Ag/ThioClickFerrophos catalyzed highly enantioselective 1,3-dipolar cycloaddition of azomethine ylides with alkenes

Article abstract of DOI:10.1016/j.tetlet.2010.07.085

A silver(I)/ThioClickFerrophos complex catalyzed the endo selective asymmetric 1,3-dipolar cycloaddition reaction of methyl N-benzylideneglycinate (the source of azomethine ylides) with α,β-unsaturated esters and maleimides to give the endo-2,4,5- and 2,3,4,5-substituted pyrrolidines in good yields with high enantioselectivities (up to 99% ee). The complex also effectively catalyzed the endo selective reactions with β-nitrostyrene to give the 4-nitropyrrolidine in a high enantioselectivity.

Full text of DOI:10.1016/j.tetlet.2010.07.085

Tetrahedron Letters 51 (2010) 5068–5070
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Ag/ThioClickFerrophos catalyzed highly enantioselective 1,3-dipolar
cycloaddition of azomethine ylides with alkenes
*
Kenta Shimizu, Kenichi Ogata, Shin-ichi Fukuzawa
Department of Applied Chemistry, Institute of Science and Engineering, Chuo University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 June 2010
Revised 9 July 2010
Accepted 16 July 2010
Available online 6 August 2010
A silver(I)/ThioClickFerrophos complex catalyzed the endo selective asymmetric 1,3-dipolar cycloaddition
reaction of methyl N-benzylideneglycinate (the source of azomethine ylides) with a,b-unsaturated esters
and maleimides to give the endo-2,4,5- and 2,3,4,5-substituted pyrrolidines in good yields with high
enantioselectivities (up to 99% ee). The complex also effectively catalyzed the endo selective reactions
with b-nitrostyrene to give the 4-nitropyrrolidine in a high enantioselectivity.
Ó 2010 Elsevier Ltd. All rights reserved.
1,3-Dipolar cycloaddition of azomethine ylide to electron-defi-
cient olefins yields chiral pyrrolidines, an important class of het-
erocyclic compounds with widespread applications to the
synthesis of biologically active compounds and natural products.1
These cycloaddition reactions represent an important class of syn-
thetic methods and have inspired much research interest in the
development of asymmetric catalytic variants. Elegant studies in
this field have often centered on chiral metal complex-catalyzed
asymmetric 1,3-dipolar additions with azomethine ylides, and
CuI and AgI/phosphine complexes often give moderate to excellent
levels of stereoselectivity with methyl N-benzylideneglycinate (the
source of azomethine ylides). Wang’s CuI or AgI/TF-BiphamPhos,2
Carretero’s CuI/Fesulphos,3 Zhang’s AgI/xylyl-FAP,4 Schreber’s AgI/
QUINAP,5 Zhou’s AgI/FPOX,6 and Sansano’s AgI/BINAP7 are the rep-
resentative effective chiral metal catalysts for the reaction. They
give either endo- or exo-diastereomer of proline derivatives with
good enantioselections (Fig. 1).
ous AgI salts (5 mol %), ligands (L1–L3) (5 mol %), and Et3N
(18 mol %).11 The endo to exo isomer ratio and enantiomeric excess
(ee) of the product were determined by 1H NMR and HPLC (Chir-
alpak AS-H), respectively. The reaction proceeded smoothly to give
a mixture of endo/exo cycloadducts. The results are summarized in
Table 1. Notably, the endo product was produced preferentially in
contrast to the previous CuI/L4 complex (entry 9).8 From the opti-
mization experiments, the combination of AgOAc and L3 (R = t-Bu)
was revealed to be the most effective catalyst for the reaction. Fur-
ther, the ee could be improved up to 98% ee by carrying out the
reaction in CH2Cl2 at 0 °C although the yield was decreased to some
extent. Then, we concluded the optimal catalyst, solvents, and the
reaction conditions are AgOAc/L3 and CH2Cl2, 0 °C for 24 h, respec-
tively to obtain the endo-adduct in good diastereo- and enantiose-
lectivities. The combination of CuI salts with L3 resulted in a lower
enantioselectivity of endo-adduct (entry 10).
