Chiral C1-symmetric diaminothiophosphoramide-Cu(I) catalyzed asymmetric addition of diethylzinc to N-sulfonylimines

Article abstract of DOI:10.1016/j.tetasy.2003.09.031

In the presence of a catalytic amount of chiral diaminothiophosphoramide L7 (6 mol%) and Cu(I) (3 mol%), the asymmetric addition of diethylzinc to N-sulfonylimines could be achieved in good yields with moderate to good e.e. (50-74% e.e.) at 0°C in toluene

Full text of DOI:10.1016/j.tetasy.2003.09.031

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3407–3414
Chiral C1-symmetric diaminothiophosphoramide–Cu(I) catalyzed
asymmetric addition of diethylzinc to N-sulfonylimines
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 22 August 2003; accepted 8 September 2003
Abstract—In the presence of a catalytic amount of chiral diaminothiophosphoramide L7 (6 mol%) and Cu(I) (3 mol%), the
asymmetric addition of diethylzinc to N-sulfonylimines could be achieved in good yields with moderate to good e.e. (50–74% e.e.)
at 0°C in toluene. A novel chiral diaminothiophosphoramide ligand system for this asymmetric addition reaction has been
explored.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
and utilize them in asymmetric catalysis. Herein, we
wish to report the synthesis of novel homochiral C1-
symmetric diaminothiophosphoramide ligands L3–L7
derived from chiral 1,2-cyclohexanediamine and 1,2-
diphenylethylenediamine and the results of our studies
on the catalytic enantioselective addition of diethylzinc
to N-sulfonylimines by means of these novel chiral
ligands.
The efficient and catalytic asymmetric synthesis of
amines is one of the most promising methodologies in
homogeneous catalysis.1 Enantioselective addition of
organometallic reagents to CꢀN of imines is a conve-
nient route to obtain optically active amines.2 This
approach has especially been used in chiral amine lig-
and-catalyzed asymmetric addition of alkyllithium;3
chiral amino alcohol ligands,4 copper–amidophos-
phines,5 and Zr-peptide-based chiral ligand-catalyzed
asymmetric addition of organozinc;6 chiral allylpalla-
dium-catalyzed allylation by allylstannane,7 and
rhodium–monophosphine-catalyzed
arylation
by
arylstannane8 with very good enantioselectivities.
Recently, we have been interested in the syntheses and
applications of novel chiral ligands based on the axially
chiral binaphthalenediamine (BINAM)9,10 and found
that in the presence of a catalytic amount of chiral
binaphthylthiophosphoramide L1 or L2 (6 mol%) and
Cu(I) (3 mol%), the asymmetric addition of diethylzinc
to N-sulfonylimines could be achieved in good yields
with moderate to high e.e. (63–93% e.e.) at 0°C in
toluene (Scheme 1).11 In order to expand this novel type
of chiral thiophosphoramide ligand to other systems,
we decide to utilize homochiral 1,2-cyclohexanediamine
or 1,2-diphenylethylenediamine as a chiral source to
prepare their corresponding thiophosphoramide ligands
Scheme 1.
2. Results and discussion
These chiral ligands L3–L7 were easily obtained from
(1R,2R)-(−)-1,2-cyclohexanediamine 1 and (1R,2R)-(+)-
1,2-diphenylethane-1,2-diamine 2.12 The procedures for
their preparation are outlined in Schemes 2–5. The
chiral ligand L3 can be easily synthesized through
lithiation of the relevant diamine with butyllithium
followed by phosphorylation with diphenylthiophos-
* Corresponding author. Fax: 86-21-64166128; e-mail: mshi@
pub.sioc.ac.cn
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.09.031

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M. Shi, W. Zhang / Tetrahedron: Asymmetry 14 (2003) 3407–3414
imidazoline 3. After refluxing a solution of 3 in neutral
ethanol–water mixture for 20 h, N-monoacylated
(1R,2R)-(−)-1,2-cyclohexanediamine 4 was produced in
good yield (Scheme 5). The N-monoethylated (1R,2R)-
(−)-1,2-cyclohexanediamine 5 was obtained by reduc-
tion of 4 with LiAlH4 which was further treated with
butyllithium and then by phosphorylation with
dimethylthiophosphoryl chloride in THF to give the
homochiral ligand L7 in moderate yield (Scheme 5). We
found that these homochiral ligands L3–L7 are stable
to ambient air and moisture and can be reused in this
asymmetric reaction. We also found that if using
methyl iodide as the alkylation reagent to modify L3,
the reaction afforded the ammonium iodide 6 rather
than the desired C1-symmetric ligand (Scheme 6). The
structure of compound 6 was determined by X-ray
diffraction (Fig. 1).14
Scheme 2.
Scheme 3.
Scheme 4.
Scheme 5.
Scheme 6.
Figure 1. The ORTEP draw of ammonium iodide 6.
Using
N-(benzylidene)-p-methylbenzenesulfonamide
(N-sulfonylimine) 7a as the substrate and diethylzinc as
the nucleophilic addition reagent, we examined this
asymmetric addition using the obtained C1-symmetric
homochiral thiophosphoramide ligands L3–L7 under
various reaction conditions to develop the optimal reac-
tion conditions. The results are summarized in Table 1.
