Enantioselective copper-catalyzed 1,4-addition of dialkylzincs to enones followed by trapping with allyl iodide derivatives

Article abstract of DOI:10.1246/bcsj.20110035

Enantioselective copper-catalyzed 1,4-addition of dialkylzincs to enones proceeded in the presence of 0.1 mol% of Cu(OTf)₂ and 0.25 mol% of an N,N,P-ligand containing a quinoline moiety to afford the corresponding conjugated adducts in 99%ee. The intermediate zinc enolates were trapped with substituted allyl iodides to give disubstituted ketones with high diastereoselectivity and enantioselectivity.

Full text of DOI:10.1246/bcsj.20110035

640
Bull. Chem. Soc. Jpn. Vol. 84, No. 6, 640–647 (2011)
© 2011 The Chemical Society of Japan
Enantioselective Copper-Catalyzed 1,4-Addition of Dialkylzincs
to Enones Followed by Trapping with Allyl Iodide Derivatives
Kenjiro Kawamura, Hitomi Fukuzawa, and Masahiko Hayashi*
Department of Chemistry, Graduate School of Science, Kobe University, Nada-ku, Kobe, Hyogo 657-8501
Received February 3, 2011; E-mail: mhayashi@kobe-u.ac.jp
Enantioselective copper-catalyzed 1,4-addition of dialkylzincs to enones proceeded in the presence of 0.1 mol % of
Cu(OTf)2 and 0.25 mol % of an N,N,P-ligand containing a quinoline moiety to afford the corresponding conjugated
adducts in 99% ee. The intermediate zinc enolates were trapped with substituted allyl iodides to give disubstituted ketones
with high diastereoselectivity and enantioselectivity.
Enantioselective 1,4-addition of organometallic species to
enones is one of the most important asymmetric carbon-carbon
bond-forming reactions in organic synthesis.1 An example of
this type of reaction is the enantioselective 1,4-addition of a
dialkylzinc to an enone, which has been the subject of various
studies.2 Following the first report of copper-catalyzed 1,4-
addition of diethylzinc to enones by Alexakis et al.,3 many
other studies have been carried out, using chiral phosphate
ligands,4 chiral phosphoramidites,5 chiral aminophosphine
ligands,6 chiral phosphines with amino acid moieties,7 N-
heterocyclic carbene ligands,8 peptide-based ligands,9 chiral
bis(oxazoline) ligands,10 and other types of ligands.4g,4o,6a,7a,11
We developed O,N,O-tridentate ligands with a Schiff base
framework (type I) for use in various asymmetric carbon-
carbon bond-forming reactions, including asymmetric silylcya-
nation of aldehydes,12 enantioselective addition of diketenes to
aldehydes,13 and enantioselective addition of dialkylzincs to
aldehydes.14 To increase the affinity of the ligands for transition
metals, we designed and synthesized new chiral P,N,P (type II)
and N,N,P (type III) tridentate ligands. Here, we report the
preparation of newly designed P,N,P-tridentate ligands and
their application to copper-catalyzed enantioselective addition
of dialkylzincs to enones.
Scheme 1. O,N,O-Ligand (type I) and P,N,P-ligand (type II).
Results and Discussion
Synthesis of Type II Ligand and Its Use in Enantio-
selective 1,4-Addition. We first designed type II ligands as
simple analogs of type I Schiff base ligands (Scheme 1).
The type II ligand was synthesized as shown in Scheme 2
(R = i-Pr). Bromination of 3,5-di-tert-butyltoluene (1) fol-
lowed by treatment with NBS afforded benzyl bromide
compound 3, which was then oxidatively converted by
hexamethylenetetramine into aldehyde 4. After protecting the
aldehyde moiety with ethylene glycol, a diphenylphosphino
group was introduced by lithiation of 5 then hydrolysis of 6
gave the phosphinoaldehyde 7. Condensation of aminophos-
phine with this aldehyde gave the type II ligand 8 in high yield.
We then examined the application of the type II ligand 8 in
the asymmetric 1,4-addition of diethylzinc to 2-cyclohexen-
1-one. However, as shown in Scheme 3, the optical yield was
Scheme 2. Preparation of type II ligand.
only moderate and the reactivity was so low so that a long
reaction time was required even at 0 °C. We concluded that the
bulkiness of two PPh2 groups and the rigidity of the imine
moiety inhibited the formation of a copper complex.
Published on the web June 4, 2011; doi:10.1246/bcsj.20110035

K. Kawamura et al.
Bull. Chem. Soc. Jpn. Vol. 84, No. 6 (2011)
641
Cu(OTf)2 (1 mol%)
Table 1. Enantioselective 1,4-Addition of Diethylzinc to
2-Cyclohexen-1-one
i-Pr
N
PPh2
(2.5 mol%)
O
O
PPh2
+
Et2Zn
toluene, 0 °C, 20 h
Et
81% yield
60% ee (S)
Cu(OTf) Temp
Time
/h
Convn
/%b)
Ee
/%b)
Scheme 3. Enantioselective 1,4-addition of diethylzinc to
2-cyclohexen-1-one.
