Stereoselective synthesis of pyrano[3,2-c]- and furano[3,2-c]quinolines: Gadolinium chloride catalyzed one-pot aza-Diels-Alder reactions

Article abstract of DOI:10.1002/hc.20612

A simple and efficient method for the cis-selective synthesis of pyrano- and furano[3,2-c]quinolines via gadolinium chloride catalyzed onepot aza-Diels-Alder reaction is described. Solvent conditions played amajor role in affecting the diastereoselectivity of the products.

Full text of DOI:10.1002/hc.20612

Heteroatom Chemistry
Volume 21, Number 5, 2010
S
tereoselective Synthesis of Pyrano[3,2-c]-
and Furano[3,2-c]quinolines: Gadolinium
Chloride Catalyzed One-Pot Aza–Diels–Alder
Reactions
Yong Yu, Jun Zhou, Zhigang Yao, Fan Xu, and Qi Shen
Key Laboratory of Organic Synthesis, College of Chemistry, Chemical Engineering and Materials
Science, Soochow University, Suzhou 215123, People’s Republic of China
Received 17 February 2010; revised 19 April 2010
wide spectrum of biological activity that tetrahydro-
ABSTRACT: A simple and efficient method for the
quinoline and its derivatives exhibited [1–4]. The
reaction is atom economical and shows high degrees
of structural diversity, so it has been explored for
catalysts, scope, and applications [5–18]. A series of
cis-selective synthesis of pyrano- and furano[3,2-
c]quinolines via gadolinium chloride catalyzed one-
pot aza–Diels–Alder reaction is described. Solvent
conditions played a major role in affecting the diastere-
oselectivity of the products. ꢀC 2010 Wiley Periodicals,
Inc. Heteroatom Chem 21:351–354, 2010; Published on-
line in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hc.20612
Lewis acids such as Ln(OTf)
3
[12,13], GdCl
3
[14],
molecular iodine [15], TMSCl [16], SbCl
3
[17], and
Selectfluor [18] have been found to be effective
catalysts for this transformation. Normally, the
process affords the products as a mixture of cis
and trans isomers, in which the trans isomer is
the major product in most of the cases. It is note-
worthy that Lewis acid catalyzed one-pot reactions
affording the tetrahydroquinolines stereoselectively
with particular preference for the cis isomers was
a relatively unexplored area with limited num-
ber of literatures in the past. Kobayashi and
Nagayama [12] observed the formation of
furano[3,2-c]quinoline with 62% cis-selectivity
using (polyallyl)scandium trifylamide ditriflate
as a catalyst. More recently, Yadav et al. [18]
demonstrated the utility of Selectfluor as a catalyst
to generate about 90% yield of cis-pyrano- and
furanoquinolines. Therefore, there still remains a
need to develop convenient and practical means for
the efficient and cis-selective synthesis of tetrahy-
droquinolines to meet the growing demand for
selective syntheses of biologically active scaffolds.
Lanthanide complexes are known to be active
Lewis acid catalysts. During our recent investi-
gations on lanthanide halides-catalyzed aza–Diels–
Alder reactions, SmI2 was found to be effective
INTRODUCTION
Stereoselective reaction is a topic of significant
interest in organic synthetic field. The efficient
generation of specific configuration-favored target
molecule by a simple and facile method remains
an aim that synthetic chemists pursued. An aza–
Diels–Alder reaction provides a very important
and powerful method for rapidly constructing aza-
heterocycles. In recent years, increasing attention
has been given to the synthesis of pyrano[3,2-c]-
and furano[3,2-c]quinolines via three-component
aza–Diels–Alder reaction of aldehyde, aryl amine
with dihydropyran or dihydrofuran, due to the
Correspondence to: Fan Xu; e-mail: xufan@suda.edu.cn. Qi
Shen; e-mail: qshen@suda.edu.cn.
Contract grant sponsor: National Natural Science Foundation
of China.
Contract grant number: 20872106, 20972107.
ꢀ
c 2010 Wiley Periodicals, Inc.
351

