Highly enantioselective conjugate addition of diethylzinc to substituted chalcones catalyzed by Cu(II) complexes of a tridentate P,N,O ligand

Article abstract of DOI:10.1016/j.tetasy.2008.02.027

A new series of tridentate P,N,O ligands having hard and soft donor atoms derived from chiral amino alcohols were developed and employed in the Cu(II)-catalyzed conjugate addition of diethylzinc to substituted chalcones. The asymmetric additions to a variety of substituted chalcones afforded products in excellent yields and good to excellent enantioselectivities up to 97% ee.

Full text of DOI:10.1016/j.tetasy.2008.02.027

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 733–738
Highly enantioselective conjugate addition of diethylzinc to substituted
chalcones catalyzed by Cu(II) complexes of a tridentate P,N,O ligand
Deepak Baburao Biradar and Han-Mou Gau*
Department of Chemistry, National Chung Hsing University, Taichung 402, Taiwan, ROC
Received 28 January 2008; accepted 22 February 2008
Abstract—A new series of tridentate P,N,O ligands having hard and soft donor atoms derived from chiral amino alcohols were developed
and employed in the Cu(II)-catalyzed conjugate addition of diethylzinc to substituted chalcones. The asymmetric additions to a variety of
substituted chalcones afforded products in excellent yields and good to excellent enantioselectivities up to 97% ee.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
both a hard oxygen and a soft phosphorus donor are rare
and only a few examples of these ligands have been re-
ported for palladium-catalyzed allylation reactions14 or
ruthenium-catalyzed hydrogenation reactions.15
The asymmetric conjugate addition of organometallic re-
agents to unsaturated carbonyl compounds is one of the
most useful techniques for C–C bond formation in organic
synthesis. Stoichiometric reactions accompanied with chi-
ral auxiliaries were successfully developed in earlier studies.
Recently, catalytic conjugate additions have attracted
much attention.1 The first breakthrough in using sub-
stoichiometric nickel complexes of ephedrine was demon-
strated by Soai et al.2 In recent studies of metal-catalyzed
1,4-additions using Grignard or dialkylzinc reagents,
chiral copper and nickel complexes are the most widely
investigated catalytic systems for inducing high enantio-
selectivities. For chiral ligands, phosphorus amidites,3
TADDOL-derived phosphates,4 and biphenol-based
phosphoramidites5 had been established to have remark-
able stereocontrol in the ZnEt2 addition to cyclic enones.
In addition, diphosphine,6 diphosphite,7 P,N ligands,8
spiro-phosphoramidites,9 and aminophosphine10 are also
efficient for this transformation. The catalytic systems for
ZnEt2 additions to acyclic enones are less common com-
pared with additions to cyclic enones.11 Recently, Hoveyda
et al.12 developed catalytic systems of peptidic phosphines
to induce high enantioselectivities for various acyclic enon-
es. Furthermore, some tridentate phosphorus-containing
amines or imines were demonstrated recently for conjugate
additions.13 However, tridentate P,N,O ligands containing
In continuation of our efforts to develop chiral ligands
derived from amino alcohols for asymmetric catalysis,16
we herein report the preparations of a series of chiral
P,N,O Schiff base ligands 2a–d and their application in
copper-catalyzed asymmetric additions of ZnEt2 to substi-
tuted chalcones. The addition reactions afforded the
desired products in good to excellent enantioselectivities
up to 97% ee.
2. Results and discussion
Amino alcohols 1a–d having one or two stereogenic centers
were prepared from L-amino acids according to standard
procedures. Treatment of amino alcohols with 2-diph-
enylphosphinobenzaldehyde in refluxing ethanol for 3–5 h
afforded chiral tridentate P,N,O ligands 2a–d in quantita-
tive yields (Scheme1). These ligands were characterized
by 1H, 13C, 31P NMR, and elemental analysis, and 1H
NMR spectra reveal a doublet at d 8–9 ppm for the imine
proton due to coupling to the phosphorus atom. In addi-
tion, 13C NMR spectra show a doublet at d 160–162 ppm
for the imine carbon, and 31P resonances appear at d ꢀ8
to ꢀ12 ppm.
The reaction conditions of the asymmetric 1,4-additions to
chalcones were optimized with the use of 5 mol % Cu-
(acac)2 and 5 mol % ligands 2a–d as the catalyst; the results
*
Corresponding author. Tel.: +886 4 22878615; fax: +886 4 22862547;
e-mail: hmgau@dragon.nchu.edu.tw
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.02.027

734
D. B. Biradar, H.-M. Gau / Tetrahedron: Asymmetry 19 (2008) 733–738
R2
R1
CuCl2, which gave 90% conversion. However, lower
R3
enantioselectivities of 26%, 23%, 21%, and 36% were ob-
served. Studies of solvent effects in CH2Cl2, THF, hexane,
or Et2O were subsequently examined (entries 5–8) and it
was found that the reaction carried out in Et2O afforded
the product in 70% ee (entry 8) at best. For reactions con-
ducted in Et2O at lower temperatures of ꢀ20 and ꢀ40 °C,
enantioselectivities increase to 72% ee and 79% ee (entries 9
and 10). When the reaction was carried out in a mixed sol-
vent of hexane and Et2O at ꢀ40 °C, the enantioselectivity
further improved to 83% ee (entry 11).