In an early study, an examination of the temperature
profile of Cu(CH3CN)4ClO4/L4-catalyzed asymmetric
addition of diethylzinc to N-sulfonylimines was per-
formed. We found that reaction temperature had a
great influence on the yield and enantioselectivity of the
addition product 8a. At room temperature, the reaction
was completed within 12 h and the desired ethylation
product 8a was given in 73% yield (56% e.e.) (Table 1,
entry 1). Lowering the reaction temperature to 0°C, the
yield of the addition product 8a was increased to 84%
with 65% e.e. (Table 1, entry 2). When the reaction was
phoryl chloride in THF in good yield (Scheme 2). The
N-substituted diphenylthiophsophoramide ligands L4
and L5 were synthesized in moderate yields by further
reaction of L3 with ethyl bromide and potassium car-
bonate in acetonitrile and treatment of L3 with NaBH4/
HC(O)H in acidic THF solution, respectively (Scheme
3). The chiral ligand L6 can be similarly synthesized
through lithiation, phosphorylation and ethylation of
the relevant diamine (Scheme 4). The preparation of
N-substituted dimethylthiophsophoramide ligand L7 is
shown in Scheme 5 according to the reported proce-
dure.13 Namely, the condensation of (1R,2R)-(−)-1,2-
cyclohexanediamine 1 with the Pinner salt derived from
acetonitrile conveniently provided the corresponding

M. Shi, W. Zhang / Tetrahedron: Asymmetry 14 (2003) 3407–3414
3409
Table 1. The asymmetric addition reaction of diethylzinc to N-sulfonylimine 7a catalyzed by copper salt and chiral ligands
L3–7
Entry
Copper salt
Ligand
Solvent
Temp. (°C)
Time (h)
Yielda (%)
E.e.b (%)
1
2
3
4
5
6
7
8
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4BF4
CuOTf·1/2C6H6
Cu(OTf)2
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
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4d
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
Et2O
12
0
−20
0
0
0
0
0
0
0
12
13
36
21
15
28
10
24
24
13
60
60
13
48
13
73
84
52
82
66
56
89
35
31
72
46
64
92
58
83
56
65
67
53
64
60
65
47
31
56
39
40
68
39
57
THF
9
CH2Cl2
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
10c
11
12
13
14
15
0
0
0
0
0
a Isolated yields.
b Determined by chiral HPLC.
c LiClO4 was added as additive.
d Recovered ligand was used.
reaction mixture in 70–80% yield through silica gel
column chromatography after usual workup, and can
be reused in this asymmetric reaction in similar yield
and with slightly lower enantioselectivity (Table 1,
entry 15). The best reaction conditions are using
Cu(CH3CN)4ClO4 (3 mol%) as a catalyst precursor and
L7 (6 mol%) as a chiral ligand in toluene at 0°C.
carried out at −20°C, the reaction was sluggish and the
achieved e.e. of 8a was slightly increased to 67% (Table
1, entry 3). Thus, the best reaction temperature is 0°C.
The catalytic activity of Cu(CH3CN)4ClO4 (84% yield,
65% e.e.) was similar as another copper salts CuOTf·1/
2C6H6 (66% yield, 64% e.e.), but better than other
copper salts such as, Cu(CH3CN)4BF4 (82% yield, 53%
e.e.) and Cu(OTf)2 (56% yield, 60% e.e.) (Table 1,
entries 4–6). The solvent effects were examined by use
of Cu(CH3CN)4ClO4/L4 catalytic system. We found
that toluene and Et2O are the solvent of choice (Table
1, entries 1, 7–9).
We next examined the asymmetric addition reaction of
diethylzinc to a variety of N-sulfonylimines 7 under the
optimized reaction conditions. The results are summa-
rized in Table 2. As can be seen from Table 2, good
yields (69–99%) and moderate to good enantioselectivi-
ties (50–74% e.e.) could be achieved for various aro-
By screening chiral ligands L3–7, we found that L7 was
the best chiral ligand for this enantioselective addition
reaction, which gave the addition product in 68% e.e.
and 92% yield at 0°C under the same conditions (Table
1, entries 11–14). It should be noted that chiral ligand
L5 having an N,N-dimethyl group gave the addition
product 8a in 64% yield with 40% e.e. under the same
conditions (Table 1, entry 12) and the N-unsubstituted
chiral ligand L3 gave the addition product 8a only in
moderate yield and e.e. as well (Table 1, entry 11).
These results suggested that the substituent on the
amino group in the diamine structure played a very
important role in asymmetric induction in this addition
reaction. The homochiral C1-symmetric ligand L6
matic N-sulfonylimines
7 having either electron-
donating groups or electron-withdrawing groups on the
benzene ring (Table 2, entries 1–8 and 10). Although
these results are not comparable with the best literature
value hitherto reported for the asymmetric addition of
diethylzinc to N-sulfonylimines,5a this is still a case for
exploring a novel ligand system for the enentioselective
addition of organozinc to CꢀN double bond. For the
methanesulfonylimine 7i, 99% yield (63% e.e.) also
could be realized (Table 2, entry 9).
