Asymmetric 1,4-addition of diethylzinc to α,β-unsaturated enones catalyzed by chiral imino-thiophosphoramide ligands and copper(I)

Article abstract of DOI:10.1016/j.tetasy.2003.11.015

In the presence of a catalytic amount of chiral imino-thiophosphoramide ligand L7 (6mol%) and Cu(I) salt (3mol%), the asymmetric addition of diethylzinc to α,β-unsaturated carbonyl compounds could be achieved in good yields with moderate ees (up to 75% ee) at -20°C in toluene. A novel chiral imino-thiophosphoramide ligand system for this asymmetric 1,4-addition reaction has been explored.

Full text of DOI:10.1016/j.tetasy.2003.11.015

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 167–176
Asymmetric 1,4-addition of diethylzinc to a,b-unsaturated enones
catalyzed by chiral imino-thiophosphoramide ligands and copper(I)
Min Shi* and Wen Zhang
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science,
354 Fenglin Lu, Shanghai 200032, China
Received 13 October 2003; accepted 1 November 2003
Abstract—In the presence of a catalytic amount of chiral imino-thiophosphoramide ligand L7 (6 mol%) and Cu(I) salt (3 mol%), the
asymmetric addition of diethylzinc to a,b-unsaturated carbonyl compounds could be achieved in good yields with moderate ees (up
to 75% ee) at )20 ꢀC in toluene. A novel chiral imino-thiophosphoramide ligand system for this asymmetric 1,4-addition reaction
has been explored.
ꢁ 2003 Elsevier Ltd. All rights reserved.
1.Introduction
applications of these novel chiral ligands in asymmetric
catalysis.9
The 1,4-conjugate addition of various organometallic
reagents to a,b-unsaturated carbonylcompounds is an
important process for C–C bond formation in organic
synthesis.1 Many chiralauxilaries and stoichiometric
reagents have been described recently, which promote
enantioselective addition.2 A prominent position in this
rapidly expanding field is occupied by the copper cata-
lyzed and chiral-ligand-accelerated 1,4-addition of
organozinc reagents originally introduced and rendered
Herein, we report the results of our novel chiral
imino-thiophosphoramide ligands and one imino-seleno-
phosphoramide ligand derived from (1R,2R)-())-1,2-
cyclohexanediamine on the catalytic enantioselective
1,4-conjugate addition of diethylzinc to a,b-unsaturated
enones. The method described here allows efficient,
catalytic and moderately enantioselective functionaliza-
tion of six and seven-membered cyclic enones. In addi-
tion, the chiral ligands can be easily recovered and
reused in the same enantioselective addition without loss
of efficiency and enantioselectivity, although this type of
imino-thiophosphoramide ligands is not effective in the
enantioselective addition of diethylzinc to five-mem-
bered cyclic enone and acyclic enones.
practical by Alexakis, Feringa and Pfaltz.3 In particular,
4a–c
chiralphosphoramidites,
phosphites,4d–i phos-
phines,4j aminophosphanes,4k–m sulfonamides4n;o and
peptide-based phosphines4p were used as ligands in the
addition to cyclic enones with very good enantioselec-
tivities. However, all-encompassing chiral ligands effec-
tive in the asymmetric conjugate addition of dialkylzincs
to all of the five-, six- and seven-membered cyclic enones
and acyclic enones has been less successful.5;6 The
development of new chiral ligands plays a pivotal role
for overcoming this substrate limitation in asymmetric
carbon–carbon bond forming reactions. Recently, we
were interested in the synthesis of a noveltype of air-
and moisture-stable chiral thiophosphoramide ligands
based on a series of chiralbinaphtheanl ediamine
(BINAM), (1R,2R)-())-1,2-cyclohexanediamine or
(1R,2R)-(+)-1,2-diphenylethane-1,2-diamime7;8 and the
2.Results and discussion
The chiralimino-thiophosphoramide igl ands
L1–L13
are readily synthesized from the reaction of (1R,2R)-())-
1-N-diphenylthiophosphorylcyclohexane-1,2-diamine 19
with arylaldehydes. In Scheme 1, we elucidated the
reaction procedures for the preparation of chiralilgands
L1–L13. In general, they can be synthesized by the
reaction of 1 with various arylaldehydes in ethanol
either at room temperature or under reflux (for sterically
bulky arylaldehydes) for 4–5 h in moderate yields
(Scheme 1). The novelchiralimino-seelnophosphora-
mide ligand L14 was synthesized in the similar way
* Corresponding author. Tel.: +86-21-64163300x342; fax: +86-21-64-
166128; e-mail: mshi@pub.sioc.ac.cn
0957-4166/$ - see front matter ꢁ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.11.015

168
M. Shi, W. Zhang / Tetrahedron: Asymmetry 15 (2004) 167–176
S
Ph
NH P
EtOH, reflux
Ph
ArCHO
S
N
Ar
NH
NH2
NH2
PPh2
1) BuLi, THF, - 40 o
2) Ph2P(S)Cl, - 40 oC ~ r.t.
C
L1-L6
S
P
NH2
Ph
Ph
NH
N
EtOH, r.t.
1
HOArCHO
OH
R
L7-L13
L7: Ar= 2-OHC6H4 (75%)
L8: Ar= 5-tBu-2-OHC6H3 (62%)
L9: Ar= 3,5-tBu2-2-OHC6H2 (51%)
L10: Ar= 3,5-Cl2-2-OHC6H2 (80%)
L11: Ar= 5-Br-2-OHC6H3 (54%)
L12: Ar= 2-OH-1-naphthyl (57%)
L1: Ar= C6H5 (62%)
L2: Ar= 2,3-Cl2C6H3 (60%)
L3: Ar= 2,6-Cl2C6H3 (60%)
L4: Ar= 2-Furyl (66%)
L5: Ar= 1-Naphthyl (55%)
L6: Ar= 2-Pyridyl (58%)
L13: Ar= 6-Me-2-OH-1-naphthyl (52%)
Scheme 1.
(Scheme 2). These chiralilgands L1–L14 are air- and
moisture-stable under ambient atmosphere (Schemes 1
and 2).
tivity of this reaction was increased to 75% ee for 6 h and
at )40 ꢀC, the enantioselectivity was slightly decreased
to 72% ee for 10 h in toluene, respectively (Table 1,
entries 8–10). The best reaction temperature for this
reaction is )20 ꢀC. The copper(I) salts such as
Cu(CH3CN)4ClO4 or Cu(CH3CN)4BF4 showed higher
catalytic activity and chiral induction ability than
CuOTf Æ 1/2C6H6 or Cu(OTf)2 salt under the same con-
ditions (Table 1, entries 11–13). The solvent effects have
been also examined using L7 as a chiralligand at )20 ꢀC
under otherwise similar conditions. Toluene is the sol-
vent of choice for this asymmetric addition reaction
(Table 1, entries 14–16). Under the optimized reaction
conditions, we next examined the remaining chiral
ligands L4–6 and L11–14 in this reaction. The results are
also summarized in Table 1 (Table 1, entries 17–23). We
found that using L11–L13 as the ligands in this reaction,
the addition product 3 can be obtained in high yields in
moderate ee (44% ee–65% ee), while, poor enantio-
selectivities were achieved in the presence of ligands
L5 and L6 (Table 1, entries 17–22). The imino-seleno-
phosphoramide ligand L14, which is very similar to
ligand L7 structurally, gave the addition product in 97%
yield with 62% ee (Table 1, entry 23). The best reaction
conditions are to carry out this reaction in toluene at
)20 ꢀC using Cu(CH3CN)4ClO4 (3 mol%) as the catalyst
precursor and L7 (6 mol%) as the chiral ligand. This
asymmetric addition reaction can be completed within
6 h under this reaction conditions. Moreover, this chiral
ligand is quite stable and can be recovered in 96% yield
1) BuLi, THF, -40 o
C
Se
2) Ph2P(Se)Cl, THF, -40 oC ~ r.t.
