Highly endo -selective and enantioselective 1,3-dipolar cycloaddition of azomethine ylide with α-enones catalyzed by a silver(I)/thioclickferrophos complex

Article abstract of DOI:10.1021/ol100336q

A silver(I)/ThioClickFerrophos complex catalyzed the highly endo-selective asymmetric 1,3-dipolar cycloaddition reaction of methyl N-benzylideneglycinate (the source of azomethine ylides) with (E)-acyclic α-enones having an endo/exo ratio of 90/10 to 99/1. The highly functionalized endo-4-acyl pyrrolidines were obtained in good yields with high enantioselectivities (up to 98% ee). The complex also effectively catalyzed endo-selective reactions with 2-cyclopentenone to give the endo-bicyclic pyrrolidine in high enantioselectivity.

Full text of DOI:10.1021/ol100336q

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1752-1755
Highly Endo-Selective and
Enantioselective 1,3-Dipolar
Cycloaddition of Azomethine Ylide with
r-Enones Catalyzed by a Silver(I)/
ThioClickFerrophos Complex
Ichiro Oura, Kenta Shimizu, Kenichi Ogata, and Shin-ichi Fukuzawa*
Department of Applied Chemistry, Institute of Science and Engineering,
Chuo UniVersity, 1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan
orgsynth@kc.chuo-u.ac.jp
Received February 10, 2010
ABSTRACT
A silver(I)/ThioClickFerrophos complex catalyzed the highly endo-selective asymmetric 1,3-dipolar cycloaddition reaction of methyl
N-benzylideneglycinate (the source of azomethine ylides) with (E)-acyclic r-enones having an endo/exo ratio of 90/10 to 99/1. The highly
functionalized endo-4-acyl pyrrolidines were obtained in good yields with high enantioselectivities (up to 98% ee). The complex also effectively
catalyzed endo-selective reactions with 2-cyclopentenone to give the endo-bicyclic pyrrolidine in high enantioselectivity.
We herein report a procedure that achieves the asymmetric
1,3-dipolar cycloaddition of azomethine ylides with (E)-
acyclic R-enones with endo-selectivity using novel silver(I)/
ThioClickFerrophos complexes and also provides endo-
selective cycloadducts with 2-cyclopentenone.
A metal-catalyzed reaction seems to be the most efficient
and reliable route. The simultaneous formation of the three
or four new stereocenters in the resulting pyrrolidine can be
achieved by using chiral complexes of silver,4 copper,5 zinc,6
or nickel.7 A wide variety of dipolarophiles have been
successfully applied in the cycloadditions, including R,ꢀ-
unsaturated esters, vinyl sulfones, and nitroalkenes.4-7 On
the other hand, the reaction with R-enones has scarcely been
studied although they have great synthetic potential.8 Re-
cently, Carretero et al. have succeeded in the first catalytic
reaction of acyclic R-enones with exo-selectivity and 2-cy-
clopentenone with endo-selectivity using their Cu(I)/Fes-
ulphos complex.9
Proline-derived structures are an important class of
heterocyclic compounds with widespread applications in the
synthesis of biologically active compounds and natural
products,1 and also have themselves been employed as
organocatalysts in many useful transformations.2 The cata-
lytic asymmetric 1,3-dipolar cycloaddition reaction of azome-
thine ylide with dipolarophiles such as electron-deficient
alkenes should provide a straightforward and atom-economi-
cal method for the enantioselective synthesis of proline
derivatives.3
We have previously reported ClickFerrophos10 and Thio-
ClickFerrophos11 ligand families (Figure 1), which are
10.1021/ol100336q  2010 American Chemical Society
Published on Web 03/16/2010

such as hydrogenation of alkenes and ketones,10a,d reductive
aldol reactions,10b and allylic substitution reactions.11 In
particular, Cu(I)/ClickFerrophos (L1) is a highly effective
catalyst for the asymmetric 1,3-dipolar cycloaddition of
methyl N-benzylideneglycinate (the source of azomethine
ylide) with vinyl sulfones with exo-selectivity.10c
We first examined the reaction of methyl N-(4-chloroben-
zylidene)glycinate 1a as an azomethine ylide source with
(E)-benzalacetone 2 (1.5 equiv to 1a) as a representative
acyclic R-enone employing the AgOAc/L1 complex. The
reaction was carried out in toluene at room temperature for
12 h with AgOAc/L1 (5 mol %) and Et3N (18 mol %). The
endo to exo isomer ratio was determined by 1H NMR
integration of the C-5 protons, and ee (%) of the product
was determined by HPLC (Chiralpak AS-H). The reaction
proceeded quantitatively to give a mixture of endo/exo
cycloadducts in a 85/15 ratio (Table 1, entry 1). Notably,
Figure 1. ClickFerrophos and ThioClickFerrophos ligands.
