Syntheses of C1-symmetric bidentate ligands having pyridyl and 1,3-Thiazolyl, 1-methylimidazolyl or pyrazinyl donor groups for enantioselective palladium-catalyzed allylic substitution and copper-catalyzed cyclopropanation

Article abstract of DOI:10.1016/j.jorganchem.2006.06.050

New chiral C₁-symmetric bidentate ligands, which possess two different nitrogen heterocycles, 1,3-thiazolyl, 1-methylimidazolyl or pyrazinyl and one pyridyl group, were prepared by Kr?hnke condensation in 36-59% overall yield. Stable Pd(II)-allyl and Cu(II) chloride complexes formed by some of the ligands were obtained in 60-65% yields. X-ray crystal structure analysis of a copper(II) complex having 1-methylimidazolyl group indicated that it is a μ-chloro bridge dimer. The Pd(II)-allyl complexes were found to be active catalysts in the asymmetric allylic substitution of 1,3-diphenylprop-2-enyl acetate. The best result observed was 85% e.e. and 99% isolated yield. In addition, the in situ generated Cu(OTf)₂ complexes were found to be active catalysts in cyclopropanation of styrene with ethyl diazoacetate.

Full text of DOI:10.1016/j.jorganchem.2006.06.050

Journal of Organometallic Chemistry 691 (2006) 5664–5672
www.elsevier.com/locate/jorganchem
Syntheses of C1-symmetric bidentate ligands having pyridyl
and 1,3-Thiazolyl, 1-methylimidazolyl or pyrazinyl donor
groups for enantioselective palladium-catalyzed allylic
substitution and copper-catalyzed cyclopropanation
a
a
a
a
Pang-Fei Teng , Chui-Shan Tsang , Ho-Lun Yeung , Wing-Leung Wong ,
b
a,
*
Wing-Tak Wong , Hoi-Lun Kwong
a
Department of Biology and Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong SAR, China
b
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, China
Received 10 May 2006; received in revised form 13 June 2006; accepted 13 June 2006
Available online 19 September 2006
Abstract
New chiral C1-symmetric bidentate ligands, which possess two different nitrogen heterocycles, 1,3-thiazolyl, 1-methylimidazolyl or
pyrazinyl and one pyridyl group, were prepared by Kro¨hnke condensation in 36–59% overall yield. Stable Pd(II)-allyl and Cu(II) chlo-
ride complexes formed by some of the ligands were obtained in 60–65% yields. X-ray crystal structure analysis of a copper(II) complex
having 1-methylimidazolyl group indicated that it is a l-chloro bridge dimer. The Pd(II)-allyl complexes were found to be active catalysts
in the asymmetric allylic substitution of 1,3-diphenylprop-2-enyl acetate. The best result observed was 85% e.e. and 99% isolated yield. In
addition, the in situ generated Cu(OTf)2 complexes were found to be active catalysts in cyclopropanation of styrene with ethyl
diazoacetate.
ꢀ 2006 Elsevier B.V. All rights reserved.
Keywords: Pyridyl; Allylic Substitution; Cyclopropanation; Palladium; Copper
1. Introduction
successfully utilized in hydrosilylation [8a] and Diels–Alder
[8b] reactions. Our group recently reported the use of C1-
symmetric pyridine ligands L3 in Cu-catalyzed allylic oxi-
dation reactions [9]. In spite of these results, heterocycles
other than oxazoline and pyridine are relatively unexplored
in the synthesis of chiral C1-symmetric ligand [10]. Aro-
matic heterocycles which have different electron density
compared to that of pyridine have different coordination
chemistry and environment. Recently, we reported biden-
tate ligand having 1,3-thiazolyl and pyridyl donors for
asymmetric allylic oxidation of cyclohexene [11] To further
develop this class of ligand, we report here several new
bidentate C1-symmetric pyridine ligands, which have het-
erocycles such as 1,3-thiazole (1 and 2), imidazole (3) or
pyrazine (4) coupled to a chiral pyridyl unit. Their applica-
tions in the asymmetric Pd-catalyzed allylic substitution of
1,3-diphenylprop-2-enyl acetate and Cu-catalyzed cyclo-
The use of nitrogen heterocycles in metal-catalyzed reac-
tions has received great attention in recent years [1]. Chiral
C2-symmetric bidentate ligands of this class, like bisoxazo-
line and bipyridine, have especially enjoyed success [2–5].
C2-Symmetric ligand can, in principle, reduce the number
of possible transition states of a reaction thus increasing
the chances of success [6]. In certain applications, however,
good results have been achieved with chiral bidentate C1-
symmetric ligands. For example, the monoterpene-derived
C1-bipyridyls L1 and amino-alcohol-derived C1-pyridino-
oxazolines L2 have been employed in Pd-catalyzed asym-
metric allylic substitutions [7]. In addition, L2 has been
*
Corresponding author.
E-mail address: bhhoik@cityu.edu.hk (H.-L. Kwong).
