Zn(II)-catalyzed synthesis of piperidines from propargyl amines and cyclopropanes

Article abstract of DOI:10.1021/ol901435k

Image Presented The reaction of benzyl-protected propargyl amines and 1,1-cyclopropane diesters in the presence of catalytic Zn(NTf₂) ₂ allows access to highly functionalized piperidines in excellent yields. The process proceeds via

Full text of DOI:10.1021/ol901435k

ORGANIC
LETTERS
2009
Vol. 11, No. 16
3770-3772
Zn(II)-Catalyzed Synthesis of Piperidines
from Propargyl Amines and
Cyclopropanes
Terry P. Lebold, Andrew B. Leduc, and Michael A. Kerr*
Department of Chemistry, The UniVersity of Western Ontario,
London, Ontario, Canada N6A 5B7
makerr@uwo.ca
Received June 24, 2009
ABSTRACT
The reaction of benzyl-protected propargyl amines and 1,1-cyclopropane diesters in the presence of catalytic Zn(NTf2)2 allows access to highly
functionalized piperidines in excellent yields. The process proceeds via a tandem cyclopropane ring-opening/Conia-ene cyclization.
The prominence of the piperidine ring in both natural
products and therapeutic agents cannot be overstated; its
ubiquity in both natural and unnatural bioactive compounds
is a testament to this1 (Figure 1 shows several representative
examples of interest to our group2). New and efficient
methods for the preparation of this heterocycle stand to be
of great importance to synthetic and medicinal chemists.3
In this paper, we present a unique process which accesses
piperidines in an extraordinarily efficient manner via a
tandem cyclopropane ring-opening/Conia-ene cyclization.
Figure 1. Biologically active piperidines.
(1) (a) Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005,
68, 1556. (b) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679.
(2) Lofentanil: (a) De Ranter, C.; Peeters, O.; Gelders, Y. Arch. Int.
Physiol. Biochim. 1979, 87, 1031. Lepadin F: (b) Wright, A. D.; Goclik,
E.; Konig, G. M.; Kaminsky, R. J. Med. Chem. 2002, 45, 3067. (c) Davis,
R. A.; Carroll, A. R.; Quinn, R. J. Nat. Prod. 2002, 65, 454. Pergolide: (d)
Cabri, W.; Roletto, J.; Olmo, S.; Fonte, P.; Ghetti, P.; Songia, S.; Mapelli,
E.; Alpegiani, M.; Paissoni, P. Org. Process Res. DeV. 2006, 10, 198, and
references therein. Arboricine: (e) Lim, K.-H.; Komiyama, K.; Kam, T.-S.
Tetrahedron Lett. 2007, 48, 1143. (f) Revised structure: Wanner, M. J.;
Boots, R. N. A.; Eradus, B.; de Gelder, R.; van Maarseveen, J. H.; Hiemstra,
H. Org. Lett. 2009, 11, 2579.
The Conia-ene4 reaction has received much attention in
recent years due to its usefulness in C-C bond formation. While
there has been considerable advancement of this reaction,5-8
it has almost exclusively focused on five-membered ring
(4) Conia, J. M.; Le Perchec, P. Synthesis 1975, 1.
(5) Five-membered rings: (a) Cruciani, P.; Aubert, C.; Malacria, M.
Tetrahedron Lett. 1994, 35, 6677. (b) Cruciani, P.; Stammler, R.; Aubert,
C.; Malacria, M. J. Org. Chem. 1996, 61, 2699. (c) Renaud, J.-L.; Aubert,
C.; Malacria, M. Tetrahedron 1999, 55, 5113. (d) Kennedy-Smith, J. J.;
Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4526. (e) Staben,
S. T.; Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem., Int. Ed. 2004, 43,
5350. (f) Gao, Q.; Zheng, B.-F.; Li, J. H.; Yang, D. Org. Lett. 2005, 7,
2185. (g) Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 2764.
See also references cited therein.
(3) For a recent review, see: (a) Harrity, J. P. A.; Provoost, O. Org.
