Br?nsted acid (HNO3)-catalyzed tandem reaction of α-ketoesters and arylamines: Efficient synthesis of 1,2-dihydroquinoline derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.03.134

A simple and convenient Br?nsted acid (HNO₃)-catalyzed tandem reaction of α-ketoesters with primary or secondary aromatic amines for the synthesis of polysubstituted 1,2-dihydroquinolines has been developed via a tandem process, which has the advantages of ready availability of catalyst, operation simplicity, atom efficiency as well as low toxicity. In particular, tricyclic dihydroquinolines, generally prepared with multi-processes, could also be constructed in this one-pot procedure.

Full text of DOI:10.1016/j.tetlet.2011.03.134

Tetrahedron Letters 52 (2011) 2903–2905
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Brønsted acid (HNO3)-catalyzed tandem reaction of
a-ketoesters
and arylamines: efficient synthesis of 1,2-dihydroquinoline derivatives
Xiao-Yu Hu a,b, Ji-Chen Zhang a,b, Wei Wei a,b, Jian-Xin Ji a,
⇑
a Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
b Graduate University of the Chinese Academy of Sciences, Beijing 100049, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and convenient Brønsted acid (HNO3)-catalyzed tandem reaction of a-ketoesters with primary
Received 14 March 2011
Accepted 28 March 2011
Available online 1 April 2011
or secondary aromatic amines for the synthesis of polysubstituted 1,2-dihydroquinolines has been devel-
oped via a tandem process, which has the advantages of ready availability of catalyst, operation simplic-
ity, atom efficiency as well as low toxicity. In particular, tricyclic dihydroquinolines, generally prepared
with multi-processes, could also be constructed in this one-pot procedure.
Keywords:
Brønsted acid
Tandem reaction
Ó 2011 Elsevier Ltd. All rights reserved.
a-Ketoesters
Arylamines
1,2-Dihydroquinoline derivatives
One of the great challenges facing chemists this century is to
develop simple, efficient, and economic transformations.1 Nowa-
days, using micromolecular Brønsted acids as catalysts has at-
tracted much extensive attention for their charming advantages
of cheapness, nontoxicity and operation simplicity.2
generally prepared with multi-processes,11 could also be con-
structed in this one-pot protocol, which demonstrated excellent
synthetic efficiency.
Initially, a series of Brønsted acids were applied to the
1,2-Dihydroquinoline and their derivatives are ubiquitous in
nature, and can serve as important subunits to design tremendous
synthetic drug candidates due to their significant pharmacological
properties.3,4 To date, numerous synthetic strategies have been re-
ported for achieving these heterocycles formation,5 such as modi-
fied Skraup reactions,6 Michael-aldol reaction7 and tandem
reactions of aromatic amines with alkynes.8 Many of these well
developed methods always employed metal salts or large organo-
metallic complexes as catalysts accompanied by the following lim-
itations: heavy atom pollutions, costliness and complex operation.
To the best of our knowledge, only one example of Brønsted acid
mediated reaction of pyruvic acid with aniline and CH2N2 has been
reported for the construction of 1,2-dihydroquinoline derivative, in
which multi-step procedure and excess of trifluroecetic acid were
employed.9 Herein, we report a simple and convenient Brønsted
ð1Þ
transformation of p-chloroaniline (2a) and methyl pyruvate
(1a) into 1,2-dihydroquinoline (3aa) (Table 1). Among various cat-
alysts examined, nitric acid exhibited the best catalytic activity
(entry 7). Hydrochloric acid, trifluoroacetic acid and methanesulf-
onic acid also gave the desired product in moderate to good yields
(entries 2, 6, and 10). While, sulphuric acid, phosphoric acid and
boracic acid were not effective for the present transformation (en-
tries 3–5). Under the standard conditions, no reaction was ob-
served in the absence of catalyst, or in the presence of formic
acid and acetic acid (entries 1, 8, and 9).
Next, other factors (solvent, temperature and proportion of the
substrates) were examined using nitric acid as catalyst (Table 2).
Acetonitrile was proved to be the appropriate reaction media while
others gave lower yields of the targets (entries 1–6). The reaction
could not proceed at room temperature, and the best yield was ob-
tained at 80 °C (entries 1, 7, and 8). In addition, the proportion of
substrates also had influence on the efficiency. Compared with
entry 1, much excess of 1a (entry 11) or 2a (entry 9) would inhibit
the transformation.
acid (HNO3)-catalyzed one-pot tandem reaction of
a-ketoesters
with primary or secondary aromatic amines for the effective syn-
thesis of polysubstituted 1,2-dihydroquinoline derivatives (Eq. 1).
Previously, these compounds could only be prepared by Au/Ag-
cocatalyzed procedure (5 mol % and 15 mol %, respectively).10 It is
worth mentioning that complex tricyclic dihydroquinolines,
⇑
Corresponding author. Tel.: +86 28 82855463; fax: +86 28 82855223.
E-mail address: jijx@cib.ac.cn (J.-X. Ji).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.134

