Highly enantioselective access to primary propargylamines: 4-Piperidinone as a convenient protecting group

Article abstract of DOI:10.1021/ol060876w

We report a highly enantioselective, catalytic three-component coupling of aldehydes, alkynes, and 4-piperidone hydrochloride hydrate to afford the corresponding tertiary propargylamines in useful yields. The selective cleavage of the piperidone protectin

Full text of DOI:10.1021/ol060876w

ORGANIC
LETTERS
2006
Vol. 8, No. 11
2437-2440
Highly Enantioselective Access to
Primary Propargylamines:
4-Piperidinone as a Convenient
Protecting Group
Patrick Aschwanden, Corey R. J. Stephenson, and Erick M. Carreira*
Laboratorium fu¨r Organische Chemie, ETH Zurich, CH-8093 Zu¨rich, Switzerland
carreira@org.chem.ethz.ch
Received April 11, 2006
ABSTRACT
We report a highly enantioselective, catalytic three-component coupling of aldehydes, alkynes, and 4-piperidone hydrochloride hydrate to
afford the corresponding tertiary propargylamines in useful yields. The selective cleavage of the piperidone protecting group using either
ammonia/EtOH or a polymer-supported scavenger amine furnishes primary propargylamines.
Propargylamines can serve as versatile building blocks and
high-value-added intermediates for organic synthesis.1 How-
ever, methods that provide reliable and convenient access
to propargylamines are few.2,3 First reported in 1963,4 the
Cu-catalyzed additions of terminal alkynes to in situ gener-
ated iminium ions have recently received increased atten-
tion.5,6 Herein, we document that 4-piperidone can be used
as the amine component in the Cu-catalyzed addition
reactions of terminal alkynes to CdN electrophiles to provide
aldimine adducts chemoselectively in useful yields and
selectivities (eq 1). The fact that 4-piperidones can be
employed in the addition reaction is surprising and leads to
the production of useful building blocks for asymmetric
synthesis. Significantly, we describe that the substituted
4-piperidone can be readily removed, conveniently furnishing
optically active primary, propargylic amines.
(1) For a review, see: Aschwanden, P.; Carreira, E. M. Addition of
Terminal Acetylides to CdO and CdN Electrophiles. In Acetylene
Chemistry: Chemistry, Biology and Material Science; Diederich, F., Stang,
P. J., Tykwinski, R. R., Eds.; Wiley: Weinheim, 2005.
(2) For addition of alkynylides to imines, see: (a) Enders, D.; Schankat,
J. HelV. Chim. Acta 1995, 78, 970. (b) Harwood, L. M.; Vines, K. J.; Drew,
M. G. B. Synlett 1996, 1051. (c) Brasseur, D.; Marek, I.; Normant, J.-F.
Tetrahedron 1996, 52, 7235. (d) Sato, Y.; Nishimata, T.; Mori, M.
Heterocycles 1997, 44, 443. (e) Cossy, J.; Poitevin, C.; Pardo, D. G.; Peglion,
J.-L.; Dessinges, A. Synlett 1998, 3, 251. (f) Courtois, G.; Desre, V.;
Miginiac, L. J. Organomet. Chem. 1998, 570, 279. (g) Florio, S.; Troisi,
L.; Capriati, V.; Suppa, G. Eur. J. Org. Chem. 2000, 65, 3793. (h) Wipf,
P.; Kendall, C.; Stephenson, C. R. J. J. Am. Chem. Soc. 2001, 123, 5122.
(i) For the copper-mediated addition of acetylene gas to N-alkyl imines at
elevated temperatures, see: Rohm & Haas Co. U.S. Patent 2 665 311, 1950.
(3) For representative additions of other carbanions to imines, see: (a)
Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J. Am. Chem. Soc. 1998,
120, 4548. (b) Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121,
268. (c) Hamada, T.; Mizojiri, R.; Urabe, H.; Sato, F. J. Am. Chem. Soc.
2000, 122, 7138. (d) Knudsen, K.; Risgaard, T.; Nishiwaki, N.; Gothelf,
K. V.; Jørgensen, K. A. J. Am. Chem. Soc. 2001, 123, 5843. (e) Porter, J.
R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J. Am. Chem. Soc.
2001, 123, 984. (f) Wipf, P.; Stephenson, C. R. J.; Okumura, K. J. Am.
Chem. Soc. 2003, 125, 14694.
We have recently reported the synthesis of a new class of
P,N-ligands, which we have termed PINAP.7 Our interest
in the chemistry of terminal alkynes8 compelled us to
10.1021/ol060876w CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/05/2006

