A convenient procedure for the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides and alkenes

Article abstract of DOI:10.1021/ol0514653

(Chemical Equation Presented) Silver fluoride and cinchona alkaloids catalyze the diastereo- and enantioselective 1,3-dipolar cycloaddition between azomethine ylides, generated from N-alkylideneglycine esters, and acrylates to give the corresponding endo-adducts. Azomethine ylides derived from aromatic and aliphatic aldehydes react in a highly diastereoselective reaction with good yields and enantioselectivities of the substituted pyrrolidines.

Full text of DOI:10.1021/ol0514653

ORGANIC
LETTERS
2005
Vol. 7, No. 21
4569-4572
A Convenient Procedure for the
Catalytic Asymmetric 1,3-Dipolar
Cycloaddition of Azomethine Ylides and
Alkenes
Carlos Alemparte,† Gonzalo Blay,†,‡ and Karl Anker Jørgensen*,†
Danish National Research Foundation, Center for Catalysis,
Department of Chemistry, Aarhus UniVersity, DK-8000 Aarhus C, Denmark, and
Departament de Qu´ımica Orga`nica, Facultat de Qu´ımica,
UniVersitat de Vale`ncia, Dr. Moliner, 50, 46100-Burjassot (Vale`ncia), Spain
kaj@chem.au.dk
Received June 23, 2005
ABSTRACT
Silver fluoride and cinchona alkaloids catalyze the diastereo- and enantioselective 1,3-dipolar cycloaddition between azomethine ylides, generated
from N-alkylideneglycine esters, and acrylates to give the corresponding endo-adducts. Azomethine ylides derived from aromatic and aliphatic
aldehydes react in a highly diastereoselective reaction with good yields and enantioselectivities of the substituted pyrrolidines.
The pyrrolidine ring is present in many biologically active
natural compounds and pharmaceuticals.1 Furthermore, pyr-
rolidines are important building blocks in organic synthesis,
and in the past years have emerged as privileged organo-
catalysts.2 The [3 + 2] cycloaddition reaction of azomethine
ylide 1,3-dipoles with olefinic dipolarophiles constitutes a
straightforward approach to the synthesis of highly substi-
tuted pyrrolidine derivatives.3
Azomethine ylides are unstable and have to be prepared
in situ. Several methods have been developed for the
synthesis of azomethine ylides: ring opening of aziridines,4
1,2-proton shift of N-arylidene-benzylamines,5 and depro-
tonation of iminium salts6 or metalated imino esters (metallo-
azomethine ylides),7 the last one being the most used in
organic chemistry. The stereoselective version of the [3 +
† Aarhus University.
‡ Universitat de Vale`ncia.
(1) (a) Gribble, G. W. In ComprehensiVe Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford,
U.K., 1996; Vol. 2, pp 207-257. (b) Pearson, W. H. In Studies in Natural
Products Chemistry; Atta-Ur-Rahman, Ed.; Elsevier: New York, 1998; Vol.
1, pp 323-358. (c) Obst, U.; Betschmann, P.; Lerner, C.; Seiler, P.
Diederich, F. HelV. Chim. Acta 2000, 83, 855-909. (d) AÄ lvarez-Ibarra, C.;
Csa´ky¨, A. G.; Lo´pez de Silanes, G. A.; Quiroga, M. L. J. Org. Chem. 1997,
62, 479-484. (e) Cheng, Y.; Huang, Z.-T-; Wang, M.-X. Curr. Org. Chem.
2004, 8, 325-351. (f) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem.
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Bajo, L.; Toupet, L.; Hurvois, J.-P.; Moinet, C. Synlett 2002, 1500-1504.
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(3) (a) Na´jera, C.; Sansano, J. M. Curr. Org. Chem. 2003, 7, 1105-
1150. (b) Gothelf, K.; Jørgensen, K. A. Chem. ReV. 1998, 98, 863-909.
(c) Gothelf, K. V. In Cycloaddition Reactions in Organic Synthesis;
Kobayashi, S., Jørgensen, K. A., Eds.; Wiley-VCH: Weinheim, 2002; pp
211-245. (d) Kanemasa, S. Synlett 2002, 1371-1387.
(4) (a) Huisgen, R.; Scheer, W.; Huber, H. J. Am. Chem. Soc. 1967, 89,
1753-1755. (b) Huisgen, R.; Scheer, W.; Szeimies, G, Huber, H.
Tetrahedron Lett. 1966, 397-404.
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45, 1723-1746 (b) Grigg, R.; Kemp. J. J. Chem. Soc., Chem. Commun.
1978, 109-111.
(2) For some recent reviews, see: (a) Dalko, P. I.; Moisan, L. Angew.
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48, 10431-10442.
10.1021/ol0514653 CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/13/2005