Although the real active species is not yet fully under-
stood in this catalytic addition reaction, we believe that
this family of chiral C1-symmetric thiophosphoramides
L3–L7 are bidentate ligands in this catalytic asymmetric
reaction because it is well known that sulfur atoms can
coordinate strongly to late transition metals.15 In order
derived
from
(1R,2R)-(+)-1,2-diphenylethane-1,2-
diamime 2 furnished the addition product 8a in 58%
yield and 39% e.e. under the same conditions (Table 1,
entry 14). Ligand L4 can be easily recovered from the

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M. Shi, W. Zhang / Tetrahedron: Asymmetry 14 (2003) 3407–3414
Table 2. The asymmetric addition of diethylzinc to various N-sulfonylimines 7 in the presence of Cu(I) (3 mol%) and L7 (6
mol%)
Entry
R
R%
Imine
Yielda (%)
E.e.b (%)
[h]2D0 (c in CHCl3)
1
2
3
4
5
6
7
8
9
C6H5
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ms
Ts
7a
7b
7c
7d
7e
7f
7g
7h
7i
8a, 92
8b, 84
8c, 67
8d, 76
8e, 74
8f, 69
8g, 71
8h, 82
8i, 99
8j, 82
68
63
50
74
74
53
64
57
63
61
−35.6 (3.17)c
−30.6 (0.85)
−23.3 (2.55)
38.5 (0.85)
−43.4 (1.88)
−28.0 (2.80)
−25.1 (3.15)
−24.6 (3.15)
−22.5 (3.10)
−4.1 (2.85)
p-MeC6H4
m-MeC6H4
p-MeOC6H4
p-ClC6H4
m-ClC6H4
p-CF3C6H4
m-FC6H4
C6H5
10
i-Me2CH
7j
a Isolated yields.
b Determined by chiral HPLC.
c The absolute configuration of 8a was assigned to S by comparing the specific rotation with the reported data.5
Figure 2. The 31P NMR spectrum of L4.
to provide evidence for the coordination of nitrogen
and sulfur atom in L4 to Cu(I), the 31P NMR studies of
a 1:1 mixture of L4 and Cu(CH3CN)4ClO4 in CDCl3 at
room temperature were carried out. In the absence of
Cu(CH3CN)4ClO4, the signal of the phosphorous con-
nected to the sulfur atom in L4 appeared at l 58.69
(Fig. 2), while it appeared a new signal at l 61.45 in L4
in the presence of Cu(CH3CN)4ClO4 (Fig. 3). More-
over, in our previous work, we have proved that the N
atom in this type of C1-symmetric thiophsophoramide
ligand system indeed coordinated to Cu metal center.11
Those results may partially indicate that Cu(I) can be
potentially coordinated by both the S and N atoms in
ligand L4.
(1R,2R)-(−)-1,2-cyclohexanediamine and (1R,2R)-(+)-
1,2-diphenylethane-1,2-diamime, which are readily
available, very stable and recoverable, and have applied
them to the copper-catalyzed asymmetric addition of
diethylzinc to N-sulfonylimines 7 in high yields and
with moderate to good enantioselectivities. Efforts are
underway to elucidate the mechanistic details of this
catalytic system and to extend the scope of these novel
chiral ligands in other asymmetric CꢁC bond forming
transformations.
4. Experimental
4.1. General remarks
3. Conclusion
All reactions were conducted in an 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
In conclusion, we have synthesized a new family of
chiral diaminothiophosphoramides derived from

M. Shi, W. Zhang / Tetrahedron: Asymmetry 14 (2003) 3407–3414
3411
Figure 3. The 31P NMR spectrum of the mixture of L4 and Cu(CH3CN)4ClO4.
1
hydride; diethyl ether, tetrahydrofuran and benzene
were distilled from sodium metal/benzophenone ketyl.
1H, 13C and 31P NMR spectra were recorded at 300, 75
and 121 MHz, respectively. Mass spectra were recorded
by the EI method. All of the solid compounds reported
in this paper gave satisfactory CHN microanalyses or
HRMS analyses. Commercially obtained reagents were
used without further purification. All reactions were
monitored by TLC with silica gel coated plates. Enan-
tiomeric ratios were determined by HPLC, using a
chiralpak AS column, a chiralpak AD column or a
chiralcel OD column with hexane and i-PrOH as sol-
vents. Melting points are uncorrected.
(CH2Cl2) w 2925, 2854, 1669, 1437, 1105, 638 cm−1; H
NMR (CDCl3, TMS, 300 MHz) l 1.07–1.25 (m, 4H,
CH2), 1.62–1.67 (m, 2H, CH2), 1.91–2.00 (m, 2H, CH2),
2.35–2.46 (m, 1H, CH), 2.92–2.99 (m, 1H, CH), 3.10–
3.14 (m, 2H, NH2), 3.38 (dd, J=6.9, 7.2 Hz, 1H, NH),
7.42–7.49 (m, 6H, Ar), 7.88–7.96 (m, 2H, Ar), 8.02–8.09
(m, 2H, Ar); 31P NMR (CDCl3, 121 MHz, 85%H3PO4)
l +59.24; 13C NMR (CDCl3, TMS, 75 MHz) l 29.36,
30.44, 34.28, 35.44, 56.02 (d, JCꢁP=6.6 Hz), 58.05 (d,
J
J
J
J
J
CꢁP=2.5 Hz), 128.01 (d, JCꢁP=13.2 Hz), 128.23 (d,
CꢁP=12.3 Hz), 130.84 (d, JCꢁP=11.0 Hz), 131.27 (d,
CꢁP=1.7 Hz), 131.30 (d, JCꢁP=3.3 Hz), 131.70 (d,
CꢁP=11.4 Hz), 135.01 (d, JCꢁP=101.8 Hz), 135.12 (d,
CꢁP=101.8 Hz); MS (EI) m/z 331 (M++1, 0.70), 234
(24.19), 217 (57.97), 139 (35.67), 97 (100); HRMS (EI)
calcd for C18H23N2PS requires: 330.13196; found:
330.12854.