Entry
R
/mol %a)
/°C
1
2
3
4
5
6
7
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
1.0
0.5
0.2
0.2
0.2
0.1
0.1
0
0
0
5
5
5
5
5
>99
>99
>99
>99
66
97 (S)
97 (S)
97 (S)
98 (S)
99 (S)
96 (S)
98 (S)
¹20
¹40
0
5
24
89
>99
¹40
8
9
10
11
t-Bu
t-Bu
t-Bu
t-Bu
1.0
0.2
0.1
0.1
0
0
0
5
5
5
>99c)
>99
95
99 (S)
95 (S)
95 (S)
96 (S)
Scheme 4. O,N,O-Ligand (type I) to N,N,P-ligand (type III).
R
R
NH2
OH
R
NHTs
¹40
24
>99
p-TsCl
aq KOH
N
Ts
a) Cu(OTf)2:ligand = 1:2.5. b) Conversions and ee values were
determined by GC analysis (Supelcoμ £-DEX-225). c) Isolated
yield was 84%.
pyridine
benzene
rt
OTs
R = i-Pr; 74%
R = t-Bu; 80%
R = i-Pr; >99%
R = t-Bu; >99%
R
NHTs
R
NH2
concd H2SO4
100 °C
KPPh2
¹40 °C. In most of the previously reported reactions, 1 mol %
catalyst or more was necessary to obtain high ee. Compared
with these reported methods,1,2 our catalyst system exhibited
high activity and enantioselectivity.
THF, 0 °C
PPh2
PPh2
R = i-Pr; 80%
R = t-Bu; 73%
R = i-Pr; 88%
R = t-Bu; 78%
Pfaltz and co-workers pointed out the utility of the
2-quinolyl moiety in the asymmetric Heck reaction and
asymmetric hydrogenation.17 The ligand containing a 2-quino-
lyl moiety gave products with higher ee values than that
containing a pyridyl moiety: when a pyridyl moiety was used
instead of a 2-quinolyl moiety under the same reaction
conditions, the product was obtained with only 55% ee, even
with the use of 1 mol % Cu(OTf)2 and 2.5 mol % chiral
ligand.11a This result clearly indicates that the 2-quinolyl
moiety is essential for achieving high enantioselectivity. It
should also be mentioned that the use of type III ligands
resulted in a remarkable enhancement in reaction rate. When
the reaction was carried out under the same conditions
(Table 1, Entries 7 and 11: 0.1 mol % Cu(OTf)2, ¹40 °C,
24 h, >99% conversion) but in the absence of ligand, the
product was obtained with a conversion of only 31%.
Under optimum conditions®that is, 0.1 mol % Cu(OTf)2 and
0.25 mol % chiral ligand®we examined the reactions of
various cyclic enones, including 2-cyclopenten-1-one (11),
2-cyclohexen-1-one (10), 4,4-dimethyl-2-cyclohexen-1-one
(12), and 2-cyclohepten-1-one (13), with dimethylzinc and
diethylzinc (Table 2). Unfortunately, the reaction of n-Bu2Zn
with enones 10 and 11 gave n-butylated ketones in low ee (12-
36% ee) (Table 2, Entries 5, 6, 13, and 14). We concluded that
the bulkiness of the ligand or the dialkylzinc substituents
affects the structure of transition state at the stage at which
enantioselection takes place. For 2-cyclopenten-1-one (11), the
N
OHC
N
R
N
Na2SO4
benzene, rt
9a: R = i-Pr; 89%
9b: R = t-Bu; 81%
PPh2
Scheme 5. Preparation of type III ligand.
Preparation of Type III Ligand. Next, we turned our
attention to a type III ligand containing a quinoline moiety
(Scheme 4),15 which was prepared as shown in Scheme 5.
Ditosylation of ¢-amino alcohols (starting from L-valinol)
followed by treatment with KOH afforded substituted azir-
idines in high yield, which were then treated with KPPh2 to
give the corresponding aminophosphines.16 Condensation of
2-quinolinecarbaldehyde with these aminophosphines gave the
desired type III ligands in high yield.
Enantioselective 1,4-Addition Using N,N,P-Ligand.
Table 1 lists the optimized reaction conditions for the reaction
of 2-cyclohexen-1-one (10) with diethylzinc, including the
amount of catalyst (Cu(OTf)2 and ligand), the reaction temper-
ature, and the ligand substituents (9a: R = i-Pr, 9b: R = t-Bu).
High enantioselectivity was observed for both R = i-Pr and
R = t-Bu. Even when the catalyst load was decreased to
0.1 mol % Cu(OTf)2 and 0.25 mol % ligand, the reaction
proceeded to afford (S)-3-ethylcyclohexanone (98% ee) at

642
Bull. Chem. Soc. Jpn. Vol. 84, No. 6 (2011)
Enantioselective 1,4-Addition of Dialkylzincs to Enones
Table 2. Enantioselective 1,4-Addition of Dialkylzinc to a
Variety of Enones
N
+
Cu(OTf)2
N
PPh2
N
L*nCu
X
N
Cu X
P
Temp Convn
/°C
Ee
/%a)
Entry
n
R1
R2
R3
Ph2
/%a)
1
2
3
4
5
6
0
0
0
0
0
0
H
H
H
H
H
H
Me
Me
Et
i-Pr
t-Bu
i-Pr
t-Bu
¹20
¹20
¹40
¹40
¹40
¹40
74
88
70
85
64
67
58 (S)
92 (S)
44 (S)
93 (S)
36 (S)
14 (S)
ZnR2
Et
n-Bu i-Pr
n-Bu t-Bu
L*nCu
X
L*nCu R + RZnX
O
OZnR
R
7
8
9
10
11
12
13
14
15
16
1
1
1
1
1
1
1
1
1
1
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Et
i-Pr
t-Bu
i-Pr
t-Bu
i-Pr
t-Bu
¹40
¹40
¹20
¹20
¹40
¹40
¹40
¹40
¹20
¹20
59
35
88
77
99
99
58
66
9
99 (S)
97 (S)
98 (S)
98 (S)
98 (S)
96 (S)
12 (S)
18 (S)
86 (R)
82 (R)
Et
O
n-Bu i-Pr
n-Bu t-Bu
L*nCu
Zn
R
X
R
Me Et
Me Et
i-Pr
t-Bu
6
Scheme 6. Proposed catalytic cycle.
