Chiral thiophosphoramide and selenophosphoramide ligands in the Cu(I)-promoted catalytic enantioselective 1,3-dipolar cycloaddition reactions of azomethine ylides and pyrrole-2,5-dione derivatives

Article abstract of DOI:10.1016/j.tetasy.2007.02.027

Chiral C₂-symmetric diphenylthiophosphoramide ligand L1 prepared from C₂-symmetric (1S,2S)-(-)-1,2-diphenylethylenediamine was found to be a fairly effective chiral ligand for Cu(I)-promoted 1,3-dipolar cycloaddition of imines and py

Full text of DOI:10.1016/j.tetasy.2007.02.027

Tetrahedron: Asymmetry 18 (2007) 645–650
Chiral thiophosphoramide and selenophosphoramide ligands
in the Cu(I)-promoted catalytic enantioselective
1,3-dipolar cycloaddition reactions of azomethine ylides
and pyrrole-2,5-dione derivatives
a
Min Shia,b, and Jing-Wen Shi
*
aSchool of Chemistry and Molecular Engineering, East China University of Science and Technology,
130 Mei Long Lu, Shanghai 200237, China
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
Received 26 January 2007; accepted 27 February 2007
Abstract—Chiral C2-symmetric diphenylthiophosphoramide ligand L1 prepared from C2-symmetric (1S,2S)-(ꢀ)-1,2-diphenylethylenedi-
amine was found to be a fairly effective chiral ligand for Cu(I)-promoted 1,3-dipolar cycloaddition of imines and pyrrole-2,5-dione deriv-
atives to give the corresponding adducts in moderate enantioselectivities and good yields.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Previously we have reported that optically active di-
phenylphosphoramides, diphenylthiophosphoramides and
diphenylselenophosphoramides of (1R,2R)-(ꢀ)-1,2-diamino-
cyclohexane, (1R,2R)-(+)-1,2-diphenylethylenediamine, or
(R)-1,10-binaphthyl-2,20-diamine (BINAM) are easily
available, relatively stable, recoverable, and effective chiral
ligands in a variety of catalytic, asymmetric C–C bond for-
mation reactions to give the corresponding products in
good yields with high ee.1 These results have promoted
us to explore more catalytic, asymmetric reactions
using these interesting chiral ligands. Herein we report
that these chiral ligands are also fairly effective in the
copper(I)-promoted 1,3-dipolar cycloaddition of azome-
thine ylides (from imines) and pyrrole-2,5-dione deriva-
tives, which allows the stereoselective synthesis of
pyrrolidines or proline derivatives in moderate enantio-
selectivities.2
Diphenylthiophosphoramides and diphenylselenophospho-
ramides L1–L4 as well as their derivatives L5–L6 were syn-
thesized from the reaction of diphenylthiophosphinic or
diphenylselenophosphinic chlorides as well as their ana-
logues with (1R,2R)-(ꢀ)-1,2-diaminocyclohexane and
(1S,2S)-(ꢀ)-1,2-diphenylethylenediamine in the presence
of diisopropylethylamine or triethylamine in dichlorometh-
ane, respectively (Fig. 1).3 Initial examinations using imine
1a and 1-phenylpyrrole-2,5-dione 2a as the substrates in
the presence of chiral diphenylthiophosphoramide ligand
L1 and various metal salts were aimed at determining the
optimal conditions, with the results of these experiments
being summarized in Table 1. We found that using
Cu(CH3CN)4ClO4 (5 mol %) as a catalyst and Et3N
(10 mol %) as a base gave the corresponding 1,3-dipolar
cycloaddition product endo-3a, which was obtained in
moderate to good yields and 5–55% ee in a variety of
solvents in the presence of L1 (5.5 mol %) at 0 ꢁC (Table
1, entries 1–5).4 Dichloromethane is the solvent of choice.
i
Next, we utilized DBU and Pr2NEt as bases for this reac-
tion under otherwise identical conditions, and found that
endo-3a was formed in 83% yield and 69% ee when using
iPr2NEt as the base (Table 1, entries 6 and 7). Using either
*
Corresponding author. Fax: +86 21 64166128; e-mail: Mshi@mail.
sioc.ac.cn
i
AgOAc or AgOTf (5 mol %) as a catalyst and Pr2NEt as
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.02.027

646
M. Shi, J.-W. Shi / Tetrahedron: Asymmetry 18 (2007) 645–650
Se
S
S
H
H
H
Ph
Ph
Ph
N PPh2
N PPh2
N PPh2
Ph
N PPh2
N PPh2
N PPh2
H
S
H
S
H
Se
L 2
L 3
L 1
S
S
S
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
N P(OPh)2
N P(OEt)2
N PEt2
N P(OPh)2
N P(OEt)2
N PEt2
H
S
H
S
H
S
L 4
L 5
L 6
Figure 1.