4.2. Materials
N-Arylidene-p-methylbenzenesulfonamides 7a–7h and
aliphatic N-tosylated imine 7j,16 N-benzylidenemethyl-
sulfonamide 7i17 were prepared by the reported syn-
thetic methods. The physical and spectroscopic data of
7a–j are in consistent with those reported in the
literature.16,17
4.3.2. Chiral ligand L4. To a solution of ligand L3 (3.3
g, 10 mmol) in CH3CN (25 ml) was added potassium
carbonate (2.76 g, 20 mmol) and bromoethane (5.0 ml,
66 mmol), then the reaction mixture was stirred at rt
for 24 h. The mixture was washed by 10% brine,
extracted twice with dichloromethane, dried over anhy-
drous MgSO4, and evaporated under reduced pressure.
The residue was purified by an alumina column chro-
matography (eluent: ethyl acetate) to give the chiral
ligand L4 as an amber oil (1.97 g, 55%). It can be easily
recovered from the reaction mixture in 70–80% yield
through silica gel column chromatography after usual
workup. [h]2D0=−53.5 (c 0.095, CHCl3); IR (CH2Cl2) w
3247, 2930, 2856, 1437, 751, 638 cm−1; 1H NMR
(CDCl3, TMS, 300 MHz) l 1.16 (t, J=8.7 Hz, 3H,
CH3), 1.53–1.55 (m, 2H, CH2), 1.68–1.73 (m, 2H, CH2),
1.83–1.88 (m, 2H, CH2), 2.10–2.13 (m, 2H, CH2), 2.34
(br, 1H, NH), 2.49–2.58 (m, 2H, CH2), 2.82–2.88 (m,
1H, CH), 3.15–3.20 (m, 1H, CH), 4.04 (br, 1H, NH),
7.39–7.47 (m, 6H, Ar), 7.86–7.94 (m, 2H, Ar), 8.02–8.10
(m, 2H, Ar); 31P NMR (CDCl3, 121 MHz, 85%H3PO4)
l +58.69; 13C NMR (CDCl3, TMS, 75 MHz) l 15.26,
24.37, 24.66, 30.88, 33.80, 39.96, 55.12 (d, JCꢁP=2.0
Hz), 61.28 (d, JCꢁP=8.7 Hz), 127.81 (d, JCꢁP=12.4 Hz),
4.3. Representative experimental procedure for the syn-
thesis of ligands L3–7
4.3.1. Chiral ligand L3. To a solution of (1R,2R)-(−)-
1,2-cyclohexanediamine 1 (1.37 g, 12 mmol) in THF
(10.0 mL) was added dropwise n-butyllithium (8.13
mL, 13.0 mmol, 1.6 M solution in hexane) at 0°C over
30 min, and the reaction mixture was stirred for 1 h at
the same temperature. Then, diphenylthiophosphinic
chloride (3.28 g, 13.0 mmol) in 5.0 mL of THF was
added dropwise and the reaction solution was slowly
warmed to rt. A saturated aqueous sodium bicarbonate
was added to quench the reaction and exacted twice
with dichloromethane. The organic layer was dries over
anhydrous MgSO4 and evaporated under reduced pres-
sure. The residue was purified by an alumina column
chromatography (eluent: dichloromethane/methanol=
80/1) to give the ligand L3 as an amber solid (2.4 g,
61%). Mp: 60–62°C; [h]2D0=−22.8 (c 0.072, CHCl3); IR

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M. Shi, W. Zhang / Tetrahedron: Asymmetry 14 (2003) 3407–3414
128.08 (d, JCꢁP=12.5 Hz), 130.45 (d, JCꢁP=10.7 Hz),
131.03 (d, JCꢁP=2.9 Hz), 131.10 (d, JCꢁP=3.2 Hz),
131.59 (d, JCꢁP=11.3 Hz), 135.24 (d, JCꢁP=103.3 Hz),
135.46 (d, JCꢁP=100.5 Hz); MS (EI) m/z 359 (M++1,
0.59), 331 (1.14), 217 (90.32), 139 (55.20), 97 (100);
HRMS (EI) calcd for C20H27N2PS requires: 358.16325;
found: 358.16111.
4.3.5. Compound 5. To a stirred suspension of LiAlH4
(456 mg, 12.0 mmol) in 20.0 mL of anhydrous THF
was added dropwise a solution of monoacetylated
diamine 412 (312 mg, 2.0 mmol) in 10.0 mL of THF.
The mixture was heated under reflux for 4 h. After
reaction, the reaction mixture was cooled in an ice-bath
and the remaining hydride was carefully quenched by
dropwise addition of water (5.0 mL) and then 10%
NaOH (5.0 mL). A white precipitate was filtered off
and thoroughly washed with ethyl acetate. The com-
bined filtrate and ethyl acetate washings were washed
with brine and dried over anhydrous MgSO4. After the
solvents were evaporated under reduced pressure,
product 5 was given in 272 mg, 96% as an amber oil.
[h]2D0=−75.3 (c 0.36, CHCl3); IR (CH2Cl2) w 1449, 1265,
1120, 739, 704 cm−1; 1H NMR (CDCl3, TMS, 300
MHz) l 0.76–1.27 (m, 11H, CH2 and CH3), 1.54–1.66
(m, 2H, NH2), 1.88–2.06 (m, 2H, CH2), 2.24–2.32 (m,
1H, NH), 2.37–2.46 (m, 1H, CH) 2.67–2.76 (m, 1H,
CH); MS (EI) m/z 142 (M+, 22.80), 126 (15.86), 110
(10.13), 97 (35.82), 84 (99.89), 56 (100).
