Convergent synthesis of 2-aryl-substituted quinolines by gold-catalyzed cascade reaction

Article abstract of DOI:10.1248/cpb.c16-00193

Gold-catalyzed auto-tandem catalysis has been developed for synthesizing 2-aryl-substituted quinolines. The reaction of an aniline bearing an acetal moiety with an aryl alkyne proceeded via formal [4+2]-cycloaddition, which involved the addition of gold acetylide to an oxonium ion to give amino alkyne intermediate and sequential 6-endo-dig cyclization of amino alkyne intermediate by attacking of nitrogen to alkyne moiety activated by gold catalyst. The cationic gold catalyst promoted two different processes by enhancing the nucleophilicity and electrophilicity of alkyne. This convergent synthetic methodology enabled the synthesis of a variety of 2-aryl-substituted quinolines.

Full text of DOI:10.1248/cpb.c16-00193

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Chem. Pharm. Bull. 64, 824–829 (2016)
Vol. 64, No. 7
Special Collection of Papers
This article is dedicated to Professor Satoshi Ōmura in celebration of his 2015 Nobel Prize.
Regular Article
Convergent Synthesis of 2-Aryl-Substituted Quinolines
by Gold-Catalyzed Cascade Reaction
Hirofumi Ueda, Minami Yamaguchi, and Hidetoshi Tokuyama*
Graduate School of Pharmaceutical Sciences, Tohoku University;
6–3 Aoba, Aramaki, Aoba-ku, Sendai 980–8578, Japan.
Received February 26, 2016; accepted March 29, 2016
Gold-catalyzed auto-tandem catalysis has been developed for synthesizing 2-aryl-substituted quinolines.
The reaction of an aniline bearing an acetal moiety with an aryl alkyne proceeded via formal [4+2]-cycload-
dition, which involved the addition of gold acetylide to an oxonium ion to give amino alkyne intermediate
and sequential 6-endo-dig cyclization of amino alkyne intermediate by attacking of nitrogen to alkyne moi-
ety activated by gold catalyst. The cationic gold catalyst promoted two different processes by enhancing the
nucleophilicity and electrophilicity of alkyne. This convergent synthetic methodology enabled the synthesis of
a variety of 2-aryl-substituted quinolines.
Key words quinoline; gold catalysis; tandem reaction; heterocyclic compound; cyclization
A quinoline skeleton is often observed in biologically the gold catalyst would occur in a 6-endo-dig fashion and,
important natural products, for example; quinoline alkaloid following aromatization by removal of the protecting group,
quinine exhibits medicinally vital antimalarial activity.1–4) would afford quinoline derivative 8. On the contrary, the
Among quinoline compounds, 2-arylquinoline has recently 5-exo-dig cyclization of 11 would give indole derivative 9.
attracted attention from biologists due to its unique biological
At the outset, we examined the reaction of anilide 7a with
activity.5–7) Therefore, quinoline compounds have inspired the a benzoyl (Bz) group and 4-methoxyphenylacetylene 12a
development of new synthetic methods8,9) for the formation (Table 1). Treatment of 7a and 12a in the presence of 10mol%
of the N-heterocyclic scaffold due to their potential utility in PPh3AuCl and AgOTf (Tf, trifluoromethanesulfonyl) in tolu-
the pharmaceutical industry. As classical and conventional ene solution at 110°C gave a quinoline 8a in 7% yield without
synthetic methods, the Skraup,10) Doebner and von Miller,11) the formation of an indole derivative (entry 1). Replacement of
Combes,12) Friedländer,13) and Pfitzinger14) quinoline synthe- the Bz group with a benzyloxycarbonyl (Cbz) group improved
ses are well known; however, these methods often encounter the yield of 8a to 20% (entry 2). Anilide 7c with a tosyl (Ts)
problems with functional group compatibility as they require group gave the desired quinoline 8a in 34% yield (entry 3). We
strong acidic or basic conditions. In recent decades, transi- then investigated the ligands of the gold catalyst. Using both
25)
tion metal-catalyzed syntheses of substituted quinolines with trialkylphosphine gold chloride/AgOTf and PPh3AuNTf2
a highly convergent manner using an alkyne have also been slightly reduced the yield of 8a (entries 4, 5). Next, a series of
developed.15–22) These reactions proceed under relatively mild catalysts26,27) with bulky biphenyl moieties (entries 6, 7) and
conditions and enable the synthesis of various multi-substitut- an N-heterocyclic carbene gold catalyst IPrAuCl28) (entry 8)
ed quinolines.