Table 1. Optimization of the reaction conditions in the 1,3-dipolar cycloaddition of azomethine ylides (from imines) and 1-phenylpyrrole-2,5-dione
Ph
N
O
O
O
Metal salts (5 mol%),
Ligand (5.5 mol%)
N
CO2Me
+
N Ph
Base (10 mol%), 0 oC, 24 h
CO2Me
N
H
Cl
Cl
O
1a
2a
3a
endo-
Entry
Ligand
Lewis acid
Base
Solvent
Toluene
THF
CH3CN
Ether
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
Cu(CH3CN)4ClO4
Cu(CH3CN)4ClO4
Cu(CH3CN)4ClO4
Cu(CH3CN)4ClO4
Cu(CH3CN)4ClO4
Cu(CH3CN)4ClO4
Cu(CH3CN)4ClO4
AgOAc
Et3N
Et3N
Et3N
Et3N
Et3N
DBU
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
85
47
76
83
84
30
83
78
28
37
5
9
55
10
69
64
69
AgOTf
Cu(OTf)2
Zn(OTf)2
54
Trace
Trace
10
11
a Isolated yields.
b Determined by chiral HPLC.
the base afforded endo-3a in 78% and 54% yields as well as
64% and 69% ee, respectively, in CH2Cl2 at 0 ꢁC in the
presence of L1 (5.5 mol %) (Table 1, entries 8 and 9). It
should be noted that copper salts, Cu(OTf)2 and Zn(OTf)2,
did not catalyze this reaction under the standard conditions
(Table 1, entries 10 and 11). The best reaction conditions
are to carry out the reaction in CH2Cl2 using Cu(CH3CN)4-
ClO4 (5 mol %) as a catalyst and iPr2NEt (10 mol %) as the
base in the presence of L1 (5.5 mol %). In this reaction,
iPr2NEt acts as a base to generate the azomethine ylide.2e
The possible transition state of this reaction has been
provided in Figure 2. We believe that diphenylthiophos-
phoramide ligand L1 is an (S,S)-bidentate ligand to the
Cu center and its steric effect played a very important role
for achieving higher ee.
slightly improved the ee of 3a to 74%, although no
improvement could be realized at ꢀ10 ꢁC and ꢀ25 ꢁC (Ta-
ble 2, entries 1–3). Other chiral thiophosphoramide ligands
L2, L4–L6 and chiral diphenylselenophosphoramide ligand
L3 produced endo-3a in lower enantioselectivities under the
standard conditions and no enantioselectivity could be ob-
served if using L4 as a chiral ligand (Table 2, entries 4–8).
Therefore, L1 is the best chiral ligand in this reaction.
The generality of this Cu(CH3CN)4ClO4/L1-catalyzed
enantioselective 1,3-dipolar cycloaddition reaction was
examined using a variety of imines and 1-methylpyrrole-
2,5-dione, 1-benzylpyrrole-2,5-dione, and 1-phenylpyr-
role-2,5-dione. The results are summarized in Table 3. All
reactions proceeded smoothly to give the corresponding
products 3 in good yields and moderate ee under the opti-
mal conditions (Table 3). As for imine 1 bearing an elec-
tron-donating methyl group on the benzene ring or
having no substituent on the benzene ring, the correspond-
With the optimized conditions in hand, we next examined
the temperature effects on this reaction. As can be seen in
Table 2, lowering the reaction temperature to ꢀ40 ꢁC

M. Shi, J.-W. Shi / Tetrahedron: Asymmetry 18 (2007) 645–650
647
O
N
Ph
O
Ph
N
R
R
Ph2
Ph2
O
O
H
N
H
N
P
P
Ph
Ph
+
Ph
Ph
S
+
S
N
N
-
-
Cu
Cu
S
P
Ph2
OMe
S
P
OMe
O
O
N
N
H
H Ph2
L1
Figure 2.
Table 2. Optimization of the reaction conditions in the 1,3-dipolar cycloaddition of azomethine ylides (from imines) and 1-phenylpyrrole-2,5-dione
Ph
O
N
O
O
Ligand (5.5 mol%),
Lewis acid (5 mol%)
N
CO2Me
N
Ph
+
iPr2NEt (10 mol%),
CH2Cl2, 24 h
CO2Me
Cl
N
H
Cl
O
endo-3a
Entry
Ligand
Lewis acid
Temperature (ꢁC)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
L1
L1
L1
L2
L3
L4
L5
L6
Cu(CH3CN)4ClO4
Cu(CH3CN)4ClO4
Cu(CH3CN)4ClO4
Cu(CH3CN)4ClO4
Cu(CH3CN)4ClO4
Cu(CH3CN)4ClO4
Cu(CH3CN)4ClO4
Cu(CH3CN)4ClO4
ꢀ10
ꢀ25
ꢀ40
0
81
78
82
87
65
48
86
90
65
63
74
48
47
0
0
0
0
0
7
17
a Isolated yields.
b Determined by chiral HPLC.
