Diels-Alder reactions of 5-vinyl-1-acyl-2-aryl-2,3-dihydro-4-pyridones: regio- and stereoselective synthesis of octahydroquinolines.

Article abstract of DOI:10.1021/ol027308a

[reaction: see text] Readily available 5-vinyldihydropyridones 2 undergo Diels-Alder cyclization with various dienophiles to afford novel octahdroquinolines. The process is highly stereoselective and provides heterocyclic products containing synthetically

Full text of DOI:10.1021/ol027308a

ORGANIC
LETTERS
2003
Vol. 5, No. 3
321-323
Diels−Alder Reactions of
5-Vinyl-1-acyl-2-aryl-2,3-dihydro-4-pyridones:
Regio- and Stereoselective Synthesis of
Octahydroquinolines
Jeffrey T. Kuethe, Clinton A. Brooks, and Daniel L. Comins*
Department of Chemistry, North Carolina State UniVersity,
Raleigh, North Carolina 27695-8204
daniel_comins@ncsu.edu
Received November 19, 2002
ABSTRACT
Readily available 5-vinyldihydropyridones 2 undergo Diels−Alder cyclization with various dienophiles to afford novel octahdroquinolines. The
process is highly stereoselective and provides heterocyclic products containing synthetically useful functionality.
The Diels-Alder reaction provides an efficient and rapid
means of constructing highly functionalized heterocyclic ring
systems with control of the regio-, diastereo-, and enantio-
selectivity.1 In particular, the Diels-Alder reaction of amino-
substituted dienes has emerged as a powerful method for
the preparation of complex piperidines.2 While reactions of
1-N-acylamino-1,3-dienes and N,N-dialkylaminodienes are
plentiful,3,4 to our knowledge no reports have surfaced
regarding the Diels-Alder reactions of substituted 5-vinyl-
1-acyl-2,3-dihydro-4-pyridones of type 2. N-Acyl-2-alkyl-
(aryl)-2,3-dihydro-4-pyridones have proven to be valuable
building blocks for alkaloid synthesis.5 As part of a program
to expand the synthetic utility of these versatile building
blocks, we have investigated the Diels-Alder reactions of
diene 2 with various dienophiles as a method of preparing
novel octahydroquinoline derivatives of general type 1. In
this Letter we disclose our initial findings in this area.
(1) For leading references, see: (a) Corey, E. J. Angew. Chem., Int. Ed.
2002, 41, 1650. (b) Nicolau, K. C.; Snyder, S. A.; Montagnon, T.;
Vassiligiannakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668. (c) Tietze, L.
F.; Kettschau, G. In Topics in Current Chemistry; Metz, P., Ed.; Springer-
Verlag: Berlin, 1997; Vol. 189, pp 1-120 and references therein. (d)
Waldmann, H. Synthesis 1994, 535.
(2) For reviews on the Diels-Alder reaction of amino-substituted dienes,
see: (a) Enders, D.; Meyer, O. Liebigs Ann. 1996, 1023. (b) Barluenga, J.;
Suarez-Sobrino, A.; Lopez, L. A. Aldrichim. Acta 1997, 32, 4.
(3) (a) Overman, L. E.; Clizbe, L. A. J. Am. Chem. Soc. 1976, 98, 2352.
(b) Overman, L. E.; Taylor, G. F.; Jessup, P. J. Tetrahedron Lett. 1976,
3089. (c) Overman, L. E.; Yaylor, G. F.; Houk, K. N.; Domelsmith, L. S.
J. Am. Chem. Soc. 1978, 100, 3182. (d) Oppolzer, W.; Bieber, L.; Francotte,
E. Tetrahedron Lett. 1979, 4537. (e) Overman, L. E.; Freerks, R. L.; Petty,
C. B.; Clizbe, L. A.; Ono, R. K.; Taylor, G. F.; Jessup, P. J. J. Am. Chem.
Soc. 1981, 103, 2816.
The study began with racemic 3, prepared by addition of
phenylmagnesium chloride to 1-((phenoxy)carbonyl)-4-meth-
oxypyridinium chloride. Iodination of 3 with NIS/cat.-
[hydroxy(tosyloxy)iodo]benzene (HTIB) followed by Stille
coupling with tributyl(vinyl) tin afforded 4 in good overall
10.1021/ol027308a CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/16/2003