4.3.3. Chiral ligand L5. A solution of ligand L3 (264
mg, 0.8 mmol) in THF (10 mL) and NaBH4 (302 mg,
8.0 mmol) were simultaneously added to a stirred solu-
tion of 20% H2SO4 (1.0 mL) and 40% formaldehyde
aqueous solution (1.0 mL, 12.0 mmol) in THF (20 mL)
with ice-cooling over a period of 15 min, the mixture
was stirred for an additional hour and then 1.0 M
NaOH was added until pH>7. After extraction with
ethyl acetate, the combined organic layers were dried
over anhydrous MgSO4. The residue obtained upon
evaporation was purified by a silica gel column chro-
matography (eluent: ethyl acetate/petroleum=1/2) to
afford the ligand L6 as a colorless oil (99 mg, 35%).
[h]2D0=−31.1 (c 2.2, CHCl3); IR (CH2Cl2) w 2932, 2859,
1437, 1104, 638 cm−1; 1H NMR (CDCl3, TMS, 300
MHz) l 0.95–1.08 (m, 2H, CH2), 1.16–1.18 (m, 2H,
CH2), 1.43–1.48 (m, 2H, CH2), 1.75–1.82 (m, 2H, CH2),
2.23 (s, 6H, CH3), 2.29–2.36 (m, 1H, CH) 3.28–3.41 (m,
1H, CH), 4.45 (br, 1H, NH), 7.39–7.48 (m, 6H, Ar),
7.78–7.86 (m, 2H, Ar), 8.09–8.17 (m, 2H, Ar); 31P
NMR (CDCl3, 121 MHz, 85%H3PO4) l +58.81; 13C
NMR (CDCl3, TMS, 75 MHz) l 20.56, 24.32, 25.22,
4.3.6. Chiral ligand L7. This compound was prepared
by the same method as that described above for the
preparation of ligand L4. An amber solid, 45% yield.
Mp: 64–65°C; [h]D20=−138.4 (c 0.6, CHCl3); IR
1
(CH2Cl2) w 2930, 2856, 1450, 1105, 942, 728 cm−1; H
NMR (CDCl3, TMS, 300 MHz) l 1.09 (t, J=7.2 Hz,
3H, CH3), 1.18–1.35 (m, 6H, CH2), 1.65 (br, 1H, NH),
1.72–1.76 (m, 2H, CH2), 1.81 (d, J=0.9 Hz, 3H, CH3),
1.85 (d, J=1.2 Hz, 3H, CH3), 2.11–2.20 (m, 2H, CH2),
2.43–2.50 (m, 1H, CH), 2.69 (br, 1H, NH), 2.76–2.82
(m, 1H, CH); 31P NMR (CDCl3, 121 MHz, 85%H3PO4)
l +60.59; 13C NMR (CDCl3, TMS, 75 MHz) l 15.30,
23.42 (d, JCꢁP=67.7 Hz), 24.46, 24.51 (d, JCꢁP=71.3
Hz), 24.86, 30.80, 34.85, 40.60, 56.16 (d, JCꢁP=3.2 Hz),
61.91 (d, JCꢁP=7.9 Hz); MS (EI) m/z 234 (M+, 0.88),
205 (0.92), 141 (8.09), 125 (100), 93 (28.72); HRMS(EI)
calcd for C10H23N2PS requires: 234.13196, found:
234.13320.
33.84, 39.60, 52.51 (d, JCꢁP=2.4 Hz), 67.11 (d, JCꢁP
10.1 Hz), 127.86 (d, JCꢁP=13.0 Hz), 128.29 (d, JCꢁP
=
=
12.7 Hz), 130.30 (d, JCꢁP=11.0 Hz), 131.05 (d,
J
J
J
CꢁP=2.9 Hz), 131.19 (d, JCꢁP=3.8 Hz), 132.09 (d,
CꢁP=10.9 Hz), 135.62 (d, JCꢁP=105.2 Hz), 136.13 (d,
CꢁP=98.9 Hz); MS (EI) m/z 358 (M+, 3.59), 217
(20.97), 141 (45.69), 125 (100), 96 (30.36); HRMS(EI)
calcd for C20H27N2PS requires: 358.16325; found:
358.16281.
4.3.4. Chiral ligand L6. This compound was prepared
by the same method as that described above for the
preparation of ligand L3 and L4 using (1R,2R)-(+)-1,2-
diphenylethane-1,2-diamime 2 as a starting material.
After purification, it was given as a light yellow solid,
yield 30%. Mp: 135–137°C; [h]2D0=−7.1 (c 1.55, CHCl3);
4.3.7. Compound 6. To a solution of ligand L3 (330 mg,
1 mmol) in CH3CN (10 ml) was added potassium
carbonate (2.76 g, 20 mmol) and methyl iodide (0.62
ml, 10 mmol), then the reaction mixture was stirred at
rt for 24 h. The mixture was washed by 10% brine,
extracted twice with dichloromethane, dried over anhy-
drous MgSO4, and evaporated under reduced pressure.