0022-328X/$ - see front matter ꢀ 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2006.06.050

P.-F. Teng et al. / Journal of Organometallic Chemistry 691 (2006) 5664–5672
5665
propanation of styrene with ethyl diazoacetate were
investigated.
chiral rigid substituent fused to the pyridine ring were
easily prepared by two step synthesis using 2-acetyl-1,3-thi-
azole, 2-acetyl-4-methyl-1,3-thiazole, 2-acetyl-1-methylimi-
dazole or 2-acetyl-pyrazine as the starting material and
pyridinium iodide 7–10 as intermediates (Scheme 1). For
example, the 1,3-thiazolyl-pyridine ligand 1a was prepared
by the cyclization of acetylheterocycle pyridinium iodide 7
with a,b-unsaturated ketone 5 in the presence of ammo-
nium acetate and acetic acid under reflux conditions. The
O
N
N
N
N
N
N
R1
R1
R2
R2
R
HO
L1
L2
L3
S
N
S
N
N
N
N
N
N
N
N
N
N
1a
4a
2a
3a
S
N
S
N
N
N
N
N
N
N
N
1b
2b
4b
3b
2. Results and discussion
pure compound 1a was obtained with 67% yield after puri-
fication by flash column chromatography. Modification of
the fused chiral substitute can be successfully carried out by
using a different chiral a,b-unsaturated ketone 6. Reaction
of 6 with heterocycle pyridinium iodide 7–10 leads to
ligands in moderate yields (28–48%).
2.1. Synthesis of 1,3-thiazolyl-, imidazolyl- and pyrazinyl-
pyridines ligands
The key step in the synthesis of the ligands is the assem-
bly of the pyridine unit, which involves reaction of a 1-(2-
hetaryl-2-oxoethyl)pyridinium salt with chiral a,b-unsatu-
rated ketones [12]. This synthetic approach, first reported
by von Zelewsky and co-worker [13], has been widely uti-
lized for preparation of chiral terpyridine [14], bipyridine
[7a,7b,7c] and phenyl-pyridine [15]. Ligands 1-4 having a
2.2. Synthesis and characterization of palladium complex
The C1-symmetric ligands formed a variety of com-
plexes with transition metals. Their coordination property
with palladium was demonstrated by reacting with
Ar
N
5
O
1a Ar = 2-thiazolyl-
O
2a
3a
4a
= 4-Methyl-2-thiazolyl-
= 1-Methyl-2-imidazolyl
= 2-Pyrazinyl-
O
S
I2, pyridine
100 οC, 3h
NH4OAc, HOAc
reflux
Ar
Ar
N+
I-
7
8
9
Ar = 2-thiazolyl-
Ar =
O
N
S
= 4-Methyl-2-thiazolyl-
= 1-Methyl-2-imidazolyl
= 2-Pyrazinyl-
6
10
N
Ar
NH4OAc, HOAc
N
reflux
N
N
N
1b Ar = 2-thiazolyl-
N
2b
3b
4b
= 4-Methyl-2-thiazolyl-
= 1-Methyl-2-imidazolyl
= 2-Pyrazinyl-
Scheme 1.

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P.-F. Teng et al. / Journal of Organometallic Chemistry 691 (2006) 5664–5672
[Pd(allyl)Cl]2. The [Pd(allyl)Cl]2 was mixed with ligand 1a
in CH2Cl2 for 2 h and treated with AgPF6. The complex
1
was isolated as ½PdðallylÞð1aÞꢀ½PF6ꢁꢀ in 60% yield. The H
NMR spectra of the complex exhibited characteristic differ-
ences in chemical shifts as compared with the free ligand
and the elemental analyses of the complex showed good
agreement with the theoretical calculated value.
2.3. Synthesis and X-ray structure of copper complex
The coordination property of the ligands with copper
was demonstrated by reacting with CuCl2 with 3b. A
CH2Cl2 solution of 3b was added to a solution of hydrated
CuCl2 in MeOH and a clear greenish-blue solution was
observed immediately. Evaporation of the solvent and
addition of diethyl ether led to green precipitates. Crystals
of the complex [Cu2 (3b)2(l-Cl)2Cl2] for X-ray analysis
were obtained by slow diffusion of diethyl ether into a
CH2Cl2 solution. The crystallographic data are summa-
rized in Table 1. The perspective view and atomic number-
ing of the crystal structure are shown in Fig. 1. The Cu
complex exists as a dimer which is bridged by two chloride
Fig. 1. X-ray crystal structure of [Cu2(3b)2(l-Cl)2Cl2].
ligands and results in a distorted trigonal bipyramidal
geometry. Selected bond distances and bond angles for
the complex are listed in Table 2. The N donor from the
N-methylimidazole, one of the bridging chlorides and one
terminal chloride form the trigonal plane (Cl(2)–Cu(1)–
Cl(1): 115.0ꢁ, N(2)–Cu(1)–Cl(1): 139.2ꢁ, N(2)–Cu(1)–Cl(2):
105.7ꢁ; Cl(3)–Cu(2)–Cl(4): 109.7ꢁ, N(5)–Cu(2)–Cl(3):
109.0ꢁ, N(5)–Cu(2)–Cl(4): 141.1ꢁ, while the N donor of
the pyridine ring and the remaining bridging chloride form
the apex. The two nonbridging chloro ligands are arranged
Table 1
Crystallographic data for [Cu2(3b)2(l-Cl)2Cl2]
Empirical formula
Cu2Cl4C32 N6H38
Formula weight
775.60
30
0.71073
Green
Temperature (ꢁC)
˚
Wavelength (A)
Crystal color
Crystal system
Space group
Trigonal
R3(#146)
˚
in an anti-fashion. The Cuꢂ ꢂ ꢂCu separation is 3.193 A. The
Unit cell dimensions
geometry of the copper(II) centres is intermediate between
square pyramidal and trigonal bipyramidal. This is more
precisely described by Reedijk’s s factor, which averages
0.67 (s = 0 for exact square pyramidal and s = 1 for exact
trigonal bipyramidal) [16].
