.1006).
2,4-diphenylquinoline (3m), a pale yellow viscous liquid, 84%
yield. 1H NMR (300 MHz, CDCl3): δ = 8.44 (d, J = 8.4 Hz, 1H),
8.35 (d, J = 8.1 Hz, 2H), 7.99 (d, J = 8.3 Hz, 1H), 7.90 (s, 1H),
7.78 (t, J = 7.6 Hz, 1H), 7.63 - 7.45 (m, 9H) ppm. 13C NMR (100
MHz, CDCl3): δ = 156.3, 148.7, 148.5, 139.2, 138.0, 129.8,
129.2, 129.1, 129.0, 128.5, 128.2, 128.0, 127.2, 126.0, 125.4,
125.2, 118.9 ppm. HRMS (EI+) 281.1204 (cal. For C21H15N
281.1204).
Supplementary data
Experimental procedures, characterization data, and copies
of the 1H NMR and 13C NMR spectra for the products are
available.
References and notes
1. Nakamura, I., Yamamoto, Y. Chem. Rev. 2004, 104, 2127-2198.
2.
(a) Bolm, C., Legros, J., Paih, J. L., Zani, L. Chem. Rev. 2004,
104, 6217-6254; (b) Sun, C. L., Li, B. J., Shi, Z. J. Chem. Rev.
2011, 111, 1293-1314.
3. Moller, K., Wienhofer, G., Schroder, K., Join, B., Junge, K.,
Beller, M. Chem. Eur. J. 2010, 16, 10300-10303.
4. Ohara, H., Itoh, T., Nakamura, M., Nakamura, E. Chem. Lett.
2001, 30 (7), 624-625.
5. Norinder, J., Matsumoto, A., Yoshikai, N., Nakamura, E. J. Am.
Chem. Soc. 2008, 130, 5858-5859.
6. The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard,
R., Eds., Academic Press: San Diego, CA, 2000.
7. Li, R. S., Wang, S. R., Lu, W. J. Org. Lett. 2007, 9 (11), 2219-
2222.
8. (a) Leardini R., Nanni D., Tundo A., Zanardi G., Ruggieri F. J.
Org. Chem. 1992, 57(6), 1842-1848; (b) Cao, K., Zhang, F. M.,
Tu, Y. Q., Zhuo, X. T., Fan, C. A. Chem. Eur. J. 2009, 15, 6332-
6334.
9. Jones, W. D., Foster, G. P., Putinas, J. M. J. Am. Chem. Soc. 1987,
109, 5047-5048.
10. (a) Atwell, G. J., Baguley, B. C., Denny, W. A. J. Med. Chem.
1989, 32, 396-401; (b) Lord, A. M., Mahon, M. F., Lloyd, M. D.,
Threadgill, M. D. J. Med. Chem. 2009, 52, 868-877; (c) Dube, D.,
Blouin, M., Brideau, C., Chan, C. -C., Desmarais, S., Ethier, D.,
Falgueyret, J. -P., Friesen, R. W., Girard, M., Girard, Y., Guay, J.,
Riendeau, D., Tagari, P., Young, R. N. Bioorg. Med. Chem. Lett.
1998, 8, 1255-1260; (d) El-Gazzar, A. B. A., Hafez, H. N.,
Nawwar, G. A. M. Eur. J. Med. Chem. 2009, 44, 1427-1436.
11. Li, Y. F., Shi, J., Wu, Z. G., Wang, X. L., Wu, X. W., Gu, J. C.,
Bu, H. Z., Ma, H. F. Tetrahedron, 2014, 70, 2472-2477.
12. Malkov, A. V., Vrankova, K., Stoncius, S., Kocovsky, P. J. Org.
Chem. 2009, 74, 5839-5849.
13. (a) Reetz, M. T., Sommer, K. Eur. J. Org. Chem. 2003, 3485-3496;
(b) Tsuchimoto, T., Maeda, T., Shirakawaa, E., Kawakami, Y.
Chem. Commun. 2000, 1573-1574; (c) Ji, X. C., Huang, H. W., Li,
Y. B., Chen, H. J., Jiang, H. F. Angew. Chem. Int. Ed. 2012, 51,
7292-7296; (d) Liu, P., Li, Y. X., Wang, H. Y., Wang, Z. M. Hu,
X. M. Tetrahedron. Lett. 2012, 53, 6654-6656.