sterically and electronically tunable bidentate chiral ferro-
cenyl diphosphine and P,S-ligands, respectively.12 These
have proven to be excellent chiral ligands in a variety of
highly enantioselective transition metal-catalyzed reactions,
Table 1. Optimization of the 1,3-Dipolar Reaction of Methyl
N-(4-Chlorobenzylidene)glycinate with (E)-Benzalacetonea
(1) For examples, (a) Agbodjan, A. A.; Cooley, B. E.; Copley, R. C. B.;
Corfield, J. A.; Flanagan, R. C.; Glover, B. N.; Guidetti, R.; Haigh, D.;
Howes, P. D.; Jackson, M. M.; Matsuoka, R. T.; Medhurst, K. J.; Millar,
A.; Sharp, M. J.; Slater, M. J.; Toczko, J. F.; Xie, S. J. Org. Chem. 2008,
73, 3094–3102. (b) Burton, G.; Ku, T. W.; Carr, T. J.; Kiesow, T.; Sarisky,
R. T.; Lin-Goerke, J.; Baker, A.; Earnshaw, D. L.; Hofmann, G. A.;
Keenana, R. M.; Dhanaka, D. Biorg. Med. Chem. Lett. 2005, 15, 1553–
1556. (c) Na´jera, C.; de. Retamosa, M. G.; Sansano, J. M.; de Co´zar, A.;
Coss´ıo, F. P. Tetrahedron: Asymmetry 2008, 19, 2913–2923, and references
cited therein.
(2) For reviews, see: (a) Pellissier, H. Tetrahedron 2007, 62, 9267–
9331. (b) Almas¸i, D.; Alonso, D. A.; Na´jera, C. Tetrahedron: Asymmetry
2007, 18, 299–365. (c) France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T.
Chem. ReV. 2003, 103, 2985–3012. (d) Mukherjee, S.; Yang, J. W.;
Hoffmann, S.; List, B. Chem. ReV. 2007, 107, 5471–5569.
entry
[M]
ligand endo/exob yield,c % eed (endo), %
1
2
3
4
5
6
7
8
AgOAc
AgOAc
AgOAc
AgOTf
AgBF4
AgSbF6
AgNO3
CuClO4
CuPF6
CuOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
L1
L2
L3
L3
L3
L3
L3
L3
L3
L3
L4
L5
L6
L7
L7
L7
L8
85/15
93/7
83
85
66
61
71
73
71
66
65
52
60
69
74
74
83
85
73
43
-26
90
55
54
70
61
54
96
68
37
85
70
92
92
96
90
80/20
85/15
80/20
85/15
83/17
90/10
72/28
68/32
73/27
81/19
85/15
85/15
90/10
92/8
(3) For reviews, see: (a) Hashimoto, T.; Maruoka, K. 1,3-Dipolar
Cycloaddition. In Handbook of Cyclization Reactions; Ma, S., Ed.; Wiley-
VCH: Weinheim, Germany, 2010; Vol. 1, pp 87-168. (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) Na´jera, 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.
9
10
11
12
13
14
15e
16f
17
(4) For selected recent examples, see: (a) Yu, S.-B.; Hu, X.-P.; Deng,
J.; Wang, D.-Y.; Duan, Z.-C.; Zheng, Z. Tetrahedron: Asymmetry 2009,
20, 621–625. (b) Wang, C.-J.; Xue, Z.-Y.; Liang, G.; Lu, Z. Chem.
