Lithium perchlorate/diethylether catalyzed aza-Diels-Alder reaction: An expeditious synthesis of pyrano, indeno quinolines and phenanthridines

Article abstract of DOI:10.1055/s-2001-10777

Lithium perchlorate in diethylether (LPDE) is found to catalyze imino-Diels-Alder reactions of N-aryl aldimines with 3,4dihydro-2H-pyran (DHP), indene, and cyclohexenone to afford the corresponding pyrano, indeno quinolines and phenanthridinone derivative

Full text of DOI:10.1055/s-2001-10777

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40
LETTER
Lithium Perchlorate/Diethylether Catalyzed Aza-Diels-Alder Reaction:
An Expeditious Synthesis of Pyrano, Indeno Quinolines and Phenanthridines#
J. S. Yadav,* B. V. Subba Reddy, R. Srinivas, Ch. Madhuri, T. Ramalingam
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad- 500 007, India
Received 6 December 2000
to LPDE medium prompted us to disclose a mild and effi-
Abstract: Lithium perchlorate in diethylether (LPDE) is found to
cient procedure for the synthesis of pyrano, indeno quino-
catalyze imino-Diels-Alder reactions of N-aryl aldimines with 3,4-
lines and phenanthridine derivatives.
dihydro-2H-pyran (DHP), indene, and cyclohexenone to afford the
corresponding pyrano, indeno quinolines and phenanthridinone de-
rivatives in high yields.
In this communication, we wish to report the 5M ethereal
LiClO catalyzed imino-Diels-Alder reaction of aldimines
4
Key words: lithium perchlorate, aza-Diels-Alder reaction, quino-
line derivatives
with various olefins like 3,4-dihydro-2H-pyran, indene,
and cyclohexenone to afford corresponding quinoline de-
rivatives. The reactions proceeded smoothly at ambient
temperature to give the products in high yields in a short
Aza-Diels-Alder is one of the most powerful synthetic reaction time with high diastereoselectivity. The en-
routes for constructing nitrogen containing six-membered hanced reaction rates and selectivity was observed in imi-
1
heterocycles. Pyrano quinoline derivatives are found to no-Diels-Alder reaction in 5M LPDE medium. The mild
2
possess a wide spectrum of biological activities such as Lewis acidity of the lithium ion in diethylether activates
psychotropic, antiallergic, anti-inflammatory and estro- the imines (Schiff’s bases) to behave as heterodienes in
genic activity. Indeno quinolines are also known to exhib- this reaction. Several aldimines (formed in situ from aro-
3
it a vast range of pharmacological activities such as 5HT- matic aldehydes and anilines in the presence of sodium
receptor binding, anti-inflammatory and anti-tumor. The sulphate in diethylether) were treated with 3,4-dihydro-
imino-Diels-Alder provides an easy access to pyrano, in- 2H-pyran in 5M LPDE medium to afford corresponding
deno quinolines and phenanthridine derivatives. Imines pyrano [3,2-c] quinolines in 80-95% yield. The products
derived from aromatic amines act as heterodienes and un- were obtained as a mixture of cis- and trans- isomers,
dergo imino-Diels-Alder reaction with various dieno- which were separated by column chromatography on sili-
4
-6
1
philes. Lewis acids
are known to catalyze these ca gel. The product ratio was determined by H NMR
7
reactions. Also, lanthanide triflates are found to be effec- spectrum of crude product.
tive. However, many Lewis acids are deactivated or some-
times decomposed by nitrogen containing reactants; even
when the desired reactions proceed, more than stoichio-
metric amounts of the Lewis acids are required because
1
the acids are trapped by nitrogen. Lithium perchlorate in
diethylether (5M LPDE) is found to retain its activity even
8
in the presence of amines . Although, aza-Diels-Alder re-
action is an important synthetic route for the construction
of a variety of heterocycles, the usage of expensive
7
9
reagents , strongly acidic conditions and stoichiometric
1
amounts of the acids always demands newer and efficient
Scheme 1
reagents which can effect the transformation under mild
and neutral reaction conditions.
Similarly, N-benzylidineanilines were treated with cyclo-
hexenone in 5M LPDE medium at ambient temperature to