352 Yu et al.
in catalyzing the one-pot reaction of aldehyde,
aromatic amine with dihydropyran or dihydrofuran
to form pyrano- or furano[3,2-c]quinolines, and a
controllable stereoselectivity of either the cis or the
trans isomers was observed under kinetic-controlled
or thermodynamic-controlled conditions [19]. How-
ever, only an average of 75% cis-selectivity could
be achieved, while changing the reaction conditions
gave an almost quantitative yield of the trans iso-
mers. Our attention was then turned to the possi-
bility using other simple and easily available lan-
thanide compounds, such as lanthanide chlorides,
as the catalysts for the synthesis of tetrahydroquino-
lines with the aim in getting better cis-selectivity. It
has come to our knowledge that Qian and co-workers
TABLE 1 Evaluation of Reaction Conditions for GdCl3-
a
Catalyzed Synthesis of Pyranoquinoline
Entry
n
Time (h) Solvent Isolated Yield (%) 4a:5ab
1
2
3
4
5
6
7
1.5
1.5
5
0.5
6
6
6
6
12
12
/
/
/
/
27
66
81
84
71
87
80
84:16
81:19
82:18
81:19
83:17
82:18
47:53
10
c
c
1.5
1.5
1.5
THF
THF
THF
d
a
Typical reaction conditions: benzaldehyde/aniline/dihydropyran =
1
:1.1: n, 1 mmol benzaldehyde, 0.25 mmol GdCl
3
, 125 mg 5 A˚ molec-
◦
ular sieves, 30 C.
b
c
d
1
Determined by H NMR spectroscopy.
.2 mL THF was used.
mL THF was used.
0
1
[
14] had reported the reaction catalyzed by gadolin-
ium trichloride (GdCl ) giving a 67% trans-selectivity
of the products. Herein, we wish to present a
GdCl -catalyzed but highly cis-selective synthesis
3
of 10 equiv dihydropyran (entry 4). From a struc-
tural point of view, dihydropyran is a kind of cyclic
ether. Thus a small amount of THF was added as
solvent in place of excessive dihydropyran to avoid
the waste of substrate, and an 83:17 cis/trans ratio
with 71% yield was obtained (entry 5). It was no-
ticed that increasing the amount of THF resulted in
a decrease in either the yield or the cis-selectivity of
the product. For example, when the amount of THF
was increased from 0.2 to 1 mL, the cis content de-
creased dramatically from 82% to 47%, indicating
that the amount of THF plays an important role in
the stereoselectivity of the reaction (entries 6 and 7).
Encouraged by the results obtained in THF, a
serial of solvents were screened and the similar
cis-selectivity was observed in most of the cases as
shown in Table 2. Among the solvents tested, those
with lower polarity and lower coordination abil-
ity, such as toluene and hexane, gave lower yields
(Table 2, entries 1–3), whereas those with moder-
ate polarity and moderate coordination ability, such
as THF and DME, gave increased yields accompa-
nied with high cis-selectivity (entries 4–7). The re-
actions carried out in pyridine and HMPA failed
3
of tetrahydroquinolines via three-component aza–
Diels–Alder reaction under given conditions.
RESULTS AND DISCUSSION
First, the one-pot aza–Diels–Alder reaction catalyzed
by GdCl
tion, which was the essential condition favorable for
the cis-selective synthesis of the product with SmI
as catalyst [19], benzaldehyde (1a), aniline (2a), and
,3-dihydropyran (3a) being used as typical sub-
strates (Scheme 1). The satisfying cis/trans ratio of
4:16 was observed, however, accompanied with a
3
was carried out under solvent-free condi-
2
2
8
rather low yield (Table 1, entry 1) which probably
was due to the poor mixing between the catalyst and
the substrates in the absence of solvent. Prolonged
reaction time led to an increase in yield, whereas
the cis content of the product decreased slightly
(entry 2). To mix the catalyst and substrates bet-
ter, an excess of dihydropyran was used. Just as we
expected, a promising good result with yield of 84%
and cis/trans ratio of 81:19 was observed by the use
H
H
H
H
CHO
NH2
O
O
O
2
5 mol% GdCl3
H
H
NH
NH
+
+
+
3
0oC
1a
2a
3a
4a
5a
cis
trans
SCHEME 1 One-pot synthesis of pyranoquinoline.
Heteroatom Chemistry DOI 10.1002/hc

