Novel and efficient Lewis acids as catalysts for single-step synthesis of pyrano- and furoquinolines

Article abstract of DOI:10.1246/cl.2004.1526

Some Lewis acids such as ZrCl₄, SnCl₄, TiCl ₄, and PtCl₄ have been found to be novel and highly efficient catalysts for one-pot coupling of the three components, anilines, aldehydes, and 3,4-dihydro-2H-pyran or 2,3-dihydrofuran to produce the corresponding pyrano- or furoqinolines in high yields and high diastereoselectivity.

Full text of DOI:10.1246/cl.2004.1526

1526
Chemistry Letters Vol.33, No.11 (2004)
Novel and Efficient Lewis Acids as Catalysts for Single-step Synthesis
of Pyrano- and Furoquinolines1
Biswanath Das,ꢀ M. Ravinder Reddy, V. Saidi Reddy, and R. Ramu
Organic Chemistry Division-I, India Institute of Chemical Technology, Hyderabad-500 007, India
(Received July 20, 2004; CL-040850)
Some Lewis acids such as ZrCl4, SnCl4, TiCl4, and PtCl4
have been found to be novel and highly efficient catalysts for
one-pot coupling of the three components, anilines, aldehydes,
and 3,4-dihydro-2H-pyran or 2,3-dihydrofuran to produce the
corresponding pyrano- or furoqinolines in high yields and high
diastereoselectivity.
column chromatography over silica gel. The trans-isomer was
the major and cis-isomer minor in each conversion. The reaction
thus proceeded with high yield and high diastereoselectivity.
The ratio of the isomers formed in a reaction was determined
by H NMR spectrum of the crude product and the structures
of the products were established from the spectral (1H NMR
and MS) data of the pure compounds.8
1
To examine the catalytic activity of different Lewis acids
such as AlCl3, FeCl3, SnCl4, TiCl4, ZrCl4, HfCl4, PtCl4, and
WCl6 each catalyst (0.1 equiv.) was added separately to a solu-
tion of aniline (1 mmol), benzaldehyde (1 mmol) and 3,4-dihy-
dro-2H-pyran (1.1 mmol, 0.1 mL) in CH3CN (10 mL) at room
temparature for 0.5 h. ZrCl4 was found to be the most effective
catalyst under the present experimental conditions in term of
the yield of pyranoquinoline (86%). The activity of SnCl4,
TiCl4, and PtCl4 was comparable forming the pyranoquinoline
with yields of 82, 78, and 76%, respectively. However, the activ-
ity of HfCl4 and WCl6 was somewhat low and the former formed
the pyranoquinoline with a yield of 67% while the latter with a
yield of 61%. The reaction with other lewis acids, AlCl3 and
FeCl3 produced the pyranoquinoline with yields of 47 and
43%, respectively.
Pyranoquinolines have been found to possess different im-
portant pharmacological activities such as anti-inflammatory,
antiallergic, and estrogenic properties.2 Various bioactive natu-
ral alkaloids are pyranoquinoline derivatives.3 The synthesis of
such compounds is thus quite necessary. Pyranoquinolines are
generally prepared by the aza-Diels–Alder reaction of imines
(derived from aromatic amines and benzaldehydes) with 3,4-di-
hydro-2H-pyran.4 Various Lewis acids are used4,5 to catalyze
this reaction. However, many of these Lewis acids are expensive
or not easily available, require longer times to complete the re-
actions and form the mixture of products. Several imines are also
unstable, hygroscopic, and difficult for purification and thus the
preparation of these compounds in pure form followed by cou-
pling with dihydropyran in steps is not advantageous. However,
a number of Lewis acids cannot be applicable for one-pot cou-
pling of anilines, aldehydes, and dihydropyran or furan as they
will be decomposed or deactivated by amines and water formed
in the intermediate imine formation stage. Thus there are a lim-
ited number of reported methods6 for single-step coupling of
these three components though different processes for multi step
coupling are well known.