Biomol. Chem. 2005, 3, 1349. (b) Buffat, M. G. P. Tetrahedron 2004, 60,
1701. (c) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R.
Tetrahedron 2003, 59, 2953. (d) Laschat, S.; Dickner, T. Synthesis 2000,
1781. (e) Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem. Commun.
1998, 633.
10.1021/ol901435k CCC: $40.75
Published on Web 07/28/2009
 2009 American Chemical Society

formation4,5 with only a handful of reports on the formation
of larger ring systems.6,7 It occurred to us that the nucleo-
philic ring-opening of a 1,1-cyclopropane diester with a
propargylic amine would provide a substrate suitable for
Conia-ene cyclization, which in turn would furnish a
piperidine ring. Furthermore, we surmised that with the
judicious choice of Lewis acid catalyst, the process (as
illustrated in Table 1) could be made both tandem and
we report an efficient synthesis of piperidines in a catalytic
tandem fashion from simple readily available starting materi-
als.
Table 1 outlines both the proof of principle and the search
for optimal reaction conditions. Our initial reaction involved
treatment of 1,1-cyclopropane diester 1a and propargyl amine
2a with 5 mol % of Sc(OTf)3 in refluxing benzene which, after
several hours, led only to the ring-opened product 3.10 However,
treatment of that reaction mixture with 2 equiv of ZnBr2
gratifyingly induced Conia-ene cyclization to give the desired
piperidine in an 82% isolated yield.11 While this two-step, one-
pot approach worked well, we still desired a single catalyst
capable of inducing both cyclopropane ring opening and
subsequent ring closure. While treatment with In(OTf)3 led to
no reaction, we were pleased to discover that treatment with
20 mol % of Zn(OTf)2 resulted in a 77% yield of the desired
piperidine along with a small amount of unreacted starting
material. However, when the more reactive Zn(NTf2)212 was
employed, we obtained the desired piperdine in 94% yield.
With the identification of Zn(NTf2)2 as the superior catalyst
we next explored the catalyst loading and amine stoichiom-
etry to find that the reaction would still proceed in excellent
yield with just 5 mol % of Zn(NTf2)2 and 1.2 equiv of the
amine (although longer reaction times were required). We
therefore settled on the use of 10 mol % of Zn(NTf2)2 since
it allowed for completion of the reaction within 24 h. Neither
the primary amine, N-Boc, or N-tosyl derivatives resulted
in the formation of the desired product.
Table 1. Optimization of Tandem Ring-Opening/Conia-Ene
Cyclization
entry cyclopropane amine
conditionsa
yieldb (%)
82
1
1a
2a
Sc(OTf)3 (5 mol %),
ZnBr2 (2 equiv),
amine (2 equiv)
2
1a
1a
1a
1b
1b
1b
1a
1a
1a
2a
2a
2a
2a
2a
2a
2b
2c
2d
Zn(OTf)2 (20 mol %), 77
amine (2 equiv)
Zn(NTf2)2 (20 mol %), 94
amine (2 equiv)
3
4
In(OTf)3 (5 mol %),
no reaction
A plausible mechanism for the tandem reaction is presented in
Scheme 1. Initial coordination of the diesters by zinc facilitates
amine (2 equiv)
Zn(NTf2)2 (20 mol %), 97
amine (2 equiv)
Zn(NTf2)2 (10 mol %), 95
amine (1.3 equiv)
Zn(NTf2)2 (5 mol %), 98
amine (1.2 equiv)
Zn(NTf2)2 (10 mol %), no reaction
amine (1.3 equiv)
Zn(NTf2)2 (10 mol %), no reaction
amine (1.3 equiv)
5
6
Scheme 1. Plausible Mechanism
7
8
9
10
Zn(NTf2)2 (10 mol %), no reaction
amine (1.3 equiv)
a Cyclopropane, propargyl amine, and catalyst were dissolved in 3 mL
of benzene, and the reaction was brought to reflux. Upon completion, a
small amount of Li2 CO3 was added and the reaction was purified by column
chromatography. b Isolated yield.
the nucleophilic ring-opening of the 1,1-cyclopropane diester by
the amine to yield intermediate 3. Subsequent coordination of the
alkyne then allows for malonate addition and ring closure.
