Nafion-H-catalyzed Mukaiyama aldol condensations and hetero Diels-Alder reactions using aldehydes and imines. Part 15: General synthetic methods

Article abstract of DOI:10.1016/S0040-4039(01)01592-1

Nafion-H catalyzes the Mukaiyama aldol condensation between aromatic aldehydes and the Danishefsky diene whereas the corresponding imines directly undergo hetero Diels-Alder cyclization to form 2,3-dihydro-γ-pyridones. Some chiral acetal derived aldehydes

Full text of DOI:10.1016/S0040-4039(01)01592-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7493–7495
Nafion-H-catalyzed Mukaiyama aldol condensations and hetero
Diels–Alder reactions using aldehydes and imines. Part 15:
General synthetic methods†
R. Kumareswaran, B. Gopal Reddy and Y. D. Vankar*
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
Received 11 June 2001; revised 10 August 2001; accepted 24 August 2001
Abstract—Nafion-H catalyzes the Mukaiyama aldol condensation between aromatic aldehydes and the Danishefsky diene whereas
the corresponding imines directly undergo hetero Diels–Alder cyclization to form 2,3-dihydro-g-pyridones. Some chiral acetal
derived aldehydes were found to undergo Mukaiyama aldol condensation in the presence of Lewis acids but not with Nafion-H.
© 2001 Elsevier Science Ltd. All rights reserved.
The hetero Diels–Alder reaction2 between a reactive
carbonyl compound or an imine and the Danishefsky
diene 1 (Scheme 1) is an excellent pathway to obtain
g-pyrones or g-pyridones due to its highly electron rich
nature. Aldehydes and imines react easily with 1. A
variety of achiral3 as well as chiral4 catalysts have been
used to catalyze this reaction. The achiral catalysts that
have been employed include MgBr2,5 ZnI2,6 LiClO4,7
CF3SO3H.8 Likewise, metallocenium complex [Cp2Ce]+
[BPh4]− catalyzes9 hetero Diels–Alder reactions and
more recently, the use of microwaves has also been
found10 to accelerate the hetero Diels–Alder reaction.
for ionic Diels–Alder reactions where the acetal moiety
of dienophiles remained unaffected. It was, therefore, of
interest to explore the behavior of Nafion-H towards
hetero Diels–Alder reactions. Since the acidity of
Nafion-H is comparable13 to 100% H2SO4, we won-
dered if the second step involving exposure of the
Mukaiyama aldol products (Scheme 1) to tri-
fluoroacetic acid could be avoided to obtain the
cyclized products directly. Our efforts in this direction
using aldehydes and imines as dienophiles are described
in this letter. Accordingly, it was found that aromatic
aldehydes react readily with 1 to form the correspond-
ing Mukaiyama aldol products 2 (Scheme 1) (1.5–3.5
h/room temperature) upon treatment with Nafion-H
(30 mg/1 mmol of aldehyde). However, contrary to our
expectations, no trace of the cyclized product 4 was
formed. But, when the catalyst was removed by filtra-
tion and the filtrate treated with 0.1 ml of CF3CO2H,
the expected cyclized products were obtained in good
yields. Our results are summarized in Table 1. Interest-
ingly, the corresponding aromatic imines underwent
direct cyclization to 2,3-dihydro-g-pyridones upon
Solid acid catalysts such as zeolites,11 clays,12 and
Nafion-H13 have enjoyed immense popularity in
organic synthesis. They offer selectivities in addition to
making the work-up simpler involving mere filtration of
the catalysts. We have been interested in making use of
the zeolite H-ZSM 5,14,15 montmorillonite K 1015 and
Nafion-H15,16 in various organic transformations.
Nafion-H was found by us16 to be an excellent catalyst
OMe
O
Me3SiX
Ar
O
CF3COOH
ArCH=X
+
OMe
Me3SiO
Ar
X
X = O: 2
X = O: 4
1
X = NPh: 5
X = NPh: 3
Scheme 1.
