Tetronamides as latent acyclic vinylogous amides in formal Aza-[3 + 3] cycloaddition reactions with α,β-unsaturated iminium salts. An unexpected rearrangement and an approach to synthesis of substituted piperidines

Article abstract of DOI:10.1021/jo049108d

A detailed account regarding formal aza-[3 + 3] cycloaddition reactions of tetronamides with α,β-unsaturated iminium salts is described here. This investigation uncovers regioisomeric cycloadducts that were not found in previous studies involving this for

Full text of DOI:10.1021/jo049108d

Tetr on a m id es a s La ten t Acyclic Vin ylogou s Am id es in F or m a l
Aza -[3 + 3] Cycloa d d ition Rea ction s w ith r,â-Un sa tu r a ted Im in iu m
Sa lts. An Un exp ected Rea r r a n gem en t a n d a n Ap p r oa ch to
Syn th esis of Su bstitu ted P ip er id in es
Nadiya Sydorenko, Richard P. Hsung,* Ossama Saleh Darwish, J uliet M. Hahn,† and J ia Liu
Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455
hsung@chem.umn.edu
Received May 26, 2004
A detailed account regarding formal aza-[3 + 3] cycloaddition reactions of tetronamides with R,â-
unsaturated iminium salts is described here. This investigation uncovers regioisomeric cycloadducts
that were not found in previous studies involving this formal cycloaddition and an unexpected
rearrangement that led to pyridines and dihydropyridines. Both stereochemical and regiochemical
issues raised in this study provide further mechanistic insights into this cycloaddition. With careful
control of reaction temperatures, the desired formal cycloadducts are obtained. Ensuing transforma-
tion of these cycloadducts into functionalized piperidines establishes the concept of employing
tetronamides as latent acyclic vinylogous amides for the formal aza-[3 + 3] cycloaddition.
In tr od u ction
Annulations of vinylogous amides with R,â-unsatur-
ated iminium salts provide a convergent and practical
approach for synthesis of alkaloids.1,2 The formation of
six-membered nitrogen heterocycles 3 [Figure 1] consti-
tutes a formal aza-[3 + 3] cycloaddition3-5 because two
of the five carbons along with the nitrogen atom originate
from vinylogous amides 1 with the remaining three
carbons from the R,â-unsaturated iminium salts.6 Specif-
ically in our studies, R,â-unsaturated iminium salts 2
have been employed to afford exclusively 1,2-dihydropy-
ridines 3 in a highly regioselective manner [Figure 1].7-10
The regiochemistry of our reactions is opposite from that
F IGURE 1. Overview of the formal [3 + 3].
† Current address: Department of Chemistry and Physics, Arkansas
State University, State University, AR 72467.
of Hickmott-Stille’s aza-annulation using acid anhy-
drides or chlorides.11-13 Mechanistically, we demon-
strated that they proceed through a 6π-electron electro-
cyclic ring-closure of 1-azatrienes 47a,b,14,15 [derived from
a Knoevenagel condensation], a process that can be
rendered highly diastereoselective.7a,15a,16
(1) Kucklander, U. Enaminones as Synthons. In The Chemistry of
Functional Groups: The Chemistry of Enamines Part I; Rappoport, Z.,
Ed.; J ohn Wiley & Sons: New York, 1994; p 523.
(2) (a) Grundon, M. F. In The Alkaloids: Quinoline Alkaloids Related
to Anthranilic Acids; Academic Press: London, 1988; Vol. 32, p 341.
(b) Daly, J . W.; Garraffo, H. M.; Spande, T. F. The Alkaloids; Cordell,
G. A., Ed.; Academic Press: New York, 1993; Vol. 43, p 185. (c) Michael,
J . P. Nat. Prod. Rep. 1999, 16, 675 and 697. (d) J ones, T. H.; Gorman,
J . S. T.; Snelling, R. R.; Delabie, J . H. C.; Blum, M. S.; Garraffo, H.
M.; J ain, P.; Daly, J . W.; Spande, T. F. J . Chem. Ecol. 1999, 25, 1179.
(e) Michael, J . P. Nat. Prod. Rep. 2000, 17, 579. (f) Lewis, J . R. Nat.
Prod. Rep. 2001, 18, 95.
