Ytterbium(III) triflate catalyzed domino reaction of arylamines and styrene oxides: Synthesis of 2-benzyl-3-arylquinoline derivatives

Article abstract of DOI:10.1016/j.tetlet.2021.152981

An efficient and straightforward method for the synthesis of 2-benzyl-3-arylquinoline derivatives is reported involving the domino reaction of substituted arylamines and styrene oxides in the presence of 10 mol% ytterbium(III) triflate in acetonitrile at

Full text of DOI:10.1016/j.tetlet.2021.152981

Tetrahedron Letters 70 (2021) 152981
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Tetrahedron Letters
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Ytterbium(III) triflate catalyzed domino reaction of arylamines and
styrene oxides: Synthesis of 2-benzyl-3-arylquinoline derivatives
⇑
Saghir Ali, Abu Taleb Khan
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and straightforward method for the synthesis of 2-benzyl-3-arylquinoline derivatives is
reported involving the domino reaction of substituted arylamines and styrene oxides in the presence
of 10 mol% ytterbium(III) triflate in acetonitrile at 80 °C. Additionally, the reaction of aliphatic epoxides
with p-anisidine provided 2,3-dialkylquinoline derivatives under identical reaction conditions. Important
features of the protocol are ease of handling, broad substrate scope, good yields, and the formation of two
CAN and two CAC bonds.
Received 26 December 2020
Revised 15 February 2021
Accepted 25 February 2021
Available online 13 March 2021
This work is dedicated to my teacher
Professor Okhil Kumar Medhi, Former Vice-
Chancellor, Gauhati University, upon his
sudden passing away on February 2, 2021.
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Domino reaction
Arylamines
Styrene oxides
Atom-economy
Easy handling
Introduction
co-workers [7a] further demonstrated the reaction of arylamines
with styrene oxides in the presence of FeCl3 to give 3-arylquinoline
The quinoline structural unit is present in numerous naturally
occurring alkaloids and well-known potent drugs [1]. These com-
pounds exhibit a broad range of biological activities, such as anti-
malarial [2a], antiasthmatic [2b], antituberculosis [2c],
antihypertensive [2d], anticancer [2e], and anti-HIV [2f] activities.
In addition, naturally occurring compounds, namely quinine and
cinchonidine, have been extensively used as chiral ligands for
asymmetric synthesis [3]. Furthermore, quinoline and its deriva-
tives have also been explored in materials science [4a,b]. Due to
its wide applications in diverse fields, the synthesis of quinoline
derivatives still attracts significant attention among synthetic
organic chemists. Recently, Beller and co-workers reported a dom-
ino reaction for the synthesis of 2-benzyl-3-phenylquinoline
derivatives from substituted anilines and styrene [5a]. Zhang and
derivatives (Scheme 1). Using a mixture of Al2O3 and MeSO3H,
Sharghi and co-workers also reported the synthesis of 3-arylquino-
lines [7b] from the same starting materials. Some of the drawbacks
of previously reported procedures are need for expensive catalysts,
harsh reaction conditions, the requirement of an inert atmosphere,
and low yields. Therefore, there is still scope to develop new
methodology for the synthesis of 2-benzyl-3-phenylquinoline
derivatives.
Very recently, Tepe and co-workers [7c] reported the synthesis
of 2-benzyl-3-phenylquinoline derivatives using arylamines and
styrene oxides in the presence of 0.5 equivalents of scandium(III)
triflate (Scheme 1) under an inert atmosphere. Though this repre-
sents a good method to access 2,3-disubstituted quinolines, it has
several disadvantages, such as requirement of a stoichiometric
amount of TEMPO (1.0 equiv.), an excess amount styrene oxide
(3 equiv.), high catalyst loading, molecular sieves, long reaction
times (24 h), and an inert atmosphere of argon. Notably, the reac-
tion does not proceed well with Yb(OTf)3, which is mentioned in
the supporting information. Herein, we report an efficient and
straightforward method for the synthesis of 2-benzyl-3-arylquino-
co-workers developed
a method to access the 2-benzyl-3-
phenylquinoline scaffold using terminal alkynes and substituted
anilines [5b]. Moreover, a few methods have been reported for
the synthesis of 2-benzyl-3-phenylquinoline derivatives using
substituted anilines and phenylacetaldehyde [6]. Zhang and
line derivatives via
a domino reaction involving substituted
⇑
Corresponding author.
E-mail address: atk@iitg.ac.in (A.T. Khan).
https://doi.org/10.1016/j.tetlet.2021.152981
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

