Enantioselective copper-catalyzed propargylic amination

Article abstract of DOI:10.1002/anie.200705264

(Chemical Equation Presented) A proper copper catalyst with a chiral pyridine-2,6-bisoxazoline (pybox) ligand was used to convert a variety of propargylic acetates with aromatic side chains (R = Ar) into their amine counterparts in high yield and with good selectivity (up to 88% ee). The resulting chiral propargylic amines can be elaborated further into P,N ligands (see scheme; DIPEA = diisopropylethylamine).

Full text of DOI:10.1002/anie.200705264

Angewandte
Chemie
DOI: 10.1002/anie.200705264
Asymmetric Catalysis
Enantioselective Copper-Catalyzed Propargylic Amination**
Remko J. Detz, Marille M. E. Delville, Henk Hiemstra, and Jan H. van Maarseveen*
Propargylic amines are versatile building blocks and inter-
mediates for organic synthesis. During the last decade,
considerable progress has been made in the asymmetric
synthesis of chiral propargylic amines. The most important
synthetic route is still based on the enantioselective addition
of terminal alkynes to imines.[1] To broaden the scope and
applicability of methods for the preparation of optically active
propargylic amines, we envisioned the direct functionaliza-
tion of the propargyl moiety. Propargylic substitution with
transition metals is a poorly developed reaction type, in
contrast to allylic substitution. A fundamental substitution
reaction of propargylic alcohol derivatives is the Nicholas
reaction, which occurs via a stoichiometric cobalt–alkyne
complex.[2] Nishibayashi et al. reported a ruthenium-cata-
lyzed process in which a wide variety of nucleophiles, such as
alcohols, amides, thiols, phosphines, and amines, can be used.
Nevertheless, amines of high basicity were not applicable
under these conditions.[3]
mercially available pybox ligands 2–5 were encouraging
(Table 1). In all cases, the propargylic amine 10a was obtained
in high yield, and asymmetric induction was observed,
although to a low extent.
Table 1: Survey of ligands for the propargylicamination. [a]
Although successful with alcohols and satisfactory with
amides, a TiCl4-mediated substitution of propargylic esters
did not proceed with primary and secondary amines.[4]
Murahashi and co-workers demonstrated the highly efficient
preparation of several propargylic amines by a copper-
catalyzed substitution reaction.[5] Rhenium, gold, rhodium,
and iron complexes were also reported recently to be effective
catalysts for propargylic amination.[6] Remarkably, enantio-
selective examples of propargylic substitution reactions are
rare,[7] and to our knowledge no asymmetric amination
reaction has been reported to date. Inspired by the results
of Murahashi and co-workers, we describe herein an enantio-
selective version of the copper-catalyzed propargylic amina-
tion of propargylic acetates.
In a first attempt to induce enantioselectivity in the
amination of racemic 1-phenylprop-2-ynyl acetate (9a), we
screened a selection of copper–pyridine-2,6-bisoxazoline
(pybox) complexes. Metal complexes of chiral pybox ligands
are well established in asymmetric catalysis.[8] We decided to
use o-anisidine in this study because of its function as a
capped primary amine.[9] Initial experiments with the com-
Entry
Ligand
Yield [%]
Config.[b]
ee [%]
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
94
93
97
74
99
97
97
97
R
R
R
R
S
S
S
S
25
17
12
28
42
76
19
61
[a] Reaction conditions: 9a (0.20 mmol), o-anisidine (0.40 mmol),
DIPEA (0.80 mmol), CuI (0.02 mmol), and the ligand (0.024 mmol)
were stirred in methanol (2 mL) at 258C. Reactions were complete within
1 h. [b] The absolute configuration was determined by comparison of the
optical rotation with a literature value.[9]
We envisaged that modification of the ligand would be
necessary to improve the enantioselectivity. Gratifyingly, the
use of ligand 6, which has aromatic substituents in a cis
relationship at the 4- and 5-positions of the two oxazoline
rings, led to higher enantioselectivity. The use of ligand 1, 7, or
8 did not lead to an improvement in this result. The synthesis
of ligands 1 and 6–8 is well documented, and 6, in particular,
was obtained readily in only two steps from commercially
available compounds.[10]
[*] R. J. Detz, M. M. E. Delville, Prof. Dr. H. Hiemstra,
Dr. J. H. van Maarseveen
Van’t Hoff Institute for Molecular Sciences
Biomolecular Synthesis
University of Amsterdam
Nieuwe Achtergracht 129, 1018 WS Amsterdam (The Netherlands)
Fax: (+31)20-525-5670
An optimization study with ligand 6 revealed that other
copper salts, such as [Cu(CH3CN)4]PF6, CuOTf·benzene, and
Cu(OAc)2, gave similar results, although CuI was slightly
superior with respect to the selectivity (Table 2, entries 1–3).
High enantioselectivity and a high reaction rate were only
observed with polar protic solvents, the best results with
E-mail: jvm@science.uva.nl
Homepage: http://www.science.uva.nl/hims-bms
[**] The National Research School Combination—Catalysis (NRSC-C) is
gratefully acknowledged for financial support of this project.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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[a]
Table 2: Effect of the reaction conditions on the propargylic amination of
9a with the pybox ligand 6.[a]
Table 3: Propargylicamination with various propargylicacetates.