The residue was purified by an alumina column chro-
matography (eluent: ethyl acetate/methol=50/1) to give
the compound 6 as a colorless solid (103 mg, 22%). Mp:
214–215°C; IR (CH2Cl2) w 3445, 3142, 2938, 1436, 637
1
IR (CH2Cl2) w 3028, 1437, 1106, 1063, 644 cm−1; H
NMR (CDCl3, TMS, 300 MHz) l 0.84–0.88 (m, 1H,
CH), 1.00 (t, J=7.0 Hz, 3H, CH3), 1.42–1.43 (m, 1H,
CH), 2.31–2.54 (m, 2H, CH2), 3.86 (d, J=7.6 Hz, 1H,
NH), 4.49–4.55 (m, 1H, NH), 6.91–7.46 (m, 16H, Ar),
7.61–7.68 (m, 2H, Ar), 7.79–7.86 (m, 2H, Ar); 31P
NMR (CDCl3, 121 MHz, 85%H3PO4) l +65.97; 13C
NMR (CDCl3, TMS, 75 MHz) l 15.13, 41.19, 60.86 (d,
1
cm−1; H NMR (CDCl3, TMS, 300 MHz) l 1.10–1.15
J
CꢁP=1.8 Hz), 68.15 (d, JCꢁP=8.4 Hz), 126.74, 127.50,
(m, 1H, CH2), 1.35–1.65 (m, 4H, CH2), 1.81–1.86 (m,
1H, CH2), 2.05–2.13 (m, 1H, CH2), 2.29–2.33 (m, 1H,
CH2), 3.38 (s, 9H, CH3), 4.26–4.34 (m, 1H, CH), 4.77–
4.85 (m, 1H, CH), 6.01–6.06 (m, 1H, Ar), 7.39–7.48 (m,
6H, Ar), 8.04–8.14 (m, 4H, Ar); 31P NMR (CDCl3, 121
MHz, 85%H3PO4) l +58.73; MS (EI) m/z 358 (M+–142,
2.68), 217 (15.06), 141 (27.42), 125 (100). Anal. calcd
for: C21H30N2PSI requires C, 50.40%; H, 6.04%; N,
5.60%. Found: C, 50.68%; H, 5.95%; N, 5.46%.
127.57 (d, JCꢁP=13.1 Hz), 127.83 (d, JCꢁP=2.9 Hz),
127.97 (d, JCꢁP=1.5 Hz), 128.05, 128.24, 130.96, 131.10,
131.44 (d, JCꢁP=11.9 Hz), 132.00 (d, JCꢁP=11.1 Hz),
132.44 (d, JCꢁP=2.7 Hz), 133.06 (d, JCꢁP=118.0 Hz),
133.33 (d, JCꢁP=113.6 Hz), 140.25 (d, JCꢁP=2.1 Hz),
141.63 (d, JCꢁP=6.5 Hz); MS (EI) m/z 457 (M++1,
0.50), 217 (17.02), 134 (100); HRMS(EI) calcd for
C28H29N2PS requires: 456.1789; found: 456.1761.

M. Shi, W. Zhang / Tetrahedron: Asymmetry 14 (2003) 3407–3414
3413
4.4. General procedure for the synthesis of the racemic
products which were used for the chiral HPLC analysis
4.8. (−)-4-Methyl-N-(1-m-tolylpropyl)benzene-
sulfonamide 8c (entry 3 in Table 2)
Under argon atmosphere, to a solution of N-(m-
1H NMR (CDCl3, TMS, 300 MHz) l 0.79 (t, J=7.5
Hz, 3H, Me), 1.61–1.85 (m, 2H, CH2), 2.18 (s, 3H, Me),
2.36 (s, 3H, Me), 4.08–4.17 (m, 1H, CH), 4.90 (br, 1H,
NH), 6.70 (s, 1H, Ar), 6.82 (d, J=7.8 Hz, 1H, Ar), 6.94
(d, J=8.1 Hz, 1H, Ar), 7.03–7.12 (m, 3H, Ar), 7.53 (d,
J=8.4 Hz, 2H, Ar); [a]2D0=−23.3 (c 2.55, CHCl3) for
49% e.e.; Chiralpak AD, hexane/i-PrOH=85/15, 0.7
mL/min, tminor=12.200 min, tmajor=17.533 min.
fluorobenzylidene)-p-methylbenzenesulfonamide
7h
(139 mg, 0.5 mmol) in THF (4.0 mL) was added
dropwise ethylmagnesium bromide (1.5 mL, 1.5 mmol,
1.0 M in THF) at 0°C. The reaction mixture was stirred
for 10 h at the same temperature, and then 1.0N HCl
(5.0 mL) was added. After extraction with ethyl acetate,
the combined organic layers were dried over MgSO4.
The residue obtained upon removal of volatiles in
vacuo was purified by column chromatography on sil-
ica gel (eluent: petroleum/ethyl acetate=10/1) to afford
the racemic product 8h (140 mg, 91%) as a colorless
solid.
4.9. (−)-4-Methyl-N-[1-(4-methoxyphenyl)propyl]benzene-
sulfonamide 8d (entry 4 in Table 2)
1H NMR (CDCl3, TMS, 300 MHz) l 0.77 (t, J=7.8
Hz, 3H, Me), 1.63–1.86 (m, 2H, CH2), 2.37 (s, 3H, Me),
3.75 (s, 3H, Me), 4.09–4.16 (m, 1H, CH), 4.67 (br, 1H,
NH), 6.69 (d, J=11.4 Hz, 2H, Ar), 6.92 (d, J=11.4 Hz,
2H, Ar), 7.13 (d, J=8.7 Hz, 2H, Ar), 7.54 (d, J=8.7
Hz, 2H, Ar); [h]2D0=−38.5 (c 0.85, CHCl3) for 74% e.e.;
Chiralpak AS, hexane/i-PrOH=75/25, 0.7 mL/min,
The other racemates 8a–j were synthesized in the same
manner as that described above.