S. Ali and Abu Taleb Khan
Tetrahedron Letters 70 (2021) 152981
(OTf)3 provided lower yields compared to Yb(OTf)3. Additionally,
the reaction did not proceed with Cu(OTf)2.
Next, different solvents, such as water, methanol, tetrahydrofu-
ran, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformide
and toluene were examined (Entries 10–16, Table 1), using
10 mol% Yb(OTf)3 as the catalyst. In all these solvents, either the
reaction did not take place or the yield was low. Hence, the best
yield was obtained in acetonitrile. From all these observations,
we concluded that the optimized reaction conditions were
10 mol% Yb(OTf)3 in acetonitrile at 80 °C (Entry 5, Table 1) in terms
of both the yield and reaction time.
With the optimal reaction conditions in hand, the scope and
generality of the developed protocol were explored with various
arylamines 1a-q and styrene oxide 2a (Table 2). The reaction of
aniline 1b with styrene oxide 2a afforded 2-benzyl-3-phenylquino-
line derivative 3b in 73% yield. Likewise, arylamines containing
electron-donating groups at the 4-position, such as 4-Me and 4-
Et, gave the corresponding products 3c and 3d in 76% and 75%
yield, respectively.
Scheme 1. Previous reports and present work for the synthesis of quinoline
derivatives.
arylamines and styrene oxides in the presence of 10 mol% ytter-
bium(III) triflate in acetonitrile at 80 °C (Scheme 1).
The reaction with arylamine 1e containing a methyl group at
the 2-position gave the desired product 3e in 69% yield. Arylamines
with substituents at the 3-position, such as 3-OMe and 3-Me, pro-
vided the expected products 3f and 3 g in 66% and 67% yield,
respectively. Similarly, di-substituted arylamines, such as 2,4-Me,
3,5-Me, 3,4-Me, 3,5-OMe, and 3,4-OMe, also worked well and sub-
stituted quinoline scaffolds 3h-l were obtained in 72–80% yield.
Notably, the sterically crowded 3,4,5-OMe-aniline also furnished
the desired product 3 m in 70% yield. Gratifyingly, bicyclic arylami-
nes, such as 2-naphthylamine, 1-naphthylamine, 5-aminoindan,
and 3,4-(methylenedioxy)-aniline, afforded the corresponding
fused quinoline derivatives 3n-q in 64–72% yield. However, the
reaction was unsuccessful with 4-substituted anilines containing
electron-withdrawing groups, such as Cl, Br, I and NO2.
Result and discussion
To ascertain suitable reaction conditions, p-anisidine 1a and
styrene oxide 2a were chosen as model substrates. Initially, the
reaction was carried out with p-anisidine (1a, 1.0 mmol) and styr-
ene oxide (2a, 2.0 mmol) in acetonitrile without a catalyst. How-
ever, the reaction did not proceed at room temperature or at
80 °C (Entries 1 and 2, Table 1). The reaction also did not proceed
in the presence of 5 mol% Yb(OTf)3 at room temperature (Entry 3,
Table 1), however, upon heating at 80 °C for 6 h, 3a was formed in
46% yield (Entry 4, Table 1).
When the catalyst loading was increased from 5% to 10% the
reaction was complete within 3 h and the yield also increased from
46% to 81% (Entry 5, Table 1). However, further increasing the cat-
alyst loading to 15 mol%, did not improve the yield (Entry 6,
Table 1). To examine the efficiency of other metal triflates, the
reaction was performed with Sc(OTf)3, Bi(OTf)3, and Cu(OTf)2
(Entries 7–9, Table 1), and it was found that Sc(OTf)3 and Bi
Inspired by above-mentioned results, we further extended the
scope and the generality of the method with substituted styrene
oxides 2b and 2c as well as with aliphatic epoxides 2d-2f (Table 3).
The reaction of p-anisidine 1a with styrene oxides 2b and 2c con-
Table 1
Optimization of the reaction conditions.a,b,c,d
Entry
Catalyst
Loading (mol%)
Solvent
Time
Yield 3a (%)b
1c
2
–
–
–
–
5
5
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
H2O
CH3OH
THF
(CH2Cl)2
DMSO
DMF
10 h
10 h
10 h
6 h
3 h
3 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
NR
NR
NR
46
81
76
46
62
NR
NR
NR
43
NR
35
NR
NR
3c
4
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Sc(OTf)3
Bi(OTf)3
Cu(OTf)2
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
5
6
7
8
10
15
10
10
10
10
10
10
10
10
10
10
9
10
11d
12d
13
14
15
16
toluene
a
b
c
Reagents and conditions: p-anisidine (1a, 1.0 mmol), styrene oxide (2a, 2.0 mmol), solvent (1.0 mL), 80 °C.
Isolated yield.
Reaction performed at room temperature.
d
Reaction performed at reflux. NR (no reaction).
2