Keywords: hetero Diels–Alder reaction; Nafion-H; Danishefsky diene; chiral acetal; ZnI2.
* Corresponding author. Fax: 0091-512-597169; e-mail: vankar@iitk.ac.in
†
For Part 14 see: Ref. 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01592-1

7494
R. Kumareswaran et al. / Tetrahedron Letters 42 (2001) 7493–7495
Table 1. Hetero Diels–Alder reaction using aromatic aldehydes and imines and Nafion H as the catalyst
treatment with Nafion-H (entries 2, 4, 6, 8, 10, 12, 14,
16: Table 1). No trace of the Mukaiyama imino aldol
product was formed suggesting that the Mukaiyama
imino aldol products, if formed, underwent direct
cyclization. Furthermore, unlike the reactions of fur-
fural and 3-pyridine aldehyde with 1 in which the
Mukaiyama aldol products were found to decompose
upon treatment with CF3CO2H, the corresponding
imines (Table 1, entries 8 and 10) underwent direct
cyclization with Nafion-H alone. After the reaction was
over, the catalyst was filtered off and the products
purified by column chromatography.
tion met with no success. Some simple aliphatic alde-
hydes such as butyraldehyde and phenyl acetaldehyde
also did not react with 1 under the present reaction
conditions. However, 6 underwent a Mukaiyama aldol
condensation with 1 under the influence of Lewis acids
such as ZnCl2, Yb(OTf)3, ZnI2 and even LiClO4.
Among these, ZnI2 gave the best results leading to the
Mukaiyama aldol adduct 7 which was treated with
CF3CO2H to obtain the cyclized product 819 in 70%
yield (Scheme 2). The diastereomeric ratio20 was only
60:40 indicating that the intermediate 9 is not very
rigid. In addition, the corresponding imine did not react
cleanly with 1 in presence of Nafion-H, but in the
presence of ZnI2, it gave the cycloadduct 1219 in 90%
yield, via 11, in a diastereomeric ratio of 65:35. The
non-enolizable aldehyde 1321 did not react with 1 in the
presence of Nafion-H, but in the presence of ZnI2, the
Our interest17 in using chiral acetals in organic synthesis
led us to investigate whether the aldehyde 618 would act
as a dienophile in the presence of Nafion-H as a
catalyst. Unfortunately, our attempts to effect this reac-
O
OMe
X
OMe
MeO
OMe
MeO
MeO
CF3CO2H
Nafion-H
O
Z
O
O
O
O
O
O
OMe
H
Z
*
8; Z = O
6: X = O
7: Z = OSiMe3
10: X = NPh
12; Z = NPh
11: Z = N(SiMe3)Ph
O
OMe
OMe
O
MeO
OMe
O
MeO
O
O
O
CF3CO2H
O
O
OMe
+ 1
Ph
O
Ph
OMe
Ph
H
Me3SiO
O
14
15
13
Scheme 2.

R. Kumareswaran et al. / Tetrahedron Letters 42 (2001) 7493–7495
7495
corresponding cyclized product 1519 was formed, via 14,
in a diastereomeric ratio of 80:20. This suggests that the
intermediate 16 is more rigid than 9 offering a some-
what better diasteroselectivity. Efforts are underway to
explore whether other catalysts will give higher
diastereoselectivities in these reactions.
9. Molander, G. A.; Rzasa, R. M. J. Org. Chem. 2000, 65,
1215.
10. Diaz-Ortiz, A.; Diez-Barra, E.; de la Hoz, A.; Prieto, P.;
Moreno, A.; Langa, F.; Prange, T.; Neuman, A. J. Org.
Chem. 1995, 60, 4160.
11. (a) Davis, M. E. Acc. Chem. Res. 1983, 26, 111; (b)
Holderich, I.; Hesse, W.; Naumann, M. Angew. Chem., Int.
Ed. Engl. 1988, 27, 236.