˚
a (A)
29.017(4)
10.655(2)
˚
c (A)
a (ꢁ)
c (ꢁ)
b = 90
120
7769(2)
3
˚
Volume (A )
Z value
9
Density (calcd.) (g/m3)
Absorption coefficient (mmꢁ1
F0 0 0
1.492
0.991
3582
2.4. Pd-catalyzed asymmetric allylic substitution
)
The ½Pdð½allylÞð1aÞꢀþPF6 complex was found to be
ꢁ
Crystal size (mm3)
0.12 · 0.23 · 0.28
1.52–28.48ꢁ.
ꢁ12 < = h < = 12,
ꢁ24 < = k < = 24,
ꢁ14 < = l < = 25
16182
active catalyst in the substitution reaction with dimethyl
malonate, N,O-bis(trimethylsilyl)acetamide (BSA) and cat-
Theta range for data collection
Index ranges
Reflections collected
Table 2
Independent reflections [Rint
]
3914 = 0.030
95.6%
Semi-empirical from equivalents
1.00 and 0.67
Selected bond angles and bond distances for [Cu2(3b)2(l-Cl)2Cl2] complex
Completeness to theta = 28.48ꢁ
Absorption correction
Maximum and minimum
transmission
˚
Atoms
Bond angles (ꢁ) Atoms
Bond distances (A)
Cl(2)–Cu(1)–Cl(1) 115.0(1)
Cu(1)–Cl(1) 2.281(4)
Cl(3)–Cu(1)–Cl(1)
N(2)–Cu(1)–Cl(1)
N(3)–Cu(1)–Cl(1)
Cu(1)–Cl(2)–Cu(2)
Cl(3)–Cu(1)–Cl(2)
N(2)–Cu(1)–Cl(2)
N(3)–Cu(1)–Cl(3)
N(3)–Cu(1)–Cl(3)
N(3)–Cu(1)–N(2)
94.3(2)
139.2(3)
94.6(3)
92.9(1)
87.4(2)
105.7(3)
90.5(4)
170.4(3)
80.4(5)
Cu(1)–Cl(2) 2.576(4)
Cu(1)–Cl(3) 2.311(6)
Cu(1)–N(2) 1.94(4)
Cu(1)–N(3) 2.07(1)
Cu(2)–Cl(2) 2.325(6)
Cu(2)–Cl(3) 2.588(4)
Cu(2)–Cl(4) 2.249(4)
Cu(2)–N(5) 2.007(9)
Cu(2)–N(6) 2.13(2)
Refinement method
Full-matrix least-squares on F
7976/0/433
0.975
Data/restraints/parameters
Goodness-of-fit indicator
Final R indices [I > 2r(I)]
R indices (all data)
Absolute structure parameter
Largest difference in
R1 = 0.0567, wR2 = 0.0987
R1 = 0.1093, wR2 = 0.1152
ꢁ0.022(16)
ꢁ3
˚
0.953 and ꢁ0.625 e A
peak and hole

P.-F. Teng et al. / Journal of Organometallic Chemistry 691 (2006) 5664–5672
5667
Table 3
Allylic alkylation of 1,3-diphenylprop-2-enyl acetate with dimethyl malonatea
OCOCH3
CH(CO2CH3)2
* C6H5
CH2(CO2CH3)2
C6H5
C6H5
C6H5
[Pd(η3-C3H5)Cl]2 + Ligand
Entry
Ligands
Solvents
Salts
Timec, h
Yieldd
% eee
Config.f
1b
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
2a
2b
3a
3b
4a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
KOAc
KOAc
NaOAc
LiOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
30
12
20
12
72
84g
14
16
15
48
12
22
96
98
78
87
99
63
99
99
94
77
91
99
79
78
76
68
85
79
24
77
18
67
31
63
S
S
S
S
S
S
S
S
S
S
S
S
9
10
11
12
a
Reaction conditions: Ligand (10 mol%) and [Pd(g3-C3H5)Cl]2 (2.5 mol%) with 1,3-diphenylprop-2-enyl acetate (0.4 mmol), CH2(CO2Me)2 (1.2 mmol),
N,O-bis(trimethylsilyl)acetamide (BSA) (1.2 mmol) and Salt (3.5 mol%) in 2 mL solvent at room temperature.
b½PdðallylÞð1aÞꢀþPF6 was used.
b
ꢁ
c
Reaction time of reactions was monitored by TLC.
d
Isolated yields.
e
Determined by HPLC analysis using a chiral column (Chiralcel-OD).
Assigned by the comparison with sample of known configuration.
