Chiral Cu(II) complex catalyzed enantioselective addition of phenylacetylene to N-aryl arylimines

Article abstract of DOI:10.1016/j.tetasy.2007.11.033

Chiral tridentate N-tosylated aminoimine ligands were used in the Cu(II)-catalyzed enantioselective addition of phenylacetylene to N-aryl arylimines, affording products up to 92% ee.

Full text of DOI:10.1016/j.tetasy.2007.11.033

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2901–2904
Chiral Cu(II) complex catalyzed enantioselective addition
of phenylacetylene to N-aryl arylimines
Bao Liu,a Ling Huang,a Juntao Liu,a Yao Zhong,a Xingshu Lia,* and Albert S. C. Chana,b,
*
aSchool of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou 510006, China
bOpen Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis and
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
Received 14 October 2007; accepted 27 November 2007
Abstract—Chiral tridentate N-tosylated aminoimine ligands were used in the Cu(II)-catalyzed enantioselective addition of phenylacety-
lene to N-aryl arylimines, affording products up to 92% ee.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Cu(I)–pyridyl-bisoxazoline,6 Zr–amino acid derivatives,7
Cu(I)–Quinap,8 Cu(I)–Pinap,9 copper(I)–bisimine10 and
norephedrine derivatives11 have been used for the synthesis
of propargylamines with good to excellent enantioselectiv-
ity. In our study of the asymmetric alkynylation of imines
and their derivatives, we have developed the synthesis of
b,c-alkynyl-a-amino acid derivatives12 and a recyclable
copper(I)–bis(oxazoline) catalyst system for the enantio-
selective addition of alkyne to imines in water with stearic
acid as an additive.13 Recently, we have devised a new class
of chiral tridentate N-tosylated aminoimine ligands, which
were effective in the preparation of propargylamines with
good enantioselectivities and yields.14
The catalytic enantioselective addition of alkynyl reagents
to imines or imine derivatives is an important and challeng-
ing field in organic synthesis. Due to the strong coordina-
tion of the amine products to the metal center, which
deactivates the catalyst, stoichiometric amounts of catalyst
are frequently used in such reactions. In recent years, some
effective methods have been developed for the metal-cata-
lyzed addition of acetylenes to imines or their derivatives.1
For example, Li et al.2 reported the use of a mixed Ru/Cu
catalyst system for the addition of terminal acetylenes to
imines. Knochel et al. employed Cu(I) or Cu(II) bromide
as a catalyst for the addition of terminal alkynes to enam-
ines, which were derived from enolisable aldehydes.3 Black
et al. reported the alkynylation of acyliminium ions with a
catalytic amount of copper(I) iodide as the promoter. Un-
der the optimized conditions, 10 mol % of CuI was enough
to obtain N-acyl-propargylamines with satisfactory yields
(76–99%).4 Yadav et al. studied the alkyne addition reac-
tion of acyliminium ions, which were prepared from aro-
matic heterocycles, such as pyridines and quinolines, with
However, the Cu(II)-catalyzed asymmetric addition of
alkynyl reagents to carbonyl compounds and imine deriva-
tives has remained less studied. We have reported a highly
enantioselective catalytic addition of alkynylzinc reagents
to aromatic ketones catalyzed by chiral Cu(II)–camphor-
sulfonamide ligands with good yields and excellent ee
values.15 Wang et al described a bis(hydroxycamphor-
sulfonamide)–Cu(II) complex16 for the same reaction.
Recently, O’Learya et al reported their study of electro-
static immobilization of copper(I) and copper(II) bis(oxaz-
olinyl)pyridine catalysts on silica: application in the
synthesis of propargylamines via direct addition of termi-
nal alkynes to imines.17 In contrast to Cu(I) complexes,
Cu(II) complexes are not sensitive to air or moisture and
are commercially available at low cost. From a practical
standpoint, it is highly desirable to develop methods for
the Cu(II)-catalyzed asymmetric addition of alkynyl
a catalyst system containing CuI and Hunig’s base.5
¨
The asymmetric metal-catalyzed addition of alkynyl
reagents to the C@N bonds of imines has also been devel-
oped in the past few years. Several chiral catalysts, such as
*
Corresponding authors. Tel.: +86 2035693517 (X.L.); e-mail addresses:
xsli219@yahoo.com; bcachan@polyu.edu.hk
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.11.033