Entry
Catalyst
Base
Solvent
t
[h]
Yield
[%]
ee
[%]
1
2
3
4
5
6
7
8
9
10
11[b]
12[c]
13[d]
[Cu(CH3CN)4]PF6
CuOTf·benzene
Cu(OAc)2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
–
MeOH
MeOH
MeOH
toluene
CH2Cl2
THF
1
76
99
99
99
97
99
99
93
2
74
73
73
21
34
36
60
56
7
33
82
85
86
Entry
R1, R2
R3
Product
Yield
[%]
ee[b]
[%]
1.5
1.5
25
25
29
1
2
3
4
5
6
7
8
9
Ph, H
2-MeOC6H4
2-MeOC6H4
2-MeOC6H4
2-MeOC6H4
2-MeOC6H4
2-MeOC6H4
2-MeOC6H4
2-MeOC6H4
2-MeOC6H4
2-MeOC6H4
2-MeOC6H4
4-MeOC6H4
Ph
10a
10b
10c
10d
10e
10 f
10g
10h
10i[c]
10j
10k
10l
10m
10n
10o
97
97
84
91
88
80
91
96
62
27
76
93
94
87
n.r.
85 (99)
83
80
88
79
4-MeOC6H4, H
4-CF3C6H4, H
2,4-Me2C6H3, H
2,4-Cl2C6H3, H
2-pyridyl, H
1-naphthyl, H
2-naphthyl, H
cinnamyl, H
iPr, H
pentyl, H
Ph, H
Ph, H
Ph, H
EtOH
1.5
4
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DBU
0.5
0.5
3
24
48
74
Cs2CO3
DIPEA
DIPEA
DIPEA
8
85 (99)
86 (99)
57
40
13
78
87
86
–
99
97
99
10[d]
11[d]
12
13
14
15
[a] Reaction conditions: 9a (0.20 mmol), o-anisidine (0.40 mmol), the
base (0.80 mmol), the Cu salt (0.02 mmol), and 6 (0.024 mmol) were
stirred in the indicated solvent (2 mL) at 258C. [b] The reaction was
performed at 08C. [c] The reaction was performed at À208C. [d] The
reaction was performed at À408C. Tf=trifluoromethanesulfonyl.
4-CF3C6H4
2-MeOC6H4
Ph, Ph
[a] The propargylicacetate (0.20 mmol), the amine (0.40 mmol), DIPEA
(0.80 mmol), CuI (0.02 mmol), and 6 (0.024 mmol) were stirred in
methanol (2 mL) at À208C. [b] The ee value after recrystallization is
given in brackets. [c] Product 10i was accompanied by (E)-2-methoxy-N-
(1-phenylpent-2-en-4-ynyl)aniline (24%, 16% ee). [d] The reaction was
performed at 408C. n.r.=no reaction.
methanol.[11] The addition of a base seemed to be crucial in
terms of both the yield and the selectivity (Table 2, entry 8).
At a first glance, the base appeared to be only a rate-
accelerating component; however, in its absence the enantio-
selectivity dropped by 20%. Stronger bases, such as 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) or cesium carbonate,
had a detrimental effect on both the yield and the selectivity
of the reaction (Table 2, entries 9 and 10). The best results
were obtained with tertiary amines, such as diisopropylethyl-
amine (DIPEA). At lower temperatures the enantioselectiv-
ity was improved further at the expense of an increase in
reaction time (Table 2, entries 11–13).
Having established an optimal reaction protocol, we
explored the scope and the generality of the method. All
substrates with an aromatic group at the propargylic position
were converted into the corresponding amine in high yield
(80–97%) and with high enantioselectivity (74–88% ee;
Table 3). Slightly higher ee values were observed with more-
electron-rich aromatic substrates (Table 3, compare entries 2
and 3, and entries 4 and 5). The reaction became more
complex when the cinnamyl derivative 9i was used (Table 3,
entry 9). In this case, two major products were isolated: 10i,
with the amino group at the propargylic position as expected
(62%, 57% ee), and an analogue in which the amino
substituent is located at the alternative allylic position next
to the phenyl moiety (24%, 16% ee).
atom.[5] Highly enantiomerically pure compounds were
obtained by the recrystallization of some of the crude
products (Table 3, entries 1, 7, and 8).
On a larger scale (with 5 mmol of the substrate; see the
Experimental Section), the reaction proceeded in a similar
manner, even with a lower catalyst loading (0.05 equiv). The
optical purity of the product was increased through two
recrystallization steps. The colorless crystals that formed were
identified as the racemate; the propargylic amine 10a was
obtained in almost enantiomerically pure form (99% ee) from
the mother liquor. Solidification of the mother liquor and
recrystallization provided the optically pure enantiomer in
46% yield.
