Copper-catalyzed synthesis of substituted quinolines via C-N coupling/condensation from ortho -acylanilines and alkenyl iodides

Article abstract of DOI:10.1021/jo502630t

An efficient cascade copper-catalyzed intermolecular Ullmann-type C-N coupling/enamine condensation reaction is described, in which ortho-acylanilines and alkenyl iodides converted to multisubstituted quinolines in good to excellent yields.

Full text of DOI:10.1021/jo502630t

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Note
Copper-Catalyzed Synthesis of Substituted Quinolines via C-N
Coupling/Condensation from ortho-Acylanilines and Alkenyl Iodides
Lingkai Kong, Yuanyuan Zhou, He Huang, Yang Yang, Yuanyuan Liu, and Yanzhong Li
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 15 Dec 2014
Downloaded from http://pubs.acs.org on December 16, 2014
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The Journal of Organic Chemistry
Copper-Catalyzed Synthesis of Substituted Quinolines via C-N
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Coupling/Condensation from ortho-Acylanilines and Alkenyl Iodides
Lingkai Kong, Yuanyuan Zhou, He Huang, Yang Yang, Yuanyuan Liu*, Yanzhong Li*
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Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East
China Normal University, 500 Dongchuan Road, Shanghai, 200241, China
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Fax: (+86) 021-54340096, E-mail: yyliu@chem.ecnu.edu.cn; yzli@chem.ecnu.edu.cn
Abstract. An efficient cascade copper-catalyzed intermolecular Ullmann-type C-N coupling/enamine
condensation reaction is described, in which ortho-acylanilines and alkenyl iodides converted to multi-
substituted quinolines in good to excellent yields.
1
Quinolines are widely found in natural products and broadly used in medicinal chemistry
2
particularly as antiviral, anticancer, antituberculosis, and antimalarial agents. Furthermore, quinolines
3
as building blocks were applied to prepare functional materials with enhanced physical properties. The
traditional methods for constructing quinolines include the Combes synthesis from anilines and 1,3-
diketones, the Skraup synthesis from anilines and glycerins, and the Friedlander (Pfitzinger,
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Niementowski) synthesis from ortho-acylanilines and
α
-methylene aldehydes/ketones. In recent years,
new approaches based on transition-metal-catalyzed C-N/C-C bond formation attracted much attention
5
due to mild reaction conditions and expanded substrate scope. Among them, ortho-substituted anilines
as important starting materials has a special position in the synthesis of quinolines. In 2006, A novel
cascade reaction of nickel-catalyzed Michael addition/deiodination was developed by Korivi group
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5
j
(
Scheme 1, a). In 2008, Weingarten and coworkers reported a two-step method from ortho-amino
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arylboronic acids via rhodium-catalyzed conjugate addition and direct palladium-catalyzed borylation
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g
(Scheme 1, b). In the same year, a useful cascade synthesis of substituted 3-quinolinecarboxylic esters
5h
via iron-catalyzed benzylation/cyclization was achieved by Wang group (Scheme 1, c). During the
course of our ongoing study on the development of transition-metal-mediated heterocycle-forming
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protocols, we have reported two methods for yielding 2,4- and 3,4-substituted quinolines from ortho-
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acylanilines and alkynones or alkynes catalyzed by Fe or Ag, respectively (Scheme 1, d-e).
Scheme 1. Metal-Catalyzed Synthesis of Quinolines from ortho-Substituted Anilines
Regarding the economy and easy-handle-system of copper-catalyzed C-N coupling, important
breakthroughs with the discovery of versatile and very efficient new copper/ligand systems have led to a
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spectacular resurgence of interest in Ullmann-type reactions in the last decade. More recently, ligand-
assisted copper catalyzed modern versions of the Ullmann-Goldberg reactions between vinyl halides
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and amides have been developed. However, few reports focused on N-vinylation of amines, especially
1
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in which ortho-substituted anilines as substrate only gave moderate yield. The difficulties might be
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caused by the bulky groups around the reactive site and unstable enamine products. We envisioned that
if anilines bearing an ortho-substituted electrophilic group were employed, it might capture the reactive
enamine formed through the C-N coupling reaction to undergo further intramolecular cyclization
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(Scheme 2). Herein, we reported a cascade copper-catalyzed intermolecular Ullmann-type C-N
coupling/enamine condensation reaction for the synthesis of substituted quinolines starting from ortho-
acylanilines and alkenyl iodides. This is the first report of Ullmann coupling reactions using sterically
hindered aniline derivatives and vinyl halides as substrates to prepare quinoline derivatives, to the best
of our knowledge.