Comumm. 2009, 2905–2907. (c) Liang, G.; Tong, M.-C.; Wang, C.-J. AdV.
Synth. Catal 2009, 351, 3101–3106. (d) Zeng, Z.; Chen, G.-Y.; Zhou, Y.-
G.; Li, Y.-X. J. Am. Chem. Soc. 2007, 129, 750–751. (e) Zeng, W.; Zhou,
Y.-G. Tetrahedron Lett. 2007, 48, 4619–4622. (f) Na´jera, C.; Retamosa,
M. D. G.; Sansano, J. M. Org. Lett. 2007, 9, 4025–4028. (g) Garner, P.;
¨
85/15
Kaniskan, H. U.; Hu, J.; Youngs, W. J.; Panzner, M. Org. Lett. 2006, 8,
a 1a (0.2 mmol), 2 (0.3 mmol), metal salt (0.01 mmol), Et3N (0.036
mmol), ligand (0.01 mmol), toluene (2.0 mL); rt, 12 h. b Determined by 1H
NMR. c Isolated yield (endo). d Determined by HPLC. e In CH2Cl2, rt, 5 h.
f In CH2Cl2, 0 °C, 5 h.
3647–3650. (h) Nyerges, M.; Bendell, D.; Arany, A.; Hibbs, D. E.; Coles,
S. J.; Hursthouse, M. B.; Groundwater, P. W.; Meth-Cohn, O. Tetrahedron
2005, 61, 3745–3753. (i) Zeng, W.; Zhou, Y.-G. Org. Lett. 2005, 7, 5055–
5058. (j) Alemparte, C.; Blay, G.; Jorgensen, K. A. Org. Lett. 2005, 7,
4569–4572.
(5) For selected recent examples, see: (a) Lo´pez-Pe´rez, A.; Adrio, J.;
Carretero, J. C. Angew. Chem., Int. Ed. 2009, 48, 340–343. (b) Lo´pez-
Pe´rez, A.; Adrio, J.; Carretero, J. C. J. Am. Chem. Soc. 2008, 130, 10084–
10085. (c) Llamas, T.; Ramo´n Go´mez, A.; Carretero, J. C. Synthesis 2007,
950–956. (d) Wang, C.-J.; Liang, G.; Xue, Z.-Y.; Gao, F. J. Am. Chem.
Soc. 2008, 130, 17250–17251. (e) Cabrera, S.; Go´mez Arraya´s, R.; Mart´ın-
Matute, B.; Coss´ıo, F. P.; Carretero, J. C. Tetrahedron 2007, 63, 6587–
6602. (f) Shi, M.; Shi, J.-W. Tetrahedron: Asymmetry 2007, 18, 645–650.
(g) Yan, X.-X.; Peng, Q.; Zhang, Y.; Zhang, K.; Hong, W.; Hou, X.-L.;
Wu, Y.-D. Angew. Chem., Int. Ed. 2006, 45, 1979–1983. (h) Cabrera, S.;
Arraya´s, R. G.; Carretero, J. C. J. Am. Chem. Soc. 2005, 127, 16394–16395.
(i) Gao, W.; Zhang, X.; Raghunath, M. Org. Lett. 2005, 7, 4241–4244.
the endo product was produced preferentially in contrast to
Carretero’s Cu(I)/Fesulphos complex.9 However, the enan-
tiomeric excess of the endo adduct 3a was low (43% ee).
Since Carretero’s Fesulphos is a P,S-ligand, we thought that
ThioClickFerrophos as a P,S-ligand could work effectively
on the reaction.13 For the representative ThioClickFerrophos
ligands, ligands bearing an ethylthio (EtS) group on the
Org. Lett., Vol. 12, No. 8, 2010
1753

ferrocene (L2) or the 1,2,3-triazole group (L3) were chosen.
The reactions with the AgOAc/L2 and L3 complexes were
carried out under the same conditions as with AgOAc/L1.
