Ytterbium triflate catalyzed synthesis of alkoxy-substituted donor-acceptor cyclobutanes and their formal [4 + 2] cycloaddition with imines: Stereoselective synthesis of piperidines

Article abstract of DOI:10.1021/ol102062t

A new synthesis of 2-alkoxy-1,1-cyclobutane diesters and their first use in dipolar cycloadditions is reported. Both the formation of the donor-acceptor cyclobutanes and their subsequent annulation with in situ formed imines are catalyzed by Yb(OTf)₃

Full text of DOI:10.1021/ol102062t

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4732-4735
Ytterbium Triflate Catalyzed Synthesis of
Alkoxy-Substituted Donor-Acceptor
Cyclobutanes and Their Formal [4 + 2]
Cycloaddition with Imines: Stereoselective
Synthesis of Piperidines
Mahmoud M. Abd Rabo Moustafa and Brian L. Pagenkopf*
Department of Chemistry, The UniVersity of Western Ontario,
London, Ontario N6A 5B7, Canada
bpagenko@uwo.ca
Received August 30, 2010
ABSTRACT
A new synthesis of 2-alkoxy-1,1-cyclobutane diesters and their first use in dipolar cycloadditions is reported. Both the formation of the
donor-acceptor cyclobutanes and their subsequent annulation with in situ formed imines are catalyzed by Yb(OTf)3. Cyclobutanes with
carbon donor groups give piperidines with high trans stereoselectivity.
Because of their unique reactivity profiles and inherent strain
energy, cyclopropanes and cyclobutanes have emerged as
important pharmacophores and versatile building blocks in
modern organic synthesis.1,2 Lewis acid catalyzed dipolar
cycloadditions involving donor-acceptor (DA) cyclopro-
panes are well documented and have been employed
extensively for the preparation of different heterocycles,3
including those leading to the synthesis of natural products.4
The ring fission can occur via an SN2-type mechanism, by
ring opening and subsequent electrophilic trapping, rear-
rangement, and ring contraction or expansion.5 In contrast,
reports that extend similar synthetic transformations to DA
cyclobutanes are comparatively rare (Scheme 1). In this
regard, aldehydes have been found to undergo [4 + 2]
cycloadditions with DA cyclobutanes, which was first
demonstrated by Saigo in 1991.6 More recently, Matsuo has
extended this work to cyclobutanones,7 and Christie and
Pritchard8 and Johnson9 have demonstrated the effective use
(3) For DA cyclopropane reviews, see: (a) Wenkert, E. Acc. Chem. Res.
1980, 13, 27–31. (b) Reissig, H.-U. Top. Curr. Chem. 1988, 144, 73–135.
(c) Reissig, H.-U.; Zimmer, R. Chem. ReV. 2003, 103, 1151–1196. (d) Yu,
M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321–347. (e) De Simone, F.;
Waser, J. Synthesis 2009, 20, 3353–3374. For selected examples, see: (f)
Lautens, M.; Han, W. J. Am. Chem. Soc. 2002, 124, 6312–6316. (g) Young,
I. S.; Kerr, M. A. Angew. Chem., Int. Ed. 2003, 42, 3023–3026. (h) Bajtos,
B.; Yu, M.; Zhao, H.; Pagenkopf, B. L. J. Am. Chem. Soc. 2007, 129, 9631–
9634. (i) Perreault, C.; Goudreau, S. R.; Zimmer, L. E.; Charette, A. B.
Org. Lett. 2008, 10, 689–692. (j) Moustafa, M. M. A. R.; Pagenkopf, B. L.
Org. Lett. 2010, 12, 3168–3171.
(4) For a review, see: (a) Carson, C. A.; Kerr, M. A. Chem. Soc. ReV
2009, 38, 3051–3060. For selected examples: (b) Young, I. S.; Kerr, M. A.
J. Am. Chem. Soc. 2007, 129, 1465–1469. (c) Bajtos, B.; Pagenkopf, B. L.
Eur. J. Org. Chem. 2009, 1072–1077. (d) Jung, M. E.; Chang, J. J. Org.
Lett. 2010, 12, 2962–2965.
(1) (a) Donaldson, W. A. Tetrahedron 2001, 57, 8589–8627. (b) Rubin,
(5) (a) Karadeolian, A.; Kerr, M. A. J. Org. Chem. 2007, 72, 10251–
10253. (b) Sapeta, K.; Kerr, M. A. J. Org. Chem. 2007, 72, 8597–8599.
(c) Pohlhaus, P. D.; Sanders, S. D.; Parsons, A. T.; Li, W.; Johnson, J. S.
J. Am. Chem. Soc. 2008, 130, 8642–8650.
M.; Rubina, M.; Gevorgyan, V. Chem. ReV. 2007, 107, 3117–3179
.
(2) (a) Lee-Ruff, E.; Mladenova, G. Chem. ReV. 2003, 103, 1449–1483.
(b) Namyslo, J. C.; Kaufmann, D. E. Chem. ReV. 2003, 103, 1485–1537.
10.1021/ol102062t  2010 American Chemical Society
Published on Web 10/06/2010

