Enantioselective conjugate addition of dialkylzincs to α,β- unsaturated enones catalyzed by Ni(acac)2 and (+)-(1S,2R)-7,7- dimethyl-1-morpholinoisonorborneol

Article abstract of DOI:10.1016/j.tetasy.2012.01.010

A mixture of chiral ligand 4 [(+)-MINBOL] and Ni(acac)₂ (12.5 and 0.5 mol % respectively) is able to successfully catalyze the enantioselective conjugate 1,4-addition of dialkylzinc to α,β- unsaturated enones in propionitrile to give the corres

Full text of DOI:10.1016/j.tetasy.2012.01.010

Tetrahedron: Asymmetry 23 (2012) 130–135
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Tetrahedron: Asymmetry
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Enantioselective conjugate addition of dialkylzincs to a,b-unsaturated enones
catalyzed by Ni(acac)2 and (+)-(1S,2R)-7,7-dimethyl-1-morpholinoisonorborneol
⇑
Chih-Hao Tseng, Yu-Ming Hung, Biing-Jiun Uang
Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A mixture of chiral ligand 4 [(+)-MINBOL] and Ni(acac)2 (12.5 and 0.5 mol % respectively) is able to suc-
cessfully catalyze the enantioselective conjugate 1,4-addition of dialkylzinc to a,b-unsaturated enones in
propionitrile to give the corresponding chiral Michael adducts in good yields and with high enantioselec-
tivities (up to 93% ee).
Received 7 December 2011
Accepted 5 January 2012
Available online 21 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
the enantioselective addition of Et2Zn to aldehydes to afford chiral
secondary alcohols with high enantioselectivities.8 Herein we re-
The catalytic asymmetric conjugate addition of carbon nucleo-
philes to ,b-unsaturated systems to generate new carbon–carbon
port our findings on the nickel-catalyzed enantioselective conju-
gate addition of dialkyl zinc onto chalcones in the presence of
[(+)-MINBOL] 4 (Fig. 2).
a
bonds with concomitant formation of a new stereogenic center in
the adduct is an important reaction in organic synthesis. This meth-
odology can be applied to the synthesis of biologically active drugs
and chiral intermediates of natural products,1 such as LG121071
2. Results and discussion
1,1a,b anthracenone 2,1c and chiral
c-aryl-1H-1,2,4-triazole deriva-
At the outset, the reaction was carried out by using 10 mol % of
(+)-MINBOL 4 at ꢀ30 °C. Although the Michael adduct was obtained
in trace amounts (6%), good enantioselectivity (81% ee) was
achieved (Table 1, entry 1). Subsequently, Ni(acac)2 (7.0 mol %)
was used in the absence of (+)-MINBOL 4 for the reaction and the
yield of Michael adduct was increased to 61% (Table 1, entry 2). To
improve the enantioselectivity and reactivity, we studied the Ni(II)
species and their ratio to (+)-MINBOL 4. The results are summarized
in entries 3–11. A better yield (85%) and a similar ee (82%) were
obtained when using Ni(acac)2/(+)-MINBOL 4 in a ratio of 0.5–
12.5 mol % at ꢀ30 °C for a shorter reaction time (2.5 h) (Table 1,
entry 7). The use of copper salts was found to be effective for the
Michael addition of diethylzinc to chalcone in other catalytic
systems.9 However, it gave poor yields with low ee in our system
(Table 1, entries 11, 12). We found that the use of Cu(acac)2 as the
catalyst showed a moderate yield, although with good ee (89%)
(Table 1, entry 13). By considering the reaction time and the yield,
we chose Ni(acac)2 (0.5 mol %) and (+)-MINBOL 4 (12.5 mol %) as
the catalyst for further studies. The requirement of excess (+)-MIN-
BOL 4 is in order to minimize the concentration of free NiII species
that catalyze the Michael addition in a compatible manner and de-
crease the enantioselectivity. The optimization was then focused on
the solvent effect. Some commonly used solvents were studied for
this reaction in the presence of Ni(acac)2/(+)-MINBOL 4 in a ratio
of 0.5–12.5 mol % and the results are shown in Table 2. The results
showed that the nitrile solvent gave higher enantioselectivities
(82–87% ee) (Table 2, entries 1–4). Other solvents such as ethers,
tives 31e (Fig. 1). The development of efficient chiral catalytic
systems has attracted much attention from organic chemists
especially for the asymmetric conjugate addition of dialkylzinc to
a
,b-unsaturated enones.2–7 In particular, the employment of
b-amino alcohol-based ligands with nickelII to catalyze the asym-
metric conjugate addition of alkylzinc to enones is one of the more
promising methods.
In
a
previous study, NiII/(1S,2R)-N,N-dibutylnorephedrine
(DBNE)/2,20-bipyridyl had been reported to catalyze the asymmet-
ric conjugate addition of alkylzincs to chalcone leading to the chiral
Michael adduct in 90% ee with a 47% yield.5 Later, the employment
of the camphor-derived b-amino alcohols (DAIB, tri- and tetraden-
tate amino alcohols) with 2,20-bipyridine as a co-ligand in the nick-
el complex catalyzed the asymmetric conjugate addition of
diethylzinc to chalcone and successfully afforded the addition
products with up to 85% enantioselectivity and a 75% yield.6
Recently, the use of the easily available ferrocenyl aziridinylmeth-
anol (FAM complexes)/nickelII complex to catalyze the enantiose-
lective conjugate addition of diethylzincs to enones with ee’s in
the range of 42–80% was reported.7 Inspired by these previous
studies, we searched for a more efficient catalytic system for the
asymmetric conjugate addition of organozincs to enones. We have
previously reported that [(+)-MINBOL] 4 is an effective catalyst for
⇑
Corresponding author.
