The synthesis of chiral N-tosylatedaminoimine ligands and their application in enantioselective addition of phenylacetylene to imines

Article abstract of DOI:10.1016/j.tetasy.2007.05.001

A class of new chiral tridentate N-tosylatedaminoimine ligands were synthesized and used in the Cu(I)-catalyzed enantioselective addition of phenylacetylene to imines. Good enantioselectivities in up to 91% ee were obtained.

Full text of DOI:10.1016/j.tetasy.2007.05.001

Tetrahedron: Asymmetry 18 (2007) 1124–1128
The synthesis of chiral N-tosylatedaminoimine ligands and their
application in enantioselective addition of phenylacetylene to imines
Bao Liu,a Juntao Liu,a Xian Jia,c Ling Huang,a Xingshu Lia,* and Albert S. C. Chana,b,
*
aSchool of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou 51006, 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
cShenyang Pharmaceutical University, Shenyang, PR China
Received 26 March 2007; accepted 2 May 2007
Available online 1 June 2007
Abstract—A class of new chiral tridentate N-tosylatedaminoimine ligands were synthesized and used in the Cu(I)-catalyzed enantioselec-
tive addition of phenylacetylene to imines. Good enantioselectivities in up to 91% ee were obtained.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
reported an enantioselective synthesis of propargylamines
catalyzed by copper(I)-bisimine complexes with up to
85% ee.9 Very recently, Bolm et al. developed a one-pot,
enantioselective synthesis of N-aryl propargylic amines
using alkynylation reagents in combination with aldehydes
and o-methoxyaniline as starting materials.10
Asymmetric catalytic reactions have attracted much atten-
tion in recent years because of their great potential in mak-
ing higher-value-added products. Many chiral ligands have
been synthesized and applied in various asymmetric reac-
tions over the past few decades.1 However, only in recent
years, limited organometallic systems have been developed
to catalyze the addition of alkynes to imines2 to produce
propargylamines, which are important synthetic intermedi-
ates in the construction of biologically active nitrogen-con-
taining compounds and natural products.3 Li et al.
developed a Cu(I) complex of pyridyl-bisoxazoline, which
catalyzed the direct alkyne addition to imines with high
ee’s and good yields.4 Hoveyda reported a Zr-catalyzed
enantioselective addition of a range of mixed alkynylzinc
reagents to various arylimines with a chiral amino acid-
based ligand.5 Knochel et al. described the addition of
functionalized alkynes to enamines catalyzed by Cu(I)-Qui-
nap complexes.6 Carreira et al. developed a new atropiso-
meric P,N ligand (Pinap) and used it in the CuBr-
catalyzed three-component reaction of dibenzylamine,
aldehydes and various acetylenes.7 We developed a versa-
tile catalytic synthesis of enantiomerically enriched b,c-
alkynyl a-amino acid derivatives by realizing the direct
asymmetric alkynylation of a-imino ester.8 Benaglia et al.
In contrast to the enantioselective alkynylation of alde-
hydes in which considerable progress has been made in
recent years, the enantioselective alkynylzinc addition to
imines still remains less developed. One of the targets in
our study of catalytic asymmetric synthesis is the develop-
ment of effective chiral ligands that can be easily prepared
and successfully applied in asymmetric synthesis. Herein
we report our preliminary study using new chiral mixed
N-tosylatedaminoimine ligands in the Cu(I) catalyzed
enantioselective addition of alkynes to imines.
2. Results and discussions
The alkyne additions to imines were usually slow and
generally required 3–4 days at room temperature,3,4a,5,7
which was mainly due to the inert nature of the imines
towards the addition. In a preliminary screen study to
develop a simple and active catalyst system for this reac-
tion, we chose TsDPEN 1, Salen 2, camphorsulfonamide
3, mixed N-tosylatedaminoimine 4 and its analogue 5 as
chiral ligands. N-Benzylideneaniline was used as the model
substrate and toluene was used as the reaction solvent for
*
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.2007.05.001