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Scheme 2. Synthesis of Quinolines via C-N Coupling/Condensation from ortho-Acylanilines
The reaction of 2-aminobenzaldehyde (1a) with 2 equiv of (E)-1-(2-iodovinyl)benzene (2a) was
screened to optimize reaction conditions, and the results are summarized in Table 1. Initially, our
investigation began with an attempt of 1a, using 10 mol % of CuI as catalyst, 20 mol % N,N'-
o
dimethylethylenediamine (DMEDA) as ligand and 2.0 equiv of K CO as base in DMF at 130 C under
2
3
N atmosphere (entry 1). The desired quinoline derivative 3a could be isolated in 72% yield within 6 h.
2
This result encouraged us to examine various common ligands, such as N,N,N',N'-
tetramethylethylenediamine (TMEDA), N,N'-dimethyl-1,2-cyclohexanediamine (DMCHDA), 1,10-
phenanthroline, 2,2’-dipyridyl, DL-proline, and glycine, and the target product 3a was obtained in 35%-
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1% yields (entries 2-7). To our delight, the glycine which is commercially available has the highest
activity for this reaction (91% yield, entry 7). Then the reaction conditions were further investigated,
o
and the results showed that 10 h reaction time-span, 130 C reaction temperature and nitrogen
atmosphere were essential for this catalytic system (entries 7-10). The excellent yield (95%) of 3a could
be achieved under these reaction conditions while only 36% yield under ambient air (entry 8 vs 10).
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Finally, the effect of base were evaluated, and the further studies showed that other bases like Na CO
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and BuOK were less effective affording 43% and 35% yield, respectively (entries 11 and 12).
a
Table 1. Optimization of Reaction Conditions
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With the standard reaction conditions (Table 1, entry 8), the substrate scope of the reaction by
employing a variety of ortho-acylanilines 1 and alkenyl iodides 2 was explored. Firstly, the screening of
different structures of alkenyl iodides 2 with 2-aminobenzaldehyde 1a was summarized in Table 2,
entries 1-7. For aryl alkenyl iodides 2a-2d, the substrates with electron-donating substituents on the
benzene ring offered higher yields (88% and 92%) compared with those with electron-withdrawing
substituents on the benzene ring (69%) (entries 2 and 3 vs 4). For alkyl alkenyl iodides 2e and 2f, the
reaction also proceeded well, and 3e and 3f were obtained in 72% and 78% yields, respectively (entries
o
5
and 6). Remarkably, raising the temperature to 160 C in DMA, the heterocyclic iodides 2g gave
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a
Table 2. Synthesis of Various Quinoline 3
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entry
1
substrate
vinyliodo
product
time (h) yield (%) b
Ph
CHO
I
10
95
Ph
2a
N
NH2
3a
Me
OMe
Cl
1a
I
2
3
1a
10
88
92
Me
10
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2b
N
3b
I
1a
15
MeO
2c
N
3c
I
4
5
1a
1a
20
25
69
78
Cl
2d
N
3d
Bu
I
Bu
2e
N
3e
Pr
Pr
I
Pr
6
1a
1a
25
20
72
57
Pr
I
N
3f
2f
7c
S
S
N
2g
3g
MeO
Br
CHO
NH2
MeO
Br
Ph
8
2a
20
78
N
1b
3h
3i
CHO
Ph
9
2a
15
12
84
83
NH2
N
1c
O
Me
Ph
10
Me
2a
NH2
N
j
1d
3
O
Ph
Ph
1
1
Ph
2a
15
93
NH2
N
k
1e
3
a
Unless otherwise noted, all reactions were carried out under N atmosphere in 0.5 mmol scale
2
b
c
o
with the ratio of 1a:2a = 1:2. Isolated yield. The reaction carried out at 160 C in DMA.
moderate yield (57%) of desired product 3g (entry 7). Secondly, the different substituted ortho-
acylanilines 1b-1e were examined in this catalytic system, resulting in 78%-93% yields of the desired
quinolines (entries 8-11). Furthermore, 3,4-substituted quinolines 3j and 3k could be smoothly accessed
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under the exact same conditions using ortho-aminophenyl ketones 1d and 1e as substrate in high yields
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(83% and 93%), of which the synthetic methods are not very sufficient (entries 10 and 11).
Scheme 3. A Proposed Mechanism
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On the basis of the reported work, a plausible mechanism is proposed with model substrates 1a
and 2a as outlined in Scheme 3. The process began with the ligand exchange with 2-aminobenzaldehyde
1a affords copper-coordinated intermediate A in the presence of K CO . Then, alkenyl iodide 2a reacts
2
3
with intermediate A through oxidative addition, furnishing the intermediate C after reductive
elimination. Intramolecular cyclization of the ß-carbon of enamine C to acyl group forms intermediate
D, which further undergoes aromatization to give the desired quinoline 3a.