E-mail address: bjuang@mx.nthu.edu.tw (B.-J. Uang).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2012.01.010

C.-H. Tseng et al. / Tetrahedron: Asymmetry 23 (2012) 130–135
OH OH
131
O
CF3
N
*
N
O
O
N
H
N
H
N
anthracenone 2
(drug for treating psoriasis)
LG1210711
chiral γ−aryl-1H-1,2,4-triazole
derivatives 3
(non-steroidal androgen antagonist)
(antifungal agent)
Figure 1. Biologically active chiral Michael derivatives.
OH
N
O
(+)-MINBOL4
Figure 2. (+)-(1S,2R)-7,7-Dimethyl-1-morpholinoisonorborneol [(+)-MINBOL] 4.
Table 1
The effect of Ni(acac)2/(+)-MINBOL 4 ratio on the asymmetric conjugate addition
(+)-MINBOL 4, metal salt
Et2Zn (1.0 M in hexane) 1.5 mol.eq
O
O
Ph
Ph
º
0.5 M, −30 C
CH3CN
Ph (S)
Ph
6a
5
Entry
(+)-MINBOL 4 (mol %)
Metal salt (mol %)
Time (h)
Yield (%)a
ee (%)b
1
2
3
4
5
10
—
10
5
10
10
12.5
12 5
12.5
12.5
10
—
30
20
6
61
88
83
80
67
85
71
73
17
4
81
—
Ni(acac)2 7.0
Ni(acac)2 1.0
Ni(acac)2 1.0
Ni(acac)2 0.5
Ni(acac)2 0.1
Ni(acac)2 0.5
Ni(TMHD)2 0.5
Ni(cycohexanebutyrate)2 0.5
NiBr2 0.5
CuI 1.0
2.0
4.0
6.5
16
2.5
19
19
18
24
24
24
73
53
79
80
82
75
81
89
63
76
89
6
7
8c
9
10
11
12
13
10
10
Cu(OTf)2 1.0
Cu(acac)2 1.0
40
62
a
b
c
Isolated yield.
Determined by HPLC using a Chiracel AD-H column.
TMHD: 2,2,6,6-tetramethyl-3,5-heptanedionato.
toluene, CH2Cl2, or hexane gave lower enantioselectivities. (Table 2,
entries 5–9). To further improve the enantioselectivity, we studied
the effect of the reaction temperature and the results are also sum-
marized in Table 2. The enantioselectivity decreased to 84% ee when
the reaction was conducted at ꢀ20 °C. However, lowering the reac-
tion temperature from ꢀ30 to ꢀ60 °C, caused the enantioselectivity
to gradually increase from 86% to 93% ee (Table 2, entries 2, 10–13)
at the expense of the reaction time.
In light of the above observations, the experimental condition
at ꢀ50 °C was adopted for studying the scope of substrate by
considering the reaction time, yield, and enantioselectivity. The
NiII-catalyzed asymmetric conjugate additions of Et2Zn to
at para- or meta-position gave the corresponding chiral adduct in
high yields and ee (87–92%) (Table 3, entries 2–10). However,
ee’s were decreased when R1 of the enone were ortho-substituted
phenyl groups (entries 11, 12). The reason for lower ee is presum-
ably due to that the ortho-substituted b-phenyl group of enone is
more sterically hindered in our catalytic reaction system.
Higher enantioselectivity was observed when R2 of the enone
was a para- or a meta-methoxyphenyl group (entries 13, 14). Mod-
erate enantioselectivities (58–70% ee) were observed for enones
with an aliphatic substituent at the b-position or when R2 was an
aliphatic group10 (entries 15–17). However, the Michael adduct
was not observed when the R2 group on the enone was a tert-butyl
(entry 18). This may be due to the steric effect that is caused by the
bulky tert-butyl group. Finally, Me2Zn, i-Pr2Zn, and Bu2Zn were
investigated in the reaction system.11–14 Due to the lower
a
,b-unsaturated aromatic enones were conducted at ꢀ50 °C and
the results were summarized in Table 3. Enones with b-phenyl
group bearing electron donating or electron withdrawing group

132
C.-H. Tseng et al. / Tetrahedron: Asymmetry 23 (2012) 130–135
Table 2
The effect of solvent and temperature on the asymmetric conjugate addition
(+)-MINBOL 4 12.5 mol%
Ni(acac)2 0.5 mol%
Et2Zn (1.0 M in hexane) 1.5 mol.eq
O
O
Ph
Ph
solvent
0.5 M, T
(S)
Ph
Ph
6a
5
Entry
Solvent
Time (h)
T (°C)
Yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
CH3CN
CH3CH2CN
CH3CH2CH2CN
(CH3)2CHCN
THF
Et2O
Toluene
CH2Cl2
n-Hexane
CH3CH2CN
CH3CH2CN
CH3CH2CN
CH3CH2CN
2.5
6.0
6.0
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ20
ꢀ40
ꢀ50
ꢀ60
85
86
81
77
88
68
50
48
13
73
87
84
88
82
86
87
85
63
47
55
42
68
84
90
92
93
21
5.5
5.5
4.0
4.0
17
6.0
21
9c
10
11
12
13
36
72
a
b
c
Isolated yield.
Determined by HPLC using a Chiracel AD-H column.
Entry 9: n-hexane (0.2 M).