B. Liu et al. / Tetrahedron: Asymmetry 18 (2007) 1124–1128
1125
the Cu(I) catalyzed enantioselective addition of alkynes to
imines. The results showed that when 1 and 2 were used as
ligands, either poor enantioselectivity or undesired side
products were obtained. Chiral camphorsulfonamide
ligand 3, which was effective in the Cu(II)-catalyzed asym-
metric alkynylation of ketones,8 was not very successful
and low ee’s were observed (Fig. 1).
(Table 1, entry 5, 51% isolated yield and 65% ee). Some fac-
tors governing the enantioselectivities of the reaction were
subsequently examined with tridentate mixed N-tosylated-
aminoimine ligands and the results are shown in Table 1.
The temperature effect was rather significant for the reac-
tion; it could proceed smoothly at room temperature
although a low yield was obtained at 0 °C. The ee values
attained herein were found to be sensitive to the choice of
solvents. At room temperature, the use of toluene, ether,
hexane, dichloromethane and tetrahydrofuran gave the
On the other hand, the use of new tridentate mixed N-tosyl-
atedaminoimine ligands gave moderate yields and ee’s
Ph
Ph
Ph
Ph
OH
N
N
O
Ph
S
TsHN
NH2
OH
HO
N
H
O
1
2
3
Ph
Ph
Ph
Ph
O
NH
O
N
O
NH
N
S
S
HO
O
HO
C(CH3)3
4
5
(H3C)3C
Figure 1.
Table 1. Enantioselective addition of phenyl acetylene to N-benzylindeneaniline in various reaction conditionsa
Ph
Ph
HN
N
CuOTf / Ligand
solvent / additive
H
Ph
H
+
Ph
Entry
Ligands
Solvents
Time (h)
Additive
Yieldb (%)
eec (%)
1
2
3
4
5
6d
7
8
9
10
11
12
13
14
15
16
17
18e
19f
1
2
3
4
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
36
36
36
36
36
36
24
36
36
36
36
24
24
24
24
24
24
24
24
—
—
—
—
—
—
—
—
52
53
84
65
51
32
41
69
85
57
71
10
47
82
12
32
76
Trace
49
5
9
0
55
65
46
63
41
5
10
0
0
29
0
CH2Cl2
EtOEt
—
—
—
Hexane
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH3ONa
(CH3)3COK
(CH3)3CONa
n-BuLi
Et3N
Zn(Me)2
Zn(Me)2
Zn(Me)2
25
42
85
—
68
a All reactions were carried out with 20 mol % CuOTf and ligands at room temperature.
b Isolated yields after purification by flash chromatography.
c Enantiomeric excess was determined by HPLC with a chiracel OD column.
d 10 mol % of catalyst was used.
e Carried out without CuOTf.
f 10 mol % of Zn(Me)2 was used.