ACCEPTED MANUSCRIPT
FeCl3-Promoted Formation of C-C Bonds: Synthesis of Substituted
Quinolines from Imines and Electron-deficient Alkynes
Yu-feng Li, a, Zheng-guang Wu, a Jie Shi, a Yi Pan, b, Hong-zhong Bu, a Hong-fei
Ma, a Jia-chao Gu, a Hao Huang a Yao-zhu Wang, a Lin Wu a
a College of Sciences, Nanjing University of Technology, Nanjing 211816, PR China
b School of Chemistry and Chemical Engineering, Nanjing University, 210093, PR
China
Supporting Information
Table of Contents
1. General procedures.................................................................................................
2
2. Spectral data of the compounds...................................................................................3
3. 1H NMR and 13C NMR spectra of the compounds......................................................7
4. X-ray crystal structure for compound 3e......................................................................20
Corresponding author. Tel.: +0-086-025-58139483; fax: +0-086-025-58139483; e-mail: yufengli@njut.edu.cn
Corresponding author. Tel.: +0-086-025-58139483; fax: +0-086-025-58139483; e-mail: yufengli@njut.edu.cn
1

ACCEPTED MANUSCRIPT
General procedures for the synthesis of quinoline 3:
Procedure A: synthesizing 3 from imine and alkyne
To a mixture of imine 1 (5.0 mmol), alkyne (2, 5.0 mmol) in DCE (25 mL) was added FeCl3 (0.5
mmol). With blowing air slowly in, the mixture was heated at 80 °C till the reaction completed. After
cooled to room temperature, the mixture was filtered and the filtrate was evaporated in vacuo. The
residue was purified by flash chromatography on silica gel to give desired 3.
Procedure B: synthesizing 3 from aromatic amine, aromatic aldehyde and alkyne in a sequential
three-component manner
A mixture of aromatic amine (5.0 mmol), aromatic aldehyde (5.0 mmol) in DCE (25 mL) was
refluxed for about 8 h. Alkyne (2, 5.0 mmol) and FeCl3 (0.5 mmol) were added, and the mixture was
further treated as Procedure A giving 3.
2

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methyl 2-phenylquinoline-3-carboxylate (3a): a yellow viscous liquid, 1H NMR (400 MHz, CDCl3):
δ = 8.65 (s, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.93 - 7.89 (m, 1H), 7.81 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.66
- 7.62 (m, 2H), 7.59 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 7.50 - 7.43 (m, 3H), 3.74 (s, 3H) ppm. 13C NMR
(101 MHz, CDCl3): δ =168.4, 158.1, 148.5, 140.6, 139.2, 131.6, 129.6, 128.7, 128.6, 128.2, 127.3,
125.8, 125.1, 52.4 ppm. HRMS (EI+) 263.0946 (cal. For C17H13NO2 263.0940).
methyl 6-methyl-2-phenylquinoline-3-carboxylate (3b): a maize-yellow solid, mp: 69.0 - 72.3 °C. 1H
NMR (400 MHz, CDCl3): δ = 8.51 (s, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.64 - 7.61 (m, 2H), 7.58 (d, J =
7.2 Hz, 2H), 7.47 - 7.40 (m, 3H), 3.70 (s, 3H), 2.49 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ =
168.5, 157.1, 147.1, 140.7, 138.5, 137.3, 134.0, 129.2, 128.6, 128.5, 128.2, 127.0, 125.8, 125.0, 52.4,
21.6 ppm. HRMS (EI+) 277.1103 (cal. For C18H15NO2 277.1105).
methyl 6-methoxy-2-phenylquinoline-3-carboxylate (3c): a deep yellow solid, mp: 102.3 - 104.4 °C.
1H NMR (400 MHz, CDCl3): δ = 8.53 (s, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.63 - 7.59 (m, 2H), 7.49 - 7.42
(m, 4H), 7.15 (d, J = 2.8 Hz, 1H), 3.95 (s, 3H), 3.73 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ =
168.6, 158.3, 155.6, 144.7, 140.7, 137.8, 131.0, 128.5, 128.4, 128.2, 126.9, 125.3, 124.5, 105.3, 55.7,
52.4 ppm. HRMS (EI+) 293.1052 (cal. For C18H15NO3 293.1053).
methyl 7-(tert-butyl)-2-phenylquinoline-3-carboxylate (3d): a yellow solid, mp: 100.1 - 103.4 °C.
1H NMR (400 MHz, CDCl3): δ = 8.63 (s, 1H), 8.18 - 8.14 (m, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.69 (dd, J
= 8.6, 1.9 Hz, 1H), 7.62 (dt, J = 8.3, 2.1 Hz, 2H), 7.50 - 7.42 (m, 3H), 3.73 (s, 3H), 1.44 (s, 9H) ppm.
13C NMR (101 MHz, CDCl3): δ = 168.4, 158.2, 155.4, 148.7, 140.9, 138.8, 128.5, 128.5, 128.2, 127.7,
3

