Gold(III) Chloride catalyzed intermolecular dimerization of 2-ethynylanilines: Synthesis of substituted quinolines

Article abstract of DOI:10.1055/s-0029-1217961

An unprecedented gold(III)-catalyzed intermolecular dimerization of 2-ethynylanilines possessing terminal triple bond offers a general synthetic pathway to a wide range of highly substituted quinolines.

Full text of DOI:10.1055/s-0029-1217961

LETTER
2795
Gold(III) Chloride Catalyzed Intermolecular Dimerization of
2-Ethynylanilines: Synthesis of Substituted Quinolines
S
ynthesis of Subs
.
titute
d
Quin
P
olines raveen, S. Jegatheesan, P. T. Perumal*
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, India
Fax +91(44)24911589; E-mail: ptperumal@gmail.com
Received 8 July 2009
However, it was limited to specific substrate classes, stoi-
chiometric use of InBr3, and longer reaction time. To cir-
cumvent such substrate limitation, use of stoichiometric
amount of catalyst, long duration of reaction time, and en-
hance the scope of the reaction, we have elected to inves-
tigate catalytic amount of gold salts for this unusual
dimerization. We realized that 2-ethynylaniline possess-
ing a terminal triple bond might undergo dimerization in
the presence of a gold catalyst. Herein we wish to report,
gold(III)-catalyzed intermolecular dimerizaton of 2-ethy-
nylanilines leading to highly substituted quinolines.
Abstract: An unprecedented gold(III)-catalyzed intermolecular
dimerization of 2-ethynylanilines possessing terminal triple bond
offers a general synthetic pathway to a wide range of highly substi-
tuted quinolines.
Key words: 2-ethynylanilines, terminal alkyne, gold(III), intermo-
lecular dimerization, substituted quinolines
The prevalence of quinolines1 in numerous natural prod-
ucts that exhibit a wide range of pharmacological activi-
ties,
such
as
antimalarial,
anti-inflammatory,
The 2-ethynylanilines required for this methodology are
readily prepared by the base-effected desilylation11 of 2-
(trimethylsilylethynyl)aniline, which in turn can be pre-
pared by the Sonogashira coupling12 of 2-iodoanilines13
with ethynyltrimethylsilane. Initial studies were directed
toward finding a general set of reaction conditions that
could be applied to a wide variety of substrates. To begin
our study, we examined the reaction of 2-ethynylaniline
(1a) with several gold catalysts in dry acetonitrile14 as
summarized in Scheme 1 and Table 1.
antineoplastic, antifungal, antiseptic/anti-infective, and
analgesic properties,2 has led to a continued interest in the
practical synthesis of this class of heterocyclic com-
pounds. They also find application in material science,3
bioorganometallic processes,4 and agrochemicals and ef-
fect chemicals such as dyestuffs and corrosion inhibitors.5
Thus it is not surprising that numerous pathways for the
synthesis of quinolines have been developed. Among var-
ious synthetic strategies,6 catalytic transformation by
means of transition-metal catalysts is one of the modern
approaches for the synthesis of substituted quinoline de-
rivatives. These include, rhodium-catalyzed condensation
of o-aminophenylboronates with a,b-unsaturated ke-
tones,7a gold-catalyzed cyclization of propargyl amines,7b
palladium-catalyzed chlorimination of imidoyl chorides,7c
[Cp*Fe(CO)2]2-catalyzed reductive cyclization of o-nitro-
substituted Baylis–Hillman acetates,7d iridium-catalyzed
condensation of 2-aminobenzyl alcohol with ketones,7e
indium-catalyzed microwave synthesis involving phenyl-
acetylene and 2¢-aminoacetophenones,7f cobalt-catalyzed
rearrangement of N,N-diallylanilines,7g palladium-cata-
lyzed multicomponent synthesis,7h and rhodium-cata-
lyzed coupling–cyclization of N-aryltrifluoroacetimidoyl
chlorides with alkynes.7i On the other hand, due to the
unique ability to activate carbon–carbon multiple bonds,
the use of gold catalysts plays an important role in modern
transition-metal catalysis.8 As part of our ongoing interest
in gold-catalyzed organic reactions,9 we have previously
reported, gold(I)-catalyzed cycloisomerization of 2-ethy-
nylanilines possessing internal triple bonds9a leading to
indole derivatives. Recently, Sakai et al. reported a novel
method for the synthesis of substituted quinolines by
InBr3-catalyzed dimerization of 2-ethynylanilines.10
Me
NH2
[Au]
2
MeCN
N
NH2
1a
2a
Scheme 1 Gold-catalyzed dimerization of 2-ethynylaniline (1a) un-
der various reaction conditions
The use of 5 mol% of gold(I) complexes like Ph3PAuCl,
Et3PAuCl, and Me3PAuCl did not show the reactivity for
this transformation (entries 1–3). The use of AuCl in-
duced the formation of indole exclusively,15 and the quin-
oline product was formed only in trace amount (entry 4).
The use of AuBr3 resulted in the formation of only 10% of
product (entry 5). Treatment of 1a with 5 mol% of AuCl3
afforded the quinoline product 2a in 30% yield (entry 6).
Gratifyingly, the use of 10 mol% of AgOTf as a cocatalyst
along with 5 mol% of AuCl3 afforded the product in high
yield (entry 7). However, when the same reaction was car-
ried out at reflux temperature, the reaction went into com-
pletion in 1 hour (entry 8). Again, when the same reaction
was tested with AuCl3 (5 mol%) to AgOTf (15 mol%) in
a 1:3 ratio, it resulted in a very good yield of the product
(entry 9), but not higher than that tested with a 1:2 ratio
(entry 8). But the use of AgOTf alone did not led to any
SYNLETT 2009, No. 17, pp 2795–2800
x
x
.x
x
.2
0
0
9
Advanced online publication: 09.09.2009
DOI: 10.1055/s-0029-1217961; Art ID: G21909ST
© Georg Thieme Verlag Stuttgart · New York