1126
B. Liu et al. / Tetrahedron: Asymmetry 18 (2007) 1124–1128
product with ee’s ranging from 5% to 65% and chemical
yields from 51% to 85%. Toluene was the best solvent for
this reaction. Base additives such as CH3ONa, (CH3)3CO-
Na, (CH3)3COK, n-BuLi and Et3N were also investigated
but no positive effects were found for accelerating the reac-
tion or improving the enantioselectivities (entries 12–16,
CH3ONa, 10% yield with 0% ee; (CH3)3CONa, 82% yield
with 5% ee; (CH3)3COK, 47% yield with 29% ee; n-BuLi,
12%yield with 25% ee; Et3N, 32% yield with 68% ee). As
organozinc reagents are highly selective and widely used
in nucleophilic addition to carbonyl compounds, we
attempted to apply alkynyl zinc reagents to the reaction.
When the alkynyl zinc reagent was prepared using a known
procedure (phenylacetylene reacted with dimethylzinc) and
then used in the enantioselective addition to imines, the
reaction was finished in 24 h with good enantioselectivity
(85% ee) and yield (76%). The procedure was very simple:
to a mixture of imine, copper(I) triflate benzene complex
and chiral ligand was added an alkynylzinc reagent and
the reaction was carried out at room temperature for 24 h
and worked up to obtain the required product.9 Only trace
amounts of the product were detected when the reaction
was carried out in the absence of copper(I) triflate benzene
complex (entry 18). The result indicated that copper(I) was
very important for catalyzing this reaction. At the same
time, decreasing the amount of dimethyl zinc led to lower
yields and enatioselectivity (e.g., 10 mol % dimethyl zinc
and phenylacetylene as a nucleophilic reagent gave 49%
yield with 68% ee, entry 19). This was probably due to di-
methyl zinc acting solely to deprotonate the alkyne to form
an alkynylzinc reagent in the reaction.
Having established the optimal reaction conditions for
conversion of the model substrate N-benzylideneaniline,
various imines derived from aromatic aldehydes and
amines were treated with phenylacetylene in the presence
of dimethylzinc catalyzed by Cu(I)-tridentate mixed N-
tosylatedamineimine ligand 5 and the results obtained are
listed in Table 2. Most imines derived from aniline and
substituted aldehydes in the reaction gave moderate to
good ee values (entries 1–5, 50–87% ee) except in the case
of 4-chlorobenzaldehyde (entry 6). On the other hand,
imines derived from substituted anilines and benzaldehyde
also provided similar results (entries 7–9, 62–86% ee with
58–87% yield).
The synthesis of the new tridentate mixed N-tosylatedami-
noimine ligand was simple. (R,R)-1,2-Diphenylethane-1,2-
diamine (R,R)-DPEDA, a commercially available chiral
starting material, was reacted with toluenesulfonic acid
chloride to afford TsDPEN in good yield according to a
known procedure.10 TsDPEN then was allowed to react
with 3,5-di-tert-butyl-2-hydroxybenzaldehyde in the pres-
ence of anhydrous sodium sulfate in methanol to give a
nearly quantitative yield of the desired product11 (Scheme
1).
Table 2. Enantioselectivity of the addition of phenylacetylene with ligand 5 in the presence of ZnMe2
Ar2
Ar2
HN
N
CuOTf / 5
H
Ph
Ar1
+
Ar1
H
ZnMe2 / Toluene
Ph
Entry
Substrates
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
Ph–CH@N–Ph
76
68
79
73
52
60
58
87
72
65
63
85
83
80
87
50
24
77
86
62
91
83
4-MeOC6H4–CH@N–Ph
2-MeOC6H4–CH@N–Ph
4-NO2C6H4–CH@N–Ph
2-ClC6H4–CH@N–Ph
4-ClC6H4–CH@N–Ph
Ph–CH@N-(4-CH3C6H4)
Ph–CH@N-(4-CH3OC6H4)
Ph–CH@N-(4-ClC6H4)
10
11
4-ClC6H4–CH@N-(4-ClC6H4)
4-MeOC6H4–CH@N-(4-CH3OC6H4)
a Isolated yields after purification by flash column chromatography.
b Enantiomeric excess was determined by HPLC with a chiracel OD column.
Ph
Ph
Ph
Ph
R
CHO
OH
Ph
Ph
O
NH
N
O
TsCl
NH
NH2
R
S
S
H2N
NH2
O
O
HO
R
R
4: R = H; 5: R = C(CH3)3
Scheme 1.