12. (a) Yadav, J. S.; Reddy, B. V. S.; Rasheed, M. A.; Sampath
Kumar, H. M. Synlett 2000, 487; (b) Torok, B.; London,
G.; Bartok, M. Synlett 2000, 631; (c) Onaka, M.; Shinoda,
T.; Izumi, Y.; Nolen, E. Tetrahedron Lett. 1993, 34, 2525;
(d) Toshima, K.; Ishizua, T.; Matsuo, G.; Nakata, M.
Synlett 1996, 306.
OMe
OMe
MeO
MeO
M+
M+
Z
O
O
O
O
O
H
Ph
+
H
9
M = Lewis Acid
16
In summary, our findings suggest that Nafion-H is a
good catalyst for effecting hetero Diels–Alder reactions
between aromatic aldehydes and imines. However, chi-
ral acetal derived aldehydes and imines are inert
towards Nafion-H, but respond well to Lewis acids,
especially ZnI2.
13. (a) Olah, G. A.; Iyer, P. S.; Prakash, G. K. S. Synthesis
1986, 513; (b) Olah, G. A.; Wang, Q.; Li, X.-Y.; Prakash,
G. K. S. Synlett 1990, 487.
14. (a) Reddy, M. V. R.; Pitre, S. V.; Bhattacharya, I.; Vankar,
Y. D. Synlett 1996, 241; (b) Gupta, A.; Haque, A.; Vankar,
Y. D. Chem. Commun 1996, 1653; (c) Pitre, S. V.; Reddy,
M. V. R.; Vankar, Y. D. J. Chem. Res. 1997, 2162.
15. Gupta, A.; Vankar, Y. D. Tetrahedron 2000, 56, 8525.
16. Kumareswaran, R.; Vankar, P. S.; Reddy, M. V. R.; Pitre,
S. V.; Roy, R.; Vankar, Y. D. Tetrahedron 1999, 55, 1099.
17. Vankar, Y. D.; Reddy, M. V. R.; Chaudhuri, N. C.
Tetrahedron 1994, 50, 11052.
18. Aldehyde 6 was prepared by the Swern oxidation of the
corresponding alcohol, which was obtained from the ketal
of ethyl acetoacetate. All the compounds gave satisfactory
spectral and analytical data.
Acknowledgements
We thank the Department of Science and Technology
and the Council of Scientific and Industrial Research,
New Delhi for financial support. We also thank Profes-
sor G. A. Olah and Professor G. K. S Prakash for the
gift of Nafion-K.
19. Selected data: Compound 8: IR spectrum (neat) wmax: 1650,
1580 cm−1. 1H NMR spectrum (CDCl3, 300 MHz): l 1.44a,
1.46b (2s, 3H, -CH3), 1.95–2.45 (m, 2H, -CH2-), 2.48–2.65
(m, 2H, -CO-CH2-), 3.38b, 3.4a (2s, 6H, 2×-OCH3), 3.45–
References
1. Reddy, B. G.; Kumareswaran, R.; Vankar, Y. D. Tetra-
hedron Lett. 2000, 41, 10333.
3.63 (m, 4H, 2×-CH6 2-OCH3), 3.86–4.09 (m, 2H, 2×methi-
nes), 4.67–4.73 (m, 1H, methine on the pyrone ring),
5.4–5.42 (m, 1H, olefinic proton), 7.34–7.36 (m, 1H, olefinic
proton); 13C NMR (CDCl3, 75 MHz): l 194.00, 163.59,
109.65, 107.50, 77.80, 77.34, 76.66, 72.90, 59.87, 45.55,
26.55; Mass spectrum (m/z): 286 (M+), 255 (M+ −31), 224
(M+ −62). [h]D25=+7.2 (c=1, CH2Cl2). Compound 12: IR
spectrum (neat) wmax: 1640, 1570 cm−1. 1H NMR spectrum
(CDCl3, 300 MHz): l 1.39 (s, 3H), 1.95–2.59 (2m, 2H),
2.85–2.94(m, 2H), 3.38, 3.39,b 3.40, 3.42a (4s, 6H), 3.46–3.62
(m, 4H), 3.83–3.94a and 4.04–4.17b (2m, 2H), 4.41–4.5a and
4.5–4.59b (2m 1H), 5.21 (d, 1H, J=7 Hz), 7.12 (d, 1H, J=7
Hz), 7.24–7.43 (m, 5H); 13C NMR (CDCl3, 75 MHz):
192.79, 147.93, 144.49, 130.03, 124.50, 118.84, 110.60,
102.20, 77.97, 77.60, 77.09, 73.47, 73.72, 68.50, 59.82, 54.36,
41.55, 38.62, 26.70, 19.20; Mass spectrum (m/z): 361 (M+),
172 (M+−189). [h]D25=+58.75 (c=2, CH2Cl2). Compound 15:
2. (a) Danishefsky, S. Acc. Chem. Res. 1981, 14, 400; (b)
Danishefsky, S.; De Nino, M. P. Angew. Chem., Int. Ed.
