Imino Diels-Alder reactions: an efficient one-pot synthesis of pyrano and furanoquinoline derivatives catalyzed by SbCl3

Article abstract of DOI:10.1016/j.tetlet.2006.06.034

Antimony trichloride (SbCl₃) was found to be an efficient catalyst for the inverse electron demand imino Diels-Alder reactions of in situ generated N-benzylidenes with 3,4-dihydro-2H-pyran and 2,3-dihydrofuran to afford pyrano and furano[3,2-c]quinolines in excellent yields.

Full text of DOI:10.1016/j.tetlet.2006.06.034

Tetrahedron Letters 47 (2006) 5733–5736
Imino Diels–Alder reactions: an efficient one-pot synthesis of
pyrano and furanoquinoline derivatives catalyzed by SbCl3
Gourhari Maiti* and Pradip Kundu
Department of Chemistry, Jadavpur University, Kolkata 700 032, India
Received 20 February 2006; revised 26 May 2006; accepted 2 June 2006
Abstract—Antimony trichloride (SbCl3) was found to be an efficient catalyst for the inverse electron demand imino Diels–Alder
reactions of in situ generated N-benzylidenes with 3,4-dihydro-2H-pyran and 2,3-dihydrofuran to afford pyrano and furano[3,2-
c]quinolines in excellent yields.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The products containing pyrano and furanoquinoline
moieties are widely distributed in nature and found to
be associated with a wide range of biological activities.
Pyranotetrahydroquinolines are found in several alka-
loids1 such as veprisine, flinderesine and oricine. These
alkaloids possess important biological activities such
as anti-allergic,2 psychrotopic,3 anti-inflammatory4 and
estrogenic activities.5 The alkaloids skimimianine and
balflouridine which contain furanoquinoline moieties
also show biological activity, which has led to the syn-
thesis of pyrano and furanoquinoline derivatives over
the years.6 Therefore, it is not surprising that many syn-
thetic methods have been developed for these types of
compounds. Amongst them, the Lewis acid catalyzed
aza-Diels–Alder reaction between N-benzylideneanilines
and nucleophilic olefins is one of the most powerful
synthetic tools for constructing nitrogen-containing
six-membered heterocyclic compounds. However, an
in situ generated diene is preferred over a preformed
heterodiene, leading to a one-pot procedure, which is
especially useful when the diene is unstable, sensitive
to moisture and difficult to purify by column chroma-
tography or distillation.7 Since the pioneering work of
Povarov,8 these reactions have been extensively studied
with protic acids9 (TFA, p-TsOH), different Lewis acids
Ln(OTf)3, Sc(OTf)3, Yb(OTf)3 and InCl3.12 Lanthanide
chloride13 (GdCl3), LiClO4 in diethyl ether,14 LiBF4,15
ZrCl4,16 Montmorillonite17 and fluorinated alcohols18
have also been used as efficient catalysts for the synthesis
19
of tetrahydroquinolines. Very recently, KHSO4 and
iodine20 have also been used as efficient catalysts for
the one-pot synthesis of the pyranoquinoline moiety.
However, most of these methods involve expensive
reagents and more than stoichiometric amounts of
Lewis acid catalysts are needed due to strong co-ordina-
tion with the heterodiene, coupled with longer reaction
times and strongly acidic conditions. Hence, a milder
and better method is desirable.
In this letter, we report the synthesis of substituted pyr-
ano and furanoquinolines via an imino Diels–Alder
reaction using antimony trichloride (SbCl3) as a catalyst.
To the best of our knowledge, there is no report of the
use of SbCl3 as a mild and inexpensive catalyst for these
types of reactions. SbCl3 is easier to handle than other
metal halides such as InCl3, GdCl3 and TiCl4. Thus,
the reaction21 of an aldehyde (2.0 mmol), an aromatic
amine (2.0 mmol) and a dihydropyran or dihydrofuran
(2.2 mmol) in the presence of anhydrous Na2SO4
(100 mg ) and SbCl3 (10 mol %) in acetonitrile at room
temperature furnished the corresponding pyrano or fur-
anoquinolines 4 and 5 in good to excellent yield (Scheme
1). A series of tetrahydropyranoquinolines were pre-
pared in good to excellent yields using this protocol as
summarized in Table 1. Various solvents were used for
this reaction and acetonitrile was found to give the best
yield of product in comparison with dichloromethane
(46%, in a cis:trans ratio of 31:69 with respect to C-4a
10
such as BF3ÆOEt2 and lanthanide triflates11 including
Keywords: Antimony trichloride; Imino Diels–Alder reaction; Quino-
line derivatives; One-pot.