Protonation of the zinc metalate leads to the desired piperidine and
regeneration of the zinc catalyst.
With our optimized conditions in hand, we next investigated
the scope of the reaction using propargyl amine 2a and a variety
of substituted 1,1-cyclopropane diesters (Table 2). Both simple
phenyl substituents (product 4a) as well as electron-rich
aromatics (products 4b,c) performed superbly. While mildly
electron-withdrawing groups on the phenyl ring (such as p-Br
and p-Cl) worked well under our standard conditions, yielding
4f and 4g, the presence of p-CN and p-CO2Me substituents
necessitated a higher catalyst loading as well as an increased
catalytic. Given the considerable interest in the annulation
reactions of 1,1-cyclopropane diesters9 and our work within this
field,9a-c we felt well-positioned to engage this project. Herein
(6) Annulations of propargyl amines and electron-deficient olefins: (a)
Morikawa, S.; Yamazaki, S.; Furusaki, Y.; Amano, N.; Zenke, K.; Kakiuchi,
K. J. Org. Chem. 2006, 71, 3540. (b) Azoulay, S.; Monteiro, N.; Balme,
G. Tetrahedron Lett. 2002, 43, 9311. (c) Clique, B.; Vassiliou, S.; Monteiro,
N.; Balme, G. Eur. J. Org. Chem. 2002, 1493. (d) Monteiro, N.; Balme, G.
J. Org. Chem. 2000, 65, 3223. (e) Clique, B.; Monteiro, N.; Balme, G.
Tetrahedron Lett. 1999, 40, 1301. (f) Dumez, E.; Rodriguez, J.; Dulce`re,
J.-P. Chem. Commun. 1997, 1831.
(7) Six-membered rings: (a) Nakamura, E.; Sakata, G.; Kubota, K.
Tetrahedron Lett. 1998, 39, 2157. (b) Kitagawa, O.; Suzuki, T.; Inoue, T.;
Watanabe, Y.; Taguchi, T. J. Org. Chem. 1998, 63, 9470. (c) Kitagawa,
O.; Fujiwara, H.; Suzuki, T.; Taguchi, T.; Shiro, M. J. Org. Chem. 2000,
65, 6819.
Org. Lett., Vol. 11, No. 16, 2009
3771

active methyl (R)-propargyl amine with either optically active
(R)-2a or (S)-2a resulted, as expected, in the formation of either
the cis- or trans-2,6-disubstituted piperidines, respectively.
In summary, we have developed a Zn(II)-catalyzed reac-
tion of 1,1-cyclopropane diesters and propargyl amines which
allows access to highly substituted piperidines in excellent
yields. Notably, the reaction is tandem, catalytic, and atom-
Table 2. Reaction Scope
Table 3. Effects of R-Chirality of the Propargyl Amine
entry
cyclopropane
amine
piperidine
yield (%)
1
2
3
rac
Ra
Sb
rac
Sc
R,R:S,S:R,S:S,R
2S,6S
2S,6R
98d
95e
96e
Sc
a 98% ee. b 98% ee. c >99% ee. d 1:1 mixture of racemic diastereomers.
e Diastereomeric purity >97%.
economical and occurs under mild reaction conditions. If
either optically active amines or 1,1-cyclopropane diesters
are employed the chirality is conserved in the piperidine
product without erosion of ee.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council (NSERC) of Canada. We
acknowledge D. Hairsine (University of Western Ontario)
for MS analysis and Dr. Michael Chong (University of
Waterloo) for the use of his polarimeter. T.P.L. and A.B.L.
are recipients of NSERC CGS-D scholarships.
a Product obtained in 96% ee. b Zn(NTf2)2 (30 mol %) and amine
(3 equiv) were employed. c Product obtained in 98% ee. d Zn (NTf2)2 (20
mol %) and amine (3 equiv) were employed in order to avoid decomposition
of product which occurred under prolonged heating. e Zn(NTf2)2 (20 mol
%) and amine (3 equiv) were employed. f Toluene was used as solvent.
g Zn(NTf2)2 (15 mol %) and amine (1.5 equiv) were employed.
