One-pot asymmetric synthesis of substituted piperidines by exocyclic chirality induction

Article abstract of DOI:10.1021/ol900708d

A highly efficient one-pot synthesis of substituted piperidines was developed through nitroalkene, amine, and enone condensation. The transformation was suitable for a large group of substrates, giving excellent yields and diastereoselectivity. Reactions

Full text of DOI:10.1021/ol900708d

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2333-2336
One-Pot Asymmetric Synthesis of
Substituted Piperidines by Exocyclic
Chirality Induction
Yunfeng Chen, Cheng Zhong, Jeffrey L. Petersen, Novruz G. Akhmedov, and
Xiaodong Shi*
C. Eugene Bennett Department of Chemistry, West Virginia UniVersity,
Morgantown, West Virginia 26506
xiaodong.shi@mail.wVu.edu
Received April 6, 2009
ABSTRACT
A highly efficient one-pot synthesis of substituted piperidines was developed through nitroalkene, amine, and enone condensation. The
transformation was suitable for a large group of substrates, giving excellent yields and diastereoselectivity. Reactions using chiral amines
revealed a chirality induction through the unusual exocyclic stereochemistry control, producing enantiomeric pure piperidines in simple steps.
Efficient new approaches for the preparation of chemically
important and biologically active complex molecules are of
great significance in chemical research, especially those with
an intriguing mechanism and good chemo/stereoselectivity.
One example is the recent fast-growing stereoselective
cascade synthesis,1 where complex building blocks are
prepared from simple starting materials in “one pot”. This
strategy is particularly important when active, unstable
intermediates are involved and the desired products cannot
be achieVed through a stepwise approach.
conducting conjugate addition with nitroalkenes. The LB
catalyst was sequentially released through an irreversible-
ꢀ-elimination, giving the corresponding allylic nitro products
(Scheme 1A). Applying this strategy, several attractive
heterocycles, such as NH-1,2,3-triazoles and isoxazoline
N-oxides, were prepared in one pot.3 This new reaction mode,
especially the amine conjugate addition to nitroalkene,4
initiated our interest in extending the cascade process to these
reactions and involved highly reactive intermediates to
Recently, we reported an intermolecular cross-conjugate
addition between carbonyl- and nitro-activated alkenes, where
primary and secondary amines served as Lewis base2 (LB),
(3) (a) Sengupta, S.; Duan, H.; Lu, W.; Petersen, J. L.; Shi, X. Org.
Lett. 2008, 10, 1493. (b) Duan, H.; Sun, X.; Liao, W.; Petersen, J. L.; Shi,
X. Org. Lett. 2008, 10, 4113.
(4) For selected examples, see: (a) Ziyaei-Halimehjani, A.; Saidi, A.;
Saidi, M. R. Tetrahedron Lett. 2008, 49, 1244. (b) Ballini, R.; Arau´jo Baz´an,
N.; Bosica, G.; Palmieri, A. Tetrahedron Lett. 2008, 49, 3865. (c) Wang,
J.; Li, H.; Zu, L.; Wang, W. Org. Lett. 2006, 8, 1391. (d) Kamimura, A.;
Kadowaki, A.; Nagato, Y.; Uno, H. Tetrahedron Lett. 2006, 47, 2471. (e)
Deng, X.; Mani, N. S. Org. Lett. 2006, 8, 3505. (f) Molteni, M.; Volonterio,
A.; Zanda, M. Org. Lett. 2003, 5, 3887. (g) Barco, A.; Benetti, S.; Risi,
C. D.; Pollini, G. P.; Romagnoli, R.; Zanirato, V. Tetrahedron Lett. 1994,
35, 9293. (h) Morris, M. L.; Sturgess, M. A. Tetrahedron Lett. 1993, 34,
43. (i) Worrall, D. E. J. Am. Chem. Soc. 1927, 49, 1598.