NH PPh2
NH2
NH2
3) 2-Hydroxybenzaldehyde, EtOH, r .t.
N
HO
L14 (58%)
Scheme 2.
Using 2-cyclohexene-1-one 2 as the substrate and
diethylzinc as the Michael addition reagent, we exam-
ined the 1,4-addition reaction in the presence of novel
imino-thiophosphoramide ligands L1–L3 and L7–L10
with various copper salts in various solvents at different
temperatures to develop the optimal reaction condi-
tions. The results are summarized in Table 1 (entries 1–
16). As can be seen from Table 1, L2 and L7 are the best
chiral ligands for this enantioselective 1,4-addition
reaction to give the product 3 with 62% ee in 97% yield
and 65% ee in 95% yield in toluene at 20 ꢀC for 2 h with
the (S)-configuration, respectively (Table 1, entries 2 and
4). Chiralligands L1 and L8 gave the addition product 3
in moderate ee as well (Table 1, entries 1 and 5). On the
other hand, chirailglands
L3, L9 and L10 having
dichloro- or di(tert-butyl) groups on the benzene ring of
the arylaldehydes gave the 1,4-addition product 3 in
0 ꢀ lower ee (7–14% ee) with the (S)-configuration under
the same conditions (Table 1, entries 3, 6 and 7). These
results suggest that the substituents of aryl group in
imino-thiophosphoramide ligands play an important
role in chiral induction for asymmetric 1,4-addition
reaction. Using L7 as a ligand at 0 ꢀC, a similar ee (64%
ee) of 3 was achieved after 3 h in toluene (Table 1, entry
8). At lower temperature, L7 is still active for this
reaction. It was found that at )20 ꢀC, the enantioselec-
after usualworkup. The recovered ilgand
reused in this reaction without loss of catalytic ability or
enantioselectivity (Table 1, entry 24).
L7 can be
Under the optimized reaction conditions, the 1,4-addi-
tions of diethylzinc to 2-cyclopentene-1-one and 2-cyclo-
heptene-1-one have been also examined. It was found
that for 2-cyclopentene-1-one, the corresponding 1,4-
addition product 4 was obtained in moderate yield with
17% ee in the presence of ligand L7 and with 22% ee in
the presence of ligand L12 and for 2-cycloheptene-1-

M. Shi, W. Zhang / Tetrahedron: Asymmetry 15 (2004) 167–176
169
Table 1. The enantioselective 1,4-addition reaction of 2-cyclohexene-1-one with ZnEt2 catalyzed by copper salt and chiral ligand
O
O
1) Cu (3 mol%)-Ligand L1-L14 (6 mol%)
*
2) 2.0 eq. Et2Zn
3
2
Entry
Copper salt
Ligand
Solv.
Temp. (ꢀC)
Time (h)
Yielda (%)
Eeb (%)
Config.c
1
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
CuOTf Æ 1/2C6H6
Cu(OTf)2
L1
L2
L3
L7
L8
L9
L10
L7
L7
L7
L7
L7
L7
L7
L7
L7
L4
L5
L6
L11
L12
L13
L14
L7
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
Et2O
20
20
2
2
2
2
2
2
2
3
6
10
6
6
6
6
6
6
6
6
6
6
6
6
6
6
97
97
97
95
92
92
90
95
97
95
95
95
94
92
95
95
92
94
95
97
98
95
97
94
55
62
0
S
S
––
S
S
S
S
S
S
S
S
S
S
S
S
S
S
R
S
S
S
S
S
S
2
3
20
20
4
65
46
7
5
20
20
6
7
20
0
14
64
75
72
68
69
74
71
8
8
9
)20
)40
)20
)20
)20
)20
)20
)20
)20
)20
)20
)20
)20
)20
)20
)20
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24d
Cu(MeCN)4BF4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
THF
CH2CI2
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
70
64
7
20
62
57
44
62
72
a Isolated yield.
b Determined by chiralGLC.
c Determined by the sign of the specific rotation.
d Recovered L7 was used as a ligand in reaction.
one, the corresponding 1,4-addition product 5 was
obtained in high yield with moderate ee (52% ee) within
6 h, respectively (Scheme 3).
O
O
1) Cu(CH3CN)4ClO4-ligand, PhMe, 20 oC
2) 2.0 eq. Et2Zn
Ph
*
Ph
Ph
Ph
7
6
L1: 97% yield, 8% ee.
L7: 70% yield, 2% ee.
L12: 50% yield, 2% ee.
This catalytic enantioselective 1,4-addition reaction
system has also been applied to acyclic enones, such as
chalcone 6. It was found that the reaction was complete
within 24 h at room temperature in 97% yield with 8% ee
in the presence of ligand L1 and in moderate yield with
2% ee in the presence of ligands L7 and L12 (Scheme 4).
Scheme 4.
This is because it is well known that the sulfur atom can
strongly coordinate to the late transition metals11 and
the Cu(I) atom has a greater affinity for soft ligands
(olefins, sulfur, phosphorus and selenium).12 In addition,
a nitrogen atom can coordinate to various transition
metals such as Cu(I) and hydroxyl group in L7 is also a
precoordinative atom in this catalytic system. In order
to verify this speculation, we attempted to get evidence
from 31P NMR and 13C NMR spectroscopic measure-
ments of L7 in the absence or presence of Cu(I) salt. We
found that the signalin the 31P NMR spectrum was
shifted upfield from +58.26 to +57.98 ppm along with
the alteration of the peak shape after adding an equal
molar amount of Cu(CH3CN)4ClO4 into L7 solution
(Figs. 1 and 2). This result suggests that the sulfur atom
on phosphorus may indeed coordinate to Cu(I). More-
over, the 13C NMR spectrum gives us more detailed
Although the real active species is not yet fully under-
stood in this catalytic addition reaction, we believe that
this series of imino-thiophosphoroamide ligands L1–
L13 and imino-selenophosphoramide ligand L14 are
bidentate ligands in this catalytic asymmetric reaction.10
O
O
*
(S)
(S)
*
5
4
L7: -20 oC, 96%, 52% ee, 6 h.
L7: -20 oC, 60%, 17% ee, 6 h.
L12: -20 oC, 71%, 22% ee, 6 h.
Scheme 3.

170
M. Shi, W. Zhang / Tetrahedron: Asymmetry 15 (2004) 167–176
Figure 1. The 31P NMR spectrum of ligand L7.
Figure 2. The 31P NMR of spectrum ligand L7 with Cu(CH3CN)4ClO4.
information on the coordination of nitrogen atom. It
was found that the signalthe carbon atom (imino car-
bon) connected with the nitrogen atom in L7 has a
significant downfield shift from +164.57 to
+196.64 ppm, while the aromatic carbon atom con-
nected to hydroxy group showed a small downfield shift,
from +161.07 to +161.58 ppm after adding the copper(I)
into L7 solution (Figs. 3 and 4). These observations
indicate that the nitrogen atom in imino group may
indeed coordinate to copper(I), but the hydroxylgroup
is not involved in the coordination to Cu(I) salt. Overall,
we can conclude that our novel chiral imino-thiophos-
phoroamide ligand system might be an S,N-bidentate
ligand system for copper(I) centre.
that the heteroatom on phosphorus is crucialfor this
catalytic asymmetric reaction, the corresponding axially
chiralphosphoramide igland
L15 was prepared by
similar procedures (Scheme 5). In addition, it was found
that no enantioselectivity could be realized by this ligand
under the same conditions (75% yield, 0% ee) (Scheme
6). This result may indicate that the S atom in ligand L7
potentially coordinates to Cu(I).
