Bifunctional AgOAc-catalyzed asymmetric [3 + 2] cycloaddition of azomethine ylides

Article abstract of DOI:10.1021/ol0520370

(Chemical Equation Presented) A bifunctional AgOAc-catalyzed asymmetric cycloaddition of azomethine ylides with electronic-deficient alkenes was developed using ferrocenyloxazoline-derived N,P ligands. The reactive metal-bound azomethine ylide dipole is formed by the deprotonation with acetate, and extra base is not necessary. The reactions proceed with high enantioselectivity. This method provides an efficient and convenient route to optically active pyrrolidine derivatives.

Full text of DOI:10.1021/ol0520370

ORGANIC
LETTERS
2
005
Vol. 7, No. 22
055-5058
Bifunctional AgOAc-Catalyzed
Asymmetric [3 2] Cycloaddition of
Azomethine Ylides
5
+
Wei Zeng and Yong-Gui Zhou*,†,‡
†
Dalian Institute of Chemical Physics, The Chinese Academy of Sciences,
57 Zhongshan Road, Dalian 116023, China, and State Key Laboratory of
Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
54 Fenglin Road, Shanghai 200032, China
4
3
ygzhou@dicp.ac.cn
Received August 24, 2005
ABSTRACT
A bifunctional AgOAc-catalyzed asymmetric cycloaddition of azomethine ylides with electronic-deficient alkenes was developed using
ferrocenyloxazoline-derived N,P ligands. The reactive metal-bound azomethine ylide dipole is formed by the deprotonation with acetate, and
extra base is not necessary. The reactions proceed with high enantioselectivity. This method provides an efficient and convenient route to
optically active pyrrolidine derivatives.
4
5
The 1,3-dipolar cycloaddition reaction is a useful tool for
constructing five-membered heterocyclic compounds. The
developed recently. Zhang and co-workers reported an
efficient catalytic system, AgOAc/FAP/i-Pr NEt, with up to
97% ee. Schreiber’s AgOAc/(S)-QUINAP/i-Pr
NEt system6
also gave excellent enantioselectivities. A zinc-catalyzed
system, Zn(OTf) /t-BuBox/Et
N, was reported by Jørgensen7
and co-workers with up to 94% ee. Komatsu’s Cu(OTf)
1
2
cycloadditon of azomethine ylides with electronic-deficient
olefins provides an efficient method for synthesizing sub-
stituted pyrrolidines contained in many biologically active
2
2
3
2
compounds. The formation of optically active pyrrolidines
2
/
3
8
in previous work was mainly based on chiral auxiliaries.
BINAP/Et
3
N system gave moderate to excellent levels of
stereoselectivity with exo selectivity.
9
And the use of chiral transition-metal catalysts has been
†
The Chinese Academy of Sciences.
Shanghai Institute of Organic Chemistry.
(3) (a) Ruano, J. L. G.; Tito, A.; Peromingo, M. T. J. Org. Chem. 2002,
67, 981-987. (b) Merino, I.; Laxmi, Y. R. S.; Florez, J.; Barluenga, J.;
Ezquerra, J.; Pedregal, C. J. Org. Chem. 2002, 67, 648-655. (c) Garner,
P.; Dogan, O.; Youngs, W. J.; Kennedy, V. O.; Protasiewicz, J.; Zaniewski,
R. Tetrahedron 2001, 57, 71-85.
‡
(1) For reviews, see: (a) Husinec, S.; Savic, V. Tetrahedron: Asymmetry
2
005, 16, 2047-2061. (b) Kanemasa, S. Synlett 2002, 1371-1387. (c)
Gothelf, K. V.; Jørgensen, K. A. Chem. ReV. 1998, 98, 863-909. (c) Pichon,
M.; Figadere, B. Tetrahedron: Asymmetry 1996, 7, 927-964.
(4) For early development of this reaction, see: (a) Grigg, R. Tetrahe-
dron: Asymmetry 1995, 6, 2475-2486. (b) Allway, P.; Grigg, R.