B. Liu et al. / Tetrahedron: Asymmetry 18 (2007) 1124–1128
1127
3. Conclusion
4.3. General procedure for the enantioselective alkynylation
of imines
In conclusion, we have developed a new class of chiral tri-
dentate N-tosylatedaminoimine ligands, which are effective
in the production of propargylic amines with good enantio-
selectivities and yields. Further studies on the scope and
mechanism of this reaction are currently underway.
A typical procedure was as follows. Phenylacetylene
(0.033 mL, 0.3 mmol) and a solution of 2.0 M dimethylzinc
in toluene (0.15 mL, 0.3 mmol) were added to a dry flask at
room temperature under N2 with continued stirring for
15 min to prepare an alkynylzinc reagent. Imine (0.2 mmol)
was added to the catalyst solution which was made from
copper(I) triflate benzene complex (0.04 mmol), chiral
ligand (0.04 mmol) and toluene (0.5 mL). The alkynylzinc
reagent was added to the mixture of the catalyst and sub-
strate via a syringe. After being stirred at room tempera-
ture for a specified period of time, the reaction mixture
was quenched with water, extracted with dichloromethane
and concentrated in vacuo. The extracts were applied
directly onto a silica gel column by flash chromatography
(1:50 ethyl acetate/petroleum ether as eluents) to give the
desired product. The enantiomeric excess was determined
4. Experimental
4.1. General methods
All reactions were performed using oven-dried glassware
under an atmosphere of dry nitrogen. THF was distilled
and dried before use. Reagents were purchased from either
Acros or Aldrich and used without further purification
except for the aldehydes, which were redistilled before
use. NMR spectra were recorded on a Varian-500 spec-
trometer. Optical rotations were measured with a Perkin–
Elmer model 341 polarimeter at 20 °C. HPLC analyses
(Chiralcel OD or OD-H column from Daicel, IPA–hexane
as eluent) were performed using a WatersTM 600 HPLC with
WatersTM 486 Tunable Absorbance Detector.
by chiral HPLC, using
a
Chiralcel OD column
(4.6 mm 250 mm) with 5% isopropanol in hexane as
*
eluents.
Acknowledgements
4.2. The preparation of chiral ligands
We thank the National Science Foundation of China
(20472116), the Guangdong Province Natural Science
Foundation (04009804), the Hong Kong Research Grants
Commercial (Project Polyu 5001/03P) and the University
Grants Committee of Hong Kong (Areas of Excellence
Scheme, AOE P/10-01) for the financial support of this
study.
4.2.1. Chiral ligand 4. To
a
solution of 2.00 g,
(5.46 mmol) of (R,R)-TsDPEN12 in 40 mL of methanol
were added 0.67 g, (5.5 mmol) of 2-hydroxy-benzaldehyde
and 3.57 g of anhydrous Na2SO4 (30 mmol). The reaction
mixture was stirred and refluxed until the reactants disap-
peared (usually requires about 8 h, as monitored by
TLC). After cooling to room temperature, the mixture
was filtrated and the solvent was removed in vacuo to
afford chiral (R,R)-4 as a yellow solid (2.54 g, 99%).
20
Mp = 155–156 °C. ½aꢀD ¼ þ12:1 (c 3.0, CH2Cl2). Anal.
References
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1626(s), 1451(m), 1161(s), 1056(w), 928(w), 818(w),
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.
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20
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3032(w), 2957(s), 1626(s), 1455(m), 1160(s), 1056(w),
.
928(w), 811(w), 773(w) cmꢁ1 1H NMR (300 MHz,
CDCl3), d: 8.18 (s, 1H), 7.40 (dd, J = 6.6 Hz, J0 = 1.5 Hz,
3H), 7.25–7.02 (m, 10H), 6.95 (dd, J = 1.8 Hz, J0 = 2.1 Hz,
3H), 5.13 (d, J = 6.6 Hz, 1H), 4.71 (dd, J = 10.5 Hz,
J0 = 3.6 Hz, 1H), 4.53 (d, J = 5.7 Hz, 1H), 2.34 (s, 3H),
1.49 (s, 9H), 1.28 (s, 9H) ppm. 13C NMR (75 MHz,
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136.9, 127.9, 63.9, 35.5, 34.5, 31.8, 29.9, 21.9 ppm.
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