Use of zinc enolate, free from other metals, in enantioselective palladium-catalyzed allylic alkylation

Article abstract of DOI:10.1016/j.tet.2005.11.053

Zinc enolate, free from other metal cations directly prepared from malonate and diethylzinc, was proven to be an excellent nucleophile for enantioselective palladium-catalyzed allylic alkylation, particularly for the allylic cation bearing aromatic rings

Full text of DOI:10.1016/j.tet.2005.11.053

Tetrahedron 62 (2006) 1756–1763
Use of zinc enolate, free from other metals, in enantioselective
palladium-catalyzed allylic alkylation
b
a
Naosumi Kinoshita,a Takeo Kawabata,b, Kazunori Tsubaki, Masahiko Bando
*
and Kaoru Fujic,
*
aMedicinal Chemistry Research Institute, Otsuka Pharmaceutical Company, Ltd, 463-10 Kagasuno, Kawauchi-cho,
Tokushima 771-0192, Japan
bInstitute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
cFaculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure,
Hiroshima 737-0112, Japan
Received 12 September 2005; revised 21 November 2005; accepted 22 November 2005
Available online 27 December 2005
This paper is dedicated to the memory of the late Professor Kiyoshi Tanaka.
Abstract—Zinc enolate, free from other metal cations directly prepared from malonate and diethylzinc, was proven to be an excellent
nucleophile for enantioselective palladium-catalyzed allylic alkylation, particularly for the allylic cation bearing aromatic rings at the 1- and
3-positions.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
the enantiomeric excess (ee) in a palladium-catalyzed
allylic alkylation with (R)-BINAP as a chiral ligand using
zinc enolates, free from other metals, and generated with
diethylzinc as a base.12 Here, we report a full account of
palladium-catalyzed asymmetric allylic alkylation using
diethylzinc as a base.
Diethylzinc is a weak nucleophile used for the nucleophilic
addition to aldehydes,1 1,4-addition to a,b-unsaturated
carbonyl compounds,2–4 the Simmons–Smith reaction,5
and the umpolung of p-allylpalladium compounds.6 It is
also known that diethylzinc is a weak Lewis acid
coordinating to oxygen, nitrogen, and halogens.7 Diethyl-
zinc has been rarely used as a base to generate enolates from
carbonyl compounds, although limited examples have been
reported for the preparation of enolates from dialkyl
malonates,8 and chiral phosphonate anions for the asym-
metric Horner–Wadsworth–Emmons reaction.9 The useful-
ness of zinc malonate free from other metals has also been
reported in iridium-catalyzed allylic alkylation.10
2. Results and discussion
Control of the regio- and stereochemistry of palladium-
catalyzed allylic alkylations relies upon the chiral ligand,
the structure of a nucleophile and an electrophile, and the
nature of counter cations. We have chosen 1,3-diphenyl-
prop-2-enyl acetate (1) as a starting material, which gives
symmetrical allylic cation, to avoid the ambiguity arising
from unsymmetrical allylic cation (Scheme 1). The test
reactions were performed with the zinc enolate of dimethyl
malonate using triphenylphosphine as a ligand and the
Zinc enolates are routinely prepared in situ by metal–metal
exchange with other metal enolates.11 Since the other metals
coexist with zinc in the reaction medium, the nature must be
quite different from that of the zinc enolate free from other
metals, which may affect the stereochemical outcome of the
reactions. We have reported a remarkable enhancement of
Keywords: Enantioselective allylic alkylation; Zinc enolate; Chiral ligand.
*
Corresponding authors. Tel.: C81 823 73 8936; fax: C81 823 73 8981;
e-mail address: fuji@ps.hirokoku-u.ac.jp
Scheme 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.053

N. Kinoshita et al. / Tetrahedron 62 (2006) 1756–1763
1757
Table 1. Palladium-catalyzed allylic alkylation of racemic 1,3-diphenylprop-2-enyl acetate (1) with dimethyl malonate using Et2Zn as a basea
Entry
Pd source
Pd (mol%)
PPh3 (mol%)
Solvent
Reaction time (h)
Yield (%)
1
2
3
4
Pd(OAc)2
5
5
5
2
20
20
20
8
THF
THF
CH2Cl2
CH2Cl2
20
19
17
4
6
4
79
74
[Pd(h3-C3H5)Cl]2
[Pd(h3-C3H5)Cl]2
[Pd(h3-C3H5)Cl]2
a
2
Two equivalents of dimethyl malonate and Et Zn were used.