The reaction was not complete.
f
g
alytic amounts of potassium acetates at room ꢁtemperature
[17]. When the loading of ½PdðallylÞð1aÞꢀþPF6 complexes
used at 5 mol%, the reaction was completed after 30 h in
96% isolated yield and 79% e.e. (Table 3, entry 1). For a
more convenient procedure, the Pd(allyl)-complex can be
prepared in situ by reacting the ligand with [Pd(g3-
C3H5)Cl]2 in CH2Cl2 solution under nitrogen. The com-
plexes formed are effective catalysts for asymmetric allylic
substitution with a similar enantioselectivity and slightly
higher reactivity ꢁ compared to isolated complex
½PdðallylÞð1aÞꢀþPF6 as the reaction completed within
12 h even with 2.5 mol% of catalysts (Table 3, entry 2). Bet-
ter results are summarized in Table 3. Ligand 1a exhibited
the best results in terms of enantioselectivity (up to 85%
e.e.) and reactivity (12 h for complete conversion). In addi-
tion, the reaction rates of allylic substitution were much
faster in CH2Cl2 than CH3CN and THF (entries 4–6).
The acetate salts (LiOAc, NaOAc and KOAc) showed
some effects in the reaction in which the KOAc was the best
in terms of yields and enantioselectivity (entries 2–4). Other
ligands such as imidazolyl-pyridine 3 and pyrazinyl-pyri-
dine 4 were examined in order to compare the heterocyclic
effects in the allylic substitution (entries 10–12). However,
the results were not as good as the 1,3-thiazolyl-pyridine
1a. Chiral ligands from a,b-unsaturated ketone 6 in general
gave lower enantioselectivity but faster reaction when com-
pared with ligands from a,b-unsaturated ketone 5 (entry 6
vs 7, 8 vs 9 and 10 vs11).
All allylic substitutions in this study favored the (S)-con-
figuration. This preference can be readily explained if one
look at the steric environment of the ligand 3b. Fig. 2
shows the steric environment of the ligand in the crystal
structures of [Cu2(3b)2(l-Cl)2Cl2]. The bulkiness of the
ligand comes from the lower side of the ligand, which has
the dimethyl group. The distance of the two methyl car-
˚
bons, C(15) and C(16), are 5.149 and 5.501 A from the
metal center respectively whereas carbons C(11) and
˚
C(14) are 4.605 and 4.808 A away from the metal. In this
environment, the methyl group of carbon C(16) points into
the open space in the direction of the p-allyl ligand of the
palladium metal. In order to minimize the steric hindrance
between phenyl group of the p-allyl group and the methyl
group, the p-allyl would favor a ‘‘W’’ orientation shown in
the proposed intermediate in Fig. 3. Nucleophilic attack
through pathway b, which should be more favored because
of the favorable arrangement of the product, would then
afford the observed allylic product.
2.5. Cu-catalyzed asymmetric cyclopropanation
Apart from the Pd-catalyzed asymmetric allylic substitu-
tion, the application of the C1-pyridine ligands in the cop-
per-catalyzed asymmetric cyclopropanation of styrene with
ethyl diazoacetate was also investigated. The copper com-
plexes were generated in situ by stirring 2.2 mol% of ligand
and 2 mol% of Cu(OTf)2 in dry CH2Cl2 under nitrogen.

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P.-F. Teng et al. / Journal of Organometallic Chemistry 691 (2006) 5664–5672
previously with chiral terpyridine ligand in asymmetric
C(1)
cyclopropanation [14c]. Further analysis of the steric envi-
ronment of ligand 3b in Fig. 2 indeed sheds some light on
the difference. The bulky methyl group of C(16) is pointing
away from the metal center, whereas the bulky methyl
group at the 8-position of the tetrahydroquinoline ring of
3a should be pointing more towards the metal center. This
may hinder the approach of alkene from pathway d and
favors pathway c (Fig. 4). On the other hand, approach
of alkene should favor pathway c with 3a because of the
hindered rotation of the carbene moiety towards the
methyl group at the 8-position. However, as the enantiose-
lectivities obtained are not high, the exact reason for the
difference may require further investigation.
C(6)
C(7)
N(1)
C(5)
C(2)
C(4)
C(8)
C(9)
C(11)
C(3)
N(3)
C(10)
C(13)
N(2)
C(12)
Cu(1)
C(14)
C(15)
C(16)
In summary, a number of new chiral C1-symmetric 1,3-
thiazolyl-, imidazolyl- and pyrazinyl-pyridines were suc-
cessfully synthesized in moderate to good yields by using
Kro¨hnke condensation reaction. The ligands were good
for asymmetric Pd-catalyzed allylic substitution and Cu-
catalyzed cyclopropanation reactions. The best enantiose-
lectivity of the allylic substituted product was 85% e.e. with
99% isolated yield. Moreover, in the cyclopropanation of
styrene with EDA, the enantioselectivity was up to 38%
e.e. The coordination properties of the ligands with transi-
tion metals and the applications in other catalytic asym-
metric reactions are under investigation in our laboratory.
Fig. 2. Crystal structures of [Cu2(3b)2(l-Cl)2Cl2] with only the ligand and
Cu centre shown and hydrogen atoms omitted.
