Stereoselective synthesis of functionalized pyrrolidines by ruthenium porphyrin-catalyzed decomposition of α-diazo esters and cascade azomethine ylide formation/1,3-dipolar cycloaddition reactions

Article abstract of DOI:10.1021/ol034614v

(Matrix presented) Ruthenium porphyrins catalyze three-component coupling reaction of α-diazo esters with a series of N-benzylidene imines and alkenes to form functionalized pyrrolidines in excellent diastereoselectivities. The reaction proceeds via a reactive ruthenium-carbene intermediate and its subsequent reaction with imine to generate azomethine ylide, which reacts with alkenes via 1,3-diploar cycloaddition.

Full text of DOI:10.1021/ol034614v

ORGANIC
LETTERS
2
003
Vol. 5, No. 12
153-2156
Stereoselective Synthesis of
2
Functionalized Pyrrolidines by
Ruthenium Porphyrin-Catalyzed
Decomposition of r-Diazo Esters and
Cascade Azomethine Ylide Formation/
1,3-Dipolar Cycloaddition Reactions
†
†
‡
†
,†,‡
Gong-Yong Li, Jian Chen, Wing-Yiu Yu, Wei Hong, and Chi-Ming Che*
Shanghai-Hong Kong Joint Laboratory on Chemical Synthesis,
Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences,
354 Feng Lin Road, Shanghai 200032, China, and Department of Chemistry and Open
Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug
DiscoVery and Synthesis, The UniVersity of Hong Kong, Pokfulam Road, Hong Kong
cmche@hku.hk
Received April 9, 2003
ABSTRACT
Ruthenium porphyrins catalyze three-component coupling reaction of r-diazo esters with a series of N-benzylidene imines and alkenes to
form functionalized pyrrolidines in excellent diastereoselectivities. The reaction proceeds via a reactive ruthenium−carbene intermediate and
its subsequent reaction with imine to generate azomethine ylide, which reacts with alkenes via 1,3-diploar cycloaddition.
Dipolar cycloaddition of carbonyl ylides to multiply bonded
dipolarophiles continues to be a subject of considerable
interest. Notably, the dirhodium carboxylate-catalyzed tan-
philes has been proven to be a powerful method for regio-
and stereoselective synthesis of functionalized nitrogen
1
1b,2
heterocycles (e.g., pyrrolidines, alkaloids). Several routes
3
dem carbonyl ylide/1,3-dipolar cycloaddition by decomposi-
tion of diazocarbonyl compounds has been employed for
such as thermal or photolytic ring opening of aziridines,
4
5
desilylation, dehydrohalogenation of iminium salts, and
2
stereoselective synthesis of oxygen heterocycles. 1,3-Dipolar
cycloaddition of azomethine ylide with olefinic dipolaro-
(2) (a) Hodgson, D. M.; Pierard, F. Y. T. M.; Stupple, P. A. Chem. Soc.
ReV. 2001, 30, 50. (b) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern
Catalytic Methods for Organic Synthesis with Diazo Compounds; John
Wiley and Sons: New York, 1998; Chapter 7, p 397. (c) Padwa, A.;
Weingarten, M. D. Chem. ReV. 1996, 96, 223.
(3) (a) Huisgen, R.; Scheer, W.; M a¨ der, H. Angew. Chem., Int. Ed. Engl.
1969, 8, 602. (b) Heine, H. W.; Peavy, R. Tetrahedron Lett. 1965, 3123.
(c) Padwa, A.; Hamilton, L. Tetrahedron Lett. 1965, 4363.
†
The Chinese Academy of Sciences.
The University of Hong Kong.
‡
(1) (a) Ho, T. L. Tandem Organic Reactions; John Wiley and Sons: New
York, 1992. (b) Synthetic Application of 1,3-Dipolar Cycloaddition
Chemistry Heterocycles and Natural Products; Padwa, A., Pearson, W. H.,
Eds.; Wiley-Interscience: New York, 2002.
1
0.1021/ol034614v CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/09/2003

