Axially chiral BINIM and Ni(II)-catalyzed highly enantioselective 1,3-dipolar cycloaddition reactions of azomethine ylides and N-arylmaleimides

Article abstract of DOI:10.1021/jo701561d

(Chemical Equation Presented) Axially chiral BINIM-Ni(II) complexes are effective catalysts in the asymmetric 1,3-dipolar cycloaddition reactions of azomethine ylides and N-arylmaleimides to give the corresponding adducts in good yields and up to 95% enan

Full text of DOI:10.1021/jo701561d

derivatives are the key units or building blocks in many
pharmaceuticals, biologically active natural products including
alkaloids, and organocatalysts in organic synthesis,3 a catalytic
asymmetric version of this 1,3-dipolar cycloaddition reaction
has attracted much attention and has developed rapidly during
the past decade.4 Thus far, many laboratories have reported
catalytic asymmetric [3+2] cycloadditions with azomethine
ylides (from imines) by means of a variety of ligand-metal
combinations.5 For example, the asymmetric cycloaddition
reactions of imines derived from glycine with electron-deficient
alkenes in the presence of chiral Zn(II)/tBu-box (up to 89% yield
and 94% ee), Ag(I)/xylyl-FAP (up to 90% yield and 96% ee),
Ag(I)-quinap (up to 92% yield and 96% ee), Ag(I)-N,P ligands
(up to 98% yield and 98% ee), and Cu(II)-Fesulphos (up to
97% yield and 99% ee) have been reported by Jørgensen,5a,b
Zhang,5c,d Schreiber,5e Zhou,5f and Carretero.5g However, com-
pared to other types of catalytic asymmetric 1,3-dipolar cy-
cloadditions, the reaction catalyzed by chiral Ni(II) complexes
is still in its infancy especially for those involving azomethine
imines as 1,3-dipoles, which remains a great challenge for us
to study its scope and limitations. Recently, Suga and his co-
workers reported a chiral catalyst consisting of Ni(ClO4)2‚6H2O
and chiral binaphthyldiimine (BINIM) ligand, indicating high
levels of asymmetric induction in Diels-Alder reactions (up
to 94% yield and 94% ee as well as >99% yield and 96% ee),6a,b
Michael additions between 2-silyloxyfurans and 3-alkenoyl-2-
oxazolidinones (up to 95% yield and 97% ee),6c and 1,3-dipolar
cycloaddition of nitrones with 3-(2-alkenoyl)-2-thiazolidineth-
iones (up to 85% yield and 95% ee),7a,b as well as fused
azomethine imines and 3-acryloyl-2-oxazolidinone (up to 93%
yield and 97% ee).8 We envisaged that this catalytic system
might be useful in the 1,3-dipolar cycloaddition of N-metalated
azomethine ylides with N-arylmaleimides. Our interests in
developing the new chiral catalytic systems with axially chiral
binaphthalenediamine (BINAM) and binaphthalenediimine
Axially Chiral BINIM and Ni(II)-Catalyzed
Highly Enantioselective 1,3-Dipolar Cycloaddition
Reactions of Azomethine Ylides and
N-Arylmaleimides
Jing-Wen Shi,† Mei-Xin Zhao,† Zhi-Yu Lei,† and
Min Shi*,†,‡
School of Chemistry & Molecular Engineering, East China
UniVersity of Science and Technology, Laboratory for AdVanced
Materials and Institute of Fine Chemicals, 130 Mei Long Road,
Shanghai 200237, China, and State Key Laboratory of
Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, China
mshi@mail.sioc.ac.cn
ReceiVed July 18, 2007
Axially chiral BINIM-Ni(II) complexes are effective cata-
lysts in the asymmetric 1,3-dipolar cycloaddition reactions
of azomethine ylides and N-arylmaleimides to give the
corresponding adducts in good yields and up to 95%
enantiomeric excesses.