CHO
PPh2
R2
R1
R3
H2N
EtOH
N
OH
+
reflux 3-5 h
OH
PPh2
1a-d
2a: R1 = H, R2 = H, R3 = Bn
2b: R1 = Ph, R2 = H, R3 = Bn
2c: R1 = Ph, R2 = Ph, R3 = Bn
2d: R1 = Ph, R2 = Ph, R3
= i-Pr
Scheme 1. Preparation of ligands.
We then explored the scope of asymmetric conjugate 1,4-
additions of diethylzinc to substituted chalcones using the
best performing catalytic system and the results are listed
in Table 2. Substituents of the R0 group at the ortho-,
meta-, or para-position on the phenyl group attached to
the carbonyl carbon were investigated first. For example,
for R0 of the methoxy substituent, 1,4-additions afforded
products in similar enantioselectivities of 81%, 85%, and
80% ee (entries 1–3). In comparison with 83% ee for the
simple chalcone, effects of the substituted positions of the
R0 group are minimal. In contrast, substantial effects of
substituted positions of the R00 substituent are observed.
For R00 of 2-methoxy, the addition product was obtained
in an excellent 96% ee (entry 4) compared with products
in 78% and 84% ee (entries 5 and 6) for R00 of 3-methoxy
or 4-methoxy, respectively. A similar effect of the ortho-
substituted group, which enhances the stereoselectivities
of the products, was also observed by Wang et al.8e To fur-
ther verify the effect, substituted chalcones having the
ortho-substituted R00 group were then investigated. For
are summarized in Table 1. In ligand 2a, having R1 and R2
as both H atoms, the asymmetric 1,4-addition of ZnEt2 to
the chalcone in toluene gave the product in 100% yield but
with a low enantioselectivity of 14% ee (entry 1). In 2b,
with R1 as a Ph substituent and R2 as an H atom, the addi-
tion reaction afforded the product with an enantioselectiv-
ity of 21% ee (entry 2). In 2c, where both R1 and R2 were
Ph groups, the product was obtained in 48% ee (entry 3). In
2d, tuning the R3 of the ligand to the i-Pr substituent
instead of the Bn group afforded the product in a low
enantioselectivity of 5% ee (entry 4). This study clearly
demonstrates that the steric bulkiness of R1 and R2 plays
a key role in stereoselectivities, and the best catalytic sys-
tem is derived from ligand 2c where both R1 and R2 are
Ph groups. Stereoselectivities are also sensitive to the R3
group. In ligand 2c, where R3 is a Bn substituent, a higher
enantioselectivity was induced compared with the i-Pr sub-
stituent. We also screened different copper salts such as
Cu(OTf)2, Cu(OTf)2ꢁTol, CuCl2, and Cu(OAc)2. All cop-
per salts gave the product in 100% conversion except for
Table 2. Asymmetric 1,4-addition of ZnEt2 to substituted chalcones
catalyzed by the catalytic system of 5 mol % 2c/Cu(acac)2
Table 1. Asymmetric ZnEt2 addition to chalcone catalyzed by in situ
formed copper complexes of P,N,O ligandsa
a
O
O
O
O
5 mol% 2c
5 mol% 2
5 mol% Cu(acac)2
5 mol% Cu(acac)2
+
Hex/Et2O, -40 oC, 16 h
R"
+
R'
R"
2 Eq. ZnEt2
R'
Solvent, Temp, 16 h
2 Eq. ZnEt2
Entry
R0
R00
Yieldb (%)
eec (%)
Entry Ligand Solvent
Temp. (°C) Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2-OMe
H
H
H
94
94
93
98
92
89
98
96
97
98
96
95
98
95
81
85
80
96
78
84
97
93
96
96
95
94
97
94
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2c
2c
2c
2c
2c
2c
2c
Toluene
Toluene
Toluene
Toluene
CH2Cl2
THF
Hex
Et2O
Et2O
Et2O
0
0
0
100
95
100
91
14 (S)
21 (S)
48 (S)
5 (S)
3-OMe
4-OMe
H
H
H
3-OMe
4-OMe
H
2-OMe
3-OMe
4-OMe
2-OMe
2-OMe
2-Br
2-Cl
2-Br
2-Br
2-Cl
0
0
0
0
0
100
90
50 (S)
36 (S)
68 (S)
70 (S)
72 (S)
79 (S)
83 (S)
100
100
100
100
100
ꢀ20
H
10
11
ꢀ40
3-OMe
4-OMe
3-OMe
4-OMe
Hex/Et2Od ꢀ40
a Chalcone/diethylzinc/Cu(acac)2/ligand = 0.25:0.50:0.0125:0.0125 mmol;
solvent, 4 mL.