3.Conclusion
We disclosed an efficient catalytic system for the enan-
tioselective 1,4-conjugate addition of diethylzinc to a,b-
unsaturated enones catalyzed by Cu(I) and novel chiral
imino-thiophosphoroamide or imino-selenophosphor-
amide ligands, which are easily available, quite stable,
Since the phosphorus signalof L7 showed only a small
shift after addition of Cu(CH3CN)4ClO4, this is not
strong evidence to prove that the sulfur atom indeed
coordinates to copper(I). In order to elucidate further

M. Shi, W. Zhang / Tetrahedron: Asymmetry 15 (2004) 167–176
171
Figure 3. The 13C NMR spectrum of ligand L7.
Figure 4. The 13C NMR spectrum of ligand L7 with Cu(CH3CN)4ClO4.
O
1) BuLi, THF, -40 o
C
O
O
1) Cu(I)-L15
2) -20 oC, 2.0 eq. Et2Zn
2) Ph2P(O)Cl, THF, -40 oC ~ r.t.
NH PPh2
NH2
NH2
*
3) 2-Hydroxybenzaldehyde, EtOH, r.t.
N
75%, 0% ee
HO
Scheme 6.
L15 (56%)
ately enantioselective functionalization of six- and
seven-membered cyclic enones, although it is not effec-
tive for five-membered cyclic enone and acylic enones.
We confirmed that this series of chiralimino-phosphor-
amide ligands are novel type of S,N-bidentate ligands
Scheme 5.
recoverable and reusable in asymmetric catalysis. The
catalytic system allows efficient, catalytic and moder-

172
M. Shi, W. Zhang / Tetrahedron: Asymmetry 15 (2004) 167–176
through 31P NMR, 13C NMR spectroscopic experiments
and the comparative experiment using phosphoramide
ligand L15. Efforts are underway to elucidate the
mechanistic details of this catalytic system and to extend
the scope of these novelchiralilgands in other asym-
metric C–C bond forming transformations.
128.45 (d, JC–P ¼ 22:8 Hz), 128.98, 129.72, 130.76,
131.26 (d, JC–P ¼ 2:5 Hz), 131.30 (d, JC–P ¼ 3:1 Hz),
131.40 (d, JC–P ¼ 11:2 Hz), 131.99 (d, JC–P ¼ 11:9 Hz),
134.20 (d, JC–P ¼ 101:9 Hz), 135.83 (d, JC–P ¼ 102:4 Hz),
136.16, 160.55; EI (MS) m=e 418 (Mþ, 12.12), 217
(41.27), 201 (100), 185 (57.22), 139 (32.71); Anal. Calcd
for C25H27N2PS Æ 1/2C2H5OH: C, 70.72; H, 6.85; N, 6.34;
found: C, 70.63; H, 6.64; N, 6.36%.
4.Experimental section
4.1. General remarks
4.2.2. Ligand 2 (L2). A yellow solid, yield 60%. Mp: 172–
20
D
173 ꢀC; ½aŠ ¼ À25:4 (c 1.225, CHCl3); IR (CH2Cl2) t
2929, 1437, 1104, 638 cmÀ1
;
1H NMR (CDCl3,
300 MHz, TMS) d 1.20–1.39 (m, 3H, CH2 and CH),
1.64–1.77 (m, 4H, 2CH2), 2.24–2.28 (m, 1H, NH), 2.45–
2.51 (m, 1H, CH), 3.14–3.22 (m, 1H, CH), 3.47–3.55 (m,
1H, CH), 7.18–7.56 (m, 8H, Ar), 7.79–7.98 (m, 5H, Ar),
8.73 (s, 1H, CH); 31P NMR (CDCl3, 121 MHz, 85%
H3PO4) d 57.94; 13C NMR (CDCl3, 75 MHz, TMS) d
24.04, 24.82, 33.43, 34.40, 55.99 (d, JC–P ¼ 1:4 Hz), 75.83
(d, JC–P ¼ 8:6 Hz), 126.92, 127.30, 128.00 (d,
JC–P ¼ 13:2 Hz), 128.24 (d, JC–P ¼ 12:1 Hz), 131.13 (d,
JC–P ¼ 3:3 Hz), 131.26 (d, JC–P ¼ 10:9 Hz), 131.38 (d,
JC–P ¼ 2:4 Hz), 131.74 (d, JC–P ¼ 11:0 Hz), 132.02,
133.09, 133.22, 134.31 (d, JC–P ¼ 107:7 Hz), 134.95,
135.83 (d, JC–P ¼ 102:9 Hz), 156.86; EI (MS) m=e 487
(Mþ, 3.05), 269 (100), 217 (66.91), 139 (55.16), 96
(29.08); Anal. Calcd for C25H25Cl2N2PS: C, 61.60; H,
5.17; N, 5.75; found: C, 61.52; H, 5.13; N, 5.49%.
All reactions were conducted in oven (135 ꢀC) and
flame-dried glassware under an inert atmosphere of dry
argon or nitrogen. Toluene was distilled from sodium
metal; dichloromethane was distilled from calcium
hydride; diethylether, tetrahydrofuran and benzene were
distilled from sodium metal/benzophenone ketyl. 1H
NMR, 13C NMR and 31P NMR spectra were recorded at
300, 75 and 121 MHz, respectively. Mass spectra were
recorded by the EI method. Commercially obtained
reagents were used without further purification. All
reactions were monitored by TLC with silica gel coated
plates. P-Arus reagent [prepared by dissolving p-anis-
aldehyde (10 mL), acetic acid (7.5 mL) and concentrated
H2SO4 (25 mL) in 95% ethanol(500 mL)] was used for
those substrates that do not have absorption in UV
region. Flash column chromatography was carried out
using 200–300 mesh silica gel at increased pressure.
Enantiomeric ratios were determined by chiralGLC or
HPLC analysis. The absolute configuration was
assigned by comparison the opticalrotation with those
reported date.13 Racemic products were synthesized
according to the literatures.14;15 Melting points are
uncorrected.
4.2.3. Ligand 3 (L3). A yellow solid, yield 60%. Mp: 140–
20
D
141 ꢀC; ½aŠ ¼ À72:6 (c 0.67, CHCl3); IR (CH2Cl2) t
2929, 1437, 1104, 777, 638 cmÀ1
;
1H NMR (CDCl3,
300 MHz, TMS) d 1.20–1.38 (m, 3H, CH2 and CH),
1.58–1.78 (m, 4H, 2CH2), 2.21–2.34 (m, 1H, NH), 2.80–
2.81 (m, 1H, CH), 3.39–3.47 (m, 1H, CH), 3.52–3.63 (m,
1H, CH), 7.20–7.45 (m, 9H, Ar), 7.94–8.12 (m, 4H, Ar),
8.53 (s, 1H, CH); 31P NMR (CDCl3, 121 MHz, 85%
H3PO4) d 57.10; 13C NMR (CDCl3, 75 MHz, TMS) d
24.19, 24.49, 32.14, 33.10, 57.21 (d, JC–P ¼ 2:2 Hz), 75.30
(d, JC–P ¼ 10:1 Hz), 128.12 (d, JC–P ¼ 12:9 Hz), 128.17
4.2. Representative experimental procedure for the syn-
thesis of chiral ligands L1–L6
A solution of (1R,2R)-())-N-diphenylthiophosphoryl-
cyclohexane-1,2-diamine 1 (66 mg, 0.2 mmol) and benz-
aldehyde (51 lL, 0.2 mmol) in ethanol (5 mL) was
refluxed for 4 h. After the reaction solution was cooled
to room temperature, the solvent was removed under
reduced pressure. The residue was recrystallized from
dichloromethane and petroleum ether solution to give
the product L1 as a pale solid.
(d, JC–P ¼ 12:5 Hz), 128.44, 130.23, 131.31 (d, JC–P
2:5 Hz), 131.35 (d, JC–P ¼ 2:7 Hz), 131.50 (d, JC–P
¼
¼
10:9 Hz), 131.60 (d, JC–P ¼ 10:7 Hz), 133.03, 134.31,
134.75 (d, JC–P ¼ 100:5 Hz), 135.84 (d, JC–P ¼ 104:0 Hz),
157.62; EI (MS) m=e 487 (Mþ, 2.31), 269 (100), 217
(50.98), 139 (40.34); Anal. Calcd for C25H25Cl2N2PS: C,
61.60; H, 5.17; N, 5.75; found: C, 61.36; H, 5.18; N,
5.62%.