2] cycloaddition reaction of azomethine ylides with alkenes
has been developed in the past years mainly using optically
pure dipolarophiles8 and more recently by using metal
complexes. After the pioneering work by Grigg et al. on the
use of chiral transition metal complexes, which required a
stoichiometric amount of the metal complex,9 a relatively
limited number of procedures that employ substoichiometric
amounts of a chiral metal complex have been reported. Zhang
et al. reported the cycloaddition of methylglycine imines with
different dipolarophiles catalyzed by Ag(I) complexes with
chiral diphosphines,10 obtaining good enantioselectivities with
doubly deactivated alkenes but modest selectivity with
methyl acrylate. We described at the same time the use of
chiral Zn(II)-bisoxazoline complexes as catalysts for the
enantioselective cycloaddition of methylglycine esters to
acrylates as a simple approach to optically active proline
derivatives.11 Schreiber et al. used the combination of silver
acetate and P,N ligands12 to give good yields and stereose-
lectivities of the expected endo-adducts. On the other hand,
Komatsu et al.13 have reported the use of chiral phosphine-
copper triflate complexes yielding the exo-adducts as the
predominant products in the cycloaddition of azomethine
ylides and N-phenylmaleimide; however, moderate enanti-
oselectivity was obtained. Although some of these procedures
afford the corresponding cycloadducts in good yields and
high enantioselectivities, they normally require preformation
of the catalysts, dry and deoxygenated solvents, and glovebox
techniques. Also, the reactions must be carried out under an
inert atmosphere, which may limit their application from a
practical point of view. Therefore, the development of new
procedures that effect this 1,3-dipolar cycloaddition with high
yields and diastereo- and enantioselectivities under more
convenient reaction conditions is an important challenge.
In this communication we present a new catalytic asym-
metric strategy for the 1,3-dipolar cycloaddition of azome-
thine ylides with alkyl acrylates, which does not require
special precautions with regard to drying, degasifying
solvents, or using an inert atmosphere and which therefore
presents several advantages from a practical point of view
with regards to the previously described metal-complex-
catalyzed procedures.
metallo-azomethine ylide-chiral base ion pair. This species
would then react with the dipolarophile in a chiral environ-
ment to afford the expected cycloadduct stereoselectively
(Scheme 1).
Scheme 1. 1,3-Dipolar Cycloaddition of Azomethine Ylides,
Activated by a Metal Salt and a Chiral Base, and Alkenes
The 1,3-dipolar cycloaddition reaction of methyl N-(4-
methylbenzylidene) glycinate 1a and methyl acrylate 2a in
the presence of a cinchona alkaloid14 as the chiral base
(Figure 1) and a metal salt was used for the screening process
(Scheme 2). Some representative results are summarized in
Table 1.
Figure 1. Cinchona alkaloids screened in this work.
Our strategy is based on the use of a metal salt and a chiral
base, both in catalytic amount. We envisioned that chelation
of the metal to the iminoester followed by deprotonation by
a cinchona alkaloid, acting as the chiral base, would form a
For the screening of metal salts, lithium, zinc, and silver
salts were explored. The reaction yielded almost exclusively
the endo-adduct 3a in all cases. With the exception of AgCl,
silver salts were superior to lithium15 and zinc salts (Table
1, entries 1-4 and 14). We believe the low solubility of AgCl
in the reaction solvent reduces its efficacy. AgNO3 and AgF
gave similar results with cinchonine in toluene (Table 1,
entries 3 and 4), but AgF gave better conversions and more
reproducible results. We therefore chose AgF for the rest of
the screening. Cinchonine and quinine (entries 4 and 5) gave
similar results when used as chiral bases, but they lead to
different enantiomers, as usually happens when comparing
reactions catalyzed by this pair of cinchona alkaloids. They
gave also better conversions and enantioselectivites than other
cinchona alkaloid derivatives (entries 6, 7, and 13). Several
solvents were tested using the combination AgF-cinchonine;
(8) (a) Copper, D. M.; Grigg, R.; Hargreaves, S.; Kennewell, P. Redpath,
J. Tetrahedron 1995, 51, 7791-7808. (b) Grigg, R. Tetrahedron: Asym-
metry 1995, 6, 2475-2486. (c) Kanemasa, S.; Hayashi, T.; Tanaka, J.;
Yamamoto, H.; Sakurai, T. J. Org. Chem. 1991, 56, 4473-4481. (d) Galley,
G.; Liebscher, J.; Pa¨tzel, M. J. Org. Chem. 1995, 60, 5005-5010. (e) Garc´ıa-
Ruano, J. L.; Tito, A.; Peromingo, M. T. J. Org. Chem. 2002, 67, 981-
987.
(9) Allway, P.; Grigg, R. Tetrahedron Lett. 1991, 32, 5871-5820.
(10) Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002,
124, 13400-13401.
(11) Gothelf, A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2002, 41, 4236-4238.
(12) (a) Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc. 2003, 125,
10174-10175. (b) Kno¨pfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe,
T.; Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 5971-5793. (c) Stohler,
R.; Wahl, F.; Pfaltz, A. Synthesis 2005, 1431-1436.
(13) Oderaotoshi, Y.; Cheng, W.; Fujitomi, S.; Kasano, Y.; Minakata,
S.; Komatsu, M. Org. Lett. 2003, 5, 5043-5046.
4570
Org. Lett., Vol. 7, No. 21, 2005