However, one severe limitation has remained in our
formal aza-[3 + 3] cycloaddition. We have been unable
(3) For recent reviews on formal carbo-[3 + 3] cycloadditions using
enamines, enol ethers, or â-ketoesters, see: (a) Filippini, M.-H.;
Rodriguez, J . Chem. Rev. 1999, 99, 27. (b) Filippini, M.-H.; Faure, R.;
Rodriguez, J . J . Org. Chem. 1995, 60, 6872 and refs 21-33 cited
therein. (c) For reviews on metal-mediated stepwise [3 + 3] cycload-
dition reactions, see: (d) Fru¨hauf, H.-W. Chem. Rev. 1997, 97, 523.
(e) Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49.
(4) The term “formal [3 + 3]” was used to describe [3 + 3] carbo-
cycloadditions. See: (a) Seebach, D.; Missbach, M.; Calderari, G.;
Eberle, M. J . Am. Chem. Soc. 1990, 112, 7625. For earlier studies on
[3 + 3] carbo-cycloadditions, see: (b) Landesman, H. K.; Stork, G. J .
Am. Chem. Soc. 1956, 78, 5129.
(6) For recent studies in this area, see: (a) Abelman, M. M.; Curtis,
J . K.; J ames, D. R. Tetrahedron Lett. 2003, 44, 6527. (b) Hedley, S. J .;
Moran, W. J .; Price, D. A.; Harrity, J . P. A. J . Org. Chem. 2003, 68,
4286. (c) Chang, M.-Y.; Lin, J . Y.-C.; Chen, S. T.; Chang, N.-C. J . Chin.
Chem. Soc. 2002, 49, 1079. (d) Hedley, S. J .; Moran, W. J .; Prenzel, A.
H. G. P.; Price, D. A.; Harrity, J . P. A. Synlett 2001, 1596. (e) Davies,
I. W.; Marcoux, J .-F.; Reider, P. J . Org. Lett. 2001, 3, 209. (f) Davies,
I. W.; Taylor, M.; Marcoux, J .-F.; Wu, J .; Dormer, P. G.; Hughes, D.;
Reider, P. J . J . Org. Chem. 2001, 66, 251. (g) Nemes, P.; Bala´zs, B.;
To´th, G.; Scheiber, P. Synlett 1999, 222. (h) Hua, D. H.; Chen, Y.; Sin,
H.-S.; Robinson, P. D.; Meyers, C. Y.; Perchellet, E. M.; Perchellet, J .-
P.; Chiang, P. K.; Biellmann, J .-P. Acta Crystallogr. 1999, C55, 1698.
(i) P. Benovsky, G. A. Stephenson, J . R. Stille, J . Am. Chem. Soc. 1998,
120, 2493. (j) Heber, D.; Berghaus, Th. J . Heterocycl. Chem. 1994, 31,
1353. (k) Paulvannan, K.; Stille, J . R. Tetrahedron Lett. 1993, 34, 215
and 6677. (l) Paulvannan, K.; Stille, J . R. J . Org. Chem. 1992, 57, 5319.
(5) For a recent review on formal oxa- and aza-[3 + 3] cycloadditions,
see: Hsung, R. P.; Wei, L.-L.; Sklenicka, H. M.; Shen, H. C.; McLaugh-
lin, M. J .; Zehnder, L. R. In Trends in Heterocyclic Chemistry. Research
Trends: Trivandrum, India, 2001; Vol. 7, pp 1-24.
10.1021/jo049108d CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/08/2004
6732
J . Org. Chem. 2004, 69, 6732-6738

Tetronamides as Latent Acyclic Vinylogous Amides
SCHEME 1. Syn th eses of Tetr on a m id es
to carry out the transformation using acyclic vinylogous
amides to construct dihydropyridines 5 as a single-ring
system. We have attributed this limitation to the fact that
the corresponding 1-azatrienes 4 are less constrained
geometrically for the desired ring-closure, and given their
reactive nature, they could competitively proceed through
other reaction pathways.17 Given the significance of
piperidinyl alkaloids,18,19 we have been developing a
latent acyclic vinylogous amide to render our formal aza-
[3 + 3] cycloaddition method amenable and practical for
syntheses of piperidines. In this article, we disclose full
details regarding the use of tetronamides as latent acyclic
vinylogous amides, an unexpected rearrangement, and
the feasibility of constructing piperidinyl derivatives.