4.2.1. Ligand 1 (L1). A pale solid, yield 62%. Mp: 126–
4.2.4. Ligand 4 (L4). A brown solid, yield 66%. Mp: 177–
20
D
20
D
128 ꢀC; ½aŠ ¼ À78:6 (c 0.245, CHCl3); IR (CH2Cl2) t
178 ꢀC; ½aŠ ¼ À9:6 (c 0.3, CHCl3); IR (CH2Cl2) t 3054,
2929, 1642, 1437, 1104, 638 cmÀ1
;
1H NMR (CDCl3,
1437, 1265, 1105, 696 cmÀ1
;
1H NMR (CDCl3,
300 MHz, TMS) d 1.13–1.35 (m, 3H, CH2 and CH),
1.57–1.76 (m, 4H, 2CH2), 2.27–2.31 (m, 1H, NH), 2.44–
2.49 (m, 1H, CH), 3.08–3.16 (m, 1H, CH), 3.38–3.47 (m,
1H, CH), 7.25–7.48 (m, 9H, Ar), 7.78–7.95 (m, 6H, Ar),
8.35 (s, 1H, CH); 31P NMR (CDCl3, 121 MHz, 85%
H3PO4) d 57.77; 13C NMR (CDCl3, 75 MHz, TMS) d
24.23, 24.82, 33.50, 34.32, 56.53 (d, JC–P ¼ 2:3 Hz),
75.50 (d, JC–P ¼ 9:5 Hz), 128.17 (d, JC–P ¼ 13:7 Hz),
300 MHz, TMS) d 1.21–1.30 (m, 3H, CH2 and CH),
1.66–1.78 (m, 4H, 2CH2), 2.25–2.29 (m, 1H, NH), 2.41–
2.44 (m, 1H, CH), 3.07–3.15 (m, 1H, CH), 3.35–3.43 (m,
1H, CH), 6.53–6.55 (m, 1H, CH), 6.81 (d, J ¼ 3:0 Hz,
1H, CH), 7.26–7.42 (m, 6H, Ar), 7.58–7.59 (m, 1H, Ar),
7.85–7.99 (m, 4H, Ar), 8.17 (s, 1H, CH); 31P NMR
(CDCl3, 121 MHz, 85% H3PO4) d 57.58; 13C NMR
(CDCl3, 75 MHz, TMS) d 24.15, 24.84, 33.53, 34.17,

M. Shi, W. Zhang / Tetrahedron: Asymmetry 15 (2004) 167–176
173
56.66 (d, JC–P ¼ 1:7 Hz), 75.73 (d, JC–P ¼ 8:6 Hz), 111.73,
114.33, 128.12 (d, JC–P ¼ 13:0 Hz), 128.16 (d,
JC–P ¼ 12:3 Hz), 131.27 (d, JC–P ¼ 11:5 Hz), 131.29 (d,
JC–P ¼ 2:9 Hz), 131.33 (d, JC–P ¼ 2:7 Hz), 132.12
(d, JC–P ¼ 11:1 Hz), 133.92 (d, JC–P ¼ 102:2 Hz), 135.80
(d, JC–P ¼ 102:5 Hz), 144.82, 149.36, 151.52; EI (MS) m=e
408 (Mþ, 14.46), 217 (46.19), 191 (100), 175 (45.71), 96
(38.54); Anal. Calcd for C23H25N2OPS: C, 67.62; H,
6.17; N, 6.86; found: C, 67.42; H, 6.22; N, 6.65%.
cipitates were obtained by filtration to give the product
L7 as a yellow solid.
4.3.1. Ligand 7 (L7). A yellow solid, yield 75%. Mp: 155–
20
D
156 ꢀC; ½aŠ ¼ À146:4 (c 0.7, CHCl3); IR (CH2Cl2) t
1628, 1435, 1140, 1094, 1063, 760 cmÀ1
;
1H NMR
(CDCl3, 300 MHz, TMS) d 1.30–1.35 (m, 3H, CH2 and
CH), 1.63–1.83 (m, 4H, 2CH2), 2.18–2.23 (m, 1H, NH),
2.54–2.55 (m, 1H, CH), 3.13–3.14 (m, 1H, CH), 3.34
(s, 1H, CH), 6.90–7.02 (m, 2H, Ar), 7.23–7.43 (m, 8H,
Ar), 7.79–7.90 (m, 4H, Ar), 8.39 (s, 1H, CH), 13.18 (br,
1H, OH); 31P NMR (CDCl3, 121 MHz, 80% H3PO4) d
58.26; 13C NMR (CDCl3, 75 MHz, TMS) d 23.88, 24.62,
33.57, 34.30, 55.01, 72.40 (d, JC–P ¼ 8:3 Hz), 116.57,
118.51, 118.71, 127.89 (d, JC–P ¼ 12:5 Hz), 128.16
(d, JC–P ¼ 12:7 Hz), 131.01 (d, JC–P ¼ 3:7 Hz), 131.06
(d, JC–P ¼ 11:0 Hz), 131.11 (d, JC–P ¼ 11:9 Hz), 131.27 (d,
4.2.5. Ligand 5 (L5). A yellow solid, yield 55%. Mp: 121–
20
D
122 ꢀC; ½aŠ ¼ À82:6 (c 0.69, CHCl3); IR (CH2Cl2) t
3054, 1438, 1265, 1104 cmÀ1
;
1H NMR (CDCl3,
300 MHz, TMS) d 1.28–1.41 (m, 3H, CH2 and CH),
1.69–1.85 (m, 4H, 2CH2), 2.33–2.37 (m, 1H, NH), 2.51–
2.55 (m, 1H, CH), 3.18–3.26 (m, 1H, CH), 3.49–3.56 (m,
1H, CH), 7.07–7.97 (m, 16H, Ar), 8.99 (s, 1H, CH), 9.05
(d, J ¼ 7:5 Hz, 1H, Ar); 31P NMR (CDCl3, 121 MHz,
85% H3PO4) d 57.70; 13C NMR (CDCl3, 75 MHz, TMS)
d 24.19, 24.81, 33.66, 34.18, 56.56 (d, JC–P ¼ 2:0 Hz),
76.63 (d, JC–P ¼ 7:7 Hz), 124.63, 125.14, 126.05, 127.18,
128.02 (d, JC–P ¼ 13:1 Hz), 128.08 (d, JC–P ¼ 13:1 Hz),
128.59, 129.30, 131.10 (d, JC–P ¼ 3:1 Hz), 131.16, 131.23
(d, JC–P ¼ 3:0 Hz), 131.26, 131.35 (d, JC–P ¼ 11:3 Hz),
JC–P ¼ 2:8 Hz), 131.64, 132.28, 135.56 (d, JC–P
¼
102:3 Hz), 136.64 (d, JC–P ¼ 99:5 Hz), 160.83, 165.24; EI
(MS) m=e 434 (Mþ, 14.82), 217 (100), 201 (29.21), 183
(28.12), 139 (50.20); Anal. Calcd for C25H27N2OPS: C,
69.10; H, 6.26; N, 6.45; found: C, 68.99; H, 6.51; N,
6.40%.
131.90 (d, JC–P ¼ 11:1 Hz), 133.85, 133.93 (d, JC–P
¼
4.3.2. Ligand 8 (L8). A yellow solid, yield 62%. Mp: 192–
102:3 Hz), 135.26, 135.72 (d, JC–P ¼ 102:2 Hz), 160.32;
EI (MS) m=e 468 (Mþ, 16.04), 251 (100), 235 (49.70), 217
(36.55), 139 (34.51); Anal. Calcd for C29H29N2PS: C,
74.33; H, 6.24; N, 5.98; found: C, 74.05; H, 6.45; N,
5.76%.