Tetrahedron Lett. 1991, 32, 5817-5820.
(2) (a) Sebahar, P. R.; Williams, R. M. J. Am. Chem. Soc. 2000, 122,
5
666-5667. (b) Denhart, D. J.; Griffith, D. A.; Heathcock, C. H. J. Org.
Chem. 1998, 63, 9616-9617. (c) Garner, P.; Cox, P. B.; Anderson, J. T.;
Protasiewicz, J.; Zaniewski, R. J. Org. Chem. 1997, 62, 493-498. (d)
Alvarez-Ibarra, C.; Csaky, A. G.; Lopez, I.; Quiroga, M. L. J. Org. Chem.
(5) Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124,
13400-13401.
(6) Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc. 2003, 125,
10174-10175.
1
997, 62, 479-484. (e) Bianco, A.; Maggini, M.; Scorrano, G.; Toniolo,
C.; Marconi G.; Villani, C.; Prato, M. J. Am. Chem. Soc. 1996, 118, 4072-
080.
(7) Gothelf, A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2002, 41, 4236-4238.
4
1
0.1021/ol0520370 CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/07/2005

The most accepted mechanism5,8 for the cycloaddition of
azomethine ylides is shown in Scheme 1. Coordination of
In our initial investigation, we found AgOAc/1a system
can efficiently catalyze the cycloaddition of 4 with dimethyl
maleate in toluene with high activity and moderate enantio-
selectivity in the absence of base (entry 1, Table 1); only
Scheme 1. Mechanism of AgOAc-Catalyzed 1,3-Dipolar
Cycloaddition
Table 1. AgOAc-Catalyzed Asymmetric Cycloaddition of 4a
b
c
entry
ligand
solvent
T (°C)
yield (%)
ee (%)
the iminoester to chiral Ag(I) or Cu(II) catalyst, followed
by deprotonation with base to form the reactive metal-bound
azomethine ylide dipole, which reacts with dipolarophiles,
was followed by elimination of cycloadduct to regenerate
the chiral catalyst. Thus, for the above catalytic systems, an
excess of base such as tertiary amine was involved. By
analyzing the above mechanism carefully, we think that extra
base is not necessary for AgOAc-catalyzed cycloaddition of
azomethine ylide because the AgOAc bearing a moderately
1
2
3
4
5
6
7
8
9
10
11
12
3
4
5
1a
1b
1c
1d
1d
1d
1d
1e
2
3a
3b
3c
3d
3d
3d
toluene
toluene
toluene
toluene
THF
DME
Et2O
Et2O
0
0
0
0
0
0
0
0
0
0
0
0
0
89
86
88
98
86
96
93
98
96
91
88
89
94
88
98
68
53
69
81
86
78
88
81
-78
84
89
83
94
98
98
Et O
2
Et2O
basic charged ligand acetate would facilitate deprotonation
of iminoesters to generate the azomethine ylide.10 Intrigued
Et2O
Et2O
Et2O
Et2O
Et2O
1
1
1
by the effectiveness of ferrocene-derived chiral N,P ligands
in asymmetric reactions,11 we developed highly enantiose-
lective AgOAc-catalyzed asymmetric [3 + 2] cycloaddition
of azomethine ylides using ferrocenyloxazoline-derived chiral
N,P ligands without extra base.
-25
-40
a
Conditions: iminoester 4 (1.0 equiv), dimethyl maleate (1.5 equiv),
b
AgOAc (3 mol %), ligand (3.3 mol %), concentration (0.15 M). Isolated
yields based on 4. c Determined by HPLC.
(
8) Oderaotoshi, Y.; Cheng, W.; Fujitomi, S.; Kasano, Y.; Minakata, S.;
Komatsu, M. Org. Lett. 2003, 5, 5043-5046.
9) During preparation of this manuscript, Zhang reported a Cu(I)/P,
1
(
the endo isomer 5 was detected by H NMR analysis of
reaction mixtures.