The mechanism of this reaction is still unclear. Never-
theless, we propose a catalytic cycle based upon our own
experimental results and other data (Scheme 1). In the first
step, the copper complex probably forms a p complex with
the alkyne (step A). The formation of this p complex lowers
the pKa value of the acetylenic hydrogen atom, as described
previously by Fokin and co-workers.[12] Deprotonation with a
base gives the copper acetylide (step B); hence the necessity
of the terminal acetylenic hydrogen atom. This intermediate
loses the acetate group through an SN1-type mechanism
(step C), as also proposed by Murahashi and co-workers.[5]
The resulting electrophilic intermediate is stabilized by
resonance involving the Cu complex and attacked by the
amine nucleophile (step D). The regio- and enantioselectivity
of the reaction is most probably determined at this stage
through the blocking of one side of the cationic intermediate
by the copper–pybox complex. After proteolysis, the product
is released to complete the catalytic cycle (step E).
Aliphatic substrates were less reactive, and a higher
temperature (408C) was necessary for sufficient conversion.
The catalytic process seems to be unsatisfactory with aliphatic
substrates: Only low enantioselectivity was observed
(Table 3, entries 10 and 11). Similar results to those with o-
anisidine were obtained when electron-rich or electron-poor
anilines were used as the nucleophile. As reported by
Murahashi and co-workers,[5] no reaction occurred with an
internal acetylene (Table 3, entry 15). This result serves as
evidence for the necessity of the terminal acetylenic hydrogen
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Scheme 1. Proposed catalytic cycle for the copper-catalyzed propargylic
amination of propargylicacetates.
Scheme 3. Synthesis of the chiral ClickPhine ligand 12 and the IrI
complex 13. c od=1,5-cyclooctadiene, BArF =tetrakis[3,5-bis(trifluoro-
This research project originated from the search for a
building block for the synthesis of a chiral ClickPhine ligand
(Scheme 2). ClickPhines are P,N ligands described recently by
our research group.[13] The key concept of this ligand class is
the use of a triazole ring, which can be prepared readily by the
methyl)phenyl]borate.
pure propargylic amines (> 99% ee) could be obtained by
recrystallization of the products. Furthermore, we demon-
strated the application of these amines as useful chiral
building blocks through the synthesis of an optically active
ClickPhine ligand.
Scheme 2. Structure of ClickPhine ligands. Bn=benzyl.
Experimental Section
Typical procedure: CuI (48 mg, 0.25 mmol) and the pybox ligand 6
(156 mg, 0.30 mmol) were stirred in MeOH (40 mL) for 30 min. The
acetate 9a (0.87 g, 5.0 mmol) was added as a solution in MeOH
(4 mL) to the resulting red mixture, which contained small white
particles, probably of excess ligand. The mixture was cooled to
À188C, and a cooled solution of o-anisidine (1.1 mL, 10 mmol) and
diisopropylethylamine (3.5 mL, 20 mmol) in MeOH (6 mL) was
added. The reaction mixture was stirred for 21 h at À188C, and then
the volatile components were removed by evaporation. Column
chromatography of the residue on silica gel (CH2Cl2/petroleum ether
1:2) gave 10a (1.15 g, 97%, 85% ee) as a yellow oil. After two
recrystallization steps (EtOAc/petroleum ether, heptane), 10a
(0.55 g, 46%) was obtained as a single enantiomer (> 99.5% ee).
copper-catalyzed 1,3-dipolar cycloaddition of alkynes with
azides, as a nitrogen donor to a metal. By this approach,
ligands can be synthesized and functionalized readily. To
retain the simplicity of the synthesis and modification of these
ligands, the route to a chiral building block should be
straightforward and short. We envisaged that a chiral
propargylic amine would be a suitable source of chirality.
Having established a practical protocol for the synthesis of
chiral propargylic amines, we investigated the synthesis of a
chiral ClickPhine ligand. The chiral propargylic amine 10a
was converted readily into the corresponding triazole 11
through CuI-catalyzed 1,3-dipolar cycloaddition. Indeed, the
transformation of the acetate 9a into 11 via the amine 10a
could even be carried out in one pot (Scheme 3). A single
enantiomer of 11 was obtained through a single recrystalliza-
tion step. The amine 11 was deprotonated with n-butyllithium
and coupled with chlorodiphenylphosphane to give the
ClickPhine ligand 12 in good yield. The formation of the IrI
complex 13 with ligand 12 gave some initial insight into the
coordination behavior of this class of ligands. Enantioselec-
tive catalysis with the newly developed chiral ClickPhine
ligand is currently under investigation.
Received: November 15, 2007
Published online: February 18, 2008
Keywords: amination · asymmetriccatalysis · P,N ligands ·
.
propargylicamines · pybox ligands
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In conclusion, we have described the first example of an
enantioselective copper-catalyzed propargylic amination
reaction. Propargylic amines were prepared in high yields
and high optical purities from a variety of readily available
propargylic acetates. The procedure is practical and does not
require the exclusion of air and moisture. Enantiomerically
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Communications
[6] a) R. V. Ohri, A. T. Radosevich, K. J. Hrovat, C. Musich, D.
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[11] More details of the optimization study can be found in Table 1 of
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