20
D
193 ꢀC; ½aŠ ¼ À83:3 (c 0.94, CHCl3); IR (CH2Cl2) t
2932, 1633, 1492, 1105, 693 cmÀ1
;
1H NMR (CDCl3,
300 MHz, TMS) d 1.25–1.38 (m, 12H, C4H9 and CH2
and CH), 1.59–1.82 (m, 4H, 2CH2), 2.19–2.23 (m, 1H,
NH), 2.52–2.53 (m, 1H, CH), 3.12–3.13 (m, 1H, CH),
3.31–3.34 (m, 1H, CH), 6.95 (d, J ¼ 9:0 Hz, 1H, Ar),
7.26–7.42 (m, 8H, Ar), 7.81–7.90 (m, 4H, Ar), 8.40
(s, 1H, CH), 12.92 (br, 1H, OH); 31P NMR (CDCl3,
121 MHz, 85% H3PO4) d 58.17; 13C NMR (CDCl3,
75 MHz, TMS) d 23.78, 24.46, 31.46, 33.44, 33.95, 34.00,
55.99, 74.25 (d, JC–P ¼ 7:8 Hz), 116.56, 117.89, 127.68,
128.21 (d, JC–P ¼ 12:4 Hz), 128.25 (d, JC–P ¼ 12:8 Hz),
129.69, 131.29 (d, JC–P ¼ 10:8 Hz), 131.37 (d, JC–P ¼ 2:6
4.2.6. Ligand 6 (L6). A brown solid, yield 58%. Mp: 167–
20
168 ꢀC; ½aŠ ¼ À75:8(c0.33, CHCl3);IR(CH2Cl2)t3054,
D
1437, 1265, 1105, 896 cmÀ1; 1H NMR (CDCl3, 300 MHz,
TMS)d1.15–1.37(m,3H,CH2 andCH),1.52–1.79(m,4H,
2CH2), 2.31–2.35 (m, 1H, NH), 2.43–2.47 (m, 1H, CH),
3.15–3.23 (m, 1H, CH), 3.50–3.58 (m, 1H, CH), 7.17–7.23
(m, 2H, Ar), 7.30–7.42 (m, 6H, Ar), 7.74–7.91 (m, 4H, Ar),
8.01 (d, J ¼ 8:1 Hz, 1H, Ar), 8.42 (s, 1H, CH), 8.67 (d,
J ¼ 4:8 Hz, 1H, Ar); 31P NMR (CDCl3, 121 MHz, 85%
H3PO4) d 57.95; 13C NMR (CDCl3, 75 MHz, TMS) d
24.10, 24.81, 33.40, 34.36, 56.15 (d, JC–P ¼ 1:3 Hz), 75.32
(d, JC–P ¼ 8:9 Hz), 121.49, 124.78, 128.01 (d,
JC–P ¼ 13:1 Hz), 128.20 (d, JC–P ¼ 12:9 Hz), 131.11 (d,
JC–P ¼ 2:9 Hz), 131.28 (d, JC–P ¼ 11:2 Hz), 131.31 (d,
JC–P ¼ 3:2 Hz), 131.80 (d, JC–P ¼ 11:3 Hz), 134.45 (d,
JC–P ¼ 102:4 Hz), 135.86 (d, JC–P ¼ 102:0 Hz), 136.49,
149.27, 154.46, 161.48; EI (MS) m=e 419 (Mþ, 7.36), 217
(29.33), 202 (100), 139 (25.10); Anal. Calcd for
C24H26N3PS: C, 68.71; H, 6.25; N, 10.02; found: C, 68.44;
H, 6.44; N, 10.02%.
Hz), 131.41 (d, JC–P ¼ 2:6 Hz), 131.87 (d, JC–P
10:8 Hz), 133.34 (d, JC–P ¼ 102:1 Hz), 135.51 (d, JC–P
¼
¼
102:3 Hz), 141.27, 158.66, 164.97; EI (MS) m=e 490 (Mþ,
22.61), 273 (100), 257 (51.97), 242 (40.02), 217 (58.04),
139 (40.11); Anal. Calcd for C29H35N2OPS: C, 70.99; H,
7.19; N, 5.71; found: C, 71.01; H, 7.38; N, 5.57%.
4.3.3. Ligand 9 (L9). A yellow solid, yield 51%. Mp: 198–
20
D
199 ꢀC; ½aŠ ¼ À84:8 (c 0.35, CHCl3); IR (CH2Cl2) t
2952, 1437, 1105, 717 cmÀ1
;
1H NMR (CDCl3,
300 MHz, TMS) d 1.20–1.30 (m, 3H, CH2 and CH), 1.48
(s, 9H, C4H9), 1.57 (s, 9H, C4H9), 1.63–1.74 (m, 3H,
CH2 and CH), 1.83–2.24 (m, 1H, NH), 2.54–2.57 (m,
1H, CH), 3.10–3.15 (m, 1H, CH), 3.28–3.31 (m, 1H,
CH), 3.71–3.75 (m, 1H, CH), 7.11 (d, J ¼ 2:4 Hz, 1H,
Ar), 7.23–7.43 (m, 7H, Ar), 7.83–7.94 (m, 4H, Ar), 8.40
(s, 1H, CH), 13.55 (br, 1H, OH); 31P NMR (CDCl3,
121 MHz, 85% H3PO4) d 58.11; 13C NMR (CDCl3,
75 MHz, TMS) d 18.42, 23.97, 24.53, 29.49, 31.55, 33.53,
34.16, 35.07, 56.26 (d, JC–P ¼ 2:0 Hz), 74.07 (d,
JC–P ¼ 8:9 Hz), 117.77, 125.92, 127.08, 128.24 (d,
JC–P ¼ 13:0 Hz), 128.28 (d, JC–P ¼ 12:8 Hz), 131.42 (d,
4.3. The representative experimental procedure for the
synthesis of ligands L7–L13
A solution of (1R,2R)-())-N-diphenylthiophosphoryl-
cyclohexane-1,2-diamine 1 (66 mg, 0.2 mmol) and sali-
cylaldehyde (22 lL, 0.2 mmol) in ethanol (5 mL) were
stirred at room temperature for 4 h. The resulted pre-

174
M. Shi, W. Zhang / Tetrahedron: Asymmetry 15 (2004) 167–176
JC–P ¼ 1:8 Hz), 131.46 (d, JC–P ¼ 2:0 Hz), 131.48 (d,
JC–P ¼ 10:9 Hz), 131.96 (d, JC–P ¼ 11:0 Hz), 133.31 (d,
JC–P ¼ 102:1 Hz), 135.48 (d, JC–P ¼ 103:2 Hz), 136.71,
140.12, 158.01, 165.79; EI (MS) m=e 546 (Mþ, 34.04),
329 (80.24), 313 (100), 217 (80.02), 139 (34.35); Anal.
Calcd for C33H43N2OPS Æ C2H5OH: C, 70.91; H, 8.33; N,
4.73; found: C, 70.73; H, 8.05; N, 4.70%.
7.65–7.98 (m, 6H, Ar), 8.93 (s, 1H, CH), 14.45 (br, 1H,
OH); 31P NMR (CDCl3, 121 MHz, 85% H3PO4) d 58.46;
13C NMR (CDCl3, 75 MHz, TMS) d 24.03, 24.43, 32.55,
34.03, 56.44, 67.94 (d, JC–P ¼ 8:9 Hz), 106.68, 118.16,
122.79, 124.38, 126.41, 128.09 (d, JC–P ¼ 17:4 Hz),
128.24, 128.31 (d, JC–P ¼ 16:1 Hz), 128.37, 129.23,
131.20 (d, JC–P ¼ 10:9 Hz), 131.50 (d, JC–P ¼ 2:5 Hz),
131.50 (d, JC–P ¼ 2:5 Hz), 131.86 (d, JC–P ¼ 11:0 Hz),
133.02 (d, JC–P ¼ 105:0 Hz), 135.04 (d, JC–P ¼ 102:3 Hz),
137.08, 157.68, 174.98; EI (MS) m=e 484 (Mþ, 35.91),
267 (56.35), 251 (100), 234 (48.18), 217 (64.27), 139
(46.16); Anal. Calcd for C29H29N2OPS: C, 71.88%; H,
6.03%; N, 5.78%; found: C, 71.77%; H, 6.08%; N,
5.70%.