were examined; however, these produced no improvement in
Recently, we developed a novel gold-catalyzed multi-substi- the yield of 8a. It was found that independently using AgOTf
tuted pyrrole synthesis.23,24) This reaction is highly versatile, or PPh3AuCl substantially prolonged the reaction time (entries
involving the assembly of two acyclic substrates 1 and 2 with 9, 10). Finally, we conducted the reaction using CuI based on
substituents installed beforehand. In addition, a cascade pro- the known quinoline synthesis,19) but the desired quinoline 8a
cess involving gold-mediated auto-tandem catalysis increases was obtained in only trace amounts (entry 11).
the efficiency and convergence of the reaction. On the basis of
To improve the yield, we investigated reaction conditions of
the advantages of this reaction, we applied this gold-catalyzed 7c and 12a with various additives (Table 2). As described in
cascade reaction to syntheses of other N-heterocyclic com- our previous paper,29) we initially added KHSO4 as a proton
pounds. Considering the above information, we envisioned source to promote the catalytic cycle by accelerating protode-
that the corresponding reaction of aniline 7 bearing an acetal auration step (entry 1). Although the yield of quinoline 8a was
moiety at the ortho-position with alkyne 12 should furnish a increased, the decomposition of the acetal moiety of 7c was
quinoline 8 or an indole derivative 9. Thus, an intermolecular facilitated to provide the aldehyde 16 in 57% yield. Thus, we
addition of gold acetylide to the oxonium ion 10 should pro- envisaged that addition of MeOH would suppress the decom-
duce propargyl ether 11. Then, cyclization via intramolecular position of the acetal moiety by inducing an oxonium-acetal
nucleophilic addition of nitrogen to the alkyne activated by equilibrium. As expected, aldehyde generation was suppressed
*To whom correspondence should be addressed. e-mail: tokuyama@m.tohoku.ac.jp
© 2016 The Pharmaceutical Society of Japan

Vol. 64, No. 7 (2016)
Chem. Pharm. Bull.
825
Chart 1. Gold-Catalyzed Multi-substituted Pyrrole Synthesis
Chart 2. Working Hypothesis
by addition of MeOH; however, the yield of quinoline was The (3,4-dimethoxyphenyl)acetylene 12e also gave the desired
remained constant (entry 2). We thought this reason would be product 8e in good yield (entry 5). However, alkynes 12f and
attributed to consumption of alkyne 12a via gold-catalyzed g, which bear electron-withdrawing groups, showed lower
methanolysis. Increasing amount of alkyne 12a to 5eq im- reactivity and produced decreased yields of the correspond-
proved the yield of 8a to 49% yield (entry 3). After extensive ing quinoline 8f and g (entries 6, 7). Additionally, the reaction
optimizations, we established the optimal conditions using of 7c with 1-naphthyl alkyne 12h afforded the corresponding
sterically demanding alcohol, such as i-PrOH, with 2,6-di-t- quinoline 8h in moderate yield (entry 8).
butylpyridine (DTBP) to afford the target quinoline in 66%
In summary, we have developed a new methodology for the
yield (entry 6). Treatment of diisopropyl acetal 7d instead of synthesis of 2-aryl-substituted quinolines in a cascade manner,
dimethyl acetal 7c with optimal conditions led to a decreased which is promoted by auto-tandem gold catalysis. This reac-
yield of 8a to 45% (entry 7). Finally, when we conducted this tion has the advantages of versatility and convergence toward
reaction on sub-gram scale (1.55mmol), the reaction proceed- the synthesis of a variety of 2-arylquinolines, which have re-
ed smoothly to give the desired quinolone 8a in 62% yield cently attracted attention due to its unique biological activity.