The complex was then activated with 0.2 equivalents of
EDA as catalysts for cyclopropanation reaction. All com-
plexes were found to be active catalysts in the reaction
and cyclopropyl esters were isolated from 46% to 90%
yields. The trans/cis ratios of the products were found
between 60:40 and 70:30. In all cases, the Cu-catalysts
favored the formation of trans-cyclopropyl esters. Selected
results are listed in Table 4. Only moderate enantioselectiv-
ities were obtained. The best case is obtained by ligand 2a
with 70% isolated yield of cyclopropyl esters and 38% e.e.
for trans-isomer and 30% e.e. for cis-isomer (Table 4, entry
3). The methyl substitutient on the 1,3-thiazole ring
increases the e.e. and six member ring pyrazine is better
compared to unsubstituted five membered 1,3-thiazolyl-
and 1-methylimidazolyl rings.
The absolute configurations of cyclopropyl ester prod-
ucts formed were determined to be (1R,2R) for the trans-
isomer and (1R,2S) for cis-isomers from the
(1R,2R,3R,5S)-(-)-isopinocampheol derived ligands (Table
4, entries 1,3,5,7). Opposite absolute configurations
(1S,2S) for the trans-isomer and (1S,2R) for cis-isomers
were obtained in the nopinone-fused pyridine ligands
(Table 4, entries 2,4,6,8). This trend is different from that
of the allylic substitution which shows the same absolute
configuration. However, similar trend has been observed
3. Experimental
3.1. General methods
Toluene was distilled over sodium under dry nitrogen.
CH2Cl2 was distilled under N2 over calcium hydride. 4-
Methyl-1,3-thiazole, 1-methylimidazole, 2-acetyl-1,3-thia-
zole and 2-acetylpyrazine were purchased from Aldrich
and used as received. Chiral a,b-unsaturated ketones 5
and 6 were prepared according to the literature procedures
[14c]. 2-Acetyl-4-methyl-1,3-thiazole and 2-acetyl-1-methy-
limidazole were readily obtained through lithiation of 4-
methyl-1,3-thiazole and 1-methylimidazole with LDA and
acylation with N,N-dimethylacetamide in THF and Et2O
respectively. Infrared spectra in the range 500–4000 cmꢁ1
as KBr plates were recorded on a Perkin Elmer Model
1
FTIR-1600 spectrometer. H and 13C NMR spectra were
recorded on a Varian 300 MHz Mercury instrument.
ESMS were recorded using a PE SCIEX API 365 mass
spectrometer. Electron ionization mass spectra were
recorded on a Hewlett–Packard 5890II GC instrument
coupled with a 5970 mass selective detector. Elemental
analyses were performed on a Vario EL elemental analyzer.
N
N
N
Pd
Ph
Ph
H C
3
CH3
3.2. Crystallographic studies
b
a
Crystal of sample was mounted on a glass fiber. All mea-
surements were made on a Bruker SMART CCD area
detector with graphite monochromated Mo Ka radiation.
Cell constants and an orientation matrix for data collection
Nu-
Nu-
Fig. 3. Proposed Pd-allyl intermediate with ligand 3b.

P.-F. Teng et al. / Journal of Organometallic Chemistry 691 (2006) 5664–5672
5669
Table 4
Asymmetric cyclopropanation of styrene with ethyl diazoacetate catalyzed by C1-heterocyclic copper complexes.
O
2 mol.% Cat.
CH2Cl2, r.t.
H
Ph
H
H
H
Ph
H
+
+
OEt
COOEt
COOEt
N2
Entry
.
Ligand
trans:cis
trans% e.e. (config.)a
cis% e.e. (config.)a
Yield (%)b
1
2
3
4
5
6
7
8
a
1a
1b
2a
2b
3a
3b
4a
4b
68 : 32
70 : 30
68 : 32
70 : 30
66 : 34
69 : 31
65 : 35
67 : 33
19 (1R,2R)
16 (1S,2S)
38 (1R,2R)
14 (1S,2S)
10 (1R,2R)
14 (1S,2S)
24 (1R,2R)
8 (1S,2S)
11 (1R,2S)
16 (1S,2R)
30 (1R,2S)
14 (1S,2R)
20 (1R,2S)
12 (1S,2R)
6 (1R,2S)
4 (1S,2R)
66
51
70
46
89
90
79
85
Enantiomeric excesses were determined by HPLC with Daicel Chiralcel OJ column. Absolute configurations were determined by comparing the order
of elution of sample with known configuration [18].
b
Isolated yield after chromatography.
corresponded to a R-centered trigonal cell (laue class: ꢁ3).
Based on the systematic absences of: hkil: ꢁh + k + l 3n,
packing considerations, a statistical analysis of intensity dis-
tribution, and the successful solution and refinement of the
structure, the space group was determined to be: R3 (#146).
The data were collected at a temperature of 30 1 ꢁC to a
maximum 2h value of 55.0ꢁ. A total of 16182 oscillation
images were collected. Of the 16182 reflections that were
collected, 3914 were unique (Rint = 0.030). Data were col-
lected and processed using CrystalClear (Rigaku). The
structure was solved by direct methods and expanded using
Fourier techniques. The non-hydrogen atoms were refined
anisotropically. Hydrogen atoms were placed at geometri-
3 h. After cooling to room temperature, the dull brown-yel-
low solid was filtered and then washed with cold ethanol.
The collected products were dried under vacuum.