2796
C. Praveen et al.
LETTER
make all the experiments comparable in Table 1 (entries
1–3, 5–7, 9, 14, and 15) were also carried out at reflux
temperature and observed no improvement in terms of
product formation.
Table 1 Effect of Different Gold Catalysts on the Intermolecular
Dimerization of 2-Ethynylaniline (1a)
Entry
Catalyst (mol%)
Ph3PAuCl (5)
Yield (%)a
1
–
Since a combination of 5 mol% of AuCl3 and 10 mol% of
AgOTf (Table 1, entry 8) provided a higher yield for the
parent system compared with other catalysts, this proce-
dure was chosen to test the scope of the dimerization pro-
cess for other substrates.17 Under this reaction conditions,
substrates possessing various functionalities such as nitro,
ester, ether, and cyano were tolerated well, affording the
corresponding quinoline derivatives in good yields
(Table 2).
2
Me3PAuCl (5)
–
3
Et3PAuCl (5)
–
4
AuCl (5)
10b
18
30
65
89c
82c
–
5
AuBr3 (5)
6
AuCl3 (5)
7
AuCl3 (5)/AgOTf (10)
AuCl3 (5)/AgOTf (10)
AuCl3 (5)/AgOTf (15)
AgOTf (10)
The result revealed that the yield of the products were in-
dependent of the groups attached on the periphery of the
substrate, since both electron-withdrawing as well as elec-
tron-releasing substrates gave almost the same yield.
Moreover, all reactions went into completion within one
hour. Thus, these reaction conditions appeared to be far
more efficient than those previously used indium proce-
dures, which requires high reaction time (>24 h).10 Fur-
thermore, the beneficial effect of this new methodology is
the dimerization of substrate 1o leading to naphthyridine
2o, albeit in moderate yield. However, in contrast InBr3
failed in the dimerization of such substrates.
8
9
10
11
AuCl3 (5)/AgBF4 (10)
AuCl3 (5)/AgSbF6 (10)
AuCl3 (5)/AgOCOCF3 (10)
AuCl3 (5)/AgOAc (10)
AgCl (10)
58c
66c
38c
35c
–
12
13
14
15
16
no catalyst
–
A tentative mechanistic pathway for the gold(III)-cata-
lyzed dimerization of 2-ethynylaniline is proposed in
Scheme 2. The alkyne coordinates to gold(III) to form p-
complex 2, which enhances the electrophilicity of the
alkyne. Subsequent nucleophilic attack of the amino
group of the other molecule of 2-ethynylaniline 1 affords
gold–vinylidene18 intermediate 3. Protonation of the inter-
mediate 3 with the proton on the ammonium gives the
neutral enamine intermediate 4 and regenerate the gold
catalyst. Gold again activates the intermediate 4 to form
intermediate 5, which undergoes cyclization to form the
intermediate 6. Again protonation of the vinyl–gold inter-
mediate 6 with the proton on the ammonium gives inter-
mediate 7, which upon subsequent rearrangement affords
the product 2.
a Isolated yield.
b Indole was obtained as the major product.
c The reaction was carried out at reflux temperature.
product formation at all (entry 10). This observation re-
vealed that neither AuCl3 nor AgOTf alone led to product
formation, rather a combination of both AuCl3 and AgOTf
effectively catalyses this process to higher yields of prod-
uct.16 The use of other silver salts as cocatalysts resulted
in product formation albeit in moderate yields (entry 11–
14) and none of them gave better yield than AgOTf. Final-
ly, the reaction in the presence of catalytic amount of
AgCl and the absence of any catalyst does not afford the
product at all (entries 15 and 16, respectively). In order to
[Au]–
[Au]
NH2
R
NH2
NH2
••
R
R
NH2
– [Au]
+
••
N
N
H
H2
R
3
1
4
R
R
2
[Au]
[Au]
[Au]–
NH2
NH2
NH2
NH2
R
R
R
R
+
N
H
– [Au]
••
N
N
N
H
R
R
R
R
7
6
2
5
Scheme 2 Tentative mechanism for the gold(III)-catalyzed dimerization of 2-ethynylaniline
Synlett 2009, No. 17, 2795–2800 © Thieme Stuttgart · New York

