Methodology for regioselective synthesis of substituted pyridines via intramolecular oximino malonate hetero Diels-Alder reactions

Article abstract of DOI:10.1021/ol006575i

(Matrix Presented) Various substituted pyridines can be prepared regioselectively by a sequence involving an intramolecular thermal or high-pressure Diels-Alder cycloaddition of an oximino malonate dienophile tethered to a dienic carboxylic acid, followed

Full text of DOI:10.1021/ol006575i

ORGANIC
LETTERS
2000
Vol. 2, No. 25
4007-4009
Methodology for Regioselective
Synthesis of Substituted Pyridines via
Intramolecular Oximino Malonate Hetero
Diels−Alder Reactions
Douglas C. Bland, Brian C. Raudenbush, and Steven M. Weinreb*
Department of Chemistry, The PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
smw@chem.psu.edu
Received September 11, 2000
ABSTRACT
Various substituted pyridines can be prepared regioselectively by a sequence involving an intramolecular thermal or high-pressure Diels−
Alder cycloaddition of an oximino malonate dienophile tethered to a dienic carboxylic acid, followed by mild aromatization of the resulting
cycloadduct with cesium carbonate in DMF at room temperature.
In recent years, Diels-Alder cyclizations of imino dieno-
philes have provided powerful methodology for construction
of a diverse array of nitrogen heterocycles and alkaloids.1
In a series of papers commencing about 30 years ago, Fleury
and co-workers found that various oximino malonate deriva-
tives 1 undergo Diels-Alder cycloadditions with cyclopen-
tadiene, as well as a few simple acyclic dienes, to afford
adducts such as 2 and 3, respectively (Scheme 1).2
however, that the regiochemistry with 1 is reversed relative
to that found with simpler imino dienophiles.1 Fleury found
that solvolysis of adduct 3 in refluxing ethanol produced
pyridine 4. Subsequent work by Breitmaier involved using
1-oxygenated butadienes in the cycloaddition with 1 (X, Y
) CN, R ) Ts),3 and it was demonstrated that these types
Scheme 1
In general, the degree of regioselectivity of this process
appears to be good, although this aspect of the chemistry
has not been extensively investigated. It does appear,
(1) For reviews and leading references to imino Diels-Alder reactions,
see: (a) Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology
in Organic Synthesis; Academic Press: Orlando, 1987; Chapter 2. (b)
Weinreb, S. M. Heterodienophile Additions to Dienes. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 4, p 401.
(2) (a) Biehler, J.-M.; Perchais, J.; Fleury, J.-P. Bull. Soc. Chim. Fr. 1971,
2711. (b) Biehler, J.-M.; Fleury, J.-P. J. Heterocycl. Chem. 1971, 8, 431.
(c) Perchais, J.; Fleury, J.-P. Tetrahedron 1972, 28, 2267. (d) Fleury, J.-P.
Chemia 1977, 31, 143. (e) Fleury, J.-P.; Desbois, M.; See, J. Bull Soc. Chim.
Fr. 1978, II-147.
10.1021/ol006575i CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/17/2000