Table 2. Palladium-catalyzed enantioselective allylic alkylationa of racemic 1,3-diphenylprop-2-enyl acetate (1) with Et2Znb as a base using (R)-BINAPc as a
ligand giving (S)-2
Entry
Solvent
Temperature (8C)
Reaction time (h)
Product 2
ee (%)
Recovered 1 yield (%)
Yield (%)
1
2
3
4
5
6
7
8
CH2Cl2
CH3CN
Et2O
Toluene
Toluene
THF
THF
THF
THF
THF
0
88
65
76
45
17
39
47
20
67
14
26
63
71
46
73
84
90
57
52
14
89
79
77
22
98
96
99
97
88
72
18
53
33
13
0
36
0
0
0
0 to rt
0
rt
0
0 to rt
rt
Reflux
0 to rt
rt
9
0.5
35
134
0
0
10
10d
11e
THF
a [Pd(h3-C3H5)Cl]2 (2 mol%) was used for all reactions.
b Two equivalents for each reaction.
c Eight mol% for each reaction.
d
2
Pd (dba)3$CHCl3 was used.
e
2
Pd (dba)3 was used.
results are shown in Table 1. The alkylated product 2 was
obtained in low yields in THF. Change of the solvent to
CH2Cl2 increased the yield dramatically (entry 3) even with
decreased amount of the catalyst (entry 4). Thus, the
possible use of diethylzinc was demonstrated for palladium-
catalyzed allylic alkylation.
confirmed by the comparison of an [a]D value with that
reported by Hayashi13 and the ee was determined by chiral
HPLC analysis. All solvents tested except for CH2Cl2 gave
moderate to high ee at 0 8C, though the chemical yield was
unsatisfactory. Increase in the reaction temperature
decreased ee in toluene (entries 4 and 5), while the high
ee was kept in THF even under refluxing conditions (entries
6–9). Change of the catalyst to Pd2(dba)3 was less effective
(entries 10 and 11).
We chose the conditions in entry 4, involving the acetate 1
(1 equiv), dimethyl malonate (2 equiv), diethylzinc
(2 equiv), [Pd(h3-C3H5)Cl]2 (2 mol%), and the ligand
(8 mol%), as a standard procedure for the asymmetric
version. The results with (R)-BINAP as a chiral ligand are
listed in Table 2. All reactions gave (S)-2, which was
We examined the effect of counter cations (Table 3) since
their importance for enantioselectivity is well demonstrated
in the allylic alkylations,14,15 The use of NaH decreased the
Table 3. Effects of counter cations in enantioselective allylic alkylation of racemic 1 with dimethyl malonatea
Entry
Base
Additive
Temperature (8C)
Reaction time (h)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
NaH
NaH
KH
LiH
LDA
LDA
n-BuLi
n-BuLi
Et2Zn
None
ZnCl2
None
None
None
ZnCl2
None
ZnCl2
LiCl
rt
rt
rt
rt
rt
rt
rt
rt
18
48
5
64
2
68
24
42
42
1
75
19 (58)b
77
35
57
59
72
76
87
56
53
82
14
84
0
68 (89)b
87
60 (71)b
91
19
67
82
9
rt
Reflux
rt
10
11
12
13
14
Et2Zn
LiCl
t-Bu–P4-base
MeMgBr
MeMgBr
MeMgI
None
None
None
None
3
192
1
82
16 (44)b
81
rt
Reflux
rt
2
0
72
26 (36)b
a Under the standard conditions with (R)-BINAP (8 mol%) in THF.
b The numbers in the parenthesis are the yields based on the recovered starting material.

1758
N. Kinoshita et al. / Tetrahedron 62 (2006) 1756–1763
Figure 1. List of ligands tested.
ee to 35% (entry 1).16 Zinc enolate prepared by the addition
of zinc chloride to the sodium enolate gave a higher ee but
with a lower yield (entry 2). No significant effect of counter
cations was observed under these reaction conditions
(entries 3–8). Adding lithium chloride to the pure zinc
enolate slightly lowered both the ee and the yield (compare
entry 8 in Table 2 with entry 9 in Table 3). The ee was
remarkably decreased at refluxing temperature in the
presence of lithium chloride (entries 9 vs 10), while
decrease in ee was not observed in the absence of lithium
chloride at the same temperature (Table 2, entries 8 vs 9).
This could be ascribed to the difference in the aggregate
structure of the enolate in the former conditions from the
latter. The phosphazene base P4–t-Bu, known to generate a
metal-free enolate, gave a fairly good yield and ee (entry
11). Magnesium enolate afforded racemic 2 (entries 12–14).
The results in Tables 2 and 3 show the advantage of using
the zinc enolate, free from other metals, in enantioselective
allylic alkylations with (R)-BINAP.