Next we examined the scope of the reaction with respect to azo-
methine ylide precursors (dipolars) 1 using 2a as an alkene (dipol-
arophile) under the optimized conditions. The results are
summarized in Table 2. High endo-selectivity (endo/exo = 98/2–
99/1) and high ee of endo-adducts (3a–h) were obtained virtually
independent of stereo and electronic properties of substituents;
electron-withdrawing (Cl, Br, CN), -donating (Me, OMe), and a po-
sition of methyl group (entries 4–6) almost did not affect on the
Recently, we reported a novel ClickFerrophos ligands (L4),
whose CuI complexes exhibited highly exo stereoselectivity and
excellent enantioselectivity in the asymmetric 1,3-dipolar cycload-
dition of azomethine ylides with a vinyl sulfone.8 We also suc-
ceeded in highly endo and enantioselective reaction with (E)-
acyclic and cyclic a
-enones by using AgI/ThioClickFerrophos com-
plexes (L1–L3).9 Extending the interest in the AgI/L1–L3-catalyzed
cycloaddition reaction with other dipolarophiles (alkenes), we
have found that it also worked effectively for
a,b-unsaturated es-
ters, amides, and b-nitrostyrene in high enantioselections.10
We initially focused on optimization of the enantioselective 1,3-
dipolar cycloaddition. Methyl N-(4-chlorobenzylidene)glycinate 1b
and methyl acrylate 2a were chosen as a dipolar (azomethine
ylide) and a dipolarophile, respectively. The model reaction was
carried out in toluene at room temperature for 12 h by using vari-
Me
Me
Fe
Ph2P
RS
Ph
Ph2P Fe
Ph2P
N
N
N
N
N
N
Ph
L-1: R = Et
L-2: R = Cy
L-3: R = t-Bu
L-4
* Corresponding author.
E-mail address: orgsynth@kc.chuo-u.ac.jp (S. Fukuzawa).
Figure 1. ClickFerrophos and ThioClickFerrophos.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.085

K. Shimizu et al. / Tetrahedron Letters 51 (2010) 5068–5070
5069
Table 1
Table 3
Optimization experiments of 1,3-dipolar reaction of azomethine ylide with methyl
The scope of the reaction with respect to dipolarophilesa
acrylate 2aa
Entry
Alkene
Product
Yieldb (%), endo/exoc
ee (%) (endo)d
CO2Me
MeO2C
1
2
3
4
5
6
7
2b
4
5
9
10
11
82, 98/2
79, 98/2
85, 94/6
86, 85/15
91, 98/2
93, 98/2
36, 65/35
96
94
91
95
99
86
91
2a
4-ClC6H4
N
CO2Me
4-ClC6H4
CO2Me
Ag(I)/Ligand
solvent, Et3N
N
H
6
12
1b
7a
7b
8
13a
13b
14
endo (major)
eec (%) (endo)
3b
Entry
Ag(I) salt
Ligand
Yieldb (%) endo/exoc
a
1
2
3
4
5
6
7
AgOAc
AgOTf
AgPF6
AgSbF6
AgOCOCF3
AgOAc
AgOAc
AgOAc
AgOAc
CuOAc
L1
L1
L1
L1
L1
L2
L3
L3
L4
L1
93, 98/2
87, 98/2
90, 98/2
91, 98/2
88, 98/2
74, 98/2
86, 98/2
78, 98/2
89, 30/70
71, 91/9
63
45
49
45
37
88
96
98
96
35
1b (0.2 mmol), dipolarophile (0.3 mmol), AgOAc (0.01 mmol), L3 (0.011 mmol),
CH2Cl2 (2.0 mL): 0 °C, 24 h.
b
Total isolated yield of endo-adduct.
c
Determined by 1H NMR.
d
Determined by HPLC.
8d
9e
10
Me
CO2Me
a
CO2R
MeO2C CO2Me
Methyl N-(p-chlorobenzylidene)glycinate (0.2 mmol), methyl acrylate
(0.3 mmol), Ag(I) salts (0.01 mmol), Et3N (0.036 mmol), ligand (0.011 mmol), tolu-
ene (2.0 mL); rt, 12 h.
2a: R = Me
4
5
2b: R = t-Bu
b
Isolated yield (endo).
Determined by HPLC (Chiralpak AS-H).
The reaction was carried out at 0 °C in CH2Cl2.