proton abstraction from imine derivatives of amino acids
have been exploited to generate the reactive azomethine
ylides in situ. Yet, interaction of metallocarbenoids with
2 2
of 2a with 1a and 3a (4 equiv) in CH Cl in the presence of
[Ru (TMP)(CO)] (0.5 mol %) at room temperature afforded
cycloadduct 4a in 78% isolated yield (Table 1). The structure
II
6
imine remains an attractive approach, because of mild
reaction conditions and excellent regio- and stereocontrol
achieved by elegant catalyst design. Padwa and co-workers
7
Table 1. Effect of Catalyst Loadinga
2 4
extensively studied the [Rh (OAc) ]-catalyzed intramolecular
cyclization of imino-substituted R-diazo carbonyl compounds
to form cyclic azomethine ylides, which subsequently
2
underwent 1,3-dipolar cycloaddition with dipolarophiles.
Examples of Cu(I)-catalyzed intermolecular reactions of
metallocarbenes with imines to give reactive azomethine
ylides are also known in the literature.8
entry
catalyst loading (mol %)
% yield of 4a
1
2
3
4
1
79
78
74
74
Metalloporphyrin-catalyzed carbenoid transformations us-
0.5
0.2
0.1
9
ing diazo compounds are currently receiving attention. We
10
and others have already reported that ruthenium porphyrins
see Figure 1) are effective catalysts for stereo- and enan-
(
a Reaction conditions: 1a/2a/3a ) 1:1.1:4 at room temperature.
1
of 4a was established by X-ray crystallography. H NMR
analysis of the crude reaction mixture detected 4a as a single
diastereomer under our experimental conditions. Different
catalyst loadings have been examined under the same
conditions. As depicted in Table 1, excellent activity was
found even at 0.1 mol % catalyst loading, and cycloadduct
4
a was obtained in 74% yield.
R-Diazo esters 2b,c also reacted uneventfully with 1a and
a under the Ru-catalyzed conditions to give 4 selectively
3
in ca. 60-75% yields (Table 2). Table 3 shows the effect of
Figure 1. Ruthenium Porphyrins
Table 2. Effect of the Ester Substituentsa
9
e-f
tioselective cyclopropanation
and C-H insertion reac-
tions9 and tandem carbonyl ylide formation/cycloaddition
reaction.9 As part of our continuing effort to develop
ruthenium-carbene-mediated stereoselective C-C bond
formations, we present herein the ruthenium porphyrin-
catalyzed tandem azomethine ylide formation/intermolecular
cycloaddition reactions to form functionalized pyrrolidines
in excellent yields and stereoselectivities.
b-d
a
entry
R
diazo ester
cycloadduct
% yield
1
2
3
Bn
Et
Me
2a
2b
2c
4a
4b
4c
74
56
76
a
II
Reaction conditions: [Ru (TMP)(CO)]/1a/2/3a ) 0.001:1:1.1:4 in
CH2Cl2 at room temperature.
solvent on the Ru-catalyzed cycloaddition with 1a, 2a, and
3
a as reactants. Apparently, halogenated solvents such as
CH Cl , CHCl , and 1,2-dichloroethane are the best solvent
2
2
3
systems. Employing toluene and benzene resulted in signifi-
cant lower yields (ca. 50%) of 4c under similar reaction
conditions.
(
4) Vedejs, E.; West, F. G. Chem. ReV. 1986, 86, 941.
(5) (a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565. (b)
Huisgen, R.; Grashey, R.; Steingruber, E. Tetrahedron Lett. 1963, 1441.
(6) (a) Grigg, R.; Kemp, J. Sheldrick, G.; Trotter, J. J. Chem. Soc., Chem.
Commun. 1978, 109. (b) Grigg, R.; Kemp, J. Tetrahedron Lett. 1980, 21,
Figure 2. Proposed Mechanism
2
461.
7) Padwa, A.; Dean, D. C.; Osterhout, M. H.; Precedo, L.; Semones,
M. A. J. Org. Chem. 1994, 59, 5347.
8) (a) Hansen, K. B.; Finney, N. S.; Jacobsen, E. N. Angew. Chem.,
(
We began by studying the Ru-catalyzed azomethine ylide
formation/cycloaddition involving benzyl diazoacetate (2a),
N-benzylidene imine (1a), and acrylate (3a). The reaction
(
Int. Ed. Engl. 1995, 34, 676. (b) Bartnik, R.; Mloston, G. Tetrahedron 1984,
40, 2569.
2154
Org. Lett., Vol. 5, No. 12, 2003