2-Cl
b Yields were calculated from the 1H NMR multiplet at 8.07 ppm of
chalcone and the multiplet at ꢂ7.91 ppm of the product.
c Ee values were determined by HPLC analysis with a Chiralcel OJ column
from Daicel.
a Chalcone/diethylzinc/Cu(acac)2/ligand = 0.25:0.50:0.0125:0.0125 mmol;
Hex/Et2O = 2/2 mL.
b Isolated yields.
c ee values were determined by HPLC analysis with a Chiralcel-OD or OJ
columns from Daicel.
dHex/Et2O = 2/2 mL.

D. B. Biradar, H.-M. Gau / Tetrahedron: Asymmetry 19 (2008) 733–738
735
substituted chalcones having R00 of 2-methoxy but R0 of
4.3. General procedures for the synthesis of ligands 2a–2d
solution of 2-diphenylphosphinobenzaldehyde
either 3-methoxy or 4-methoxy, the addition products were
obtained in excellent 97% and 93% ee (entries 7 and 8). For
substituted chalcones with R0 of H but with R00 of 2-Br or
2-Cl, both products were obtained in excellent 96% ee (en-
tries 9 and 10). For substituted chalcones having R00 of 2-Br
but R0 of either 3-methoxy or 4-methoxy, the addition
products were obtained in excellent 95% and 94% ee (en-
tries 11 and 12). Similarly, the additions to substituted
chalcones with R00 of 2-Cl afforded products in 97% and
94% ee (entries 13 and 14).
A
(1.00 mmol, 0.289 g) in 5 mL dry EtOH was added to a
solution of amino alcohol (1.05 mmol) and Na2SO4
(2.50 mmol, 0.355 g) in 5 mL dry EtOH. The mixture was
heated at reflux for 3–5 h under nitrogen. The mixture
was filtered and reduced under reduced pressures to pro-
duce a yellow liquid. Diethyl ether (3 mL) was then added
and the solvent was removed to give the product in quan-
titative yield.
4.3.1.
(S)-2-(2-(Diphenylphosphino)benzylideneamino)-3-
phenylpropan-1-ol 2a. A yellow semisolid compound was
25
3. Conclusion
obtained in quantitative yield. ½aꢃD ¼ ꢀ117:0 (c 1,
CH2Cl2). 1H NMR (400 MHz, CDCl3): d 8.29 (d, J =
3.6 Hz, 1H, CH@N), 7.60–6.87 (m, 19H, ArH), 3.58–3.55
(m, 2H, CH2OH), 3.43–3.40 (m, 1H, CHN), 2.71 (dd,
J = 5.2, 13.6 Hz, 1H, PhCHAHB), 2.48 (dd, J = 8.4,
13.6 Hz, 1H, PhCHAHB), 1.87 (br, 1H, OH) ppm.
In conclusion, a new series of P,N,O Schiff base ligands
containing both hard and soft donors have been prepared
and the best performing catalytic system of 5 mol % 2c/
Cu(acac)2 was successfully applied to asymmetric 1,4-con-
jugate additions of diethylzinc to substituted chalcones to
afford products in high yields with enantioselectivities up
to 97% ee. This study has shown that the ortho-substituted
R00 bearing lone-paired electrons such as Cl, Br, or methoxy
enhances stereoselectivities of the 1,4-addition products.
To the best of our knowledge, the above-mentioned cata-
lytic system gives the highest enantioselectivities with excel-
lent yields for substituted chalcone substrates derived from
ortho-substituted benzaldehyde and meta- or para-substi-
tuted acetophenones.
13C{1H} NMR (100 MHz, CDCl3):
d
160.47 (d,
J = 9.2 Hz, C@N), 139.21, 139.05, 138.51, 137.88, 137.77,
137.70, 137.64, 137.31, 137.11, 134.12, 134.00, 133.92,
133.69, 133.50, 129.77, 129.43, 129.25, 128.61, 128.48,
128.41, 128.33, 128.04, 125.97, 73.76, 65.77, 38.71 ppm.
31P NMR (162 MHz, CDCl3): d ꢀ8.74 (s) ppm. Anal.
Calcd for C28H26NOP: C, 79.41; H, 6.19; N, 3.31. Found:
C, 79.03; H, 6.24; N, 2.87.
