Radical cation salts induced aza-diels-alder reaction: Synthesis of hexahydrofuro[3,2-c]-quinoline derivatives

Article abstract of DOI:10.2174/157017812800167484

Aza-Diels-Alder reaction between imines and 2,3-dihydrofuran under radical cation induced conditions was achieved and series of hexahydrofuro[3,2-c] quinoline derivatives was prepared. The stereoselectivity was affected by the substituents on imines, whic

Full text of DOI:10.2174/157017812800167484

Letters in Organic Chemistry, 2012, 9, 221-224
221
Radical Cation Salts Induced aza-Diels-Alder Reaction: Synthesis of
Hexahydrofuro[3,2-c]- quinoline Derivatives
Zhong Jia*,a, Yan Renb, Cong-De Huob, Xiang-Ning Chenb, Chong-Xiang Tonga and
Xiao-Dong Jia*,b
aDepartment of Pharmacy, Pulmonary Hospital of Lanzhou, Lanzhou 730046, P. R. China
bKey Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education, P. R. China
Received June 30, 2011: Revised October 24, 2011: Accepted January 26, 2012
Abstract: Aza-Diels-Alder reaction between imines and 2,3-dihydrofuran under radical cation induced conditions was
achieved and series of hexahydrofuro[3,2-c]quinoline derivatives was prepared. The stereoselectivity was affected by the
substituents on imines, which revealed a stepwise mechanism. A radical cation mediated mechanism was proposed to
rationalize the formation of the products.
Keywords: Aza-Diels-Alder reaction, Hexahydrofuro[3,2-c]quinolines, radical cation.
INTRODUCTION
yields and with high selectivity. Herein, we wish to report
the synthesis of hexahydrofuro[3,2-c]quinoline derivatives
via this kind of aza-Diels-Alder reaction induced by radical
cation salts.
Tetrahydroquinoline scaffold is present in various
biologically active alkaloids and many tetrahydroquinoline
derivatives exhibit numerous biological activities, [1-3] in
which furanoquinoline derivatives are an important class of
natural products and exhibit a wide spectrum of biological
activities, such as antiallergic, anti-inflammatory, antipy-
retic, analgesic, antiplatelet, psychotropic and estrogenic
activity. [4-8] Many biologically active alkaloids, such as
teclealbine and flindersiamine, contain furanoquinoline
moieties. The probably most powerful method for the
construction of tetrahydroquinolines is aza-Diels-Alder
reaction between N-arylimines and 2,3-dihydrofuran (DHF),
due to its efficiency and the ready availability of starting
materials. [2, 3, 9-12] Recently, new progress including
domino reaction among anilines and DHF has been achieved
[13ꢀ16], but some shortcomings of this methodology also
exist. In most cases, more than stoichiometric amounts of the
catalysts are required and furthermore, most of the imines
are hygrosopic, unstable at high temperatures and are
difficult to purify by distillation or column chromatography.
Therefore, it is necessary to develop more simple, con-
venient and efficient catalysts to synthesize tetrahydro-
quinolines under mild conditions.
Our studies began with the reaction of imine 1a and DHF
(2) catalyzed by TBPA+.. An anhydrous solution of 1a and 2
in CH2Cl2 was added dropwise to a stirred solution of a
catalytic amount of TBPA+. suspended in anhydrous
dichloromethane at ambient temperature. The reaction
completed within 10–15 minutes as detected by TLC, giving
exclusively two diasteroisomers of the tetrahydroquinoline
derivative
3
and
4
in excellent yield. Column
chromatographic purification (silica gel, hexane/acetone 40:1
to 20:1) gave the pure products, which were fully
characterised. Based on these results, we chose the reaction
of imine 1a and 2 as a model reaction to optimize the
reaction conditions. The results are summarized in Table 1.
[26] Initially, we added the same equivalent of the reactants
to the reaction solution and the products 3a and 4a were
obtained in 82% yield. Higher yield was obtained when the
ratio of imine: DHF was raised to 2:1 (entry 2). Addition of
more DHF did not improved the yield. We then screened the
solvents. CHCl3 and CH3CN lead to lower yields, probably
due to lower solubility of TBPA+.. Lower catalysts load also
decreased the yields of the desired products.
Commercially available, stable radical cation salt tris(4-
bromophenyl)aminium hexachloroantimonate (TBPA+.)
induced reactions have been investigated for more than 20
years, and many valuable reactions initiated by such catalyst
have been discovered in organic chemistry. [17, 18] As part
of our ongoing research program on exploring the synthetic
potentials of such catalyst, [19ꢀ25] we recently found that
TBPA+. could efficiently induce aza-Diels–Alder reaction to
accomplish the synthesis of tetrahydroquinolines in good
With the optimized reaction conditions in hand, we then
explored the scope of the reaction by varying the substituents
on the aromatic ring of the imines. The results are
summarized in Table 2.
Imines 1 with either electron-withdrawing or electron-
donating substituents were synthesized to test the generality
of this methodology. From Table 1 we can see that all imines
reacted with 2a smoothly giving exclusively the
corresponding tetrahydroquinoline derivatives. But the
stereoselectivity was affected obviously by the substituents
on imines. Electron-withdrawing groups on Ar1 or electron-
donating groups on Ar2 increased the exo selectivity, giving
more trans-products in the products mixture and inverse
*Address correspondence to these authors at the Gansu Key Laboratory of
Polymer Materials, College of Chemistry and Chemical Engineering,
Northwest Normal University, Lanzhou, Gansu 730070, P. R. China; Tel:
+86-931-7975550; Fax: +86-931-7971989; E-mail: jiaxd1975@163.com
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