(1) For selected reviews, see: (a) Tietze, L. F. Chem. ReV. 1996, 96,
115. (b) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem.,
Int. Ed. 2006, 45, 7134. (c) Enders, D.; Grondal, C.; Hu¨ttl, M. R. M. Angew.
Chem., Int. Ed. 2007, 46, 1570. (d) Padwa, A.; Bur, S. K. Tetrahedron.
2007, 63, 5341.
(2) (a) Sun, X.; Sengupta, S.; Petersen, J. L.; Wang, H.; Lewis, J. P.;
Shi, X. Org. Lett. 2007, 9, 4495. (b) Zhong, C.; Chen, Y.; Petersen, J. L.;
Akhmedov, N. G.; Shi, X. Angew. Chem., Int. Ed. 2009, 48, 1279.
10.1021/ol900708d CCC: $40.75
Published on Web 05/13/2009
 2009 American Chemical Society

Scheme 1
.
Amine Conjugate Addition to Nitroalkene as a New
Table 1. One-Pot Condensation for the Synthesis of Piperidinesa
Reaction Mode in Promoting the Cascade Process
solvent
time (h)
yieldb (%)
drc
recovered 1a (%)
4a MeOH
THF
4b MeOH
THF
12
36
12
72
65
97
60
85
5:1
7:1
10:1
15:1
30
trace
35
trace
a General reaction conditions: compounds 1a (1.0 equiv), 2 (1.5 equiv),
3a (2.0 equiv) were mixed in solvents (c ) 0.2 M of 1a). b Isolated yields
of both major and minor isomers. 3a was consumed at the end of the reaction
in all cases. c dr determined by crude NMR.
produce complex products that are difficult to access through
conventional stepwise approaches. Herein, we report the
asymmetric synthesis of substituted piperidines with excellent
diastereoselectivity through an unusual exocyclic stereoelec-
tronic effect controlled complete chirality induction.
Substituted piperidines are an attractive group of hetero-
cycles in chemical and biological research.5 As a result,
considerable interest is centered on the synthesis of these
heterocycles with focus on high efficiency and good stereo-
selectivity.6 This need is particularly emphasized by the fast
growing call for enantiomeric pure, diverse piperidines in
alkaloid7 and aza-sugar8 researches.
Revealed by our previous experimental and computational
studies, the addition of amine to nitroalkene involves a fast
equilibrium.2a,9 We then postulated that the amine-nitroalkene
adduct A may be suitable for sequential Michael addition
and ring closure, providing the substituted piperidines
through a one-pot cascade process (Scheme 1B). As rather
complex reaction mixtures, different reaction pathways are
possible (i.e., Baylis-Hillman reactions, Rauhut-Currier
reaction). However, to our surprise, reactions between
ꢀ-nitrostyrene 1a, amine 2a/2b, and methyl vinyl ketone
(MVK) 3a proceeded through one dominant pathway, giving
the substituted piperidines 4a and 4b in excellent yields and
good diastereoselectivity (Table 1).
aza-Michael additions are known to be a challenging
transformation.10 However, through a cascade process, the
aza-Michael adduct B was successfully trapped by the
sequential Henry-aldol cyclization, giving the substituted
piperidines that cannot be achieved by a stepwise synthesis.
Although three stereogenic centers were generated in
piperidine 4, only two C-4 isomers were observed.11 The
major products were the cis isomers of C-3 nitro and C-4
hydroxy groups. Even though other condensation products
were possible, amazingly, the only side reaction observed
was the polymerization of enone 3a, when the reaction was
conducted in MeOH. With THF as solvent, this side reaction
was successfully minimized, giving the substituted pip-
eridines in excellent yields (Table 1). The diastereoselectivity
was also improved under this optimized condition.12 Dif-
ferent nitroalkenes, amines, and enones were then applied
to investigate the reaction substrate scope, and the results
are summarized in Table 2.