we report a modified procedure for the synthesis of DA
cyclobutanes that are activated by an alkoxy donor group
and geminal diester withdrawing groups. Furthermore, the
subsequent application of these cyclobutanes for the first time
in imine dipolar cycloadditions to afford highly substituted
piperidine and piperideine derivatives is also reported.
The 2-alkoxy-1,1-cyclobutane diesters are interesting latent
1,4-dipole equivalents that can be prepared from enol ethers
and methylidene malonates. The preparation of this class of
cyclobutanes was reported by Roberts in 1986 (Scheme 3),13
Scheme 1. Cyclopropanes and Cyclobutanes as Dipolar
Equivalents
Scheme 3. ZnBr2-Mediated Synthesis of DA Cyclobutanes
of carbon-based activating groups. Although Saigo obtained
a mixture of stereoisomers with his amine-activated cyclobu-
tanes, subsequent reports have disclosed that ring opening
and cycloaddition occurred smoothly to afford tetrahydro-
pyrans in moderate to excellent diastereoselectivity.7-9
Imines have been utilized by us3d and others10 as dipo-
larophiles in Lewis acid catalyzed [3 + 2] cycloadditions
with DA cyclopropanes to furnish pyrrolidine derivatives in
a stereoselective manner. At the onset of this project there
were no reports that extend this to DA cyclobutanes,11 and
thus we sought to access the piperidine nucleus through a
Lewis acid catalyzed formal [4 + 2] cycloaddition of
appropriately substituted DA cyclobutanes and imines (Scheme
2). Given our ongoing interest in alkoxy-substituted DA
yet it was somewhat surprising that the use of these
cyclobutanes in dipolar cycloadditions had not been realized
prior to this work.
Duplication of the conditions reported by Roberts for the
reaction of dihydropyran with di-tert-butyl methylidene
malonate in our hands gave a poor yield (39% Table 1, entry
Table 1. Optimizing Cyclobutane Formation
Scheme 2
.
Formal [4 + 2] Cycloaddition of DA Cyclobutanes
and Imines
entry
R
catalyst
temp (°C)
yield (%)a
1
2
3
4
5
6
tBu 1 equiv of ZnBr2
-130 to -78
-130 to -78
-130 to -78
39b
17b
0c
Et
Et
Et
Et
Et
1 equiv of ZnBr2
1 equiv of ZnCl2
1 equiv of TMSOTf -78
10 mol % Sc(OTf)3
10 mol % Yb(OTf)3
0c
cyclopropanes,3h,j,12 the analogous cyclobutanes were chosen
as substrates for the exploration of this chemistry. Herein
-78
-78
78
84
a Isolated yield. b Product contaminated by ring-opened and polymeric
substance. c Polymeric substances observed.
(6) Shimada, S.; Saigo, K.; Nakamura, H.; Hasegawa, M. Chem. Lett.
1991, 20, 1149–1152.
(7) (a) Matsuo, J.-I.; Sasaki, S.; Tanaka, H.; Ishibashi, H. J. J. Am. Chem.
Soc. 2008, 130, 11600–11601. (b) Matsuo, J.-I.; Sasaki, S.; Hoshikawa,
T.; Ishibashi, H. Org. Lett. 2009, 11, 3822–3825. (c) Matsuo, J.-I.; Negishi,
S.; Ishibashi, H. Tetrahedron Lett. 2009, 50, 5831–5833.
(8) Allart, E. A.; Christie, S. D. R.; Pritchard, G. J.; Elsegood, M. R.
Chem. Commun. 2009, 7339–7341.
1), and isolation of the cyclobutane was complicated by both
considerable byproducts and the stoichiometric ZnBr2. More
problematic, however, was our inability to extend this
methodology to the more readily available and reactive
diethyl methylidene malonate, and only trace amounts of the
desired cyclobutane were observed along with a complex
mixture of polymerization and ring-opened byproducts (entry
2). A variety of other Lewis acids were then screened, and
Sc(OTf)3 and Yb(OTf)3 quickly emerged as competent
catalysts, with Yb(OTf)3 being the catalyst of choice as a
(9) Parsons, A. T.; Johnson, J. S. J. Am. Chem. Soc. 2009, 131, 14202–
14203.
(10) (a) Alper, P. B.; Meyers, C.; Lerchner, A.; Siegel, D. R.; Carreira,
E. M. Angew. Chem., Int. Ed. 1999, 38, 3186–3189. (b) Lautens, M.; Han,
W.; Liu, J. H.-C. J. Am. Chem. Soc. 2003, 125, 4028–4029. (c) Bertozzi,
F.; Gustafsson, M.; Olsson, R. Org. Lett. 2002, 4, 3147–3150. (d) Carson,
C. A.; Kerr, M. A. J. Org. Chem. 2005, 70, 8242–8244. (e) Xing, S.; Pan,
W.; Liu, C.; Ren, J.; Wang, Z. Angew. Chem., Int. Ed. 2010, 49, 3215–
3218.
(11) While this manuscript was in preparation, Matsuo reported a
[4 + 2] cycloaddition between cyclobutanones and imines. See: Matsuo,
J.-I.; Okado, R.; Ishibashi, H. Org. Lett. 2010, 12, 3266–3268.
(12) (a) Yu, M.; Pagenkopf, B. L. Org. Lett. 2003, 5, 5099–5101. (b)
Morales, C. L.; Pagenkopf, B. L. Org. Lett. 2008, 10, 157–159. (c) Bajtos,
(13) (a) Baar, M. R.; Ballesteros, P.; Roberts, B. W. Tetrahedron Lett.
1986, 27, 2083–2086. (b) Mangelinckx, S.; Vermaut, B.; Roland, V.; De
Kimpe, N. Synlett 2008, 17, 2697–2701. (c) Canales, E.; Corey, E. J. J. Am.
Chem. Soc. 2007, 129, 12686–12687.
B.; Pagenkopf, B. L. Org. Lett. 2009, 11, 2780–2783
.
Org. Lett., Vol. 12, No. 21, 2010
4733