*
Corresponding author. Tel.: +91 33 2414 6223; fax: +91 33 2414
6484; e-mail: ghmaiti123@yahoo.co.in
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.034

5734
G. Maiti, P. Kundu / Tetrahedron Letters 47 (2006) 5733–5736
9
9
10
8
10
8
CHO
H
H
7
7
O
O
O
NH2
+
R2
R2
SbCl3 (10 mol%)
rt, CH3CN
10b
2
3
10b
2
3
H
H
4a
+
+
4a
NH
NH
n
5
n
n
5
H
R2
R1
H
1
2
3
(n = 0,1)
R1
R1
4
5
Scheme 1.
Table 1. One-pot synthesis of pyrano and furanoquinolines catalyzed
indicating a cis ring junction between the quinoline
and pyran rings which is in accord with literature
values.16a Similarly, a series of in situ generated N-aryl-
benzylidenes reacted with 2,3-dihydrofuran to give the
corresponding tetrahydrofuranoquinolines in good to
excellent yields (Table 1).
by antimony trichloride (SbCl3)a
Entry R1
R2
n
Time Product
Yield Ref.
(min) ratio (4:5)b (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
H
H
H
H
H
H
H
4-Cl
4-OCH3
H
H
H
H
H
H
H
1
1
1
1
1
1
1
1
1
1
0
0
0
0
0
0
0
0
40
40
15
90
90
50
40
45
80
120
15
20
18
18
15
25
25
20
28:72
31:69
—
90
75
73c
78
84
84
72
80
86
86
92
83
91
80
86
84
82
85
13
13
13
13
16a
13
16a
16a
20
13
13
13
—
13
—
16a
—
13
4-Cl
3-Cl
2-CH3
4-CH3
4-OCH3
4-Br
H
H
2-OH
H
4-OCH3
4-CH3
4-Cl
4-Br
H
Phenanthridine skeletons22 are present in lycorine,
chelidonine and haemanthamine alkaloids. Antimony
trichloride also catalyzed effectively the imino Diels–
Alder reaction (Scheme 2) of in situ generated N-benzyl-
idene-1-naphthylamine 6 with 3,4-dihydro-2H-pyran
and 2,3-dihydrofuran to afford the phenanthridine
derivatives 7 and 8 as a mixture of cis and trans isomers
in good overall yields (54–62%) (Table 2).
26:74
30:70
33:67
28:72
32:68
28:72
31:69
52:48
54:46
52:48
43:57
48:52
57:43
62:38
33:67
In conclusion, we have developed a new and effective
methodology for the synthesis of tetrahydropyranoquin-
olines and furanoquinolines in one-pot using a catalytic
amount of antimony trichloride. Mild and neutral reac-
tion conditions, high yields of products, the low cost of
reagents, enhanced reactivity and selectivity, operational
simplicity and ease of isolation of the products are the
main advantages over existing procedures for the syn-
thesis of pyrano and furanoquinoline derivatives.
4-Cl
2-OCH3
H
H
2-CH3
a All reactions were conducted at room temperature using 10 mol %
SbCl3 in acetonitrile.
b Products were characterized by mp, IR and 1H NMR. The product
ratio was based on isolation by chromatography.
c Ratio (17:22:43:18) of four products characterized by 1H NMR.
Table 2. One-pot synthesis of pyrano and furanophenanthridines
and C-5), diethyl ether (31%, cis:trans; 45:55), tetra-
hydrofuran (63%, cis:trans; 18:82) and toluene (44%,
cis:trans; 68:32).
catalyzed by antimony trichloride (SbCl3)a
Entry
R
n
Time (h) Product ratio (7:8)b Yield (%)
1
2
3
4
H
4-Cl
H
1
1
0
0
12
9
0.5
49:51
30:70
35:65
23:77
59
62
58
54
The pyran ring was cis-fused in the tetrahydroquinoline
moiety and the stereochemistry of the products was
established based on the coupling constants. The cou-
pling constant of C5–H (J4a,5 = 4.6–5.5 Hz) in 4 indi-
cated the cis relationship between C-4a and C-5,
whereas in 5 (J4a,5 = 10.2–11.10 Hz) the coupling was
trans. In all cases, J4a,10b was found to be 2.6–2.9 Hz
4-OCH3
1
a All reactions were conducted at room temperature using 10 mol %
SbCl3 in acetonitrile.
b Products were characterized by mp, IR and 1H NMR. The product
ratio was based on isolation by chromatography.