17
18
19
20
2
2
2
2
H
H
H
H
Me
Me
Et
i-Pr
t-Bu
i-Pr
t-Bu
¹40
¹40
¹40
¹40
44
32
61
47
88 (S)
83 (S)
79 (S)
68 (S)
H
H
H
H
t-Bu
t-Bu
Et
N
Cu
Et
N
Cu
Et
N
N
a) Conversions and ee values were determined by GC analysis
(Supelcoμ £-DEX-225 for Entries 1-16; Supelcoμ ¢-DEX-225
for Entries 17-20).
O
P
P
O
Ph
Ph
Ph
Ph
effect of the ligand substituent R3 was remarkable, with a
dramatic increase in enantioselectivity (the ee increased from
58 to 92% in the case of Me2Zn and from 44 to 93% in the case
of Et2Zn: Table 2, Entries 1-4). In the case of enones 10 and
12, the nature of R3 did not markedly influence reactivity or
selectivity. For the reaction of 2-cyclohepten-1-one (13), the
use of a ligand containing an i-Pr group gave a higher ee than
one containing a t-Bu group. This may be compared with the
results of the equivalent reaction of 2-cyclopenten-1-one (11)
(Table 2, Entries 17-20).
favored
disfavored
O
O
Et
S-product
Et
R-product
Scheme 7. Enantioselectivity of 1,4-addition.
Proposed Catalytic Cycle and Enantioselection Mecha-
nism.
Considering Reiser’s proposed mechanism,10a we
suggested mechanisms for the catalytic cycle and enantio-
selection as shown below (Schemes 6 and 7, respectively). In
the catalytic cycle, the reaction of the chiral copper complex
and dialkylzinc gives an alkyl-copper species that acts as an
alkyl donor. The enone is then activated by the copper and zinc
species, coordinated to an alkene moiety and a carbonyl
oxygen, respectively (Scheme 6).
plane of the paper, we suggest that the enone attacks from front
side because of the bulkiness of the t-Bu group at the chiral
center. In addition, the plane of the enone itself is also fixed
by the presence of the quinoline and PPh2 moieties to avoid
steric hindrance: (i) According to Scheme 6, zinc species
would be coordinated with carbonyl oxygen as Lewis acid so
that the carbonyl group became bulky. As a result, enone
approaches the catalyst plane upward. (ii) Since the copper
center of the catalyst would activate the olefin moiety, the sp3
To explain the enantioselectivity, we proposed the mecha-
nism shown in Scheme 7. Assuming the molecule is in the

K. Kawamura et al.
Bull. Chem. Soc. Jpn. Vol. 84, No. 6 (2011)
643
Table 3. Enantioselective 1,4-Addition Followed by Trap-
ping of Zinc Enolate by Allyl Iodides
(1.0 equiv)
[Pd(PPh ) ] (2 mol%)
3 4
1.0 equiv
(5 equiv)
Scheme 8. Asymmetric conjugate addition (Feringa).
Time Yield
/h /%a)
Ee of trans
Entry
n
R1 R2
R3
trans:cisb)
/%b)
1
2
3
4
5
1
1
1
1
0
Et i-Pr
Me i-Pr
Et i-Pr Me
Me i-Pr Me 24
Et t-Bu
H
H
5
24
5
76
71
85
83
44
95:5
93:7
97:3
96:4
95:5
99c)
99d)
99e)
99f)
97d)
H
5
a) Combined yield of trans- and cis-isomers. b) Determined by
GC analysis. The absolute configuration was determined by
comparison with literature values of retention time for
Entry 1.18a c) Supelcoμ ¢-DEX-225. d) Supelcoμ £-DEX-
225. e) CHIRALDEX· G-TA. f) Supelcoμ ¡-DEX-325.
(1.5 equiv)
7 mol% [Ni(acac)2]
Scheme 9. Asymmetric conjugate addition (Alexakis).
carbons in 2-cyclohexenone should parry the PPh2 group
(Scheme 7). Thus, we surmised that the enantioselectivity is
triple-controlled by the chiral center, quinoline moiety, and
PPh2 group.
Trapping of Intermediate Zinc Enolates.
We next
examined the trapping of intermediate zinc enolates by allyl
iodide and substituted derivatives.18 Feringa and his co-workers
reported three-component coupling using allyl acetate and a
catalytic amount of [Pd(PPh3)4],18a,18b as shown in Scheme 8.
As an example of Pd-free allylation of zinc enolate, Alexakis
and his co-workers reported a one-pot procedure by using
activated electrophile (Scheme 9).19
We investigated direct trapping of intermediate zinc enolates
with allyl iodide. The results are summarized in Table 3. The
reactions were carried out using 1 mol % Cu(OTf)2 and
2.5 mol % ligand.