4.3.2. (1R,2S)-2-[2-(Diphenylphosphino)-benzylideneamino]-
1,3-diphenylpropan-1-ol 2b. A yellow solid was obtained
25
in quantitative yield. ½aꢃD ¼ ꢀ87:5 (c 1, CH2Cl2) 1H
NMR (400 MHz, CDCl3): d 8.12 (d, J = 3.6 Hz, 1H,
CH@N), 7.58–6.89 (m, 22H, ArH), 6.55–6.53 (m, 2H,
ArH), 4.72 (d, J = 3.2 Hz, 1H, CHOH), 3.58 (br, 1H,
OH), 3.51–3.47 (m, 1H, CHN), 2.64–2.54 (m, 2H, PhCH2)
ppm. 13C{1H} NMR (100 MHz, CDCl3): d 160.20 (d,
J = 9.1 Hz, C@N), 140.54, 139.33, 139.10, 138.94, 137.79,
137.73, 137.66, 137.39, 137.18, 134.33, 134.19, 133.99,
133.83, 133.63, 130.32, 130.27, 129.89, 129.50, 129.21,
128.69, 128.65, 128.60, 128.53, 128.47, 128.34, 128.16,
128.03, 127.80, 127.17, 126.33, 125.64, 78.70, 76.53,
34.69 ppm. 31P NMR (162 MHz, CDCl3): d ꢀ9.37 (s)
ppm. Anal. Calcd for C34H30NOP: C, 81.74; H, 6.05; N,
2.80. Found: C, 80.72; H, 6.08; N, 2.63.
4. Experimental
4.1. General
1H NMR and 13C spectra were obtained with a Varian
Mercury-400 (1H, 400 MHz; 13C, 100 MHz) spectrometer,
and chemical shifts were measured relative to tetramethyl-
silane as the internal reference. 31P NMR spectra were
recorded with the Varian Mercury-400 (162 MHz)
spectrometer, and chemical shifts were relative to H3PO4,
85% (31P, 0.0 ppm) as an external standard. Elemental
analysis were performed using a Heraeus CHN-OS-RA-
PID instrument and Mass spectroscopy were performed
by using MAT 95 XL ThermoQuest Finnigan and JMS-
SX/SX 102A Tendam Mass Spectrometer.
4.3.3. (S)-2-(2-(Diphenylphosphino)benzylideneamino)-1,1,3-
triphenylpropan-1-ol 2c. A yellow solid was obtained in
25
1
quantitative yield. ½aꢃD ¼ ꢀ83:5 (c 1, CH2Cl2) H NMR
(400 MHz, CDCl3): d 7.88 (d, J = 3.2 Hz, 1H, CH@N),
7.67–6.65 (m, 29H, ArH), 4.34 (s, 1H, CHN), 4.31 (s, 1H,
OH), 2.79–2.65 (m, 2H, PhCH2), ppm. 13C{1H} NMR
(100 MHz, CDCl3): d 161.10 (d, J = 9.2 Hz, C@N),
146.94, 144.49, 139.73, 138.98, 138.81, 138.16, 138.03,
137.93, 137.24, 137.02, 134.63, 133.91, 133.85, 133.71,
133.65, 133.56, 130.60, 130.56, 129.78, 129.63, 129.23,
128.86, 128.61, 128.58, 128.55, 128.50, 128.48, 128.45,
128.37, 128.27, 127.89, 127.79, 127.22, 126.90, 126.85,
126.48, 126.02, 125.76, 79.50, 79.30, 36.88 ppm. 31P
NMR (162 MHz, CDCl3): d ꢀ10.16 (s) ppm. Anal. Calcd
for C40H34NOP: C, 83.45; H, 5.95; N, 2.43. Found: C,
83.46; H, 6.03; N, 2.23.
4.2. Reagents and solvents
Amino alcohols with one or two stereogenic centers were
synthesized based on the modified procedures reported by
Reetz et al.17 Diphenylphosphinobenzaldehyde was synthe-
sized based on procedures reported by Hoots et al.18 Dieth-
ylzinc was purchased from Aldrich. Absolute ethanol was
dried over CaH2 and freshly distilled prior to use. Other
solvents were dried by refluxing for at least 24 h over
P2O5 (dichloromethane) or sodium-benzophenone and
were freshly distilled prior to use. All syntheses and manip-
ulations were carried out under a dry nitrogen atmosphere.

736
D. B. Biradar, H.-M. Gau / Tetrahedron: Asymmetry 19 (2008) 733–738
4.3.4.
(S)-2-(2-(Diphenylphosphino)benzylideneamino)-3-
hexane/i-PrOH = 99:1, 0.5 mL/min, tmajor = 17.3 min,
tminor = 19.8 min.
methyl-1,1-diphenylbutan-1-ol 2d. A yellow solid was ob-
25
tained in quantitative yield. ½aꢃD ¼ ꢀ16:05 (c 1, CH2Cl2)
1H NMR (400 MHz, CDCl3): d 8.70 (d, J = 4.8 Hz, 1H,
CH@N), 7.68–6.80 (m, 24H, ArH), 4.12 (br, 1H, OH),
4.01 (d, J = 2.4 Hz, 1H, CHN), 1.86 (dsept, J = 2.4, 6.8,
6.8 Hz, 1H, CH3CHCH3), 0.71 (d, J = 6.8 Hz, 3H, CH3),
0.51 (d, J = 6.8 Hz, 3H, CH3) ppm. 13C{1H} NMR
(100 MHz, CDCl3): d 161.11 (d, J = 16.9 Hz, C@N),
147.85, 146.11, 144.80, 143.65, 139.36, 137.28, 137.17,
137.07, 136.88, 136.78, 134.63, 133.99, 133.97, 133.94,
133.81, 133.77, 133.75, 133.55, 130.21, 129.12, 129.08,
129.03, 128.77, 128.66, 128.59, 128.52, 128.33, 128.30,
128.27, 128.23, 128.06, 127.95, 127.78, 127.67, 127.38,
126.96, 126.72, 126.18, 126.07, 125.89, 125.66, 125.59,
88.08, 87.95, 87.88, 80.64, 79.89, 73.74, 29.18, 22.25,
21.97, 17.89, 17.48 ppm. 31P NMR (162 MHz, CDCl3): d
ꢀ12.08 (s) ppm. Anal. Calcd for C36H34NOP: C, 81.95;
H, 6.50; N, 2.65. Found: C, 82.13; H, 6.29; N, 2.62.
