Imino Diels-Alder reactions: Efficient synthesis of pyrano- and furanoquinolines catalyzed by 4-nitrophthalic acid

Article abstract of DOI:10.1007/s00706-007-0765-4

4-Nitrophthalic acid was found to be an effective catalyst for the imino Diels-Alder reaction of N-benzylideneanilines with 3,4-dihydro-2H-pyran and 2,3-dihydrofuran to afford pyrano- and furanoquinolines in good yields. It was also found that aryl amines

Full text of DOI:10.1007/s00706-007-0765-4

Monatshefte fu¨r Chemie 139, 141–145 (2008)
DOI 10.1007/s00706-007-0765-4
Printed in The Netherlands
Imino Diels-Alder Reactions: Efficient Synthesis of Pyrano-
and Furanoquinolines Catalyzed by 4-Nitrophthalic Acid
A. Srinivasa1, Kittappa M. Mahadevan1;ꢀ, K. M. Hosamani2, and Vijaykumar Hulikal3
1
Department of Post Graduate Studies and Research in Chemistry, School of Chemical Sciences,
Kuvempu University, Shankaraghatta, Karnataka, India
2
Department of Studies in Chemistry, Karnatak University, Karnataka, India
3
BioOrganics and Applied Materials Pvt. Ltd., Bangalore, India
Received July 13, 2007; accepted (revised) July 29, 2007; published online January 11, 2008
# Springer-Verlag 2008
Summary. 4-Nitrophthalic acid was found to be an effective
Therefore, it is not surprising that many synthesis
catalyst for the imino Diels-Alder reaction of N-benzylidene-
anilines with 3,4-dihydro-2H-pyran and 2,3-dihydrofuran to
afford pyrano- and furanoquinolines in good yields. It was
also found that aryl amines react smoothly with 3,4-dihydro-
2H-pyran and 2,3-dihydrofuran under the same condition to
afford the corresponding pyrano- and furanoquinolines in high
yields. This catalyst is inexpensive, easily available, water
soluble, and stable to aqueous reaction conditions.
methods have been developed for these types of
compounds. Among them, the Lewis acid catalyzed
imino Diels-Alder reaction between N-benzylidene-
anilines and nucleophilic olefins is one of the
powerful synthesis tools for constructing nitrogen
containing six membered hetrocyclic compounds.
Since the pioneering work of Povarov [7], this
reaction has been extensively studied with use of
different Lewis acids, such as BF3 ꢁ OEt2 [8], GbCl3
[9], InCl3 [10], LiClO4 [11], ZrCl4 [12], BiCl3 [13],
SbCl3 [14], and protic acids such as TFA [15], TsOH
[16], (COOH)2 [17]. Although the imino Diels-Alder
reaction promoted by Lewis acid is known, more
then stoichiometric amounts of the Lewis acid are
required due to co-ordination of the Lewis acid to
the imine nitrogen and generally, these Lewis acid
catalysts are moisture sensitive and get easily de-
composed or deactivated in the presence of even
trace amounts of water and are thus difficult to han-
dle. Further disposal of these acids leads to environ-
mental pollution. The imino Diels-Alder reaction has
also been successfully carried out using K-10 clay
[18], urea nitrate [19], lanthanide triflates [20], CAN
[21], KHSO4 [22], and I2 [23]. In the quest for de-
veloping a less toxic, potential green catalyst, we
thought of using 4-nitrophthalic acid (4-npa) as a
catalyst for this reaction. The 4-npa is inexpensive,
Keywords. 4-Nitrophthalic acid; Imino Diels-Alder reac-
tions; 3,4-Dihydro-2H-pyran; 2,3-Dihydrofuran; Tetrahydro-
quinolines.
Introduction
The products containing pyrano- and furanoquinoline
moieties are widely distributed in Nature and found
to associate with a wide range of biological activi-
ties. Pyranotetrahydroquinolines are found in several
alkaloids [1] such as veprisine, flinderesine, and ori-
cine. These alkaloids possess important biological
activities such as anti-allergic [2], psychotropic [3],
anti-inflammatory [4], and estrogenic activities [5].
The alkaloids skimimianine and balflouridine which
contain furanoquinoline moieties also show biologi-
cal activity, which has led to the synthesis of pyrano-
and furanoquinolines derivatives over the years [6].
ꢀ
Corresponding author. E-mail: mady_kmm@yahoo.co.uk