examine these ligands in the Cu-catalyzed three-component
coupling of alkynes, aldehydes, and secondary amines. We
have observed that the CuI PINAP complexes of (R,R)-1 and
(R,S)-1 catalyze the formation of the propargylamines in 90-
99% ee, which are among the best values obtained to date
(Scheme 1).
benefits from the use of an inexpensive base metal (Cu)
should resort to a subsequent deprotection step involving Pd
catalysis. Thus, we sought alternative secondary amines for
this process that would meet two criteria: (1) propargylamine
formation in high yield and selectivities and (2) subsequent
facile, chemoselective cleavage to give rise to primary
propargylamines.
In a key experiment, commercially available 4-piperidone
hydrochloride hydrate10 was subjected to a suspension of 5
mol % of CuBr, triethylamine, isobutyraldehyde, pheny-
lacetylene, and 4 Å molecular sieves in toluene giving rise
to the corresponding tertiary propargylamine (Table 1). In
Scheme 1. CuBr-Catalyzed Three-Component Coupling
Table 1. Three-Component Coupling Using 4-Piperidone‚HCl
The tertiary propargylamines derived from the aldimines
formed in situ in the condensation of N,N-dibenzylamine,
and aldehyde reagents have a limitation: the selective
cleavage of the N,N-dibenzyl protecting groups cannot be
effected with ease without sacrificing the triple bond.
Consequently, the addition reactions have also been per-
formed with N,N-diallylamine; however, the utility of these
alternative adducts is not without its own limitations because
the enantioselectivities of the products isolated from the
corresponding N,N-diallyl aldimines were at best 78% ee,
and the deprotection could only be effected with Pd catalysts
and a large excess (8 equiv) of allyl scavengers.9 Although
alternative amines have been employed, they all ultimately
rely on the use of a noble metal catalyst (Pd) in the
deprotection. It would seem regrettable that a process that
(4) Brannock, K. C.; Burpitt, R. D.; Thweatt, J. G. J. Org. Chem. 1963,
28, 1462.
(5) (a) Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed.
2002, 41, 2535. (b) Li, C.-J.; Wei, C. Chem. Commun. 2002, 268. (c) Wei,
C.; Li, C.-J. J. Am. Chem. Soc. 2002, 124, 5638. (d) Wei, C.; Li, Z.; Li,
C.-J. Org. Lett. 2003, 5, 4473. (e) Wei, C.; Li, C.-J. J. Am. Chem. Soc.
2003, 125, 9584. (f) Koradin, C.; Gommermann, N.; Polborn, K.; Knochel,
P. Chem.-Eur. J. 2003, 9, 2797. (g) Gommermann, N.; Koradin, C.;
Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 5763.
(6) For the Ir-catalyzed addition of terminal alkynes to iminiums, see:
Fischer, C.; Carreira, E. M. Org. Lett. 2001, 3, 4319.
a Because of its volatility, isobutyraldehyde (1.0 mmol, 2.0 equiv) was
used in slight excess under otherwise identical reaction conditions. b An
equimolar amount of alkyne (0.50 mmol, 1.0 equiv) was used under
otherwise identical reaction conditions. c After desilylation using K2CO3
in MeOH, ee’s were determined by GC or HPLC. d PINAP ligand (R,S)-1
was used. e PINAP ligand (S,S)-1 was used. f Determined by conversion
of the deprotected product to its corresponding MTPA amide.
(7) Kno¨pfel, T. E.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.; Carreira,
E. M. Angew. Chem., Int. Ed. 2004, 43, 5971.
(8) (a) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 1999,
121, 11245. (b) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem.
Soc. 2000, 122, 1806. (c) Boyall, D.; Lopez, F.; Sasaki, H.; Carreira, E. M.
Org. Lett. 2000, 2, 4233. (d) Sasaki, H.; Boyall, D.; Carreira, E. M. Helv.
Chim. Acta 2001, 84, 964. (e) El-Sayed, E.; Anand, N. K.; Carreira, E. M.
Org. Lett. 2001, 3, 3017. (f) Anand, N. K.; Carreira, E. M. J. Am. Chem.
Soc. 2001, 123, 9687. (g) Boyall, D.; Frantz, D. E.; Carreira, E. M. Org.
Lett. 2002, 4, 2605. (h) Diez, R. S.; Adger, B.; Carreira, E. M. Tetrahedron
2002, 58, 8341. (i) Reber, S.; Kno¨pfel, T. F.; Carreira, E. M. Tetrahedron
2003, 59, 6813. (j) Kno¨pfel, T. F.; Carreira, E. M. J. Am. Chem. Soc. 2003,
125, 6054. (k) Fischer, C.; Carreira, E. M. Org. Lett. 2004, 6, 1497. (l)
Kno¨pfel, T.; Zarotti, P.; Ichikawa, T.; Carreira, E. M. J. Am. Chem. Soc.
2005, 127, 9682.
the course of optimization studies, a variety of different
ligands were examined in the reaction conditions described
above revealing that ligand (R,R)-1 afforded the desired
products in the highest ee’s and favorable yields. In addition,
it was found that the complex formed between CuBr and
(9) For the use of bis(2-phenylallyl)amine in the asymmetric addition
of Cu acetylides to iminium ions, see: Gommermann, N.; Knochel, P. Chem.
Commun. 2005, 4175.
(10) To obtain fast conversion, the crystalline 4-piperidone hydrochloride
hydrate had to be crushed to a fine powder.
2438
Org. Lett., Vol. 8, No. 11, 2006

