Synthesis of 2,3-disubstituted quinolines from in situ generated imines and its enamine tautomer under radical cation induced conditions

Article abstract of DOI:10.1016/j.tetlet.2013.07.014

A tandem cyclization/aromatization of anilines and aldehydes was achieved under catalytic radical cation salt induced conditions, producing a series of 2,3-disubstituted quinolines in good yields. In this reaction, the in situ generated imine tautomerizes to enamine, which acts as a dienophile to participate in the tandem cyclization, and further elimination of the anilino group triggers the aromatization of tetrahydroquinolines, avoiding harsh conditions.

Full text of DOI:10.1016/j.tetlet.2013.07.014

Tetrahedron Letters xxx (2013) xxx–xxx
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Tetrahedron Letters
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Synthesis of 2,3-disubstituted quinolines from in situ generated
imines and its enamine tautomer under radical cation induced
conditions
⇑
⇑
Xiaodong Jia , Fangfang Peng, Chang Qing, Congde Huo, Yaxin Wang, Xicun Wang
Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education, China
Gansu Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A tandem cyclization/aromatization of anilines and aldehydes was achieved under catalytic radical cation
salt induced conditions, producing a series of 2,3-disubstituted quinolines in good yields. In this reaction,
the in situ generated imine tautomerizes to enamine, which acts as a dienophile to participate in the tan-
dem cyclization, and further elimination of the anilino group triggers the aromatization of tetrahydro-
quinolines, avoiding harsh conditions.
Received 14 March 2013
Revised 25 June 2013
Accepted 3 July 2013
Available online xxxx
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
2
,3-Disubstituted quinolines
Enamine tautomer
Radical cation
Aromatization
1
7a
The quinoline ring system is a key structural motif found in a
broad range of natural and unnatural compounds. Substituted
quinolines are known to display a wide range of biological activi-
amides.
Different from most literatures’ results (route A,
1
8
Fig. 1), this reaction occurred between imine A and its tautomer,
enamine B, producing a series of 4-anilino-1,2,3,4-tetrahydroquin-
olines in high yield (route B, Fig. 1). The main reason lies in that un-
der single electron oxidation conditions, enamine B prefers to be
1
2
3
7
ties, such as antiinflammatory, antibacterial, antiprotozoan,
4
5
6
antimalarial, antiasthmatic, antituberculosis, antihypertensive,
8
9
10
+Å
antihelmintic, anti-HIV, and anticancer activity. In view of the
remarkable importance of this class of heterocyclic compounds,
great efforts have been devoted to the synthesis of substituted
quinolines. The Conrad–Limpach–Knorr synthesis, the Skraup–
Doebner–Von Miller synthesis, the Friedländer synthesis, and
other methods, are widely recognized synthetic routes for the
preparation of quinoline derivatives. Alternatively, oxidation of
tetrahydroquinoline is also an available method to get quinoline,
oxidized by TBPA than the corresponding N-vinyllactams, for
the anilino group is a stronger electron-donating substituent than
amide. However, most N-alkenyl amides are not available and need
to be pre prepared, so we wondered if aliphatic aldehydes could be
used as candidates to participate in the formation of imine and fur-
ther tandem reactions. Additionally, we also wondered if the ani-
line group can be eliminated under certain reaction conditions, it
11
12
13
1
4
1
5
since the imino Diels–Alder reaction, known as Povarov reaction,
Route A: reported methods
has become one of the most powerful protocols for the synthesis of
tetrahydroquinoline derivatives, due to its efficiency and the ready
availability of starting materials. However, some shortcomings
based on such methodology also exist. Oxidation of tetrahydro-
quinoline is performed under harsh conditions, which limits its
applications in synthesis of quinolines.16 Furthermore, the Povarov
reaction was mostly used to synthesize 4-substituted quinolines,
due to its regioselectivity, so the routes to 3-substituted quinolines
are still limited.
NH
2
X
X
X
LA
N
N
H
Route B: ref. 17a
NH
O
2
R
1
NHPh
N
R2
TBPA+.
TBPA+.
N
A
N
H
As a part of our ongoing research program on synthesis of tetra-
hydroquinolines and quinolines,17 we recently reported a radical
cation salt induced cycloaddition between anilines and N-vinyl
Route C: this work
+.
R = H
65%
TBPA
CH CN
NH2
3
R
R
CHO
TBPA+.
N
H
B
⇑
Corresponding authors. Tel.: +86 931 797 5500; fax: +86 931 7971 989.
E-mail address: jiaxd1975@163.com (X. Jia).
TBPA+.
CH
3
CN
R
N
Figure 1. Different routes to quinoline skeleton.
0
040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.014
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2
X. Jia et al. / Tetrahedron Letters xxx (2013) xxx–xxx
Table 1
NH2
a
Optimization of the reaction conditions
TBPA+. (10 mol%)
+
2a
N
CH CN, reflux
3
MeO
MeO
catalyst
CHO
+
3p
solvent
refluxing