S. Ali and Abu Taleb Khan
Tetrahedron Letters 70 (2021) 152981
Table 2
Reaction of various arylamines 1a-q with styrene oxide 2a.a,b
Scheme 2. Plausible mechanism for the formation of product 3b.
taining Br and Cl substituents at the 4-position gave the desired
products 3r and 3s in 75% and 72% yield, respectively. In order to
incorporate aliphatic chains at the C-2 and C-3 positions of the
quinoline derivatives, the reaction was performed with p-anisidine
1a and 1,2-epoxybutane 2d which gave the desired product 3-
ethyl-6-methoxy-2-propylquinoline 3t in 79% yield.
Furthermore, the reaction was also carried out with epoxides
containing extended alkyl chains (e.g. 1,2-epoxyhexane 2e and
1,2-epoxydodecane 2f), where the anticipated products 3u and
3v were isolated in 76% and 65% yield, respectively.
a
A plausible mechanism for product formation is outlined in
Scheme 2. Initially, aniline 1b reacts with styrene oxide 2a in the
presence of Yb(OTf)3, which acts as a Lewis acid to provide b-amino
alcohol A by attacking the less hindered side [6a]. Subsequently,
removal of water from intermediate A, affords enamine B that
can be tautomerized to the corresponding imine C. Based on the
proposed mechanism by Beller and co-workers [5a], intermediates
B and C react via an intermolecular Mannich reaction to generate
intermediate D, which undergoes intramolecular electrophilic aro-
matic substitution followed by aromatization to give cyclized
intermediate F. Finally, elimination of aniline 1b from intermediate
F forms dihydroquinoline G, which upon aerial oxidation gives the
desired product 3b.
Reagents and conditions: arylamines (1a-q, 1.0 mmol), styrene oxide (2a,
2.0 mmol), Yb(OTf)3 (10 mol%), CH3CN (1.0 mL), 80 °C.
b
Isolated yield. NR: (no reaction).
Table 3
Reaction of p-anisidine 1a with styrene oxides 2b and 2c and aliphatic epoxides 2d-
f.a,b
In conclusion, we have developed a new, one-pot methodology
for the straightforward access to a variety of 2-benzyl-3-arylquino-
line scaffolds. In this protocol, we have utilized the domino reac-
tion of readily available substituted arylamines and epoxide
derivatives in the presence of 10 mol% Yb(OTf)3 in acetonitrile at
80 °C under an air atmosphere. The advantages of this strategy
are its ease of handling, consecutive formation of two CAN and
two CAC bonds, and broad substrate scope with good yields. It is
noteworthy that aliphatic epoxides also worked well to afford
2,3-dialkylquinoline derivatives.
Declaration of Competing Interest
The authors declare that they no known competing financial
interests or personal relationships that could have appeared to
influence the work reported in this paper.
Acknowledgements
SA is thankful to IIT Guwahati for providing the fellowship. We
are also grateful to CIF, IIT Guwahati for instrument facilities and to
3

S. Ali and Abu Taleb Khan
Tetrahedron Letters 70 (2021) 152981
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the Department of Science and Technology, New Delhi for financial
support (Research grant No.: CRG/2018/002120/OC) to Professor A.
T. Khan. We are also thankful to MHRD for use of their 400 MHz
NMR facility.
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.152981.
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