TABLE 1. Gen er a lity of Aza -[3 + 3] Cycloa d d ition s
Usin g Tetr on a m id es
Resu lts a n d Discu ssion s
1. Syn th etic F ea sibility, Scop e, a n d Ster eoselec-
tivity. Although reactions of tetronic acid itself did not
proceed well with R,â-unsaturated iminium salts 2 to
(7) For intermolecular formal aza-[3 + 3] cycloadditions, see: (a)
Sklenicka, H. M.; Hsung, R. P.; McLaughlin, M. J .; Wei, L.-L.;
Gerasyuto, A. I.; Brennessel, W. W. J . Am. Chem. Soc. 2002, 124,
10435. (b) Sklenicka, H. M.; Hsung, R. P.; Wei, L.-L.; McLaughlin, M.
J .; Gerasyuto, A. I.; Degen, S. J .; Mulder, J . A. Org. Lett. 2000, 2, 1161.
(c) Hsung, R. P.; Wei, L.-L.; Sklenicka, H. M.; Douglas, C. J .;
McLaughlin, M. J .; Mulder, J . A.; Yao, L. J . Org. Lett. 1999, 1, 509.
(8) For intramolecular formal aza-[3 + 3] cycloaddition, see: Wei,
L.-L.; Sklenicka, H. M.; Gerasyuto, A. I.; Hsung, R. P. Angew. Chem.,
Int. Ed. 2001, 40, 1516.
(9) For our applications in natural product syntheses, see: (a) Luo,
S.; Zificsak, C. Z.; Hsung, R. P. Org. Lett. 2003, 5, 4709. (b) McLaughlin,
M. J .; Hsung, R. P.; Cole, K. C.; Hahn, J . M.; Wang, J . Org. Lett. 2002,
4, 2017.
(10) The advantage of using R,â-unsaturated iminium salts in
regiochemical control has also recently been noted; see: Cravotto, G.;
Nano, G. M.; Tagliapietra, S. Synthesis 2001, 49.
(11) Hickmott, P. W.; Sheppard, G. J . Chem. Soc. C 1971, 2112.
(12) (a) Benovsky, P.; Stephenson, G. A.; Stille, J . R. J . Am. Chem.
Soc. 1998, 120, 2493. (b) Paulvannan,; K.; Stille, J . R. Tetrahedron
Lett. 1993, 34, 6677. (c) Paulvannan, K.; Stille, J . R. Tetrahedron Lett.
1993, 34, 215. (d) Paulvannan, K.; Stille, J . R. J . Org. Chem. 1992,
57, 5319.
(13) (a) Greenhill, J . V.; Mohamed, M. J . Chem. Soc., Perkin Trans.
1 1979, 1411. (b) Chaaban, J .; Greenhill, J . V.; Rauli, M. J . Chem.
Soc., Perkin Trans. 1 1981, 3120.
(14) For leading references on electrocyclic ring-closures involving
1-azatrienes, see: (a) Maynard, D. F.; Okamura, W. H. J . Org. Chem
1995, 60, 1763. (b) de Lera, A. R.; Reischl, W.; Okamura, W. H. J . Am.
Chem. Soc. 1989, 111, 4051. For an earlier account, see: (c) Oppolzer,
V. W. Angew. Chem. 1972, 22, 1108.
(15) For recent elegant accounts on stereoselective ring-closure of
1-azatrienes, see: (a) Tanaka, K.; Katsumura, S. J . Am. Chem. Soc.
2002, 124, 9660. (b) Tanaka, K.; Mori, H.; Yamamoto, M.; Katsumura,
S. J . Org. Chem. 2001, 66, 3099.
(16) For a review on rotational preferences leading to diastereomeric
induction during a 6π-electron electrocyclic ring closure, see: Okamura,
W. H.; de Lera, A. R. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Paquette, L. A., Volume Ed.; Pergamon Press:
1991, Vol. 5, pp 699-750.
(17) For other studies involving 1-heterotrienes in formation of a
single-ring system, see: (a) Moorhoff, C. M. Synthesis 1997, 685. (c)
J onassohn, M.; Sterner, O.; Anke, H. Tetrahedron 1996, 52, 1473. (d)
Krasnaya, Z. A.; Bogdanov, V. S.; Burova, S. A.; Smirnova, Y. V. Russ.