The amount of dialkylzinc is the most important factor in
this reaction. Because dialkylzinc would behave as a strong
base to generate the enolate from monoallylated product, the
presence of excess dialkylzinc complicated the reaction so
that the diallylated product was obtained. Therefore, it was
concluded that strict control of the number of dialkylzinc
equivalents was necessary.
Scheme 10. Ni-Catalyzed asymmetric 1,4-addition.
combination of this ligand and [Ni(acac)2]. Although a large
amount of catalyst was required in the Ni system compared
with the Cu system, our newly developed ligands 9a and 9b®
particularly 9b®gave high enantioselectivity (Scheme 10).
The combination of [Ni(acac)2] with the type III ligands 9a and
9b afforded the 1,4-adduct in 78% ee (82% yield) and 90% ee
(77% yield), respectively, as shown in Scheme 10. It should be
noted that in hitherto reported studies of the utility of Ni
catalyst systems in the enantioselective addition of dialkylzincs
to enones, most involved addition to acyclic enones; reports of
addition to cyclic enones are few.20 This Ni catalyst system
proved to be useful for cyclic enones.
Finally, we examined the reaction of an acyclic enone,
chalcone, with Et2Zn using 0.1 mol % Cu(OTf)2 and the type III
ligands 9a and 9b to give the 1,4-adduct in 8% ee (36% yield)
and 63% ee (52% yield), as shown in Scheme 11.
Application of Type III Ligand to a Ni-Catalyzed System.
To demonstrate the utility of our new ligand, we examined the

644
Bull. Chem. Soc. Jpn. Vol. 84, No. 6 (2011)
Enantioselective 1,4-Addition of Dialkylzincs to Enones
then evaporated. The crude product was purified by silica gel
column chromatography (hexane) to give the colorless solid 3
(8.62 g, 23.8 mmol, 99%). Rf 0.55 (hexane); mp 54.7-55.7 °C;
IR (KBr): ¯max (cm¹1) 2950, 2866, 1700, 1696, 1653, 1589,
1
1476, 1457, 1437, 1400, 1390, 1363, 1268, 1239; H NMR
(400 MHz, CDCl3): ¤ 1.31 (s, 9H), 1.54 (s, 9H), 4.72 (s, 2H),
7.33 (d, J = 2.4 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H); 13C NMR
(100.6 MHz, CDCl3): ¤ 30.1, 31.1, 34.7, 36.7, 37.5, 122.1,
125.9, 126.4, 138.0, 148.4, 150.0; MS m/z: 361 (M + H+);
Anal. Calcd for C15H22Br2: C, 49.75; H, 6.12; N, 0.0%. Found:
C, 49.74; H, 6.11; N, 0.22%.
Scheme 11. Cu-Catalyzed asymmetric 1,4-addition of chal-
cone.
Synthesis of 2-Bromo-3,5-di-tert-butylbenzaldehyde (4).
A mixture of 3 (17.75 g, 49 mmol) and hexamethylenetetramine
(19.2 g, 137 mmol) in chloroform (110 mL) was refluxed for
24 h, and the resulting solution was cooled to room temperature
and then evaporated to give a yellow residue. To this residue
were added hexamethylenetetramine (19.2 g, 137 mmol) and
50% acetic acid (110 mL), and the solution was refluxed for
24 h. Then, concd HCl (24 mL) was added to the solution and
the mixture was stirred at 110 °C for 15 min. The resulting
solution was cooled to room temperature and then extracted
with Et2O. The separated organic layer was quickly washed
with 2 M HCl (80 mL © 3) and water (80 mL), dried over
Na2SO4, and then filtered and evaporated to provide the crude
material, which was purified by short silica gel column
chromatography (80:1 hexane/Et2O) to give 4 as a colorless
oil (6.85 g, 23.0 mmol, 47%). Rf 0.57 (20:1 hexane/ethyl
acetate); IR (KBr): ¯max (cm¹1) 3001, 2963, 2871, 1750, 1689,
Conclusion
Our new chiral N,N,P-tridentate ligand promotes highly
enantioselective 1,4-addition of dialkylzinc to enones (up to
99% ee) in combination with Cu(OTf)2.15 The zinc enolate
intermediates were trapped with substituted allyl iodides in the
absence of a palladium catalyst to give disubstituted ketones
with high diastereoselectivity (up to 97:3 trans:cis) and
enantioselectivity (up to 99% ee).
Experimental
General Methods and Materials.
carried out in oven-dried glassware with magnetic stirring. All
starting materials were obtained from commercial sources and
All reactions were
1
used without further purification unless otherwise stated. H
and 13C NMR spectra (400 and 100.6 MHz, respectively) were
recorded using Me4Si as an internal standard (0 ppm). The
following abbreviations are used: s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet. Gas chromatographic
(GC) analysis was carried out using an instrument equipped
with an FID detector and a capillary column, £-DEX-225,
¢-DEX-225, ¡-DEX-325, and G-TA (30 m © 0.25 mm i.d.,
0.25 ¯m film). Chiral HPLC was performed using an instru-
ment equipped with a diode array detector and a chiral column
CHIRALPAK AD (250 mm © 4.6 mm © 5 ¯m).