N-ligand-catalyzed asymmetric 1,3-polar cycloaddition of azomethine ylides
with high exo selectivity; see: (a) Gao, W.; Zhang, X.; Raghunath, M. Org.
Lett. 2005, 7, 4241-4244. (b) Pfaltz reported a base-free AgOAc/PHOX-
catalyzed intramolecular [3 + 2] cycloaddition of azomethine ylides; see:
Stohler, R.; Wahl, F.; Pfaltz, A. Synthesis 2005, 1431-1436.
Encouraged by these results, the effect of substituent of
oxazoline ring on the conversion and enantioselectivity was
investigated in toluene (Table 1). The results showed that
Bn-substituted ligand 1d (entry 4) is superior to 1a (R )
i-Pr), 1b (R ) t-Bu) and 1c (R ) Ph). The solvent effect
was also studied (entries 4-7), the reaction proceeded well
(10) For a recent example using this strategy in the Henry reaction, see:
Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.; Downey,
C. W. J. Am. Chem. Soc. 2003, 125, 12692-12693.
(11) For recent examples, see: (a) Lu, S. M.; Han, X. W.; Zhou, Y. G.
AdV. Synth. Catal. 2004, 346, 909-912. (b) Dai, L. X.; Tu, T.; You, S. L.;
Deng, W. P.; Hou, X. L. Acc. Chem. Res. 2003, 36, 659-667. (c) You,
S.-L.; Hou, X.-L.; Dai, L.-X.; Yu, Y.-H.; Xia, W. J. Org. Chem. 2002, 67,
in Et
2
O, THF and DME, and low activity was observed in
. The highest enantioselectivity was obtained in ether.
CH Cl
2
2
4
684-4695. (d) Deng, W. P.; Hou, X. L.; Dai, L. X.; Yu, Y. H.; Xia, W.
J. Am. Chem. Soc. 2001, 123, 6508-6519. (e) Bolm, C.; Mu n˜ iz, K. Chem.
Eur. J. 2000, 2309-2316. (f) Deng, W. P.; Hou, X. L.; Dai, L. X.; Dong,
X. W. Chem. Commun. 2000, 285-286. (g) Deng, W. P.; Hou, X. L.; Dai,
L. X.; Yu, Y. H.; Xia, W. Chem. Commun. 2000, 1483-1484. (h) Shintani,
R.; Lo, M. M. C.; Fu, G. C. Org. Lett. 2000, 2, 3695-3697. (i) Bolm, C.;
Mu n˜ iz-Fern a´ ndez, K.; Hildebrand, J. P. Org. Lett. 1999, 1, 491-494. (j)
Donde, Y.; Overman, L. E. J. Am. Chem. Soc. 1999, 121, 2933-2934. (k)
Zhang, W.; Shimanuki, T.; Kida, T.; Nakatusuji, Y.; Ikeda, I. J. Org. Chem.
To investigate the effect of planar chirality on the
enantioselectivity and absolute configuration of the prod-
11
ucts, (S
ee was observed (81% ee, entry 8). (S,R
central chirality and opposite planar chirality to (S,S
P
)-1e with only planar chirality was used, and lower
)-2 with the same
)-1d
P
P
was also used in the cycloaddition of 4 with dimethyl
maleate. Under the same conditions, lower enantioselectivity
and the opposite absolute configuration were observed
1999, 64, 6247-6251. (l) Bolm, C.; Mu n˜ iz-Fern a´ ndez, K.; Seger, A.; Raabe,
G.; G u¨ nther, K. J. Org. Chem. 1998, 63, 7860-7867. (m) You, S. L.; Zhou,
Y. G.; Hou, X. L.; Dai, L. X. Chem. Commun. 1998, 2765-2766. (n) Togni,
A.; Pastor, S. D. J. Org. Chem. 1990, 55, 1649-1664. (o) Hayashi, T.;
Konoshi, M.; Fukushima, M.; Mise, T.; Kagotani, M.; Tajika, M.; Kumada,
M. J. Am. Chem. Soc. 1982, 104, 180-186.
P
(-78% ee, entry 9). The lower ee with (S,R )-2 suggests
the mismatched nature of the (R) planar chirality with the
5056
Org. Lett., Vol. 7, No. 22, 2005

(S) central chirality on the oxazolinyl ring. It is noteworthy
that, compared to the enantioselectivity of the reaction
Table 2. Effect of Silver Precursors on Enantioselectivity and
Conversion of Cycloaddition of 4 with Dimethyl Maleate
catalyzed by 1a with the counterpart of the phenyloxazoline
a
6
i-Pr-Phox, low ee (14%) was obtained.