4.4.3. 1-(4-Methoxyphenyl)-3-phenylpentan-1-one (entry 3 in
Table 2). This compound was obtained in 93% yield.
25
½aꢃD ¼ ꢀ21:65 (c 1, CH2Cl2). 1H NMR (400 MHz, CDCl3):
d 7.91–7.87 (m, 2H), 7.30–7.16 (m, 5H), 6.92–6.88 (m, 2H),
3.86 (s, 3H), 3.25–3.17 (m, 3H), 1.81–1.73 (m, 1H), 1.67–
1.56 (m, 1H), 0.80 (t, J = 7.2 Hz, 3H) ppm. 13C{1H}
NMR (100 MHz, CDCl3): d 197.75, 163.32, 144.81,
130.41, 130.31, 128.34, 127.62, 126.18, 113.63, 55.39,
45.24, 43.21, 29.15, 12.03 ppm. Enantiomeric excess:
80%, Chiralcel OD, hexane/i-PrOH = 99:1, 1.0 mL/min,
tmajor = 13.2 min, tminor = 15.4 min.
4.4.4. 3-(2-Methoxyphenyl)-1-phenylpentan-1-one (entry 4 in
Table 2). This compound was obtained in 98% yield.
25
1
½aꢃD ¼ ꢀ11:7 (c 1, CH2Cl2). H NMR (400 MHz, CDCl3):
d 7.95–7.91 (m, 2H), 7.55–7.51 (m, 1H), 7.45–7.41 (m, 2H),
7.19–7.15 (m, 2H), 6.92–6.89 (m, 1H), 6.84 (d, J = 8.4 Hz,
1H), 3.78 (s, 3H), 3.68–3.61 (m, 1H), 3.30 (dd, J = 6.4,
16.0 Hz, 1H), 3.20 (dd, J = 7.6, 15.6 Hz, 1H), 1.79–1.69
(m, 2H), 0.80 (t, J = 7.2 Hz, 3H) ppm. 13C{1H} NMR
(100 MHz, CDCl3): d 199.80, 157.49, 137.40, 132.67,
132.51, 128.39, 128.14, 128.08, 127.10, 120.53, 110.72,
55.27, 44.55, 37.09, 27.25, 12.08 ppm. Enantiomeric excess:
96%, Chiralcel OD, hexane/i-PrOH = 99:1, 1.0 mL/min,
tmajor = 7.6 min, tminor = 10.6 min.
4.4. General procedures for the asymmetric conjugate
additions of diethylzinc to substituted chalcones
A suspension of Cu(acac)2 (33.0 mg, 0.0125 mmol) and the
ligand (0.0125 mmol) in 2 mL hexane was stirred for 1.5 h
at room temperature under a dry nitrogen atmosphere. The
mixture was cooled to ꢀ40 °C and stirred for 10 min. To
the solution, diethylzinc (0.50 mmol, 0.50 mL of 1.0 M
solution in hexane) was added slowly and the mixture
was stirred for another 15 min followed by the addition
of a solution of chalcone (0.25 mmol) in 2 mL diethyl ether.
The solution was stirred at ꢀ40 °C for 16 h, quenched with
saturated aqueous NH4Cl solution (4 mL), and extracted
with diethyl ether (2 ꢄ 15 mL). The combined organic layer
was dried over MgSO4 and concentrated under reduced
pressure to give a crude product, which was purified by col-
umn chromatography using hexane/EtOAc as eluant to
afford the ethylated product for HPLC analysis.
4.4.5. 3-(3-Methoxyphenyl)-1-phenylpentan-1-one (entry 5 in
Table 2). This compound was obtained in 92% yield.
25
1
½aꢃD ¼ ꢀ5:3 (c 1, CH2Cl2). H NMR (400 MHz, CDCl3):
d 7.92–7.89 (m, 2H), 7.56–7.51 (m, 1H), 7.45–7.41 (m,
2H), 7.23–7.19 (m, 1H), 6.84–6.71 (m, 3H), 3.79 (s, 3H),
3.31–3.18 (m, 3H), 1.82–1.72 (m, 1H), 1.68–1.57 (m, 1H),
0.81 (t, J = 7.2 Hz, 3H) ppm. 13C{1H} NMR (100 MHz,
CDCl3): d 199.17, 159.65, 146.44, 137.33, 132.86, 129.33,
128.51, 128.05, 120.06, 113.69, 111.28, 55.12, 45.56,
43.07, 29.12, 12.05 ppm. Enantiomeric excess: 78%, Chiral-
cel OD, hexane/i-PrOH = 99:1, 1.0 mL/min, tmajor
10.1 min, tminor = 11.3 min.