(entry 8).
Having established the optimal conditions, we then focused
on the alkyne scope of the reaction (Table 2). Phenylacetylene
Experimental
Unless otherwise noted, all reactions were performed using
(12b) and substituted phenyl groups with a methyl and bromo oven-dried glassware, sealed with a rubber septum under
groups at their para position (12c, d) uneventfully gave the a slight positive pressure of argon. Anhydrous MeCN and
corresponding quinoline products in good yields (entries 2–4). dichloromethane were purchased from Kanto Chemical Co.,

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Chem. Pharm. Bull.
Vol. 64, No. 7 (2016)
Table 1. Screening of Catalyst for Quinoline Synthesis
Entry
R
Catalyst
Time (h)
Yield (%)
1
2
Bz
Cbz
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ph3PAuCl/AgOTf
Ph3PAuCl/AgOTf
Ph3PAuCl/AgOTf
Et3PAuCl/AgOTf
Ph3PAuNTf2
2
2
7
20
34
29
29
31
25
26
5
3
2
4
3
5
3
6
RuPhosAuCl/AgOTf
Cy-JohnPhosAuCl/AgOTf
IPrAuCl/AgOTf
Ph3PAuCl
1
7
1
8
1
9
28
15
13
10
11
AgOTf
26
trace
CuI
Table 2. Optimization of Gold-Catalyzed Quinoline Synthesis
Entry
R
X (equiv)
Additive
Time (h)
Yield (%)
1a)
2b)
3
Me
Me
Me
Me
Me
Me
i-Pr
Me
3
3
5
5
5
5
5
5
KHSO4 (15mol%)
MeOH (5 equiv)
2
2
2
2
3
7
4
7
39
38
49
50
44
66
45
62
MeOH (5 equiv)
4
MeOH (20 equiv)
5
MeOH (20 equiv) 2,6-di-t-butylpyridine (40mol%)
i-PrOH (20 equiv) 2,6-di-t-butylpyridine (40mol%)
i-PrOH (20 equiv) 2,6-di-t-butylpyridine (40mol%)
i-PrOH (20 equiv) 2,6-di-t-butylpyridine (40mol%)
6
7
8c)
a) Aldehyde 16 was obtained in 57% yield. b) Aldehyde 16 was obtained in 17% yield. c) The reaction on sub-gram scale (7c: 500mg).
1
Inc. Anhydrous i-PrOH, MeOH, toluene, pyridine, and Et3N a JNM-AL400 spectrometer. For H spectra, chemical shifts
were dried and distilled according to the standard protocols. were expressed in ppm downfield from internal tetramethyl-
Unless otherwise mentioned, materials were obtained from silane (δ 0) or relative internal CHCl3 (δ 7.26). For 13C spec-
commercial suppliers and used without further purification. tra, chemical shifts were expressed in ppm downfield from
Reactions and chromatographical fractions were monitored by relative internal CHCl3 (δ 77.0). J-Values were expressed in
TLC analysis with pre-coated silica gel plates 60F254 (Merck). hertz. Mass spectra were recorded on a Bruker micrOTOF
Flash column chromatography was carried out using Kanto spectrometer.
silica gel 60N (spherical, neutral, 40–50µm). Preparative TLC
2-(Dimethoxymethyl)aniline To a solution of 2-nitro-
was performed on pre-coated silica gel plates 60F254 (Merck). benzaldehyde (303mg, 2.00mmol) and trimethyl orthofor-
Gel permeation chromatography was carried out using a Japan mate (0.285mL, 2.60mmol) in MeOH (10mL) was added
Analytical Industry Co., Ltd., LC-9201. IR spectra were mea- p-TsOH·H2O (38.0mg, 0.200mmol). After stirring for an hour
sured on a Shimadzu FTIR-8300 spectrometer or a JASCO at 70°C, the reaction was quenched with saturated aqueous
FT/IR-4100 spectrometer. NMR spectra were measured on NaHCO3 and the resulting mixture was extracted with CH2Cl2

Vol. 64, No. 7 (2016)
Chem. Pharm. Bull.