In conclusion, we have developed an efficient procedure of the cascade copper-catalyzed C-N
coupling/cyclization reaction to construct various substituted quinoline derivatives. This catalytic
system, which sterically hindered anilines and vinyl iodides were used in Ullmann coupling reactions,
gave a variety of 3- or 3,4-substituted quinolines in good to excellent yields.
Experimental Section
High-resolution mass spectra were performed on a mass spectrometer with a TOF (for EI or ESI) or FT-
ICR (for MALDI) analyzer.
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Typical Procedure. To a solution of ortho-acylaniline 1 (0.5 mmol) in DMF (2.0 mL) was added
alkenyl iodide 2 (1.0 mmol), copper(I) iodide (9.5 mg, 0.05 mmol), glycine (7.5 mg, 0.1 mmol) and
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K CO (138.2 mg, 1.0 mmol) at room temperature. Then the mixture was slowly warmed up to 130 C
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and stirred for corresponding time. After that the mixture was quenched with deionized water, extracted
with ethyl acetate, washed with brine and dried over anhydrous Na SO . The solvent was evaporated
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and the residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to
afford product 3.
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3
ꢀPhenylquinoline (3a): Yellow oil, 95% yield (98 mg). H NMR (400 MHz, CDCl ) δ7.42-7.59 (m,
3
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H), 7.70-7.74 (m, 3H), 7.87 (d, J = 7.6 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 9.20
1
3
(d, J = 1.6 Hz, 1H); C NMR (100 MHz, CDCl ) δ 127.0, 127.4, 128.0, 128.1 (2C), 129.2, 129.2, 129.4,
3
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33.2, 133.8, 137.9, 147.4, 150.0.
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ꢀ(pꢀTolyl)quinoline (3b): Light yellow solid, 88% yield (96 mg), mp 81-82 C. H NMR (400 MHz,
CDCl ) δ 2.44 (s, 3H), 7.34 (d, J = 7.6 Hz, 2H), 7.57 (t, J = 7.6 Hz, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.71 (t,
3
J = 7.2 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 9.18 (d, J =
1
3
2
1
.0 Hz, 1H); C NMR (100 MHz, CDCl ) δ 21.1, 127.0, 127.3, 128.0, 128.1, 129.3 (2C), 130.0, 132.9,
3
33.8, 135.0, 138.1, 147.3, 150.0.
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3
ꢀ(4ꢀMethoxyphenyl)quinoline (3c): Light yellow solid, 92% yield (108 mg), mp 80-81 C. H NMR
(400 MHz, CDCl ) δ 3.85 (s, 3H), 7.01-7.06 (m, 2H), 7.53-7.56 (m, 1H), 7.61-7.70 (m, 3H), 7.82 (t, J =
3
1
3
7
.2 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 5.6 Hz, 1H), 9.15 (s, 1H); C NMR (100 MHz,
CDCl ) δ 55.3, 114.6, 126.9, 127.8, 128.1, 128.5, 129.0, 129.2, 130.2, 132.3, 133.4, 147.0, 149.8, 159.8.
3
1
3
o
1
3ꢀ(4ꢀChlorophenyl)quinoline (3d): Light yellow solid, 69% yield (82 mg), mp 149-150 C. H NMR
(
400 MHz, CDCl ) δ7.45 (d, J = 8.0 Hz, 2H), 7.53-7.60 (m, 3H), 7.71 (t, J = 8.0 Hz, 1H), 7.83 (d, J =
3
13
8
.0 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H), 8.21 (s, 1H), 9.11 (s, 1H); C NMR (100 MHz, CDCl ) δ 127.1,
3
1
27.8, 128.0, 128.6, 129.2, 129.3, 129.6, 132.5, 133.1, 134.3, 136.2, 147.4, 149.4.
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1
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ꢀButylquinoline (3e): Light yellow oil, 78% yield (72 mg). H NMR (400 MHz, CDCl ) δ 0.93 (t, J
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
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2
2
2
2
2
2
2
2
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=
7.6 Hz, 3H), 1.34-1.40 (m, 2H), 1.62-1.68 (m, 2H), 2.74 (t, J = 7.6 Hz, 2H), 7.47 (t, J = 7.2 Hz, 1H),
7.61 (t, J = 7.2 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 8.06 (d, J = 8.6 Hz, 1H), 8.76 (d, J = 1.6
13
Hz, 1H); C NMR (100 MHz, CDCl ) δ 13.7, 22.0, 32.7, 33.0, 126.4, 127.2, 128.1, 128.4, 129.1, 134.0,
3
1
35.3, 146.7, 152.1.