Scheme 2. 1,3-Dipolar Cycloaddition of
Table 2. [1,3]-Dipolar Cycloaddition of Azomethine Ylides;
Substrate Scope
N-(4-Methylbenzylidene) Glycinate 1a with Methyl Acrylate 2aa
yield
(%)a
ee
(%)b
entry
R1, R2
1
R3
2
3
1c
2c
3c
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
p-Me-C6H4, Me
p-Me-C6H4, t-Bu
p-Me-C6H4, Me
p-Me-C6H4, Me
o-Me-C6H4, Me
C6H4, Me
o-MeO-C6H4, Me
m-MeO-C6H4, Me
p- MeO-C6H4, Me
1a Me 2a >95d
1b Me 2a 93d
1a t-Bu 2b >95d
1a t-Bu 2b 89
1c t-Bu 2b 97
1d t-Bu 2b 88
1e t-Bu 2b 63
1f t-Bu 2b 93
1g t-Bu 2b 89
3a 41
3b 32
3c 50
3c 70
3d 64
3e 64
3f 56
3g 70
3h 56
a Room temperature, overnight, 20 mol% base, 20 mol% metal
salt.
the best and most reproducible results (full conversion, 41%
ee at room temperature) were obtained in CH2Cl2. Finally,
hydrocinchonine was the best of the chiral bases tested,
providing full conversion and 57% ee at room temperature
(entry 12), higher than those obtained with cinchonine at
-24 °C (entry 11).
p-Me2N-C6H4, Me 1h t-Bu 2b 86 (41)e 3i 67 (92)e
p-Br-C6H4, Me
p-NC-C6H4, Me
p-MeO2C-C6H4, Me 1k t-Bu 2b 82 (41)e 3l 61 (85)e
1i t-Bu 2b 88
1j t-Bu 2b 86
3j 66
3k 70
2-furyl, Me
1l t-Bu 2b 86
1m t-Bu 2b 88
1n t-Bu 2b 86
1o t-Bu 2b 65
1p t-Bu 2b 78
1q t-Bu 2b 67
3m 73
3n 64
3o 62
3p 41
3q 41
3r 52
1-naphthyl, Me
2-naphthyl, Me
cyclohexyl, Me
t-Bu-CH2, Me
i-Pr, Me
Table 1. Screening of Metal Salts and Chiral Bases
metal
salt
conversiona
(%)
eeb
(%)
a Yields after column chromatography. b Determined by HPLC analysis
using Daicel Chiralpack AS. c Room temperature, overnight, 20 mol% base,
20% mol metal salt. d Conversions determined by 1H NMR analysis. e Yield
and ee after recrystallization.
entry
chiral base
solvent
1
2
3
4
5
6
7
8
LiBr
ZnCl2
AgNO3
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgCl
C
C
C
C
Q
toluene
toluene
toluene
toluene >95
toluene >95
43
<5
72
0
5
22
19
-20
2
of the ester group in the acrylate brought about an increase
in the enantioselectivity (Table 2, entry 3). This result
contrasts with that observed in the Zn-bisoxazoline catalyzed
reaction.10 Hence, we established that imines derived from
methyl glycine as the best dipole precursors and tert-butyl
acrylate 2b are the best dipolarophiles for this reaction. A
further improvement was achieved by carrying out the
reaction at -24 °C. Under these conditions the endo-adduct
was obtained in 89% isolated yield and 70% ee (Table 2,
entry 4).
(DHQD)2 PHAL toluene >95
â-ICD
C
C
C
C
HC
O-BnQ
C
toluene
Et2O
MeCN
CH2Cl2 >95
CH2Cl2 >95 (3 days)
CH2Cl2 >95
74
>95
>95
7
10
13
41
50
57
-13
9
10
11c
12
13
14
DCE
DCE
>95
0
a Conversions determined by 1H NMR analysis. b Determined by HPLC
analysis using Daicel Chiralpack AS. c Reaction carried out at -24 °C
during 3 days.
We also found that catalyst loading could be decreased to
5 mol %, both for AgF and hydrocinchone, without notice-
able effect on yield and enantioselectivity.
To assess the scope of the process, we investigated the
reaction between tert-butyl acrylate 2b and a variety of
R-imino esters 1 prepared from methyl glycinate and
aromatic and aliphatic aldehydes (Table 2, entries 4-19).
Utilizing the optimized conditions, the reaction showed
excellent levels of diastereoselectiviy with the endo-adduct
being obtained almost exclusively in all the cases. Aromatic
imino esters yielded the expected pyrrolidine derivatives with
We also investigated the effect exerted by the ester groups
on the imine 1 and the acrylate 2 (Scheme 3). Increasing
Scheme 3. 1,3-Dipolar Cycloaddition of Azomethine Ylides
with Acrylates
(14) For examples of the use of cinchona alkaloids in asymmetric
catalysis, see: (a) Cortez, G. S.; Tennyson, R. L.; Romo, D. J. Am. Chem.
Soc. 2001, 123, 7945-7946. (b) Tian, S.-K.; Deng, L. J. Am. Chem. Soc.
2001, 123, 6195-6196. (c) Acocella, M. R.; Garc´ıa Manchen˜o, O.; Bella,
M.; Jørgensen, K. A. J. Org. Chem. 2004, 69, 8165-8167. (d) Bella, M.;
Kobbelgaard, S.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 3670-
3671. (e) Saaby, S.; Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004,
126, 8120-8121. (f) Poulsen, T. B.; Alemparte, C.; Saaby, S.; Bella, M.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 2896-2899. (g) Bella,
M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 5672-5673.
(15) Tsuge, O.; Kanemasa, S.; Yoshioka, M. J. Org. Chem. 1988, 53,
1384-1391.
the bulkiness of the ester group in the imino ester (Table 2,
entries 1 and 2) had a negative effect on the enantioselectivity
of the reaction. On the other hand, increasing the bulkiness
Org. Lett., Vol. 7, No. 21, 2005
4571