The results of applying the standard conditions at
refluxing temperature to other chiral ligands are listed in
Figure 1 and Table 4. The advantage of the zinc enolate
free from other metals was not observed with other chiral
Table 4. Assessment of chiral ligands for the enantioselective allylic alkylation of racemic 1 using Et2Zn as a base
Entry
Liganda
Reaction time (h)
Yield (%)b
ee of 2 (%)c
2
Ad
1
2
3
4
5
6
7
8
L1:(R)-Tol-BINAP
L2:(R)-Cl-MeO-BIPHEP
L3:(R)-PHOX
L4:(R)-(S)-JOSIPHOS
L5:(R)-(S)-BPPFA
L6:(R,R)-Trost ligand
L7:(S,S)-DIOP
0.5
0.5
3
0.5
0.5
0.5
0.5
0.5
0.5
3
3
0.5
1
0.5
0.5
89
91
72
86
—
—
—
—
—
—
—
—
—
—
—
84
52
—
—
91 (S)
98 (S)
96 (R)
84 (S)
54 (S)
—
11 (S)
36 (R)
—
77 (S)
—
—
34 (S)
—
—
86
(3)e
86
L8:(S,S)-BDPP
88
0
9
L9:(S,S)-CHIRAPHOS
L10:(R)-(R)-Et-DUPHOS
L11:(R)-(R)-Et-BPE
L12:(R)-MeO-MOP
L13
10
11
12
13
14
15
28
(10)e
—
33
L14:(R)-MonoPhos
L15
(5)e
—
a Structures of chiral ligands are listed in Figure 1.
b Isolated yield.
c
2
Determined by HPLC on CHIRALCEL OJ-R (MeOH/H OZ80:20).
d Similar reduction of allyl acetates with alkyl zinc/Pd (0) system has been reported, see Ref. 21.
1
e The number in parenthesis indicates the yield determined by H NMR of crude product.

N. Kinoshita et al. / Tetrahedron 62 (2006) 1756–1763
1759
Table 5. Palladium-catalyzed enantioselective allylic alkylation of the racemic acetate 1 with various nucleophiles (Nu-H) in THF
Entry
Nu-H
Base
Temperature (8C)
Reaction time (h) Producta
Yield (%)b
ee (%)
1
2
3
4
CH2(CO2Bn)2
CH2(CO2Bn)2
CH2(CO2Bn)2
CH2(CO2Bn)2
CH2(SO2Ph)2
CH2(SO2Ph)2
CH2(SO2Ph)2
CH2(SO2Ph)2
CH2(SO2Ph)2
CH2(CN)2
Et2Zn
Et2Zn
NaH
n-BuLi
Et2Zn
Et2Zn
Et2Zn
Et2Zn
NaH
Et2Zn
Et2Zn
NaH
Et2Zn
Et2Zn
Et2Zn
NaH
rt
Reflux
rt
rt
rt
rt
Reflux
rt
20
1
2
18
72
72
2
72
45
48
3ac
3a
3a
3a
3be
3b
3b
3b
3b
3ci
3c
81
78
83
88
24 (44)
43
70
62 (76)
36 (60)
48
92d
95d
0d
67d
92f
91f
39f
88f
88f
85j
7j
5
6g
7
8h
9
rt
10
11
12
13
14
15h
16m
17
18
19
rt
Reflux
rt
rt
Reflux
rt
CH2(CN)2
CH2(CN)2
1.5
89
48
168
3
168
211
20
3
3c
33 (62)
47 (53)
92
55 (65)
45
13 (76)
70
86
75j
70l
76l
84l
0l
BnCH(CO2Me)2
BnCH(CO2Me)2
BnCH(CO2Me)2
BnCH(CO2Me)2
AcCH2CO2Me
AcCH2CO2Me
AcCH2CO2Me
3dk
3d
3d
3d
3en
3e
rt
rt
Et2Zn
Et2Zn
NaH
96o
97o
57o
Reflux
rt
3
3e
a
D
The absolute configuration was determined by comparison of the [a] value with that in the literature.
b The number in parenthesis indicates the yield based on the consumed starting material.
c New compound. The absolute configuration was not confirmed.
d Determined by HPLC on CHIRALPAK AD (hexane/2-propanolZ9:1).
e Known; see Ref. 17.
f
Determined by HPLC on CHIRALCEL OJ-R (MeOH).
3
CH (SO2Ph)2 (10 equiv), base (10 equiv), [Pd(h -C3H5)Cl]2 (2 mol%), and (R)-BINAP (8 mol%) were used.
g
2
h DMF as a solvent.
i
Known; see Ref. 18.
Determined by HPLC on CHIRALCEL OJ (hexane/2-propanolZ9:1).
j
k Known; see Ref. 16; where the absolute configuration was assigned without evidence. Absolute configuration was postulated from the optical rotation of the
corresponding diethyl ester. See Ref. 19.
l
Determined by HPLC on CHIRALPAK AD (hexane/2-propanolZ92:8).
mTaken from Ref. 16, where [Pd(h3-C3H5)Cl]2 (0.5 mol%), and (S)-BINAP (1.2 mol%) were used.
n Known; see Ref. 13.