Table 3
NiII-catalyzed asymmetric conjugate addition of dialkylzinc to aromatic enones with (+)-MINBOL 4
(+)-MINBOL 4, 12.5 mol%
Ni(acac)2, 0.5 mol%
O
R3
O
(R3)2Zn, 1.5 mol.eq
R1
R1
R2
R2
(S)
CH3CH2CN, 0.5 M, −50 ºC
5
6a-u
Entry
R1
R2
R3
Time (h)
Yield (%)a
ee (%)b
1
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Bu
i-Pr
36
48
50
48
48
30
48
30
24
48
48
48
48
48
48
48
48
48
48
48
48
6a
6b
6c
6d
6e
6f
6g
6h
6i
84
81
82
76
93
87
87
76
83
83
80
67
67
90
42
71
13
—
92
89
89
91
87
89
87
90
92
91
51
81
89
88
70
64
58
—
p-MeC6H4
p-MeOC6H4
p-CF3C6H4
p-NCC6H4
P-FC6H4
p-ClC6H4
P-BrC6H4
m-ClC6H4
m-MeOC6H4
o-MeOC6H4
o-ClC6H4
Ph
Ph
c-C6H11
Me
Ph
Ph
3
4c
5c
6
7
8c
9
10
11
12
13
14
15d
16c
17d
18
19
20
21
6j
6k
6l
p-MeOC6H4
m-MeOC6H4
Ph
Ph
Me
t-Bu
Ph
Ph
Ph
6m
6n
60
6p
6q
6r
6s
6t
Ph
Ph
Ph
11
79
52
80
82
7
6u
a
b
c
Isolated yield.
Determined by HPLC using a Chiracel AD-H or Chiracel OD column.
CH3CH2CN (0.34 M).
The configuration is R form.
d
reactivity of the Me2Zn reagent, it gave the methylated Michael
adduct in an 11% yield although 80% ee was observed. In the case
of i-Pr2Zn, a low enantioselectivity (7% ee) and a moderate yield
(52%) were observed. The reaction using Bu2Zn gave the corre-
sponding butylated Michael adduct in good yields (79%) and
enantioselectivity (82%) (entries 19–21). However, the phenylzinc
reagent derived from phenylboronic acid and diethylzinc gave no
addition product using this catalytic system.
3. Conclusion
We have shown that [(+)-MINBOL] 4 can be effectively applied
in the nickel-catalyzed asymmetric conjugate 1,4-addition of some
dialkylzinc to enones without the addition of a co-ligand, such as
2,20-bipyridine,6 to produce chiral Michael adduct with up to 93%
ee and good yields. This highly enantioselective 1,4-addition
reaction may provide another useful entry to the synthesis of

C.-H. Tseng et al. / Tetrahedron: Asymmetry 23 (2012) 130–135
133
biologically active molecules and chiral intermediates for natural
product synthesis.
J = 9.6 Hz, 2H), 6.80 (d, J = 9.6 Hz, 2H), 3.75 (s, 3H), 3.24ꢀ3.14 (m,
3H), 1.77ꢀ1.69 (m, 1H), 1.63ꢀ1.54 (m, 1H), 0.79 (t, J = 7.6 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 199.4 (C), 157.9 (C), 137.3 (C),
136.6 (C), 132.8 (CH), 128.5 (CH), 128.5 (CH), 128.0 (CH), 113.7
(CH), 55.2 (CH3), 45.8 (CH2), 42.2 (CH), 29.3 (CH2), 12.1 (CH3); IR
(neat) 3060, 3031, 2997, 2960, 2931, 2874, 2835, 1682, 1611,
1597, 1581, 1513, 1448, 1363, 1248, 1178, 1115, 1036, 978, 923,
4. Experimental
4.1. General
830 cmꢀ1
; HPLC analysis: Chiralcel AD-H, 2-propanol/hexane
All reactions were performed in flame-dried apparatus under an
atmosphere of Ar(g). All chemicals and solvents were used as re-
ceived unless otherwise stated. CH3CN (CaH2), CH3CH2CN (CaH2),
CH3CH2CH2CN (CaH2), (CH3)2CHCN (CaH2), THF (K), toluene
(CaH2), hexanes (CaH2), CH2Cl2 (CaH2) were distilled under argon
from the drying agent indicated. Column chromatography was per-
formed on silica gel with the eluent indicated. 1H and 13C NMR spec-
tra were recorded with 400 MHz NMR instrument. Abbreviations
for 1H NMR: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet. Carbon atoms were determined by DEPT experiments.
(1:99), 1.0 mL/min, uv 254 nm; tR = 16.1 min (S, 94.4%), 27.3 min
(R, 5.6%); 89% ee.
4.5. 1-Phenyl-3-(4-trifluoromethyl-phenyl)-pentanone 6d9c
½
a 2D4
ꢁ
¼ ꢀ6:8 (c 1.0, EtOH); 1H NMR (400 MHz, CDCl3) d 7.90 (d,
J = 8.0 Hz, 2H), 7.52(t, J = 6.8 Hz, 3H), 7.42 (t, J = 7.6 Hz, 2H), 7.35
(d, J = 8.0 Hz, 2H), 3.29ꢀ3.34 (m, 3H), 1.64ꢀ1.69 (m, 1H),
1.78ꢀ1.83 (m, 1H), 0.81 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 198.3 (C), 148.9 (C), 136.9 (C), 133.0 (CH), 128.8 (CH),
128.5 (CH), 127.9 (CH), 125.2 (CH), 122.9 (q, J = 270 Hz, C), 44.9
(CH2), 42.6 (CH), 29.0 (CH2), 11.8 (CH3); IR (neat) 3064, 2966,
2933, 2878, 1689, 1618, 1598, 1449, 1391, 1279, 1247, 1164,
1119, 1068, 1017, 980, 923, 840 cmꢀ1; HPLC analysis: Chiralcel
AD-H, 2-propanol/hexane (1:99), 1.0 mL/min, UV 254 nm;
tR = 7.7 min (S, 95.5%), 12.1 min (R, 4.5%); 91% ee.
