A single step approach to piperidines via ni-catalyzed β-carbon elimination

Article abstract of DOI:10.1021/ol300534j

An easy and expeditious route to substituted piperidines is described. A Ni-phosphine complex was used as catalyst for [4 + 2] cycloaddition of 3-azetidinone and alkynes. The reaction has broad substrate scope and affords piperidines in excellent yields a

Full text of DOI:10.1021/ol300534j

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2026–2029
A Single Step Approach to Piperidines
via Ni-Catalyzed β-Carbon Elimination
Puneet Kumar and Janis Louie*
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City,
Utah 84102, United States
louie@chem.utah.edu
Received March 1, 2012
ABSTRACT
An easy and expeditious route to substituted piperidines is described. A Ni-phosphine complex was used as catalyst for [4 þ 2] cycloaddition of
3-azetidinone and alkynes. The reaction has broad substrate scope and affords piperidines in excellent yields and excellent regioselectivity. In the
reaction of an enantiopure azetidinone, complete retention of stereochemistry was observed.
The ubiquity of piperidines in pharmaceuticals and
natural products makes them attractive targets for organic
synthesis.1 Over the past few years, tremendous progress
has been made in accessing substituted piperidines.2 Spe-
cifically, aza-Achmatowicz rearrangement3 and ring clos-
ing metathesis4 provideaccesstothese motifsinanefficient
fashion (Scheme 1). However, synthesizing highly substi-
tuted piperidines is still a challenging problem. Also, most
of the existing strategies rely on multistep routes, which
urges the need for an operationally simple, expeditious,
and efficient methodology to access these heterocycles.
Recently, we and others have reported a Ni-catalyzed
coupling of carbonyl compounds with alkynes and alkenes.5
Most importantly, the nickel-catalyst system has enabled
the oxidative coupling of alkynes/alkenes and unactivated
ketones to provide dienones and pyrans.5a,5b,6 This is in
contrast to other reports where use of activated ketones
was critical for the success of the reaction.7 Murakami and
co-workers discovered that transition metal catalysts can be
utilized to exploit the ketone moiety of cyclobutanone that
can render β-carbon elimination in reactive intermediates.8
Scheme 1. Existing Strategies to 3-Piperidones
(1) (a) Strunz, G. M.; Findlay, J. A. In The Alkaloids; Brossi, A., Ed.;
Academic Press: London, 1985; Vol. 26, pp 89ꢀ183.
(2) (a) Baliah, V.; Jeyaraman, R.; Chandrasekaran, L. Chem. Rev.
1983, 83, 379. (b) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette,
A. B. Chem. Rev. 201210.1021/cr200251d. (d) Sardina, F. J.; Rapoport, H.
€
Chem. Rev. 1996, 96, 825. (e) Schneider, C.; Borner, C.; Schuffenhauer,
A. Eur. J. Org. Chem. 1999, 1999, 3353. (f) Tambar, U. K.; Lee, S. K.;
Leighton, J. L J. Am. Chem. Soc. 2010, 132, 10248.
(3) Leverett, C. A.; Cassidy, M. P.; Padwa, A. J. Org. Chem. 2006, 71,
8591.
(4) Cossy, J.; Willis, C.; Bellosta, V.; BouzBouz, S. J. Org. Chem.
2002, 67, 1982.
(6) (a) Miller, K. M.; Jamison, T. F. Org. Lett. 2005, 7, 3077.
(b) Murakami, M.; Ashida, S. Chem. Commun. 2006, 4599. (c) Ogoshi,
S.; Ueta, M.; Arai, T.; Kurosawa, H. J. Am. Chem. Soc. 2005, 127,
12810.
(7) (a) Kong, J.-R.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc.
2005, 128, 718. (b) Otake, Y.; Tanaka, R.; Tanaka, K. Eur. J. Org. Chem.
2009, 2009, 2737.
(5) (a) Tekavec, T. N.; Louie, J. Org. Lett. 2005, 7, 4037. (b) Tekavec,
T. N.; Louie, J. J. Org. Chem. 2008, 73, 2641. (c) Miller, K. M.;
Huang, W.-S.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 3442.
(d) Montgomery, J.; Sormunen, G. J. Top. Curr. Chem. 2007, 279, 1.
(e) Malik, H. A.; Sormunen, G. J.; Montgomery, J. J. Am. Chem. Soc.
2010, 132, 5966. (f) Kumar, P.; Troast, D. M.; Cella, R.; Louie, J. J. Am.
Chem. Soc. 2011, 133, 7719.
r
10.1021/ol300534j
Published on Web 04/02/2012
2012 American Chemical Society