The AgOAc/L3 complex gave the endo adduct 3a prefer-
entially with 90% ee (Table 1, entry 3), while AgOAc/L2
gave the enantiomer of 3a with low ee (Table 1, entry 2).
The stereochemistry and absolute configuration of 3a were
confirmed by X-ray crystallographic analysis (Supporting
Infomation) and revealed to be (2S,3R,4S,5R). ThioClick-
Ferrophos L3 was found to be the most suitable ligand.
Next, combinations with several metal salts were screened.
Several kinds of Ag(I) and Cu(I) salts were examined (Table
1, entries 3-10). The reaction proceeded smoothly to give
the endo adduct preferentially, using all combinations with
Ag(I) or Cu(I) salts. The combination with Cu(MeCN)4PF6
gave the endo adduct in the highest ee (96% ee) but with
low endo-selectivity (endo/exo ) 72/28) (entry 9). We
concluded that AgOAc was the most suitable salt to obtain
the endo adduct in good diastereo- and enantioselectivities.
Thus, AgOAc/ThioClickFerrophos is the first catalyst that
can achieve the endo-selective 1,3-dipolar cycloaddition of
azomethine ylide with acyclic R-enones in high enantiose-
lectivity.
product in 92% ee with endo/exo ) 90/10 (entry 15). The
ee was further improved (96% ee) by carrying out the
reaction in dichloromethane at 0 °C, and the reaction was
complete in 5 h (entry 16).
From the optimization experiments shown in Table 1,
we concluded that AgOAc/L7, dichloromethane, and Et3N
were the optimal catalyst, solvent, and base, respectively.
The reaction should be carried out at 0 °C to obtain a
higher ee value of the product, but the ratio of endo/exo
is only slightly improved. The reaction with 2 was then
expanded to other azomethine ylide precursors (dipoles)
including 4-substituted phenyl derivatives, 2-naphthyl, and
cyclohexyl derivatives (1a-f) under the optimized condi-
tions. The results are summarized in Table 2. The
Table 2. Scope of the Reaction of (E)-Benzalacetone with
Respect to Azomethine Ylidea
We prepared variations of L3 by replacing the EtS group
with other alkyl- and arylthio groups differing in steric and
electronic properties, and screened these ligands (L4-L8)
for improved stereoselectivity (Table 1, entries 11-17).14
The 4-phenyl group in the 1,2,3-triazole ring was found to
be essential for high stereoselectivity. The ee value was
drastically decreased when using L4 (without the phenyl
group of L3) (entry 11). The tert-butylthio (t-BuS) derivative
L7 was the most effective for the reaction giving the endo
entry
R
product yield,b endo/exoc eed (endo), %
%
1
4-ClPh
4-BrPh
4-MeOPh
Ph
2-Naph
2-Naph
Cy
3a
3b
3c
3d
3e
3e
3f
85
82
85
74
78
78
70
92/8
90/10
95/5
95/5
90/10
91/9
94
96
96
94
86
94
92
2
3e
4
5
6e
7e
92/8
a 1a-f (0.2 mmol), benzalacetone (0.3 mmol), AgOAc (0.01 mmol),
Et3N (0.036 mmol), L7 (0.01 mmol), CH2Cl2 (2.0 mL); 0 °C, 5 h. b Isolated
yield (endo). c Determined by 1H NMR. d Determined by HPLC. e The
reaction was carried out at -20 °C for 12 h.
¨
(6) (a) Dogan, O.; Koyuncu, H.; Garner, P.; Bulut, A.; Youngs, W. J.;
¨
¨
¨
Panzner, M. Org. Lett. 2006, 8, 4687–4690. (b) Dogan, O.; Oner, I.; Ulku¨,
D.; Arici, C. Tetrahedron: Asymmetry 2002, 13, 2099–2104. (c) Gothelf,
A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2002, 41, 4236–4238.
(7) Shi, J.-W.; Zhao, M.-X.; Lei, Z.-Y.; Shi, M. J. Org. Chem. 2008,
73, 305–308.