Stereoselective Synthesis of Pyrano[3,2-c]- and Furano[3,2-c]quinolines 353
TABLE 2 Solvent Screening for GdCl -Catalyzed One-Pot
endo mode (forming cis-diastereomer). On the other
hand, the presence of CH CN as a linear molecule of
3
Synthesis of Pyranoquinolinea
3
small bulk may block or diminish the coordination
of Gd(III) ion to enol ether by occupancy of the free
coordination site of Gd(III) (Fig. 1, B), and the addi-
tion in the exo mode (forming trans-diastereomer) is
preferred because it suffers fewer steric repulsion in-
teraction. The systematic studies of solvent-effect on
the stereoselectivity of the reaction are under further
investigation currently.
Entry
Solvent
Isolated Yield (%)
4a:5ab
1
2
3
4
5
6
7
8
9
Hexane
c-Hexane
Toluene
DME
DEE
Dioxane
THF
44
43
62
74
75
80
87
85:15
82:18
83:17
79:21
86:14
80:20
82:18
–
c
Pyridine
HMPA
n.d.
n.d.
Subsequently, the effects of temperature and
time on the yield and stereoselectivity were exam-
ined to optimize the reaction conditions further. De-
c
–
10
CH CN
84
39:61
3
a
◦
◦
Typical reaction conditions: benzaldehyde/aniline/dihydropyran =
creasing the reaction temperature from 30 C to 0 C
led to an increase in the cis-content of the product
from 83% to 90% but accompanied with an inferior
yield of 42%. However, a satisfactory isolated yield
of 80% and cis-selectivity of 88% was achieved when
the reaction time was prolonged from 12 h to 30 h
1
:1.1:1.5, 1 mmol benzaldehyde, 0.25 mmol GdCl
3
, 125 mg 5 A˚
◦
molecular sieves, 0.2 mL solvent, 30 C, 12 h.
b
c
1
Determined by H NMR spectroscopy.
Not detected.
to afford the target products, probably because the
strong electron-donating ability of these solvents
shuts down the reaction by blocking the coordina-
tion of the substrates with Gd(III) ions (entries 8
and 9). To our surprise, with CH CN the reverse of
stereoselectivity happened (entry 10).
The reaction should proceed via an aza–Diels–
Alder process of N-phenylimine, which is generated
in situ from benzaldehyde and aniline, with cyclic
enol ether resulting in the formation of tetrahydro-
quinoline. Generally, the cis–trans diastereoselectiv-
ity of aza–Diels–Alder reaction can be explained by
secondary orbital interactions, steric repulsive inter-
actions, and so on. The Lewis acid used in the reac-
tion, including its coordination ability and manner,
is another a key factor affecting the ratio of two iso-
mers. The significant difference in the stereochem-
istry of the products presented between THF and
◦
at 0 C.
The generality of the present aza–Diels–Alder re-
action for the cis-favored synthesis of tetrahydro-
quinolines was investigated with structurally varied
aromatic aldehydes and aromatic amines with dihy-
dropyran or dihydrofuran under the established con-
ditions (Scheme 2). The results are summarized in
Table 3. All the reactions proceeded smoothly except
for that involving p-tolualdehyde, affording the cor-
responding tetrahydroquinolines with moderate to
high yields, and the cis products were obtained with
3
86% selectivity on average. When 2,3-dihydrofuran
was employed as substrate, a faster reaction rate
was observed. The marked rate sensitivity to the
TABLE
3 GdCl -Catalyzed One-Pot Synthesis of
3
a
Tetrahydroquinolines
CH CN may be rationalized by the ligand effect of
3
Entry R1
R2
n Time (h) Isolated Yield (%) 4:5b
them. When the reaction takes place in small amount
of THF (1 mmol PhCHO/0.2 mL THF), partly sol-
vated Gd(III) [20] may coordinate with imine and
enol ether at the same time (Fig. 1, A), which fa-
vors the addition of the two components in the
1
2
3
4
5
6
7
8
H
4-F
4-Cl
4-Br
4-Me
2-Cl
3-F
H
H
H
H
H
H
H
H
H
H
H
H
4-F
4-Cl
4-Br
4-Me
2
2
2
2
2
2
2
2
2
2
2
30
36
30
30
30
30
30
36
30
30
36
36
3
80
93
93
99
55
63
99
70
82
82
90
62
96
90
88:12
85:15
83:17
84:16
88:12
84:16
89:11
82:18
80:20
82:18
89:11
97:3
9
N
N
10
11
12
1
1
[Gd](CH CN)
3 n
[Gd]
Ph
O
Ph
4-MeO 2
O
3
4
H
4-Me
H
H
1
1
76:24
84:16
3
A
B
a
Typical reaction conditions: aldehyde/amine/enol ether = 1:1.1:1.5,
1
mmol aldehyde, 0.25 mmol GdCl
3
, 125 mg 5 A˚ molecular sieves,
◦
FIGURE 1 Proposed addition modes for Gd(III)-catalyzed
aza–Diels–Alder reaction.
0.2 mL THF, 0 C.
b
1
Determined by H NMR spectroscopy.
Heteroatom Chemistry DOI 10.1002/hc