,3ꢀDipropylquinoline (3f): Light yellow oil, 72% yield (76 mg). H NMR (400 MHz, CDCl ) δ 0.98-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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0
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9
0
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2
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2
3
1
.09 (m, 6H), 1.66-1.76 (m, 2H), 1.79-1.89 (m, 2H), 2.75 (t, J = 8.0 Hz, 2H), 2.95 (t, J = 8.0 Hz, 2H),
7.42 (t, J = 7.2 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.81(s, 1H), 8.02 (d, J = 8.4
13
Hz, 1H); C NMR (100 MHz, CDCl ) δ 13.9, 14.2, 22.8, 23.4, 34.3, 37.7, 125.5, 126.9, 127.2, 128.3,
3
+
1
28.5, 133.9, 134.8, 146.5, 162.1. HRMS (EI) for C H N [M ] calcd 213.1517, found 213.1521.
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1
5
1
Thieno[2,3ꢀb]quinoline (3g): Light yellow oil, 57% yield (52 mg). H NMR (400 MHz, CDCl ) δ
3
7
.34 (d, J = 6.0 Hz, 1H), 7.52-7.58 (m, 2H), 7.72-7.77 (m, 1H), 7.95 (d, J = 8.0 Hz, 1H), 8.15-8.18 (m,
1
3
1
H), 8.52 (s, 1H); C NMR (100 MHz, CDCl ) δ 121.2, 125.5, 125.6, 128.3, 128.4, 128.5, 129.3, 130.1,
3
131.5, 146.7, 163.4.
ꢀMethoxyꢀ3ꢀphenylquinoline (3h): Light yellow solid, 78% yield (92 mg). H NMR (400 MHz,
CDCl ) δ 3.96 (s, 3H), 7.14 (d, J = 2.4 Hz, 1H), 7.38 (dd, J = 2.4, 9.2 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H),
13
1
6
3
7
.53 (t, J = 7.6 Hz, 2H), 7.71 (d, J = 7.6 Hz, 2H), 8.03 (d, J = 9.2 Hz, 1H), 8.21 (s, 1 H), 9.03 (d, J = 1.6
13
Hz, 1H); C NMR (100 MHz, CDCl ) δ 55.5, 105.3, 122.3, 127.5, 128.1, 129.2, 129.2, 130.7, 132.2,
3
134.2, 138.1, 143.6, 147.5, 158.2.
1
3
o
1
6
ꢀBromoꢀ3ꢀphenylquinoline (3i): Light yellow solid, 84% yield (119 mg), mp 114-115 C. H NMR
(400 MHz, CDCl ) δ 7.45 (t, J = 7.6 Hz, 1H), 7.53 (t, J = 8.0 Hz, 2H), 7.68-7.70 (m, 2H), 7.70 (dd, J =
3
13
2.0, 8.8 Hz, 1H), 7.98-8.02 (m, 2H), 8.18 (d, J = 2.4 Hz, 1H), 9.17 (d, J = 2.0 Hz, 1H); C NMR (100
MHz, CDCl ) δ 120.9, 127.5, 128.5, 129.2, 129.3, 130.0, 131.0, 132.1, 132.8, 134.7, 137.4, 145.9, 150.4.
3
o
1
4
ꢀMethylꢀ3ꢀphenylquinoline (3j): Light yellow solid, 83% yield (90 mg), mp 58-61 C. H NMR (400
MHz, CDCl ) δ 2.50 (s, 3H), 7.25-7.38 (m, 5H), 7.46 (t, J = 7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.93
3
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1
3
(
d, J = 8.4 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 8.70 (s, 1H); C NMR (100 MHz, CDCl ) δ 15.4, 124.1,
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
26.6, 127.5, 127.9, 128.4, 128.8, 129.9, 129.9, 134.3, 138.5, 140.5, 146.9, 151.5. HRMS (ESI) for
+
C H N [M+H ] calcd 220.1126, found 220.1123.
16
14
16
1
3
,4ꢀDiphenylquinoline (3k): Light yellow solid, 93% yield (130 mg). H NMR (400 MHz, CDCl ) δ
3
7
1
1
.17-7.24 (m, 7H), 7.33-7.35 (m, 3H), 7.47 (t, J = 7.6 Hz, 1H), 7.69-7.73 (m, 2H), 8.20 (d, J = 8.0 Hz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
H), 9.01 (s, 1H); C NMR (100 MHz, CDCl ) δ 126.6, 126.9, 127.1, 127.2, 127.7, 128.1, 128.2, 129.1,
3
29.5, 130.2, 130.5, 133.1, 136.3 138.1, 145.5, 147.6 151.9.
Supporting Information Available. NMR spectra for all products. This material is available free of
charge via the Internet at http://pubs.acs.org.
Author Information
Corresponding Authors
*
*
E-mail: yyliu@chem.ecnu.edu.cn.
E-mail: yzli@chem.ecnu.edu.cn.
Notes
The authors declare no competing financial interest.
Acknowledgements. We thank the National Natural Science Foundation of China (Grant No.
2
1272074) and Program for Changjiang Scholars and Innovative Research Team in University
(PCSIRT) for financial support.
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