1
o Determined by H NMR with Eu(hfc)3.
ligands, although modified BINAP analogues (L1 and L2)
gave good results comparable to (R)-BINAP (entries 1 and
2). Since the combination of (R)-BINAP as a chiral ligand
and diethylzinc for the generation of enolate was shown to
be the best for allylic alkylation, we applied this system to
other nucleophiles. The results, together with those with
NaH, are compiled in Table 5. The standard conditions
were shown to be applicable to other nucleophiles to give
high ee’s, though yields are sometimes low (entries 5, 10,
13, and 17). The close inspection of Table 5 reveals that
the reaction time was remarkably shortened at refluxing
temperature without decrease in the ee with the
nucleophiles stabilized by carbonyl groups (compare
entries 1 and 2, 13 and 14, 17 and 18). Use of NaH
dramatically decreased the ee, with these nucleophiles
(entries 3, 16, and 19), while nucleophiles stabilized by
the sulfonyl or the cyano group gave comparable ee’s
(compare entries 5 and 9, 10 and 12). Another
characteristic disposition of the latter nucleophiles
includes low ee’s at refluxing temperature (entries 7 and
11). These findings suggest that the structure and/or the
aggregation state of the enolates generated from malonate
is quite different from those generated from the active
methylene compounds with sulfonyl and cyano groups.
The results of enantioselective allylic alkylation of racemic
acetates 4–7 and 12 with dimethyl malonate are listed in
Table 6. All of the starting material except for the nitro
substituted compound 7 showed characteristic features
associated with a combination of a malonate and
diethylzinc, in which the high ee’s were kept under refluxing
conditions (entries 2, 6, 10, and 17). The (S)-configuration
of the carbon center, newly created in 9, was determined by
X-ray crystallography (Fig. 2). The same absolute configur-
ations for other products 8, 10, 11, and 13 can be postulated
by the reaction mechanism, though direct evidence is
lacking. The advantage of diethylzinc as a base was not
observed with 1,3-dialkylallylic esters 14, 15, and 17–19
(Table 7).
3. Conclusion
Zinc enolate free from other metal cations, directly
prepared from malonate, was proven to be a good

1760
N. Kinoshita et al. / Tetrahedron 62 (2006) 1756–1763
Table 6. Palladium-catalyzed enantioselective allylic alkylation of the racemic acetate 4–7 and 12 with dimethyl malonate in THFa
Entry
Substrate
Base
Temperature (8C)
Reaction time (h)
Product
Yield (%)
ee (%)
1
2
4
4
4
4
5
5
5
5
6
6
6
6
7
7
7
Et2Zn
Et2Zn
NaH
rt
Reflux
rt
20
0.5
4
1
40
1
4
1
72
1
4
8
8
8
8
9
9
9
9
10
10
10
10
11
11
11
13
13
13
13
92
95
88
91
60c
40
90
84
73
91
78
83
21
44
75
73
95
88
83
97
96
30
0
97
97
34
0
78
80
19
0
32
36
0
3
4b
5
NaH
rt
Et2Zn
Et2Zn
NaH
rt
Reflux
rt
6
7
8b
9
NaH
rt
Et2Zn
Et2Zn
NaH
rt
Reflux
rt
rt
rt
10
11
12b
13
14
15b
16
17
18
19b
NaH
1
Et2Zn
NaH
NaH
Et2Zn
Et2Zn
NaH
72
24
0.5
48
2
rt
rt
12
12
12
12
rt
Reflux
rt
rt
88
90
67
0
8
10
NaH
a Unless otherwise stated, dimethyl malonate (2 equiv), base (2 equiv), [Pd(h3-C3H5)Cl]2 (2 mol%), and (R)-BINAP (8 mol%) were used for all of the
reactions.
b
3
PPh was used as a ligand.
c A 7% of starting material was recovered.
Figure 2.
nucleophile for palladium-catalyzed allylic alkylation to
give a product with good yield and high ee. In particular,
the allylic cation bearing aromatic rings at the 1- and
3-positions gave excellent results with BINAP or modified
BINAP analogues. Advantage to use zinc enolates free
from other metals involves marked decrease in the
reaction time by using refluxing conditions without any
loss of the ee. The present results may suggest that the
use of zinc enolates free from other metals is the
method of choice to increase ee’s and/or chemical yields
in other types of enantioselective reactions involving
enolates.

