Indium(III)-catalyzed tandem hydroamination-hydroarylation of naphthylamines with phenylacetylenes

Article abstract of DOI:10.1055/s-0033-1341234

A one-pot, three-component method for the synthesis of benzo-fused quinolines has been developed by tandem reaction between phenylacetylenes and naphthylamines. The first step of the reaction is hydroamination of the alkyne followed by a hydroarylation re

Full text of DOI:10.1055/s-0033-1341234

1448▌
LETTER
lIenttedr ium(III)-Catalyzed Tandem Hydroamination–Hydroarylation of
Naphthylamines with Phenylacetylenes
Hydroamination–Hydroarylation of Naphthylamines with Phenylacetylenes
Nimmakuri Rajesh,a Rupam Sarma,b Dipak Prajapati*a
a
Medicinal Chemistry Division, CSIR-North-East Institute of Science & Technology, Jorhat, Assam 785006, India
Fax +91(376)2370011; E-mail: dr_dprajapati2003@yahoo.co.uk
b
Department of Chemistry, Nalbari College, Nalbari, Assam 781335, India
Received: 26.02.2014; Accepted after revision: 24.03.2014
pounds.8 Although a large number of organic transforma-
tions have been reported to take place under indium
catalysis,9 relatively little effort has been directed toward
the development of tandem processes under one-pot con-
Abstract: A one-pot, three-component method for the synthesis of
benzo-fused quinolines has been developed by tandem reaction be-
tween phenylacetylenes and naphthylamines. The first step of the
reaction is hydroamination of the alkyne followed by a hydroaryla-
tion reaction to form the quinolines. Indium(III) trifluoromethane- ditions. Previously, we have demonstrated that indium
trifluoromethanesulfonate10 can be employed as an effi-
cient catalyst for the activation of terminal alkynes for
sulfonate was shown to be an efficient catalyst for the
transformations, and the reaction proceeded in the absence of any
other co-catalyst or additive to give the corresponding quinolines in
various reactions such as coupling reactions, nucleophilic
good to excellent yields.
addition, and hydrothiolation reactions in the absence of
any other additives or co-catalysts.11 Moreover, indium
Key words: indium, alkynes, hydroamination, hydroarylation,
domino reactions
triflate has also been shown to catalyze the tandem hy-
droamination–hydroalkylation reaction of terminal al-
kynes with anilines for the generation of α,β-unsaturated
ketimines (Scheme 1).12 This result encouraged us to
study the reaction between terminal alkynes and naphthyl-
amine under indium-catalyzed conditions. Interestingly,
we observed that, in presence of indium(III) catalyst, un-
like anilines, naphthylamine reacted with phenylacetylene
through a tandem hydroamination–hydroarylation path-
way to give quinoline derivatives.13,14 This type of tandem
hydroamination–hydroarylation reaction of aniline with
arylalkynes is known to proceed under silver and gold ca-
talysis; however, those processes require co-catalysts, ad-
ditives, and an excess amount of the alkyne for the
transformation to take place.15
In recent years, tandem processes for the construction of
complex molecules by employing simple starting materi-
als has emerged as an attractive alternative to convention-
al synthesis.1 The popularity of tandem processes2 over
traditional multi-step procedures can be attributed to the
significant reduction in cost, time, and waste generation as
well as enhancement in the atom economy of the reaction,
which is in accordance with the ‘green chemistry’ proto-
col.3 In this regard, exploitation of suitable catalyst sys-
tems for the promotion of sequential reaction steps under
one-pot conditions, especially in the absence of any other
co-catalyst or additives, is an interesting and intriguing
option that needs to be explored further.4
Quinolines are one of the most important heterocyclic
subunits because of their natural abundance and immense
pharmacological potency.5 This has resulted in the devo-
tion of considerable effort towards the development of
newer methodologies for their synthesis.6 Although sig-
nificant numbers of efficient protocols have been devel-
oped for assembling this important substructure, the
design of new one-pot tandem processes7 for the construc-
tion of complex annulated quinolines remains a challeng-
ing area.
NH2
N
In(OTf)3
+
Scheme 1
In this paper, we report our preliminary findings for an in-
dium(III)-catalyzed tandem hydroamination–hydroaryla-
tion of phenylacetylenes with naphthylamines for the
synthesis of fused quinolines (Scheme 2). Preliminary
studies were carried out to investigate the reaction be-
tween 2-naphthylamine and phenylacetylene. When 2-
naphthylamine (1a) was heated to reflux with an excess of
phenylacetylene (2a) in toluene by employing indium(III)
triflate as catalyst, a 1,2-dihydrobenzo[f]quinoline prod-
uct was obtained.
Over the last decade, the chemistry of indium catalysis has
contributed enormously to the field of organic synthesis
because of the ability of indium(III) reagents to catalyze
carbon–carbon bond-forming reactions. In this context, of
particular interest is the indium(III)-mediated activation
of π-electrons of alkynes for the generation of a diverse
range of synthetically and biologically important com-
SYNLETT 2014, 25, 1448–1452
Advanced online publication: 13.05.2014
DOI: 10.1055/s-0033-1341234; Art ID: st-2014-d0166-l
© Georg Thieme Verlag Stuttgart · New York
The reaction was optimized by varying the type and
amount of catalyst, the amount of alkyne, and the reaction
time; the results are summarized in Table 1. It was ob-
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