Engl. 1987, 26, 15; (c) Boger, D. L.; Weinreb, S. M. Hetero
Diels–Alder Methodology in Organic Synthesis; Academic
Press: New York, 1987; (d) Waldman, H. Synthesis 1994,
535.
3. (a) Swindell, C. S.; Tao, M. J. Org. Chem. 1993, 58, 5889;
(b) Barluenga, J.; Aznar, F.; Valdes, C.; Ribas, C. J. Org.
Chem. 1998, 63, 3918.
4. (a) Jorgensen, K. A. Angew. Chem., Int. Ed. 2000, 39, 3559
and references cited therein; (b) Keck, G. E.; Li, X.-Y.;
Krishnamurthy, D. J. Org. Chem. 1995, 60, 5998; (c)
Midland, M. M.; Koops, R. W. J. Org. Chem. 1990, 55,
4647; (d) Bednarski, M.; Danishefsky, S. J. Am. Chem. Soc.
1986, 108, 7060; (e) Dossetter, A. G.; Jamison, T. F.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 1999, 38, 2398; (f)
Hu, Y.-J.;Hung, X.-D.;Yao, Z.-J.;Wu, Y.-L. J. Org. Chem.
1998, 63, 2456; (g) Hattori, K.; Yamamoto, H. Tetrahedron
1993, 49, 1749; (h) Wang, B.; Feng, X.; Cui, X.; Jiang, Y.
Chem. Commun. 2000, 1605.
IR spectrum (neat) wmax: 1660, 1580 cm−1 1H NMR
.
spectrum (CDCl3, 300 MHz): l 2.38–2.79 (m, 2H), 3.30,
3.42 (2s, 6H), 3.62–3.65 (m, 4H), 3.85–4.2 (m, 2H), 4.57a
and 4.79b (2dd, 1H, J=8, 5 Hz), 5.37 (d, 1H, J=6 Hz),
7.27–7.54 (m, 6H). Mass spectrum (m/z): 334 (M+), 303
(M+−31), 272 (M+−62). [h]D25=+19 (c=1, CH2Cl2). [Note:
‘a’ and ‘b’ refer to the peaks for major and minor
diastereomers, respectively.]
5. Badorrey, R.; Cativiela, C.; Diaz-de-Villegas; Galvez, J. A.
Tetrahedron 2000, 38, 2547.
6. Grieco, P. A.; Moher, E. D. Tetrahedron Lett. 1993, 34,
5561.
7. Molander, G. A.; Rzasa, R. M. J. Org. Chem. 2000, 65,
1215.
8. Aggarwal, V. K.; Vennall, G. P.; Davey, P. N.; Newman,
C. Tetrahedron Lett. 1997, 38, 2569.
20. The diastereoselectvity was determined from the 1H NMR
by using Eu(hfc)3 as a shift reagent.
21. This aldehyde was prepared by the Swern oxidation of the
corresponding alcohol, which was obtained by the LiAlH4
reduction of the ketal of ethyl benzoyl formate.