827
Table 3. Scope of Alkynes
Entry
R
Time (h)
7
Yield (%)
66
1
8a
2
3
8b
8c
7
7
55
68
4
5
6
8d
8e
7
67
55
11
8f
8g
8h
7
11
7
31
35
39
7
8
three times. The combined organic extracts were washed with TLC on silica gel (hexanes:AcOEt=8:2) to afford benzamide
brine, dried over Na2SO4, and concentrated under reduced 7a (32.9mg, 0.121mmol, 63%) as a pale yellow oil; Rf=0.48
pressure to give the crude acetal. The residue was directly (Silica gel, hexanes:AcOEt=8:2); IR attenuated total reflec-
subjected to the next reaction without further purification. tance (ATR) 3367, 2936, 2830, 1678, 1592, 1533, 1452, 1310,
1
A mixture of crude acetal, 10% Pd/C (203mg, 0.197mmol), 1066, 759cm−1; H-NMR (400MHz, CD3CN, 70°C, a mixture
MeOH (2.0mL) and AcOEt (2.0mL) was stirred under a hy- of rotamers) δ: 9.61 (brs, 0.8H), 9.38 (brs, 0.2 H), 8.39 (d,
drogen atmosphere at room temperature for 3h. The reaction J=8.4Hz, 0.8H), 8.19 (d, J=8.4Hz, 0.2H), 7.95–7.85 (m, 2H),
mixture was filtered through a pad of Celite and concentrated 7.64–7.49 (m, 3H), 7.45–7.26 (m, 2H), 7.20–7.11 (m, 1H), 5.42
under reduced pressure. The residue was purified by flash (s, 1H), 3.42 (s, 6H); 13C-NMR (100MHz, CD3CN, 70°C, a
column chromatography on silica gel (hexanes:AcOEt=9:1) mixture of rotamers) δ: 161.1, 138.3, 136.7, 133.0, 130.6, 130.5,
to afford aniline (263mg, 1.58mmol, 79% over 2 steps) as a 130.12, 130.07, 129.9, 129.7, 128.5, 128.23, 128.17, 125.4, 124.8,
1
yellow oil; Its H-NMR spectra data was completely identical 123.5, 123.0, 106.7, 74.4, 58.6, 55.1; electrospray ionization
1
with that reported30); H-NMR (400MHz, CDCl3) δ: 7.29 (d, (ESI)-MS m/z Calcd for C16H17NNaO3 294.1101 (M++Na).
J=7.2Hz, 1H), 7.13 (dd, J=8.0, 7.2Hz, 2H), 6.73 (dd, J=8.0, Found 294.1104.
7.6Hz, 1H), 6.65 (d, J=7.6Hz, 1H), 5.32 (s, 1H), 4.23 (brs,
2H), 3.35 (s, 6H).
Benzyl (2-(Dimethoxymethyl)phenyl)carbamate (7b) To
a mixture of the benzyl (2-formylphenyl)carbamate (56.5mg,
N-(2-(Dimethoxymethyl)phenyl)benzamide (7a) To a so- 0.221mmol) and trimethyl orthoformate (36µL, 0.33mmol) in
lution of a 2-(dimethoxymethyl)aniline (31.9mg, 0.191mmol) MeOH (1.1mL) was added p-TsOH (3.8mg, 0.022mmol). After
in CH2Cl2 (0.65mL) were added Et3N (0.13mL, 0.96mmol) stirring for 12h at reflux, the reaction was quenched with satu-
and benzoyl chloride (24µL, 0.21mmol) at 0°C. After stir- rated aqueous NaHCO3 and the resulting mixture was extract-
ring for an hour, the reaction was quenched with saturated ed with CH2Cl2 three times. The combined organic extracts
aqueous NH4Cl and the mixture was extracted with AcOEt were washed with brine, dried over Na2SO4, and concentrated
three times. The combined organic extracts were washed with under reduced pressure. The residue was purified by flash
brine, dried over Na2SO4, filtered, and concentrated under column chromatography on silica gel (hexanes:AcOEt=9:1)
reduced pressure. The residue was purified by preparative to afford acetal 7b (49.7mg, 0.165mmol, 75%) as a colorless

828
Chem. Pharm. Bull.
