Enantioselective Cu-catalyzed decarboxylative propargylic amination of propargyl carbamates

Article abstract of DOI:10.1016/j.tetlet.2014.02.030

A copper-catalyzed asymmetric propargylic amination with a chiral ketimine P,N,N-ligand that proceeds via decarboxylation of propargyl carbamates has been developed. The reaction can be performed under the mild condition for a broad range of substrates, providing the corresponding propargylic amines in high yields and with up to 97% ee. This reaction represents a new and facile access to optically active propargylic amines.

Full text of DOI:10.1016/j.tetlet.2014.02.030

Tetrahedron Letters 55 (2014) 2033–2036
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Tetrahedron Letters
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Enantioselective Cu-catalyzed decarboxylative propargylic amination
of propargyl carbamates
Yuan Zou a,b, Fu-Lin Zhu b, Zheng-Chao Duan c, Ya-Hui Wang b, De-Yang Zhang b, Zhong Cao a,
Zhuo Zheng b, Xiang-Ping Hu b,
⇑
a School of Chemistry and Biological Engineering, Changsha University of Science and Technology, Changsha 410004, China
b Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
c School of Chemical and Environmental Engineering, Hubei University for Nationalities, Enshi 445000, Hubei, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A copper-catalyzed asymmetric propargylic amination with a chiral ketimine P,N,N-ligand that proceeds
via decarboxylation of propargyl carbamates has been developed. The reaction can be performed under
the mild condition for a broad range of substrates, providing the corresponding propargylic amines in
high yields and with up to 97% ee. This reaction represents a new and facile access to optically active
propargylic amines.
Received 13 December 2013
Revised 7 February 2014
Accepted 13 February 2014
Available online 20 February 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Copper
Asymmetric catalysis
Decarboxylation
Propargylic amination
Propargyl carbamate
Chiral propargylic amines are widely used as intermediate
products in the preparation of biologically active compounds and
polyfunctional amino derivatives.1 Among various methods for
the synthesis of these compounds,2 catalytic asymmetric propargy-
lic amination should be one of the most attractive strategies.3
Although great progress has been made in the transition-metal cat-
alyzed propargylic substitution in the past decades,4 the synthesis
of chiral propargylic amines via the catalytic asymmetric propargy-
lic amination is still highly limited. In 1994, Murahashi and
co-workers5 found that propargylic amines could be obtained via
the copper-catalyzed propargylic amination of propargylic esters
with various amines, which sets the stage for the development of
an asymmetric version. In 2008, van Maarseveen and co-workers6
and Nishibayashi and co-workers7 independently reported the first
copper-catalyzed asymmetric propargylic amination of propargylic
acetates with primary amines and secondary amines, respectively.
Following them, some copper-catalyzed asymmetric propargylic
aminations have been reported.8 Despite these advances, the
development of a new strategy for the catalytic asymmetric syn-
thesis of optically active propargylic amines remains a highly
desirable and challenging task.
Very recently, we have reported the first copper-catalyzed
asymmetric decarboxylative propargylic alkylation of propargyl
b-ketoesters.9 In this method, the loss of CO2 replaces the need
to selectively prepare preformed enolate equivalents, and both
the nucleophile and the electrophile are formed in situ in catalytic
concentration. The reaction could be performed under the mild
condition, and proceeded in highly enatioselective form. We envis-
aged that this strategy should also provide an ideal solution for the
synthesis of optically active propargylic amines if a propargyl car-
bamate is employed as the substrate instead of propargyl b-ketoes-
ter (Scheme 1). As
a result, herein we described the first
enantioselective copper-catalyzed decarboxylative propargylic
amination of propargyl carbamates with a tridentate ketimine
P,N,N-ligand, in which excellent performance could be achieved
(Fig. 1).
The corresponding propargyl carbamates can be easily prepared
by the reaction of carbamic chlorides with various substituted
O
Cu +
O
O-
CO2
O
Ph
.
.
[Cu]
?