result of slightly higher yields and lower catalyst cost (entries
5 and 6). The use of catalytic Yb(OTf)3 rather than
stoichiometric ZnBr2 made the reactions operationally much
simpler to perform (up to 12 g scale), requiring only a simple
filtration to provide the cyclobutane in high purity and yield.
Having identified Yb(OTf)3 as a superior catalyst for the
synthesis of alkoxy-substituted DA cyclobutanes, the feasi-
bility of using it to catalyze the [4 + 2] cycloaddition of
these cyclobutanes with imines was explored.14 To our
delight, upon exposure of cyclobutane 3b and imine 4a
(prepared in situ) to catalytic Yb(OTf)3 at -50 °C, the
bicyclic piperidine 5a as a single diastereomer and piperi-
deine 6a were observed (Scheme 4). On the other hand,
Scheme 5
.
Yb(OTf)3-Catalyzed Synthesis of DA Cyclobutanes
and Piperideines
Scheme 4
.
Formal [4 + 2] Cycloaddition of Alkoxy-Substituted
DA Cyclobutanes and Imines
reaction of imine 4b gave cycloadduct 5b as a 2:1 mixture
of diastereomers as well as piperideine 6b. The relative
stereochemistry of trans-5b and cis-5b was assigned on the
basis of NOE interactions and ultimately confirmed by single-
crystal X-ray analysis (Figure 1). In order to isolate only
of compatible methylidene malonates has been expanded
beyond di-tert-butyl methylidene malonate to now encompass
the more reactive diethyl and dimethyl methylidene mal-
onates. The range of enol ethers that participated in the
cycloaddition was quite broad with cyclic, acyclic, and
higher-substitution patterns being tolerated (3b-g). Regard-
ing the [4 + 2] reaction, electron-rich or electron-deficient
aromatic and heteroaromatic imines were found to participate
in the cycloaddition to form piperideines 6b-g in moderate
to excellent yield. Unfortunately, the more reactive cyclobu-
tanes 3e-g gave complex mixtures when subjected to the
same reaction conditions.
Next, the ability of Yb(OTf)3 to catalyze the synthesis of
cyclobutanes with carbon-donating groups was explored
(Scheme 6). The [2 + 2] reaction of methylidene malonates
with p-vinyl anisole and anethole gave cyclobutanes 3h-k
as single diastereomers. Unfortunately, no reaction was
observed with styrene, and only polymerization products
were observed. In contrast to the cyclobutanes activated by
alkyl ethers, the cycloaddition of imines with cyclobutane
3h required higher temperatures and longer reaction times
(0 °C for 10 h vs -50 °C for 1 h). Nonetheless, the
cycloaddition provided pentasubstituted piperidines with
electron-deficient or -rich aromatic, cinnamyl, and heteroaro-
matic imines. All of the cycloadducts 6h-m were obtained
in moderate to good yields and exclusively as the trans-
diastereomer. The cyclobutanes 3i-k failed to react pro-
ductively with imines, and only decomposition was observed.
Finally, the possibility of carrying out the cyclobutane
formation/imine cycloaddition reaction sequence in one
Figure 1. Single crystal X-ray structures of trans-5b and cis-5b.
the piperideine product, the reaction was warmed to room
temperature for 1 h after consumption of the cyclobutane,
to drive the product from the piperidine 5a to the piperideine
6a.
Having demonstrated that both the cyclobutane and
piperideine syntheses were successful, the scope of both
reactions was explored, and the results are summarized in
Scheme 5. In regard to the cyclobutane formation, the range
(14) (a) Marshman, R. W. Aldrichimica Acta 1995, 28, 77–84. (b)
Shibasaki, M.; Matsunaga, S.; Kumagai, N. Acid Catalysis in Modern
Organic Synthesis; Yamamoto, H., Ishihara, K., Eds.; Wiley-VCH: Wein-
heim, 2008; Vol. 2, pp 635-710.
4734
Org. Lett., Vol. 12, No. 21, 2010