4.3.4. Ligand 10 (L10). A yellow solid, yield 80%. Mp:
20
D
205–206 ꢀC; ½aŠ ¼ À182:5 (c 0.62, CHCl3); IR (CH2Cl2)
1
t 2928, 1633, 1436, 1104, 714 cmÀ1; H NMR (CDCl3,
300 MHz, TMS) d 1.27–1.43 (m, 3H, CH2 and CH),
1.68–1.87 (m, 4H, 2CH2), 2.29–2.34 (m, 1H, NH), 2.45–
2.48 (m, 1H, CH), 3.29–3.31 (m, 1H, CH), 3.33–3.39 (m,
1H, CH), 7.11 (d, J ¼ 2:4 Hz, 1H, Ar), 7.24–7.46 (m, 7H,
Ar), 7.74–7.82 (m, 4H, Ar), 8.24 (s, 1H, CH); 31P NMR
(CDCl3, 121 MHz, 85% H3PO4) d 58.62; 13C NMR
(CDCl3, 75 MHz, TMS) d 23.53, 24.34, 32.83, 33.84,
55.50, 72.23 (d, JC–P ¼ 7:1 Hz), 118.94, 121.91, 123.20,
128.18 (d, JC–P ¼ 12:5 Hz), 128.38 (d, JC–P ¼ 12:8 Hz),
128.97, 131.07 (d, JC–P ¼ 11:1 Hz), 131.49 (d,
JC–P ¼ 3:7 Hz), 131.59 (d, JC–P ¼ 2:5 Hz), 131.63 (d,
JC–P ¼ 10:9 Hz), 132.29, 133.26 (d, JC–P ¼ 103:1 Hz),
135.27 (d, JC–P ¼ 102:0 Hz), 157.65, 162.95; EI (MS) m=e
503 (Mþ, 4.92), 285 (100), 217 (75.23), 139 (54.05); Anal.
Calcd for C25H25Cl2N2OPS: C, 59.65; H, 5.01; N, 5.56;
found: C, 59.73; H, 4.90; N, 5.41%.
4.3.7. Ligand 13 (L13). A yellow solid, yield 52%. Mp:
20
D
166–167 ꢀC; ½aŠ ¼ À56:8 (c 0.29, CHCl3); IR (CH2Cl2)
t 2925, 1620, 1506, 1275 cmÀ1
;
1H NMR (CDCl3,
300 MHz, TMS) d 1.24–1.80 (m, 6H, CH2), 2.06–2.12
(m, 1H, NH), 2.36–2.45 (m, 1H, CH), 2.51 (s, 3H, Me),
2.62–2.66 (m, 1H, CH), 3.20–3.29 (m, 1H, CH), 3.37–
3.41 (m, 1H, CH), 6.92 (d, J ¼ 9:0 Hz, 1H, Ar), 7.12–
7.25 (m, 5H, Ar), 7.32–7.35 (m, 2H, Ar), 7.56 (d,
J ¼ 8:1 Hz, 1H, Ar), 7.70 (d, J ¼ 9:3 Hz, 1H, Ar), 7.75
(s, 1H, Ar), 7.78–7.90 (m, 4H, Ar), 8.93 (s, 1H, CH); 31P
NMR (CDCl3, 121 MHz, 85% H3PO4) d 58.54; 13C
NMR (CDCl3, 75 MHz, TMS) d 22.10, 24.09, 24.47,
32.65, 34.14, 55.37 (d, JC–P ¼ 3:5 Hz), 67.82 (d,
JC–P ¼ 8:0 Hz), 106.36, 118.04, 123.28, 124.41, 124.49,
128.19 (d, JC–P ¼ 13:4 Hz), 128.30 (d, JC–P ¼ 13:1 Hz),
129.06, 131.20 (d, JC–P ¼ 12:7 Hz), 131.45 (d, JC–P ¼ 1:9
Hz), 131.47 (d, JC–P ¼ 1:1 Hz), 131.86 (d, JC–P ¼ 11:5
Hz), 132.97 (d, JC–P ¼ 109:6 Hz), 133.88, 135.00 (d,
JC–P ¼ 101:8 Hz), 136.94, 137.80, 157.71, 175.16; EI
(MS) m=e 498 (Mþ, 2.79), 217 (29.18), 183 (20.19), 139
(17.79), 97 (31.82), 57 (100); Anal. Calcd for
C30H31N2OPS Æ 1/3EtOH: C, 71.66%; H, 6.47%; N,
5.45%; found: C, 71.74%; H, 6.26%; N, 5.44%.
4.3.5. Ligand 11 (L11). A yellow solid, yield 54%. Mp:
20
D
229–230 ꢀC; ½aŠ ¼ À84:9 (c 0.34, CHCl3); IR
(CH2Cl2) t 3733, 3055, 1438, 869 cmÀ1
;
1H NMR
(CDCl3, 300 MHz, TMS) d 1.22–1.38 (m, 3H, CH2 and
CH), 1.62–1.87 (m, 4H, 2CH2), 2.19–2.23 (m, 1H,
NH), 2.47–2.51 (m, 1H, CH), 3.11–3.16 (m, 1H, CH),
3.41–3.42 (m, 1H, CH), 6.88 (d, J ¼ 9:0 Hz, 1H, Ar),
7.24–7.44 (m, 8H, Ar), 7.74–7.85 (m, 4H, Ar), 8.26 (s,
1H, CH), 13.13 (br, 1H, OH); 31P NMR (CDCl3,
121 MHz, 85% H3PO4) d 58.46; 13C NMR (DMSO-d6,
75 MHz, TMS) d 24.33, 25.17, 33.93, 34.82, 55.33,
72.81 (d, JC–P ¼ 8:4 Hz), 109.40, 119.59, 120.80, 128.28
(d, JC–P ¼ 12:2 Hz), 128.64 (d, JC–P ¼ 12:6 Hz), 131.36
(d, JC–P ¼ 3:9 Hz), 131.44 (d, JC–P ¼ 10:8 Hz), 131.46
(d, JC–P ¼ 11:2 Hz), 131.70 (d, JC–P ¼ 3:1 Hz), 133.87,
4.4. The synthesis of ligand 14 (L14)
This ligand was synthesized in the similar method as
that described for the preparation of ligand 7 (L7).
135.07, 136.22 (d, JC–P
¼
102:8 Hz), 137.44 (d,
JC–P ¼ 99:5 Hz), 160.74, 164.31; EI (MS) m=e 514
(Mþ+1, 18.46), 512 (Mþ)1, 17.75), 297 (100), 295
(97.17), 217 (99.53), 139 (67.60); Anal. Calcd for
C25H26BrN2OPS: C, 58.48; H, 5.10; N, 5.46; found: C,
58.30; H, 5.33; N, 5.20%.