Recently, Murakami reported that cyclobutanone can be
very elegantly coupled with alkynes to afford highly sub-
stituted cyclohexenones.9 We surmised the coupling of
3-aza-cyclobutanones with alkynes could provide piperi-
dines in a single step (eq 1).
conditions. Higher catalyst/ligand loading, higher tempera-
ture (110 °C), and prolonged reaction times were not
necessary.11
The substrate scope of this reaction was then investi-
gated using 1-Boc-3-azetidinone with a variety of alkynes
(Figure 2). The reaction with 3-octyne afforded the piper-
idine (1a) in excellent yields. We also investigated the
cycloaddition with a volatile alkyne, i.e., 2-butyne, which
resulted into the desired product (1b) in 95% yield. To test
the effect of sterics on cycloaddition, tert-butyl-methyl and
trimethylsilyl-methyl alkynes were investigated. Surpris-
ingly, both alkynes exhibited contrary regioselectivity pat-
terns; i.e., the silyl group prefers to be on R-position and
tert-butyl group on β-position (1c, 2c vs 1e). Thestructureof
For reaction optimization, we chose commercially avail-
able 1-Boc-3-azetidinone and 3-octyne as model sub-
strates. Gratifyingly, a combination of Ni(COD)2 and
a variety of monodentate as well as bidentate ligands
effected the desired cycloaddition. However, PPh3 ligand
proved to be optimal in our case.10 A report recently
appeared with a similar finding that the combination of
Ni(0) and PPh3 catalyzes the coupling of azetidinones and
alkynes.11 However, in contrast to their findings, we found
that the cycloaddition of alkyne and 3-azetidinones pro-
ceeds with lower catalyst loading (5 mol % rather than
10ꢀ20mol %), lowerligandloading (10mol % ratherthan
30ꢀ80 mol %), at lower temperatures (60ꢀ100 °C rather
than 90ꢀ110 °C), and in shorter times (6 h rather than 17 h).
Figure 1. Investigation of protecting groups on “N” of azetidi-
nones. Reaction conditions: azetidinone (1 equiv, 0.2 M),
3-octyne (1.5 equiv), 6 h. Isolated yields.
Several azetidinones bearing different N-protecting
groups were prepared and investigated. The tert-butoxy-
carbonyl- and tosyl-azetidinones could be converted
to piperidone products in excellent yields (Figure 1).
However, the use of a benzhydryl protecting group did
not lead to the desired cycloadduct under our optimized
reaction conditions. Notably, the reaction of 3-octyne and
N-Ts-azetidinone proceeded smoothly under our optimized
Figure 2. Ni-catalyzed coupling of azetidinones and alkynes. Meth-
od A (for 1bꢀag except 1d): 5 mol % Ni(COD)2, 10 mol % PPh3,
toluene, 60 °C, azetidinon (1 equiv, 0.2 M), alkyne (1.5 equiv).
Method B (for 1d and 1hꢀ1o): 5 mol % Ni(COD)2, 10 mol % PPh3
toluene, 100 °C, azetidinone (1 equiv, 0.2 M), alkyne (3.0 equiv and
slow addition). Isolated yield. Regioselectivty (denoted in
parentheses) was calculated by NMR of crude reaction mixture.
(8) Murakami, M.; Amii, H.; Ito, Y. Nature 1994, 370, 540.
(9) (a) Murakami, M.; Ashida, S.; Matsuda, T. J. Am. Chem. Soc.
2005, 127, 6932. (b) Murakami, M.; Ashida, S.; Matsuda, T. Tetrahedron
2006, 62, 7540.
(10) A provisional patent for this synthetic technology was filed in
August, 2011 (U-5169).
(11) Ho, K. Y. T.; Aıssa, C. Chem.;Eur. J. 2012, 18, 3486.
¨
Org. Lett., Vol. 14, No. 8, 2012
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2c was unambiguously determined by single crystal X-ray
crystallography (Figure 3).
couples with azetidinone regioselectively (1d). Interest-
ingly, these results are in contrast to the reactivity of
cyclobutanones, which fail to react with terminal alkynes
as well as sterically hindered alkynes.9 Stannyl piperidine
(1f) can also be obtained regioselectively in excellent yields
when tributylstannyl-methyl alkyne was employed as a
substrate. The use of1,3-enyne led to selective formation of
vinyl-piperidine (1g) with good regioselectivity. The reac-
tion is not limited to alkyl substituted alkynes, as diphenyl
acetylene can also be successfully coupled with azetidinone
to afford the piperidine (1h).11,12 However, these alkynes
were less reactive than alkylꢀalkyl alkynes, and higher
temperature (100 °C) was necessary to effect the desired
cycloaddition.13 The mixed alkynes (i.e., arylꢀalkyl alkynes)
also react to yield the piperidine (1iꢀ1k) in a regioselective
fashion. Retention of regioselectivity was observed even
when the electronics on the aryl ring of arylꢀalkyl alkynes
were perturbed (1j, 1k). The extremely challenging arylꢀ
silyl alkynes afforded the product (1l) in very good yields
and excellent regioselectivity, for the desired cycloadduct
was observed. Furanyl (1m) as well as thiophenyl (1n)
piperidine skeleton can also be easily accessed. Interest-
ingly, when stannyl-phenyl alkyne is employed, the pro-
duct (1o) is obtained where the stannyl group is on the
R-carbon. Thus, the aryl group, instead of the large stannyl
group, seems to have a stronger affect on the regio-
selectivity.
Figure 3. Ortep diagram of 2c.
Scheme 2. Proposed Mechanism of Cycloaddition
Because of recent interest in macrocyclic heterocycles,14
we subjected the cyclododecyne p under our reaction
conditions. Gratifyingly, excellent yield of the piperidine
product (1p) was obtained (eq 2).
The regioselective outcome of the reaction may be
explained on the basis of mechanism shown in Scheme 2.
Initially, oxidative coupling between the alkyne and the
carbonyl of the azetidinone occurs. Two intermediates, A
or B, are possible. However, metallacycle A is favored over
metallacycle B since the regioselectivity of A positions the
RL away from the quaternary center. Intermediate A
undergoes β-carbon elimination to form a seven-membered
nickelacycle, which undergoes subsequent reductive elim-
ination to afford the piperidine product.
To gain insight into the migratory aptitude of a 2-
substituted azetidinone, we prepared 2-benzyl-3-Boc-
azetidinone (4) from Boc-protected phenylalanine amino
acid. When we subjected substituted azetidinone 4 to our
standard reaction conditions, regioselective formation of
the piperidine product (4a) with complete retention of
enantioselecitivity (>99% ee) was obtained (eq 3). This
observation reveals the preference for the migration of less
Terminal alkynes are one of the most challenging
substrates because of their rapid oligomerization. After
a brief screening, we successfully incorporated terminal
alkynes in our cycloaddition. That is, tert-butyl acetylene
(13) The reaction can also be performed with less alkyne (i.e.,
1.5 equiv); however, consistently excellent conversions and yields were
obtained in short reaction times with 3.0 equiv of aryl substituted
alkynes.
~
(12) A trace of amount of an unidentified side product was formed.
(14) Bonaga, L. V. R.; Zhang, H.-C.; Moretto, A. F.; Ye, H.;
This side product is possibly an R-alkenylation product, which has been
observed by Aıssa and co-workers (see ref 11).
¨
Gauthier, D. A.; Li, J.; Leo, G. C.; Maryanoff, B. E. J. Am. Chem.
Soc. 2005, 127, 3473.
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Org. Lett., Vol. 14, No. 8, 2012