(3) (a) Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127,
3240. (b) Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2003, 125, 10808. (c) Pearson, W. H. In Studies in Natural
Products Chemistry; Atta-Ur-Rahman, Ed.; Elsevier: New York,1998; Vol.
I, pp 323-358. (d) Obst, U.; Betschmann, P.; Lerner, C.; Seiler, P.;
Diederich, F. HelV. Chim. Acta 2000, 83, 855.
The catalytic asymmetric 1,3-dipolar cycloaddition reaction
is one of the most useful methods for the construction of
optically active five-membered heterocycles.1 More importantly,
the reactions between azomethine ylides (from imines) and
activated alkenes afforded tetrasubstituted pyrrolidine or proline
derivatives in one step along with the four contiguous chiral
centers.2 Since it is well-known that pyrrolidine or proline
(4) (a) Saito, S.; Tsubogo, T.; Kobayashi, S. J. Am. Chem. Soc. 2007,
129, 5364. (b) Dogan, O¨ .; Koyuncu, H.; Garner, P.; Bulut, A.; Youngs, W.
J.; Panzner, M. Org. Lett. 2006, 8, 4687. (c) Zeng, W.; Chen, G.-Y.; Zhou,
Y.-G.; Li, Y.-X. J. Am. Chem. Soc. 2007, 129, 750. (d) Saito, S.; Tsubogo,
T.; Kobayashi, S. J. Am. Chem. Soc. 2007, 129, 5364. (e) Na´jera, C.;
Sansano, J. M. Angew. Chem., Int. Ed. 2005, 44, 6272. (f) Shi, M.; Shi, J.
W. Tetrahedron: Asymmetry 2007, 18, 645. (g) Na´jera, C.; de Gracia
Retamosa, M.; Sansano, J. M. Org. Lett. 2007, 9, 4025-4028.
(5) (a) Gothelf, A. S.; Gothelf, K. V.; Hazell, R. G.; Jøgensen, K. A.
Angew. Chem., Int. Ed. 2002, 41, 4236. (b) Alemparte, C.; Blay, G.;
Jørgensen, K. A. Org. Lett. 2005, 7, 4569. (c) Longmire, J. M.; Wang, B.;
Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400. (d) Gao, W.; Zhang, X.;
Raghunath, M. Org. Lett. 2005, 7, 4241. (e) Chen, C.; Li, X.; Schreiber, S.
L. J. Am. Chem. Soc. 2003, 125, 10174. (f) Zeng, W.; Zhou, Y. G. Org.
Lett. 2005, 7, 5055. (g) Carbrera, S.; Gomez, R.; Carretero, J. C. J. Am.
Chem. Soc. 2005, 127, 16394.
(6) (a) Suga, H.; Kakehi, A.; Mitsuda, M. Chem. Lett. 2002, 900. (b)
Suga, H.; Kakehi, A.; Mitsuda, M. Bull. Chem. Soc. Jpn. 2004, 77, 561.
(c) Suga, H.; Kitamura, T.; Kakehi, A.; Baba, T. Chem. Commun. 2004,
1414.
(7) (a) Suga, H.; Kakehi, A.; Ito, S.; Sugimoto, H. Bull. Chem. Soc. Jpn.
2003, 76, 327. (b) Suga, H.; Nakajima, T.; Itoh, K.; Kakehi, A. Org. Lett.
2005, 7, 1431.
* Address correspondence to this author. Fax: 86-21-64166128.
† East China University of Science and Technology.
‡ Shanghai Institute of Organic Chemistry.
(1) For recent reviews, see: (a) Gothelf, K. V. In Cycloaddition Reactions
in Organic Synthesis; Kobayashi, S., Jørgensen, K. A., Eds.; Wiley-VCH:
Weinheim, Germany, 2002; p 211. (b) Gothelf, K. V.; Jørgensen, K. A. In
Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward
Heterocycles and Natural Products; Padwa, A., Pearson, W., Eds.; Wiley
& Sons: New York, 2002; Chapter 12, p 817. (c) Kanemasa, S. Synlett
2002, 1371. (d) Pellissier, H. Tetrahedron 2007, 63, 3235.