LETTER
Synthesis of Substituted Quinolines
2797
Table 2 Gold-Catalyzed Synthesis of Quinolines via Dimerization of 2-Ethynylanilinesa
Entry
1
2-Ethynylaniline
Substituted quinolineb
Time (min)
Yield (%)c
Me
NH2
N
20
89
84
NH2
1a
2a
Me
Me
NH2
Me
Me
2
3
4
5
20
45
45
30
N
NH2
1b
2b
Me
F
NH2
F
74
78
73
N
NH2
1c
F
2c
Me
N
O2N
NH2
NO2
O2N
NH2
1d
2d
Me
Cl
NH2
Cl
N
NH2
1e
Cl
2e
Me
N
NC
NH2
NC
6
7
30
40
76
79
NH2
1f
CN
2f
Me
NH2
MeO
N
MeO
NH2
OMe
1g
2g
Synlett 2009, No. 17, 2795–2800 © Thieme Stuttgart · New York

2798
C. Praveen et al.
LETTER
Table 2 Gold-Catalyzed Synthesis of Quinolines via Dimerization of 2-Ethynylanilinesa (continued)
Entry
2-Ethynylaniline
Substituted quinolineb
Time (min)
Yield (%)c
Me
Me
NH2
Me
8
25
86
77
78
75
88
81
85
Me
N
Me
NH2
Me
1h
Me
2h
Me
N
Br
Br
NH2
Cl
9
10
11
12
13
14
30
25
40
30
40
35
NH2
Cl
Cl
Br
1i
2i
Me
N
Me
NH2
Me
Me
NH2
NH2
NH2
Me
Me
1j
Me
2j
Me
N
Me
NH2
Me
Cl
Cl
Cl
Me
1k
2k
Me
N
Br
NH2
Br
Br
Br
Br
Br
1l
2l
Me
O2N
NH2
O2N
OMe
N
NH2
OMe
OMe
NO2
1m
2m
Me
N
MeOOC
MeOOC
NH2
OMe
NH2
OMe
OMe
1n
COOMe
2n
Synlett 2009, No. 17, 2795–2800 © Thieme Stuttgart · New York