142
A. Srinivasa et al.
stable solid, water soluble, and easily available. 4-
npa is easier to handle than metal halides such as
ZrCl4, BiCl3, SbCl3, and protic acids such as TFA or
TsOH. In this paper we report on the synthesis of
substituted pyrano- and furanoquinolines via an imi-
no Diels-Alder reaction using 4-npa as a catalyst. To
the best of our knowledge there is no report of the
use of 4-npa as a mild and inexpensive catalyst for
this type of reactions.
Though the reaction proceeds at room temperature,
the isolated yields are low and the reaction is slug-
gish. At reflux temperature, the formation of impu-
rities was observed. At 50ꢂC, the reaction proceeds
smoothly and gave desired products in good yields.
Among the various solvents, acetonitrile was found
to be the best solvent for this transformation. Also,
we examined the reaction in the acetonitrile=water
system. Remarkably, the reaction proceeded smooth-
ly in CH3CN=H2O (3=1, v=v) system and afforded
the desired product in good yield. At 10 mol% of
catalyst, the reaction was sluggish and at 25 mol%,
the optimal results were obtained. Increasing the con-
centration of the catalyst beyond 25 mol% did not
show an appreciable advantage.
Results and Discussion
Preliminary studies were carried out to study the
effect of solvents, catalytic concentration, and tem-
perature on the model reaction of N-benzylidene
1a and 3,4-dihydropyran (DHP) in the presence of
4-npa, and the results are summarized in Table 1.
Thus, in the presence of 25mol% of 4-npa, N-ben-
zylidene derivative 1a was treated with DHP in ace-
tonitrile at 50ꢂC. After 3 h the pyranoquinolines 3a
and 4a were obtained in a ratio of 39:61 in overall
yields of 90% (Scheme 1). The structures of the com-
Table 1. Screening catalytic activity of 4-npa for the synthe-
sis of tetrahydroquinolines
1
Entry
Solvent
Mol% Temperature= Time= Yield=
ꢂC
pounds were established by IR, H NMR, and mass
a
4-npa
h
%
spectral analysis. It was observed that the pyran ring
was cis-fused in the tetrahydroquinoline moiety and
the stereochemistry of the products was established
based on the coupling constant of C2–H (J3,2 ¼ 4.4–
5.7 Hz) in 3 indicating the cis relationship between
C3–H and C2–H, whereas in 4 (J3,2 ¼ 10.08–
11.12 Hz) the coupling indicated trans. In all cases,
J3,4 was found to be 2.6–3.0 Hz indicating a cis ring
junction between the quinoline and pyran rings
which is in accordance with literature values [12].
The results obtained with substituted N-benzylidene-
anilines and dihydrofuran=3,4-dihydro-2H-pyran are
summarized in Table 2.
1
2
3
4
5
6
7
8
9
10
CH3CN
CH3CN
CH3CN
CH3CN
Toluene
MeOH
EtOH
THF
CH2Cl2
CH3CN
25
10
25
25
25
25
25
25
25
40
25
25
50
50
reflux
50
50
50
50
8.00
5.00
3.00
2.10
5.00
4.00
4.00
3.45
3.30
2.45
3.00
72
74
90
78
55
76
72
56
65
88
80
reflux
50
50
11 CH3CN=H2O
(3=1, v=v)
a
Isolated yields
Scheme 1