afford corresponding phenanthridinone derivatives in
good yields. 2-Cyclohexenone is a dienophile of low reac-
tivity. The coordination of the carbonyl function of the cy-
clohexenone with LPDE increases the reactivity of
dienophile and enhances the yield. The reaction of cyclo-
hexenone with Schiff’s base gave the product as a mixture
of cis- and trans- isomers, which were separated by col-
umn chromatography.
In recent years, lithium perchlorate in diethyl ether has re-
ceived considerable attention as a powerful reaction me-
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0
dium for effecting various organic transformations such
as cycloaddition reactions, sigmatropic rearrangements,
ring opening reactions of epoxides, glycoside synthesis,
selective carbonyl protection as dithioacetals, Michael ad-
dition and aldol condensation reactions. The lithium ion
acts as a mild Lewis acid in diethylether and shows en-
hanced rates and selectivity in cycloaddition reactions. In
addition, LPDE medium offers a convenient procedure to
carry out the reactions under essentially neutral reaction
and work-up conditions. These special properties inherent
Synlett 2001, No. 2, 240–242 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Lithium Perchlorate/Diethylether Catalyzed Aza-Diels-Alder Reaction
241
Table 5M LPDE mediated aza-Diels-Alder reaction
Scheme 2
The reaction of indene with aldimines gave only a single
1
isomer, which was confirmed by H NMR spectra and is
5
b
also in agreement with earlier observation.
Scheme 3
The reaction of aldimines with indene and cyclohexenone
took longer reaction time to afford corresponding indeno
quinolines and phenanthridinone derivatives in compara-
ble yields with pyrano quinolines. Similarly various ald-
imines were treated with different dienophiles in 5M
LPDE medium to give the corresponding quinoline deriv-
atives and the results are presented in the Table.
In conclusion, we have described 5M LPDE to be an ex-
cellent medium for the synthesis of pyrano, indeno quino-
lines and phenanthridinone derivatives through imino-
Diels-Alder reaction of aldimines with 3,4-dihydro-2H-
pyran, indene and cyclohexenone, respectively. The pro-
cedure offers several advantages like mild/neutral reac-
tion conditions, high yields of products, low cost of the
reagents, enhanced rates & selectivity, operational sim-
plicity and ease of isolation of the products which makes
it a useful procedure for the synthesis of these compounds.
a
Isolated yields after purification; all the products were characteri-
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zed by H NMR, C NMR, IR and Mass spectra.
b
1
Product ratio was determined by the H NMR spectrum of the cru-
de product.
(
(
3) a) Anzino, M.; Cappelli, A.; Vomero, S.; Cagnotto, 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, 891-892.
Acknowledgement
BVS & RS thanks CSIR New Delhi for the award of fellowship.
4) a) Cabral, J.; Laszlo, P. Tetrahedron Lett. 1989, 30, 7237-
7238. b) Worth, D. F.; Perricone, S. C. and Elsager, E. F. J.
Heterocycl. Chem. 1970, 7, 1353-1356. c) Povarov, L. S.
Russ. Chem. Rev. 1967, 36, 656-670. d) Crousse, B.; Bejue,
J.P.; Bonnet-Delphon, D. Tetrahedron Lett. 1998, 39, 5765-
5768.
References and Notes
#
IICT Communication: 4574
(
1) a) Boger, D. L.;Weinreb, S. M.; Hetero Diels-Alder
methodology in Organic Synthesis, Academic: San Diego
(5) a) Babu, G.; Perumal, P. T. Tetrahedron Lett. 1998, 3225-
3228. b) Babu, G.; Perumal, P. T. Tetrahedron Lett. 1997, 38,
5025-5026.
(6) Ma, Y.; Qian, C.; Xie, M.; Sun, J. J. Org. Chem. 1999, 64,
6462-6467.
(7) a) Hadden, M.; Stevenson, P. J. Tetrahedron Lett. 1999, 40,
1215-1218. b) Makioka, Y.; Shindo, T.; Taniguchi, Y.;
Takaki, K.; Fujwara, Y. Synthesis 1995, 801-804.
1987, Chaps 2 and 9. b) Weinreb, S. M. Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford 1991, 5, pp 401-449.
(
2) a) Yamada, N.; Kadowaki, S.; Takahashi, K., Umezu, K.
Biochem. Pharmacol. 1992, 44, 1211, b) Faber, K.; Stueckler,
H.; Kappe, T. Heterocyl. Chem. 1984, 21, 1177-1181.
Synlett 2001, No. 2, 240–242 ISSN 0936-5214 © Thieme Stuttgart · New York