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B. Liu et al. / Tetrahedron: Asymmetry 18 (2007) 2901–2904
reagents to imines or imine derivatives with good
stereocontrol, so that the related chemical application
can be easily amplified on a larger scale. Herein we
report the utilization of chiral N-tosylated amine–imine
ligands in Cu(II)-catalyzed enantioselective addition of
alkynes to imines. The catalyst system is easy to prepare
and handle, which can be conveniently applied to
asymmetric synthesis.
2. Results and discussion
Chiral N-tosylated aminoimine 4 (Scheme 1) was proven to
be effective in the Cu(I)-catalyzed enantioselective addi-
tions of alkynes to imines in our previous study.14 In a pre-
liminary screen study to develop a chiral Cu(II) catalyst, we
first chose ligand 4 as the chiral ligand. When N-benzylidene-
aniline was used as the model substrate and toluene as the
Ph
Ph
N
Ph
Ph
O
NH
OH
Ph
S
O
O
CH3
TsHN
NH2
S
N
H
O
H3C
1
2
3
Ph
Ph
Ph
Ph
O
O
NH
N
NH
O
N
S
S
O
HO
C(CH3)3
HO
(H3C)3C
4
5
Scheme 1. Chiral ligands.
Table 1. Enantioselective addition of phenyl acetylene to N-benzylindeneaniline under various reaction conditionsa
Ph
Ph
HN
N
Cu(OTf)2 / Ligand
solvent / additive
H
Ph
+
H
Ph
Entry
Ligands
Solvents
Metal
Additives
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10e
11
12
13
14
15d
16
17
4
5
1
2
3
5
5
5
5
5
5
5
5
5
5
4
5
Toluene
Toluene
Toluene
Toluene
Toluene
THF
CH2Cl2
Et2O
Hex
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Cu(II)
Cu(II)
Cu(II)
Cu(II)
Cu(II)
Cu(II)
Cu(II)
Cu(II)
Cu(II)
Cu(II)
Cu(II)
Cu(II)
Cu(II)
Cu(II)
Cu(II)
Cu(I)
—
—
—
—
—
—
—
—
65
51
70
56
36
43
55
51
65
18
82
83
43
61
45
51
65
63
73
0
2
11
47
12
4
52
58
63
75
55
47
58
65
55
—
—
(CH3)3CONa
Zn(Me)2
CH3OK
n-BuLi
—
—
—
Cu(I)
a All reactions were carried out with 20 mol % Cu (OTf)2 and the same amount of ligands at room temperature for 24 h.
b Isolated yields after purification by flash column chromatography.
c Enantiomeric excess was determined by HPLC with a Chiralcel OD column.
d 10 mol % of catalyst was used.
e The reaction was carried out at 0 °C.

B. Liu et al. / Tetrahedron: Asymmetry 18 (2007) 2901–2904
2903
Table 2. Enantioselective addition of phenylacetylene to N-aryl arylimines using ligand 5 in the presence of ZnMe2
Ar2
Ar2
HN
N
Cu(OTf)2 / 5
H
Ph
Ar1
+
Ar1
H
ZnMe2 / Toluene
Ph
Entry
Ar1
Ph
4-MeOC6H4
4-ClC6H4
4-NO2C6H4
2-MeOC6H4
2-ClC6H4
Ph
Ar2
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
83
67
89
56
51
80
77
60
42
70
63
75
78
77
73
73
81
81
85
83
92
87
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-MeC6H4
4-MeOC6H4
Ph
2-MeOC6H4
4-MeC6H4
4-MeOC6H4
10
11
a Isolated yields after purification by flash column chromatography.
b Enantiomeric excesses were determined by HPLC with a Chiralcel OD column.
solvent, 65% yield and 63% ee were obtained (Table 1, en-
try 1), compared with the Cu(I) complex with the same chi-
ral ligand (Table 1, entry 16: 51% yield with 65% ee). This
result indicated that the oxidation state of the metal did not
have much effect on the enantioselectivity of the reaction
with 4 as the chiral ligand. In contrast, the utilization of
N-tosylated aminoimine ligand 5 gave relatively poorer
enantioselectivity (Table 1, entry 17: 65% yield with 55%
ee) in Cu(I)-catalyzed enantioselective addition of phenyl-
acetylene to N-benzylideneaniline, while better results (Ta-
ble 1, entry 2: 51% yield and 73% ee) were obtained with
the use of Cu(II)-catalyzed system under the same reaction
conditions. Other bidentate ligands, such as TsDPEN 1,
camphorsulfonamide 2 and N-tosylated aminoimine ligand
3 were also tested. However, either poor enantioselectivities
or low yields were obtained (Table 1, entry 3: TsDPEN:
70% yield, 0% ee; entry 4: camphorsulfonamide: 56% yield,
2% ee; entry 5: bidentate N-tosylated aminoimine ligand:
36% yield, 11% ee). Detailed studies of the Cu(II) complex
of ligand 5 were carried out to optimize the reaction
conditions including the choice of solvent and reaction
temperature, which might influence the enantioselectivities
of the reaction. The results shown in Table 1 clearly
revealed that toluene was the best solvent and room
temperature was a good choice for this reaction. Strong
bases, such as CH3OK, (CH3)3CONa and butyllithium,
were tested on the terminal acetylenic C–H bond to form
alkynyl-metal reagents. (CH3)3CONa gave good results in
yield improvement but poor results with regard to the
enantioselectivity [Table 1, entry 11, (CH3)3CONa: 82%
yield with 63% ee]. CH3OK and butyllithium gave neither
high yield nor good enantioselectivity (Table 1, entry 13:
43% yield with 55% ee; entry 14: 61% yield with 47% ee).
When dimethylzinc was added to form the alkynylzinc
reagent, the yield was distinctly improved and also the
enantioselectivity was slightly increased (Table 1, entry
12: 83% yield with 75% ee). This result was consistent with
our previous study of Cu(I) complexes, which proved that
organozinc reagents were favorable for both Cu(I) and
Cu(II) complexes.
Various N-aryl arylimines derived from aromatic aldehydes
and amines reacted with phenylacetylene in the presence of
dimethylzinc, catalyzed by Cu(II)–tridentate N-tosylated
amine–imine ligand 5 under optimal reaction conditions
and the results are listed in Table 2. All the N-aryl aryl-
imines derived from aniline and substituted aldehydes in
the reaction gave moderate to good ee values (Table 2,
entries 1–6: 51–89% yields with 73–81% ees). N-Aryl aryli-
mines derived from substituted anilines and benzaldehyde
also provided good results (Table 2, entries 7–9: 42–77%
yields with 81–85% ees). The results revealed that electron
donor groups on the phenyl ring of the substrates were
favorable for enantioselectivity (Table 2, entries 10 and
11). The highest ee value was obtained with the substrate
derived from p-methyl aniline and p-methyl benzaldehyde
(Table 2, entry 10: 70% yield with 92% ee).
3. Conclusion
In conclusion, we have demonstrated that a new catalyst
system consisting of Cu(II) and chiral tridentate
N-tosylated aminoimine ligands was effective in the
enantioselective addition of phenylacetylene to N-aryl
arylimines. Further studies on the scope and mechanism
of this reaction are currently underway.
4. Experimental
4.1. General methods
All reactions were performed using oven-dried glassware
under an atmosphere of dry nitrogen. All solvents were dis-
tilled and dried before use. Reagents were purchased from
either Acros or Aldrich. The aldehydes were redistilled
before use. NMR spectra were recorded on a Varian-300
spectrometer. Optical rotations were measured with a
Perkin Elmer 341 polarimeter. Chiral HPLC analysis was