1
1586, 1477, 1427, 1396, 1270, 1230, 1140, 1109; H NMR
(400 MHz, CDCl3): ¤ 1.33 (s, 9H), 1.58 (s, 9H), 7.73 (d, J =
2.4 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 10.56 (s, 1H); 13C NMR
(100.6 MHz, CDCl3): ¤ 30.1, 31.0, 34.9, 37.5, 124.6, 124.9,
131.0, 135.3, 148.4, 150.3, 194.1; MS m/z: 297 (M + H+);
Anal. Calcd for C15H21BrO: C, 60.61; H, 7.12; N, 0.0%.
Found: C, 60.24; H, 7.25; N, 0.20%.
Synthesis of 2-Bromo-3,5-di-tert-butyl-1-(1,3-dioxolan-2-
yl)benzene (5). A mixture of 4 (5.3 g, 17.8 mmol), ethylene
glycol (5.52 g, 89 mmol), and p-toluenesulfonic acid (0.24 g,
1.4 mmol) in benzene (140 mL) was refluxed for 24 h in a flask
equipped with a Dean-Stark apparatus. The resulting solution
was separated and the organic layer was washed with water
(80 mL © 3) and brine (80 mL), dried over Na2SO4, and then
filtered and evaporated to provide the crude material, which
was purified by silica gel column chromatography (80:1
hexane/Et2O) to give 5 as a colorless solid (6.1 g, 17.8 mmol,
99%). Rf 0.32 (10:1 hexane/diethyl ether); mp 39-41 °C; IR
(KBr): ¯max (cm¹1) 3455, 2960, 2877, 1636, 1458, 1396, 1362,
Synthesis of 2-Bromo-3,5-di-tert-butyltoluene (2). To a
solution of 3,5-di-tert-butyltoluene (5.0 g, 24.4 mmol) in CCl4
(50 mL) was added Fe powder (0.3 g, 5.1 mmol), and the
mixture was cooled to 0 °C. A solution of Br2 (1.25 mL,
24.4 mmol) in CCl4 (12 mL) was added with a dropping funnel
for 3 h, after which the mixture was stirred at 0 °C for 2 h and
then filtered. The filtrate was washed with 10% NaHCO3
(80 mL © 3) and brine (80 mL © 3), dried over Na2SO4, and
then filtered and evaporated to provide the crude product,
which was purified by silica gel column chromatography
(hexane) to give the colorless solid 2 (6.83 g, 24.0 mmol, 98%).
Rf 0.69 (hexane); mp 27.1-28.1 °C; IR (KBr): ¯max (cm
¹1
1
)
1266, 1237, 1207, 1178; H NMR (400 MHz, CDCl3): ¤ 1.31
2966, 2869, 1700, 1653, 1476, 1457, 1395, 1363, 1268, 1239,
1210, 1180; H NMR (400 MHz, CDCl3): ¤ 1.30 (s, 9H), 1.54
(s, 9H), 1.54 (s, 9H), 4.04-4.12 (m, 2H), 4.13-4.20 (m, 2H),
6.24 (s, 1H), 7.50 (s, 2H); 13C NMR (100.6 MHz, CDCl3): ¤
30.1, 31.2, 34.8, 37.4, 65.3, 103.6, 120.7, 122.4, 126.3, 137.4,
147.6, 149.6; MS m/z: 341 (M + H+); Anal. Calcd for
C17H25BrO2: C, 59.83; H, 7.38; N, 0.0%. Found: C, 59.84;
H, 7.46; N, 0.26%.
Synthesis of 3,5-Di-tert-butyl-2-diphenylphosphino-1-
(1,3-dioxolan-2-yl)benzene (6). To a solution of 5 (6.14 g,
18 mmol) in THF (30 mL) and hexane (150 mL), tert-butyl-
lithium (24 mL, 1.6 M in pentane, 37.8 mmol) was added
dropwise at ¹45 °C for 20 min. The reaction solution was
1
(s, 9H), 2.44 (s, 3H), 7.13 (d, J = 2.4 Hz, 1H), 7.32 (d,
J = 2.4 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): ¤ 25.6, 30.1,
31.3, 34.5, 37.2, 122.6, 122.9, 125.9, 139.2, 147.3, 149.1; MS
m/z: 283 (M + H+); Anal. Calcd for C15H23Br: C, 63.61; H,
8.18; N, 0.0%. Found: C, 63.47; H, 8.31; N, 0.27%.
Synthesis of 2-Bromo-3,5-di-tert-butyl-1-bromomethyl-
benzene (3). A mixture of 2 (6.8 g, 24.0 mmol) and NBS
(4.7 g, 26.4 mmol) in CCl4 (9 mL) was stirred at 100 °C for 2 h,
and the resulting solution was cooled to room temperature and

K. Kawamura et al.
Bull. Chem. Soc. Jpn. Vol. 84, No. 6 (2011)
645
stirred at ¹45 °C for 90 min, and then chlorodiphenylphosphine
(4.6 mL, 35.2 mmol) was added. The solution was stirred at
¹45 °C for 1 h, then allowed to warm to room temperature
and stirred for 12 h. The resulting solution was filtered and
evaporated and then purified by silica gel column chromatog-
raphy (50:1 hexane/ethyl acetate) to give the crude product,
which was recrystallized from hexane-ethyl acetate under an
argon atmosphere to give 6 as colorless crystals (3.5 g,
7.8 mmol, 44%). Rf 0.47 (4:1 hexane/diethyl ether); mp 163-
167 °C; IR (KBr): ¯max (cm¹1) 3047, 2961, 2906, 2880, 1598,
152.6, 157.6, 162.3; MS m/z: 656 (M + H+); Anal. Calcd for
C44H51NP2: C, 80.58; H, 7.84; N, 2.14%. Found: C, 80.49; H,
8.02; N, 2.32%.