Table 3. Enantioselective 1,3-dipolar cycloaddition of azomethine ylides (from imines) and 1-phenylpyrrole-2,5-dione catalyzed by Cu(CH3CN)4ClO4 in
the presence of L1
R3
O
Ligand L1 (5.5 mol%),
Cu(CH3CN)4ClO4 (5 mol%)
N
O
O
N
CO2R2
N R3
+
iPr2NEt (10 mol%), CH2Cl2, -40 oC
CO2R2
R1
N
H
O
R1
1
2
endo-3
Entry
R1
R2
R3
Product
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
p-Cl
p-Br
o-Cl
H
p-Me
p-Cl
m-Br
H
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Benzyl
3a
3b
3c
3d
3e
3f
82
85
82
89
76
72
60
77
86
83
74
58
57
47
26
62
52
79
77
68
3g
3h
3i
p-Cl
p-Cl
10
3j
a Isolated yields.
b Determined by chiral HPLC.
ing 1,3-dipolar cycloaddition adducts 3e and 3f were ob-
and 5). In other cases, 1,3-dipolar cycloaddition adducts
tained in 47% and 26% ee, respectively (Table 3, entries 4
3 were formed in 55–77% ee (Table 3, entries 1–3, 6, and

648
M. Shi, J.-W. Shi / Tetrahedron: Asymmetry 18 (2007) 645–650
7). Using either 1-methylpyrrole-2,5-dione or 1-benzylpyr-
role-2,5-dione as the substrate, the corresponding 1,3-dipo-
lar cycloaddition adducts 3 were obtained in similar
enantioselectivities (Table 3, entries 8–10).
CH2Cl2 (25 mL) was added Et3N (3.4 mL, 23.9 mmol).
The mixture was stirred at room temperature for 1 h, then
the corresponding aldehyde (20.0 mmol) was added. The
reaction was stirred at room temperature overnight, and
then the resulting precipitate was removed by filtration.
The filtrate was washed with water (15 mL), the aqueous
phase was extracted with CH2Cl2 (10 mL) and the com-
bined organic phases were washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The
resulting pure imino esters were used in 1,3-dipolar cyclo-
additions without further purification.
3. Conclusion
In conclusion, chiral C2-symmetric diphenylthiophosphor-
amide L1, prepared from C2-symmetric (1S,2S)-(ꢀ)-1,2-
diphenylethylenediamine, has been found to be a fairly
effective chiral ligand for Cu(I)-promoted 1,3-dipolar
cycloaddition of imines and pyrrole-2,5-dione derivatives
to give the corresponding adducts in moderate enantio-
selectivities. These results will allow us to design and syn-
thesize new effective sulfur-containing chiral ligands for
this interesting asymmetric 1,3-dipolar cycloaddition reac-
tion. Efforts are currently underway to elucidate the mech-
anistic details of this asymmetric 1,3-dipolar cycloaddition
reaction and to disclose the exact structure of the active
species in this catalytic system.
4.3. General procedure for the preparation of chiral diphen-
ylthiophosphoramides and diphenylselenophosphoramides
L1–L6
To a solution of (1S,2S)-(ꢀ)-1,2-diphenylethylenediamine
(212 mg, 1.0 mmol) and triethylamine (303 mg, 3.0 mmol,
0.42 mL) in dichloromethane (20 mL) was added diphenyl-
thiophosphinic chloride (504 mg, 2.0 mmol) at 0 ꢁC. After
stirring the reaction mixture for 10 h, the solvent was
removed under reduced pressure. The crude product was
extracted with ether and washed with water (3 · 50 mL),
10% Na2CO3 (50 mL), and brine. The organic layer was
dried over anhydrous Na2SO4 and then evaporated under
reduced pressure. The residue was recrystallized from
dichloromethane and hexane (4:1) to give L1 as colorless
crystals (534 mg, 86%).
4. Experimental
4.1. General methods
Melting points were measured with a Yanagimoto micro
melting point apparatus and are uncorrected. Optical
rotations were determined in a solution of CHCl3 at
20 ꢁC by using a Perkin–Elmer-241 MC polarimeter;
4.3.1. Ligand L1. This is a known compound.3a Yield:
(534 mg, 86%). White solid. Mp: 230.0–230.3 ꢁC. 1H
NMR (300 MHz, CDCl3, TMS) d 4.45–4.55 (m, 2H),
5.65–5.69 (m, 2H), 6.87 (d, J = 7.8 Hz, 4H), 7.03–7.15
(m, 10H), 7.26–7.29 (m, 2H), 7.40–7.46 (m, 4H), 7.50–
7.52 (m, 2H), 7.60–7.66 (m, 4H), 7.83–7.90 (m, 4H); 31P
[a]D-values are given in units of 10ꢀ1 deg cm2 gꢀ1 1H
.