4.5. General procedure for the Cu-catalyzed addition of
diethylzinc to sulfonylimine
A solution of Cu(CHCN)4ClO4 (5.0 mg, 0.015 mmol)
and ligand L7 (7.0 mg, 0.03 mmol) in dry toluene (3.0
mL) was stirred for 1 h at rt under an argon atmo-
sphere. N-(Benzylidene)-p-methylbenzenesulfonamide
7a (129 mg, 0.5 mmol) was added and the solution was
stirred for a further 10 min, then Et2Zn (1 mL, 1 mmol,
1.0 M solution in hexane) was added dropwise within
30 seconds at 0°C. The resulting mixture was stirred for
about 13 h at the same temperature, 1.0 M HCl (4.0
mL) was added. After extraction with ethyl acetate
(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 column
chromatography on silica gel (eluent: petroleum/ethyl
acetate=10/1) to afford the addition product (127 mg,
92%) as a colorless solid.
tminor=20.260 min, tmajor=28.473 min.
4.10. (−)-4-Methyl-N-[1-(4-chlorophenyl)propyl]benzene-
sulfonamide 8e (entry 5 in Table 2)
1H NMR (CDCl3, TMS, 300 MHz) l 0.78 (t, J=7.5
Hz, 3H, Me), 1.63–1.82 (m, 2H, CH2), 2.38 (s, 3H, Me),
4.14–4.21 (m, 1H, CH), 5.01 (br, 1H, NH), 6.96 (d,
J=9.0 Hz, 2H, Ar), 7.09–7.14 (m, 4H, Ar), 7.51 (d,
J=9.0 Hz, 2H, Ar); [h]2D0=−43.4 (c 1.88, CHCl3) for
74% e.e.; Chiralpak AS, hexane/i-PrOH=75/25, 0.7
mL/min, tminor=12.243 min, tmajor=18.990 min.
4.11. (−)-4-Methyl-N-[1-(3-chlorophenyl)propyl]benzene-
sulfonamide 8f (entry 6 in Table 2)
4.6. (S)-(−)-4-Methyl-N-(1-phenylpropyl)benzene-
sulfonamide 8a (entry 1 in Table 2)
1H NMR (CDCl3, TMS, 300 MHz) l 0.80 (t, J=7.2
Hz, 3H, Me), 1.60–1.80 (m, 2H, CH2), 2.37 (s, 3H, Me),
4.14–4.21 (m, 1H, CH), 4.87 (br, 1H, NH), 6.86 (s, 1H,
Ar), 6.92–6.96 (m, 1H, Ar), 7.09–7.14 (m, 4H, Ar), 7.51
(d, J=7.2 Hz, 2H, Ar); [h]2D0=−28.0 (c 2.8, CHCl3) for
53% e.e.; Chiralpak AD, hexane/i-PrOH=85/15, 0.7
mL/min, tminor=11.470 min, tmajor=12.477 min.
1H NMR (CDCl3, TMS, 300 MHz) l 0.79 (t, J=7.2
Hz, 3H, Me), 1.69–1.82 (m, 2H, CH2), 2.36 (s, 3H, Me),
4.15–4.22 (m, 1H, CH), 4.73 (br, 1H, NH), 6.99–7.02
(m, 2H, Ar), 7.10–7.18 (m, 5H, Ar), 7.53 (d, J=6.3 Hz,
2H, Ar); [h]2D0=−35.6 (c 3.17, CHCl3) for 68% e.e.;
Chiralpak AS, hexane/i-PrOH=75/25, 0.7 mL/min,
tmajor=15.050 min, tminor=20.414 min.
4.7. (−)-4-Methyl-N-(1-tolylpropyl)benzenesulfonamide
8b (entry 2 in Table 2)
4.12. (−)-4-Methyl-N-(1-(4-trifluoromethylphenyl)propyl)-
benzenesulfonamide 8g (entry 7 in Table 2)
1H NMR (CDCl3, TMS, 300 MHz) l 0.77 (t, J=7.5
Hz, 3H, Me), 1.65–1.86 (m, 2H, CH2), 2.27 (s, 3H, Me),
2.37 (s, 3H, Me), 4.07–4.17 (m, 1H, CH), 4.72 (br, 1H,
NH), 6.88 (d, J=8.4 Hz, 2H, Ar), 6.97 (d, J=8.1 Hz,
2H, Ar), 7.12 (d, J=8.1 Hz, 2H, Ar), 7.54 (d, J=8.4
Hz, 2H, Ar); [h]2D0=−30.6 (c 0.85, CHCl3) for 63% e.e.;
Chiralpak AS, hexane/i-PrOH=75/25, 0.7 mL/min,
1H NMR (CDCl3, TMS, 300 MHz) l 0.82 (t, J=7.5
Hz, 3H, Me), 1.64–1.83 (m, 2H, CH2), 2.33 (s, 3H, Me),
4.24–4.31 (m, 1H, CH), 5.08 (br, 1H, NH), 7.06 (d,
J=7.8 Hz, 2H, Ar), 7.11 (d, J=8.1 Hz, 2H, Ar), 7.36
(d, J=8.4 Hz, 2H, Ar), 7.46 (d, J=8.4 Hz, 2H, Ar);
[h]2D0=−25.1 (c 3.15, CHCl3) for 64% e.e., Chiralcel OD,
hexane/i-PrOH=9/1, 0.7 mL/min, tminor=14.848 min,
tminor=13.737 min, tmajor=17.710 min.
tmajor=17.621 min.

3414
M. Shi, W. Zhang / Tetrahedron: Asymmetry 14 (2003) 3407–3414
4.13. (−)-4-Methyl-N-[1-(3-fluorophenyl)propyl]-
benzenesulfonamide 8h (entry 8 in Table 2)
Tomioka, K.; Inoue, I.; Shindo, M.; Koga, K. Tetra-
hedron Lett. 1991, 32, 3095–3098.