(R,R)-1 was completely soluble in dichloromethane thus
leading to an increase (up to 5-fold) in reaction rate compared
to that using toluene as solvent. This is well worth highlight-
ing, as the reactions reported earlier prescribed long reaction
times (>48 h). To determine the scope and limitations of
the improved protocol, a representative set of aldehydes and
terminal alkynes were subjected to the reaction conditions.
Aside from the necessity of column chromatography,
handling the low molecular weight primary amines proved
difficult. Isolating the product as its hydrochloric acid salt
was an attractive option; however, the desired propargylic
amine salts were inseparable from the piperidone hydro-
chloride. The use of a solid-supported scavenger13 to im-
mobilize the piperidone byproduct was investigated to
streamline the isolation process. Indeed, heating of a mixture
of 2h, amino-methylated polystyrene resin (1.5 equiv),14 and
NH4Cl (1 equiv) in EtOH at 100 °C (sealed tube) resulted
in complete conversion of 2h to the desired primary amine
(Table 2, entry 1). After filtration of the mixture, the solution
Trimethylsilylacetylene was the alkyne of choice in the
three-component coupling as it not only allowed for subse-
quent cleavage to the terminal alkyne but also afforded the
desired propargylamines in good yields and superior enan-
tioselectivities. Subjecting phenylacetylene or 4-phenyl-1-
butyne to the reaction conditions led to diminished ee’s. The
new protocol has been shown to tolerate a variety of different
aldehydes to afford the desired products in useful optical
purity and yields. Volatile aldehydes, such as isobutyralde-
hyde, can be used in excess to consistently obtain optimal
yields. It is noteworthy that n-alkyl aldehydes were excellent
substrates for this method (Table 1, entry 1). They are often
challenging in other asymmetric processes because of low
steric hindrance (leading to low ee’s) and oligomerization
side reactions (leading to low yields). Interestingly, 2-fural-
dehyde was also shown to participate in the three-component
coupling affording the corresponding propargylamine in high
enantiomeric excess. The use of benzaldehyde did not lead
to satisfactory results even under prolonged stirring providing
the desired product in only 22% yield after 48 h.
Table 2. Deprotection Using a Resin-Bound Dienone
Scavengera
entry
amine
R2
Ph
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
product
time (h)
yield (%)
1
2
3
4
5
6
7
2h
2a
ent-2b
2c
2e
5h
5a
5b
5c
5e
5f
5
14
14
14
14
14
14
91
82
81
79
86
71
85
It is interesting to note that the additions are chemoselec-
tive for the aldehyde-derived iminium and that no addition
is observed to either the aldehyde or the ketone. To the best
of our knowledge, there is only one mention in the literature
of the use of N-substituted piperidones as a precursor to
primary amines.11 It was reported that optimal conditions
for deprotection involved the use of excess 2-butylamine.
For the substrates we investigated, this was not the case.
Thus, the application of this method to the deprotection of
the tertiary propargylamines was unsuccessful because of
difficulties in separating the desired primary propargylamine
from 2-butylamine by either chromatography on silica or
bulb-to-bulb distillation. We thus proceeded to examine other
amines and their hydrochloride salts, which could be easily
separated in the end from the desired primary products. We
were particularly interested in the use of ammonia because
it would enhance the practical aspects of the route to primary
amines. In preliminary studies, a suspension of propargy-
lamine 2h, ammonium chloride, and ammonia-saturated
ethanol was stirred at 90 °C in a pressure tube for 14 h (eq
2). Removal of the solvent under reduced pressure afforded
a dark yellow oil which was purified by chromatography on
silica gel (5% MeOH in EtOAc) to furnish the desired
primary propargylamine 4 in 75% yield.12
2f
2g
5g
a A suspension of piperidone (1 equiv), PS-NH2 (1.5 equiv), and NH4Cl
(1 equiv) in EtOH was heated at 100 °C for 14 h, cooled, and filtered.
K2CO3 (1.5 equiv) was added to the filtrate, and the reaction was stirred
for 2-5 h followed by aqueous workup. The organic layer was cooled to
0 °C, treated with a solution of HCl in MeOH, and concentrated. The residue
was dissolved in MeOH, treated with activated charcoal, filtered, and
concentrated to afford the desired amine hydrochloride salts.
was cooled to 0 °C, treated with a solution of HCl in MeOH,
and concentrated to afford 5h. For the corresponding
trimethylsilyl propargylamines (entries 2-7), partial desi-
lylation of the alkyne was observed on treatment with the
(11) Renaud, P.; Betrisey, I. Synth. Commun. 1995, 25, 3479.
(12) Hydrogenation of the triple bond in 4 afforded the known primary
amine 3-amino-2-methyl-5-phenylpentane, which allowed for the assignment
of the absolute configuration obtained in the three-component coupling
reaction. The observed optical rotation for this amine was found to be in
good agreement with the known value for the (R)-enantiomer. See: Son,
Y. C.; Park, C. H.; Koh, J. S.; Choy, N. Y.; Lee, C. S.; Choi, H.; Kim, S.
C.; Yoon, H. S. Tetrahedron Lett. 1994, 35, 3745.
(13) (a) Flynn, D. L.; Crich, J. Z.; Devraj, R. V.; Hockerman, S. L.;
Parlow, J. J.; South, M. S.; Woodard, S. J. Am. Chem. Soc. 1997, 119,
4874. (b) Eames, J.; Watkinson, M. Eur. J. Org. Chem. 2001, 1213. (c)
Ley, S. V.; Baxendale, I. R. Nat. ReV. Drug DiscoVery 2002, 1, 573. (d)
Cork, D.; Hird, N. Drug DiscoVery Today 2002, 7, 56. (e) Handbook of
Reagents for Organic Synthesis: Reagents for High-Throughput Solid-Phase
and Solution-Phase Organic Synthesis; Wipf, P., Ed.; Wiley: Chichester,
2005.
(14) Aminomethylated polystyrene EHL (200-400 mesh, 2.5% cross-
linking with divinylbenzene, loading of 3 mmol/g) was purchased from
Novabiochem.
Org. Lett., Vol. 8, No. 11, 2006
2439