4-substituent on the phenyl group had little effect on the
reaction. Similar high endo-selectivity and high ee (94-96%
ee) of endo adducts (3a-d) were obtained (entries 1-4)
with the electron-withdrawing (Cl and Br) and -donating
(OMe) groups. The reaction with 2-naphthyl derivative
1e resulted in a lower enantioselectivity than the phenyl
derivatives, and ee could be improved by decreasing the
reaction temperature (-20 °C) (entry 6). The reaction
could be applied to cyclohexyl derivative 1f, yielding the
endo adduct with 92% ee (entry 7).
(8) The diastereoselective reaction with chiral 2-sulfinyl 2-cyclope-
ntenone has been reported: Ruano, J. L. G.; Tito, A.; Peromingo, M. T. J.
Org. Chem. 2003, 68, 10013–10019.
(9) Herna´ndez-Torbio, J.; Arraya´s, R. G.; Mart´ın-Mature, B.; Carretero,
J. C. Org. Lett. 2009, 11, 393–396.
(10) (a) Oki, H.; Oura, I.; Nakamura, T.; Ogata, K.; Fukuzawa, S.-i.
Tetrahedron: Asymmetry 2009, 19, 2185–2191. (b) Kato, M.; Oki, H.; Ogata,
K.; Fukuzawa, S.-i. Synlett 2009, 1299–1302. (c) Fukuzawa, S.-i.; Oki, H.
Org. Lett. 2008, 10, 1747–1750. (d) Fukuzawa, S.-i.; Oki, H.; Hosaka, M.;
Sugasawa, J.; Kikuchi, S. Org. Lett. 2007, 9, 5557–5560.
(11) Kato, M.; Nakamura, T.; Ogata, K.; Fukuzawa, S-i. Eur. J. Org.
Chem. 2009, 5232–5238.
(12) For recent reviews for chiral ferrocenyl phosphines, see: (a)
Ferrocenes: Ligands, Materials and Biomolecules; Steˇpnicˇka, P., Ed.; John
ˇ
To evaluate the scope of the 1,3-dipolar cycloaddition, we
applied the AgOAc/L7 catalyst to the reaction with (E)-
acyclic R-enones including (E)-chalcone derivatives 4, (E)-
3-pentene-2-one (Table 3), using 1a as a dipole. In the
reaction with chalcone (4: R1 ) R2 ) Ph), the reaction
completed in 10 min to give almost a single isomer of the
adduct 5 in good yield. In this case, the stereochemistry of
the adduct 5 was determined by 1H NMR spectroscopy. The
methyl ester group appears at around 3.7 ppm as in the
benzalacetone adduct, while the methyl ester group of the
exo isomer shifted upfield to 3.3 ppm due to the shielding
Wiley & Sons: West Sussex, UK, 2008. (b) Cheng, W.; Blaser, H.-U. In
Phosphorus Ligands in Asymmetric Catalysis; Bo¨rner, A., Ed.; Wiley-VCH:
Weinheim, Germany, 2008; Vol. 1, pp 345-393; Malacea, R.; Manoury,
E. In Phosphorus Ligands in Asymmetric Catalysis; Bo¨rner, A., Ed.; Wiley-
VCH: Weinheim, Germany, 2008; Vol. 2, pp 749-784. (c) Arraya´s, R. G.;
Adrio, J.; Carretero, J. C. Angew. Chem., Int. Ed. 2006, 45, 7674–7715.
(13) For an example of chiral ferrocenyl P,S-ligand other than FeSulphos
in asymmetric 1,3-dipolar addition with azomethine ylides, see: Zeng, W.;
Zhou, Y.-G. Tetrahedron Lett. 2007, 48, 4619–4622.
(14) X-ray crystallographic structure of AgOAc/L5 complex was
obtained. The crystallographic coordinates have been deposited with the
Cambridge Crystallographic Data Centre; deposition no. 704687. These data
can be obtained free of charge from the Cambridge Crystallographic Data
Centre, 12 Union Rd., Cambridge CB2 1EZ, UK or via www.ccdc.
cam.ac.uk/conts/retrieving.html.