N
*
N
O
N
O
Ph
O
Ph
1aa
2aa
⇑
Corresponding author. Tel.: +86 411 84379276; fax: +86 411 84684746.
E-mail address: xiangping@dicp.ac.cn (X.-P. Hu).
Scheme 1. General reaction scheme for Cu-catalyzed asymmetric decarboxylative
propargylic amination.
http://dx.doi.org/10.1016/j.tetlet.2014.02.030
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

2034
Y. Zou et al. / Tetrahedron Letters 55 (2014) 2033–2036
Table 2
Cu-catalyzed decarboxylative propargylic amination of carbamates: scope of
N
N
propargyl moietiesa
PPh2
PPh2
O
O
N
PPh2
O
N
N
Fe
O
R1
Cu(OAc)2.H2O (5 mol %)
L5
Ph
Ph
N
*
(S)-
(5.5 mol %)
Ph-pybox (L2)
(Rc,Sp)-L3
(S)-BINAP (L1)
N
O
R1
Et3N (1.2 equiv)
MeOH, 0 oC, 12 h
O
Ph
1aa-al
2aa-al
N
N
N
Yieldb (%)
eec (%)
N
Entry
Substrate
Product
PPh2
L4
(R)-
PPh2
L5
(S)-
1
2
3
4
5
6
7
8
9
1aa: R1 = Ph
2aa
2ab
2ac
2ad
2ae
2af
2ag
2ah
2ai
96
91
90
93
95
92
94
93
92
95
90
—
94
95
96
94
92
94
94
96
83
92
89
1ab: R1 = 2-ClC6H4
1ac: R1 = 3-ClC6H4
1ad: R1 = 4-ClC6H4
1ae: R1 = 4-FC6H4
1af: R1 = 4-BrC6H4
1ag: R1 = 4-CF3C6H4
1ah: R1 = 4-CH3C6H4
1ai: R1 = 4-CH3OC6H4
1aj: R1 = 2-naphthyl
1ak: R1 = thienyl
1al: R1 = Me
Figure 1. Ligands for Cu-catalyzed decarboxylative propargylic amination.
O
Ph
O
OH
Et3N, DMAP
N
O
N
Cl
+
Ph
O
O
CH2Cl2, 0 oC-rt
3
4
1aa
10
11
12
2aj
2ak
2al
d
Scheme 2. Synthesis of propargyl carbamate 1aa.
—
a
Reaction conditions: 1 (0.5 mmol), Cu(OAc)2ÁH2O (0.025 mmol, 5 mol %), (S)-L5
(0.0275 mmol, 5.5 mol %), Et3N (0.6 mmol, 1.2 equiv), 2 mL of MeOH, 0 °C, 12 h.
b
Yield of isolated product.
The ee values were determined by HPLC analysis (for 2aa–ah: chiralcel OJ-H,
prop-2-yn-1-ols, as exemplified by the synthesis of 1-phenylprop-
2-yn-1-yl morpholine-4-carboxylate (1aa) in Scheme 2.
c
n-hexane/i-PrOH = 95:5, 0.8 mL/min, 254 nm, 40 °C; for 2ai and 2ak: chiralpak
AD-H, n-hexane/i-PrOH = 98:2, 0.8 mL/min, 254 nm, 40 °C; for 2aj: chiralpak AD-H,
n-hexane/i-PrOH = 95:5, 0.8 mL/min, 254 nm, 40 °C).
At the outset of our studies on the copper-catalyzed asymmetric
decarboxylative propargylic amination, 1-phenylprop-2-yn-1-yl
morpholine-4-carboxylate (1aa) was selected as the model sub-
strate for the optimization of reaction conditions, and the results
are summarized in Table 1. Initially, ligand effect was investigated,
and ligands including BINAP (L1),10 Ph-pybox (L2),11 and P,N,N-li-
gand (L3–L5),9,12 that have proved to be efficient in the Cu-cata-
lyzed asymmetric propargylic substitution, were examined. The
reaction was conducted with 0.5 mmol of 1aa, 5 mol % of the cop-
per catalyst prepared in situ from Cu(CH3CN)4BF4 and chiral ligand,
and 1.2 equiv of Et3N in 2 mL of MeOH at room temperature for
12 h. The result disclosed that the structure of ligand had a signif-
icant influence on the reactivity and enantioselectivity, although
the desired propargylic amine 2aa could be obtained in all cases
d
Not determined because of low conversion.