12
The influence of the electronic property of the phosporus
substituent in ligand 1d was also studied (entries 10-13,
Table 1). Four ligands were synthesized13 by replacing the
phenyl groups in 1d to 4-methoxylphenyl (3a), 3,5-dimeth-
ylphenyl (3b), 3,5-ditrifluoromethylphenyl (3c), and 4-tri-
fluoromethylphenyl (3d), respectively. Interestingly, the
change of electronic property of aromatic ring has a clear
effect on enantioselectivity, although ligands 3a-d all can
catalyze this reaction smoothly. Ligand 3a (entry 10) and
ligand 3c (entry 12) slightly decreased the enantioselectivity.
Gratifyingly, an improvement in enantioselectivity (94% ee,
entry 13) was observed with ligand 3d bearing a strong
electronic-withdrawing trifluoromethyl at the para position
of the phenyl ring under the same conditions. The ee could
be enhanced to 98% (entry 14) at -25 °C, but no further
improvement in enantioselectivity was obtained at -40 °C.
Thus, the optimal conditions for asymmetric cycloaddition
b
c
entry
silver(I)
AgOAc
time (h)
yield (%)
ee (%)
1
2
3
4
5
3
2
2
24
20
20
93
95
94
35e
<5
48
88
89
87
94
AgOCOPh
10
c-C6H11(CH2)3CO2Ag
AgOCOCF CF CF
2
3
3
AgOTf
AgOTf
d
f
6
91
a
Conditions: 4 (1.0 equiv), dimethyl maleate (1.5 equiv), silver(I) (3
mol %), ligand 1d (3.3 mol %), concentration (0.15 M) at 0 °C. Isolated
b
c
d
yields based on 4. Determined by HPLC. 10 mol % of i-Pr2NEt was
added. e 46% conversion of 4 detected by 1 H NMR of the crude reaction
mixture. 62% conversion of 4 detected by 1 H NMR of the crude reaction
f
mixture.
of azomethine ylides are AgOAc/3d/Et O/-25 °C. AgOAc-
2
ester was less reactive (entry 11), requiring prolonged
reaction time and yielding cycloaddition product with slightly
low enantiselectivty. It is noteworthy that the enantioselec-
tiVity is the best for asymmetric cycloaddition of azomethine
ylides with dimethyl maleate.
We also probed other three dipolarophiles as outlined in
Figure 1. The iminoester 6a reacted smoothly with N-
phenylmaleimide in 93% ee (endo/exo > 20:1). For tert-
butyl arcylate, relatively low reactivity was observed when
reacted at -25 °C, and 88% ee and 97% isolated yield were
achieved when the reaction occurred at 0 °C for 20 h.
Dimethyl fumarate gave the major endo cycloadduct 10
catalyzed cycloaddition of 4 and dimethyl maleate can
proceed for 2 h at -25 °C with equally high enantioselec-
tivity when catalyst loading is reduced to only 1%.
To further understand the role of silver salts, AgOCOPh,
silver 4-cyclohexylbutyrate, AgOTf, and AgOCOCF
CF were investigated in the cycloaddition of 4 with dimethyl
maleate using the Ag(I)/1d/Et O system at 0 °C (Table 2).