(2) Recent reviews: (a) Husinec, S.; Savic, V. Tetrahedron: Asymmetry
2005, 16, 2047. (b) Harwood, L. M.; Vickers, R. J. In Synthetic Applications
of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural
Products; Padwa, A., Pearson, W., Eds.; Wiley & Sons: New York, 2002;
Chapter 3. (c) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. ReV. 2006,
106, 4484.
(8) Suga, H.; Funyu, A.; Kakehi, A. Org. Lett. 2007, 9, 97.
10.1021/jo701561d CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/05/2007
J. Org. Chem. 2008, 73, 305-308
305

FIGURE 1. Structures of chiral ligands.
TABLE 1. Optimization of the Reaction Conditions in the 1,3-Dipolar Cycloaddition of Azomethine Ylides (from Imines) and
N-Phenylmaleimide
entry
Lewis acid
CH3CO2Ag
Cu(CH3CN)4ClO4
Mg(ClO4)2
solvent
yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
53
41
22
4
2
9
Zn(OTf)2
Ni(ClO4)2‚6H2O
Ni(ClO4)2‚6H2O
Ni(ClO4)2‚6H2O
Ni(ClO4)2‚6H2O
78
66
30
trace
79
78
8
CH3CN
toluene
a Isolated yields. b Determined by chiral HPLC.
(BINIM),9,4f which can be easily prepared and handled in very
simple experimental procedures, for 1,3-dipolar cycloadditions
led us to undertake the current study. Herein we wish to report
our investigations on this subject.
The chiral binaphthalenediimine (BINIM) ligands L1-L3
were synthesized from the reaction of commercially available
(R)-1,1′-binaphthyl-2,2′-diamine (binaphthalenediamine, BI-
NAM) with a variety of aldehydes in the presence of 4 Å MS
in toluene, respectively.8,10 The ligands L411 and L512 were also
prepared from BINAM according to the previous literature
(Figure 1).
ing adduct endo-3a in 78% yield and 79% ee in CH2Cl2 (Table
1, entry 5). Other metal salts, such as CH3CO2Ag or Cu(CH3-
CN)4ClO4 and Mg(ClO4)2 (5 mol %), produced endo-3a in
moderate yields and lower enantioselectivities under the standard
conditions (Table 1, entries 1-3). No reaction occurred if using
Zn(OTf)2 as a Lewis acid under otherwise identical conditions
(Table 1, entry 4). Among the solvents examined, in CH3CN,
a more polar solvent, endo-3a, was formed in 30% yield along
with 8% ee, and when using toluene as the solvent, a trace of
endo-3a was observed (Table 1, entries 7 and 8). Although endo-
3a could be produced in comparable enantioselectivity (78%
ee) in THF, the isolated yield slightly decreased (Table 1, entry
6). Therefore, Ni(ClO4)2‚6H2O is the most effective Lewis acid
and dichloromethane is the solvent of choice in this reaction.
Initial examinations with imine 1a and N-phenylmaleimide
2a as the substrates in the presence of chiral BINIM ligand L1
i
(5.5 mol %), Pr2NEt (10 mol %), and various metal salts (5
mol %) at 0 °C were aimed at determining the optimal
conditions and the results of these experiments are summarized
in Table 1. As expected, Ni(ClO4)2‚6H2O was found to be a
fairly effective catalyst to promote 1,3-dipolar cycloaddition of
imine 1a and N-phenylmaleimide 2a, affording the correspond-
Having the partially optimized reaction conditions in hand,
we next carefully examined the temperature effect on this
reaction. No significant improvement could be realized at
-20 °C or under reflux in CH2Cl2 at 40 °C (Table 2, entries 1
and 4). However, to our delight, raising the temperature to
15 °C improved the yield of 3a to 84% along with 82% ee
(Table 2, entry 2).