(entries 1–5). Thus, with BINAP (L1) and ferrocenyl P,N,N-ligand
L3, the reaction provided 2aa in moderate yield and with very
low enantioselectivity (entries 1 and 3). By use of tridentate N-li-
gand, Ph-pybox (L2), good yield but with low enantioselectivity
was achieved (entry 2). The result indicated that 1-phenylethyl-
amine-derived tridentate P,N,N-ligands L4 and L5 were highly
efficient to this reaction with the ketimine ligand L5 being optimal
in terms of the yield and the enantioselectivity (entries 4 and 5).
The following investigation on copper salt showed a dramatic ef-
fect on the reactivity and enantioselectivity (entries 5–10), and
Table 1
Optimization of asymmetric Cu-catalyzed decarboxylative propargylic amination of 1-phenylprop-2-yn-1-yl morpholine-4-carboxylate (1aa)a
O
O
Ph
[Cu] (5 mol %)
L* (5.5 mol %)
N
*
N
O
Ph
reaction conditions
O
1aa
2aa
Entry
[Cu]
Ligand
Base
Solvent
Temp (°C)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4ClO4
CuCl
L1
L2
L3
L4
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
—
DBU
iPr2NEt
Et3N
Et3N
Et3N
Et3N
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
CH2Cl2
THF
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0
51
92
50
91
90
86
60
65
87
96
56
73
91
85
83
80
96
<5
35
10
84
88
82
45
73
90
92
59
15
88
31
10
15
94
CuI
Cu(OTf)2
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
toluene
MeOH
a
b
c
Reaction conditions: 1aa (0.5 mmol), [Cu] (0.025 mmol, 5 mol %), L⁄ (0.0275 mmol, 5.5 mol %), base (0.6 mmol, 1.2 equiv), 2 mL of solvent, indicated temperature, 12 h.
Isolated yields.
The ee values were determined by HPLC analysis (chiralcel OJ-H, n-hexane/i-PrOH = 95:5, 0.8 mL/min, 254 nm, 40 °C).

Y. Zou et al. / Tetrahedron Letters 55 (2014) 2033–2036
2035
Cu(OAc)2ÁH2O was found to be the best choice (entry 10). The addi-
tion of a base was crucial for this reaction, and poor performance
was observed in its absence (entry 11). With other base additives
at the different positions of the phenyl ring gave similar outcomes
(entries 2–4). It appeared that the electronic properties of the sub-
stituent at the para position of the phenyl ring also showed little
influence on the reactivity and enantioselectivity (entries 4–8).
An exception was the substrate 1ai with a methoxy group at the
para position of the phenyl ring, which led to somewhat decreased
enantioselectivity of 83% ee (entry 9). 2-Naphthyl substrate 1aj
served well for this reaction, giving the corresponding chiral amine
2aj in 95% yield and with 92% ee (entry 10). 2-Thienyl substrate
1ak also proved to be a suitable reaction partner, providing 2ak
in 90% yield and with 89% ee (entry 11). However, the present
catalytic system showed less efficiency to aliphatic substrate
(1al) (entry 12), which is consistent with the observation in the
Cu-catalyzed asymmetric propargylic substitution.8
We also investigated the reaction of propargyl carbamates bear-
ing various amino moieties. The results in Table 3 indicated that a
variety of tertiary carbamates including those derived from cyclic
and acyclic amines undergo the decarboxylative coupling under
the optimized reaction condition, providing the corresponding
tertiary propargylic amines in good yields and with high enanti-
oselectivities (entries 1–5). The reaction also tolerated a secondary
carbamate. Thus, 1-phenylprop-2-yn-1-yl phenylcarbamate 1ga
led to N-(1-phenylprop-2-yn-1-yl)aniline 2ga in 93% yield and
with 82% ee (entry 6).