Chem. Bull. 1995, 44, 2118
a
All reactions were carried out in EtOAc/toluene [2:3] at 120-
150 °C in a sealed tube for 36-72 h unless otherwise noted.
Iminium salt was generated by addition of 2.0 equiv of piperidine
b
to the enal at -10 °C in EtOAc. After stirring for 5 min, 2.0 equiv
of Ac2O was added and the mixture was heated at 80 °C for 1 h in
a sealed tube before being transferred to the respective tetrona-
mide. c Isolated yields only. NA: not applicable. Ratios were
d
determined by 1H NMR. e An additional 10-38% of the regioisomer
was also isolated. See Section 2. f In entries 7-16, the R* group
denotes the corresponding chiral auxiliaries present in 17-20.
g
h
i
Heated at 180 °C. Heated at 200 °C for 7 days. Reaction took
96 h. Heated at 170 °C for 96 h.
j
construct pyrans 6 en route to highly substituted dihy-
dropyrans 7 [W ) O in Scheme 1], we prepared a series
of achiral [8A] and chiral [8B-E] tetronamides by con-
densing the corresponding amines with tetronic acid in
refluxing toluene [Scheme 1]. The feasibility, scope, and
stereoselectivity for reactions of tetronamides with R,â-
unsaturated iminium salts are summarized in Table 1.
It was quickly evident that reactions of various tetrona-
mides 8A-E with R,â-unsaturated iminium salts gener-
ated from aldehydes 9-12 were feasible. There were
three features that captured our attention. First, yields
(18) For a recent review on preparations of piperidines, see: Laschat,
S.; Dickner, T. Synthesis 2000, 1781.
(19) For recent approaches to dihydropyridines and related pip-
eridines, see: (a) Comins, D. L.; Sandelier, M. J .; Grillo, T. A. J . Org.
Chem. 2001, 66, 6829. (b) Charette, A. B.; Grenon, M.; Lemire, A.;
Pourashraf, M.; Martel, J . J . Am. Chem. Soc. 2001, 123, 11829. (c)
Brooks, C. A.; Comins, D. L. Tetrahedron Lett. 2000, 41, 3551. (d)
Matsumura, Y.; Nakamura, Y.; Maki, T.; Onomura, O. Tetrahedron
Lett. 2000, 41, 7685. (e) Comins, D. L.; Zhang, Y.; J oseph, S. P. Org.
Lett. 1999, 1, 657. (f) Comins, D. L.; Brooks, C. A.; Al-awar, R. S.;
Goehring, R. R. Org. Lett. 1999, 1, 229. (g) Comins, D. L.; Kuethe, J .
T.; Hong, H.; Lakner, F. J . J . Am. Chem. Soc. 1999, 121, 2651. (h)
References 15 and 13b-e.
J . Org. Chem, Vol. 69, No. 20, 2004 6733

Sydorenko et al.
SCHEME 2. Regioisom er s
SCHEME 3. Com p etin g Exp er im en t
reaction temperature was less than 130 °C, very little
[<5%] regioisomers 22a -c were observed from their
respective reactions, but when the temperature was
greater than 130 °C, as much as 10-38% of 22a -c could
be seen.
Retrospectively, if we had pursued this investigation
first, we might have abandoned the entire methodology,
since it would be no different from Hickmott-Stille’s aza-
annulation, which provides exclusively head-to-tail re-
gioselectivity. Consequently, we revisited our previous
work by allowing vinylogous amide 24 to react with 9b
at a temperature greater than 150 °C [Scheme 3]. Only
if we were very careful could we see the head-to-tail
regioisomer 26 in the crude 1H NMR and isolate it in
4.5% yield. This result reaffirms that reaction tempera-
ture is a critical factor and that when this reaction was
first carried out in the range of 100 to <150 °C, we
observed no significant amounts of any other regioiso-
mers.7 We are not certain at this point why the reaction
temperature is impacting the two reaction pathways.
Furthermore, when a mixed experiment was carried
out using both 24 and 8A, we found that at temperatures
greater than 150 °C, the head-to-tail regioisomer 22b,
derived from reacting 8A with 9b, was consistently
isolated in higher yields than 26, deriving from vinylo-
gous amide 24. This suggests that for reasons unknown
at this point, tetronamides such as 8A are more prone
than vinylogous amides such as 24 to annulate with R,â-
unsaturated iminium salts in a head-to-tail manner.