(9) Zhang, W.; Shi, M. Synlett 2007, 19-30 and references cited therein.
(10) Colombo, F.; Benaglia, M.; Orlandi, S.; Usuelli, F.; Celentano, G.
J. Org. Chem. 2006, 71, 2064.
(11) Bernardo, K. D. S.; Robert, A.; Dahan, F.; Meunier, B. New J. Chem.
1995, 19, 129.
(12) Lin, J.; Che, C.; Lai, T.; Poon, C.; Cui, Y. J. Chem. Soc., Chem.
Commun. 1991, 7, 468.
To better understand the nature of the catalytic system and
to propose a possible transition state for the reaction, a few
experiments for comparison with the performance of the ligands
L2-L5 were carried out under the standard conditions. The
306 J. Org. Chem., Vol. 73, No. 1, 2008

TABLE 2. Optimization of the Reaction Conditions in the 1,3-Dipolar Cycloaddition of Azomethine Ylides (from Imines) and
N-Phenylmaleimide
entry
ligand
temp (°C)
yield (%)a
ee (%)b
1c
2
3
4
5
6
7
8
L1
L1
L1
L1
L2
L3
L4
L5
40
15
0
72
84
78
67
20
45
trace
trace
75
82
79
56
8
-20
0
0
0
0
2
a Isolated yields. b Determined by chiral HPLC. c Reaction time is 2 h.
FIGURE 2. Proposed mechanism for the enantioselectivity.
results are summarized in Table 2 (entries 5-8). As can be seen
from Table 2, the strong interaction of the nitrogen atoms in
imine moiety and pyridine seems to be very important in the
assembly of chiral ligand with nickel cation. For those ligands
without imine or pyridine structure, 3a could not be obtained
in satisfactory yields and enantioselectivities (Table 2, entries
6-8). However, to our surprise, BINIM ligand L2 bearing two
quinoline moieties also did not effectively catalyze the 1,3-
dipolar cycloaddition to give 3a in only 20% yield along with
8% ee presumably due to the steric hindrance, which blocks
out the approach of N-phenylmaleimide (Table 2, entry 5).
Therefore, the best reaction conditions is to carry out the reaction
with Ni(ClO4)2‚6H2O as a metal salt and L1 as a chiral ligand
in CH2Cl2 at 15 °C. The possible transition state of this highly
enantioselective 1,3-dipolar addition can be explained as the
approach of N-phenylmaleimide toward the hexacoordinated Ni-
(II) complex as illustrated in Figure 2.10
91% ee values (Table 3, entries 1, 2, and 4-9). By using other
N-arylmaleimides as the substrates, the corresponding 1,3-
dipolar cycloaddition adducts 3k-n were obtained in 73-83%
yields and 84-90% ee values (Table 3, entries 11-14).
In conclusion, chiral binaphthalenediimine (BINIM) ligand
L1, which can be readily prepared from commercially available
(R)-1,1′-binaphthyl-2,2′-diamine (BINAM) and 2-pyridinecar-
boxaldehyde, has been found to be an effective chiral ligand
for Ni(II)-promoted 1,3-dipolar cycloaddition of azomethine
ylides and N-arylmaleimides to give the corresponding adducts
in good to high yields and enantioselectivities. These results
will allow us to design and synthesize a new effective chiral
catalytic system for this interesting asymmetric 1,3-dipolar
cycloaddition reaction. Further investigations to explore other
diploes as well as azomethine ylides and dipolarophiles are
currently underway.
