Formal cycloaddition reactions of vinylogous amides with α,β-Unsaturated iminiums. A strategy for constructing piperidinyl heterocycles

Article abstract of DOI:10.1021/ol990107v

(Formula presented) A formal [3 + 3] cycloaddition strategy for constructing piperidinyl heterocycles from vinylogous amides and α,β-unsaturated iminiums is described here. These reactions proceed well, leading to various heterocycles that could serve as

Full text of DOI:10.1021/ol990107v

ORGANIC
LETTERS
1999
Vol. 1, No. 3
509-512
Formal Cycloaddition Reactions of
Vinylogous Amides with
r,â-Unsaturated Iminiums. A Strategy
for Constructing Piperidinyl
Heterocycles
Richard P. Hsung,* Lin-Li Wei, Heather M. Sklenicka, Christopher J. Douglas,1
Michael J. McLaughlin, Jason A. Mulder, and Letitia J. Yao2
Department of Chemistry, The UniVersity of Minnesota, Minneapolis, Minnesota 55455
hsung@chem.umn.edu
Received May 26, 1999
ABSTRACT
A formal [3 + 3] cycloaddition strategy for constructing piperidinyl heterocycles from vinylogous amides and r,â-unsaturated iminiums is
described here. These reactions proceed well, leading to various heterocycles that could serve as useful synthetic building blocks. Comparative
studies between the reactivities of vinylogous amides and other 1,3-diketo systems have also been examined. Preferences for the nitrogen
atom during the electrocyclic ring closure step are noted in these reactions, and preliminary calculations suggest that these preferences
could result from electronic factors.
We recently reported a formal [3 + 3] cycloaddition reaction3
in which R,â-unsaturated iminium intermediates were con-
densed with 4-hydroxy-2-pyrones through a sequence in-
volving C-1,2-addition, possible reversible â-elimination, and
six-π-electron electrocyclic ring closure.4 This formal cy-
cloaddition reaction proved to be a useful entry to a diverse
array of pyranyl heterocycles specifically fused to 2-pyrones.4
This initial study provided a significant solution to the
regiochemical problems caused by the competing 1,2- versus
1,4-additions and the C- versus O-addition in these reac-
tions.5,6 However, the synthetic scope remained largely
limited because only 4-hydroxy-2-pyrones have been em-
ployed. The synthetic utility of this formal cycloaddition
reaction would be greatly expanded if other 1,3-dicarbonyl
systems could also be employed as nucleophilic equivalents
of 4-hydroxy-2-pyrones. As illustrated in Figure 1, if 1,3-
dicarbonyl systems (A) such as vinylogous amides are used,
by proceeding through the proposed intermediates, this
reaction could lead to useful nitrogen-containing heterocyclic
structures (C). Given this novel strategy for constructing
complex heterocycles and its potential in the synthesis of
relevant natural products,6a,7,8 we investigated reactions of
various of 1,3-dicarbonyl equivalents with R,â-unsaturated
iminiums. We report here our first realization of this formal
(1) UMN Undergraduate Research Participant, 1998-1999, and a
Recipient of 1998 Pharmacia-Upjohn Summer Research and LANDO-NSF
REU Fellowships.
(2) UMN Chemistry Department Research Scientist for NMR Spectros-
copy.
(3) Examples of [3 + 3] cycloaddition reactions in the truest sense are
extremely scarce, and there are only limited examples of metal-mediated
[3 + 3] cycloaddition reactions. For recent reviews, see: (a) Fru¨hauf, H.-
W. Chem. ReV. 1997, 97, 523. (b) Lautens, M.; Klute, W.; Tam, W. Chem.
ReV. 1996, 96, 49.
(5) de March, P.; Moreno-Man˜as, M.; Casado, J.; Pleixats, R.; Roca, J.
L.; Trius, A. J. Heterocycl. Chem. 1984, 21, 1369.
(6) (a) Hua, D. H.; Chen, Y.; Sin, H.-S.; Maroto, M. J.; Robinson, P.
D.; Newell, S. W.; Perchellet, E. M.; Ladesich, J. B.; Freeman, J. A.;
Perchellet, J.-P.; Chiang, P. K. J. Org. Chem. 1997, 62, 6888. (b) Jonassohn,
M.; Sterner, O.; Anke, H. Tetrahedron 1996, 52, 1473.
(4) Hsung, R. P.; Shen, H. C.; Douglas, C. J.; Morgan, C. D.; Degen, S.
J.; Yao, L. J. J. Org. Chem. 1999, 64, 690.
10.1021/ol990107v CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/17/1999