=
4.4.1. 1-(2-Methoxyphenyl)-3-phenylpentan-1-one (entry 1 in
Table 2). This compound was obtained in 94% yield.
25
½aꢃD ¼ ꢀ16:05 (c 1, CH2Cl2). 1H NMR (400 MHz, CDCl3):
4.4.6. 3-(4-Methoxyphenyl)-1-phenylpentan-1-one (entry 6 in
Table 2). This compound was obtained in 89% yield.
d 7.48–6.92 (m, 9H), 3.86 (s, 3H), 3.29 (d, J = 2.0 Hz, 1H),
3.27 (d, J = 0.4 Hz, 1H), 3.19–3.12 (m, 1H), 1.79–1.68 (m,
1H), 1.65–1.54 (m, 1H), 0.78 (t, J = 7.2 Hz, 3H) ppm.
13C{1H} NMR (100 MHz, CDCl3): d 202.07, 158.09,
145.00, 132.99, 130.10, 129.09, 128.19, 127.71, 126.00,
120.63, 111.37, 55.45, 50.58, 43.20, 29.33, 12.03 ppm.
Enantiomeric excess: 81%, Chiralcel OJ, hexane/i-
25
1
½aꢃD ¼ ꢀ14:3 (c 1, CH2Cl2). H NMR (400 MHz, CDCl3):
d 7.91–7.88 (m, 2H), 7.55–7.51 (m, 1H), 7.45–7.41 (m, 2H),
7.16–7.12 (m, 2H), 6.84–6.81 (m, 2H), 3.77 (s, 3H), 3.26–
3.15 (m, 3H), 1.81–1.71 (m, 1H), 1.66–1.55 (m, 1H), 0.80
(t, J = 7.6 Hz, 3H) ppm. 13C{1H} NMR (100 MHz,
CDCl3): d 199.38, 158.01, 137.37, 136.71, 132.83, 128.49,
128.06, 113.81, 55.20, 45.84, 42.30, 29.35, 12.05 ppm.
Enantiomeric excess: 84%, Chiralcel OD, hexane/
PrOH = 99:1, 1.0 mL/min, tminor = 15.9 min, tmajor
=
25.9 min.
i-PrOH = 99.5:0.5, 0.4 mL/min, tminor = 33.5 min, tmajor
=
4.4.2. 1-(3-Methoxyphenyl)-3-phenylpentan-1-one (entry 2 in
Table 2). This compound was obtained in 94% yield.
36.3 min.
25
1
½aꢃD ¼ ꢀ16 (c 1, CH2Cl2). H NMR (400 MHz, CDCl3):
d 7.50–7.06 (m, 9H), 3.83 (s, 3H), 3.31–3.21 (m, 3H),
1.83–1.73 (m, 1H), 1.70–1.59 (m, 1H), 0.81 (t, J = 7.2 Hz,
3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): d 199.04,
159.82, 144.67, 138.71, 129.47, 128.40, 127.63, 126.26,
120.69, 119.41, 112.33, 55.41, 45.72, 43.11, 29.22,
12.05 ppm. Enantiomeric excess: 85%, Chiralcel OD,
4.4.7. 3-(2-Methoxyphenyl)-1-(3-methoxyphenyl) pentan-1-
one (entry 7 in Table 2). This compound was obtained in
25
98% yield. ½aꢃD ¼ ꢀ9:05 (c 1, CH2Cl2). 1H NMR
(400 MHz, CDCl3): d 7.54–7.52 (m, 1H), 7.46–6.89 (m,
6H), 6.85–6.83 (m, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 3.67–
3.60 (m, 1H), 3.30 (dd, J = 6.0, 16.0 Hz, 1H), 3.17 (dd,
J = 8.0, 16.0 Hz, 1H), 1.78–1.70 (m, 2H), 0.80 (t,

D. B. Biradar, H.-M. Gau / Tetrahedron: Asymmetry 19 (2008) 733–738
737
J = 7.2 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): d
199.58, 159.73, 157.47, 138.76, 132.48, 129.35, 128.05,
127.08, 120.78, 120.52, 119.14, 112.47, 110.71, 55.36,
55.26, 44.63, 37.15, 27.21, 12.06 ppm. HRMS: [M+] calcd
for C19H22O3, 298.1569; found, 298.1578. Enantiomeric
excess: 97%, Chiralcel OD, hexane/i-PrOH = 99:1,
1.0 mL/min, tmajor = 9.9 min, tminor = 14.7 min.