62%
NH2
N
3a
1a
2a
NH
2
TBPA+. (10 mol %)
+
2a
CH CN, reflux
3
N
3
q
5
0%
Entry
Catalyst
TBPA+
TDBPA
CAN
Mol %
Solvent
1:2
Time (h)
Yieldb (%)
Scheme 1. Tandem cyclization of naphthylamines.
1
2
3
4
5
6
7
8
9
5
5
5
5
5
5
5
5
5
1
10
20
10
10
CH
3
CH
3
CH
3
CH
3
CH
3
CH
2
CN
CN
CN
CN
CN
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2.2
1:2.5
2
2
65
20
0
0
0
40
53
50
35
30
70
70
77
85
+
24
24
24
12
12
12
12
24
2
Cu(ClO
4
)
2
R1
NH2
R2
Mn(OAc)
3
R2
N
A
CHO
H2O
+
R1
TBPA
Cl
2
NHAr
-
+
R2
TBPA
CHCl
THF
3
R1
TBPA+. R1
R2
R2
A
R1
+
R2
TBPA
N
H
B
N
H
N
H
+
TBPA
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
OH
CN
CN
CN
CN
CN
B+.
+.
C
+
1
1
1
1
1
0
1
2
3
4
TBPA
+
NHAr
TBPA
B+.
B
R2
R2
R2
+
-NH2Ar
TBPA
2
2
2
R1
R1
[O]
R1
R2
R2
R2
+
TBPA
N
H
N
H
N
+
TBPA
C
a
The reaction was performed with the condenser open to the air.
Determined by 1H NMR analysis of the crude reaction mixture.
Scheme 2. Proposed mechanism.
b
At the outset, we chose the reaction of aniline 1a and aldehyde
a as a model reaction to optimize the reaction conditions. The re-
2
sults are summarized in Table 1.
Table 2
+Å
Initially, we chose TBPA (tris(4-bromophenyl)-aminium hexa-
chloroantimonate, 5 mol %) as a single electron oxidant to induce
this reaction, and the desired quinoline product was obtained in
Scope of radical cation mediated tandem cyclizationa
NH2
R2
+
R2
TBPA . (10 mol %)
+.
R1
CHO
R1
+
R2
65% yield after 20 min (entry 1). But TDBPA (tris(2,4-dibromophe-
CH CN
refluxing
3
N
3
nyl)aminium hexachloroantimonate) gave only 20% yield (entry 2).
No desired product was detected when other oxidants were used
after 24 h (entries 3–5). A solvent screening was then performed
to identify the best reaction conditions. Among the various organic
1
2
MeO
Me
N
N
N
N
3
a
3b
77%
CH3
OMe
3c
70%
3d
7
solvents tested, CH
THF, and CH OH resulted in lower yields of the desired product
entries 6–9). Evaluation of the catalyst loading was also con-
ducted, and the best yield was obtained in the presence of
3 3 2 2
CN was the best solvent while CHCl , CH Cl ,
78%
2%
OMe
OMe
H C
3
3
Cl
(
N
N
N
N
CH3
+Å
10 mol % TBPA (entry 11). Reducing the catalyst loading to
mol % led to a remarkable decrease in the yield (entry 10), but
3e
3f
3g
74%
3h
65%
75%
70%
1
Br
O N
2
MeO
MeO
a higher catalyst loading did not improve the yield (entry 12).
When the equivalent of 2a was increased to 2.5, the quinoline
product 3a was obtained in 85% yield (entry 14).
N
N
N
N
3
i
3j
53%
3l
76%
3
k
5
7%
82%
Next, to extend the generality of this reaction, the tandem cycli-
zation of various anilines 1 with aldehydes 2 was carried out under
optimal conditions, and the results are shown in Table 2. In most
cases, the reactions proceeded smoothly to afford the desired prod-
ucts in good yields. Good results were gained by using electron
donating group substituted anilines (3a–g). When weak electron-
withdrawing groups are connected to anilines, lower yields of
the desired products were obtained (3h and 3i). Strong electron-
withdrawing group, nitro group, made the reaction more difficult,
due to its poor nucleophilicity to form imine intermediate, and the
desired product was isolated in 53% yield (3j). In addition, the
influence of the aldehydes was then investigated. Acetaldehyde
gave the quinoline in 82% yield (3k) and other straight-chain alde-
hydes afforded the corresponding products in medium yields (3l–
n). Aldehyde with a bulky group can also give an acceptable yield
(3m). Phenylacetaldehyde was also used in this reaction, but the
reaction was dirty and only trace of the desired product was found
MeO
MeO
MeO
N
N
N
3
m
3n
3o
6
2%
53%
56%
a
Reaction condition: substrate
1 (0.5 mmol), aldehyde 2 (1.25 mmol), and
TBPA+ . (10 mol %) in 5 mL CH
Å
3
CN, under refluxing. All the yields are isolated yields.
would trigger the aromatization of tetrahydroquinolines to yield
quinoline products (route C, Fig. 1). To our delight, we found if
acetonitrile was used as solvent, the anilino group would be taken
off under radical cation catalyzed conditions, yielding the aromati-
zation product, quinoline, in 65% yield (Fig. 1). This result suggests
that synthesis of 2,3-disubstituted quinolines from commercially
available substrates, anilines, and aldehydes, is possible.
Herein, we report the development of a radical cation salt in-
duced domino cyclization/aromatization between anilines and
aldehydes. This methodology allows access to 2,3-disubstituted
quinolines under mild reaction conditions.
1
according to the crude H NMR. The reason probably lied in that
the existence of another active benzyl position caused additional
side reaction that occurred under the oxidative conditions. Under
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X. Jia et al. / Tetrahedron Letters xxx (2013) xxx–xxx
3
the standard conditions,
pate in this reaction and the desired benzoquinolines were isolated
in 62% and 50% yields, respectively (Scheme 1).
a
- and b-naphthylamine can also partici-
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