Mechanistically, regioisomers 22a -c could be derived
from an initial N-1,2-addition of 8A to give aminal 28
[Scheme 4]. A subsequent loss of an amino group would
give the 3-azatriene 29, and an ensuing pericyclic ring
closure followed by an appropriate tautomerization would
give the desired regioisomers 22a -c. It could also be
derived from an initial C-1,4-addition followed by an aza-
[3,3] sigmatropic rearrangement to yield the same aminal
are mostly poor to modest with the exception of aldehydes
9b [entry 2], 9c [entry 3], 10 [entry 4], and 12 [entries 6
and 16], which provided the desired cycloadducts in good
yields. Yields are noticeably poor when using chiral
tetronamides 8B-E [entries 7-16] or aldehydes 9a and
11 [entries 1 and 5].
Second, none of the chiral tetronamides 8B-E [entries
7-16] were useful in providing reasonable diastereose-
lectivity, the best dr being 65:35 with 8C and 8D but
again in poor yields [entries 10-15]. Chiral tetronamide
8B, containing the auxiliary that was very useful in
highly diastereoselective aza-[3 + 3] cycloadditions as
reported previously,7a provided cycloadducts in a stereo-
random manner [entries 7-9].
Third, we found noticeable byproducts from reactions
of 8A with 9a -c and 11 [entries 1-3 and 5]. Although
these byproducts resembled the desired formal [3 + 3]
cycloadducts [13a -c and 15] with similar chemical shift
1
patterns in H NMR and fragmentation patterns in the
mass spectrum, they are not the same. In addition,
reactions of chiral tetronamide 8E with 9a -c [not shown
in Table 1] provided no desired formal cycloadducts but
unknowns that puzzled us for quite some time.
2. Regioch em ica l Issu es. The aforementioned pecu-
liarities led us to further examine the formal aza-[3 + 3]
cycloaddition reaction of tetronamides more carefully. As
shown in Scheme 2, in addition to desired cycloadducts
13a -c [head-to-head: See the lower left box for defini-
tions], formal cycloaddition reactions of tetronamide 8A
with iminium salts 21a -c, generated from the corre-
sponding aldehydes 9a -c, provided the respective head-
to-tail regioisomers 22a -c as byproducts.
Regiochemistry was unambiguously assigned via posi-
tive and negative NOE experiments using both 13a and
22a .20 While 13a -c were likely derived from respective
ring-closure of 1-azatrienes 23, isolation of these regioi-
somers was surprising since we have not seen head-to-
tail products in any of our previous formal aza-[3 + 3]
cycloaddition studies. A closer examination revealed that
this is a temperature-dependent phenomenon. When the
(20) The head-to-head regiochemistry resulting from formal aza-[3
+ 3] cycloadditions of these tetronamides was also unambiguously
assigned using the X-ray structure of the hydrogenated cycloadduct
16. Please see Supporting Information for the X-ray information.
6734 J . Org. Chem., Vol. 69, No. 20, 2004

Tetronamides as Latent Acyclic Vinylogous Amides
SCHEME 4. Mech a n istic Mod el for th e
Regioisom er
F IGURE 2. X-ray structure of 35c.
SCHEME 5. F or m a tion of P yr id in es
SCHEME 6. Mech a n istic Mod el for th e P yr id in e
F or m a tion
28. An alternative pathway from 28 would involve an
intramolecular SN2′ addition followed by an appropriate
tautomerization. These assessments are in accord with
those described in Hickmott-Stille’s aza-annulation.11-13
3. An Un exp ected Rea r r a n gem en t. In addition to
isolating the respective regioisomers 22b and 22c in
reactions of tetronamide 8A with aldehydes 9b and 9c,
we found that when the reaction temperature was raised
to 240 °C, the respective pyridines 30b and 30c accounted
for the major mass balance [Scheme 5]. Pyridines 30b
and 30c were initially assigned using NMR and mass
spectroscopy but later unambiguously assigned on the
basis of the X-ray structure of a related example.