Vol. 64, No. 7 (2016)
oil; Rf=0.60 (Silica gel, hexanes:AcOEt=8:2); IR (neat) 3375, at room temperature. The mixture was allowed to warm
1
2938, 1734, 1594, 1531, 1455, 757cm−1; H-NMR (400MHz, to 110°C and the suspension was stirred until TLC (hex-
CDCl3) δ: 8.16–8.08 (m, 2H), 7.45–7.32 (m, 7H), 7.03 (dd, anes : AcOEt=8:2) indicated a complete consumption of 7c.
J=8.0, 8.0Hz, 1H), 5.32 (s, 1H), 5.20 (s, 2H), 3.33 (s, 6H); The reaction mixture was filtered through a pad of Celite and
13C-NMR (100MHz, CDCl3, a mixture of rotamers) δ: 153.5, concentrated under reduced pressure. The residue was puri-
136.3, 132.4, 129.6, 129.3, 128.5, 128.3, 128.2, 128.1, 127.9, fied by preparative TLC on silica gel (hexanes:AcOEt=8:2,
125.2, 124.1, 122.6, 120.2, 103.1, 99.9, 66.8, 54.6, 53.2; ESI- then toluene; hexanes=3:1) to afford quinoline 8a (24.8mg,
MS m/z Calcd for C17H19NNaO4 324.1212 (M++Na). Found 0.105mmol, 66%). 1H-NMR spectra data was completely
1
324.1207.
identical with that reported32); H-NMR (400MHz, CDCl3) δ:
N-(2-(Hydroxymethyl)phenyl)-4-methylbenzenesulfon- 8.21–8.11 (m, 4H), 7.84 (d, J=8.8Hz, 1H), 7.80 (d, J=8.4Hz,
amide To a solution of (2-aminophenyl)methanol (616mg, 1H), 7.71 (dd, J=8.8, 8.4Hz, 1H), 7.50 (dd, J=8.4, 8.4Hz, 1H),
5.00mmol) and pyridine (0.485mL, 6.00mmol) in CH2Cl2 7.05 (d, J=9.2Hz, 2H), 3.89 (s, 3H).
(25mL) was added a solution of p-toluenesulfonyl chloride
(906mg, 4.75mmol) in CH2Cl2 (10mL) at 0°C. After stirring
for 6h, the reaction was quenched with saturated aqueous
Sub-gram Scale Reaction
2-(4-Methoxyphenyl)quinoline (8a)
A 30mL two-necked round-bottom flask with a mag-
NH4Cl and the mixture was extracted with CH2Cl2 three netic stirring bar and Liebig condenser was charged with
times. The combined organic extracts were washed with AgOTf (40.0mg, 0.156mmol, 10mol%), PPh3AuCl (77.0mg,
brine, dried over Na2SO4, filtered, and concentrated under 0.156mmol, 10mol%) and toluene (6.5mL, 0.25M). To the so-
reduced pressure to give sulfonamide as a white solid; Its lution were added alkyne 12a (900 µL, 7.78mmol, 5.0 equiv),
1H-NMR spectra data was completely identical with that DTBP (140µL, 0.622mmol, 40mol%), i-PrOH (2.40mL, 20
1
reported31); H-NMR (400MHz, CDCl3) δ: 7.86 (brs, 1H), 7.65 equiv) and amide 7c (500mg, 1.56mmol) at room temperature.