3.4. Pyridinium iodide salt 7
2-Acetyl-1,3-thiazole (1.02 g) was used. Yield: 85%
1
(2.26 g). H NMR (300 MHz, DMSO-d6): d 6.48 (s, 2H),
8.05 (t, J = 6.9 Hz, 1H), 8.28–8.37 (m, 3H), 8.76 (t,
J = 7.2 Hz, 1H), 9.04 (d, J = 6.3 Hz, 2H).
3.5. Pyridinium iodide salt 8
˚
cal sites with C–H = 0.95 A and refined using the riding
2-Acetyl-4-methyl-1,3-thiazole (1.13 g) was used. Yield:
1
model. All calculations were performed using the Crystal-
Structure crystallographic software package. The structure
has been solved using space group R-3 (#148), however, the
R and Rw values are larger with some of the C & H atoms
showing signs of disorder, which support the selection of
space group R3 (#146).
90% (2.49 g). H NMR (300 MHz, DMSO-d6): d 2.56 (s,
3H), 6.44 (s, 2H), 8.04 (t, J = 7.5 Hz, 1H), 8.27–8.32 (m,
2H), 8.75 (t, J = 7.8 Hz, 1H), 9.02 (d, J = 6.6 Hz, 2H).
3.6. Pyridinium iodide salt 9
2-Acetyl-1-methyl-imidazole (0.87 g) was used. Yield:
1
3.3. Synthesis of pyridinium iodide salt
85% (2.24 g). H NMR (300 MHz, DMSO-d6): d 3.94 (s,
3H), 6.35 (s, 2H), 7.33 (s, 1H), 7.74 (s, 1H), 8.27 (t,
J = 7.8 Hz, 2H), 8.73 (t, J = 7.8 Hz, 1H), 9.01 (d,
J = 5.7 Hz, 2H).
To a pyridine solution (6 mL) of 2-acetylheterocycle
(8 mmol) was added a solution of iodine (2.03 g, 8 mmol)
in pyridine (6 mL). The mixture was heated at 110 ꢁC for
3.7. Pyridinium iodide salt 10
N
2-Acetylpyrazine (0.98 g) was used. Yield: 88% (2.30 g).
1H NMR (300 MHz, DMSO-d6): d 6.50 (s, 2H), 8.31 (t,
J = 6.9 Hz, 2H), 8.76 (t, J = 7.8 Hz, 1H), 8.99–9.01 (m,
3H), 9.09 (s, 1H), 9.25 (s, 1H).
N
N
Cu
H
H C
3
CH3
3.8. Synthesis of chiral heterocyclyl-pyridine ligands
by Kro¨hnke condensation
d
COOEt
Alkene
c
Alkene
The pyridinium iodide salt (1.5 mmol), chiral a,b-unsat-
urated ketone (4.5 mmol) and ammonium acetate (2 g)
Fig. 4. Proposed Cu carbenoid intermediates with ligand 3b.

5670
P.-F. Teng et al. / Journal of Organometallic Chemistry 691 (2006) 5664–5672
1
were added to the glacial acetic acid (2 mL). The mixture
was heated to reflux at 120 ꢁC overnight. The saturated
NaHCO3 solution was added to the reaction mixture
slowly and the resulting solution was adjusted to pH 8.
The mixture then was extracted with Et2O (3 · 50 mL).
The combined organic layers were dried over MgSO4. After
removal of solvents under reduced pressure, a brown resi-
due was obtained and then purified by flash column
chromatography.
tography gave 0.21 g (52%) of 3a. H NMR (300 MHz,
CDCl3): d 0.66 (s, 3H), 1.31 (d, J = 10.8 Hz, 1H), 1.40 (d,
J = 7.2 Hz, 3H), 1.43 (s, 3H), 2.15–2.19 (m, 1H), 2.54–
2.61 (m, 1H), 2.72–2.80 (m, 1H), 3.18–3.21 (m, 1H), 4.15
(s, 3H), 6.95 (s, 1H), 7.09 (s, 1H), 7.28 (d, J = 9.3 Hz,
1H), 7.83 (d, J = 8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d 18.10, 20.81, 26.28, 26.83, 28.61, 38.84, 40.18, 46.76,
47.10, 119.51, 123.68, 127.71, 133.46, 140.67, 145.65,
147.81, 159.30; ESI-MS m/z: 268 (M++H).
Ligand 1a: a,b-Unsaturated ketone 5 and pyridinium
iodide 7 were used. Purification by flash column chroma-
tography (petroleum ether-EtOAc = 20:1) gave 67% yield
(0.27 g) of 1b. 1H NMR (300 MHz, CDCl3): d 0.68 (s,
3H), 1.31 (d, J = 9.9 Hz, 1H), 1.43 (s, 3H), 1.44 (d,
J = 6.9 Hz, 3H), 2.15–2.20 (m, 1H), 2.55–2.62 (m, 1H),
2.81 (t, J = 5.7 Hz, 1H), 3.22–3.26 (m, 1H), 7.29 (d,
J = 7.8 Hz, 1H), 7.37 (d, J = 3.3 Hz, 1H), 7.86 (d,
J = 7.8 Hz, 1H), 7.87 (d, J = 3.3 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d 18.16, 20.97, 26.31, 28.53, 38.71,
41.49, 46.64, 47.326, 116.58, 120.44, 133.54, 143.28,
148.39, 152.21, 161.00, 170.64; ESI-MS m/z: 271 (M++H).