NMR spectra were recorded on a Bruker AM-300 spec-
trometer for solution in CDCl3 with tetramethylsilane
(TMS) as the internal standard; J-values are given in
Hz. Mass spectra were recorded with a HP-5989 instru-
ment and HRMS was measured by a Finnigan MA+ mass
spectrometer. The organic solvents used were dried by
standard methods when necessary. All solid compounds
reported in this paper gave satisfactory CHN microanaly-
ses with an Italian Carlo-Erba 1106 analyzer. Commer-
cially obtained reagents were used without further
purification. All reactions were monitored by TLC with
Huanghai 60F254 silica gel coated plates. Flash column
chromatography was carried out using 300–400 mesh sil-
ica gel at increased pressure. All 1,3-dipolar cycloaddition
reactions were performed under argon using standard
Schlenk techniques. Enantiomeric excesses of sec-alcohols
were determined by HPLC analysis using a chiral station-
ary phase column (column, Daicel Co. Chiralcel AD, AS,
and OD) and the absolute configuration of the major
enantiomer was assigned according to the sign of the
specific rotation. Diphenylthiophosphinic and diphenyl-
selenophosphinic chlorides were prepared upon heating
chlorodiphenylphosphine with selenium at 120 ꢁC for
6 h. 1-Phenylpyrrole-2,5-dione 2a was synthesized accord-
ing to the literature procedures.5
NMR (CDCl3, 121 MHz, 85% H3PO4)
½aꢁD ¼ þ92:7 (c 0.94, CH2Cl2).
d
+66.0;
20
4.3.2. Ligand L2. This is a known compound.3b Yield:
(475 mg, 89%). White solid. Mp: 139.9–140.0 ꢁC; 1H
NMR (CDCl3, TMS, 300 MHz) d 1.05–1.60 (6H), 1.80–
1.87 (m, 2H), 3.26–3.36 (m, 2H), 4.00–4.04 (m, 2H),
7.31–7.37 (m, 4H), 7.44–7.51 (m, 8H), 7.76–7.83 (m, 4H),
20
8.02–8.09 (m, 4H); ½aꢁD ¼ þ20:8 (c 1.28, CH2Cl2).
4.3.3. Ligand L3. This is a known compound.3c Yield:
(644 mg, 87%). White solid. Mp: 170–172 ꢁC; 1H NMR
(CDCl3, TMS, 300 MHz) d 4.55–4.69 (m, 2H), 5.62–5.67
(m, 2H), 6.89 (d, J = 7.8 Hz, 4H), 7.02–7.12 (m, 10H),
7.22–7.27 (m, 2H), 7.40–7.46 (m, 4H), 7.49–7.52 (m, 2H),
20
7.57–7.64 (m, 4H), 7.87–7.94 (m, 4H); ½aꢁD ¼ þ117:2 (c
1.17, CH2Cl2).
4.3.4. Ligand L4. Yield: (495 mg, 70%). White solid. Mp:
130.0–130.1 ꢁC; 1H NMR (CDCl3, TMS, 300 MHz) d
4.27–4.34 (m, 2H), 4.90–4.98 (m, 2H), 6.89–6.92 (m, 4H),
6.95–6.98 (m, 4H), 7.05–7.29 (m, 22H); 13C NMR (CDCl3,
TMS, 75 MHz) d 61.6 (d, JC–P = 7.5 Hz), 121.03, 121.09,
121.15, 121.2, 125.06, 125.08, 125.22, 125.24, 127.98,
128.02, 128.3, 129.32, 129.34, 129.49, 129.51, 138.5 (d,
4.2. General procedure for the synthesis of a-imino esters
To a suspension of the corresponding amino acid ester
hydrochloride (23.9 mmol) and MgSO4 (25.0 mmol) in
JC–P = 3.5 Hz), 150.6 (d, JC–P = 7.5 Hz), 150.8 (d, JC–P
=
8.0 Hz); 31P NMR (CDCl3, 121 MHz, 85% H3PO4) d

M. Shi, J.-W. Shi / Tetrahedron: Asymmetry 18 (2007) 645–650
649
+63.5; IR (CHCl3) m 1590, 1489, 1455, 1188, 918 cmꢀ1
;
4.6. (1S,3R,3aS,6aR)-Methyl-4,6-dioxo-3-(p-bromophenyl)-
5-phenyl-octahydropyrrole[3,4-c]pyrrole-1-carboxylate
endo-3b
HRMS(ESI) calcd for C38H35N2O4P2S2 (M+H+):
20
709.1514, found: 709.1513. ½aꢁD ¼ ꢀ47:8 (c 0.86, CH2Cl2).