supported amine. An intermediate step was thus introduced
to complete desilylation, and treatment with a solution of
HCl in MeOH and activated charcoal to remove colored
impurities followed by concentration afforded the desired
hydrochloride salts in 71-86% yield.
on a smaller scale, to optically active primary amines without
the need for purification by chromatography. The use of
4-piperidinone as an ammonia equivalent sets the stage for
further investigations in other processes where an ammonia
equivalent may be necessary (such as arene amination and
Strecker), the results of which will be reported as they
become available.
In summary, we have developed a highly enantioselective,
catalytic three-component coupling of aldehydes, alkynes,
and 4-piperidone hydrochloride hydrate using PINAP ligands
and CuBr. The desired tertiary propargylamines are isolated
in useful yields and enantioselectivity. The use of 4-piperi-
done as the amine component not only provides access to a
useful building block but also highlights the exquisite
chemoselectivity of the process. With respect to practicality,
we have shown that the tertiary amine adducts undergo
deprotection when treated with ammonia/ethanol as well as
in the presence of a polymer-supported amine scavenger. The
former method may find use on a larger scale, whereas the
latter offers experimentally convenient access, particularly
Acknowledgment. We thank the ETH for support of this
research in the form of a TH-Gesuch. We are grateful to F.
Hoffmann-LaRoche, Lilly, and Boehringer Ingelheim for
generous support of our research program.
Supporting Information Available: Experimental pro-
cedures and spectral data for all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL060876W
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Org. Lett., Vol. 8, No. 11, 2006