4.1.1. General procedure for the asymmetric conjugate addition
of dialkylzinc to enones
To a flask were added chiral ligand (MINBOL) 4 (0.028 g,
0.125 mmol), Ni(acac)2 (0.0013 g, 0.005 mmol), and propionitrile
(1.0 mL). The mixture was heated at reflux for 1 h, then cooled to
room temperature and followed by the addition of enone (1 mmol)
in propionitrile (1.0 mL). The resulting mixture was stirred for
15 min at room temperature and then cooled to ꢀ50 °C. A dialkyl-
zinc solution (1.5 mmol)14 was gradually added to the mixture via
4.6. 1-Phenyl-3-(4-cyanophenyl)-pentanone 6e
½
a 2D4
ꢁ
¼ ꢀ17:8 (c 1.0, EtOH); 1H NMR (400 MHz, CDCl3) d 7.77 (d,
a 250 lL gas-tight syringe and the reaction mixture was stirred for
J = 7.2 Hz, 2H), 7.45ꢀ7.41 (m, 3H), 7.32 (d, J = 8.2 Hz, 2H), 7.23 (d,
J = 8.2 Hz, 2H), 3.23ꢀ3.17 (m, 3H), 1.71ꢀ1.66 (m, 1H), 1.57ꢀ1.50
(m, 1H), 0.69 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
198.0 (C), 150.4 (C), 136.7 (C), 133.0 (CH), 132.0 (CH), 128.5 (CH),
128.4 (CH), 127.8 (CH), 118.8 (C), 109.9 (C), 44.6, (CH2), 42.8
(CH), 28.9 (CH2), 11.8 (CH3); IR (neat) 3064, 2964, 2931, 2876,
48 h, then quenched by the addition of 1 M HCl(aq). The mixture
was extracted with ether, and the combined organic solution was
dried over Na2SO4, filtered, and concentrated to give the crude
product, which was purified by column chromatography (ethyl
acetate:hexane = 1:9) to yield the corresponding adduct.
2227, 1683, 1607, 1505, 1449, 1214, 1179, 1017, 978, 838 cmꢀ1
;
4.2. 1,3-Diphenyl-1-pentanone 6a15
HRMS (EI) calculated for C18H17NO 263.1310, found 263.1307.
HPLC analysis: Chiralcel AD-H, 2-propanol/hexane (5:95), 1.0 mL/
min, uv 254 nm; tR = 17.6 min (S, 93.4%), 27.2 min (R, 6.6%); 87% ee.
½
a 2D4
ꢁ
¼ þ7:4 (c 1.0, EtOH); 1H NMR (400 MHz, CDCl3) d 7.91ꢀ7.89
(m, 2H), 7.54ꢀ7.51 (m, 1H), 7.44ꢀ7.40 (m, 2H), 7.31ꢀ7.16 (m, 5H),
3.31ꢀ3.22 (m, 3H), 1.83ꢀ1.75 (m, 1H), 1.70ꢀ1.61 (m, 1H), 0.81 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 199.1 (C), 144.6 (C),
137.2 (C), 132.8 (CH), 128.4 (CH), 128.3 (CH), 128.0 (CH), 127.5
(CH), 126.2 (CH), 45.5, (CH2), 42.9 (CH), 29.1 (CH2), 12.0 (CH3); IR
(neat) 3062, 3028, 2963, 2930, 2875, 1682, 1597, 1449, 1368,
1279, 1201, 1180, 1104, 1075, 1015, 978, 924 cmꢀ1; HPLC analysis:
Chiralcel AD-H, 2-propanol/hexane (1:99), 1.0 mL/min, UV 254 nm;
tR = 9.3 min (S, 95.8%), 12.3 min (R, 4.2%); 92% ee.
4.7. 1-Phenyl-3-(4-flourophenyl)-pentanone 6f12
½
a 2D4
ꢁ
¼ þ5:1 (c 1.0, EtOH); 1H NMR (400 MHz, CDCl3) d 7.87 (d,
J = 7.6 Hz, 2H), 7.53ꢀ7.49 (m, 1H), 7.43ꢀ7.39 (m, 2H), 7.20ꢀ7.15
(m, 2H), 6.98ꢀ6.95 (m, 2H), 3.27ꢀ3.20 (m, 3H), 1.81ꢀ1.74 (m,
1H), 1.64ꢀ1.57 (m, 1H), 0.80 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 198.8 (C), 161.3 (d, J = 242.7 Hz, C), 140.2 (C),
137.1 (C), 132.8 (CH), 128.9 (CH), 128.4 (CH), 127.9 (CH), 115.1
(CH), 45.5 (CH2), 42.2 (CH), 29.3 (CH2), 11.9 (CH3); IR (neat)
3063, 2963, 2931, 2876, 2227, 1683, 1599, 1581, 1510, 1449,
1362, 1278, 1222, 1159, 1109, 1015, 976, 923, 834 cmꢀ1; HPLC
analysis: Chiralcel AD-H, 2-propanol/hexane (1:99), 1.0 mL/min,
UV 254 nm; tR = 9.8 min (S, 94.5%), 13.6 min (R, 5.5%); 89% ee.
4.3. 1-Phenyl-3-(4-methylphenyl)-pentanone 6b15c
½
a 2D4
ꢁ
¼ þ14:2 (c 1.0, EtOH); 1H NMR (400 MHz, CDCl3) d 7.92 (d,
J = 8.0 Hz, 2H), 7.53 (t, J = 6.8 Hz, 1H), 7.43 (t, J = 7.2 Hz, 2H),
7.15ꢀ7.10 (m, 4H), 3.30ꢀ3.23 (m, 3H), 2.32 (s, 3H), 1.82ꢀ1.76
(m, 1H), 1.68ꢀ1.61 (m, 1H), 0.83 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 199.2 (C), 141.5 (C), 137.2 (C), 135.5 (C),
132.8 (CH), 129.0 (CH), 128.4 (CH), 128.0 (CH), 127.4 (CH),
45.6(CH2), 42.5 (CH), 29.1 (CH2), 20.9 (CH3), 12.0 (CH3); IR (neat)
3063, 3023, 2963, 2923, 2875, 1683, 1597, 1581, 1514, 1448,,
1361, 1279, 1248, 1199, 1116, 1017, 978, 923, 817 cmꢀ1; HPLC
analysis: Chiralcel AD-H, 2-propanol/hexane (1:99), 1.0 mL/min,
UV 254 nm; tR = 7.2 min (S, 94.3%), 9.5 min (R, 5.7%); 89% ee.