General Procedure for Asymmetric 1,4-Addition.
A
solution of Cu(OTf)2 (0.01 mmol) and ligand (0.025 mmol) in
dichloromethane (5 mL) was stirred under an Ar atmosphere at
room temperature for 0.5 h. This catalyst solution was used for
ten separate experiments (0.1 mol % catalyst load). The enone
(1 mmol), the catalyst solution (0.5 mL), and dichloromethane
(1 mL) were added to a dried ampoule, and the solution was
stirred at room temperature for 10 min and then cooled to
¹40 °C and stirred for 15 min. Next, Et2Zn (1.5 mmol, 1.5 mL
of 1.0 M solution in hexane) was added slowly, and the
resulting mixture was stirred at ¹40 °C for 24 h and then
quenched with a 1 M HCl solution (2 mL). After warming to
room temperature, the reaction mixture was extracted with
diethyl ether (10 mL © 3).
1
1484, 1392, 1253, 1166; H NMR (400 MHz, CDCl3): ¤ 1.34
(s, 9H), 1.66 (s, 9H), 3.28 (dt, J = 3.8, 9.4 Hz, 2H), 3.80 (dt,
J = 3.8, 9.4 Hz, 2H), 5.53 (d, JPC = 0.8 Hz, 1H), 7.2-7.3 (m,
10H), 7.50 (d, J = 2.0 Hz, 1H), 7.66 (dd, JPC = 5.2 Hz,
J
HH = 2.0 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): ¤ 31.1,
33.1, 35.0, 37.9, 64.7, 101.88, 124.1, 125.1, 127.2, 128.2,
129.4, 131.0, 137.9, 143.9, 152.9, 157.1; MS m/z: 447
(M + H+); Anal. Calcd for C29H35O2P: C, 78.00; H, 7.90; N,
0.00%. Found: C, 77.87; H, 8.05; N, 0.10%.
Conversions and ee values were determined by chiral-phase
GC analysis with a £-DEX-225 (Supelcoμ) column (30 m ©
0.25 mm i.d.) or ¢-DEX-225 (Supelcoμ) column (30 m © 0.25
mm i.d.) using undecane as an internal standard.
Synthesis of 3,5-Di-tert-butyl-2-diphenylphosphinobenz-
aldehyde (7). To a solution of 6 (0.89 g, 2.0 mmol) in THF
(12 mL) and water (1.3 mL) was added p-toluenesulfonic acid
(9 mg, 0.054 mmol) at room temperature. The mixture was
refluxed for 7 h and then cooled to room temperature, diluted
with water (24 mL), extracted with Et2O (30 mL © 3), dried
over Na2SO4, filtered and evaporated to provide the crude
product, which was recrystallized from hexane-ethyl acetate
under an argon atmosphere and then purified by silica gel
column chromatography (5:1 hexane/ethyl acetate) to give 7 as
a yellow solid (0.78 g, 1.94 mmol, 97%). Rf 0.40 (4:1 hexane/
diethyl ether); mp 144-146 °C; IR (KBr): ¯max (cm¹1) 3049,
2965, 2881, 1683, 1589, 1479, 1252; 1H NMR (400 MHz,
CDCl3): ¤ 1.37 (s, 9H), 1.68 (s, 9H), 7.2-7.3 (m, 10H), 7.81 (d,
J = 2.0 Hz, 1H), 7.84 (dd, JPC = 7.4 Hz, JHH = 2.0 Hz, 1H),
9.84 (s, 1H); 13C NMR (100.6 MHz, CDCl3): ¤ 31.0, 32.8, 35.2,
38.0, 125.1, 127.8, 128.2, 128.6, 131.0, 133.9, 137.5, 141.3,
153.4, 158.3, 193.4; MS m/z: 403 (M + H+); Anal. Calcd for
C27H31OP: C, 80.57; H, 7.76; N, 0.0%. Found: C, 80.52; H,
7.96; N, 0.04%.
(S)-(¹)-3-Methylcyclopentan-1-one (Table 2, Entry 2) (14a):
92% ee (tR of S-isomer, 22.54 min; tR of R-isomer, 22.89 min;
GC conditions: £-DEX-225, initial temp 60 °C, initial time
29
20 min, progress rate 5 °C min¹1, final temp 120 °C); ½¡ꢀD
20
¹141.1° (c 0.20, CHCl3) (lit.21a ½¡ꢀD +152.5° (c 1.20, CHCl3,
99% ee (R))).
(S)-(¹)-3-Ethylcyclopentan-1-one (Table 2, Entry 4) (14b):
93% ee (tR of S-isomer, 27.34 min; tR of R-isomer, 28.03 min;
GC conditions: £-DEX-225, initial temp 70 °C, initial time
29
25 min, progress rate 5 °C min¹1, final temp 120 °C); ½¡ꢀD
25
¹81.2° (c 0.50, CHCl3) (lit.7a ½¡ꢀD +94.7° (c 1.02, CHCl3,
97% ee (R))).