Ligand 1b: a,b-Unsaturated ketone 6 and pyridinium
iodide 7 were used. Purification by flash column chroma-
tography gave 45% yield (0.17 g) of 1c. 1H NMR
(300 MHz, CDCl3): d 0.71 (s, 3H), 1.33 (d, J = 9.6 Hz,
1H), 1.45 (s, 3H), 2.33–2.38 (m, 1H), 2.71–2.78 (m, 1H),
2.98 (d, J = 2.4 Hz, 2H), 3.08 (t, J = 5.4 Hz, 1H), 7.38 (d,
J = 3.0 Hz, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.88 (d,
J = 3.3 Hz, 1H), 7.97 (d, J = 7.5 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d 21.51, 26.18, 31.02, 31.62, 39.36,
40.30, 50.43, 117.49, 120.61, 131.95, 136.10, 143.93,
147.60, 166.67, 170.34; ESI-MS m/z: 257 (M++H).
Ligand 2a: a,b-Unsaturated ketone 5 and pyridinium
iodide 8 were used. Purification by flash column chroma-
tography (petroleum ether-EtOAc = 20:1) gave 65% yield
(0.28 g) of 2a. 1H NMR (300 MHz, CDCl3): d 0.67 (s,
3H), 1.31 (d, J = 9.9 Hz, 1H), 1.43 (s, 3H), 1.44 (s, 3H),
2.14–2.21 (m, 1H), 2.54 (s, 3H), 2.56–2.61 (m, 1H), 2.80
(t, J = 5.4 Hz, 1H), 3.21–3.25 (m, 1H), 6.95 (d,
J = 0.9 Hz, 1H), 7.27 (s, 1H), 7.95 (d, J = 7.5 Hz, 1H);
13C NMR (75 MHz, CDCl3): d 17.30, 18.11, 20.91, 26.28,
28.50, 38.66, 41.42, 46.61, 47.24, 115.12, 116.26, 133.33,
143.08, 148.60, 153.62, 160.80, 169.64; ESI-MS m/z: 285
(M++H).
Ligand 3b: a,b-Unsaturated ketone 7 and pyridinium
iodide 9 were used. Purification by flash column chroma-
tography gave 28% yield (0.11 g) of 3b. 1H NMR
(300 MHz, CDCl3): d 0.68 (s, 3H), 1.33 (d, J = 9.6 Hz,
1H), 1.44 (s, 3H), 2.30–2.37 (m, 1H), 2.70–2.77 (m, 1H),
2.89–2.92 (m, 1H), 2.97–3.00 (m, 2H), 4.11 (s, 3H), 6.94
(s, 1H), 7.09 (s, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.91 (d,
J = 8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 21.51,
26.07, 30.80, 31.19, 36.05, 40.22, 40.32, 50.42, 120.47,
123.64, 127.83, 129.02, 135.77, 145.61, 146.46, 164.92;
ESI-MS m/z: 254 (M++H).
Ligand 4a: a,b-Unsaturated ketone 5 and pyridinium
iodide 10 were used. Purification by flash column chroma-
tography gave 48% yield (0.19 g) of 4a. 1H NMR
(300 MHz, CDCl3): d 0.69 (s, 3H), 1.34 (d, J = 9.9 Hz,
1H), 1.45 (s, 3H), 1.48 (d, J = 6.9 Hz, 3H), 2.14–2.25 (m,
1H), 2.57–2.64 (m, 1H), 2.78–2.85 (m, 1H), 3.24–3.34 (m,
1H), 7.35 (d, J = 7.5 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H),
8.55–8.59 (m, 2H), 9.68 (s, 1H); 13C NMR (75 MHz,
CDCl3): d 18.16, 20.88, 26.25, 28.50, 38.85, 41.39, 46.64,
47.20, 118.24, 133.53, 143.05, 143.20, 143.34, 143.62,
151.18, 151.82, 160.73; ESI-MS m/z: 266 (M++H).
Ligand 4b: a,b-Unsaturated ketone 6 and pyridinium
iodide 10 were used. Purification by flash column chroma-
tography gave 48% yield (0.19 g) of 4b. 1H NMR
(300 MHz, CDCl3): d 0.70 (s, 3H), 1.34 (d, J = 10.2 Hz,
1H), 1.45 (s, 3H), 2.33–2.39 (m, 1H), 2.73–2.80 (m, 1H),
3.00–3.04 (d, J = 2.4 Hz, 1H), 3.10–3.14 (t, J = 5.7 Hz,
1H), 7.55 (d, J = 7.8 Hz, 1H), 8.10–8.13 (d, J = 7.8 Hz,
1H), 8.54–8.58 (d, J = 12.3 Hz, 2H), 9.60 (s, 1H) ppm;
13C NMR (75 MHz, CDCl3): d 21.27, 25.96, 30.74, 31.28,
39.11, 39.97, 50.32, 119.24, 131.64, 136.03, 143.14,
143.49, 143.62, 149.77, 151.72, 166.32 ppm; ESI-MS m/z:
252 (M++H).