N. Kinoshita et al. / Tetrahedron 62 (2006) 1756–1763
1761
Table 7. Enantioselective allylic alkylation of the racemic 1,3-dialkyl allyl ester derivatives 14, 15, and 17–19 under the standerd conditions
Entry
Substrate
Solvent
Temperature (8C)
Reaction time (h)
Product
Yield (%)a
ee (%)b
1
2
3
4
5
6
14
14
14
15
15
17
17
17
18
18
18
19
THF
THF
THF
THF
DMF
THF
DMF
THF
THF
THF
DMF
THF
Reflux
rt
rt
rt
rt
Reflux
70
Reflux
rt
Reflux
70
Reflux
0.5
6
16
16
16
16
16
20
20
20
20
20
20
20
54
21
40
63
27
62
31
88
0
41
63
45
41
28
66
77
68
—
82
78
78
24
24
24
16
36
1
360
4
8
7
8c
9
10
11
12
16
23
67
8
a Isolated yield.
b Determined by GLC (Chirasil-DXE CB) for 1620 and 1H NMR with Eu(hfc)3 for 20.20
c NaH was used as a base.
4. Experimental
476.1996. Anal. Calcd for C32H28O4: C, 80.65; H, 5.92.
Found C, 80.72; H, 5.96.
4.1. Standard procedure of allylic alkylation (entry 9 in
Table 2)
4.1.2. (E)-1,3-Bis(4-methylphenyl)prop-2-enyl acetate
(6). To a suspension of (E)-1,3-bis(4-methylphenyl)prope-
none (1.18 g, 5.0 mmol) and CeCl3$7H2O (1.86 g,
5.0 mmol) in MeOH was added NaBH4 (0.19 g,
5.0 mmol) portionwise under ice-cooling and the mixture
was stirred for 30 min. Usual extractive work-up with Et2O
afforded (E)-1,3-bis(4-methylphenyl)prop-2-en-1-ol (1.1 g,
94%). To a solution of (E)-1,3-bis(4-methylphenyl)prop-2-
en-1-ol (0.55 g, 2.3 mmol) and DMAP (2.8 mg, 0.01 equiv)
in CH2Cl2 (2 ml) was successively added Et3N (0.38 ml,
2.7 mmol) and Ac2O (0.24 ml, 2.5 mmol) under ice-cooling
and the mixture was stirred for 1 h. Extractive work-up with
[Pd(h3-C3H5)Cl]2 (1.82 mg, 0.005 mmol, 2 mol%), and
(R)-BINAP (12.5 mg, 0.02 mmol, 8 mol%) were dissolved
in THF (0.5 ml) and stirred for 1 h at room temperature.
After cooling to 0 8C, 1,3-diphenylprop-2-enyl acetate
(1.59 mg, 0.25 mmol) in THF (0.5 ml) was added to prepare
the solution A. Diethylzinc (1.0 M in hexane, 0.5 ml,
0.5 mmol) was added to a solution of dimethyl malonate
(67 mg, 0.5 mmol) in THF (1.5 ml) and stirred for 1 h at
room temperature, to which the solution A was introduced
via Teflon tube. After the mixture was stirred at refluxing
temperature for 30 min, it was diluted with 1 N HCl
followed by the extraction with AcOEt. Organic layer was
successively washed with aq NaHCO3 and brine and dried
over MgSO4. Evaporation of the solvent gave an oil, which
was purified by PTLC over silica gel (AcOEt/hexaneZ1:7).
1
Et2O afforded 6 (0.61 g, 95%) as an oil. H NMR (CDCl3,
500 MHz) d 2.11 (s, 3H), 2.32 (s, 3H), 2.35 (s, 3H), 6.29 (dd,
JZ15.8, 6.8 Hz, 1H), 6.40 (d, JZ6.9 Hz, 1H), 6.58 (d, JZ
15.8 Hz, 1H), 7.10 (d, JZ8.0 Hz, 2H), 7.18 (d, JZ8.0 Hz,
2H), 7.26–7.31 (m, 4H). 13C NMR (CDCl3, 125 MHz) d
21.2, 21.2, 21.4, 76.2, 126.6, 127.1, 129.2, 129.3, 132.3,
133.4, 136.4, 137.9, 137.9, 170.1. IR (neat) cmK1: 1738,
1513, 1369, 1233, 1017, 965, 818, 800. MS m/z: 280 (MC),
238, 220 (base peak), 205, 129, 119. HRMS m/z: Calcd for
C19H20O2 (MC): 280.1463. Found: 280.1452. Anal. Calcd
for C19H20O2: C, 81.40; H, 7.19. Found: C, 81.60; H, 7.24.