H
H
O
O
O
SbCl3 (10 mol%)
rt, CH3CN
+
H
H
NH
NH
+
n
n
n
H
H
N
C
3
(n = 0,1)
H
R
R
7
8
R
6
Scheme 2.

G. Maiti, P. Kundu / Tetrahedron Letters 47 (2006) 5733–5736
5735
acetonitrile (1.5 mL) and a solution of aniline (205 mg,
2.2 mmol) in acetonitrile (2 mL) at room temperature. The
mixture was stirred for 10 min at room temperature. To
this mixture, dihydropyran (218 mg, 2.6 mmol) was added
and the reaction stirred for the period of time as
mentioned in Table 1. After completion of the reaction
(monitored by TLC), it was quenched with water and
extracted with CH2Cl2 (3 · 20 mL). The organic layer was
washed with water (2 · 10 mL) and dried (Na2SO4). The
solvent was removed under reduced pressure and the crude
residue obtained was purified by column chromatography
over silica gel (5% ethyl acetate in petroleum ether) to give
pure tetrahydropyranoquinolines 4 and 5 (475 mg, 90%).
Spectral data of tetrahydropyranoquinolines, Table 1, entry
Acknowledgements
P.K. thanks Jadavpur University, Kolkata, India, for
awarding a fellowship.
References and notes
1. (a) Anzino, M.; Cappelli, A.; Vomero, S.; Cagnatto, A.;
Skorupska, M. Med. Chem. Res. 1993, 3, 44; (b) Quraishi,
M. A.; Thakur, V. R.; Dhawan, S. N. Indian J. Chem. Sec.
B 1989, 28B, 891; (c) Ramesh, M.; Mohan, P. S.;
Shanmugam, P. Tetrahedron 1984, 40, 4041.
2. Yamada, N.; Kadowaki, S.; Takahashi, K.; Umezu, K.
Biochem. Pharmacol. 1992, 44, 1211.
1
9: Cis isomer: mp 159 ꢁC; H NMR (300 MHz, CDCl3):
d 1.41–1.62 (m, 4H), 2.14–2.15 (m, 1H), 3.41 (dt, J = 2.3,
8.9 Hz, 1H), 3.60 (dd, J = 3.2, 11.9 Hz, 1H), 3.84 (s, 3H),
4.64 (d, J = 2.0 Hz, 1H), 5.29 (d, J = 5.5 Hz, 1H), 6.65
(d, J = 7.9 Hz, 1H), 6.86 (d, J = 7.5 Hz, 1H), 6.92 (d, J =
8.4 Hz, 2H), 7.09 (t, J = 7.9 Hz, 1H), 7.39 (d, J = 8.3 Hz,
2H), 7.45 (d, J = 7.7 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d 18.0, 25.4, 39.0, 55.3, 58.7, 60.6, 72.7, 113.7
(2), 114.3, 118.2, 119.8, 127.6, 127.8 (2), 128.0, 133.1,
145.2, 158.9; HRMS calcd for [C19H21O2N+H+]
296.1550, found 296.1651.
3. Nesterova, I. N.; Alekseeva, L. M.; Andreeva, L. M.;
Andreeva, N. I.; Golovira, S. M.; Granic, V. G. Khim.
Farm. Zh. (Russ.) 1995, 29, 31; Chem. Abstr. 1996, 124,
117128t.
4. Faber, K.; Stueckler, H.; Kappe, T. J. Heterocycl. Chem.
1984, 21, 1177.
5. Akhmed Khodzhaeva, Kh. S.; Bessonova, I. A. Dokl.
Akad., Nauk. Uzh., SSR 1982, 34 (Russ.); Chem. Abstr.
1983, 98, 83727q.
6. (a) Weinreb, S. M. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 5, p 401; (b) Lucchini, V.; Prato, M.; Scorrano, G.;
Stivanello, M.; Valle, G. J. Chem. Soc., Perkin Trans. 2
1992, 259; (c) Kametani, T.; Takeda, H.; Suzuki, Y.;
Kasai, H.; Honda, T. Heterocycles 1986, 24, 3385.
7. Lucchini, V.; Prato, M.; Scorrano, G.; Tecilla, P. J. Org.
Chem. 1988, 53, 2251.
8. Povarov, L. S. Russ. Chem. Rev. 1967, 36, 656.
9. (a) Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder
Methodology in Organic Synthesis; Academic Press: San
Diego, 1987; Chapters 2 and 9; (b) Grieco, P. A.; Bahsas,
A. Tetrahedron Lett. 1988, 29, 5855; (c) Mellor, J. M.;
Merriman, G. D.; Riviere, P. Tetrahedron Lett. 1991, 32,
7103.