A white solid. Mp: 175.6–176.7 ꢁC; 1H NMR (CDCl3,
TMS, 300 MHz) d 2.47–2.50 (m, 1H), 3.56 (t, J = 8.4 Hz,
1H), 3.75 (t, J = 7.2 Hz, 1H), 3.87 (s, 3H), 4.11–4.16 (m,
1H), 4.56 (dd, J = 4.8, 8.4 Hz, 1H), 7.12–7.15 (m, 2H),
7.31–7.50 (m, 7H); 13C NMR (CDCl3, TMS, 75 MHz) d
47.9, 49.0, 52.3, 61.7, 63.3, 122.2, 126.0, 128.6, 128.8,
129.1, 131.4, 131.5, 135.8, 169.9, 173.5, 174.9; IR (CH2Cl2)
m 3333, 2948, 2837, 1747, 1713, 1489, 1381, 1206,
1010 cmꢀ1; MS (ESI) m/z: 451 [M+Na+]. Anal. Calcd for
4.3.5. Ligand L5. Yield: (412 mg, 80%). White solid. Mp:
70.2–70.9 ꢁC; 1H NMR (CDCl3, TMS, 300 MHz) d 1.02 (t,
J = 6.9 Hz, 6H), 1.26 (t, J = 6.9 Hz, 6H), 3.53–3.64 (m,
2H), 3.86–4.02 (m, 8H), 4.44–4.55 (m, 2H), 6.95–6.98 (m,
4H), 7.18–7.28 (m, 6H); 13C NMR (CDCl3, TMS,
75 MHz) d 15.4 (d, JC–P = 9.2 Hz), 15.8 (d, JC–P
=
8.6 Hz), 61.1 (d, JC–P = 6.8 Hz), 62.9 (d, JC–P = 4.7 Hz),
63.1 (d, JC–P = 5.2 Hz), 127.51, 127.55, 128.0, 139.3 (d,
JC–P = 2.7 Hz); 31P NMR (CDCl3, 121 MHz, 85%
H3PO4) d +71.6; IR (CH2Cl2) m 2970, 2839, 1738, 1454,
1376, 1167, 972 cmꢀ1; HRMS(ESI) calcd for C22H35-
C20H17BrN2O4 requires: C, 55.96; H, 3.99; N, 6.53. Found:
20
C, 56.66; H, 3.64; N, 6.25. ½aꢁD ¼ þ76:4 (c 1.07, CH2Cl2),
for 58% ee; Chiralcel AD-H, hexane/iPrOH = 50:50,
0.7 mL/min, 230 nm, tminor = 12.14 min, tmajor = 24.24 min.
N2O4P2S2 (M+H+): 517.1514, found: 517.1515.
20
½aꢁD ¼ ꢀ18:8 (c 1.16, CH2Cl2).
4.7. (1S,3R,3aS,6aR)-Methyl-4,6-dioxo-3-(o-chlorophenyl)-
5-phenyl-octahydropyrrole[3,4-c]pyrrole-1-carboxylate
endo-3c
4.3.6. Ligand L6. Yield: (352 mg, 78%). White solid. Mp:
1
154.7–155.8 ꢁC; H NMR (CDCl3, TMS, 300 MHz) d 0.76
(dt, J = 7.5, 20.1 Hz, 6H), 1.31 (dt, J = 7.5, 19.5 Hz, 6H),
1.59–1.71 (m, 4H), 2.09–2.21 (m, 4H), 4.41–4.49 (m, 2H),
4.76–4.80 (m, 2H), 6.93–6.97 (m, 4H), 7.11–7.13 (m, 6H);
A white solid. Mp: 153.0–154.8 ꢁC; 1H NMR (CDCl3,
TMS, 300 MHz) d 2.41–2.44 (m, 1H), 3.75 (t, J = 7.2 Hz,
1H), 3.84–3.90 (m, 4H), 4.18 (dd, J = 4.8, 6.3 Hz, 1H),
4.88 (dd, J = 4.8, 8.1 Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H),
7.25–7.43 (m, 6H), 7.67–7.70 (m, 1H); 13C NMR (CDCl3,
TMS, 75 MHz) d 46.5, 47.7, 52.3, 60.5, 61.4, 126.0, 126.9,
127.2, 128.4, 128.9, 129.2, 131.5, 133.3, 134.9, 144.9,
170.0, 173.3, 175.1; IR (CH2Cl2) m 3333, 1748, 1713,
13C NMR (CDCl3, TMS, 75 MHz) d 6.8 (d, JC–P
=
3.2 Hz), 6.9 (d, JC–P = 4.4 Hz), 24.0 (d, JC–P = 6–5.1 Hz),
27.2 (d, JC–P = 68.4 Hz), 60.7 (d, JC–P = 5.1 Hz), 127.1,
127.7, 127.9, 141.3 (d, JC–P = 3.8 Hz); 31P NMR (CDCl3,
121 MHz, 85% H3PO4) d +82.0; IR (CHCl3) m 2970,
2841, 1738, 1455, 1376, 1167, 973 cmꢀ1; HRMS(ESI) calcd
1500, 1383, 1206 cmꢀ1
;
HRMS (ESI) calcd for
for C22H35N2P2S2 (M+H+): 453.1717, found: 453.1714.
C20H17ClN2O4 (M+Na+): 407.0775, found: 407.0770.
20
½aꢁD ¼ þ76:5 (c 0.87, CH2Cl2).