(d, J=8.4Hz, 2H), 7.43 (d, J=7.6Hz, 1H), 7.30–7.19 (m, 3H), The mixture was allowed to warm to 110°C and the suspen-
7.13–7.05 (m, 2H), 4.40 (s, 2H), 2.38 (s, 3H), 2.13 (brs, 1H).
sion was stirred until TLC (hexanes:AcOEt=8:2) indicated a
N-(2-(Dimethoxymethyl)phenyl)-4-methylbenzenesul- complete consumption of 7c. The reaction mixture was filtered
fonamide (7c) To the solution of N-(2-(hydroxymethyl)- through a pad of Celite and concentrated under reduced pres-
phenyl)-4-methylbenzenesulfonamide (777mg, 2.80mmol), sure. The residue was purified by flash column chromatogra-
N-methylmorphine N-oxide (NMO) (492mg, 4.20mmol), 4Å phy on silica gel (hexanes:AcOEt=92:8) to afford quinoline
moleculer sieves (powdered, 1.4mg), CH2Cl2 (14mL), and 8a (225mg, 0.956mmol, 62%).
MeCN (1.5mL) was added tetrapropylammonium perruthenate
(TPAP) (49.2mg, 0.140mmol). After stirring for 11h, the reac-
2-Phenylquinoline (8b)
According to the general procedure described for 8a,
tion mixture was passed through a silica gel pad. The filtrate quinoline 8b was obtained from 7c with phenylacetylene
was concentrated under reduced pressure to give the crude 12b in 32.0µmol scale (3.7mg, 18µmol, 56%); a white solid;
1
aldehyde. The crude aldehyde was directly subjected to the Its H-NMR spectra data was completely identical with that
1
next reaction without further purification. To a mixture of the reported32); H-NMR (400MHz, CDCl3) δ: 8.22 (d, J=8.8Hz,
above crude aldehyde and trimethyl orthoformate (0.530mL, 1H), 8.20–8.13 (m, 3H), 7.88 (d, J=8.4Hz, 1H), 7.83 (d,
4.80mmol) in MeOH (10mL) was added p-TsOH·H2O J=8.0Hz, 1H), 7.73 (d, J=8.4, 8.4Hz, 1H), 7.59–7.42 (m, 4H).
(60.3mg, 0.240mmol). After stirring for 2h at 70°C, the reac-
2-(p-Tolyl)quinoline (8c)
tion was quenched with saturated aqueous NaHCO3 and the
According to the general procedure described for 8a, quino-
resulting mixture was extracted with CH2Cl2 three times. line 8c was obtained from 7c with (4-methylphenyl)acetylene
The combined organic extracts were washed with brine, dried 12c in 32.0µmol scale (4.8mg, 22µmol, 68%); a yellow solid;
1
over Na2SO4, and concentrated under reduced pressure. The Its H-NMR spectra data was completely identical with that
1
residue was purified by flash column chromatography on reported32); H-NMR (400MHz, CDCl3) δ: 8.20 (d, J=8.8Hz,
silica gel (hexanes:AcOEt=8:2) to afford acetal 7c (557mg, 1H), 8.16 (d, J=8.4Hz, 1H), 8.07 (d, J=8.0Hz, 2H), 7.87 (d,
1.73mmol, 62%) as a white solid; Rf=0.30 (Silica gel, hex- J=8.4Hz, 1H), 7.81 (d, J=8.8Hz, 1H), 7.72 (d, J=8.4, 7.6Hz,
anes : AcOEt=8:2); mp 63–66°C (hexanes/CH2Cl2); IR (neat) 1H), 7.51 (dd, J=8.4, 7.6Hz, 1H), 7.33 (d, J=8.0Hz, 2H), 2.44
1
3310, 2941, 1495, 1338, 1154, 1060, 768, 665cm−1; H-NMR (s, 3H).
(400MHz, CDCl3) δ: 8.13 (brs, 1H), 7.67 (d, J=8.4Hz, 2H),
7.64 (d, J=8.4Hz, 1H), 7.35–7.18 (m, 4H), 7.06 (dd, J=8.0,
2-(4-Bromophenyl)quinoline (8d)
According to the general procedure described for 8a, quino-
7.7Hz, 1H), 4.89 (s, 1H), 3.19 (s, 6H), 2.36 (s, 3H); 13C-NMR line 8d was obtained from 7c with alkyne 12d in 32.0µmol
(100MHz, CDCl3) δ: 143.6, 136.9, 135.5, 129.7, 129.4, 128.4, scale (6.1mg, 22µmol, 67%); a yellow solid; Its 1H-NMR
127.2, 127.1, 124.0, 121.4, 103.5, 53.3, 21.4; ESI-MS m/z Calcd spectra data was completely identical with that reported32)
;
for C16H19NNaO4S 344.0927 (M++H). Found 344.0927.