4. (a) Soai, K.; Hatanaka, T.; Miyazawa, T. J. Chem. Soc.,
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Guijarro, D.; Tanner, D. J. Org. Chem. 1997, 62, 7364–
7375; (c) Brandt, P.; Hedberg, C.; Lawonn, K.; Pinho, P.;
Andersson, P. G. Chem. Eur. J. 1999, 5, 1692–1699; (d)
Jimeno, C.; Reddy, K. S.; Sola, L.; Moyano, A.; Pericas,
M. A.; Riera, A. Org. Lett. 2000, 2, 3157–3159; (e)
Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem.
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Am. Chem. Soc. 2002, 124, 5940–5941.
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A. B. J. Am. Chem. Soc. 2003, 125, 1692–1693.
6. (a) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snap-
per, M. L. J. Am. Chem. Soc. 2001, 123, 984–985 and
10409–10410; (b) Wipf, P.; Kendall, C.; Stephenson, C.
R. J. J. Am. Chem. Soc. 2001, 123, 5122–5123; (c) Wei,
C.-M.; Li, C.-J. J. Am. Chem. Soc. 2002, 124, 5638–5939.
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Chem. Soc. 1998, 120, 4242–4243; (b) Bao, M.; Naka-
mura, H.; Yamaoto, Y. Tetrahedron Lett. 2000, 41, 131–
134.
1H NMR (CDCl3, TMS, 300 MHz) l 0.79 (t, J=7.2
Hz, 3H, Me), 1.63–1.80 (m, 2H, CH2), 2.36 (s, 3H, Me),
4.16–4.23 (m, 1H, CH), 4.95 (br, 1H, NH), 6.65–6.69
(m, 1H, Ar), 6.80–6.86 (m, 2H, Ar), 7.09–7.17 (m, 3H,
Ar), 7.54 (d, J=8.1 Hz, 2H, Ar); [h]2D0=−24.6 (c 3.15,
CHCl3) for 57% e.e.; Chiralcel OD, hexane/i-PrOH=9/
1, 0.7 mL/min, tminor=14.946 min, tmajor=18.921 min.
4.14. (−)-N-(1-Phenylpropyl)methanesulfonamide 8i
(entry 9 in Table 2)
1H NMR (CDCl3, TMS, 300 MHz) l 0.91 (t, J=7.5
Hz, 3H, Me), 1.77–1.91 (m, 2H, CH2), 2.56 (s, 3H, Me),
4.32–4.39 (m, 1H, CH), 4.86 (br, 1H, NH), 7.27–7.41
(m, 5H, Ar); [h]2D0=−22.5 (c 3.1, CHCl3) for 63% e.e.;
Chiralpak AS, hexane/i-PrOH=75/25, 0.7 mL/min,
t
minor=12.578 min, tmajor=13.716 min.
4.15. (−)-4-Methyl-N-(1-ethyl-2-methylpropyl)benzene-
sulfonamide 8j (entry 10 in Table 2)
1H NMR (CDCl3, TMS, 300 MHz) l 0.69–0.89 (m, 9H,
3Me), 1.22–1.29 (m, 1H, CH), 1.37–1.47 (m, 1H, CH),
1.71–1.77 (m, 1H, CH), 2.42 (s, 3H, Me), 2.99–3.04 (m,
1H, CH), 4.35 (br, 1H, NH), 7.28 (d, J=9.0 Hz, 2H,
Ar), 7.77 (d, J=8.7 Hz, 2H, Ar); [h]2D0=−4.1 (c 2.85,
CHCl3) for 61% e.e.; Chiralpak AD, hexane/i-PrOH=
85/15, 0.7 mL/min, tmajor=10.177 min, tminor=11.517
min.
8. Hayashi, T.; Ishigedani, M. J. Am. Chem. Soc. 2000, 122,
976–977.
9. (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.
10. Miyano, S.; Nawa, M.; Mori, A.; Hashimoto, H. Bull.
Chem. Soc. Jpn. 1984, 57, 2171–2176.
11. Shi, M.; Wang, C.-J. J. Org. Chem. 2003, 68, 6229–6237.
12. Pini, D.; Iuliano, A.; Rosini, C.; Salvadori, P. Synthesis
1990, 11, 1023–1024.
Acknowledgements
13. Mitchell, J. M.; Finney, N. S. Tetrahedron Lett. 2000, 41,
8431–8434.
14. C21H30N2PSI, formula weight: 500.40, temperature:
We thank the State Key Project of Basic Research
(Project 973) (No. G2000048007), Shanghai Municipal
Committee of Science and Technology, and the
National Natural Science Foundation of China for
financial support (20025206, 203900502, and 20272069).
293(2) K, crystal system, space group: monoclinic, P2(1),
,
,
unit cell dimensions: a=8.9294(8) A, b=8.7601(8) A,
,
c=14.5754(13) A, h=90°, i=91.826(2)°, k=90°, V=
1139.54(18) A , Zvalue=2, Dcalcd=1.458 g/cm3, F000=508,
3
,
crystal size: 0.470×0.255×0.168 mm, data/restraints/
parameters=4643/2/246, final R indices [I>2|(I)]: R1=
0.0423, wR2=0.1018, R indices (all data): R1=0.0501;
wR2=0.1333. Its crystal structure has been deposited at
the Cambridge Crystallographic Data Center and has
been allocated the deposition number: CCDC 217719.
15. For selected X-rays of Cu complexes coordinated by S, N
ligands, see: (a) Knotter, D. M.; Grove, D. M.; Smeets,
W. J. 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, 299–302.
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