20
½aꢁD ¼ þ42:2 (c 0.83, CH2Cl2) for 57% ee; Chiralcel AD-
H, hexane/iPrOH = 50:50, 0.7 mL/min, 230 nm, tmajor
11.93 min, tminor = 30.13 min.
=
4.4. Typical reaction procedure
4.8. (1S,3R,3aS,6aR)-Methyl-4,6-dioxo-3,5-diphenyl-octa-
hydropyrrole[3,4-c]pyrrole-1-carboxylate endo-3d
The catalyst was prepared by stirring Cu(CH3CN)4ClO4
(4.9 mg, 0.015 mmol, 5 mol %) and ligand L1 (11.9 mg,
0.0165 mmol, 5.5 mol %) in CH2Cl2 (2 mL) for 1 h at room
temperature. The reaction mixture was then cooled to
ꢀ40 ꢁC, after which imine substrate 1 (0.30 mmol), 1-phen-
ylpyrrole-2,5-dione 2 (0.45 mmol, 1.5 equiv) and base
(0.03 mmol, 10 mol %) were subsequently added and the
resulting mixture was stirred at ꢀ40 ꢁC for 24 h. When
the reaction was complete, as monitored by TLC, the cor-
responding pure adduct was purified by column chroma-
tography on silica gel (petroleum ether/ethyl acetate/1%
triethylamine).
This is a known compound.4 A white solid. Mp: 178.2–
1
180.5 ꢁC; H NMR (CDCl3, TMS, 300 MHz) d 2.51–2.54
(m, 1H), 3.57 (t, J = 8.4 Hz, 1H), 3.73 (t, J = 7.2 Hz,
1H), 3.87 (s, 3H), 4.12–4.16 (m, 1H), 4.61 (dd, J = 5.1,
8.4 Hz, 1H), 7.14 (d, J = 7.2 Hz, 2H), 7.29–7.47 (m, 8H);
20
½aꢁD ¼ þ44:1 (c 0.73, CH2Cl2) for 47% ee; Chiralcel AD-
H, hexane/iPrOH = 50:50, 0.7 mL/min, 230 nm, tminor
13.79 min, tmajor = 22.21 min.
=
4.9. (1S,3R,3aS,6aR)-Methyl-4,6-dioxo-3-(p-methylphenyl)-
5-phenyl-octahydropyrrole[3,4-c]pyrrole-1-carboxylate
endo-3e
4.5. (1S,3R,3aS,6aR)-Methyl-4,6-dioxo-3-(p-chlorophenyl)-
5-phenyl-octahydropyrrole[3,4-c]pyrrole-1-carboxylate
endo-3a
A white solid. Mp: 176.9–177.5 ꢁC; 1H NMR (CDCl3,
TMS, 300 MHz) d 2.33 (s, 3H), 2.49 (br, 1H), 3.54 (t,
J = 8.4 Hz, 1H), 3.72 (t, J = 7.2 Hz, 1H), 3.87 (s, 3H),
4.11–4.15 (m, 1H), 4.58 (dd, J = 4.8, 8.7 Hz, 1H), 7.14–
7.18 (m, 4H), 7.29–7.42 (m, 5H); 13C NMR (CDCl3,
TMS, 75 MHz) d 21.2, 48.3, 49.3, 52.3, 61.8, 64.1, 126.1,
126.9, 128.4, 129.0, 129.2, 131.5, 133.5, 138.0, 170.1,
173.7, 175.2; IR (CH2Cl2) m 3333, 2956, 2844, 1748, 1714,
1500, 1382, 1206 cmꢀ1; MS (ESI) m/z: 387 [M+Na+]. Anal.
Calcd for C21H20N2O4 requires: C, 69.22; H, 5.53, N,
This is a known compound.6 A white solid. Mp: 140.7–
1
148.9 ꢁC; H NMR (CDCl3, TMS, 300 MHz) d 2.48–2.50
(m, 1H), 3.56 (t, J = 8.1 Hz, 1H), 3.74 (t, J = 7.2 Hz,
1H), 3.87 (s, 3H), 4.14 (dd, J = 4.8, 6.6 Hz, 1H), 4.58
(dd, J = 4.8, 7.8 Hz, 1H), 7.14 (d, J = 7.8 Hz, 2H), 7.31–
20
7.43 (m, 7H); ½aꢁD ¼ þ91:5 (c 0.80, CH2Cl2) for 74% ee;
Chiralcel AS-H, hexane/iPrOH = 50:50, 1.5 mL/min, 220
nm, tmajor = 8.33 min, tminor = 30.61 min.

650
M. Shi, J.-W. Shi / Tetrahedron: Asymmetry 18 (2007) 645–650
20
7.28%. Found: C, 69.13; H, 5.29, N, 7.49. ½aꢁD ¼ þ42:2 (c
0.83, CH2Cl2), for 26% ee; Chiralcel AD-H, hexane/
iPrOH = 50:50, 0.7 mL/min, 230 nm, tminor = 14.09 min,
tmajor = 30.21 min.