1H-NMR (400MHz, CDCl3) δ: 8.23 (d, J=8.8Hz, 1H), 8.15 (d,
General Procedure for Gold-Catalyzed Quinoline J=8.8Hz, 1H), 8.06 (d, J=8.4Hz, 2H), 7.84 (d, J=8.8Hz, 1H),
Synthesis
2-(4-Methoxyphenyl)quinoline (8a)
A 10mL test tube equipped with a magnetic stirring bar
was charged with AgOTf (4.1mg, 0.016mmol, 10mol%),
7.83 (d, J=8.8Hz, 1H), 7.74 (dd, J=8.8, 7.6Hz, 1H), 7.65 (d,
J=8.4Hz, 2H), 7.54 (dd, J=8.8, 7.6Hz, 1H).
2-(3,4-Dimethoxyphenyl)quinoline (8e)
According to the general procedure described for 8a, quino-
PPh3AuCl (7.9mg, 0.016mmol, 10mol%) and toluene (0.74mL, line 8e was obtained from 7c with alkyne 12e in 32.0µmol
0.25M). To the solution were added alkyne 12a (93 µL, scale (4.9mg, 19µmol, 58%); a white solid; Its 1H-NMR
0.80mmol, 5.0 equiv), DTBP (14µL, 0.064mmol, 40mol%), spectra data was completely identical with that reported34)
;
i-PrOH (245µL, 20 equiv) and amide 7c (51.5mg, 0.160mmol) 1H-NMR (400MHz, CDCl3) δ: 8.18 (d, J=8.8Hz, 1H), 8.15

Vol. 64, No. 7 (2016)
Chem. Pharm. Bull.
829
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(d, J=8.4Hz, 1H), 7.90 (d, J=2.4Hz, 1H), 7.85 (d, J=8.8Hz,
1H), 7.81 (d, J=8.0Hz, 1H), 7.72 (dd, J=8.4, 8.0Hz, 1H), 7.67
(dd, J=8.8, 2.4Hz, 1H), 7.51 (dd, J=8.0, 8.0Hz, 1H), 7.00 (d,
J=8.8Hz, 1H), 4.06 (s, 3H), 3.97 (s, 3H).
Methyl 4-(Quinolin-2-yl)benzoate (8f)
According to the general procedure described for 8a, quino-
line 8f was obtained from 7b with alkyne 12f in 32.0µmol
scale (2.6mg, 6.3µmol, 31%); a white solid; Its 1H-NMR
spectra data was completely identical with that reported33)
;
1H-NMR (400MHz, CDCl3) δ: 8.30–8.17 (m, 6H), 7.92 (d,
J=8.8Hz, 1H), 7.85 (d, J=8.4Hz, 1H), 7.76 (ddd, J=8.4, 8.4,
1.6Hz, 1H), 7.57 (ddd, J=8.4, 8.4, 1.6Hz, 1H), 3.97 (s, 3H).
2-(4-Nitrophenyl)quinoline (8g)
According to the general procedure described for 8a, quino-
line 8g was obtained from 7c with alkyne 12g in 32.0µmol
scale (2.8mg, 11µmol, 35%); a yellow solid; Its 1H-NMR
spectra data was completely identical with that reported;
1H-NMR (400MHz, CDCl3) δ: 8.42–8.33 (m, 4H), 8.31 (d,
J=8.4Hz, 1H), 8.19 (d, J=8.4Hz, 1H), 7.94 (d, J=8.4Hz, 1H),
7.88 (d, J=8.4Hz, 1H), 7.79 (dd, J=8.4, 7.6Hz, 1H), 7.60 (dd, 16) Xiao F., Chen Y., Liu Y., Wang J., Tetrahedron, 64, 2755–2761
(2008).