high yields ranging from 80% to 97%, with the only
exception of methyl N-(2-methoxybenzylidene) glycinate
(1e). Remarkably, the efficiency of the reaction is nearly
independent of the characteristics of the aromatic ring. Thus,
a strong electron-donating substituent such as p-Me2N (entry
10) and electron-withdrawing groups such as Br, CN, or
CO2Me (entries 11-13) afford the corresponding cycload-
ducts in high yields (82-88%) and good enantioselectivities
(61-70%). In the same way, ortho (1b), meta (1e), or
unsubstituted (1c) derivatives (entries 5, 8, and 6, respec-
tively) as well as 1- (1l) and 2-naphthylmethylidene (1m)
glycinates (entries 15 and 16) give similar results (86-97%
yield, 62-70% ee). The highest ee was obtained with the
heterocyclic imino ester 1l (entry 14).
tion. For instance, pyrrolidines 3i and 3l could be enriched
up to 94% ee and 85% ee (entries 10 and 13), respectively,
upon crystallization from hexane-CH2Cl2.
In summary, we present here the first example of enan-
tioselective 1,3-dipolar cycloaddition of azomethine ylides
and alkenes, which is carried out under conditions that do
not require moisture or air exclusion. The reaction between
N-alkylidene glycine esters and tert-butyl acrylate catalyzed
by silver fluoride and a commercially available chiral base
(hydrocinchonine) proceeds with high endo diastereoselec-
tivity and fair enantioselectivity to give proline derivatives
bearing two esters groups, orthogonally protected. Enantio-
meric excesses can be increased upon recrystallization of
the adducts.
On the other hand, the less stable aliphatic imino esters
(entries 17-19) gave somewhat lower yield (65-78%) and
moderate enantioselectivities (41-52%).
Acknowledgment. This work was made possible by a
grant from The Danish National Research Foundation. G.B.
thanks UV and MEC (Spanish Government) for supporting
his stay at Aarhus University.
It is worth mentioning that the use of tert-butyl acrylate
not only gives higher enantioselectivity than methyl acrylate
but also the resulting pyrrolidines having two ester groups
orthogonally protected. This feature will allow independent
manipulation of both ester groups in the case of further
transformations on these products. Furthermore, most of the
pyrrolidine derivatives obtained from tert-butyl acrylate are
solids that may be enantiomerically enriched by crystalliza-
Supporting Information Available: Experimental pro-
1
cedures and characterization of the products. H NMR and
13C NMR spectra of compounds 3c-r. This material is
available free of charge via the Internet at http://pubs.acs.org.
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Org. Lett., Vol. 7, No. 21, 2005