In the present process the imines generated in situ by con-
densation of anilines and benzaldehydes act as heterodienes
which undergo the aza-Diels–Alder reaction with the electron
rich dienophile, 3,4-dihydro-2H-pyran or 2,3-dihydrofuran in
the presence of ZrCl4 to produce the corresponding pyrano- or
furoquinolines. The conversion could not be achieved in absence
In continuation of our work7 on the development of novel
synthetic methodologies, we have recently discovered that ZrCl4
is a highly effective catalyst for the preparation of pyrano- or fur-
anoquinolines by coupling of anilines (1), benzaldehydes (2),
and 3,4-dihydro-2H-pyran or 2,3-dihydrofuran (3) (Scheme 1).
A series of pyrano- and furoquinolines were prepared8 by
following the above method. The products (4 and 5) were the
mixture of trans- and cis-isomers which could be separated by
Table 1. Preparation of pyrano- and furoquinolines using
a
ZrCl4
Aniline
(1)
Benzaldehyde Olefin
Isolated Product
Yield Ratiob
Time
/min
Entry
(2)
(3)
n
R1 R2
R3
R4
H
/%
(4:5)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
H
H
H
H
H
H
H
2
2
2
2
2
2
2
2
1
1
1
1
1
1
35
45
30
45
35
40
45
50
45
50
40
55
50
60
88
91
93
90
94
91
90
80
85
88
90
92
86
75
87:13
90:10
94:6
88:12
92:8
86:14
85:15
78:22
89:11
90:10
92:8
89:11
82:18
80:20
OMe
Cl
H
H
H
H
OCH2O
H
H
Cl
H
H
H
H
H
H
Cl
H
H
Cl
Cl
H
H
H
OMe
Cl
Cl
H
O
(
)
n
R2
H
H
Me
H
Me
OMe
H
CHO
NH2
ZrCl4
R1
CH3CN
(
)
n
R3
R4
N
+
R3
+
H
rt
O
R1
4 (trans)
H
0.5 −1 h
R4
R2
H
H
+
1
2
3
O
H
H
R2
(
)
n
H
H
R3
R4
H
Me
OMe
H
N
H
H
R1
5 (cis)
aAll the products were characterized from their spectral data.
bProduct ratio was determined from the 1H NMR spectrum of the
crude product.
Scheme 1.
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.11 (2004)
1527
of the catalyst. However, the imines (prepared separately) when
treated with the dihydropyran or furan using ZrCl4 formed the
desired quinolines in high yields.
dron Lett., 45, 2425 (2004).
8
General experimental procedure for the preparation of pyar-
ano- and furoquinolines: To a solution of an aniline
(1 mmol), a benzaldehyde (1 mmol) and 3,4-dihydro-2H-
pyran or 2,3-dihydrofuran (0.1 mL) in CH3CN (10 mL)
was added ZrCl4 (0.1 equiv., 0.1 mmol). The mixture was
stirred at room temperature and the reaction was monitored
by TLC. After completion the mixture was filtered and the
filtrate was concentrated to a viscous mass. This was subject-
ed to column chromatography on silica gel and the column
was eluted with hexane-EtOAc (20:1) to produce the pyrano-
or furoquinolines. The spectral data of some representative
pyrano- and furoquinolines are given here: 4b: mp 145–
146 ꢁC; 1H NMR (200 MHz, CDCl3): ꢀ 7.32 (2H, d, J ¼