Scheme 6
.
Synthesis of Cyclobutanes and Pentasubstituted
Piperidines
Scheme 7. One-Pot, Multistep Synthesis of Piperideines
In summary, a new and reliable procedure for the
preparation of alkoxy-substituted DA cyclobutanes has been
developed, and these cyclobutanes have been shown for the
first time to undergo dipolar cycloadditions. They undergo
a formal [4 + 2] cycloaddition with imines to afford highly
substituted piperidines and piperideines. Additionally, a one-
pot procedure for cyclobutane synthesis and subsequent imine
cycloaddition has been demonstrated. Efforts are currently
underway to develop new cycloaddition reactions utilizing
these cyclobutanes.
Acknowledgment. We thank the National Sciences and
Engineering Research Council of Canada for financial
assistance. We thank Prof. J. Peter Guthrie (UWO) and
Prof. Michael A. Kerr (UWO) and his group for helpful
discussions. We thank Dr. Guerman Popov (UWO) and
Ms. Jackie Price (UWO) for determination of the X-ray
structures. We thank Mr. Andrew C. Stevens (UWO) for
help with manuscript preparation. M.M. thanks the
Egyptian Academy of Scientific Research and Technology
for financial support.
reaction vessel was examined (Scheme 7). When a CH2Cl2
solution of imine was added to a concentrated solution of
the in situ formed cyclobutane, the cycloadduct was obtained
in yields ranging from 59% to 84%. While isolating the
cyclobutane is advantageous for building chemical libraries,
obviating cyclobutane isolation with a one-vessel three-step
reaction sequence can be a practical option for large scale
target-specific synthesis.15
Supporting Information Available: General experimental
procedures and characterization of all new compounds and
copies of NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(15) For a one-pot procedure, methylidene malonate should be freshly
prepared.
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