LETTER
Hydroamination–Hydroarylation of Naphthylamines with Phenylacetylenes
1449
NH2
In(OTf)3
+
NH
toluene, reflux
1a
2a
3a
Scheme 2
served that a maximum yield of 85% could be obtained
when one equivalent of amine was reacted with four
equivalents of alkyne in the presence of 10 mol% indi-
um(III) triflate as catalyst (Table 1, entry 6). Other indi-
um(III) catalysts such as indium(III) chloride or
indium(III) bromide, or metallic indium did not give en-
couraging results (Table 1, entries 9–11). Similarly, other
triflates such as zinc, scandium, or ytterbium triflates also
gave poor yields compared with indium(III) triflate (Table
1, entries 12–14). The structure of 3a was ascertained
Table 1 Optimization Studies for the Synthesis of Quinoline Deriv-
ative 3a
Entry Catalyst
Cat. amount Alkyne
Time
(h)
Yield
(%)
(mol%)
(equiv)
1
2
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
InCl3
0.5
5
10
10
10
10
7
15
10
10
10
10
10
10
10
15
15
18
20
15
15
trace
25
3
10
20
10
10
10
10
10
10
10
10
10
10
85
1
4
82
from spectroscopic data and elemental analysis. The H
NMR spectra of the compound showed the presence of the
NH proton at δ = 4.72 ppm, a vinylic proton at δ =
5.82 ppm, and methyl protons at δ = 1.73 ppm as singlets.
The IR spectra showed the presence of the NH group at
3374 cm–1.16
5
85
6
4
85
7
3
60
8
2
20
The scope of the reaction was then investigated with a
number of different alkynes and amines by employing the
optimized conditions; the results are summarized in Table
2. It was observed that both 1-naphthylamine and 2-naph-
thylamine participated in the reaction to give fused ben-
zo[g]quinoline and benzo[f]quinoline, respectively, with
comparable yields. The reaction was also successful with
alkynes with either electron-donating or electron-with-
drawing groups (Table 2, entries 2–8). However, some
uncharacterized compounds were detected in all cases,
which could be separated by column chromatography. All
the products obtained were characterized by IR, NMR
spectroscopy and mass spectrometry.
9
4
55
10
11
12
13
14
InBr3
4
55
In
4
10
Zn(OTf)2
Sc(OTf)3
Yb(OTf)3
4
trace
50
4
4
50
lation to give quinoline 3a as the final product. The
significant difference in reactivity of naphthylamine as
compared with anilines12 toward the second molecule of
phenylacetylene under identical reaction conditions re-
sults from the difference in reactivity of the hydroamina-
tion intermediate formed in the first step of the reaction.
The presence of the highly electrophilic C-1 carbon atom
in naphthylamine facilitates formation of the cyclic quin-
oline product through intramolecular hydroarylation. On
the other hand, aniline does not have such favorable elec-
trophilic centers adjacent to the imine double bond and,
thus, is unable to undergo the cyclization step.
Although mechanistic studies were not performed, the
formation of the quinoline product may be rationalized by
initial hydroamination of the alkyne followed by a second
hydroarylation step (Scheme 3). In the first step, an elec-
trophilic indium–alkyne complex is believed to form from
indium(III) triflate and phenylacetylene, which then re-
acts with 2-naphthylamine to give a ketimine intermediate
through Markovnikov addition. The next step may start
with nucleophilic addition of an alkynylindium intermedi-
ate to the ketimine, followed by intramolecular hydroary-
NH2
In(OTf)3
N
+
NH
hydroamination
In(OTf)3
hydroarylation
2a
1a
3/a
3a
Scheme 3
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1448–1452