i
such as DBU and Pr2NEt, lower reactivity and enantioselectivity
were achieved in comparison with Et3N (entries 12 and 13). The ef-
fect of the solvent was also investigated, and an obvious solvent
dependency was observed. Except in MeOH, all reactions in other
solvents such as CH2Cl2, THF, and toluene furnished the desired
propargylic amine 2aa in low enantioselectivity albeit good yield
(entries 14–16). This is different with those observed on the corre-
sponding decarboxylative propargylic alkylation of propargyl
b-ketoesters, in which no obvious solvent influence was observed.9
By lowering the reaction temperature to 0 °C, the enantioselectiv-
ity could be further increased to 94% ee without loss of the yield
(entry 17).
Under the optimized reaction conditions (Table 1, entry 17),13
we next investigated the effect of the propargyl moiety of
propargyl carbamates on the copper-catalyzed asymmetric decarb-
oxylative propargylic amination, and typical results are shown in
Table 2. To our delight, the reaction worked efficiently for all of
phenyl-substituted substrates (entries 1–9). The results indicated
that the position of the substituent on the phenyl ring had little
effect in the reaction. Thus, all three substrates with a Cl group
In conclusion, we have developed the first Cu-catalyzed
asymmetric decarboxylative propargylic amination of propargyl
carbamates, furnishing a variety of chiral propargylic amines in
good yields and with high enantioselectivities. The reaction can
be performed under the mild conditions with a broad substrate
spectrum, which represents a new and complementary strategy
for the catalytic asymmetric synthesis of optically active propargy-
lic amines. The further development and application of this reac-
tion, as well as study of the mechanism, is underway in our
laboratory.
Table 3
Cu-catalyzed decarboxylative propargylic amination of carbamates: scope of amino
moietiesa
Cu(OAc)2.H2O (5 mol %)
R2
R3
O
Ph
R2
L5
N
*
(S)-
(5.5 mol %)
N
O
R3
Ph
Et3N (1.2 equiv)
MeOH, 0 oC, 12 h
1ba-ga
2ba-ga
Entry
1
Substrate
Product
Yieldb (%)
eec (%)
93
O
N
Ph
O
N
95
94
92
Acknowledgments
*
Ph
1ba
2ba
Support for this research was from the Dalian Institute of
Chemical Physics (CAS). The authors also thank Professor Hong-
chao Guo for providing several chiral ligands (synthesized in the
National Key Technologies R&D Program of China, 2012BAK25B03,
CAU). Dr. Duan Z.-C. acknowledges the National Natural Science
Foundation of China (No. 21262011) for financial support.
O
Ph
N
N
O
2
3
91
97
*
Ph
1ca
2ca
O
Ph
N
O
N
*
Supplementary data
Ph
1da
2da
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.02. 030.
O
O
Ph
N
N
4
93
84
*
1ea
References and notes
Ph
2ea
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a
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c
The ee values were determined by HPLC analysis (for 2ba: chiralcel OJ-H,
n-hexane/i-PrOH = 95:5, 0.8 mL/min, 254 nm, 40 °C; for 2ca: chiralcel OJ-H, n-
hexane/i-PrOH = 90:10, 0.8 mL/min, 254 nm, 40 °C; for 2da–fa: chiralcel OD-H,
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hexane/i-PrOH = 98:2, 0.6 mL/min, 254 nm, 40 °C).
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with EtOAc (5 mL Â 2). The combined extracts were washed with brine, dried
over anhydrous Na2SO4, and concentrated under vacuum. The residue was
then purified by silica gel chromatography, and was submitted to ee analysis
by HPLC with a chiral column.
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