Further studies revealed that interesting spirocycles such
as 3 and 4 could also be obtained in 62% and 66% yield,
respectively, under the same reaction conditions in 20-36
h using cycloalkylidene acetaldehydes. When 4-keto-6-
phenyl-δ-lactone was used as a 1,3-dicarbonyl equivalent
and condensed with 3-methyl-2-butenal, the desired cyclo-
adduct 5 was obtained in 56% yield. However, this reaction
had to be carried out at 85 °C, and the reaction time was
much longer (120 h). At higher temperatures, decomposition
of the starting lactone occurred. Compounds 1-5 should be
synthetically useful because these pyranyl heterocycles are
functionally rich, and the pyranyl heterocycle 5 in particular
contains the lactone moiety that can provide further synthetic
utility.
Figure 1.
Having established the reactivity of 1,3-diketo systems,
we quickly turned our focus to vinylogous amides with the
intention of constructing piperidinyl heterocycles. The reac-
tion of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with the
R,â-unsaturated iminium derived from 3-methyl-2-butenal
was carried out at 85 °C in EtOAc to give the piperidine
derivatives 6a and 6b in 24% and 7% yields, respectively
(Scheme 2).11 The compound 6b was likely a result of
cycloaddition reaction involving vinylogous amides as a
unique approach for synthesis of piperidinyl heterocycles.
Our preliminary studies of the cycloaddition reactions of
1,3-diketones with R,â-unsaturated iminium revealed the
relatively low reactivity of diketones in comparison with that
of 4-hydroxy-2-pyrones.4 A series of attempts to effect the
reaction of 1,3-cyclohexadione were unsuccessful. When 1,3-
cyclohexadione was heated to 85 °C in EtOAc with the R,â-
unsaturated iminium intermediate pregenerated from 3-methyl-
2-butenal using equimolar piperidine and acetic anhydride,
the desired pyranyl product 19 was isolated in only e9%
yield after prolonged reaction time (Scheme 1). However,
Scheme 2
Scheme 1
acetylation of 6a under the reaction conditions. Although
the combined yield was rather low, formation of the
cycloadduct indicated the feasibility of constructing pip-
eridinyl heterocycles via this methodology. Given the
proposed mechanism, this reaction suggests a preference for
the imine nitrogen12 over the keto oxygen during the six-π-
(8) For isolation of arisugacin see: (a) Otoguro, K.; Kuno, F.; O˜ mura,
S. Pharmacol. Ther. 1997, 76, 45. For another study related to arisugacin
see: (b) Obata, R.; Sunazuka, T.; Tian, Z.; Tomoda, H.; Harigaya, Y.;
O˜ mura, S.; Smith, A. B., III. Chem. Lett. 1997, 935.
when the temperature was raised and the solvent system was
switched to a toluene/EtOAc mixture, the reaction proceeded
in a synthetically useful manner to give the pyranyl cyclo-
adducts 1 and 2 in 80% and 55% yields, respectively.10
(9) All new compounds have been characterized by 1H NMR, 13C NMR,
FTIR, and mass spectroscopy.
(10) For earlier examples of reactions of 1,3-diketones with R,â-
unsaturated aldehydes see: (a) Tietze, L. F.; van Kiedrowski, G.; Berger,
B. Synthesis 1982, 683. (b) de Groot, A.; Jansen, B. J. M. Tetrahedron
Lett. 1975, 3407. There were some disagreements in these citations regarding
reaction yields and conditions.
(11) The regiochemical issues were assigned by nOe experiments later
on compound 14.
(12) We are assuming that the imine nitrogen rather than an iminium
species is involved in the ring closure because of the presence of excess
piperidine. For a related reference see: Kametani, T.; Kajiwara, M.;
Fukumoto, K. Tetrahedron 1974, 30, 1053.
(7) For our studies related to arisugacin see: (a) Hsung, R. P. J. Org.
Chem. 1997, 62, 7904. (b) Hsung, R. P. Heterocycles 1998, 48, 421. (c)
Granum, K. G.; Merkel, G.; Mulder, J. A.; Debbins, S. A.; Hsung, R. P.
Tetrahedron Lett. 1998, 9597. (d) Degen, S. J.; Mueller, K. L.; Shen, H.
C.; Mulder, J. A.; Golding, G. M.; Wei, L.-L.; Zificsak, C. A.; Hsung, R.
P. Bioorg. Med. Chem. Lett. 1999, 9, 973. (e) Douglas, C. J.; Skelenica, H.
M.; Shen, H. C.; Mathias, D. S.; Golding, G. M.; Hsung, R. P.; Degen, S.
J.; Morgan, C. D.; Mueller, K. L.; Seurer, L. M.; Shih, R. A. Tetrahedron,
submitted for publication.
510
Org. Lett., Vol. 1, No. 3, 1999