substituted β-carbon of azetidinone on the metal (Ni)
center.
Inconclusion, we havedeveloped aNi-catalyzedmethod
for the [4 þ 2]-cycloaddition reaction of azetidinones and
alkynes. This reaction mechanism includes an interesting
CꢀC bond cleavage that ultimately affords 3-piperidone
products. Reaction conditions are both mild and practical
and afford the N-heterocycles in excellent yields. Impor-
tantly, minimal side products such as CꢀH activation
products are formed.
Acknowledgment. The NSF (0911017) is acknowledged
for financial support. We thank Professor Sigman of the
University of Utah for the use of a chiral SFC-instrument.
We thank Dr. J. Muller and Dr. Atta Arif (both of the
University of Utah) for providing HRMS and X-ray
crystallographic data, respectively.
Further functionalization of the piperidine skeleton
is also possible. The carbonyl moiety can be selectively
reduced to the alcohol (1a0) using NaBH4/CeCl3 (eq 4). No
loss of yield was observed for this two-step one-pot pro-
tocol. Similarly, ketone and carbamate can be reduced
using LAH and the hydroxylated N-methyl piperidine (1l0)
can be accessed in good yields (eq 5).
Supporting Information Available. Experimental de-
tails, 1H and 13C NMR spectra, and crystal structure data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
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