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126.3, 125.0, 124.3, 123.8, 52.3, 35.5, 31.1 ppm. HRMS (EI+) 319.1572 (cal. For C21H21NO2
319.1572).
methyl 6-chloro-2-phenylquinoline-3-carboxylate (3e): a pale yellow solid, mp: 91.1 - 95.0 °C. 1H
NMR (400 MHz, CDCl3): δ = 8.52 (s, 1H), 8.10 (d, J = 9.0 Hz, 1H), 7.86 (d, J = 2.2 Hz, 1H), 7.72 (dd,
J = 9.0, 2.3 Hz, 1H), 7.65 - 7.60 (m, 2H), 7.50 - 7.44 (m, 3H), 3.74 (s, 3H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 168.1, 158.2, 146.8, 140.1, 138.1, 133.0, 132.5, 131.2, 128.9, 128.6, 128.3, 126.7, 126.4,
126.0, 52.6 ppm. HRMS (EI+) 297.0557 (cal. For C17H12ClNO2 297.0555).
1
methyl 6-fluoro-2-phenylquinoline-3-carboxylate (3f): a pale yellow solid, mp: 91.0 - 94.2 °C. H
NMR (400 MHz, CDCl3): δ = 8.57 (s, 1H), 8.18 (dd, J = 9.2, 5.2 Hz, 1H), 7.63 (dd, J = 7.8, 1.6 Hz,
2H), 7.59 - 7.54 (m, 1H), 7.52 (dd, J = 8.5, 2.8 Hz, 1H), 7.49 - 7.44 (m, 3H), 3.74 (s, 3H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 168.2, 159.6, 157.3, 145.6, 140.2, 138.3, 132.2, 128.8, 128.5, 128.3,
126.5, 125.9, 122.0, 121.7, 111.0, 52.5 ppm. HRMS (EI+) 281.0852 (cal. For C17H12FNO2 281.0850).
1
methyl 2-(p-tolyl)quinoline-3-carboxylate (3g): a deep yellow solid, mp: 90.2 - 95.0 °C. H NMR
(400 MHz, CDCl3): δ = 8.54 (s, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.72 (t, J = 7.3
Hz, 1H), 7.51 - 7.45 (m, 3H), 7.20 (d, J = 7.8 Hz, 2H), 3.69 (s, 3H), 2.34 (s, 3H) ppm. 13C NMR (101
MHz, CDCl3): δ = 168.6, 158.0, 148.5, 139.1, 138.6, 137.7, 131.5, 129.6, 128.9, 128.5, 128.2, 127.1,
125.7, 125.1, 52.4, 21.4 ppm. HRMS (EI+) 277.1103 (cal. For C18H15NO2 277.1105).
1
methyl 2-(4-methoxyphenyl)quinoline-3-carboxylate (3h): a yellow solid, mp: 92.1 - 95.7 °C. H
NMR (400 MHz, CDCl3): δ = 8.58 (s, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.80 -
4