3.98 (d, J = 6.6 Hz, 1H), 4.40 (d, J = 8.7 Hz, 1H), 7.20–
7.27 (m, 4H); 13C NMR (CDCl3, TMS, 75 MHz) d 25.0,
47.8, 49.1, 52.3, 61.4, 63.1, 128.4, 128.6, 133.9, 135.2,
170.0, 174.5, 175.8; IR (CH2Cl2) m 3341, 2933, 1749,
1698, 1437, 1215 cmꢀ1; MS (ESI) m/z: 345 [M+Na+]. Anal.
4.10. (1S,3R,3aS,6aR)-Ethyl-4,6-dioxo-3-(p-chlorophenyl)-
5-phenyl-octahydropyrrole[3,4-c]pyrrole-1-carboxylate
endo-3f
Calcd for C15H15ClN2O4 requires: C, 55.82; H, 4.68; N,
20
8.68. Found: C, 55.73; H, 4.53; N, 8.54. ½aꢁD ¼ þ86:2 (c
0.75, CH2Cl2) for 77% ee; Chiralcel AS-H, hexane/
iPrOH = 50:50, 1.5 mL/min, 220 nm, tmajor = 7.40 min,
tminor = 35.47 min.
1
A white solid. Mp: 75.7–76.9 ꢁC; H NMR (CDCl3, TMS,
300 MHz) d 1.37 (t, J = 7.2 Hz, 1H), 2.48–2.50 (m, 1H),
3.56 (t, J = 8.1 Hz, 1H), 3.74 (t, J = 7.5 Hz, 1H), 4.12
(dd, J = 4.8, 6.3 Hz, 1H), 4.30–4.38 (m, 2H), 4.57 (dd,
J = 4.8, 6.0 Hz, 1H), 7.14 (d, J = 8.1 Hz, 2H), 7.31–7.42
(m, 7H); 13C NMR (CDCl3, TMS, 75 MHz) d 14.1, 47.9,
49.2, 61.5, 61.9, 63.4, 126.0, 128.4, 128.56, 128.63, 129.1,
131.4, 134.0, 135.2, 169.4, 169.8, 173.5, 174.8; IR (CH2Cl2)
m 3336, 2983, 2844, 1716, 1597, 1492, 1381, 1205 cmꢀ1; MS
(ESI) m/z: 421 [M+Na+]. Anal. Calcd for C21H19ClN2O4
4.14. (1S,3R,3aS,6aR)-Methyl-4,6-dioxo-3-(p-chlorophen-
yl)-5-benzyl-octahydropyrrole[3,4-c]pyrrole-1-carboxylate
endo-3j
A white solid. Mp: 155.4–155.7 ꢁC; 1H NMR (CDCl3,
TMS, 300 MHz) d 2.29 (br, 1H), 3.37 (t, J = 8.1 Hz, 1H),
3.56 (t, J = 7.2 Hz, 1H), 3.88 (s, 3H), 4.04 (d, J = 7.2 Hz,
1H), 4.41–4.61 (m, 3H), 7.04–7.17 (m, 4H), 7.31 (s, 5H);
13C NMR (CDCl3, TMS, 75 MHz) d 42.6, 47.9, 49.0,
52.3, 61.6, 63.3, 127.9, 128.42, 128.44, 128.5, 129.0, 133.7,
134.9, 135.5, 169.9, 174.1, 175.4; IR (CH2Cl2) m 3348,
2956, 5852, 1749, 1704, 1398, 1207 cmꢀ1; MS (ESI) m/z:
421 [M+Na+]. Anal. Calcd for C21H19ClN2O4 requires:
requires: C, 63.24; H, 4.80; N, 7.02. Found: C, 63.42; H,
20
4.55; N, 6.94. ½aꢁD ¼ þ111:5 (c 1.08, CH2Cl2) for 62% ee;
Chiralcel OD-H, hexane/iPrOH = 50:50, 0.7 mL/min,
230 nm, tmajor = 18.93 min, tminor = 26.58 min.
4.11. (1S,3R,3aS,6aR)-Methyl-4,6-dioxo-3-(m-bromophen-
yl)-5-phenyl-octahydropyrrole[3,4-c]pyrrole-1-carboxylate
endo-3g
C, 63.24; H, 4.80; N, 7.02. Found: C, 63.07, H, 4.68, N,
20
6.83. ½aꢁD ¼ þ69:5 (c 0.62, CH2Cl2), for 68% ee; Chiralcel
AS-H, hexane/iPrOH = 50:50, 1.5 mL/min, 220 nm,
tmajor = 7.04 min, tminor = 25.33 min.