The reaction can proceed smoothly with AgOCOPh or silver
-cyclohexylbutyrate, anions having similar basicity with
acetate, giving the same enantioselectivities. The activity
decreased dramatically using AgOCOCF CF CF as a cata-
2 3
CF -
3
2
4
2
3
3
lyst, probably due to its anion’s weak basicity. The reaction
could not occur under the same conditions when AgOTf was
used as a catalytic precursor without extra base. Only 62%
(endo/exo ) 93/7) in 89% ee with 96% combined yield.
2
conversion was obtained even if 10 mol % of (i-Pr) NEt was
added. Therefore, AgOAc proved to be an efficient Lewis
acid catalyst as well as a base, playing a bifunctional role in
this reaction.
Table 3. Variation of the R-Substituent on 6 for the
Cycloaddition with Dimethyl Maleatea
2
To explore the scope of the AgOAc/3d/Et O catalyzed
[3 + 2] azomethine ylide cycloaddition, we investigated a
variety of R-iminoester substrates derived from aldehydes
with a variety of steric and electronic properties (Table 3).
The reaction of R-iminoester 6a-j with dimethyl maleate
proceeds in excellent levels of yield and enantioselectivity.
The reaction is also highly diastereoselective, and only endo
isomers were obtained. Excellent enantioselectivity (entries
b
c
entry
R in 6
Ph (6a)
time (h)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
3
3
3
3
3
3
3
3.5
3
3.5
20
85
94
99
96
91
98
99
85
95
76
56
97
98
97
97
97
97
98
98
98
93
88
p-anisole(6b)
4-chlorophenyl (6c)
4-fluorophenyl (6d)
4-cyanophenyl (6e)
2-chlorophenyl (6f)
o-toluyl (6g)
1-naphthyl (6h)
2-naphthyl (6i)
3-pyridyl (6j)
1-9) and high isolated yield were obtained regardless of
the electronic properties and steric hindrance of the phenyl
ring of iminoester 6. A slightly lower ee was obtained when
R was heteroaromatic 3-pyridyl (entry 10). R-(Alkylimino)
(12) (a) Tu, T.; Deng, W. P.; Hou, X. L.; Dai, L. X.; Dong, X. C. Chem.
10
Eur. J. 2003, 9, 3073-3081. (b) RajanBabu, T. V.; Ayers, T. A.; Halliday,
G. A.; You, K. K.; Calabrese, J. C. J. Org. Chem. 1997, 62, 6012-6028.
11
i-Pr (6k)
(
6
c) Jacobsen, E. N.; Zhang, W.; G u¨ ler, M. L. J. Am. Chem. Soc. 1991, 113,
a
703-6704.
Conditions: iminoester (1.0 equiv), dimethyl maleate (1.5 equiv),
(13) (a) Richards, C. J.; Mulvaney, A. W. Tetrahedron: Asymmetry 1996,
AgOAc (3 mol %), ligand (3.3 mol %), concentration (0.15 M) at -25 °C.
b
Isolated yields by silica gel chromatography. c Determined by HPLC.
7
, 1419-1430. (b) Casalnuovo, A. L.; RajanBabu, T. V.; Ayers, T. A.;
Warren, T. H. J. Am. Chem. Soc. 1994, 116, 9869-9882.
Org. Lett., Vol. 7, No. 22, 2005
5057

bound azomethine ylide dipole is formed by the deprotona-
tion with acetate that plays a role of base, and extra base is
not necessary. This method provides an efficient and
convenient route to synthesize optically active highly sub-
stituted pyrrolidine derivatives.
Acknowledgment. We are grateful for financial support
from the State Key Laboratory of Organometallic Chemistry
(04-29) and Talented Scientist Program, The Chinese Acad-
emy of Sciences.
Figure 1. Cycloaddition of 6a with other dipolarophiles catalyzed
by AgOAc/3d.
Supporting Information Available: Spectroscopic data,
GC and HPLC spectra, and experimental details. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we have developed a system for bifunctional
AgOAc-catalyzed asymmetric cycloaddition of azomethine
ylides with electronic-deficient alkenes in high yield and
excellent levels of enantioselectivity. The reactive metal-
OL0520370
5058
Org. Lett., Vol. 7, No. 22, 2005