These pyridines are likely derived from some kind of
rearrangement of the desired formal aza-[3 + 3] cycload-
ducts because pericyclic ring closures of 1-azatrienes are
completely reversible at temperatures as high as 240
°C.7a,21 We heated a sample of 13b at 220-240 °C for 64
h and found exclusively 30b in 55% yield. This experi-
ment was actually designed originally to explore whether
13b was equilibrating with 22b. However, there was no
such equilibration between these two regioisomers. In-
stead, we isolated only the pyridine product 30b. This
experiment thoroughly supports the notion that the pyri-
dines were derived from the desired cycloadducts that
were formed initially.
SCHEME 7. F or m a tion of Dih yd r op yr id in es
31 to 2-azatriene 32 [Scheme 6]. Subsequent pericyclic
ring-closure of 2-azatriene 32 would lead to 2,3-dihydro-
pyridine 33, and upon aromatization at high tempera-
tures, pyridines 30b and 30c could be obtained.
With an understanding of this rearrangement, we re-
examined the unknowns isolated from the reactions of
chiral tetronamide 8E with 9a -c [those that are not dis-
played in Table 1]. These unknowns turned out to be 1,2-
dihydropyridines 35a -c derived from 9a -c, respectively
[Scheme 7]. An X-ray structure of compound 35c was
obtained to unambiguously identify these rearranged pro-
ducts [Figure 2]. The formation of 35b-c could be ration-
alized in the same manner as described for 30b and 30c
with the exception that the aromatization is arrested for
35b-c leaving behind a quaternary carbon adjacent to
the nitrogen atom.
On the basis of these results, one can suggest that
pyridine products 30b and 30c were mechanistically
derived via an imine isomerization going from 1-azatriene
(21) Shen, H. C.; Wang, J .; Cole, K. P.; McLaughlin, M. J .; Morgan,
C. D.; Douglas, C. J .; Hsung, R. P.; Coverdale, H. A.; Gerasyuto, A. I.;
Hahn, J . M.; Liu, J .; Wei, L.-L.; Sklenicka, H. M.; Zehnder, L. R.;
Zificsak, C. A. J . Org. Chem. 2003, 68, 1729.
J . Org. Chem, Vol. 69, No. 20, 2004 6735

Sydorenko et al.
SCHEME 8. Attem p ts to Im p r ove th e
Ster eoch em istr y
However, in comparison with 40, there is a loss in the
selectivity for cycloadduct 42 derived from vinylogous
amides containing a five-membered ring. To rationalize
this loss, we had suggested that the steric interaction
between the C2′-H and the C-10 methylene in 1-azatriene
39 [boxed] could be critical.7 To alleviate such steric
interaction in 39 to give 40-major, the C2′-Ph would need
to be pushed further toward the C5-6 vinyl strand,
leading to a greater biasing of the rotational preference
in favor of direction a .
In the case of cycloadduct 42, the corresponding
interaction between the C2′-H and the methylene unit
[boxed] in 1-azatriene 41 is diminished on the basis of
molecular modeling, thereby leading to a diminished
interaction between the C2′-Ph and C5-6 vinyl strand
and the rotational bias. For reactions of 8B, a similar
rationale could be invoked using 1-azatriene 43, but given
the structural similarity between 1-azatriene 41 and 43,
we did not expect that the dr for 17a would be as low as
55:45.
Nevertheless, this presents an opportunity to further
examine our original mechanistic model. If we bulk up
the methylene unit shown in the box of 43 to enhance
its interaction with the C2′-H, the C2′-Ph group could
again be closer to the C5-6 vinyl strand to enhance the
rotational bias in favor of direction a to enhance the
diastereoselectivity.
As shown in Scheme 8, chiral tetronamide 44 could be
prepared in three steps [40% overall yield] from methyl
R-hydroxy-R-methyl propanoic ester,23 but its reaction
with the iminium salt 21a [generated from 9a ] provided
the regioisomeric cycloadducts 45a and 45b in 25% yield
with a ratio of 52:48. While the diastereomeric ratio is
not all that surprising, the regioselectivity prompted us
to speculate that the desired cycloadduct would have been
much too congested. However, using chiral tetronamide
46 and iminium salt 21a also gave the undesired regioi-
someric cycloadducts 47a and 47b in only 8% yield with
a ratio of 52:48. These experiments unfortunately at this
time do not provide conclusive support for the aforemen-
tioned mechanistic analysis. Identifying new insights to
ultimately achieve highly stereoselective formal aza-[3
+ 3] cycloaddition reactions using chiral tetronamides
will remain as a future endeavor.
F IGURE 3. Stereochemical model.