The generality of this Ni(ClO4)2‚6H2O/L1-catalyzed enanti-
oselective 1,3-dipolar cycloaddition reaction was examined by
using a variety of imines and several N-arylmaleimides. The
results are summarized in Table 3. All reactions proceeded
smoothly to give the corresponding products 3 in moderate to
good yields and good to high enantioselectivities under the
optimal conditions (Table 3). As for imine 1 bearing an electron-
donating methoxy group on the benzene ring, the corresponding
1,3-dipolar cycloaddition adduct 3c was obtained in 52% yield
and 72% ee (Table 3, entry 3). Higher enantioselectivity was
obtained in the reaction of imine 1j, derived from 1-naphthy-
laldehyde, with 2a to afford the adduct 3j in 90% yield and up
to 95% ee (Table 3, entry 10). In other cases, 1,3-dipolar
cycloaddition adducts 3 were formed in good yields and 82-
Experimental Section
Typical Reaction Procedure. The catalyst was prepared by
stirring Ni(ClO4)2‚6H2O (5.5 mg, 0.015 mmol, 5 mol %), powdered
4 Å MS (100 mg), and ligand L1 (7.6 mg, 0.0165 mmol, 5.5 mol
%) in CH2Cl2 (2.0 mL) for 1 h at room temperature. After imine
substrate 1 (0.30 mmol), N-phenylmaleimide 2 (0.45 mmol, 1.5
i
equiv),13 and Pr2NEt (0.03 mmol, 5.0 µL, 10 mol %) were added
subsequently to the catalyst suspension, the resulting mixture was
stirred at 15 °C for 24 h. When the reaction was complete as
monitored by TLC plates, and the corresponding crude adduct was
purified by column chromatography on silica gel [petroleum ether/
(13) Yoshitake, Y.; Misaka, J.; Setoguchi, K.; Abe, M.; Kawaji, T.; Eto,
M.; Harano, K. J. Chem. Soc., Perkin Trans. 2 2002, 1611.
J. Org. Chem, Vol. 73, No. 1, 2008 307

TABLE 3. Enantioselective 1,3-Dipolar Cycloaddition of Azomethine Ylides (from Imines) and N-Arylmaleimides Catalyzed by
Ni(ClO4)2‚6H2O in the Presence of L1
entry
R1
R2
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
p-Me (2b)
m-Cl (2c)
p-MeO (2d)
p-F (2e)
product
yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
p-Cl (1a)
p-Br (1b)
p-MeO (1c)
p-Me (1d)
o-Cl (1e)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
84
86
52
84
92
81
80
78
82
90
75
73
82
83
82
89
72
84
91
87
82
84
85
95
88
84
90
86
H (1f)
m-Br (1g)
p-F (1h)
o-Br (1i)
1-naphthyl (1j)
1-naphthyl (1j)
1-naphthyl (1j)
1-naphthyl (1j)
1-naphthyl (1j)
a Isolated yields. b Determined by chiral HPLC.
ethyl acetate (1% of triethylamine) ) 2:1] to give the pure product.
Since a trace of exo-adducts might be included in the products, in
some cases the 13C NMR spectra are not very clean.
pure imino esters were directly used in 1,3-dipolar cycloadditions
without further purification.
Acknowledgment. Financial support from the Shanghai
Municipal Committee of Science and Technology (04JC14083,
06XD14005), the National Natural Science Foundation of China
(203900502, 20472096, 20672127, and 20732008), and the
Cheung Kong Scholar Program is greatly appreciated.
General Procedure for the Synthesis of R-Imino Esters.4f To
a suspension of the corresponding amino acid ester hydrochloride
(23.9 mmol) and anhydrous MgSO4 (25.0 mmol) in 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 combined
organic phases were washed with brine, dried over anhydrous
MgSO4, and concentrated under reduced pressure. The resulting
Supporting Information Available: The 1,3-dipolar cycload-
dition procedures, spectroscopic data of adducts 3, and chiral HPLC
traces of the enantiomeric excesses of adducts 3. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO701561D
308 J. Org. Chem., Vol. 73, No. 1, 2008