222 Letters in Organic Chemistry, 2012, Vol. 9, No. 3
Jia et al.
Table 1. Optimization of the Reaction Conditions
O
O
TBPA+.
solvent
cis and trans
+
N
N
H
1a
3a and 4a
2
Entry
Solvent
Substrate 1a : 2
Timea (h)
Yieldb (%)
cis : trans (%)
1 c
2 c
3 c
4 c
5 c
6 d
7 e
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
1:1
2:1
3:1
2:1
2:1
2:1
2:1
0.5
0.5
0.5
0.5
0.5
0.5
0.5
82
95
95
79
80
85
83
> 90:10
> 90:10
> 90:10
85:15
CH3CN
CH2Cl2
CH2Cl2
83:17
> 90:10
> 90:10
aMonitored by TLC. bDetected by crude 1HNMR. c5 mol % TBPA+. was added. d2 mol % TBPA+. was added. e1 mol % TBPA+. was added.
Table 2. Scope of the Reaction of 1 and 2
O
TBPA+.
R1
O
(5 mol %)
R1
+
N
cis and trans
R2
R2
CH2Cl2
N
H
1
2
3 and 4
Entry
R1
R2
Timea (h)
Yieldb (%)
cis : trans
1
2
H
H
H
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
93
85
83
77
75
79
87
90
81
80
84
78
>90:10 (3a : 4a)
37:63(3b : 4b)
<10:90 (3c : 4c)
74:26 (3d : 4d)
48:52 (3e : 4e)
<10:90 (3f : 4f)
48:52 (3g : 4g)
48:52 (3h : 4h)
>90:10 (3i : 4i)
51:49 (3j : 4j)
50:50 (3k : 4k)
31:69 (3l : 4l)
p-NO2
p-NO2
p-NO2
p-NO2
p-NO2
p-CN
p-F
3
p-OCH3
p-Cl
p-Br
p-CH3
p-CH3
H
4
5
6
7
8
9
H
p-Cl
H
10
11
12
p-Cl
p-Br
p-CH3
H
H
aObserved by TLC. bIsolated yields. cDetermined by crude 1HNMR.
electrical property led to lower exo selectivity. However, in
the most cases, the stereoselectivity was about 1:1, which
implied that a stepwise instead of concerted mechanism was
involved in the reaction.
and thus for a successful cation radical aza-Diels–Alder
reaction to take place. This criterion was also supported in
this reaction. Therefore the following radical cation
mechanism was proposed to rationalize the formation of the
products.
Firstly, DHF was oxidized by TBPA+., producing its
cation radical intermediate 2. This radical cation added to an
Our previous research have revealed that the oxidation
potential of the dienophile must be lower than that of the
imine in order for the former to be preferentially oxidized

Radical Cation Salts Induced aza-Diels-Alder Reaction
Letters in Organic Chemistry, 2012, Vol. 9, No. 3 223
O
O
Ar1
O
O
O
TBPA+.
N
Ar2
N
Ar2
N
Ar2
2
2+.
6
5
O
O
2
2+.
1,3-H shift
N
Ar2
N
Ar2
H
3 and 4
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imine forming a new cation radical intermediate and
intramolecular addition is followed. After the second
electron transfer with another DHF to propagate the radical
chain reaction and 1,3-H shift, the hexahydrofuro[3,2-
c]quinoline derivatives were produced in a stereoselective
way.
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In summary, we have executed a efficient approach
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focused on promoting this transformation and further
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ACKNOWLEDGEMENT
We thank Science and Technology Development Project
of Lanzhou (2010-1-61) for supporting our research.
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DISCLOSURE
Part of information included in this article has been
published in our previous paper (Chinese Chemical Letters
Volume 22, Issue 6, June 2011, Pages 671-674).
[14]
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CONFLICT OF INTEREST
Declared none.
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75.9, 114.9, 119.1, 122.7, 126.5, 127.6, 128.3, 128.6, 130.1, 142.1,
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3H), 4.05-4.11 (m, 1H), 4.59 (d, J = 5.2 Hz, 1H), 6.63 (d, J = 8.0
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(100%); ESI-HRMS: m/z Calcd for C17H17NO+H: 252.1383,
found: 252.1379.
Representative Spectral Data of the Products. 3a (syn-): 1H
NMR (400 MHz, CDCl3): ꢀ 1.48-1.56 (m, 1H), 2.16-2.26 (m, 1H),
2.75-2.82 (m, 1H), 3.68-3.74 (m, 1H), 3.79-3.85 (m, 2H), 4.69 (d, J