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Org. Lett., Vol. 12, No. 8, 2010

Table 3. Reaction of Various Acyclic R-Enones with Azomethine Ylidesa
entry
R1
R2
product
yield,b
%
endo/exoc
eed (endo), %
1
2
3
4
Ph
Ph
Ph
Ph
Ph
5
6
7
8
91
86
91
74
90
89
92
92
91
83
75
95/5
94/6
95/5
95/5
97/3
90/10
93/7
93/7
98/2
98/2
98/2
98
97
97
95
95
87
96
96
90
98
95
4-ClC6H4
4-MeOC6H4
2-Naph
Ph
Ph
Ph
5
4-ClC6H4
4-MeOC6H4
4-MeO C6H4
4-CF3 C6H4
2-Naph
9
6
10
10
11
12
13
14
7e
8
Ph
Ph
9
10
11
Me
Ph
Me
CHdCHPh
a Imine (0.2 mmol), R-enone (0.3 mmol), AgOAc (0.01 mmol), Et3N (0.036 mmol), ligand (0.01 mmol), CH2Cl2 (2.0 mL); 0 °C, 10 min. b Isolated yield
c
(endo). Determined by H NMR. d Determined by HPLC. e The reaction was carried out at -20 °C for 0.5 h.
1
effect of the adjacent cis-phenyl group.9 A similar effect and
upfield shift (4.17 ppm) was observed in the C-2 proton of
5 compared to that of the exo adduct (4.4-4.5 ppm). The
downfield shift of the methyl ester and the upfield shift of
the C-2 proton suggest that the ester and phenyl groups are
trans (the protons are cis) to each other, identifying 5 as an
endo adduct. The stereochemistry was confirmed by the
NOESY spectrum (Supporting Information).
Reactions with 4-aryl-substituted chalcones were carried
out, and the results are also summarized in Table 3. These
results demonstrate that the reaction displays a wide scope
and high endo-selectivity (endo/exo ) 90/10 to 98/2) with
high enantioselectivity (up to 98% ee), tolerating the presence
of electron-withdrawing and -donating groups in both aryl
groups of 4. The endo cycloadducts were also obtained
selectively from the reaction with (E)-3-penten-2-one and
dibenzylidene acetone in good yields with high ee (entries
10 and 11).15
The reaction of 1a with a cyclic R-enone such as
2-cyclopentenone 15 proceeded but required a long reaction
time (24 h) and more catalyst loading (10 mol %) to give
the endo bicyclic pyrrolidine 16 as the sole isomer (73%,
Scheme 1). This is in contrast to Carretero’s Cu/Fesulphos
catalyst which gave the endo bicyclic product from 16,9 while
it gave exo products from acyclic R-enones. Thus, the Ag(I)/
ThioClickFerrophos complex catalyzed endo-selective 1,3-
dipolar cycloaddition with both acyclic and cyclic R-enones.
In conclusion, Ag(I)/ThioClickFerrophos is an efficient
catalyst for the endo-selective asymmetric 1,3-dipolar cy-
cloaddition of azomethine ylide with (E)-acyclic and cyclic
R-enones. The endo-4-acyl-substituted pyrrolidines can be
obtained in good yields with high endo/exo selectivities and
enantioselectivities (up to 98% ee).
Acknowledgment. This study was financially supported
by a Chuo University Grant for Special Research.
Supporting Information Available: Full experimental
procedures, characterization data, HPLC, and NMR spectra
(PDF) for L3-L8, pyrrolidine derivatives 3a-f, 5-14, and
16, and crystallographic data in CIF files for L7, 3a, and
the AgOAc/L5 complex. This material is available free of
charge via the Internet at http://pubs.acs.org.
Scheme 1. Reaction of 1a with 2-cyclopentenone 15
OL100336Q
(15) The reaction with a vinyl kenone such as 1-phenyl-2-propen-1-
one was also examined (Supporting Information).
Org. Lett., Vol. 12, No. 8, 2010
1755