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J. S. Yadav et al.
LETTER
(
(
8) Heydari, A.; Larijani, H.; Emami, J.; Karami, B. Tetrahedron
Lett 2000, 41, 2471-2473.
9) Kametani, T.; Takedo, H.; Suzuki, Y.; Honda, T. Synth.
Commun. 1985, 15, 499-509.
6.80 (t, J = 7.8 Hz, 1H), 7.05 (t, J = 7.8 Hz, 1H), 7.25 (d,
J = 7.8 Hz, 1H), 7.35-7.45 (m, 5H). EIMS (m/z): 265 M , 206,
+
194, 129, 91, 77. IR (KBr) ν: 3340.
5g: Viscous oil, 0.76 g (70% yield), H NMR (CDCl ) δ: 1.75
1
3
(
10) a) Sankararaman, S.; Nesakumar, J. E. Eur. J. Org. Chem.
(m, 2H), 2.05 (m, 1H), 2.35 (m, 1H), 2.05 (m, 1H), 2.65 (m,
1H), 2.75 (m, 1H), 4.70 (d, J = 2.1 Hz, 1H), 4.85 (d, J = 2.5
Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.80 (t, J = 8.0 Hz, 1H),
7.15 (t, J = 8.0 Hz, 1H), 7.20-7.40 (m, 6H). EIMS (m/z) :
2000, 2003-2011. b) Grieco, P. A. Aldrichimica Acta 1991,
24, 59. c) Balasubramanian, K. K. Acros Organics Acta. 1999,
6, 12.
+
(
11) Experimental: A mixture of aldimine (5 mmol), olefin (5
277M , 206, 91, 77. IR (KBr) ν: 3370, 2950, 1740, 1590.
1
0
mmol) and 5M Lithium perchlorate in diethylether (5 mL)
was stirred at ambient temperature for an appropriate time
Analysis calculated for C H NO: C 82.28; H 6.90; N 5.05.
1
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19
Found: C 82.30; H 6.92; N 5.10. HRMS: Calculated for
C H NO: 277.37. Found: 277.41.
(Table). After complete conversion, as indicated by TLC, the
1
9
19
1
reaction mixture was quenched by addition of water (20 mL)
and extracted twice with dichloromethane (2 × 20 mL). The
combined organic layers were dried over anhydrous Na SO ,
6g: semi-solid, 0.32 g (30% yield), H NMR (CDCl ) δ: 1.80
3
(m, 2H), 2.18 (m, 2H), 2.50 (m, 1H), 2.75 (m, 1H), 2.85 (m,
1H), 4.65 (m, 1H), 4.80 (d, J = 2.5 Hz, 1H), 6.60 (d, J = 8.0
Hz, 1H), 6.75 (t, J = 8.0 Hz, 1H), 7.10 (t, J = 8.0 Hz, 1H),
2
4
and purified by column chromatography on silica gel (Merck,
00-200 mesh, ethyl acetate-hexane, 0.5-9.5) gave pure
+
1
7.25-7.35 (m, 6H). EIMS (m/z): 227 M , 206, 91, 77. IR (KBr)
quinoline derivative. Spectroscopic data for compound 3a:
solid, mp 129-131 °C, 0.88 g (70% yield), H NMR (CDCl )
ν: 3368, 2975, 1738, 1587.
7f: Viscous oil, 1.19 g (80% yield), H NMR (CDCl ) δ: 2.35
1
1
3
3
δ : 1.25-1.55 (m, 4H), 2.15 (m, 1H), 3.35-3.65 (m, 3H), 4.70
(m, 1H), 3.15 (m, 1H), 3.35 (m, 1H), 3.85 (brs, 1H), 4.5 (d,
J = 6.5 Hz, 1H), 4.70 (d, J = 2.8 Hz, 1H), 6.55 (d, J = 8.0 Hz,
1H), 6.70 (t, J = 8.0 Hz, 1H), 6.95 (t, J = 8.0 Hz, 1H), 7.15-
7.65 (m, 9H), 7.85 (d, J = 8.0 Hz, 1H). EIMS (m/z): 297M ,
206, 91, 77. IR (KBr) ν: 3345, 3050, 1570. Analysis
(d, J = 2.8 Hz, 1H), 5.34 (d, J = 5.6 Hz, 1H), 6.55 (d, J = 7.8
Hz, 1H), 6.75 (t, J = 7.8 Hz, 1H), 7.05 (t, J = 7.8 Hz, 1H),
+
+
7
7
8
.25-7.45 (m, 6H). EIMS: (m/z) : 265M , 206, 194, 129, 91,
7. IR (KBr) ν : 3335. Analysis calculated for C H NO: C
1.5; H 7.16; N 5.28. Found: C 81.56; H 7.20; N 5.31. HRMS:
1
8
19
calculated for C H N: C 88.85; H 6.44; N 4.71. Found: C
2
2
19
Calculated for C H NO : 265.14. Found: 265.16.
88.83; H 6.45; N 4.73. HRMS: Calculated for C H N:
297.15. Found: 297.18.
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19
22 19
1
4a: Viscous oil, 0.38 g (30% yield), H NMR (CDCl ) δ : 1.25
3
(
m, 1H), 1.50 (m, 1H), 1.65 (m, 1H), 1.85 (m, 1H), 2.15 (m,
H), 3.75 (t, J = 11.7 Hz, 1H), 3.95 (m, 2H), 4.40 (d, J = 2.8
Hz, 1H), 4.75 (d, J = 10.5 Hz, 1H), 6.50 (d, J = 7.8 Hz, 1H),
1
Article Identifier:
437-2096,E;2001,0,02,0240,0242,ftx,en;S04000ST.pdf
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Synlett 2001, No. 2, 240–242 ISSN 0936-5214 © Thieme Stuttgart · New York