Ligand 2b: a,b-Unsaturated ketone 6 and pyridinium
iodide 8 were used. Purification by flash column chroma-
tography gave 48% yield (0.19 g) of 2b. 1H NMR
(300 MHz, CDCl3): d 0.68 (s, 3H), 1.33 (d, J = 9.9 Hz,
1H), 1.40 (s, 3H), 2.27–2.36 (m, 1H), 2.51 (s, 3H), 2.64–
2.88 (m, 1H), 2.97 (d, J = 2.4 Hz, 2H), 3.07 (t,
J = 5.7 Hz, 1H), 6.92 (s, 1H), 7.49 (d, J = 7.8 Hz, 1H),
7.93 (d, J = 7.8 Hz, 1H); 13C NMR (75 MHz, CDCl3): d
17.34, 21.26, 26.10, 31.03, 31.37, 39.24, 40.30, 50.21,
115.12, 117.22, 131.49, 135.77, 147.43, 153.85, 161.33,
166.38; ESI-MS m/z: 271 (M++H).
3.9. Preparation of pþalladium allyl complex
ꢁ
½Pdðg3 ꢁ C3H5Þð1aÞꢀ PF6
The [Pd(g3-C3H5)Cl]2 complex (40 mg, 0.11 mmol) and
ligand 1a (62 mg, 0.23 mmol) were dissolved a in CH2Cl2
(6 mL) solution at room temperature and a THF solution
(5 mL) of AgPF6 (60 mg, 0.24 mmol) was then added. After
reaction for 10 min, the resulting solution was filtered
through a Celit-packed column. The filtrate was washed with
saturated NaCl solution. After drying with MgSO4 and
evaporation of solvent, the ½Pdðg3 ꢁ C3H5Þð1aÞꢀþPF6ꢁ com-
1
Ligand 3a: a,b-Unsaturated ketone 5 and pyridinium
iodide 9 were used. Purification by flash column chroma-
plex was isolated as a white solid in 60% yield (78 mg). H
NMR (300 MHz, CDCl3): d 0.71 (s, 3H), 1.34 (d,

P.-F. Teng et al. / Journal of Organometallic Chemistry 691 (2006) 5664–5672
5671
J = 6.6 Hz, 1H), 1.45–1.47 (m, 6H), 2.25–2.38 (m, 1H), 2.62–
2.29 (m, 1H), 2.96 (t, J = 5.4 Hz, 1H), 3.17–3.29 (m, 3H),
4.42–4.45 (m, 2H), 5.67–5.82 (m, 1H), 7.60 (d, J = 7.8 Hz,
1H), 7.82 (s, 1H), 7.93 (d, J = 7.8 Hz, 1H), 8.08 (d,
J = 3 Hz, 1H).
umn. Absolute configurations were determined by compar-
ing the order of elution with samples of known
configurations [18]. The diastereoselectivities (trans/cis
ratio) were measured by GC with Ultra 2-crosslinked 5%
PhMesilcone (25 m · 0.2 mm · 0.33 lm) column.
3.10. Preparation of copper chloride complexes
Acknowledgement
3.10.1. Cu(3b)Cl2 complex
Financial support for this research project from the
Hong Kong Research Grants Council CERG grant (CityU
101203) and the City University of Hong Kong (9610020)
are gratefully acknowledged.
A solution of ligand 3b (25 mg, 0.1 mmol) in CH2Cl2
(5 mL) was added to a solution of CuCl2u2H2O (18 mg,
0.1 mmol) in EtOH (5 mL). The mixture was stirred for 2
h. Greenish blue solution was observed immediately. The
solvent was evaporated and the resulting solid was recrys-
tallized from CH2Cl2/diethyl-ether mixture to give 65%
yield (25 mg) of Cu(3b)Cl2 complex as a yellow solid. Anal.
Calcd for CuN3Cl2C16H19: C, 49.56; H, 4.94; N, 10.84.
Found: C, 48.47; H, 4.95; N, 10.69%. ESI-MS m/z: 351
(MꢁCl).
Appendix A. Supplementary data
CCDC 606930 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free
of charge via http://www.ccdc.cam.ac.uk/conts/retriev-
ing.html, or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
(+44) 1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk.
CCDC . Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.jorganchem.2006.06.050.
3.11. General procedures for Pd-catalyzed allylic substitution
The [Pd(g3-C3H5)Cl]2 complex (4 mg, 0.01 mmol) and
the chiral ligand (0.04 mmol) were dissolved in dry CH2Cl2
solvent (1 mL) under N2 and stirred for 1 h at room tem-
perature. The racemic 1,3-diphenyl-2-propenyl acetate
(0.10 g, 0.4 mmol) in dry CH2Cl2(1 mL) was added drop-
wise into the solution. The dimethylmalonate (0.105 mL,
1.2 mmol), BSA (0.37 mL, 1.2 mmol) and acetate salts
(1.4 mg, 3.5 mol%) were added sequentially to the reaction
mixture at room temperature. The reaction was then mon-
itored by TLC. After complete reaction, the mixture was
diluted with H2O and CH2Cl2. The organic layer was sep-
arated, washed with brine and dried over MgSO4. The fil-
trate was concentrated under reduced pressure. The
product of dimethyl 1,3-diphenylprop-2-enylmalonate
was purified by flash column chromatography. The e.e.
were determined by HPLC (Daicel chiralcel-OD column;
mobile phase: 2-propanol/hexane = 1/100, flow rate:
0.5 mL/min, UV 254 nm, tR: 28.5 min, tS: 31.5 min).
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