1450
N. Rajesh et al.
LETTER
Table 2 Substrate Scopea
Entry
Amine 1
Alkyne 2
Quinoline 3
Time (h)
Yield (%)
NH2
1
10
84
NH
1a
1a
3a
3b
NH
2
3
6
6
82
80
NH
1a
1a
1a
1a
3c
Br
Br
NH
4
5
6
7
7
7
70
65
50
Br
3d
F
F
NH
F
3e
F
F
F
F
F
NH
F
3f
7
1a
7
82
NH
3g
Synlett 2014, 25, 1448–1452
© Georg Thieme Verlag Stuttgart · New York

LETTER
Hydroamination–Hydroarylation of Naphthylamines with Phenylacetylenes
1451
Table 2 Substrate Scopea (continued)
Entry
Amine 1
Alkyne 2
Quinoline 3
Time (h)
Yield (%)
8
1a
9
62
NH
3h
NH2
HN
9
10
84
1b
1b
3i
HN
10
10
80
3j
a Reaction conditions: amine (1 mmol), alkyne (4 mmol), In(OTf)3 (10 mol%), toluene (5 mL), reflux.
b Isolated yield.
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In summary, we have developed an efficient one-pot,
three-component, tandem reaction strategy for the con-
struction of fused quinoline derivatives in good to excel-
lent yield. Indium(III) triflate has been shown to mediate
two fundamentally different reaction steps under one-pot
conditions in the absence of any other co-catalyst or addi-
tive. This methodology offers an alternate approach for
the synthesis of benzo[f]quinolines from simple starting
materials with excellent atom-economy.
Acknowledgment
(f) Cabrera, A.; Sharma, P.; Ayala, M.; Rubio-Perez, L.;
Amezquita-Valencia, M. Tetrahedron Lett. 2011, 52, 6758.
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Perumal, P. T. Tetrahedron Lett. 2010, 51, 994.
We thank CSIR New Delhi for financial support of this work under
Network Project. Nimmakuri Rajesh thanks UGC, New Delhi for a
research fellowship. We also thank the Director, NEIST, Jorhat for
his keen interest and constant encouragement.
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Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000083.SunpfgIpi
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nr
i
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1448–1452

1452
N. Rajesh et al.
LETTER
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(16) Synthesis of 3a–i; General Procedure: 2-Naphthylamine
(1 mmol), alkyne (4 mmol), and In(OTf)3 (0.1 mmol) were
heated at reflux in toluene (10 mL) for 10 h under air. Upon
completion of the reaction (as indicated by TLC), the solvent
was evaporated and the crude product mixture was dissolved
in chloroform and purified by column chromatography
(EtOAc–hexane, 15:85) to give pure 3.
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2-Methyl-2,3-diphenyl-1,2-dihydrobenzo[f]quinoline
(3a): Light-yellow liquid; 1H NMR (300 MHz, CDCl3): δ =
7.96 (d, J = 7.46 Hz, 3 H), 7.61 (m, 6 H), 7.28 (m, 5 H), 7.04
(m, 2 H), 5.82 (s, 1 H), 4.72 (s, 1 H), 2.59 (s, 3 H). 13C NMR
(75 MHz, CDCl3): δ = 148.1, 142.9, 142.7, 137.1, 137.0,
133.1, 130.6, 130.1, 128.8, 128.6, 128.3, 128.2, 127.0,
126.7, 126.0, 125.3, 124.9, 121.5, 117.2, 113.1, 55.8, 26.6.
IR (CHCl3): 3415, 1381, 1239, 755 cm–1. GC-MS: m/z = 347
[M]+. Anal. Calcd for C26H21N: C, 89.88; H, 6.09; N, 4.03.
Found: C, 89.98; H, 6.15; N, 4.01.
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Synlett 2014, 25, 1448–1452
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