Ref. 8, ee % is for exo adduct.
c
d
e
ButO2C
Me
MeO2C
p-ClPh
CO2Me
CO2Me
CO2Me
MeO2C
p-ClPh
p-ClPh
MeO2C
CO2Me
N
H
N
H
N
H
Table 2
The scope of the reactions with respect to dipolesa
9
10
11
MeO2C
Ar
CO2Me
R
N
2a
Ph
Ar
N
CO2Me
O
CO2Me
O
N
H
AgOAc/L3
CO2Me
NO2
1
CH2Cl2, Et3N
endo (major)
3
6
7a: R = Me
7b: R = Ph
8
Entry
Dipole
Ar
Ph
Product and yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
3a, 71
3b, 78
3c, 91
3d, 81
3e, 84
3f, 78
3g, 91
3h, 57d
3i, 74
97
98
98
95
98
98
98
97
98
R
4-ClC6H4
N
O
O2N
Ph
O
MeO2C
p-ClPh
CO2Me
CO2Me
4-BrC6H4
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-MeOC6H4
4-CNC6H4
2-C8H9
p-ClPh
CO2Me
N
H
p-ClPh
CO2Me
N
N
H
H
12
13a: R = Me
13b: R = Ph
14
Ar = 4-ClC6H4
a
Dipole (0.2 mmol), methyl acrylate (0.3 mmol), AgOAc (0.01 mmol), L3
(0.011 mmol), CH2Cl2 (2.0 mL): 0 °C, 15–24 h.
Figure 2. Dipolarophiles and products.
b
Isolated yield of endo product.
ee of endo isomer (endo/exo = 98/2–99/1) was determined by HPLC.
c
d
endo/exo = 95/5.
(endo:exo = 98:2) and 99% ee (entry 5). Enantioselectivity was de-
creased by displacing N-methyl group by N-phenyl group 7b, ee
value being 86% (entry 6). The reaction with b-nitrostyrene gave
a low yield of the cycloadduct 14 as a mixture of diastereomers
(endo/exo = 65/35), yield and ee of endo isomer being 36% and
91% ee, respectively (entry 7).
enantioselectivity, although yield was low in the reaction with 1h
(Ar = 4-CNC6H4). The reaction with 2-naphthyl derivative 1i also
gave the high ee values as phenyl derivatives (entry 9).
Finally, we examined the scope of the reaction with respect to
alkenes (dipolarophiles) using 1b as an azomethine source. The re-
sults are outlined in Table 3. In the reaction with tert-butyl acrylate
2b, endo and enantioselectivities were almost the same as the reac-
tion with methyl acrylate (entry 1). In the reaction with methyl
methacrylate 4, endo-adduct 10 was produced regioselectively
with 94% ee (entry 2). It must be noteworthy that high enantiose-
lectivity was achieved by using AgI/L3 complex, while Oh and co-
workers reported that AgI/brucine-derivative complex affords the
adduct in 60% ee.12 In the reactions with dimethyl maleate 5 and
fumarate 6 the corresponding endo isomers 11 and 12 were ob-
tained, respectively (endo:exo = 98:2) with a high enantioselectivi-
ty (95% ee, entries 3–4). The reaction with N-methyl-maleimide
7a gave the endo-adduct 13a with high diastereoselectivity
In conclusion AgI/L3 complex-catalyzed asymmetric 1,3-dipo-
lar cycloaddition of azomethine ylide could be extended to
unsaturated esters, amides, and b-nitrostyrene in addition to
previous -enones. The reaction proceeded to give the endo
a,b-
a
cycloadduct predominantly with excellent enantioselectivities
(Fig. 2).
Acknowledgments
This study was financially supported by a Grant-in-Aid, No.
22550044, for the Scientific Research from the Japan Society for
the Promotion of Science (JSPS) and a Chuo University Grant for
Special Research.

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K. Shimizu et al. / Tetrahedron Letters 51 (2010) 5068–5070
Zhang, Y.; Zhang, K.; Hong, W.; Hou, X.-L.; Wu, Y.-D. Angew. Chem., Int. Ed. Engl.
References and notes
2006, 45, 1979–1983.
7. (a) Martín-Rodríguez, M.; Nájera, C.; Sansano, J. M.; Costa, P. R. R.; de Lima, E.
C.; Dias, A. G. Synlett 2010, 962–966; (b) Nájera, C.; de Gracia Retamosa, M.;
Sansano, J. M.; de Cózar, A.; Cossío, F. P. Tetrahedron: Asymmetry 2008, 19,
2913–2923; (c) Nájera, C.; de Gracia Retamosa, M.; Sansano, J. M. Org. Lett.
2007, 9, 4025–4028.