LETTER
Synthesis of Substituted Quinolines
2799
Table 2 Gold-Catalyzed Synthesis of Quinolines via Dimerization of 2-Ethynylanilinesa (continued)
Entry
15
2-Ethynylaniline
Substituted quinolineb
Time (min)
Yield (%)c
Me
O2N
NH2
O2N
55
48
N
N
N
N
NH2
1o
NO2
2o
a All reactions were carried out at reflux temperature in MeCN solvent using 5 mol% of AuCl3 and 10 mol% of AgOTf under nitrogen atmo-
sphere.
b All products were characterized by IR, 1H NMR, 13 C NMR, and MS.
c Isolated yield.
Chem. Mater. 1993, 5, 633. (g) Jenekhe, S. A.; Lu, L.;
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In summary, a catalytic system of AuCl3/AgOTf effects
the dimerization of 2-ethynylanilines leading to polysub-
stituted quinolines in good to excellent yield. This proto-
col is amenable to substrates possessing functionalities
such as nitro, ether, cyano, ester, and heteroaromatic ex-
hibiting good functional-group tolerance. No solvent ex-
traction, the safe catalyst, and short reaction time are some
of the noteworthy advantages of this protocol. Further
synthetic applications of this novel dimerization to more
complex heterocyclic ring systems are currently under in-
vestigation.
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Acknowledgment
The authors thank the Council of Scientific and Industrial Research,
New Delhi, India for the research fellowship.
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Synlett 2009, No. 17, 2795–2800 © Thieme Stuttgart · New York

2800
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LETTER
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(17) General Procedure for the Gold-Catalyzed Dimerization
of 2-Ethynylanilines 2a–o; Representative Procedure for
2,4-Dibromo-6-(6,8-dibromo-4-methyl-2-quinolinyl)-
phenylamine (2l, Table 2, Entry 12)
To a mixture of AuCl3 (27.57 mg, 0.09 mmol) and AgOTf
(46 mg, 0.181 mmol) under N2 was added dry MeCN (2 mL)
and stirred for 15 min at 25 °C. To the mixture was added a
solution of 2,4-dibromo-6-ethynylaniline (1l, 500 mg, 1.81
mmol) in dry MeCN (2 mL) at 25 °C, and the whole was
gradually warmed up to reflux temperature and stirred for
the specified time (Table 2). After completion of the reaction
as indicated by TLC, the reaction mixture was concentrated
under reduced pressure and purified by column chromatog-
raphy over silica gel (100–200 mesh) to afford pure product
2,4-dibromo-6-(6,8-dibromo-4-methyl-2-quinolinyl)phenyl-
amine(2l) as a yellow solid; mp 186–188 °C. IR (KBr):
3751, 3473, 2956, 2430,1457, 766 cm–1. 1H NMR (500
MHz, CDCl3): d = 2.51 (s, 3 H), 4.12 (br s, 2 H), 7.10 (d, 1
H, J = 2.3 Hz), 7.65 (d, 1 H, J = 2.2 Hz), 8.14 (d, 1 H, J = 2.3
Hz), 8.19 (d, 1 H, J = 2.3 Hz), 8.71 (s, 1 H). 13C NMR (125
MHz, CDCl3): d = 26.9, 109.2, 110.1, 120.7, 124.7, 126.6,
126.7, 129.9, 131.4, 132.1, 134.9, 136.0, 141.6, 143.2,
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152.1, 162.8. MS (ESI+): m/z = 551 [M+ + H]+, 553 [M2+
+
H]+, 555 [M4+ + H]+. Anal. Calcd for C16H10Br4N2: C, 34.95;
H, 1.83; N, 5.09. Found: C, 35.07; H, 1.78; N, 5.00.
(18) Seregin, I. V.; Gevargyan, V. J. Am. Chem. Soc. 2006, 128,
12050.
Synlett 2009, No. 17, 2795–2800 © Thieme Stuttgart · New York

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