2904
X.-Y. Hu et al. / Tetrahedron Letters 52 (2011) 2903–2905
Table 1
Table 3
Screening of the catalystsa
Brønsted acid-catalyzed tandem reaction of various
a-ketoesters and aromatic
aminesa
Products (Yieldsb)
Products (Yieldsb)
Entry
Catalystc
Yieldb (%)
3aa (88%)
3ac (64%)
3ae (96%)
3ag (83%)
3ab (95%)
3ad (31%)
3af (94%)
3ah (69%)
1
2
3
4
5
6
7
8
9
None
HCl
H2SO4
H3PO4
H3BO3
CF3COOH
HNO3
HCOOH
CH3COOH
CH3SO3H
None
83
13
Trace
9
70
88
None
None
61
10
a
Reaction conditions: compound 1a (1.5 mmol) and 2a (1 mmol) in CH3CN
(1.5 mL) for 12 h.
Isolated yields based on 1a.
Concentration of the acids: HCl (34–37.5%), H2SO4 (95–98%), H3PO4 (85%), HNO3
(65–70%).
b
c
3ai (92%)
3ba (80%)
Table 2
Optimization of the reactiona
a
Reaction conditions: HNO3 (10 mol%),
a
-ketoester (1.5 mmol) and arylamine
(1 mmol) in CH3CN (1.5 mL) for 8-24 hours.
Entry
T (°C)
Solvent
1a (mmol)
2a (mmol)
Yieldb (%)
b
Isolated yields based on a-ketoester.
1
2
3
4
5
6
7
8
9
80
80
80
80
Reflux
80
rt
60
80
CH3CN
DMF
DMSO
Toluene
THF
1,4-Dioxane
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1
1
1
1
1
1
1
1
1
88
40
18
23
23
32
None
64
61
1
1
0.5
10
11
80
80
2
1.5
68
78c
a
Reaction conditions: HNO3 (10 mol %), compound 1a (1.5 mmol), 2a (1 mmol)
in CH3CN (1.5 mL) for 12 h.
b
Isolated yields based on 1a.
Isolated yields based on 2a.
c
Scheme 1. Preparation of tricyclic dihydroquinolines.
The scope and generality of this process were explored with re-
spect to various aromatic amines, and a series of 1,2-dihydroquin-
oline derivatives were obtained in good to excellent yields under
the optimized conditions (Table 3). Electronic effect on the aro-
matic ring of amines had significant influence on the productivity.
Those containing electron-donating or neutral groups gave the de-
sired products in good to excellent yields (3ab, 3ae, 3af, and 3ai),
however, amines bearing electron-withdrawing groups gave the
targets in comparatively lower yields (3aa, 3ac, 3ad, and 3ag).
Ortho-substituted amines also gave relatively lower yields, be-
cause of the steric effect (3ah).
It was worth mentioning that indoline (2j) and 3-quinolinamine
(2k) could also tolerate in this process and produced the tricyclic
compounds in moderate yields. Hence, our methodology will pro-
vide a convenient route for construction of complex tricyclic dihy-
droquinolines (Scheme 1, 3aj and 3ak), which are usually prepared
through multi-step reactions and need cumbersome and laborious
procedures.11
Scheme 2. Proposed mechanism.
In order to obtain further insights into this reaction, control
experiments were performed as shown in Eq. 2–3.9 When methyl
pyruvate (1a) reacted with p-methoxyaniline (2f) in the absence
of catalyst, imine 4af could be isolated together with a trace
amount of enamine isomer (Eq. 2). Furthermore, treatment of 4af
with 1a under the standard procedure led to the formation of de-
sired product 3af (Eq. 3). The above results indicated that imine
or enamine complex might be the critical intermediate in this tan-
dem reaction.

X.-Y. Hu et al. / Tetrahedron Letters 52 (2011) 2903–2905
2905
References and notes
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ð2Þ
ð3Þ
On the basis of the above results and previous studies,10
tentative mechanism was proposed and shown in Scheme 2.
Firstly, a-ketoester (1) reacts with amine (2) to generate the imine
a
or enamine intermediate 4, which is followed by addition of the
enolate (quickly formed from the tautomerization of ketoester),
and produces intermediate 5. Subsequently, the electron-rich
benzene ring could add to the keto group to give intermediate 6.
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In summary, we have developed a simple and efficient method
for the synthesis of polysubstituted 1,2-dihydroquinoline deriva-
tives including tricyclic ones via
a one-pot tandem process
employing nitric acid as catalyst. Taking into account the combina-
tion of desirable features, such as operation simplicity, cheap and
readily available catalyst, atom efficiency as well as low toxicity,
this catalytic system is expected to provide an expedient access
to construct versatile dicyclic and tricyclic 1,2-dihydroquinoline
building blocks, which can be used for the synthesis of new drug
candidates and other potential biological active molecules. The
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a
multi-step reaction for the synthesis of 1,2-
dihydroquinoline from pyruvic acid and aniline, in which self-aldol
condensation of pyruvic acid was considered as the key step. However, in
our reaction system, when methyl pyruvate (1a) was performed separately in
the presence of HNO3, no self-aldol condensation product of methyl pyruvate
was detected, suggesting that
involved in this process.
a different reaction mechanism might be
Acknowledgments
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We are grateful for the financial support from the National
Science Foundation of China (20802072).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.03.134.