4.8. 1-Phenyl-3-(4-chlorophenyl)-pentanone 6g15b,c
½
a 2D5
ꢁ
¼ þ1:4 (c 1.0, EtOH); 1H NMR (400 MHz, CDCl3)
d
7.88ꢀ7.82 (m, 2H), 7.54ꢀ7.50 (m, 1H), 7.44ꢀ7.37 (m, 2H), 7.17
(d, J = 6.4 Hz, 2H), 7.14 (d, J = 6.4 Hz, 2H), 3.21 (m, 3H), 1.77ꢀ1.72
(m, 1H), 1.61ꢀ1.52 (m, 1H), 0.77 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 198.8 (C), 143.1 (C), 137.1 (C), 133.0 (CH),
131.8 (C), 129.0 (CH), 128.6 (CH), 128.5 (CH), 128.0 (CH), 45.4
(CH2), 42.3 (CH), 29.2 (CH2), 12.0 (CH3); IR (neat) 3062, 3028,
2963, 2930, 2875, 1684, 1596, 1580, 1491, 1448, 1362, 1275,
1245, 1213, 1180, 1092, 1013, 979, 829 cmꢀ1; HPLC analysis: Chi-
ralcel AD-H, 2-propanol/hexane (1:99), 1.0 mL/min, UV 254 nm;
tR = 10.7 min (S, 93.3%), 16.9 min (R, 6.7%); 87% ee.
4.4. 1-Phenyl-3-(4-methoxyphenyl)-pentanone 6c15b,c
½
a 2D4
ꢁ
¼ þ16:0 (c 1.0, EtOH); 1H NMR (400 MHz, CDCl3) d 7.88 (d,
J = 8.4 Hz, 2H), 7.53ꢀ7.49 (m, 1H), 7.43ꢀ7.39 (m, 2H), 7.11 (d,

134
C.-H. Tseng et al. / Tetrahedron: Asymmetry 23 (2012) 130–135
4.9. 1-Phenyl-3-(4-bromophenyl)-pentanone 6h2k,16a,b
(CH), 127.9 (CH), 127.2 (CH), 126.8 (CH), 44.3 (CH2), 38.5 (CH),
27.9 (CH2), 11.6 (CH3); IR (neat) 3064, 2964, 2933, 2874, 1686,
1596, 1474, 1448, 1365, 1202, 1034, 973, 750 cmꢀ1; HPLC analysis:
Chiralcel AD-H, 2-propanol/hexane (5:95), 1.0 mL/min, UV
254 nm; tR = 5.8 min (S, 90.4%), 7.1 min (R, 9.6%); 81% ee.
½
a 2D4
ꢁ
¼ þ1:4 (c 1.0, EtOH); 1H NMR (400 MHz, CDCl3) d 7.88 (d,
J = 7.2 Hz, 2H), 7.49ꢀ7.54 (m, 1H), 7.36ꢀ7.43 (m, 4H), 7.10 (d,
J = 6.8 Hz, 2H), 3.19ꢀ3.25 (m, 3H), 1.73ꢀ1.80(m, 1H), 1.56ꢀ1.63
(m, 1H), 0.79 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
198.5 (C), 143.6 (C), 136.9 (C), 132.9 (CH), 131.3 (CH), 129.3 (CH),
128.5 (CH), 127.9 (CH), 119.8 (C), 45.2 (CH2), 42.2 (CH), 29.1
(CH2), 11.9 (CH3); IR (neat) 3061, 3027, 2963, 2931, 2875, 1689,
1597, 1580, 1487, 1449, 1361, 1273, 1244, 1213, 1181, 1073,
1010, 979, 923, 825 cmꢀ1; HPLC analysis: Chiralcel AD-H, 2-propa-
nol/hexane (1:99), 1.0 mL/min, uv 254 nm; tR = 10.2 min (S, 94.9%),
15.6 min (R, 5.1%); 90% ee.
4.14. 1-(4-Methoxyphenyl)-3-phenyl-pentanone 6m2k,5b,9b,16b,18
½
a 2D4
ꢁ
¼ ꢀ1:6 (c 1.0, EtOH); 1H NMR (400 MHz, CDCl3) d 7.90 (d,
J = 8.8 Hz, 2H), 7.16ꢀ7.30 (m, 5H), 6.91 (d, J = 8.8 Hz, 2H), 7.11 (d,
J = 8.8 Hz, 2H), 3.86(s, 3H), 3.18ꢀ3.25 (m, 3H), 1.76ꢀ1.80 (m, 1H),
1.61ꢀ1.68 (m, 1H), 0.80 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 197.7 (C), 163.3 (C), 144.8 (C), 130.3 (CH), 128.3 (CH),
127.6 (CH), 126.1 (CH), 113.6 (CH), 55.4 (CH3), 45.2 (CH2), 43.1
(CH), 29.1 (CH2), 12.0 (CH3); IR (neat) 3030, 2950, 2930, 2875,
1674, 1601, 1510, 1451, 1422, 1376, 1353, 1258, 1170, 1023,
980, 846 cmꢀ1; HPLC analysis: Chiralcel AD-H, 2-propanol/hexane
(5:95), 1.0 mL/min, UV 254 nm; tR = 13.6 min (S, 94.3%), 22.0 min
(R, 5.7%); 89% ee.