4.1.1. Dibenzyl[(1,3-diphenyl)prop-2-enyl]malonate (3a).
The crude product obtained through the standard procedure
was purified by PTLC over silica gel (Et2O/CH2Cl2/
hexaneZ1:1:5). Oil (95% ee, determined by CHIRALPAC
AD, hexane/2-propanolZ9:1, flow rate 0.5 ml/min., detec-
tion at 254 nm, tR 47 and 59 min), [a]2D0 K7.1 (c 1.0,
CHCl3). 1H NMR (CDCl3, 500 MHz) d 4.04 (d, JZ10.9 Hz,
1H), 4.30 (dd, JZ10.8, 8.5 Hz, 1H), 4.93 (dd, JZ17.5,
12.3 Hz, 2H), 5.11 (dd, JZ16.3, 12.2 Hz, 2H), 6.31 (dd,
JZ15.7, 8.5 Hz, 1H), 6.41 (d, JZ15.8 Hz, 1H), 7.04–7.06
(m, 2H), 7.20–7.28 (m, 18H). 13C NMR (CDCl3, 125 MHz)
d 49.3, 57.8, 67.1, 67.4, 126.4, 127.2, 127.5, 127.9, 128.1,
128.2, 128.3, 128.4, 128.4, 128.5, 128.7, 129.0, 131.9,
4.1.3. (E)-1,3-Bis(4-nitrophenyl)prop-2-enyl acetate (7).
To a suspension of (E)-1,3-bis(4-nitrophenyl)propenone
(2.98 g, 10.0 mmol) and CeCl3$7H2O (3.73 g, 10.0 mmol)
in MeOH was added NaBH4 (0.38 g, 10.0 mmol) portion-
wise under ice-cooling and the mixture was stirred for 2 h.
Usual extractive work-up with Et2O afforded (E)-1,3-bis(4-
nitrophenyl)prop-2-en-1-ol (2.2 g, 75%) after column
chromatography over silica gel (AcOEt/hexaneZ35:65).
To a solution of (E)-1,3-bis(4-nitrophenyl)prop-2-en-1-ol
(2.18 g, 7.26 mmol) and DMAP (9 mg, 0.01 equiv) in
CH2Cl2 (15 ml) was successively added Et3N (1.21 ml,
135.1, 135.1, 136.7, 140.1, 167.2, 167.6. IR (neat) cmK1
:
1758, 1773, 1469, 1455, 1375, 1257, 1216, 1150, 966, 744,
695. MS m/z: 476 (MC), 385, 341, 91 (base peak). HRMS
m/z: Calcd for C32H28O4 (MC): 476.1988. Found:

1762
N. Kinoshita et al. / Tetrahedron 62 (2006) 1756–1763
8.71 mmol) and Ac2O (0.82 ml, 8.71 mmol) under ice-
cooling and the mixture was stirred for 30 min. Extractive
work-up with Et2O followed by column chromatography
over silica gel (AcOEt/hexaneZ20:80) afforded 7 (1.76 g,
71%) as yellow needles, mp 127–129 8C (from AcOEt–
MrZ482.17, orthorhombic, space group P212121, aZ
˚
˚
˚
13.655 (3) A, bZ25.107 (5) A, cZ5.796 A, aZ908, bZ
3
3
˚
908, gZ908, VZ1987 (2) A , ZZ4, DcZ1.612 g/cm ,
F(000)Z960 and mZ41.128 cmK1. The structure was
refined to RZ0.200, RwZ0.114. Crystallographic data
(excluding structure factors) for the structure in this paper
have been deposited with Cambridge Crystallographic Data
Centre as supplementary publication number CCDC
282742. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [fax: C44 1223 336033 or e-mail: deposit@ccdc.
cam.ac.uk].
1
hexane). H NMR (CDCl3, 500 MHz) d 2.20 (s, 3H), 6.46
(dd, JZ15.7, 6.6 Hz, 1H), 6.52 (d, JZ6.8 Hz, 1H), 6.74 (d,
JZ15.7 Hz, 1H), 7.51–7.53 (m, 2H), 7.59–7.60 (m, 2H),
8.18–8.19 (m, 2H), 8.26 (dd, JZ6.9, 1.8 Hz, 2H). 13C NMR
(CDCl3, 125 MHz) d 21.1, 74.5, 124.0, 124.1, 127.4, 127.8,
130.7, 131.4, 141.9, 145.4, 147.5, 147.8, 169.6. IR
(KBr) cmK1: 1736, 1600, 1516, 1346, 1233, 859. MS m/z:
342 (MC), 300 (base peak), 282, 271, 236, 189, 178. HRMS
m/z: Calcd for C17H14N2O6 (MC): 342.0852. Found:
342.0874. Anal. Calcd for C17H14N2O6: C, 59.65; H, 4.12.
Found: C, 59.69; H, 4.09.