Table 1. Diels-Alder Reactions of 4 with Various Dienophiles
1
a Scale 0.1-0.2 mmol. b Isolated yields. c Ratio determined by H NMR or HPLC.
yield.6 Reaction of 4 with N-phenylmaleimide in refluxing
toluene afforded cycloadduct 5 as a single diastereomer in
96% isolated yield. The relative stereochemistry of 5 was
unequivocally established by single-crystal X-ray analysis,
which showed the exclusive preference for endo approach
of the dieneophile.7 Since the C-2 phenyl group of diene 4
occupies a pseudoaxial orientation,8 excellent diastereofacial
control was observed where addition of the dieneophile
occurred exclusively anti to the phenyl substituent, thus
setting the three new contiguous chiral centers with complete
stereocontrol. The Diels-Alder reactions of 4 with various
dienophiles are summarized in Table 1. When cis-disubsti-
tuted dienophiles were employed (entries 1-5), the cyclo-
adducts 6-10 were obtained as single diastereomers in good
1
to excellent yields. The structures were determined by H
NMR analysis by comparison of coupling constants with
those observed for cycloadduct 5. On the other hand, when
dimethyl fumarate served as the dienophile (entry 6), no
endo/exo selectivity was observed and cycloadducts 11a and
11b were obtained as a 1:1 mixture of diastereomers.
Interestingly, reaction of 4 with methyl acrylate, acrylonitrile,
and phenyl vinyl sulfone (entry 7) only showed modest
preference for the endo adducts 12a. However, in each case
the products were in full accord with that predicted by
Scheme 1
(4) (a) Ha, J. D.; Kang, C. H.; Belmore, K. A.; Cha, J. K. J. Org. Chem.
1998, 63, 3810 and references therein. (b) Aelterman, W.; De Kimpe, N.
Tetrahedron 1998, 54, 2563. (c) Brosius, A. D.; Overman, L. E.; Schwink,
L. J. Am. Chem. Soc. 1999, 121, 700. (d) Jiang, J.; DeVita, R. J.; Doss, G.
A.; Goulet, M. T.; Wyvratt, M. J. J. Am. Chem. Soc. 1999, 121, 593. (e)
Barluenga, J.; Fernandez, M. A.; Aznar, F.; Valdes, C. Tetrahedron Lett.
2002, 43, 8159 and references therein.
(5) For leading references, see: (a) Comins, D. L.; Al-awar, R. S.; Foti,
C. J. J. Org. Chem. 1999, 64, 2184. (b) Comins, D. L.; Brooks, C. A.;
Al-awar, R. S.; Goehring, R. R. Org. Lett.1999, 1, 229. (c) Comins, D. L.;
Fulp, A. B. Org. Lett. 1999, 1, 1941. (d) Kuethe, J. T.; Comins, D. L. Org.
Lett. 2000, 2, 855. (e) Huang, S.; Comins, D. L. Chem. Commun. 2000, 7,
569.
(6) Comins, D. L.; Joseph, S. P.; Chen, X. Tetrahedron Lett. 1995, 36,
9141.
(7) Details can be found in Supporting Information.
(8) Comins, D. L.; Joseph, S. P. In AdVances in Nitrogen Heterocycles;
Moody, C. J., Ed.; JAI Press: Greenwich, CT, 1996; Vol. 2, pp 251-294
and references therein.
322
Org. Lett., Vol. 5, No. 3, 2003

To further explore the synthetic utility of the process, the
Diels-Alder chemistry of dienes 13 and 14 was also
explored. Luche reduction of 4 provided 13 and 14 as a
83:17 mixture (13:14) in a combined yield of 89%. The
isomers were easily separated by silica gel chromatography.
Individual reaction of 13 and 14 with N-phenylmaleimide
in refluxing toluene for 30 min gave cycloadducts 15 and
16 as single diastereomers in 87% and 93% yield, respec-
tively. In similar fashion, reaction of 13 with cyclopentenone
provided 17 in 68% isolated yield. In conclusion, the Diels-
Alder reaction of 5-vinyl-1-acyl-2-aryl-2,3-dihydro-4-pyri-
dones provides a highly diastereoselective means of preparing
octahydroquinolines containing various functionalities. By
taking advantage of the C-2 axial substituent, three contigu-
ous centers can be set in a single synthetic operation.
Although this study used racemic starting material, the
methodology can lead to enantiopure products by starting
with readily available nonracemic dihydropyridones.9 Ap-
plication of this chemistry to the synthesis of natural products
is underway in our laboratories and will be reported in due
course.
Scheme 2
Acknowledgment. We express appreciation to the Na-
tional Institutes of Health (grant GM 34442) for financial
support of this research. The authors thank Dr. Paul Boyle
for X-ray crystallographic analysis of 5. NMR and mass
spectra and X-ray data were obtained at NCSU instrumenta-
tion laboratories, which were established by grants from the
North Carolina Biotechnology Center and the National
Science Foundation (grants CHE-9509532, CHE-0078253).
Supporting Information Available: Experimental and
spectral data for compounds 5-17. ORTEP plot and X-ray
crystal data for 5. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL027308A
(9) (a) Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am. Chem. Soc.
1994, 116, 4719. (b) Comins, D. L.; LaMunyon, D. H. Tetrahedron Lett.
1994, 35, 7343. (c) Comins, D. L.; Guerra-Weltzien, L. Tetrahedron Lett.
1996, 37, 3807.
HOMO diene-LUMO dienophile interaction. In all cases
(entries 1-7), there was no detectable amount of double bond
isomerization of the cycloadducts.
Org. Lett., Vol. 5, No. 3, 2003
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