4.10. 1-Phenyl-3-(3-chlorophenyl)-pentanone 6i2h
½
a 2D4
ꢁ
¼ ꢀ4:4 (c 1.0, EtOH); 1H NMR (400 MHz, CDCl3) d 7.92 (d, J
= 7.6 Hz, 2H), 7.54ꢀ7.57 (m, 1H), 7.43ꢀ7.47 (m, 2H), 7.13ꢀ7.27 (m,
4H), 3.27 (m, 3H), 1.71ꢀ1.83 (m, 1H), 1.60ꢀ1.67 (m, 1H), 0.83 (t,
J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 198.6 (C), 146.8 (C),
137.0 (C), 134.1 (C), 133.0 (CH), 129.6 (CH), 128.5 (CH), 128.0
(CH), 127.6 (CH), 126.4 (CH), 126.0 (CH), 45.2 (CH2), 42.6 (CH),
29.1 (CH2), 12.0 (CH3); IR (neat) 3062, 2964, 2932, 2875, 1683,
1597, 1574, 1449, 1362, 1202, 1086, 1001, 979, 880 cmꢀ1; HPLC
analysis: Chiralcel AD-H, 2-propanol/hexane (1:99), 1.0 mL/min,
UV 254 nm; tR = 7.7 min (S, 95.9%), 8.3 min (R, 4.1%); 92% ee.
4.15. 1-(3-Methoxyphenyl)-3-phenyl-pentanone 6n2i,19
½
a 2D4
ꢁ
¼ þ11:5 (c 1.0, EtOH); 1H NMR (400 MHz, CDCl3) d 7.50 (d,
J = 7.2 Hz, 1H), 7.43 (s, 1H), 7.08ꢀ7.35 (m, 6H), 7.07 (d, J = 2.4 Hz,
1H), 3.82 (s, 3H), 3.22ꢀ3.30 (m, 3H), 1.76ꢀ1.79 (m, 1H),
1.63ꢀ1.68 (m, 1H), 0.81 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 199.0 (C), 159.8 (C), 144.7 (C), 138.7 (C), 129.5 (CH),
128.4 (CH), 127.6 (CH), 126.3(CH), 120.7 (CH), 119.4 (CH), 112.3
(CH), 55.41 (CH3), 45.7 (CH2), 43.1 (CH), 29.2 (CH2), 12.1 (CH3);
IR (neat) 3062, 3028, 2962, 2931, 2874, 1683, 1597, 1583, 1453,
1429, 1368, 1332, 1258, 1167, 1046, 1026, 995, 876 cmꢀ1; HPLC
analysis: Chiralcel AD-H, 2-propanol/hexane (5:95), 1.0 mL/min,
UV 254 nm; tR = 6.6 min (S, 94.2%), 7.4 min (R, 5.8%); 88% ee.
4.11. 1-Phenyl-3-(3-methoxyphenyl)-pentanone 6j7
½
a 2D4
ꢁ
¼ þ5:9 (c 1.0, EtOH); 1H NMR (400 MHz, CDCl3) d 7.90 (d,
J = 7.6 Hz, 2H), 7.50 (m, 1H), 7.40 (m, 2H), 7.20 (t, J = 8.0 Hz, 1H),
6.83 (d, J = 7.2 Hz, 1H), 6.79 (s, 1H), 6.72 (d, J = 8.0 Hz, 1H),
3.77(s, 3H), 3.20ꢀ3.29 (m, 3H), 1.76ꢀ1.79 (m, 1H), 1.61ꢀ1.67 (m,
1H), 0.82 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 199.0
(C), 159.5 (C), 146.3 (C), 137.1 (C), 132.8 (CH), 129.2 (CH), 128.4
(CH), 127.9 (CH), 119.9 (CH), 113.5 (CH), 111.1 (CH), 54.9 (CH3),
45.4 (CH2), 42.9 (CH), 29.0 (CH2), 12.0 (CH3); IR (neat) 3028,
2961, 2931, 2874, 2836, 1682, 1598, 1583, 1487, 1449, 1362,
1214, 1155, 1045, 979, 874 cmꢀ1; HPLC analysis: Chiralcel AD-H,
2-propanol/hexane (5:95), 1.0 mL/min, UV 254 nm; tR = 7.0 min
(S, 95.7%), 8.3 min (R, 4.3%); 91% ee.
4.16. 3-Cyclohexyl-1-phenyl-pentanone 6o15b
½
a 2D6
ꢁ
¼ ꢀ2:1 (c 0.5, EtOH); 1H NMR (400 MHz, CDCl3) d 7.94 (d,
J = 7.6 Hz, 2H), 7.54ꢀ7.41 (m, 3H), 2.96 (dd, J = 16.2, 5.5 Hz, 1H),
2.75 (dd, J = 16.2, 7.4 Hz, 1H), 1.97ꢀ1.91 (m, 1H), 1.761.62 (m,
5H), 1.471.00 (m, 8H), 0.85 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 201.1 (C), 137.5 (C), 132.7 (CH), 128.5 (CH), 128.1 (CH),
41.0(CH), 40.2 (CH), 40.2 (CH2), 30.2 (CH2), 29.3 (CH2), 26.8 (CH2),
24.0 (CH2), 12.0 (CH3); IR (neat) 3061, 2959, 2924, 2852, 1683,
4.12. 1-Phenyl-3-(2-methoxyphenyl)-pentanone 6k2i,17
1598, 1581, 1448, 1373, 1314, 1276, 1205, 1012, 971, 750 cmꢀ1
;
½
a 2D4
ꢁ
¼ þ4:4 (c 1.0, EtOH); 1H NMR (400 MHz, CDCl3) d 8.00 (d,
HPLC analysis: Chiralcel AD-H, 2-propanol/hexane (1:99), 1.0 mL/
min, UV 254 nm; tR = 6.1 min (R, 85.2%), 6.9 min (S, 14.8%); 70% ee.