Imino Diels-Alder Reactions
143
Table 2. The synthesis of 2-aryltetrahydroquinolines using 4-
npa at 50ꢂC
to form the N-benzylideneaniline which undergoes
imino Diels-Alder reaction to yield pyranoquino-
lines of the type 6a and 7a. In this 4-npa catalyzed
domino reaction, benzaldehyde remained un-
reacted. Encouraged by these interesting results,
we carried out the reaction of various aryl amines
with dihydropyran and dihydrofuran (Scheme 2)
and results are summarized in Table 3. A similar
domino reaction of aromatic amines with cyclic
enol ethers catalyzed by InCl3 has been reported
[10b]. These results indicate that 4-npa can be used
has an efficient catalyst in the imino Diels-Alder
reaction of N-benzylideneanilines with cyclic enol
ethers and also in the domino reaction of anilines
with cyclic enol ethers leading to the formation of
pyrano- and furanoquinolines.
Products
R
R1
n
Time=
h
Product
ratioa 3:4
Yield=
%
b
a
b
c
d
e
f
g
h
i
H
Me
OMe
F
Cl
H
OMe
Cl
Me
H
H
H
H
H
H
H
H
H
1
1
1
1
1
0
0
0
0
3.00
3.00
3.00
4.00
4.00
4.00
4.00
5.00
4.00
39:61
42:58
35:65
30:70
45:55
49:51
56:44
43:53
52:48
90
92
93
78
81
80
82
77
82
a
Product ratio was based on isolation by column
chromatography
Isolated yields
b
From these results, we propose the following pos-
sible mechanism to account for the reaction. An
aromatic amine first reacts with cyclic enol ether to
form 2-azadiene and the second step proceeds via
the imino Diels-Alder reaction between this 2-aza-
diene and another molecule of cyclic enol ether
(Scheme 3).
In conclusion, a very interesting and a facile syn-
thesis of substituted pyrano- and furanoquinolines
using cheaper, water stable, and water soluble 4-
nitrophthalic acid catalyzed imino Diels-Alder reac-
tion of N-benzylideneanilines with cyclic enol ethers
There are reports in literature on the three com-
ponent one pot synthesis of pyrano- and furano-
quinolines using aryl amines, aryl aldehydes, and
DHP [9, 14]. Hence anticipating similar results,
we tried one pot synthesis by using benzaldehyde,
aniline, and DHP catalyzed by 4-npa. However, the
reaction did not give the expected pyranoquinolines
3a or 4a, instead we got pyranoquinolines of type
6a and 7a in the ratio of 48:52. The results indicate
that in the presence of 4-npa, the masked aldehyde
DHP reacts faster than benzaldehyde with aniline
Scheme 2

144
A. Srinivasa et al.
Table 3. The synthesis of 2-alkoxytetrahydroquinolines us-
ing 4-npa at 50ꢂC
and the domino reaction of anilines with cyclic enol
ethers are described.
Products
R2
n
Time=h
Product
ratioa 6:7
Yield=%b
Experimental
a
b
c
d
e
f
g
h
i
H
Me
OMe
Cl
F
Br
1
1
1
1
1
1
0
0
0
0
0
0
4.00
3.30
3.30
4.00
4.00
4.00
4.00
5.00
4.00
4.00
5.00
5.00
48:52
42:58
45:55
51:49
58:42
49:51
60:40
74:26
70:30
72:38
80:20
78:22
82
85
86
75
75
76
80
75
78
78
76
76
All melting points were recorded in open capillaries. The
purity of the compounds was checked by TLC on silica gel
1
and they were purified by column chromatography. H NMR
spectra were recorded on a Bruker-300MHz spectrometer
using TMS as an internal standard. IR spectra were obtained
using a FTS-135 spectrometer instrument. Mass spectra were
recorded on a JEOL SX 102=DA-6000 (10 kV) FAB mass
spectrometer. The compounds 3a–3h [12], 4a–4h [9], 6a–6l
[10b], and 7a–7l [10b] are known, their identities were proven
by means of IR, NMR, and mass spectra.
H
Me
OMe
Cl
F
Br
j
k
l
General Procedure for the Synthesis of Tetrahydroquinolines
3 and 4
a
Product ratio was based on isolation by column chromatog-
raphy
b
Isolated yields
4-npa (0.25 mmol) was added to a mixture of 1.0 mmol
N-benzylidene 1 and 1.2 mmol 3,4-dihydro-2H-pyran or 2,3-
Scheme 3
Scheme 4