of cycloadducts could also be converted to pyridines by base-
promoted elimination in low to modest yields. More recently,
Katagiri4 and Danheiser5 have explored [4 + 2]-cycloaddi-
tions with Meldrum’s acid analogues of dienophiles 1. In
addition, the latter group developed methodology for efficient
conversion of these adducts to pyridines.5
One simple strategy for controlling regiochemistry of
imino Diels-Alder reactions is to make the process intramo-
lecular.6 To our knowledge, however, intramolecular cy-
cloadditions of oximino dienophiles have not previously been
reported. Herein we demonstrate the feasibilty of this
approach and also report good methodology for aromatization
of the resulting cycloadducts to pyridines.
room temperature effects aromatization to pyridines 10. Other
bases such as DBU, triethylamine, and Dowex 1X8-400 ion-
exchange resin afforded the pyridines in irreproducible or
considerably lower yields. Table 1 contains examples of these
transformations in several systems.
It was observed that all intramolecular cycloadditions
involving the unsymmetrical oximino dienophile 6 afforded
products which were single stereoisomers. We have probed
these interesting stereochemical issues with the help of X-ray
crystallography.8 Thus, it was found by crystallography that
oxime 6 is in fact the E-geometrical isomer. X-ray analysis
also demonstrated that the cycloadduct formed from diene
ester 11 is the stereoisomer shown in 15 (Table 1 entry 2,
and Scheme 3).
Various dinitrile substrates 8 (X ) CN) for the cycload-
ditions were prepared by O-acylating commercially available
sodium (hydroxyimino)malononitrile (5) with the acid chlo-
rides derived from diene acids 7 (Scheme 2).2
Scheme 3
Scheme 2
Assuming that oxime isomerization of 6 does not occur
during the esterification of the diene acid, and that Diels-
Alder precursor 11 has the anticipated E-geometry, cycload-
dition must occur via a transition state having the cyano
group endo. Molecular mechanics calculations (PCModel,
version 6) indicate that pseudo boat 14 is ∼2.8 kcal/mol more
stable than the exo-cyano pseudo boat conformation 12,
which would lead to the alternative stereoisomer 13. The
corresponding pseudo chairs related to 12 and 14 are both
considerably higher in energy. Cyclization of conformer 14
leads initially to a cis azadecalin, which then inverts to the
trans system as is evident from the X-ray data (see
Supporting Information). Moreover, cyclization of 12 would
lead directly to a trans azadecalin.
X-ray analysis of the cycloadduct in Table 1, entry 4 (X
) CO2Et) demonstrates that the same stereochemical prefer-
ence for an endo cyano group applies in the 6,5-fused system.
It might also be noted that Fleury et al. found that the
intermolecular cycloaddition between the tosylate of oxime
6 and cyclopentadiene gave exclusively the product (cf. 2)
having the cyano group exo.2b
The corresponding ester nitrile precursors 8 (X ) CO2Et)
were synthesized directly from oxime 6 and the diene acids
using DCC as the coupling reagent (see Supporting Informa-
tion). It was found that heating acyl oximes 8 in refluxing
toluene overnight promoted [4 + 2]-cycloaddition to afford
the desired cycloadducts 9. The best yields of compounds 9
were obtained if the thermolyses were conducted in dilute
solution (0.005 M) since at higher concentrations consider-
able amounts of tarry material were formed. Table 1 shows
examples of these Diels-Alder reactions. In addition, the
cycloadditions could be promoted by high pressure (12 Kbar,
rt) in similar yields.
After screening a variety of bases, it was found that
treatment of adducts 9 with cesium carbonate in DMF at
(3) Dormagen, W.; Rotscheidt, K.; Breitmaier, E. Synthesis 1988, 636.
(4) Katagiri, N.; Nochi, H.; Kurimoto, A.; Sato, H.; Kaneko, C. Chem.
Pharm. Bull. 1994, 42, 1251.
(5) Renslo, A. R.; Danheiser, R. L. J. Org. Chem. 1998, 63, 7840.
(6) Weinreb, S. M. Acc. Chem. Res. 1985, 18, 16.
In summary, we have found that substituted pyridines can
be produced regioselectively by a sequence utilizing an
(7) For preparation of these types of dienic acids, see inter alia: (a)
Hudlicky, T.; Koszyk, F. J.; Kutchan, T. M.; Sheth, J. P. J. Org. Chem.
1980, 45, 5020. (b) Martin, S. F.; Tu, C.; Chou, T. J. Am. Chem. Soc. 1980,
102, 5274. (c) Gutierrez, A. J.; Shea, K. J.; Svoboda, J. J. J. Org. Chem.
1989, 54, 4335.
(8) We are grateful to Dr. M. Shang (University of Notre Dame) for
conducting the X-ray analyses of compound 6 and the cycloadduct shown
in entry 4, Table 1 (X ) CO2Et) and Dr. D. Powell (University of
Wisconsin) for analysis of 15.
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Org. Lett., Vol. 2, No. 25, 2000

Table 1. Intramolecular Diels-Alder Reactions of Oximino Malonates and Aromatization of the Resulting Cycloadducts
a PhMe (0.005 M), reflux, 24-48 h. b 12 Kbar, CH2Cl2, rt, overnight. c Cs2CO3 in DMF, rt, overnight. d For ease of isolation in this case, the acid was
converted to the ethyl ester (see Supporting Information for details).
intramolecular oximino malonate hetero Diels-Alder reac-
tion, followed by mild base-catalyzed aromatization of the
resulting cycloadduct. This methodology should be particu-
larly useful in preparation of pyridines involving cases of
functionally unsymmetrical but electronically symmetrical
dienes. We are currently investigating extensions and ap-
plications of this chemistry.
support of this research and to Professor R. L. Funk for
helpful discussions and assistance in performing the molec-
ular mechanics calculations.
Supporting Information Available: Experimental details
and spectral data for compounds in Table 1 and an ORTEP
drawing of compound 15. This material is free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. We are grateful to the National
Institutes of Health (GM-32299) for generous financial
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