J = 8.0 Hz, 2H), 7.60ꢀ7.56 (m, 1H), 7.48 (t, J = 7.6 Hz, 2H),
7.30ꢀ7.21 (m, 2H), 6.97 (t, J = 7.2 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H),
3.88 (s, 3H), 3.763.69 (m, 1H), 3.37 (dd, J = 16.0, 6.0 Hz, 1H), 3.27
dd, J = 16.0, 8.0 Hz, 1H) 3.24 (m, 2H), 1.86ꢀ1.78 (m, 2H) 0.88 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 199.5 (C), 157.2 (C),
137.1 (C), 132.5 (CH), 132.2 (C), 128.2 (CH), 127.9 (CH), 127.8
(CH), 126.9 (CH), 120.3 (CH), 110.5 (CH), 55.0 (CH3), 44.3 (CH2),
36.8 (CH), 27.1 (CH2), 11.9 (CH3); IR (neat) 3063, 3028, 2962,
2934, 2874, 2837, 1682, 1598, 1582, 1492, 1462, 1449, 1368,
1288, 1241, 1123, 1029, 978, 924 cmꢀ1; HPLC analysis: Chiralcel
AD-H, 2-propanol/hexane (5:95), 1.0 mL/min, UV 254 nm;
tR = 6.6 min (S, 75.4%), 8.2 min (R, 24.6%); 51% ee.
4.17. 3-Methyl-1-phenyl-pentanone 6p5a,15a
½
a 2D4
ꢁ
¼ þ8:9 (c 1.0, EtOH); 1H NMR (400 MHz, CDCl3) d 7.93 (d,
J = 7.2 Hz, 2H), 7.54ꢀ7.50 (m, 1H), 7.44ꢀ7.41 (m, 2H), 2.93 (dd,
J = 15.6, 5.6 Hz, 1H), 2.72 (dd, J = 15.6, 8.0 Hz, 1H), 2.09ꢀ2.02 (m,
1H), 1.44ꢀ1.35 (m, 1H), 1.31ꢀ1.21 (m, 1H), 0.90 (t, J = 7.6 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 200.4 (C), 137.3 (C), 132.8 (CH), 128.5
(CH), 128.0 (CH), 45.5 (CH2), 31.3 (CH), 29.6 (CH2), 19.5(CH3), 11.4
(CH3); IR (neat) 3062, 2961, 2928, 2876, 1683, 1598, 1581, 1449,
1367, 1284, 1207, 1181, 1017, 966, 915 cmꢀ1; HPLC analysis:
Chiralcel OD, 2-propanol/hexane (0.2:99.8), 1.0 mL/min, UV
254 nm; tR = 51.2 min (S, 18.1%), 53.9 min (R, 81.9%); 64% ee.
4.13. 1-Phenyl-3-(2-chlorophenyl)-pentanone 6l17
½
a 2D4
ꢁ
¼ ꢀ32:0 (c 1.0, EtOH); 1H NMR (400 MHz, CDCl3) d 7.93 (d,
4.18. 4-Phenyl-hexan-2-one 6q10a–c
J = 7.2 Hz, 2H), 7.53 (m, 1H), 7.40ꢀ7.50 (m, 2H), 7.34 (d, J = 7.6 Hz,
1H), 7.20ꢀ7.26 (m, 2H), 7.08ꢀ7.18 (m, 1H), 3.83ꢀ3.90 (m, 1H),
3.17ꢀ3.34 (m, 2H), 1.71ꢀ1.83 (m, 1H), 1.64ꢀ1.86 (m, 2H), 0.82
(t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 198.6 (C), 141.7
(C), 136.8 (C), 134.2 (C), 132.9 (CH), 129.6 (CH), 128.4 (CH), 128.0
½
a 1D8
ꢁ
¼ ꢀ19:7 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d
7.29ꢀ7.24 (m, 2H), 7.19ꢀ7.14 (m, 3H), 3.02ꢀ2.97 (m, 1H), 2.70
(d, J = 7.2 Hz, 1H), 2.00 (s, 3H), 1.69ꢀ1.50 (m, 3H), 0.75 (t,
J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 208.0 (C), 144.2 (C),

C.-H. Tseng et al. / Tetrahedron: Asymmetry 23 (2012) 130–135
135
128.4(CH), 127.5 (CH), 126.3 (CH), 50.5 (CH2), 42.9 (CH), 30.5 (CH3),
References
29.3(CH2), 11.9 (CH3); IR (neat) 2962, 1711, 1490, 1452,
1354 cmꢀ1; HPLC analysis: Chiralcel AD-H, 2-propanol/hexane
(1:99), 0.5 mL/min, UV 254 nm; tR = 12.1 min (S, 21.3%), 13.2 min
(R, 78.7%); 58% ee.
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4.19. 1,3-Diphenyl-butanone 6s11a,b
2. (a) Bolm, C.; Ewald, M. Tetrahedron Lett. 1990, 31, 5011–5012; (b) Bolm, C.
Tetrahedron: Asymmetry 1991, 2, 701–704; (c) Uemura, M.; Miyake, R.;
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21, 1105–1107; (k) Wu, X. W.; Zhang, T. Z.; Yuan, K.; Hou, X. L. Tetrahedron:
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Pavlov, V. A. Tetrahedron 2008, 64, 1147–1179.