Although we did not vigorously reexamine the other
reactions involving chiral tetronamides 8B-D at lower
temperatures, it is reasonable to suggest that the gener-
ally observed poor yield is likely due to the formation of
related dihydropyridine byproducts and/or regioisomers.
This could be reasonable especially considering that most
of these reactions had to be carried out at temperatures
much higher than 130 °C. Ultimately, our work suggests
that temperature is critical to controlling various reaction
pathways and maximizing the formal aza-[3 + 3] cy-
cloadditions to afford the desired cycloadduct as the major
product.
4. Ster eoch em ica l Issu es. The lack of diastereose-
lectivity using chiral tetronamides 8B-E prompted us
to revisit the stereochemical model proposed in our
previous studies.7a,b As shown in Figure 3, although the
ring-closure is reversible at high temperature, and
although the observed diastereoselectivity ultimately can
be attributed to thermodynamic control, it is evident that
a selective rotation of the C5-6 vinyl strand in 1-aza-
triene 39 also contributes significantly to the observed
diastereoselectivity. Rotational preferences leading to
stereoselective constructions of sp2- and sp3-hybridized
stereocenters have excellent precedents in various peri-
cyclic processes, and such stereoselectivity has been
appropriately termed torquoselectivity.16,22
We had proposed that 1-azatriene 39 assumes a
conformation similar to that observed in an X-ray struc-
ture of the final product 40-major,7a,b and that prior to
the ring-closure, the C2′-Ph ring is π-stacked underneath
with the C5-6 vinyl strand. This results in two possible
rotations for the C5-C6 vinyl strand in 39 during the
ring-closure. Rotation a should be favored, leading to 40-
major [the minor isomer not drawn], while rotation b is
less favored, for it leads to severe steric interaction
between the R and the C2′-Ph groups.7a,b
(22) For some examples involving torquoselective processes, see: (a)
Giese, S.; Kastrup, L.; Stiens, D.; West, F. G. Angew. Chem., Int. Ed.
2000, 39, 1970. (b) Hsung, R. P.; Quinn, J . F.; Weisenberg, B. A.; Wulff,
W. D.; Yap, G. P. A.; Rheingold, A. L. J . Chem. Soc., Chem. Comm.
1997, 615.
(23) Synthesis of 44: Ireland, R. E.; Thompson, W. J . J . Org. Chem.
1979, 44, 3041.
6736 J . Org. Chem., Vol. 69, No. 20, 2004

Tetronamides as Latent Acyclic Vinylogous Amides
SCHEME 9. Hyd r ogen a tion s of Aza -[3 + 3]
Cycloa d d u cts
5. Syn th eses of Su bstitu ted P ip er id in es. To con-
struct substituted piperidines, primary tasks are (1) to
hydrogenate the C2-3 tetrasubstituted olefin and (2) to
open the γ-lactone ring. These exercises were carried out
using the aza-[3 + 3] formal cycloadduct 13b [only one
enantiomer is shown in Scheme 9 for clarity of the
relative stereochemistry in later substrates].
F IGURE 4. Mechanistic model for stereoselective hydrogena-
tions.
SCHEME 10. Rin g-Op en in g of th e La cton e
As shown in Scheme 9, the C4-5 olefin in cycloadduct
13b was readily hydrogenated under standard conditions
to give the unsaturated lactone 48 in 93% yield. We then
ran into problems with the C2-3 olefin. We were able to
initially hydrogenate the C2-3 tetrasubstituted olefin
employing 60-80 psi H2 to give lactone 49 as a single
diastereomer with the best yield of 60%.24 However, we
soon found that the usage of Pd-C or Pd(OH)2 was
erratic, for the rate of the reaction varied greatly even
when the pressure was elevated to 1500 psi, and the yield
of 49 was quite unpredictable. When we switched to using
PtO2 as the catalyst,25 the hydrogenation behaved more
consistently and afforded 50 in 50% yield using only at
1 atm of H2, but instead of a concomitant debenzylation,
the phenyl ring was hydrogenated. The isomeric ratio of
50 was 9:1 in favor of an anti relative stereochemistry
at C2 and C6 as shown with NOE experiments.
To complete the hydrogenation of the C2-3 olefin, the
unsaturated lactone 48 was cleanly debenzylated using
60-80 psi H2 to provide 51 in 83% yield [Scheme 10].