4.4.1. Ligand 14 (L14). A yellow solid, yield 58%. Mp:
20
D
171–172 ꢀC; ½aŠ ¼ À146 (c 0.24, CHCl3); IR (CH2Cl2) t
3054, 1629, 1421, 1265, 895 cmÀ1
;
1H NMR (CDCl3,
300 MHz, TMS) d 1.24–1.34 (m, 3H, CH2 and CH),
1.63–1.88 (m, 4H, CH2), 2.17–2.21 (m, 1H, NH), 2.48–
2.51 (m, 1H, CH), 3.13–3.21 (m, 1H, CH), 3.37–3.43 (m,
1H, CH), 6.91 (dt, J ¼ 7:5, 0.9 Hz, 1H, Ar), 6.99 (d,
J ¼ 9:0 Hz, 1H, Ar), 7.22–7.42 (m, 7H, Ar), 7.78–7.87
(m, 5H, Ar), 8.39 (s, 1H, CH), 13.06 (br, 1H, OH); 31P
NMR (CDCl3, 121 MHz, 85% H3PO4) d 54.90; 13C
NMR (CDCl3, 75 MHz, TMS) d 23.73, 24.35, 33.39,
33.68, 56.64 (d, JC–P ¼ 1:4 Hz), 73.89 (d, JC–P ¼ 8:2 Hz),
117.03, 118.56, 118.64, 128.17 (d, JC–P ¼ 12:8 Hz),
128.22 (d, JC–P ¼ 12:9 Hz), 131.32, 131.45 (d,
JC–P ¼ 11:6 Hz), 131.46 (d, JC–P ¼ 2:0 Hz), 131.52 (d,
4.3.6. Ligand 12 (L12). A yellow solid, yield 57%. Mp:
20
D
232–233 ꢀC; ½aŠ ¼ À171:6 (c 0.44, CHCl3); IR
(CH2Cl2) t 2928, 1623, 1538, 1104 cmÀ1
;
1H NMR
(CDCl3, 300 MHz, TMS) d 1.32–1.48 (m, 4H, CH2),
1.67–1.79 (m, 2H, CH2), 2.07–2.11 (m, 1H, NH), 2.43–
2.47 (m, 1H, CH), 2.57–2.62 (m, 1H, CH), 3.02–3.28 (m,
1H, CH), 3.04–3.44 (m, 1H, CH), 6.98 (d, J ¼ 9:3 Hz,
1H, Ar), 7.13–7.34 (m, 8H, Ar), 7.45–7.48 (m, 1H, Ar),

M. Shi, W. Zhang / Tetrahedron: Asymmetry 15 (2004) 167–176
175
JC–P ¼ 1:6 Hz), 131.97 (d, JC–P ¼ 11:6 Hz), 132.34,
133.16 (d, JC–P ¼ 91:2 Hz), 135.06 (d, JC–P ¼ 91:7 Hz),
161.01, 164.82; EI (MS) m=e 481 (Mþ, 3.37), 401 (14.95),
217 (100), 201 (26.97); Anal. Calcd for C25H27N2OPSe:
C, 62.37; H, 5.65; N, 5.82; found: C, 62.15; H, 5.75; N,
5.63%.
5 ꢀC/min, 112 ꢀC (2 min) 10.0 psi N2, tR ¼ 12:503 min,
tS ¼ 12:620 min.
(S)-())-3-Ethylcyclopentanone 4 (Scheme 3). 40 mg,
71% yield. 1H NMR (CDCl3, TMS, 300 MHz) d 0.95 (t,
J ¼ 7:5 Hz, Me), 1.41–1.58 (m, 3H), 1.75–1.85 (m, 1H),
20
2.10–2.44 (m, 5H); ½aŠ ¼ À9:7 (c 0.1, CHCl3) for 22%
D
ee; Rt-bDEXcstTM, 30 m · 0.25 mm, 70 ꢀC (20 min), 70–
115 ꢀC, 1 ꢀC/min, 115 ꢀC (10 min), 8.4 psi N2, tS ¼
59:488 min, tR ¼ 60:235 min.
4.5. The synthesis of ligand 15 (L15)
This ligand was synthesized in the similar method as
that described for the preparation of ligand 7 (L7).
(S)-())-3-Ethylcycloheptanone 5 (Scheme 3). 68 mg,
96% yield. 1H NMR (CDCl3, TMS, 300 MHz) d 0.91 (t,
J ¼ 7:5 Hz, Me), 1.25–1.45 (m, 4H), 1.51–1.70 (m, 2H),
20
D
1.80–1.95 (m, 3H), 2.35–2.52 (m, 4H); ½aŠ ¼ À13:2 (c
4.5.1. Ligand 15 (L15). A yellow solid, yield 56%. Mp:
2.1, CHCl3) for 52% ee; Chiraldex G-BP column,
20 m · 0.25 mm, 90 ꢀC (30 min), 8.0 psi N2, tS ¼
9:618 min, tR ¼ 10:138 min.
20
D
215–216 ꢀC; ½aŠ ¼ À59:3 (c 0.4, CHCl3); IR (CH2Cl2) t
3175, 1631, 1437, 1280, 1185, 754 cmÀ1
;
1H NMR
(CDCl3, 300 MHz, TMS) d 1.25–1.73 (m, 7H, CH2 and
CH), 1.72–1.73 (m, 1H, CH), 2.43–2.49 (m, 1H, CH),
2.57–2.63 (m, 1H, CH), 3.06–3.09 (m, 1H, NH), 6.96 (t,
J ¼ 7:5 Hz, 1H, Ar), 7.05 (d, J ¼ 7:8 Hz, 1H, Ar), 7.27–
7.46 (m, 8H, Ar), 7.68–7.82 (m, 4H, Ar), 8.45 (s, 1H,
CH), 13.19 (br, 1H, OH); 31P NMR (CDCl3, 121 MHz,
85% H3PO4) d 23.62; 13C NMR (CDCl3, 75 MHz, TMS)
d 24.12, 24.99, 33.76, 35.64, 55.83 (d, JC–P ¼ 1:9 Hz),
75.01 (d, JC–P ¼ 9:2 Hz), 117.40, 118.93, 119.02, 128.63
(d, JC–P ¼ 10:9 Hz), 128.80 (d, JC–P ¼ 10:1 Hz), 131.48
(d, JC–P ¼ 130:3 Hz), 131.58, 131.83 (d, JC–P ¼ 9:2 Hz),
131.93 (d, JC–P ¼ 2:7 Hz), 132.01 (d, JC–P ¼ 3:0 Hz),
132.73, 132.87 (d, JC–P ¼ 9:4 Hz), 133.89 (d,
JC–P ¼ 126:5 Hz), 161.34, 164.78; EI (MS) m=e 418 (Mþ,
15.43), 216 (39.11), 201 (100), 142 (23.97); ESI (HRMS)
for C25H27O2NaN2P: 441.17007; found: 441.17024.
(S)-(+)-1,3-Diphenylpentan-1-one 7 (Scheme 4). 115 mg,
97%. 1H NMR (CDCl3, TMS, 300 MHz) d 0.80 (t,
J ¼ 7:5 Hz, Me), 1.61–1.82 (m, 2H), 3.20–3.29 (m, 3H),
7.16–7.31 (m, 5H), 7.40–7.45 (m, 2H), 7.50–7.56 (m,
20
1H), 7.89–7.92 (m, 2H); ½aŠ ¼ +0:4 (c 2.8, EtOH) for
D
8% ee; Chiralpak AD, hexane/i-PrOH ¼ 95/5, 0.7 mL/
min, tS ¼ 9:426 min, tR ¼ 11:081 min.
Acknowledgements
We thank the State Key Project of Basic Research
(Project 973) (no. G2000048007), Shanghai Municipal
Committee of Science and Technology, and the
NationalNaturalScience Foundation of China for
financialsupport (20025206, 203900502 and 20272069).
4.6. General procedure for the Cu(I)-catalyzed 1,4-
conjugate addition
A solution of Cu(CH3CN)4ClO4 (5.0 mg, 0.015 mmol)
and L7 (13.0 mg, 0.03 mmol) in dry toluene (3 mL) was
stirred for 1 h at room temperature under an argon
References and Notes
1. (a) Perlmutter in Conjugate Addition Reactions in Organic
Synthesis; Baldwin, J. E., Magnus, P. D., Eds. Tetrahedron
Organic Chemistry Series; Pergamon: Oxford, 1992; Vol.
9; (b) Yamamoto, Y. Methoden Organic Chemistry, 4th
ed.; Houben-Weyl, 1995; Vol. E21b, 4, Chapter 1.5.2.1.