Trans isomer: mp 132 ꢁC; 1H NMR (300 MHz, CDCl3): d
1.29–1.33 (m, 1H), 1.50–1.54 (m, 1H), 1.60–1.80 (m, 2H),
2.16–2.19 (m, 1H), 3.71 (dt, J = 2.1, 11.7 Hz, 1H), 3.84 (s,
3H), 4.09 (dd, J = 2.1, 3.9 Hz, 1H), 4.42 (d, J = 2.2 Hz,
1H), 4.72 (d, J = 11.1 Hz, 1H), 6.53 (d, J = 8.1 Hz, 1H),
6.81 (t, J = 7.1 Hz, 1H), 6.93 (d, J = 8.4 Hz, 2H), 7.09 (t,
J = 7.5 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H), 7.41 (d,
J = 8.4 Hz, 2H); 13C NMR (75 MHz, CDCl3): d 21.9,
24.1, 38.8, 54.1, 55.3, 68.8, 74.6, 113.9 (2), 114.3, 117.5,
120.8, 128.9 (2), 129.3, 130.9, 134.1, 144.6, 159.2; HRMS
calcd for [C19H21O2N+H+] 296.1550, found 296.1653.
Spectral data of tetrahydrofuranoquinolines, Table 1, entry
13: Cis isomer: mp 115 ꢁC; 1H NMR (300 MHz, CDCl3): d
1.55–1.64 (m, 1H), 2.35 (s, 3H), 2.84–2.88 (m, 1H), 3.74–
3.82 (m, 2H), 3.88–3.95 (m, 1H), 4.72 (d, J = 2.7 Hz, 1H),
5.33 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 8.1 Hz, 1H), 6.99 (d,
J = 7.9 Hz, 1H), 7.26 (s, 1H), 7.39–7.56 (m, 5H); 13C NMR
(75 MHz, CDCl3): d 20.5, 24.7, 45.9, 57.8, 66.9, 76.1, 115.0,
122.7, 126.5 (2), 127.6, 128.4, 128.6 (2), 129.1, 130.3, 142.3,
142.7; HRMS calcd for [C18H19ON+H+] 266.1545, found
266.1577.
10. Kametani, T.; Takeda, H.; Suzuki, Y.; Honda, T. Synth.
Commun. 1985, 15, 499.
11. (a) Hadden, M.; Stevenson, P. J. Tetrahedron Lett. 1999,
40, 1215; (b) Makioka, Y.; Shindo, T.; Taniguchi, Y.;
Takaki, K.; Fujiwara, Y. Synthesis 1995, 801; (c) Koba-
yashi, S.; Ishitani, H.; Nagayama, S. Chem. Lett. 1995, 6,
423.
12. Babu, G.; Perumal, P. T. Tetrahedron Lett. 1998, 39, 3225.
13. Ma, Y.; Qian, C.; Xie, M.; Sun, J. J. Org. Chem. 1999, 64,
6462, and references cited therein.
14. Yadav, J. S.; Subba Reddy, B. V.; Srinivas, R.; Madhuri,
C.; Ramalingam, T. Synlett 2001, 240.
15. Yadav, J. S.; Subba Reddy, B. V.; Madhurai, C. R.;
Sabitha, G. Synthesis 2001, 1065.
16. (a) Mahesh, M.; Venkateswar Reddy, C.; Srinivasa
Reddy, K.; Raju, P. V. K.; Narayana Reddy, V. V. Synth.
Commun. 2004, 34, 4089; (b) Reddy, Ch. V.; Mahesh, M.;
Raju, P. V. K.; Babu, T. R.; Reddy, V. V. N. Tetrahedron
Lett. 2002, 43, 2657.
17. Cabral, J.; Laszlo, P.; Montaufier, M. T. Tetrahedron Lett.
1988, 29, 547.
18. Spanedda, M. V.; Hoang, V. D.; Crousse, B.; Bonnet-
Delphon, D.; Begue, J. P. Tetrahedron Lett. 2003, 44, 217.
19. Kumar, R. S.; Nagarajan, R.; Perumal, P. T. Synthesis
2004, 949 and references therein.