8:0 Hz), 7.18 (2H, d, J ¼ 8:0 Hz), 7.04 (1H, t, J ¼ 8:0 Hz),
6.84 (2H, d, J ¼ 8:0 Hz), 6.64 (1H, t, J ¼ 8:0 Hz), 6.45
(1H, d, J ¼ 8:0 Hz), 4.64 (1H, d, J ¼ 10:0 Hz), 4.36 (1H,
d, J ¼ 2:5 Hz), 4.06 (1H, m), 3.97 (1H, d, J ¼ 3:0 Hz),
3.82 (3H,s), 3.63 (1H, t, J ¼ 10:0 Hz), 2.02 (1H, m), 1.82
(1H, m), 1.64 (1H, m), 1.44 (1H, m), 1.28 (1H, m); FABMS:
m=z 296 (Mþ þ 1). 5b: mp 154–155 ꢁC; 1H NMR (200 MHz,
CDCl3): ꢀ 7.38 (1H, d, J ¼ 8:0 Hz), 7.30 (2H, d,
J ¼ 8:0 Hz), 7.00 (1H, m), 6.82 (2H, d, J ¼ 8:0 Hz), 6.77
(1H, t, J ¼ 8:0 Hz), 6.50 (1H, d, J ¼ 8:0 Hz), 5.26 (1H, d,
J ¼ 3:0 Hz), 4.60 (1H, d, J ¼ 3:0 Hz), 3.84 (1H, m), 3.82
(3H, s), 3.58 (1H, m), 3.22 (1H, m), 2.04 (1H, m), 1.58–
1.30 (4H, m); FABMS: m=z 296 (Mþ þ 1). 4d: mp 152–
153 ꢁC; 1H NMR (200 MHz, CDCl3): ꢀ 7.18 (1H, d,
J ¼ 8:0 Hz), 7.04 (1H, t, J ¼ 8:0 Hz), 6.92 (1H, d, J ¼
2:5 Hz), 6.84–6.62 (3H, m), 6.46 (1H, d, J ¼ 8:0 Hz), 5.96
(2H, s), 4.62 (1H, d, J ¼ 10:0 Hz), 4.36 (1H, d, J ¼
3:5 Hz), 4.10 (1H, m), 3.98 (1H, brs), 3.70 (1H, m), 2.02
(1H, m), 1.85–1.22 (4H, m); FABMS: m=z 310 (Mþ þ 1).
5d: mp 159–160 ꢁC; 1H NMR (200 MHz, CDCl3): ꢀ 7.38
(1H, d, J ¼ 8:0 Hz), 7.04 (1H, t, J ¼ 8:0 Hz), 6.92–6.76
(4H, m), 6.56 (1H, d, J ¼ 8:0 Hz), 5.96 (2H, s), 5.24 (1H,
d, J ¼ 6:0 Hz), 4.60 (1H, d, J ¼ 3:0 Hz), 3.78 (1H, brs),
3.60–3.38 (2H, m), 2.05 (1H, m), 1.60–1.38 (4H, m);
ZrCl4, as well as some catalysts examined here, is easily
available and less costly. Industrially its catalytic applications
are recently steadily increasing.9 Multicomponent reactions are
also of growing importance in current organic synthesis owing
to their speed, diversity, and efficiency. ZrCl4 is thus a very suit-
able catalyst for single-step synthesis of pyrano- or furanoquino-
lines from the three components, anilines, benzaldehydes and
3,4-dihydro-2H-pyran- or 2,3-dihydrofuran.
In conclusion, we have applied novel and highly efficient
catalysts for simple one-pot synthesis of pyrano- and furoquino-
lines in high yields and high diastereoselectivity. The present
process may be a useful attractive alternative to the existing
methods for the synthesis of quinoline derivatives.
The authors thank CSIR, New Delhi, for financial assis-
tance.
References and Notes
1
Part 45 in the series, ‘‘Studies on novel synthetic methodol-
ogies’’ IICT Communication No. 041016.
2
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FABMS: m=z 310 (Mþ þ 1). 4k: mp 148–149 ꢁC; H NMR
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8:0 Hz), 7.05 (1H, t, J ¼ 8:0 Hz), 6.64 (1H, d, J ¼ 8:0 Hz),
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Published on the web (Advance View) October 27, 2004; DOI 10.1246/cl.2004.1526