1. For reviews: (a) Chen, Q.-A.; Wang, D.-S.; Zhou, Y.-G. Chem. Commun. 2010, 46,
4043–4051; (b) Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108, 2887–2902; (c)
Pandey, G.; Banerjee, P.; Gadre, S. Chem. Rev. 2006, 106, 4484–4517; (d)
Husuinec, S.; Savic, V. Tetrahedron: Asymmetry 2005, 16, 2047–2061; (e) Nájera,
C.; Sansano, J. M. Angew. Chem., Int. Ed. 2005, 44, 6272–6276; (f) Mukherjee, S.;
Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471–5569; (g) Dalko, P.
I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138–5175.
2. (a) Xue, Z.-Y.; Liu, T.-L.; Lu, Z.; Huang, H.; Tao, H.-Y.; Wang, C.-J. Chem. Commun.
2010, 46, 1727–1729; (b) Wang, C.-J.; Xue, Z.-Y.; Liang, G.; Lu, Z. Chem.
Commun. 2009, 45, 2905–2907; (c) Liang, G.; Tong, M.-C.; Wang, C.-J. Adv. Synth.
Catal. 2009, 351, 3101–3106; (d) Wang, C.-J.; Liang, G.; Xue, Z.-Y.; Gao, F. J. Am.
Chem. Soc. 2008, 130, 17250–17251.
3. (a) Hernández-Torbio, J.; Arrayás, R. G.; Martín-Mature, B.; Carretero, J. C. Org.
Lett. 2009, 11, 393–396; (b) López-Pérez, A.; Adrio, J.; Carretero, J. C. Angew.
Chem., Int. Ed. 2009, 48, 340–343; (c) López-Pérez, A.; Adrio, J.; Carretero, J. C. J.
Am. Chem. Soc. 2008, 130, 10084–10085; (d) Llamas, T.; Ramón Gómez, A.;
Carretero, J. C. Synthesis 2007, 950–956; (e) Cabrera, S.; Gómez Arrayás, R.;
Martín-Matute, B.; Cossío, F. P.; Carretero, J. C. Tetrahedron 2007, 63, 6587–
6602; (f) Cabrera, S.; Gómez Arrayás, R.; Carretero, J. C. J. Am. Chem. Soc. 2005,
127, 16394–16395.
4. Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400–13401.
5. Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc. 2003, 125, 10174–10175.
6. (a) Zeng, W.; Zhou, Y.-G. Org. Lett. 2005, 7, 5055–5058; Similar
ferrocenyloxazoline type ligand/Cu complex has been reported (b) Gao, W.;
Zhang, X.; Raghunath, M. Org. Lett. 2005, 7, 4241–4244; (c) Yan, X.-X.; Peng, Q.;
8. Fukuzawa, S.-i.; Oki, H. Org. Lett. 2008, 10, 1747–1750.
9. Oura, I.; Shimizu, K.; Ogata, K.; Fukuzawa, S.-i. Org. Lett. 2010, 12, 1752–1755.
10. For an example, for 1,3-dipolar cycloaddition using Ag/ferrocenyl P,S-ligand
Zeng, W.; Zhou, Y.-G. Tetrahedron Lett. 2007, 48, 4619–4622.
11. The following provide a typical experimental procedure of asymmetric 1,3-
dipolar cycloaddition of azomethine ylide with dipolarophiles. In a 20-mL
Schlenk tube containing a stirring bar, AgOAc (1.7 mg, 0.01 mmol) and L3
(6.9 mg, 0.011 mmol) were dissolved in CH2Cl2 (1.0 mL) and stirred at room
temperature for 30 min under nitrogen. The mixture was cooled to 0 °C, and
then a CH2Cl2 (1.0 mL) solution of methyl N-(p-chlorobenzylidene)glycinate 1a
(42.4 mg, 0.2 mmol), methyl acrylate 2a (26.0 mg, 0.3 mmol), and Et3N (5 lL,
0.036 mmol) was added. The resulting solution was stirred at the same
temperature for 24 h and then filtered through Celite and concentrated. The 1
NMR measurement of the crude product showed the presence of
H
a
diastereomeric mixture of adducts (endo/exo = 98/2). The residue was
purified by preparative PTLC (n-hexane/EtOAc = 2:1) to afford endo-3b, yield
46.5 mg (78%). Enantiomeric excess of endo-3b was determined by HPLC
(Chiralpak As-H): i-PrOH/hexane 10:90, flow rate 1.0 mL/min, 210 nm):
tR = 15.8 min (2S,4S,5R)-isomer, 23.8 min (2R,4R,5S)-isomer.
12. Kim, H. Y.; Shih, H.-J.; Knabe, W. E.; Oh, K. Angew. Chem., Int. Ed. 2009, 48,
7420–7423.