J=8.4, 7.6Hz, 1H).
2-(Naphthalen-1-yl)quinoline (8h)
According to the general procedure described for 8a, quino-
line 8h was obtained from 7cw with alkyne 12h in 32.0µmol
17) Huang H., Jiang H., Chen K., Liu H., J. Org. Chem., 74, 5476–5480
(2009).
18) Huo Z., Gridnev I. D., Yamamoto Y., J. Org. Chem., 75, 1266–1270
(2010).
scale (3.2mg, 13µmol, 39%); an orange oil; Its 1H-NMR
19) Patil N. T., Raut V. S., J. Org. Chem., 75, 6961–6964 (2010).
spectra data was completely identical with that reported32)
;
20) Kothandaraman P., Mothe S. R., Toh S. S. M., Chan P. W. H., J.
Org. Chem., 76, 7633–7640 (2011).
21) Yao C., Qin B., Zhang H., Lu J., Wang D., Tu S., RSC Adv., 2,
3759–3764 (2012).
22) Patil N. T., Raut V. S., Curr. Sci., 104, 1671–1680 (2013).
23) Ueda H., Yamaguchi M., Kameya H., Sugimoto K., Tokuyama H.,
Org. Lett., 16, 4948–4951 (2014).
24) Yamaguchi M., Itagaki D., Ueda H., Tokuyama H., J. Antibiot., 69,
253–258 (2016).
25) Mézailles N., Ricard L., Gagosz F., Org. Lett., 7, 4133–4136 (2005).
26) Nieto-Oberhuber C., López S., Echavarren A. M., J. Am. Chem.
Soc., 127, 6178–6179 (2005).
27) Hashmi A. S. K., Bechem B., Loos A., Hamzic M., Rominger F.,
Rabaa H., Aust. J. Chem., 67, 481–499 (2014).
28) Fructos M. R., Belderrain T. R., de Frémont P., Scott N. M., Nolan
S. P., Díaz-Requejo M. M., Pérez P. J., Angew. Chem. Int. Ed., 44,
5284–5288 (2005).
1H-NMR (400MHz, CDCl3) δ: 8.30 (d, J=8.4Hz, 1H), 8.23 (d,
J=8.8Hz, 1H), 8.13 (d, J=8.4Hz, 1H), 7.99–7.89 (m, 3H), 7.82
(dd, J=8.4, 7.2Hz, 1H), 7.75–7.69 (m, 2H), 7.64–7.56 (m, 2H),
7.55–7.44 (m, 2H).
Acknowledgments This work was financially supported
by the Cabinet Office, Government of Japan through its “Fund-
ing Program for Next Generation World-Leading Researchers
(LS008), JSPS KAKENHI Grant Numbers JP26253001 and
JP24790003, and the Platform Project for Supporting in Drug
Discovery and Life Science Research（Platform for Drug
Discovery, Informatics, and Structural Life Science）from the
Ministry of Education, Culture, Sports, Science and Technolo-
gy (MEXT) of Japan and Japan Agency for Medical Research
and development (AMED).
29) Sugimoto K., Toyoshima K., Nonaka S., Kotaki K., Ueda H.,
Tokuyama H., Angew. Chem. Int. Ed., 52, 7168–7171 (2013).
30) Akue-Gedu R., Gautret P., Lelieur J.-P., Rigo B., Synthesis, 2007,
3319–3322 (2007).
Conflict of Interest The authors declare no conflict on
interest.
31) Nishiguchi A., Ikemoto T., Ito T., Miura S., Tomimatsu K., Hetero-
cycles, 71, 1183–1192 (2007).
32) Xing R.-G., Li Y.-N., Liu Q., Han Y.-F., Wei X., Li J., Zhou B., Syn-
thesis, 2011, 2066–2072 (2011).
33) Li S.-M., Huang J., Chen G.-J., Han F.-S., Chem. Commun., 47,
12840–12842 (2011).
34) Cho C. S., Lee N. Y., Kim T.-J., Shim S. C., J. Heterocycl. Chem.,
41, 409–411 (2004).
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