Supporting Information Available: Full experimental
procedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL901435K
amount of amine to achieve high yields of 4d and 4e.
Heteroaromatic substituents could also be employed leading to
excellent conversions to piperidines 4h-j. The cyclopropane
could also bear alkenyl groups, alkyl groups, or no substitution
at all. Furthemore, when homochiral cyclopropanes13 were
employed the chirality was maintained in the piperidine product
without erosion of ee (products 4a and 4g).
We next investigated the effect of an R chiral amine on the
diastereoselectivity of the reaction (Table 3). In order to see if
any innate diastereoselectivity could be observed, we treated
racemic cyclopropane 2a with an excess of racemic propargyl
amine 6; however, only a 1:1 mixture of racemic diastereomers
was obtained albeit in excellent yield.14 The use of optically
(9) (a) Young, I. S.; Kerr, M. A. Angew. Chem., Int. Ed. 2003, 42, 3023.
(b) Carson, C. A.; Kerr, M. A. J. Org. Chem. 2005, 70, 8242. (c) Jackson,
S. K.; Karadeolian, A.; Driega, A. B.; Kerr, M. A. J. Am. Chem. Soc. 2008,
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A. B. Org. Lett. 2008, 10, 689. (e) Pohlhaus, P. D.; Sanders, S. D.; Parsons,
A. T.; Li, W.; Johnson, J. S. J. Am. Chem. Soc. 2008, 130, 8642. (f)
Pohlhaus, P. D.; Johnson, J. S. J. Am. Chem. Soc. 2005, 127, 16014. (g)
Korotkov, V. S.; Larionov, O. V.; Hofmeister, A.; Magull, J.; de Meijere,
A. J. Org. Chem. 2007, 72, 7504. (h) Ivanova, O. A.; Budynina, E. M.;
Grishin, Y. K.; Trushkov, I. V.; Verteletskii, P. V. Angew. Chem., Int. Ed.
2008, 47, 1107.
(10) For ring-opening of 1,1-cyclopropane diesters with amines, see:
(a) Blanchard, L. A.; Schneider, J. A. J. Org. Chem. 1986, 51, 1372. (b)
Lifchits, O.; Charette, A. B. Org. Lett. 2008, 10, 2809. See also references
cited therein.
(11) For related Zn(II)-catalyzed ring closures to form heterocyclic six-
membered rings, see: (a) Lorthiois, E.; Marek, I.; Normant, J. F. J. Org.
Chem. 1998, 63, 566. (b) Yamazaki, S.; Inaoka, S.; Yamada, K. Tetrahedron
Lett. 2003, 44, 1429.
(8) Seven- to 15-membered rings: (a) Ochida, A.; Ito, H.; Sawamura,
M. J. Am. Chem. Soc. 2006, 128, 16486. (b) Tsuji, H.; Yamagata, K.-i.;
Itoh, Y.; Endo, K.; Nakamura, M.; Nakamura, E. Angew. Chem., Int. Ed.
2007, 46, 8060. (c) Takahashi, K.; Midori, M.; Kawano, K.; Ishihara, J.;
Hatakeyama, S. Angew. Chem., Int. Ed. 2008, 47, 6244. (d) Yoshimitsu, I.;
Tsuji, H.; Yamagata, K.-i.; Endo, K.; Tanaka, I.; Nakamura, M.; Nakamura,
E. J. Am. Chem. Soc. 2008, 130, 17161.
(12) Earle, M. J.; Hakala, U.; McAuley, B. J.; Nieuwenhuyzen, M.;
Ramani, A.; Seddon, K. R. Chem. Commun. 2004, 1368.
(13) (R)-Dimethyl 2-phenylcyclopropane-1,1-dicarboxylate 98% ee, (R)-
dimethyl 2-(4-chlorophenyl)cyclopropane-1,1-dicarboxylate 98% ee.
(14) It is noteworthy that an excess of racemic cyclopropane with
optically pure amine showed no kinetic resolution.
3772
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