4.2.3. Dimethyl[1,3-bis(4-methylphenyl)prop-2-enyl]ma-
lonate (10) in entry 10. Purified by PTLC (silica gel,
AcOEt/hexaneZ1:6), 80% ee determined by HPLC
(CHIRALPAK AD, 2-propanol/hexaneZ6:94, flow rate
0.5 ml/min, detection at 254 nm, tR 29, 40 min), [a]D20
K13.4 (c 1.0, CHCl3). 1H NMR (CDCl3, 500 MHz) d 2.30
(s, 6H), 3.53 (s, 3H), 3.69 (s, 3H), 3.92 (d, JZ10.9 Hz, 1H),
4.21 (dd, JZ10.7, 8.8 Hz, 1H), 6.25 (dd, JZ15.7, 8.7 Hz,
1H), 6.42 (d, JZ15.7 Hz, 1H), 7.07 (d, JZ8.0 Hz, 2H), 7.11
(d, JZ7.9 Hz, 2H), 7.18 (dd, JZ13.6, 8.1 Hz, 4H). 13C
NMR (CDCl3, 125 MHz) d 21.0, 21.1, 48.9, 52.4, 52.6,
57.8, 126.3, 127.7, 128.3, 129.1, 129.4, 131.5, 134.1, 136.7,
137.3, 137.3, 167.9, 168.3. IR (neat) cmK1: 1760, 1739,
1513, 1434, 1321, 1256, 1159. MS m/z: 352 (MC), 221
(base peak), 129. HRMS m/z: Calcd for C22H24O4 (MC):
352.1675. Found: 352.1689. Anal. Calcd for C22H24O4: C,
74.98; H, 6.86. Found: C, 74.75; H, 6.74.
4.2. Products in Table 6
All reactions were performed with the same ratio of the
substrate and reagents as those of described in standard
procedure and under the conditions in Table 6.
4.2.1. Dimethyl [1,3-bis(4-chlorophenyl)prop-2-enyl]ma-
lonate (8) in entry 1. An oil, purified by PTLC (silica gel,
AcOEt/hexaneZ1:6), 97% ee, determined by HPLC
(CHIRALPAK AD, 2-propanol/hexaneZ15:85, flow rate
0.8 ml/min, detection at 254 nm, tR 19, 25 min), [a]2D0 K3.1
(c 1.0, CHCl3). 1H NMR (CDCl3, 500 MHz) d 3.55 (s, 3H),
3.70 (s, 3H), 3.89 (d, JZ10.7 Hz, 1H), 4.26 (dd, JZ10.6,
8.7 Hz, 1H), 6.26 (dd, JZ15.7, 8.5 Hz, 1H), 6.40 (d, JZ
15.8 Hz, 1H), 7.21–7.26 (m, 6H), 7.28–7.30 (m, 2H). 13C
NMR (CDCl3, 125 MHz) d 48.4, 52.6, 52.7, 57.4, 127.6,
128.7, 129.0, 129.2, 129.3, 131.1, 133.1, 133.4, 135.1,
138.5, 167.5, 167.9. IR (neat) cmK1: 1758, 1739, 1491,
1435, 1255, 1159, 1093. MS m/z: 394 (MC), 392 (MC), 263,
261 (base peak), 226, 191, 149. HRMS m/z: Calcd for
C20H18O4Cl2 (MC): 394.0553, 392.0582. Found: 394.0541,
392.0604. Anal. Calcd for C20H18O4Cl2: C, 61.08; H, 4.61.
Found: C, 61.36; H, 4.57.
4.2.4. Dimethyl[1,3-bis(4-nitrophenyl)prop-2-enyl]malo-
nate (11) in entry 14. An oil, purified by PTLC (Silica gel,
AcOEt/hexaneZ1:2), 36% ee determined by HPLC
(CHIRALCEL OJ-R, MeOH/H2OZ85:15, flow rate
0.4 ml/min, detection at 300 nm, tR 79, 87 min), [a]D20
K127.7 (c 1.2, CHCl3). 1H NMR (CDCl3, 500 MHz) d 3.58
(s, 3H), 3.74 (s, 3H), 3.99 (d, JZ10.5 Hz, 1H), 4.44 (dd, JZ
10.4, 8.1 Hz, 1H), 6.50 (dd, JZ15.8, 8.1 Hz, 1H), 6.57 (d,
JZ15.8 Hz, 1H), 7.45–7.50 (m, 4H), 8.15–8.17 (m, 2H),
8.20–8.23 (m, 2H). 13C NMR (CDCl3, 125 MHz) d 48.7,
52.9, 53.0, 56.7, 124.0, 124.2, 127.1, 128.9, 131.3, 132.2,
142.5, 146.9, 147.3, 167.1, 167.5. IR (neat) cmK1: 1755,
1738, 1597, 1520, 1346, 858, 756. MS m/z: 414 (MC, base
peak), 354, 295, 283, 249, 237, 203, 191. HRMS m/z: Calcd
for C20H18N2O8 (MC): 414.1063. Found: 414.1078. Anal.
Calcd for C20H18N2O8: C, 57.97; H, 4.38; N, 6.76. Found:
C, 57.90; H, 4.40; N, 6.82.
