Asymmetric addition of alkynes to imines in water catalyzed with a recyclable Cu(I)-bis(oxazoline) and stearic acid system

Article abstract of DOI:10.1016/j.tetasy.2007.02.005

Stearic acid and its zinc salt were used as additives in the enantioselective alkyne addition to imines catalyzed by copper(I)-bis(oxazoline) (box) in water. The reactions took place smoothly with good yields and high enantioselectivities (up to 97% ee).

Full text of DOI:10.1016/j.tetasy.2007.02.005

Tetrahedron: Asymmetry 18 (2007) 396–399
Asymmetric addition of alkynes to imines in water catalyzed
with a recyclable Cu(I)–bis(oxazoline) and stearic acid system
Juntao Liu,a Bao Liu,a Xian Jia,b Xingshu Lia,* and Albert S. C. Chana,c
aSchool of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou 51006, China
bShenyang Pharmaceutical University, Shenyang, PR China
cOpen 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 21 December 2006; revised 1 February 2007; accepted 2 February 2007
Available online 2 March 2007
Abstract—Stearic acid and its zinc salt were used as additives in the enantioselective alkyne addition to imines catalyzed by copper(I)–
bis(oxazoline) (box) in water. The reactions took place smoothly with good yields and high enantioselectivities (up to 97% ee). Good
enantioselectivities were maintained in a catalyst recycle study.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Water as a solvent in chemical reactions has many advan-
tages over the usual organic solvents. It is safe, nontoxic,
very economical and environmentally friendly. From an
industrial point of view, the low solubility of many organ-
ic compounds in water makes it possible to form a
two-phase system that allows an easy separation of the
products from the water-soluble organometallic catalyst
by simple phase separation. However, the low solubility
of many organic compounds in water also limits its appli-
cation in various chemical transformations. To circumvent
this problem, surfactants, which improve the solubility of
organic materials or form a colloidal dispersion with them
in water, have been used in some reactions such as the
Diels–Alder reaction,10 aldol reactions,11 Suzuki cou-
pling,12 alkylation,13 asymmetric hydrogenation14 and
transfer hydrogenation.15
Chiral propargylamines are important synthetic intermedi-
ates for the construction of biologically active nitrogen-
containing compounds and natural products.1–3 In contrast
to extensive studies on the asymmetric alkynylation of
aldehydes,4 only a limited number of catalyst systems have
been reported for the addition of acetylenes to imines. 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.5 Hoveyda reported a Zr-cata-
lyzed enantioselective addition of a range of mixed alkynyl-
zinc reagents to various arylimines with a chiral amino
acid-based ligand.6 Knochel et al.7 described the addition
of functionalized alkynes to enamines catalyzed by
Cu(I)–Quinap complexes. Carreira et al. developed a new
atropisomeric P,N ligand (Pinap), structurally related to
Quinap, which showed similar reactivity and stereochemi-
cal efficiency in promoting the CuBr-catalyzed three-com-
ponent reaction of dibenzylamine, aldehydes and various
acetylenes.8 Recently, Afonso et al. reported the enantio-
selective alkyne addition to imines catalyzed by copper(I)–
pyridylbis(oxazoline) (pybox), performed in the ionic liquid
1-n-butyl-3-methyl imidazolium bis(trifluoromethylsulfon-
yl)imide [bmim][NTf2].9
On the other hand, the recycle or reuse of the chiral catalyst
in organic reactions has attracted much attention in recent
years. Many methods such as the immobilization of the
catalyst on homogenous or heterogeneous supports,16 sol-
vent extractions based on the large different affinities of
the catalysts and the reaction products in each liquid phase
have been developed. Supercritical CO2 (scCO2),17 fluori-
nated solvents18 and room temperature ionic liquids
(RTILs)19 are typical examples. Herein, we report our pre-
liminary studies on the enantioselective addition of alkynes
to imines in water, catalyzed with Cu(I)–bis(oxazoline)
using stearic acid as the surfactant.
*
Corresponding author. Tel.: +86 2035693517; e-mail: xsli219@
yahoo.com
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.02.005