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B. Liu et al. / Tetrahedron: Asymmetry 18 (2007) 2901–2904
performed on a Waters 600 instrument with Chiralcel OD
Acknowledgments
column (4.6 mm ꢀ 250 mm).
We thank the National Science Foundation of China
(20472116), the Guangdong Province Natural Science
Foundation (04009804), the Hong Kong Research Grants
Commercial (Project Polyu 5002/05P) and the University
Grants Committee of Hong Kong (Areas of Excellence
Scheme, AOE P/10-01) for the financial support of this
study.
4.2. Preparation of chiral ligands
Chiral ligands 4 and 5 were prepared according to the pro-
cedure, which we previously reported.14
Chiral ligand 3: To a solution of 2.00 g (5.46 mmol) of
(R,R)-TsDPEN in 40 ml of methanol were added 0.73 g
(5.5 mmol) of 3,5-dimethylbenzaldehyde and 3.57 g of
anhydrous Na2SO4 (30 mmol). The reaction mixture was
stirred and refluxed for 8 h until the reaction was com-
pleted (monitored by TLC). After cooling to room temper-
ature, the mixture was filtrated and the solvent was
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4.2.1. General procedure for the enantioselective alkynyl-
ation of N-aryl arylimines. To a solution of 2.0 M dimeth-
ylzinc in toluene (0.15 ml, 0.3 mmol) was added
phenylacetylene (0.033 ml, 0.3 mmol) under nitrogen at
room temperature. The mixture was stirred for 15 min to
produce the alkynylzinc reagent. Copper(II) triflate
(14.4 mg, 0.04 mmol) was added to a solution of the chiral
ligand (0.04 mmol) and N-aryl arylimines substrate
(0.2 mmol) in 0.5 ml of toluene. The preformed alkynylzinc
reagent was added to the mixture of the catalyst and sub-
strate via a syringe. After a certain period of time, the reac-
tion was quenched by the addition of 2 ml of water. The
mixture was extracted twice with 2 ml of dichloromethane,
and then the combined organic phase was concentrated in
vacuo. The residue was purified by flash chromatography
(2% ethyl acetate in petroleum ether as eluents) to give
the desired product. The enantiomeric excess was deter-
mined by chiral HPLC using a Chiralcel OD column (5%
isopropanol in hexane as eluents).
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