Various kinds of substrates were suitable for this trans-
formation, and only the C-4 isomers were obtained in all
cases. Besides aryl (including heterocycles)-substituted ni-
troalkenes, alkyl-substituted nitroalkenes could also be
applied in this transformation, providing variation on the C-2
position (i.e., 4h, 4i, 4k, 4o). In addition, both alkyl and aryl
ketones were suitable for this cascade process, giving
different choices of substituents on the C-4 position (i.e.,
4a, 4m). The R-substituted enone, though giving a lower
dr, could also be applied to introduce different functional
groups on the C-5 position (4t). The ꢀ-substituted enone did
not work well with alkyl amines due to possible steric
hindrance in the aza-Michael addition. However, with NH3
as the amine nucleophile, the desired piperidines were
The condensation products were generated through the
proposed reaction path A shown in Scheme 1B. Notably,
(5) For reviews, see: (a) Kallstrom, S.; Leino, R. Bioorg. Med. Chem.
2008, 16, 601. (b) Yamashita, T.; Yasuda, K.; Kizu, H.; Kameda, Y.;
Watson, A. A.; Nash, R. J.; Fleet, G. W. J.; Asano, N. J. Nat. Prod. 2002,
65, 1875. For recent example, see: (c) Mochizuki, A.; Nakamoto, Y.; Naito,
H.; Uoto, K.; Ohta, T. Bioorg. Med. Chem. Lett. 2008, 18, 782.
(6) For review, see: (a) Buffat, M. G. P. Tetrahedron. 2004, 60, 1701.
(b) For recent examples, see: Sarkar, N.; Banerjee, A.; Nelson, S. G. J. Am.
Chem. Soc. 2008, 130, 9222. (c) Denmark, S. E.; Baiazitov, R. Y. J. Org.
Chem. 2006, 71, 593. (d) Kobayashi, T.; Nakashima, M.; Hakogi, T.;
Tanaka, K.; Katsumur, S. Org. Lett. 2006, 8, 3809.
(7) For review, see. (a) Felpin, F. X.; Lebreton, J. Eur. J. Org. Chem.
2003, 19, 3693. For recent examples, see: (b) Movassaghi, M.; Hunt, D. K.;
Tjandra, M. J. Am. Chem. Soc. 2006, 128, 8126. (c) Nilsson, B. L.; Overman,
L. E.; de Alaniz, J. R.; Rohde, J. M. J. Am. Chem. Soc. 2008, 130, 11297.
(8) For selected reviews, see: (a) Cipolla, L.; La Ferla, B.; Nicotra, F.
Curr. Top. Med. Chem. 2003, 3, 485. (b) Okitsu, O.; Suzuki, R.; Kobayashi,
S. J. Org. Chem. 2001, 66, 809. (c) Pearson, M. S. M.; Mathe-Allainmat,
M.; Fargeas, V.; Lebreton, J. Eur. J. Org. Chem. 2005, 11, 2159.
(9) At room temperature, the reaction reaches equilibrium within 1 h,
and around 60% to 95% nitroalkene is converted to adduct A various by
(10) For selected examples, see: (a) Enders, D.; Narine, A. A.; Toulgoat,
F.; Bisschops, T. Angew. Chem., Int. Ed. 2008, 47, 5661. (b) Munro-
Leighton, C.; Blue, E. D.; Gunnoe, T. B. J. Am. Chem. Soc. 2006, 128,
1246. (c) Sani, M.; Bruch, L.; Chiva, G.; Fustero, S.; Piera, J.; Volonterio,
A.; Zanda, M. Angew. Chem., Int. Ed. 2003, 42, 2060. (d) Fadini, L.; Togni,
A. Chem. Commun. 2003, 1, 30. (e) Kawatsura, M.; Hartwig, J. F.
Organometallics 2001, 20, 1960.
(11) See detailed X-ray and 1D, 2D NMR information in the Supporting
Information.
solvents and substrates
.