2. (a) Rossiter, B. E.; Swingler, N. M. Chem. Rev. 1992, 92,
771–806; (b) Krause, N.; Gerold, A. Angew. Chem., Int.
Ed. 1997, 36, 186–204; (c) Feringa, B. L.; de Vries, A. H.
M. In Advances in Catalytic Process; Doyle, M. P., Ed.;
JAL: Greenwich, CT, 1995; Vol. 1, pp 151–192.
3. (a) Alexakis, A.; Vastra, J.; Mangeney, P. Tetrahedron:
Asymmetry 1993, 4, 2427–2430; (b) Knobel, A. K. H.;
Escher, I. H.; Pfaltz, A. Synlett 1997, 1429–1431; (c)
Arnold, L. A.; Naasz, R.; Minnaard, A. J.; Feringa, B. L.
J. Org. Chem. 2003, 67, 7244–7254; (d) For a brief review.
see: Feringa, B. L. Acc. Chem. Res. 2000, 33, 346–353; (e)
Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 171–196;
(f) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002,
3221–3226.
atmosphere. Then, 2-cyclohexene-1-one
2
(48 lL,
0.5 mmol) was added into the reaction mixture and the
solution was stirred for a further 10 min. Et2Zn (1.2 mL,
1.0 mmol, 0.87 M solution in hexane) was added drop-
wise within 30 s. The resulting mixture was stirred at
)20 ꢀC for 6 h. The reaction was quenched by addition
of saturated ammonium chloride aqueous solution
(4.0 mL). After extraction with ether (3 · 5.0 mL), the
combined organic layers were dried over anhydrous
MgSO4. The residue obtained upon removal of volatiles
in vacuo was purified by a flash column chromatogra-
phy on silica gel (eluent: pentane/ether ¼ 30/1) to afford
(S)-())-ethylcyclohexanone 3 (61 mg, 97%) as a colour-
less oil. And ligand 7 was recovered in 96% yield.
(S)-())-3-Ethylcyclohexanone 3 (Table 1, entry 9).
61 mg, 97% yield, 75% ee. 1H NMR (CDCl3, TMS,
300 MHz) d 0.90 (t, J ¼ 7:6 Hz, Me), 1.44–1.25 (m, 3H),
4. (a) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.;
de Vries, A. H. M.; Naasz, R.; Keller, E. Angew. Chem., Int.
Ed. 1997, 36, 2620–2623; (b) Alexakis, A.; Benhaim, C.;
Rosset, S.; Humam, M. J. Am. Chem. Soc. 2002, 124, 5262–
5263; (c) Huttenloch, O.; Waldmann, H. Chem. Commun.
1.58–1.70 (m, 2H), 1.85–2.10 (m, 3H), 2.20–2.46 (m,
20
3H); ½aŠ ¼ À10:3 (c 2.9, CHCl3) for 75% ee; Chiraldex
D
G-BP column, 20 m · 0.25 mm, 50 ꢀC (2 min), 50–112 ꢀC,

176
M. Shi, W. Zhang / Tetrahedron: Asymmetry 15 (2004) 167–176
2002, 673–675; (d) Escher, I. H.; Pfaltz, A. Tetrahedron
8. (a) Wang, C.-J.; Shi, M. Eur. J. Org. Chem. 2003, 2823–
2828; (b) Wang, C.-J.; Shi, M. J. Org. Chem. 2003, 68,
6229–6237; (c) Shi, M.; Wang, C.-.J. Adv. Synth. Catal.
2003, 345, 971–973.
9. Shi, M.; Zhang, W. Tetrahedron: Asymmetry 2003, 14,
3407–3414.
10. (a) For selected examples on Cu-catalyzed asymmetric
conjugate addition of Grignard reagents to enones using
chiralS, N igl ands, see: Lamber, F.; Koten, D. M.;
Janssen, D. M.; van Klaveren, M.; Boersma, J.; van
Koten, G. Tetrahedron: Asymmetry 1991, 2, 1097–1100;
(b) Zhou, Q. L.; Pfaltz, A. Tetrahedron Lett. 1993, 34,
7725–7728; (c) Seebach, D.; Jeasche, G.; Pichota, A.;
Audergon, L. Helv. Chim. Acta 1997, 80, 1519–2515.
11. (a) For selected X-rays on Cu complexes coordinated by S,
N ligand, see: Koten, D. M.; Grove, D. M.; Smeets, W. J.;
Spek, A. L.; van Koten, G. J. Am. Chem. Soc. 1992, 114,
3400–3410; (b) Brubaker, G. R.; Brown, J. N.; Yoo, M.
K.; Kutchan, T. M.; Mottel, E. A. Inorg. Chem. 1979, 18,
299.
2000, 56, 2879–2888, and references cited therein; (e)
Pamies, O.; Net, G.; Ruiz, A.; Claver, C. Tetrahedron:
Asymmetry 1999, 10, 2007–2014; (f) Yan, M.; Chan, A. S.
C. Tetrahedron Lett. 1999, 40, 6645–6648; (g) Yan, M.;
Yang, L. W.; Wong, K. Y.; Chan, A. S. C. Chem. Commun.
1999, 11–12; (h) Liang, L.; Au-Yeung, T. T.; Chan, A. S. C.
Org. Lett. 2002, 4, 3799–3801; (i) Reetze, M. T.; Gosberg,
A.; Moulin, D. Tetrahedron Lett. 2002, 43, 1189–1191; (j)
Taira, S.; Crepy, K. V. L.; Imamoto, T. Chirality 2002, 14,
386–392; (k) Mori, T.; Kosaka, K.; Nakagawa, Y.; Naga-
oka, Y.; Tomioka, K. Tetrahedron: Asymmetry 1998, 9,
3175–3178; (l) Hu, X. Q.; Chen, H. L.; Zhang, X. Angew.
Chem., Int. Ed. 1999, 37, 283–285; (m) Shintani, R.; Fu, G.
C. Org. Lett. 2002, 4, 3699–3702; (n) Chataigner, I.;
Gennari, C.; Piarulli, U.; Ceccarelli, S. Angew. Chem.,
Int. Ed. 2000, 39, 916–918; (o) Chataigner, I.; Gennari, C.;
Ongeri, S.; Piarulli, U.; Ceccarelli, S. Chem. Eur. J. 2001,
20, 2628–2634; (p) Degrado, S. J.; Mizutani, H.; Hoveyda,
A. H. J. Am. Chem. Soc. 2001, 123, 755–756.
5. (a) Bertz, S. H.; Dabbagh, G.; Sundararajan, G. J. Org.
Chem. 1986, 51, 4953–4959; (b) Johnoson, C. R.; Marren,
T. J. Tetrahedron Lett. 1987, 28, 27–30.
6. Alexakis, A.; Mutti, S.; Normant, J. F. Tetrahedron Lett.
1988, 29, 3325–4411.
7. (a) Shi, M.; Sui, W. S. Chirality 2000, 12, 574–580; (b) Shi,
M.; Sui, W. S. Tetrahedron: Asymmetry 2000, 11, 773–779;
(c) Shi, M.; Sui, W. S. Tetrahedron: Asymmetry 2000, 11,
835–841; (d) Shi, M.; Sui, W. S. Tetrahedron: Asymmetry
1999, 10, 3319–3325.
12. Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.;
Wiley-VCH, 2000.
13. (a) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am.
Chem. Soc. 2001, 123, 755–756; (b) Hu, X. Q.; Chen, H. L.;
Zhang, X. M. Acta Chmica. Sinic. 2000, 58, 1163–1167.
14. (a) Alexakis, A.; Vastra, J.; Mangeney, P. Tetrahedron
Lett. 1997, 38, 7745–7748; (b) Della, E.; Janowski, W.
Aust. J. Chem. Soc. 1999, 52, 367–372.
15. Wang, Y.; Gladysz, J. A. J. Org. Chem. 1995, 60, 903–
909.