J. Liu et al. / Tetrahedron: Asymmetry 18 (2007) 396–399
397
2. Results and discussion
stearic acid as surfactant. The procedure for recycling of
the reaction was very simple: hexane was added to extract
the product after each batch reaction and the residue
containing the catalyst was reused by changing fresh
N-benylideneaniline and phenylacetylene for the next cycle.
The enantioselectivities (78–85% ee) were quite consistent
(Table 2).
The alkyne addition to imines in water was slow and gen-
erally needed 2–4 days.5 We believed this reaction could be
accelerated by using a surfactant, which formed a colloidal
dispersion with the alkyne and imines in water. PEG was
initially used as a surfactant for the addition of alkynes
to imines with a chiral bis(oxazolinyl) CuOTf catalyst.
The results were quite unsatisfactory: both the chemical
yields and the enatioselectivities in aqueous solutions con-
taining 5%, 25% and 50% PEG aqueous solution were low.
The cationic surfactant, cetyltrimethylammonium bromide
(CTAB), which was effective in the asymmetric transfer
hydrogenation of ketones, gave very good chemical yields19
but no enantioselectivity. Other cationic surfactants, such
as dodecyltrimethyl ammonium bromide (DATB), cetyl-
trimethyl ammonium chloride (CATC) and tetrabutyl
ammonium bromide (TBAB) afforded similar results. On
the other hand, sodium dodecyl sulfate (SDS), sodium
dodecylbenzenesulfonate (SDBS) and sodium carboxy-
methyl cellulose (SCMC) provided low to modest chemical
yields and low ee’s. However, when stearic acid and zinc
stearate were used as the surfactant in the reaction, both
enatioselectivity and chemical yields were greatly im-
proved. Furthermore, the asymmetric addition of alkynes
to imines could be completed within 24 h with an 85% ee
and 86% yield, which were substantially superior to that
obtained without the surfactant (48 h, 80% ee and 77%
yield) (Table 1).
Table 2. Recycle of catalyst with stearic acid as surfactant in water
Ar2
Ar2
HN
Ar1
CuOTf / Ligand
N
+
H
Ph
Ar1
H
H2O / Stearic acid
Ph
Imine-1: Ar1 = Ar2 = Ph;
Imine-2: Ar1 = 4-CH3C6H4, Ar2 = Ph
Cycle
Imine
Time (h)
Yielda (%)
eeb (%)
1
2
3
4
5
1
2
3
4
Imine-1
Imine-1
Imine-1
Imine-1
Imine-1
Imine-2
Imine-2
Imine-2
Imine-2
24
24
24
24
24
24
24
24
24
67
78
75
62
45
70
83
78
75
78
85
85
80
79
97
97
96
95
a Isolated yields after purification by flash chromatography.
b Enantiomeric excess was determined by HPLC with a chiracel OD
column.
The recycling of Cu(I)–bis(oxazoline) was investigated with
imine-1 and imine-2 as the substrates and 0.12 equiv of
Table 3 shows the results of the addition of phenylacetylene
to a series of substrates in water with Cu(I)–bis(oxazoline)
Table 1. Screening of surfactants as additives for the enantioselective alkynylation of imines
Ph
Ph
H
HN
N
O
O
N
CuOTf / Ligand
H2O / Surfactant
N
N
+
H
Ph
Ph
Ph
Ph
Ligand
Entry
Surfactants
Timea (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
12
13
14
—
48
48
48
48
48
48
48
24
24
24
24
48
48
48
48
24
24
77
52
30
12
—
32
68
87
90
83
80
38
69
35
88
86
80
80
38
35
35
—
26
35
2
0
0
5
12
79
82
80
85
30
5% PEGd
25% PEG
50% PEG
100% PEGe
SDS
SDBS
TBAB
CTAB
DTAB
CTAC
CMC
Calcium stearate
Sodium stearate
Zinc stearate
Stearic acid
D-Camphorsulfonic acid
a All reactions were carried out with 10 mol % CuOTf and 10 mol % Ph–Pybox in water at room temperature.
b Isolated yields after purification by flash chromatography.
c Enantiomeric excess was determined by HPLC with a chiracel OD column.
d 5% PEG-400 aqueous solution (m/m).
e PEG-400 was used as solvent.

398
J. Liu et al. / Tetrahedron: Asymmetry 18 (2007) 396–399
Table 3. Enantioselectivity of the addition of phenylacetylene with
catalyst and stearic acid in water
4.2. General procedure for recycle of catalyst with stearic
acid in water
Ar2
Ar2
HN
Ar1
CuOTf / Ligand
To a mixture of N-benylideneaniline (180 mg, 1 mmol),
copper(I) triflate benzene complex (50 mg, 10 mol %),
chiral ligand (37 mg, 10 mol %) and water (5 mL) in a
10 mL round bottom flask, were added phenylacetylene
(0.165 mL, 1.5 mmol) and stearic acid (28 mg, 10 mol %).
The mixture was stirred at room temperature for 24 h,
and then extracted with hexane (5 mL · 3). The combined
organic phase was concentrated under reduced pressure,
and purified by chromatography through silica gel (1:50
ethyl acetate/petroleum ether as eluents) to give the prop-
argylamine. The residue containing catalyst was reloaded
with N-benylideneaniline (180 mg, 1 mmol) and phenyl-
acetylene (0.165 mL, 1.5 mmol) for the next cycle reaction
and the process was repeated for five times. The ee values
were determined by chiral HPLC analysis using a Chiralcel
N
+
H
Ph
Ar1
H
H2O / Stearic acid
Ph
Entry
Ar1
Ar2
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
C6H5
C6H5
C6H5
C6H5
4-CH3C6H4
2-ClC6H4
2-CH3OC6H4
4-CH3OC6H4
4-CH3C6H4
4-CH3OC6H4
3,5-Di-CH3C6H3
3,5-Di-CH3C6H3
C6H5
86
80
85
60
80
78
83
89
82
81
83
85
85
88
86
35
97
86
62
90
94
91
95
85
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
C6H5
C6H5
C6H5
C6H5
4-CH3C6H4
4-CH3C6H4
C6H5
10
11
12
4-CH3C6H4
OD column (4.6 mm 250 mm, 5% isopropanol in hexane
*
a Isolated yields after purification by flash column chromatography.
b Enantiomeric excess was determined by HPLC with a chiracel OD
column.
as eluents).
Acknowledgements
as the catalyst precursor and stearic acid as the additive.
The reactions took place smoothly to give propargylamines
in good yield and high enantioselectivity in most cases. The
results also revealed that an electron donating group on the
phenyl ring of the substrates enhanced the enatioselectivity,
while an electron-withdrawing group gave somewhat nega-
tive effects. The best ee value was obtained in the addition
to the imine formed by 4-methylbenzyl aldehyde and ani-
line (entry 5, 97% ee).
We thank the National Science Foundation of China
(20472116) and the Guangdong Province Natural Science
Foundation (04009804) for financial support of this study.
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