(12) See reaction conditions screening in the Supporting Information.
2334
Org. Lett., Vol. 11, No. 11, 2009

rather stable under strong basic conditions (no ring-opening
products were observed even upon treating 4a with NaOMe in
MeOH for 24 h). All these results strongly suggested that the
irreversible Henry-aldol cyclization was the rate-determining
step, which accounts for the piperidine diastereoselectivity. We
then wondered whether chiral amines could deliver the chirality
into the piperidine ring by involving in the spatial arrangement
in the chair transition state, through the dynamic kinetic
resolution of intermediate A.
Table 2. Reaction Substrate Scopea
To investigate the chirality induction by chiral amines,
arylethanamines 5a-c were applied. As expected, piperidines
6a-c were obtained in good yields. With the formation of two
possible C-4 isomers, introduction of new stereogenic center
on C-7 position could result in the formation of four diastere-
omers as indicated in Table 3. Excellent diastereoselectivity on
C-4 position was obtained in 6a and 6b (comparing P1 to P3
and P2 to P4), giving dr >10:1. For amine 5c, MeOH was
required for optimal outcome, due to the slow reaction rate in
THF, which caused a slight decrease of dr on C-4 selectivity.
However, to evaluate the chirality transfer by chiral amine, the
relative stereochemistry of the exocyclic C-7 and the piperidine
ring is the key (comparing the C-7 isomers: P1 to P2 or P3 to
P4). With possible free rotation of the exocyclic N-C bond,
one may expect poor stereochemistry control. To our surprise,
modest chirality induction was obtained in all three cases, giving
dr on C-7 around 4:1.
Based on the X-ray crystallography and NMR spectroscopy,
structures of all obtained isomers were identified. Interestingly,
as shown in all crystal structures, the exocyclic C-7 adopted
perfect a staggered conformation with the ring.11 Moreover,
the chemical shift of the C-8 and C-9 carbons were significantly
shifted upfield when they were at the antiparallel position
relative to nitrogen lone pair electrons (C-8 in P1/P3 and C-9
in P2, Table 3)13 Therefore, it suggested that the N1-C7 σ-bond
rotation was restricted. Considering all these results, a
Henry-aldol cyclization chair transition state is proposed in
Scheme 3.
a General reaction conditions: compounds 1 (1.0 equiv), 2 (1.5 equiv),
and 3 (2.0 equiv) were mixed in THF (c ) 0.2 M of 1). The reactions were
monitored by TLC until compound 1 was totally consumed. b Isolated yields
of both isomers. c dr determined by NMR of crude reaction mixtures.
d Structure and relative stereochemistry were determined by X-ray
crystallography.
obtained with excellent yields and diastereoselectivity (i.e.,
4m-q). Therefore, the C-6 position could also be modified
by using different ꢀ-substituted enones.
Considering the great efficiency and good diastereoselec-
tivity of this new cascade process, we then focused on
investigating the stereochemistry with the hope of achieving
enantiomeric pure piperidine derivatives. With the formation
of C-2 stereogenic center in the amine conjugate addition to
nitroalkene, it is possible that the stereochemistry of the final
piperidine product is driven by this stereogenic center through
the chair transition state. However, the reaction NMR studies
revealed one important mechanistic insight: recharging pure
adduct A into the reaction condition produced nitroalkene
1a in 30 min (Scheme 2).
Scheme 3. Proposed Exocyclic Chirality Induction
As part of the six-membered ring, the N-1 nitrogen lone pair
electrons adopted the axial position. Thus, with the preferred
staggered N1-C7 conformation, three syn-pentane interactions
would be generated in the transition state: [C-2-R to C-7-H]
and [C-2/C-6-H to C-7-Rsmall]. This proposed transition-state
model was consistent with the experimental observation in the
synthesis of piperidine 6a-c, where in the major stereoisomers
Scheme 2. Equilibrium in the Nitroalkene Conjugate Addition:
Recharging Pure A into the Reaction Gave 1a in 30 min
Moreover, the aza-Michael adduct B (Scheme 1) was never
observed by reaction NMR, and piperidine products 4 were
(13) See experimental details of gHMBC and HETCRO-LR NMR
studies in the Supporting Information.