(100 MHz, CDCl3): d 198.40, 159.81, 143.50, 138.41,
133.06, 129.46, 127.79, 127.60, 127.53, 125.34, 120.74,
119.54, 112.30, 55.38, 44.65, 41.19, 28.22, 11.62 ppm.
HRMS: [M+] calcd for C18H19BrO2, 346.0568; found,
346.0572. Enantiomeric excess: 95%, Chiralcel OD, hex-
ane/i-PrOH = 99:1, 1.0 mL/min, tmajor = 9.7 min, tminor
=
15.0 min.
4.4.8. 3-(2-Methoxyphenyl)-1-(4-methoxyphenyl)pentan-1-
one (entry 8 in Table 2). This compound was obtained
4.4.12.
3-(2-Bromophenyl)-1-(4-methoxyphenyl)pentan-1-
one (entry 12 in Table 2). This compound was obtained
25
in 96% yield. ½aꢃD ¼ ꢀ10:1 (c 1, CH2Cl2). 1H NMR
25
in 95% yield. ½aꢃD ¼ ꢀ39:3 (c 1, CH2Cl2). 1H NMR
(400 MHz, CDCl3): d 7.95–7.91 (m, 2H), 7.19–7.15 (m,
2H), 6.93–6.88 (m, 3H), 6.84 (d, J = 8.4 Hz, 1H), 3.86 (s,
3H), 3.79 (s, 3H), 3.66–3.59 (m, 1H), 3.25 (dd, J = 6.0,
15.6 Hz, 1H), 3.13 (dd, J = 8.0, 15.6 Hz, 1H), 1.78–1.68
(m, 2H), 0.79 (t, J = 7.2 Hz, 3H) ppm. 13C{1H} NMR
(100 MHz, CDCl3): d 198.40, 163.23, 157.53, 132.74,
130.60, 130.42, 128.09, 127.05, 120.56, 113.56, 110.78,
55.41, 55.33, 44.29, 37.28, 27.24, 12.07 ppm. HRMS:
[M+] calcd for C19H22O3, 298.1569; found, 298.1574.
Enantiomeric excess: 93%, Chiralcel OD, hexane/
(400 MHz, CDCl3): d 7.95–7.92 (m, 2H), 7.56–7.54 (d,
1H), 7.29–7.23 (m, 2H), 7.06–7.02 (m, 1H), 6.93–6.90 (m,
2H), 3.87–3.80 (m, 1H), 3.86 (s, 3H), 3.25 (dd, J = 6.4,
16.4 Hz, 1H), 3.15 (dd, J = 7.6, 16.0 Hz, 1H), 1.85–1.61
(m, 2H), 0.82 (t, J = 7.2 Hz, 3H) ppm. 13C{1H} NMR
(100 MHz, CDCl3): d 197.17, 163.40, 143.66, 133.05,
130.41, 130.17, 127.86, 127.56, 127.52, 125.33, 113.66,
55.41, 44.32, 41.41, 28.16, 11.64 ppm. HRMS: {[M+]+1}
calcd for C18H19BrO2, 347.0568; found, 347.0645. Enantio-
meric excess: 94%, Chiralcel OD, hexane/i-PrOH = 99:1,
1.0 mL/min, tmajor = 13.1 min, tminor = 25.4 min.
i-PrOH = 99:1, 1.0 mL/min, tmajor = 14.4 min, tminor
=
39.6 min.
4.4.13.
3-(2-Chlorophenyl)-1-(3-methoxyphenyl)pentan-1-
4.4.9. 3-(2-Bromophenyl)-1-phenylpentan-1-one (entry 9 in
Table 2). This compound was obtained in 97% yield.
one (entry 13 in Table 2). This compound was obtained
25
in 98% yield. ½aꢃD ¼ ꢀ33:0 (c 1, CH2Cl2). 1H NMR
25
1
½aꢃD ¼ ꢀ35:7 (c 1, CH2Cl2). H NMR (400 MHz, CDCl3):
d 7.96–7.93 (m, 2H), 7.57–7.53 (m, 2H), 7.46–7.42 (m, 2H),
7.29–7.23 (m, 2H), 7.07–7.03 (m, 1H), 3.89–3.82 (m, 1H),
3.31 (dd, J = 6.0, 16.4 Hz, 1H), 3.22 (dd, J = 7.6,
16.4 Hz, 1H), 1.86–1.75 (m, 1H), 1.73–1.64 (m, 1H), 0.84
(t, J = 7.2 Hz, 3H) ppm. 13C{1H} NMR (100 MHz,
CDCl3): d 198.65, 143.53, 137.06, 133.10, 132.95, 128.54,
128.13, 127.85, 127.63, 127.55, 125.36, 44.63, 41.21,
28.21, 11.66 ppm. HRMS: {[M+]+1} calcd for C17H17BrO,
317.0463; found, 317.0539. Enantiomeric excess: 96%,
Chiralcel OJ, hexane, 1.0 mL/min, tmajor = 22.1 min,
tminor = 30.1 min.