A white solid. Mp: 157.2–157.3 ꢁC; 1H NMR (CDCl3,
TMS, 300 MHz) d 2.51 (br, 1H), 3.56 (t, J = 8.4 Hz, 1H),
3.74 (t, J = 6.9 Hz, 1H) 3.87 (s, 3H), 4.13 (dd, J = 4.5,
6.6 Hz, 1H), 4.57 (dd, J = 4.5, 9.0 Hz, 1H), 7.14–7.24 (m,
3H), 7.34–7.46 (m, 5H), 7.67 (s, 1H); 13C NMR (CDCl3,
TMS, 75 MHz) d 47.9, 49.0, 52.3, 61.6, 63.2, 122.7, 126.0,
126.1, 128.6, 129.1, 130.0, 131.4, 131.5, 139.3, 145.3,
169.8, 173.5, 174.9; IR (CH2Cl2) m 3337, 2948, 2837,
1747, 1713, 1500, 1382, 1206 cmꢀ1; MS (ESI) m/z: 451
[M+Na+]. Anal. Calcd for C20H17BrN2O4 requires: C,
Acknowledgments
Financial support from the Shanghai Municipal Commit-
tee of Science and Technology (04JC14083, 06XD14005),
the National Natural Science Foundation of China
(203900502, 20472096 and 20672127), and the Cheung
Kong Scholar Program is greatly appreciated.
55.96; H, 3.99; N, 6.53. Found: C, 56.05; H, 3.67; N,
References
20
6.36. ½aꢁD ¼ þ58:3 (c 0.80, CH2Cl2) for 52% ee; Chiralcel
OD-H, hexane/iPrOH = 50:50, 1 mL/min, 230 nm, tmajor
19.51 min, tminor = 36.26 min.
=
1. Zhang, W.; Shi, M. Synlett 2007, 19–30, and references cited
therein.
2. For recent reviews of 1,3-dipolar cycloaddition reactions of
´
azomethine ylides, see: (a) Najera, C.; Sansano, J. M. Curr.
4.12. (1S,3R,3aS,6aR)-Methyl-5-methyl-4,6-dioxo-3-phen-
yl-octahydropyrrole[3,4-c]pyrrole-1-carboxylate endo-3h
Org. Chem. 2003, 7, 1105–1150; (b) Synthetic Applications of
1,3-Dipolar Cycloaddition Chemistry Towards Heterocycles and
Natural Products; Padwa, A., Pearson, W. H., Eds.; Wiley:
New York, 2003; (c) Kanemasa, S. Synlett 2002, 1371–1387;
(d) Gothelf, K. V. In Cycloaddition Reactions in Organic
Synthesis; Kobayashi, S., Jørgensen, K. A., Eds.; Wiley-VCH:
This is a known compound.4 A white solid. Mp: 152.1–
1
153.7 ꢁC; H NMR (CDCl3, TMS, 300 MHz) d 2.42 (br,
1H), 2.88 (s, 3H), 3.43 (t, J = 8.4 Hz, 1H), 3.57 (t,
J = 7.2 Hz, 1H), 3.89 (s, 3H), 4.04–4.08 (m, 1H), 4.50
´
Weinheim, 2002; pp 211–245; (e) Najera, C.; Sansano, J. M.
Angew. Chem., Int. Ed. 2005, 44, 6272–6276.
20
(dd, J = 4.8, 8.7 Hz, 1H), 7.35 (s, 5H); ½aꢁD ¼ þ30:5 (c
3. (a) Shi, M.; Sui, W.-S. Tetrahedron: Asymmetry 1999, 10,
3319–3325; (b) Shi, M.; Wu, X.-F.; Rong, G. Chirality 2002,
14, 90–95; (c) Shi, M.; Sui, W.-S. Tetrahedron: Asymmetry
2000, 11, 835–841.
0.60, CH2Cl2) for 79% ee; Chiralcel AD-H, hexane/
iPrOH = 50:50, 0.7 mL/min, 220 nm, tmajor = 29.54 min,
tminor = 33.29 min.
4. The endo-configuration of 3a was determined by 1H NMR
4.13. (1S,3R,3aS,6aR)-Methyl-5-methyl-4,6-dioxo-3-(p-
chlorophenyl)-octahydropyrrole[3,4-c]pyrrole-1-carboxylate
endo-3i
´
spectroscopic data reported in Cabrera, S.; Arrayas, R. G.;
Carretero, J. C. J. Am. Chem. Soc. 2005, 127, 16394–16395.
5. Yoshitake, Y.; Misaka, J.; Setoguchi, K.; Abe, M.; Kawaji, T.;
Eto, M.; Harano, K. J. Chem. Soc., Perkin Trans. 2 2002,
1611–1619.
6. Oderaotoshi, Y.; Cheng, W.-J.; Fujitomi, S.; Kasano, Y.;
Minakata, S.; Komatsu, M. Org. Lett. 2003, 5, 5043–5046.
A white solid. Mp: 210.7–211.1 ꢁC; 1H NMR (CDCl3,
TMS, 300 MHz) d 2.32 (br, 1H), 2.81 (s, 3H), 3.35 (t,
J = 8.1 Hz, 1H), 3.50 (t, J = 7.2 Hz, 1H), 3.81 (s, 3H),