½
a 2D8
ꢁ
¼ þ32:1 (c 2.0, CCl4); 1H NMR (400 MHz, CDCl3)
d = 7.87ꢀ7.89 (m, 2H), 7.47ꢀ7.51 (m, 1H), 7.37ꢀ7.41 (m, 2H),
7.14ꢀ7.28 (m, 5H), 3.46 (m, 1H), 3.26 (dd, J = 16.8 Hz, 5.6 Hz,
1H), 3.14 (dd, J = 16.4 Hz, 8.4 Hz, 1H), 1.30 (d, J = 6.8 Hz, 3H)
ppm; 13C NMR (100 MHz, CDCl3) d 199.0 (C), 146.5 (C), 137.1(C),
132.9 (CH), 128.5 (CH), 128.5 (CH), 128.0 (CH), 126.8 (CH), 126.2
(CH), 47.0 (CH2), 35.5 (CH), 21.8 (CH3); IR (neat) 2963, 1634,
1493, 1448, 1270, 1202, 990 cmꢀ1; HPLC analysis: Chiralcel AD-
H, 2-propanol/hexane (1:99), 1.0 mL/min, UV 254 nm;
tR = 10.4 min (S, 90.1%), 12.7 min (R, 10.0%); 80% ee.
4.20. 1,3-Diphenyl-heptanone 6t12
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516–517.
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4479–4491; (b) de Vries, A. H. M.; Imbos, R.; Feringa, B. L. Tetrahedron:
Asymmetry 1997, 8, 1467–1473.
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1556–1560.
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2000, 2507–2511; (b) Hu, X.; Hu, Y.; Liang, X.; Wang, J.; Zheng, Z. J. Org. Chem.
2003, 68, 4542–4545; (c) Imamoto, T.; Takahashi, Y.; Yamamoto, Y.; Katagiri,
K.; Danjo, H.; Yamaguchi, K. J. Org. Chem. 2005, 70, 9009–9012.
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(b) Hajra, A.; Yoshikai, N.; Nakamura, E. Org. Lett. 2006, 8, 4153–4155; (c)
Laschat, S.; Sammet, K.; Gastl, C.; Baro, A.; Fischer, P.; Fettiga, I. Adv. Synth.
Catal. 2010, 352, 2281–2290.
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14. In Table 3, dialkylzincs are commercially available. (such as: Et2Zn 1.0 M
solution in hexane), Me2Zn (10 wt% solution in hexane), Bu2Zn (1.0 M solution
in heptane), i-Pr2Zn (1.0 M solution in toluene).
½
a 2D8
ꢁ
¼ ꢀ3:4 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) d = 7.94 (d,
J = 8.8 Hz, 2H), 7.50ꢀ7.54 (m, 1H), 7.41ꢀ7.45 (m, 2H), 7.27ꢀ7.34 (m,
4H), 7.19ꢀ7.23 (m, 1H), 3.28ꢀ3.40 (m, 3H), 1.68ꢀ1.79 (m, 2H),
1.19ꢀ1.35 (m, 4H), 0.87 (t, 3H) ppm; 13C NMR (100 MHz, CDCl3) d
199.0 (C), 144.9 (C), 137.1(C), 132.8 (CH), 128.4 (CH), 128.3 (CH),
127.9 (CH), 127.5 (CH), 126.1 (CH), 45.9 (CH2), 41.2 (CH), 36.0
(CH2), 29.6 (CH2), 22.5 (CH2), 13.9 (CH3); IR (neat) 3020, 2952,
2927, 1685, 1594, 1448, 1359, 1015, 973 cmꢀ1; HPLC analysis: Chi-
ralcel AD-H, 2-propanol/hexane (1:99), 1.0 mL/min, UV 254 nm;
tR = 9.3 min (S, 90.8%), 13.0 min (R, 9.2%); 82% ee.
4.21. 4-Methyl-1,3-diphenyl-pentan-1-one 6u13
½
a 2D0
ꢁ
¼ þ0:3 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
d = 7.92ꢀ7.94 (m, 2H), 7.54ꢀ7.57 (m, 1H), 7.43ꢀ7.47 (m, 2H),
7.28ꢀ7.33 (m, 2H), 7.18ꢀ7.22 (m, 3H), 3.41 (d, 2H, J = 7.2 Hz),
3.20ꢀ3.25 (m, 1H), 1.97ꢀ2.02 (m, 1H), 1.04 (d, 3H, J = 6.8 Hz), 0.85
(d, 3H, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) d 199.4 (C), 143.5
(C), 137.2 (C), 132.7 (CH), 128.5 (CH), 128.4 (CH), 128.3 (CH),
127.9 (CH), 126.0 (CH), 47.7 (CH), 42.4 (CH2), 33.2 (CH), 20.9
15. (a) Brienne, M. J.; Ouannes, J.; Jacques, J. Bull. Chem. Soc. Chim. Fr. 1967, 613–
623; (b) Shintani, R.; Fu, G. C. Org. Lett. 2002, 4, 3699–3702; (c) Wan, H.; Hu, Y.;
Liang, Y.; Gao, S.; Wang, J.; Zheng, Z.; Hu, X. J. Org. Chem. 2003, 68,
8277–8280.
16. (a) Shi, M.; Duan, W. L.; Rong, G. B. Chirality 2004, 16, 642–651; (b) Shi, M.;
Wang, C. J.; Zhang, W. Chem. Eur. J. 2004, 10, 5507–5516.
17. Soai, K.; Hayasaka, T.; Ugajin, S. J. Chem. Soc., Chem. Commun. 1989, 8, 516–517.
18. Asami, M.; Usui, K.; Higuchi, S.; Inoue, S. Chem. Lett. 1994, 2, 297–298.
19. Biradar, D. B.; Gau, H. M. Tetrahedron: Asymmetry 2008, 19, 733–738.
(CH3), 20.3 (CH3); IR (neat) 1637, 1493, 1448, 1366, 1259 cmꢀ1
HPLC analysis: Chiralcel AD-H, 2-propanol/hexane (1:99), 1.0 mL/
min, UV 254 nm; tR = 10.8 min (S, 52.4%), 13.8 min (R, 45.9%); 7% ee.
;
Acknowledgments
We thank the National Science Council, Republic of China (Tai-
wan), for the financial support (NSC96-2113-M-007-014-MY3,
NSC99-2113-M-007-010-MY3 and NTHU-100N2010E1).