(400 MHz, CDCl3): d 7.53–7.52 (m, 1H), 7.46–7.45 (m,
1H), 7.37–7.32 (m, 2H), 7.27–7.19 (m, 2H), 7.14–7.07 (m,
2H), 3.90–3.80 (m, 1H), 3.83 (s, 3H), 3.32 (dd, J = 6.4,
16.4 Hz, 1H), 3.22 (dd, J = 7.6, 16.4 Hz, 1H), 1.86–1.64
(m, 2H), 0.83 (t, J = 7.2 Hz, 3H) ppm. 13C{1H} NMR
(100 MHz, CDCl3): d 198.46, 159.80, 141.81, 138.42,
134.34, 129.72, 129.46, 127.88, 127.24, 126.87, 120.70,
119.51, 112.27, 55.36, 44.44, 38.76, 28.01, 11.67 ppm.
HRMS: [M+] calcd for C18H19ClO2, 302.1074; found,
302.1079. Enantiomeric excess: 97%, Chiralcel OD,
hexane/i-PrOH = 99:1,
tminor = 11.8 min.
1.0 mL/min,
tmajor = 8.7 min,
4.4.10. 3-(2-Chlorophenyl)-1-phenylpentan-1-one (entry 10
in Table 2). This compound was obtained in 98% yield.
4.4.14.
3-(2-Chlorophenyl)-1-(4-methoxyphenyl)pentan-1-
25
1
½aꢃD ¼ ꢀ32:5 (c 1, CH2Cl2). H NMR (400 MHz, CDCl3):
d 7.95–7.92 (m, 2H), 7.55–7.51 (m, 1H), 7.45–7.41 (m, 2H),
7.36–7.34 (m, 1H), 7.27–7.19 (m, 2H), 7.13–7.09 (m, 1H),
3.90–3.83 (m, 1H), 3.32 (dd, J = 6.4, 16.8 Hz, 1H), 3.24
(dd, J = 7.6, 16.4 Hz, 1H), 1.87–1.76 (m, 1H), 1.74–1.64
(m, 1H), 0.82 (t, J = 7.6 Hz, 3H) ppm. 13C{1H} NMR
(100 MHz, CDCl3): d 198.65, 141.77, 137.01, 134.31,
132.89, 129.70, 128.48, 128.03, 127.88, 127.23, 126.85,
44.33, 38.67, 27.97, 11.66 ppm. Enantiomeric excess: 96%,
Chiralcel OJ, hexane, 1.0 mL/min, tmajor = 20.1 min,
tminor = 26.8 min.
one (entry 14 in Table 2). This compound was obtained
25
in 95% yield. ½aꢃD ¼ ꢀ38:6 (c 1, CH2Cl2). 1H NMR
(400 MHz, CDCl3): d 7.94–7.90 (m, 2H), 7.36–7.34 (m,
1H), 7.27–7.19 (m, 2H), 7.13–7.09 (m, 1H), 6.92–6.89 (m,
2H), 3.88–3.81 (m, 1H), 3.85 (s, 3H), 3.26 (dd, J = 6.0,
16.0 Hz, 1H), 3.17 (dd, J = 7.6, 16.0 Hz, 1H), 1.86–1.64
(m, 2H), 0.81 (t, J = 7.6 Hz, 3H) ppm. 13C{1H} NMR
(100 MHz, CDCl3): d 197.22, 163.36, 141.94, 134.31,
130.34, 130.16, 129.68, 127.92, 127.19, 126.84, 113.64,
55.37, 44.05, 38.92, 27.95, 11.67 ppm. Enantiomeric excess:
94%, Chiralcel OD, hexane/i-PrOH = 99:1, 1.0 mL/min,
tmajor = 12.0 min, tminor = 19.4 min.
4.4.11.
3-(2-Bromophenyl)-1-(3-methoxyphenyl)pentan-1-
one (entry 11 in Table 2). This compound was obtained
25
in 96% yield. ½aꢃD ¼ ꢀ33:8 (c 1, CH2Cl2). 1H NMR
(400 MHz, CDCl3): d 7.56–7.52 (m, 2H), 7.46–7.45 (m,
1H), 7.36–7.32 (m, 1H), 7.28–7.22 (m, 2H), 7.10–7.02 (m,
2H), 3.89–3.85 (m, 1H), 3.83 (s, 3H), 3.30 (dd, J = 6.4,
16.4 Hz, 1H), 3.20 (dd, J = 7.6, 16.4 Hz, 1H), 1.85–1.63
(m, 2H), 0.83 (t, J = 7.2 Hz, 3H) ppm. 13C{1H} NMR
Acknowledgment
Financial support from the National Science Council of
Taiwan, ROC, under the Grant No. NSC96-2113-M-005-
007-MY3 is appreciated.

738
D. B. Biradar, H.-M. Gau / Tetrahedron: Asymmetry 19 (2008) 733–738
Fu, Y.; Xie, J.-H.; Shi, W.-J.; Wang, L.-X.; Zhou, Q.-L. J.
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