An ensuing hydrogenation of 51 employing PtO2 as the
studies illustrate the concept of transforming these
formal aza-[3 + 3] cycloadducts into piperidinyl deriva-
tives and the concept of tetronamides serving as useful
latent acyclic vinylogous amides. However, the relative
stereochemistry observed deserves some comments as
shown in Figure 4.
25
catalyst and 1 atm of H2 led to 49 in 69% yield with a
diastereomeric ratio of g15:1. The relative stereochem-
istry of 49 was assigned using NOE experiments with
the C2-C6 relative stereochemistry being syn. Reductive
ring-opening of the lactone in 49 using LAH gave
piperidine 52 in 83% yield as a single stereoisomer.
On the other hand, Dibal-H reduction of 48 followed
by hydrogenation of the C2-3 olefin using 60-80 psi H2
and Pd-C did give diol 53 in 67% yield with an isomeric
ratio of g15:1. The relative stereochemistry of 53 was
assigned using NOE with C2-C6 being anti, and sub-
sequent debenzylation afforded diol 54 with the comple-
mentary C2-C6 anti stereochemistry. These collective
From our own previous work7a and those reported in
the literature,26 when the R substituent on the nitrogen
atom is not hydrogen, the conformer B [55b in Figure 4]
can be favored, in which the N-R and C6-n-Pr group are
anti or diaxial to alleviate the pseudo A1,2 strain [or the
gauche interaction] between these two respective groups.26
With the top face blocked by the pseudoaxial R group,
which is more proximal than the pseudoaxial C6-n-Pr
group, hydrogenation from the bottom face should give
lactone 49 with C2 and C6 being anti. A similar analysis
can be invoked using 56b to rationalize the observation
of the anti relative stereochemistry at C2 and C6 in 53
[see inside the box].
(24) Debenzylated product 51 was also occasionally isolated in 16%
yield.
(25) (a) Akhrem, A. A.; Lakhvich, F. A.; Lis, L. G.; Pshenichnyi, V.
N.; Arsen’ev, A. S. Zh. Org. Khim. 1980, 16, 1290. (b) Akhrem, A. A.;
Lakhvich, F. A.; Lis, L. G.; Kuz’mitskii, B. B.; Mizulo, N. A.; Gor-
bacheva, I. A. Zh. Org. Khim. 1985, 21, 1348.
(26) Kolocouris, A.; Outeirino, J . G.; Anderson, J . E.; Fytas, G.;
Foscolos, G. B.; Kolocouris N. J . Org. Chem. 2001, 66, 4989.
J . Org. Chem, Vol. 69, No. 20, 2004 6737

Sydorenko et al.
On the other hand, when R ) H, conformers A, C, and
D [55a , 55c, and 55d , respectively] can dominate, with
all three providing the top face as the relatively more
open one.7a Hydrogenation should then lead to lactone
49 with the complementary C2-C6 syn stereochemistry.
Such a stereodivergence should be useful for natural
product synthesis.
mechanistic insights into this formal aza-[3 + 3] cycload-
dition. More importantly, it allowed us to recognize that
when the reaction temperature is carefully controlled, the
desired formal cycloadduct could be obtained in syntheti-
cally useful yields using tetronamides. Ensuing trans-
formations of these formal cycloadducts into functional-
ized piperidinyl derivatives illustrate the concept of
utilizing tetronamides as latent acyclic vinylogous amides
for the formal aza-[3 + 3] cycloaddition.
Con clu sion
We have described here a detailed investigation of
formal aza-[3 + 3] cycloaddition reactions of tetronamides
with R,â-unsaturated iminium salts. In the process of this
investigation, we uncovered interesting regioisomeric
cycloadducts, which were not found in previous studies
involving related formal aza-[3 + 3] cycloadditions, and
unexpected rearrangements that led to pyridine and 1,2-
dihydropyridine products. Both regiochemical and ster-
eochemical issues raised in this study provide further
Ack n ow led gm en t. R.P.H. thanks NIH [N.S.38049]
for funding. We are grateful to Dr. L. G. Lis for the key
suggestion of using PtO2 as the hydrogenation catalyst.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures, characterization data for all new compounds, 1H NMR
spectra, NOE data, and X-ray information. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O049108D
6738 J . Org. Chem., Vol. 69, No. 20, 2004