(S)-(¹)-3-Butylcyclopentan-1-one (Table 2, Entry 5) (14c):
36% ee (tR of S-isomer, 32.59 min; tR of R-isomer, 33.34 min;
GC conditions: £-DEX-225, initial temp 90 °C, initial time
29
30 min, progress rate 5 °C min¹1, final temp 120 °C); ½¡ꢀD
25
¹56.0° (c 0.75, CHCl3) (lit.7a ½¡ꢀD +157.0° (c 1.14, CHCl3,
98% ee (S))).
Synthesis of (S)-1-Diphenylphosphino-2-[N-(3,5-di-tert-
butyl-2-diphenylphosphinobenzylidene)amino]-3-methyl-
(S)-(¹)-3-Methylcyclohexan-1-one (Table 2, Entry 7) (14d):
99% ee (tR of S-isomer, 33.74 min; tR of R-isomer, 35.10 min;
GC conditions: £-DEX-225, initial temp 70 °C, initial time
butane (8).
A mixture of 7 (201 mg, 0.5 mmol), (S)-1-
28
diphenylphosphinomethyl-2-methylpropylamine,15 and Na2SO4
in benzene (5 mL) was stirred at 80 °C for 3 days. The resulting
mixture was filtered and the filtrate was evaporated to give a
yellow residue, which was purified by silica gel column
chromatography (10:1 hexane/ethyl acetate) to give the P,N,P-
type Schiff base 8 as a yellow solid (268 mg, 0.408 mmol,
30 min, progress rate 5 °C min¹1, final temp 120 °C); ½¡ꢀD
25
¹13.4° (c 0.60, CHCl3) (lit.7k ½¡ꢀD ¹6.7° (c 1.14, CHCl3,
45% ee (S))).
(S)-(¹)-3-Ethylcyclohexan-1-one (Table 1, Entry 5) (14e):
99% ee (tR of S-isomer, 42.23 min; tR of R-isomer, 42.76 min;
GC conditions: £-DEX-225, initial temp 80 °C, initial time
29
28
82%). Rf 0.65 (5:1 hexane/ethyl acetate); mp 60-62 °C; ½¡ꢀD
40 min, progress rate 10 °C min¹1, final temp 150 °C); ½¡ꢀD
26
¹15.6° (c 1.00, CHCl3) (lit.4o ½¡ꢀD ¹8.8° (c 1.60, CHCl3,
¹42.98 (c 1.0, CHCl3); IR (KBr): ¯max (cm¹1) 3052, 3013,
2961, 2905, 1949, 1884, 1810, 1628, 1584, 1536, 1479, 1392,
82% ee (S))).
1
1361, 1340, 1231, 1160; H NMR (400 MHz, CDCl3): ¤ 0.49
(S)-(¹)-3-Butylcyclohexan-1-one (Table 2, Entry 14) (14f):
18% ee (tR of S-isomer, 34.77 min; tR of R-isomer, 35.07 min;
GC conditions: £-DEX-225, initial temp 100 °C, initial time
(d, J = 6.8 Hz, 3H), 0.59 (d, J = 6.8 Hz, 3H), 1.35 (s, 9H), 1.55
(m, 2H), 1.64 (s, 9H), 2.0-2.1 (m, 1H), 2.2-2.3 (m, 1H), 7.0-
7.3 (m, 20H), 7.68 (dd, JPC = 5.2 Hz, JHH = 2.0 Hz, 1H), 7.98
(d, J = 2.0 Hz, 1H), 8.05 (s, 1H); 13C NMR (100.6 MHz,
CDCl3): ¤ 16.7, 19.5, 31.1, 31.2, 32.1, 33.0, 35.0, 37.9, 71.8,
124.3, 125.6, 127.3, 128.0, 128.1, 128.1, 128.3, 128.5, 129.7,
130.4, 131.3, 132.7, 133.0, 137.3, 138.2, 139.3, 139.4, 142.2,
27
30 min, progress rate 5 °C min¹1, final temp 150 °C); ½¡ꢀD
26
¹4.1° (c 1.00, CHCl3) (lit.21b ½¡ꢀD +19.3° (c 1.00, CHCl3,
58% ee (R))).
(S)-(¹)-3-Methylcycloheptan-1-one (Table 2, Entry 17) (14h):
88% ee (tR of S-isomer, 33.92 min; tR of R-isomer, 35.60 min;

646
Bull. Chem. Soc. Jpn. Vol. 84, No. 6 (2011)
Enantioselective 1,4-Addition of Dialkylzincs to Enones
GC conditions: ¢-DEX-225, initial temp 80 °C, initial time
24.1, 26.0, 26.8, 36.7, 40.3, 43.6, 53.6, 111.4, 143.7, 213.6;
Anal. Calcd for C12H20O: C, 79.94; H, 11.18; N, 0.00%.
Found: C, 79.84; H, 11.15; N, 0.37%.
26
30 min, progress rate 5 °C min¹1, final temp 120 °C); ½¡ꢀD
26
¹6.2° (c 1.00, CHCl3) (lit.21c ½¡ꢀD +64.0° (c 0.59, CH3OH,
(R))).