354 Yu et al.
R2
+
R2
H
H
H
H
CHO
NH2
O
n
O
n
O
H
2
5 mol% GdCl3
0oC, THF
H
+
+
NH
NH
n
R1
R2
n = 1, 2
R1
R1
1
2
3
4
5
SCHEME 2 One-pot synthesis of tetrahydroquinolines.
structure of enol ether is similar to that found in
vacuo and purified by chromatography on silica gel
[eluant: EtOAc/petroleum ether (60–90 C) 1:30] to
◦
InCl
3
-catalyzed domino reactions [21].
In conclusion, we demonstrated here a simple
and efficient method for the cis-selective synthesis
of pyrano- and furano[3,2-c]quinolines via one-pot
aza–Diels–Alder reactions in the presence of catalytic
afford the pyrano[3,2-c]quinoline.
REFERENCES
amount of GdCl . The solvent conditions, particu-
3
larly the type and amount of the solvent, are the
predominant factors affecting the stereoselectivity
of the product. The further applications of this cat-
alytic system and its solvent-controlled stereoselec-
tivity are now underway.
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EXPERIMENTAL
General Remarks
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1
[
300 spectrometers using tetramethylsilane (TMS) as
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and chemical shifts of protons, which was accordant
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General Procedure
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A mixture of aniline (0.1 mL, 1.1 mmol), ben-
1
zaldehyde (0.1 mL, 1.0 mmol), GdCl
3
(65.9 mg,
˚
0.25 mmol), and 5 A molecular sieves (125 mg) was
stirred in THF (0.2 mL) for 10 min at room tempera-
ture. Then 2,3-dihydropyran (0.13 mL, 1.5 mmol)
was added, and the mixture was allowed to stir
at an appropriate temperature for a given time.
Water was added to the residue, and the mixture
extracted with EtOAc. The combined organic layers
were dried over anhydrous Na
2
SO , concentrated in
4
Heteroatom Chemistry DOI 10.1002/hc