4.2.2. Dimethyl [1,3-bis(4-bromophenyl)prop-2-enyl]ma-
lonate (9) in entry 5. An oil, purified by PTLC (silica gel,
AcOEt/hexaneZ1:7), 97% ee, determined by HPLC
(CHIRALPAK AD, 2-propanol/hexaneZ20:80, flow rate
0.6 ml/min, detection at 254 nm, tR((R)-9) 25 min, tR((S)-9)
35 min), [a]2D0 C3.1 (c 1.0, CHCl3). 1H NMR (CDCl3,
500 MHz) d 3.55 (s, 3H), 3.70 (s, 3H), 3.89 (d, JZ10.7 Hz,
1H), 4.22 (dd, JZ10.6, 8.7 Hz, 1H), 6.27 (dd, JZ15.7,
8.4 Hz, 1H), 6.39 (d, JZ15.8 Hz, 1H), 7.16 (d, JZ8.2 Hz,
4H), 7.39 (d, JZ8.4 Hz, 2H), 7.44 (d, JZ8.4 Hz, 2H). 13C
NMR (CDCl3, 125 MHz) d 48.5, 52.6, 52.7, 57.3, 121.2,
121.6, 127.9, 129.3, 129.6, 131.2, 131.7, 131.9, 135.5,
139.0, 167.5, 167.9. IR (neat) cmK1: 1758, 1738, 1487,
1434, 1255, 1161, 1072, 1010, 757. MS m/z: 484 (MC), 482
(MC), 480 (MC), 353, 351, 349, 272, 270, 191 (base peak),
189. HRMS m/z: Calcd for C20H18O4Br2 (MC): 483.9531,
481.9552, 479.9572. Found: 483.9534, 481.9573, 479.9546.
Anal. Calcd for C20H18O4Br2: C, 49.82; H, 3.76. Found: C,
49.98; H, 3.74.
4.2.5. Dimethyl(1,3-di-naphthalen-1-ylprop-2-enyl)ma-
lonate (13) in entry 17. Purified by PTLC (silica gel,
AcOEt/hexaneZ2:9). The sample for [a]D measurement
was obtained by recycling preparative HPLC followed by
recrystallization from Et2O–hexane, mp 82–85 8C, 94% ee
determined by HPLC (CHIRALPAK AD, 2-propanol/
hexaneZ10:90, flow rate 1.0 ml/min, detection at 295 nm,
tR 10, 22 min), [a]D20 K37.5 (c 0.5, CHCl3). 1H NMR
(CDCl3, 500 MHz) d 3.45 (s, 3H), 3.75 (s, 3H), 4.31 (d, JZ
10.7 Hz, 1H), 5.30–5.34 (m, 1H), 6.43 (dd, JZ15.5, 8.6 Hz,
1H), 7.30 (d, JZ15.5 Hz, 1H), 7.34–7.60 (m, 8H), 7.72 (d,
JZ8.1 Hz, 1H), 7.77–7.81 (m, 2H), 7.87 (d, JZ8.1 Hz, 1H),
7.95–7.97 (m, 1H), 8.39 (d, JZ8.6 Hz, 1H). 13C NMR
(CDCl3, 125 MHz) d 44.2, 52.5, 52.7, 57.4, 123.4, 123.8,
A crystal for the X-ray analysis was obtained from MeOH,
mp 78–80 8C. X-ray crystallographic data: C20H18O4Br2,

N. Kinoshita et al. / Tetrahedron 62 (2006) 1756–1763
1763
Yamazaki, J.; Bedekar, A. V.; Watanabe, T.; Tanaka, K.; Fuji,
K. Tetrahedron: Asymmetry 2002, 13, 729–734.
10. Kinoshita, N.; Marx, K. H.; Tanaka, K.; Tsubaki, K.;
Kawabata, T.; Yoshikai, N.; Nakamura, E.; Fuji, K. J. Org.
Chem. 2004, 69, 7960–7964.
124.0, 124.3, 125.4, 125.5, 125.7, 125.8, 126.0, 126.4,
127.9, 127.9, 128.4, 129.0, 130.0, 131.1, 131.4, 132.3,
133.5, 134.2, 134.7, 136.3, 167.8, 168.6. IR (neat) cmK1
:
1760, 1733, 1432, 1252, 1158, 797, 778, 757. MS m/z: 424
(MC), 293, 165 (base peak), 141. HRMS m/z: Calcd for
C28H24O4 (MC): 424.1675. Found: 424.1653. Anal. Calcd
for C28H24O4: C, 79.22; H, 5.70. Found: C, 79.27; H, 5.71.
11. Zinc enolates of ketones free from other metals were generated
from a-iodoketones or a-iodoaldehydes with diethylzinc; see:
Ito, S.; Shinokubo, H.; Oshima, K. Tetrahedron Lett. 1998, 39,
5253–5256.
12. Fuji, K.; Kinoshita, N.; Tanaka, K. Chem. Commun. 1999,
1895–1896.
References and notes
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