electron electrocyclic ring closure (7 vs 8). Along with our
earlier studies4 and the isolation of compound 5, it appears
that the keto oxygen is preferred over ester oxygen in the
ring closure step (9 vs 10).
Further experiments showed that protection of the viny-
logous amides as well as higher reaction temperatures were
key to the success of the cycloaddition reaction. When the
vinylogous amide 11 containing a benzyl group was sub-
jected to the optimized reaction conditions, the piperidine
12 was isolated in 64% yield (Scheme 3). The synthetic scope
In further comparative studies between 1,3-diketones and
vinylogous amides in [3 + 3] cycloadditions, we observed
an intriguing contrast between the reactivities of 1,3-
cyclopentadione and vinylogous amide 26. When 1,3-
cyclopentadione was reacted with a variety of R,â-unsatur-
ated iminiums under these conditions, no desired product
(shown as 21 in Scheme 4) was isolated. Although only the
Scheme 4
Scheme 3
of this reaction was quickly established by the preparations
of various piperidinyl heterocycles 13-15 in good yields
(62%-77%) with comparable reaction duration (15-36 h).
These piperidinyl heterocycles were specifically selected
because they represent potentially useful synthetic building
blocks. For example, we are currently exploring the pos-
sibility of using compound 13 as an intermediate for synthesis
of pumilotoxins.13 Compounds 14 and 15 demonstrated that
the nitrogen can contain a tethered functionality and that
piperidinyl spirocycles can also be prepared under these
conditions.
diketone 22 was rigorously isolated (68% yield) and char-
acterized, in all other cases, the only identifiable product was
the structural analogue of 22. Formation of compound 22
can be envisioned to occur through dehydration of the
intermediate 25, which could be derived from a second 1,4-
addition of 1,3-cyclopentadione to the dienone intermediates
23 and 24 (two possible conformers). Hence, the isolation
of 22 suggests that, for reactions of 1,3-cyclopentadione, the
electrocyclic ring closure step is either slow or is arrested at
the dienone intermediate 24 and that a second 1,4-addition
either occurs faster or is more favored.
Finally, reactions of 6-methyl-4-(benzylamino)-2-pyrone
were also examined, leading to piperidinyl compounds 16-
18 in high yields (81%-88%). Since acyclic vinylogous
amides have not been successful in this formal cycloaddition
reaction, 4-amino-2-pyrones could serve as an equivalent of
acyclic vinylogous amides, given ample precedents of
efficient ring opening of the adjacent 2-pyrones.8b Hence,
compounds 16-18 are essentially functionalized 2H-pyridine
derivatives, and the spirocycle 18 may serve as a model entry
to natural products such as histrionicotoxin.14
In contrast, the vinylogous amide 26 reacted well under
the same reaction conditions. For example, the reaction of
26 with 2-hexenal provided the desired piperidine 28 in 60%
yield. This suggests that the electrocyclic ring closure was
more favored for the diene imine intermediate 2712 than for
the intermediate 24. Our preliminary empirical calculations
indicate that these reactivity differences as well as those
mentioned earlier (see Scheme 2) are likely due to the
electronic preference for the nitrogen atom during the
electrocyclic ring closure.15,16 We are currently investigating
details of these preferences. Nevertheless, this experimental
observation not only provides important mechanistic details
but, more significantly, also suggests a much broader
synthetic scope of vinylogous amides in this formal cyclo-
addition reaction.
(13) For a review see: Daly, J. W.; Garraffo, H. M.; Spande, T. F. In
The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1993; Vol.
43, p 185.
(14) For recent syntheses of histrionicotoxin see: (a) Carey, S. C.;
Aratani, M.; Kishi, Y. Tetrahedron Lett. 1985, 5887. (b) Stork, G.; Zhao,
K. J. Am. Chem. Soc. 1990, 112, 5875.
Org. Lett., Vol. 1, No. 3, 1999
511

We have described here a formal [3 + 3] cycloaddition
strategy that is synthetically useful for constructing piperi-
dinyl heterocycles from vinylogous amides and R,â-unsatur-
ated iminiums. We are currently exploring the synthesis of
various relevant natural products involving this strategy as
well as addressing other stereochemical issues.
Acknowledgment. R.P.H. wishes to thank Professors
Steve Ley and Gilbert Stork for invaluable discussions. We
also thank the University of Minnesota for financial support
in the forms of Start-up Fund and Grant-in-Aid of Research,
Artistry and Scholarship (CUFS No. 1003-519-5984). H.M.S.
thanks the UMN Chemistry Department for a Kolthoff
Graduate Fellowship.
(15) Our semiempirical molecular orbital calculations (Spartan Pro-
gram: PM3) suggest that the HOMO of the imine nitrogen in the
intermediate 7 or 27 appears to overlap the best with the LUMO of the
carbon at which the bond formation occurs, and the HOMO of the keto
oxygen atom in the intermediate 24 appears to have the worst overlap with
the LUMO of the carbon at which the bond formation occurs. The
assumption here is that the direction of the ring closure starts with the
heteroatom.16
Supporting Information Available: Text giving experi-
mental procedures as well as figures giving 1H NMR spectral
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(16) Shishido, K.; Ito, M.; Shimada, S.-I.; Fukumoto, K.; Kametani, T.
Chem. Lett. 1984, 1943.
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