Org. Lett., Vol. 11, No. 11, 2009
2335

Table 3. Investigation of Chirality Induction by Chiral Aminesa
13C chemical shift of C-8
13C chemical shift of C-9
dr (%)
P1:P2:P3:P4c
Ar
solvent
yieldb (%)
P1
P2
P3
P4
P1
P2
P3
P4
5a
5b
5c
THF
THF
MeOH
88
84
88
82:18:0:0
78:15:7:0
73:16:11:0
8.6
8.7
8.8
18.8
19.1
18.4
143.3
135.3
151.1
137.9
130.0
145.8
8.3
8.6
135.0
150.8
a General reaction condition as described in Table 2. b Combined isolated yields of all isomers. Structures of all reported isomers were determined by
either X-ray crystallography or comprehensive 1D and 2D NMR experiments. c dr determined by NMR of crude reaction mixtures.
the less bulky methyl group (relative to the aryl groups) was
placed on the R1 position to generate the energetically favored
transition state by minimizing the syn-pentane steric repulsion.
Scheme 4. Enhanced Exocyclic Stereochemistry Control by
Amino Esters: 100% Chirality Induction
However, besides the steric interaction, the stability of the chair
transition state could also be influenced by the p-σ* electronic
interaction between nitrogen lone pair electrons and exocyclic
axial Rsmall group. Compared to the methyl group, the more
bulky phenyl group could form stronger p-σ* interactions if
it were placed on the R1 position. Therefore, we wondered
whether this chirality induction could be further enhanced by
application of the chiral amine with a less bulky group that
would produce stronger p-σ* interaction. The readily available
amino acid derivatives become ideal chiral amines for this
application with the smaller COOMe group that provides
stronger p-σ* interaction, giving energetically a more favored
transition state than other different alternatives (Scheme 4). As
expected, reactions among 1a, 3a and amino esters 5d and 5e
generated the desired enantiomeric pure piperidine 6d and 6e
with only C-4 isomers observed: 100% chirality induction was
achieVed through the chirality control by exocyclic asymmetry.
Based on the reaction crude NMR, the C-4 isomers were
the only piperidine products observed. Under the reaction
conditions, 25% of unreacted 1a was recovered in both cases,
making the theoretical isolated yields of 6d and 6e to 83% and
87%. This result was exciting since it revealed a possible new
strategy in transition state stereochemistry control, which could
be applied into other amine-related heterocycle synthesis. No
epimerization occurred under the reaction conditions and
compounds 6d and 6e were indeed prepared with 100%
enantiomeric purity.14 Through some simple transformations,
the two C-4 isomers were converted into single enantiomer 7a
and 7b (Scheme 4).
In conclusion, applying the one-pot cascade strategy, sub-
stituted piperidines were prepared with excellent yields and great
stereoselectivity. The transformation was suitable for a large
group of substrates and selective functionalization on each
position of the piperidine ring have been achieved. Moreover,
based on an exocyclic stereochemistry control, 100% chirality
induction was achieved with amino esters, giving enantiomeric
pure substituted piperidines in less than three steps. It is our
belief that this new stereochemistry control strategy may be
further applied into similar systems for the synthesis of other
chemical and biological important heterocycles.
Acknowledgment. We thank the WV Nano Initiative at
West Virginia University and American Chemical Society
PRF for financial support.
(14) The functional group transformation confirmed that no epimerization
occurred during the reaction.
Supporting Information Available: Experimental details,
spectrographic data, and XRD information. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL900708D
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Org. Lett., Vol. 11, No. 11, 2009