(2S,3S)-(¹)-2-Methallyl-3-methylcyclohexan-1-one (Table 3,
(S)-(¹)-3-Ethylcycloheptan-1-one (Table 2, Entry 19) (14i):
79% ee (tR of S-isomer, 48.11 min; tR of R-isomer, 49.47 min;
GC conditions: ¢-DEX-225, initial temp 90 °C, initial time
Entry 4) (15d):
83% yield, trans:cis = 96:4, 99% ee for
trans (tR of trans-isomer: minor enantiomer 29.97 min, major
enantiomer 30.38 min; tR of cis-isomer, 33.15 min. GC con-
ditions: ¡-DEX-325, initial temp 100 °C, initial time 30 min,
30
40 min, progress rate 5 °C min¹1, final temp 120 °C); ½¡ꢀD
20
¹43.9° (c 0.75, CHCl3) (lit.7k ½¡ꢀD ¹52.7° (c 1.09, CH3OH,
30
progress rate 5 °C min¹1, final temp 150 °C); ½¡ꢀD ¹9.4° (c
86% ee (S))).
1.04, CHCl3).
(R)-(¹)-1,3-Diphenylpentan-1-one (Scheme 11): 63% ee
(tR of S-isomer, 8.11 min; tR of R-isomer, 10.87 min; HPLC
conditions: column, CHIRALCEL AD (Daicel); eluent, hex-
(2R,3S)-(¹)-2-Allyl-3-ethylcyclopentan-1-one (Table 3,
Entry 5) (15e):
44% yield, trans:cis = 95:5, 97% ee for
trans (tR of trans-isomer: minor enantiomer 34.88 min, major
enantiomer 35.43 min; tR of cis-isomer, 37.18 min. GC con-
ditions: £-DEX-225, initial temp 90 °C, initial time 30 min,
29
ane/2-propanol (99:1); 1.0 mL min¹1; ½¡ꢀD ¹1.7° (c 0.50,
26
CHCl3) (lit.4o ½¡ꢀD ¹2.6° (c 1.20, CHCl3, 98% ee (R))).
30
General Procedure for Asymmetric 1,4-Addition Fol-
progress rate 5 °C min¹1, final temp 150 °C); ½¡ꢀD ¹4.1° (c
lowed by Trapping of Zinc Enolate with Allyl Iodide.
A
0.69, CHCl3); IR (thin film): ¯max (cm¹1) 3072, 2954, 1741,
1
solution of Cu(OTf)2 (0.01 mmol) and ligand (0.015 mmol) in
dichloromethane (2 mL) was stirred under an Ar atmosphere at
room temperature for 0.5 h. Dialkylzinc (1.0 mmol) was added
slowly, followed by the enone (1.0 mmol) was added to an
ampoule tube and the solution stirred at ¹40 °C until the
reaction was finished. Allyl iodide was added at ¹40 °C and the
reaction solution was stirred at room temperature for 48 h. The
reaction was quenched by the addition of saturated NH4Cl
solution (5 mL) in an ice bath. The reaction mixture was
extracted with diethyl ether (10 mL © 3), and the organic layer
was dried over Na2SO4, filtered, and evaporated to give the
crude product, which was purified by silica gel column
chromatography (10:1 hexane/diethyl ether).
1460, 1158; H NMR (400 MHz, CDCl3): ¤ 0.9-1.0 (m, 5H),
1.2-1.4 (m, 4H), 1.8-1.9 (m, 1H), 2.0-2.2 (m, 1H), 2.2-2.5 (m,
2H), 5.0-5.1 (m, 2H), 5.7-5.8 (m, 1H); 13C NMR (100.6 MHz,
CDCl3): ¤ 11.3, 26.4, 27.0, 32.3, 37.8, 42.5, 54.3, 116.8, 135.5,
220.5; Anal. Calcd for C10H16O: C, 78.90; H, 10.59; N, 0.00%.
Found: C, 78.65; H, 10.97; N, 0.37%.
This work was supported by Grants-in-Aid for Scientific
Research on Priority Areas “Advanced Molecular Transforma-
tions of Carbon Resources” and No. B17340020 from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy, Japan. K.K. is grateful for a Grant-in-Aid for JSPS
Fellows.
The trans:cis ratios and ee values were determined by chiral-
phase GC analysis using £-DEX-225 (Supelcoμ), ¢-DEX-225
(Supelcoμ), ¡-DEX-325 (Supelcoμ), and G-TA (CHIRAL-
DEX·).
Supporting Information
Details of experimental procedures and characterization data
(1H and 13C NMR, IR, mass spectrometry, and elementary
analyses) for all new compounds. This material is available free
of charge on the web at http://www.csj.jp/journals/bcsj/.
(2R,3S)-(¹)-2-Allyl-3-ethylcyclohexan-1-one
(Table 3,
Entry 1) (15a): 76% yield, trans:cis = 95:5, 99% ee for
trans (tR of trans-isomer: major enantiomer 34.35 min, minor
enantiomer 34.77 min; tR of cis-isomer, 36.24 min. GC con-
ditions: ¢-DEX-225, initial temp 100 °C, initial time 30 min,
References
28
progress rate 5 °C min¹1, final temp 150 °C); ½¡ꢀD ¹11.1° (c
1
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71% yield, trans:cis = 93:7, 99% ee for
trans (tR of trans-isomer: minor enantiomer 35.42 min, major
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ditions: £-DEX-225, initial temp 90 °C, initial time 30 min,
29
progress rate 5 °C min¹1, final temp 150 °C); ½¡ꢀD ¹14.1° (c
2
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29
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3
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