Imino Diels-Alder Reactions
145
dihydrofuran 2 in 5 cm3 acetonitrile. The reaction mixture was
stirred at 50ꢂC for the appropriate time. After completion,
the reaction mixture was quenched with 25cm3 saturated
NaHCO3 aqueous solution and extracted with ethyl ace-
tate (3ꢃ10 cm3). The combined organic layer was dried
(Na2SO4), concentrated, and purified by column chromatogra-
phy on SiO2 with an ethyl acetate and petroleum ether mixture
as elutent to afford the corresponding tetrahydroquinolines
3 and 4.
[6] a) Weinred SM (1991) In: Trost BM, Fleming I (eds)
Comprehensive Organic Synthesis, Permagon, Oxford
vol. 5, p 401; b) Lucchini V, Prato M, Scorrano G,
Stivanello M, Valle G (1992) J Chem Soc Perkin Trans 2
259; c) Kametani T, Takeda H, Suzuki Y, Kasai H,
Honda T (1986) Heterocycles 24: 3385
[7] Povarov LS (1967) Russ Chem Rev 36: 656
[8] Kametani T, Takeda H, Suzuki Y, Honda T (1985) Synth
Commun 15: 499
[9] Ma Y, Qian C, Xie M, Sun J (1999) J Org Chem 64: 6462
[10] a) Babu G, Perumal PT (1997) Tetrahedron Lett 38:
5025; b) Zhang J, Li C-J (2002) J Org Chem 67:
3969; c) Zhang J, Li C-J (2002) J Org Chem 67: 3969
[11] Yadav JS, Subba Reddy BV, Srinivas R, Madhuri C,
Ramalingam T (2001) Synlett 1089
[12] Mahesh M, Venkateshwar Reddy C, Srinivasa Reddy K,
Raju PVK, Narayana Reddy VV (2004) Synth Commun
34: 4089
[13] Kouznetsov VV, Astrudillosaavedra L, Vargas Mendez
LY, Ramirez MC (2004) J Chil Chem Soc 49: 319
[14] Maiti G, Kundu P (2006) Tetrahedron 62: 349
[15] a) Boger DL, Weinreb SM (1987) Hetero Diels-Alder
Methodology in Organic Synthesis. Academic Press,
San Diego, p 9; b) Mellor JM, Merriman GD, Riviere
P (1991) Tetrahedron Lett 32: 7103
General Procedure for the Synthesis of Tetrahydroquinolines
6 and 7
4-npa (0.25 mmol) was added to a mixture of 1.0 mmol aryl
amine 1 and 2.5 mmol 3,4-dihydro-2H-pyran or 2,3-di-
hydrofuran 2 in 5 cm3 acetonitrile. The reaction mixture
was stirred at 50ꢂC for the appropriate time. After comple-
tion, the reaction mixture was quenched with 25 cm3 satu-
rated NaHCO3 aqueous solution and extracted with ethyl
acetate (3ꢃ10 cm3). The combined organic layer was dried
(Na2SO4), concentrated, and purified by column chroma-
tography on SiO2 with an ethyl acetate and petroleum ether
mixture as elutent to afford the corresponding tetrahydro-
quinolines 6 and 7.
[16] Grieco PA, Bahasas A (1988) Tetrahedron Lett 29: 5855
[17] Nagarajan R, Perumal PT (2001) Synth Commun 31:
1733
[18] Jadav JS, Reddy BVS, Sadasiv K, Reddy PSR (2002)
Tetrahedron Lett 43: 3853
References
[1] a) Anzino M, Cappelli A, Vomero S, Cagnatto A,
Skorupska M (1993) Med Chem Res 3: 44; b) Qurasishi
MA, Thakur VR, Dhawan SN (1989) Indian J Chem Sec
28B: 891; c) Ramesh M, Mohan PS, Chanmugam P
(1984) Tetrahedron 40: 4041
[19] Anniyappan M, Nagarajan R, Perumal PT (2002) Synth
Commun 32: 99
[2] Yamada N, Kadowaki S, Takahasi K, Umezu K (1992)
Biochem Pharmacol 44: 1211
[3] Nesterova IN, Alekseeva LM, Andreeva LM, Andreeva
NI, Golovira SM, Granic VG, (1995) Khim Farm Zh
(Russ) 29: 31
[20] a) Habben M, Stevenson PJ (1999) Tetrahedron Lett 40:
1215; b) Makioka Y, Taniguchi Y, Takaki K, Fuliwara Y
(1995) Synthesis 801; c) Kobayashi S, Ishitani H,
Nagayama S (1995) Chem Lett 6: 423
´
[21] Sridharan V, Avendan˜o C, Menendez JC (2007) Tetra-
hedron 63: 673
[22] Kumar RS, Nagarajan R, Perumal PT (2004) Synthesis:
[4] Faber K, Stueckler H, Kappe T (1984) J Heterocycl
Chem 21: 1177
[5] Akhmed Khodzhaeva KhS, Bessonova IA (1983) Chem
Abstr 98: 83727q
949
[23] Xia M, Lu Y-D (2005) Synlett: 2357