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7.75 (m, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.00 (d, J = 8.7 Hz, 2H), 3.85 (s, 3H),
3.77 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ = 168.7, 160.3, 157.4, 148.5, 139.1, 132.9, 131.5,
130.1, 129.4, 128.2, 127.0, 125.6, 125.0, 113.8, 55.3, 52.5 ppm. HRMS (EI+) 293.1052 (cal. For
C18H15NO3 293.1050).
methyl 2-(4-chlorophenyl)quinoline-3-carboxylate (3i): a maize-yellow solid, mp: 111.2 - 114.4 °C.
1H NMR (400 MHz, CDCl3): δ = 8.67 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.85 -
7.79 (m, 1H), 7.63 - 7.56 (m, 3H), 7.46 - 7.43 (m, 2H), 3.77 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 168.0, 156.9, 148.5, 139.6, 139.1, 134.9, 131.9, 130.0, 129.5, 128.4, 128.3, 127.5, 125.9, 124.6,
52.5 ppm. HRMS (EI+) 297.0557 (cal. For C17H12ClNO2 297.0556).
methyl 2-(4-methoxyphenyl)-6-methylquinoline-3-carboxylate (3j): a yellowish-brown solid, mp:
85.2 - 91.4 °C. 1H NMR (400 MHz, CDCl3): δ = 8.43 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.58 - 7.50 (m,
4H), 6.92 (d, J = 8.6 Hz, 2H), 3.79 (s, 3H), 3.70 (s, 3H), 2.48 (s, 3H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 168.9, 160.1, 156.6, 147.1, 138.4, 137.0, 133.9, 133.1, 130.0, 129.1, 126.9, 125.7, 125.0,
113.7, 55.3, 52.4, 21.6 ppm. HRMS (EI+) 307.1208 (cal. For C19H17NO3 307.1204).
1
ethyl 2-phenylquinoline-3-carboxylate (3k): a pale yellow viscous liquid. H NMR (300 MHz,
CDCl3): δ = 8.65 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.80 (t, J = 7.7 Hz, 1H),
7.68 - 7.62 (m, 2H), 7.58 (t, J = 7.5 Hz, 1H), 7.51 - 7.43 (m, 3H), 4.25 - 4.15 (m, 2H), 1.08 (td, J = 7.1,
1.6 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.8, 158.0, 148.3, 140.7, 138.9, 131.4, 129.4,
128.5, 128.4, 128.1, 128.0, 127.1, 125.7, 125.4, 61.4, 13.6 ppm. HRMS (EI+) 277.1103 (cal. For
C18H15NO2 277.1100).
5

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1
dimethyl 2-phenylquinoline-3,4-dicarboxylate (3l): a kelly viscous liquid. H NMR (500 MHz,
CDCl3): δ = 8.21 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.68 (d, J = 7.0
Hz, 2H), 7.63 (t, J = 7.6 Hz, 1H), 7.51 - 7.43 (m, 3H), 4.04 (s, 3H), 3.70 (s, 3H) ppm. 13C NMR (126
MHz, CDCl3): δ = 167.5, 166.1, 156.2, 147.9, 139.4, 138.7, 131.0, 129.6, 128.6, 128.0, 128.0, 127.8,
126.9, 124.9, 122.6, 52.7, 52.3 ppm. HRMS (EI+) 321.1001 (cal. For C19H15NO4 321.1006).
N
3m
2,4-diphenylquinoline (3m): a pale yellow viscous liquid. 1H NMR (300 MHz, CDCl3): δ = 8.44 (d, J
= 8.4 Hz, 1H), 8.35 (d, J = 8.1 Hz, 2H), 7.99 (d, J = 8.3 Hz, 1H), 7.90 (s, 1H), 7.78 (t, J = 7.6 Hz, 1H),
7.63 - 7.45 (m, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ = 156.3, 148.7, 148.5, 139.2, 138.0, 129.8,
129.2, 129.1, 129.0, 128.5, 128.2, 128.0, 127.2, 126.0, 125.4, 125.2, 118.9 ppm. HRMS (EI+) 281.1204
(cal. For C21H15N 281.1204).
6

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3a
3a
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N
COOMe
3b
N
COOMe
3b
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N
MeO
COOMe
3c
N
MeO
COOMe
3c
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3d
3d
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3e
3e
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3f
3f
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3g
3g
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3h
3h
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3i
3i
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3j
3j
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3k
3k
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3l
3l
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3m
3m
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X-ray crystal structure for compound 3e
20