1
Trans isomer: mp 82 ꢁC; H NMR (300 MHz, CDCl3): d
1.68–1.75 (m, 1H), 1.98–2.06 (m, 1H), 2.28 (s, 3H), 2.49–
2.53 (m, 1H), 3.76–3.87 (m, 2H), 3.99–4.07 (m, 1H), 4.60 (d,
J = 5.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.95 (d,
J = 8.1 Hz, 1H) 7.23 (s, 1H), 7.35–7.47 (m, 5H); 13C
NMR (75 MHz, CDCl3): d 20.4, 28.8, 43.5, 58.0, 65.2, 76.1,
114.7, 120.1, 127.6, 128.0, 128.2 (2), 128.5 (2), 129.6, 131.2,
141.7, 143.0; HRMS calcd for [C18H19ON+H+] 266.1545,
found 266.1533.
Spectral data of tetrahydrofuranoquinolines, Table 1, entry
1
15: Cis isomer: mp 152 ꢁC; H NMR (300 MHz, CDCl3):
d 1.53–1.63 (m, 1H), 2.11–2.22 (m, 1H), 2.73–2.82
(m, 1H), 3.70–3.87 (m, 2H), 4.69 (d, J = 2.6 Hz, 1H),
5.21 (d, J = 7.8, 1H), 6.52 (d, J = 8.6 Hz, 1H), 7.17 (dd,
J = 2.3, 8.8 Hz, 1H), 7.31–7.48 (m, 6H); 13C NMR
(75 MHz, CDCl3): d 24.4, 45.3, 57.2, 66.9, 75.4, 110.7,
116.5, 124.6, 126.4 (2), 127.8, 128.7 (2), 131.1, 132.6,
141.7, 143.7; HRMS calcd for [C17H16ONBr+H+]
330.0593, found 330.0591.
20. Xia, M.; Lu, Y.-d. Synlett 2005, 2357, and reference cited
therein.
21. Representative procedure: To a suspension of SbCl3
(46 mg, 0.2 mmol) and anhydrous Na2SO4 (200 mg) were
added a solution of benzaldehyde (212 mg, 2.0 mmol) in
Trans isomer: mp 104 ꢁC; 1H NMR (300 MHz, CDCl3): d
1.66–1.76 (m, 1H), 1.96–2.08 (m, 1H), 2.45–2.50 (m, 1H),
3.75–3.87 (m, 2H), 3.98–4.06 (m, 1H), 4.56 (d, J = 5.2 Hz,
1H), 6.53 (d, J = 8.6 Hz, 1H), 7.20 (dd, J = 2.0, 8.6 Hz,

5736
G. Maiti, P. Kundu / Tetrahedron Letters 47 (2006) 5733–5736
1H), 7.34–7.45 (m, 5H), 7.52 (d, J = 1.8 Hz, 1H); 13C
Trans isomer: mp 128 ꢁC; 1H NMR (300 MHz, CDCl3): d
1.36–1.41 (m, 1H), 1.52–1.56 (m, 1H), 1.69–1.77 (m, 1H),
1.79–1.90 (m, 1H), 2.22–2.26 (m, 1H), 3.78 (dt, J = 1.7,
11.0 Hz, 1H), 4.11–4.15 (m, 1H), 4.53 (d, J = 2.4 Hz, 1H),
4.85 (d, J = 10.9 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.35–
7.59 (m, 8H), 7.69–7.78 (m, 2H); 13C NMR (75 MHz,
CDCl3): d 22.2, 24.1, 38.7, 55.2, 68.6, 74.7, 114.7, 117.3,
120.0, 122.6, 124.7, 125.9, 127.9, 128.0 (2), 128.5, 128.6,
128.7 (2), 134.4, 139.8, 142.3; HRMS calcd for
[C22H21ON+H+] 316.1701, found 316.1699.
NMR (75 MHz, CDCl3): d 28.7, 43.1, 57.7, 65.2, 75.6,
109.8, 116.3, 122.2, 128.2 (2), 128.3, 128.7 (2), 131.7,
133.6, 141.1, 144.3; HRMS calcd for [C17H16ONBr+H+]
330.0593, found 330.0601.
Spectral data of phenanthridine derivatives, Table 2, entry 1:
Cis isomer: light brown viscous liquid; 1H NMR (300 MHz,
CDCl3): d 1.36–1.44 (m, 2H), 1.49–1.66 (m, 2H), 2.27–2.31
(m, 1H), 3.33–3.41 (m, 1H), 3.61–3.64 (m, 1H), 4.83 (d,
J = 1.7 Hz, 1H), 5.52 (d, J = 5.5 Hz, 1H), 7.33–7.46 (m,
5H), 7.55–7.64 (m, 4H), 7.77–7.83 (m, 2H); HRMS calcd
for [C22H21ON+H+] 316.1701, found 316.1675.
22. Wildman, W. C. Alkaloids 1960, 6, 289, and references
therein.