duct 4c was isolated in 80% yield. For the analogous
Table 3. Effect of Solventsa
reactions using other ruthenium porphyrin catalysts, however,
4
equiv of 3a would be needed to achieve similar yields of
the cycloadducts.
To define the scope and generality of the tandem azome-
thine ylide cycloaddition, we extended our studies by in-
cluding more benzylidine imines. Using methyl diazoacetate
as carbenoid source, dimethyl acetylene-dicarboxylate as a
dipolarophile, and [Ru (TDCPP)(CO)] as catalyst, all the
imines employed in this study were found to give the desired
cycloadducts in good to excellent yields as shown in Table
entry
solvent
% yield of 4c
1
2
3
4
5
CH2Cl2
CHCl3
1,2-dichloroethane
toluene
benzene
68
72
73
49
53
II
5
.
a
II
Reaction conditions: [Ru (TMP)(CO)]/1a/2c/3a ) 0.001:1:1:4 at room
temperature.
Table 5. Cycloaddition with Various N-Benzylidene Imines 1
The effect of ligand structure on the ruthenium porphyrin-
catalyzed cycloadditon reactions has been examined. As
depicted in Table 4, up to 91% yield of 4c was obtained
entry
R1
R2
cycloadduct
% yield
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
5a
5b
5c
5d
5e
5f
5g
5h
5i
90
84
85
59
92
87
98
90
69
nil
Table 4. Effect of Porphyrin Structurea
p-CH3OC6H4
p-ClC6H4
Ph
Ph
Ph
Ph
Ph
m-ClC6H4
o-ClC6H4
p-NO2C6H4
p-ClC6H4
p-CH3OC6H4
p-MeC6H4
m-CH3OC6H4
Ph
entry
catalyst
% yield of 4c
II
1
2
3
4
[Ru (TMP)(CO)]
78
79
91
61
1
0
Ph
5j
II
[Ru (TPP)(CO)]
II
[Ru (TDCPP)(CO)]
II
[Ru (TDMPP)(CO)]
As shown in Table 5, imine 1d (R
Ph) bearing an electron-withdrawing NO
cycloadduct 5d with the lowest yield (59%). However, 5g
1
) p-NO
2
-C
6 4 2
H , R
group gave
a
Reaction conditions: Ru catalyst/1a/2c/3a ) 0.001:2.0:1.0:4 at room
temperature.
)
2
was obtained in almost quantitative yield (98%) for the
II
reaction with imine 1g (R
containing an electron-donating substituent.
A less pronounced influence was observed when varying
the substituent R (see Table 5, entries 1-3). The yield of
the cycloaddition is dependent on the steric factors of the
imine. For example, the reaction of 1i (R ) Ph, R ) m-Cl-
) gave 5i in lower yield of 69%, compared to 85% yield
obtained when 1c (R ) Ph, R ) p-Cl-C ) was the
substrate. Notably, with 1j (R ) Ph, R ) o-Cl-C ) as
1
) p-CH
3
-C
6 4 2
H , R ) Ph)
when [Ru (TDCPP)(CO)] [H
2
TDCPP ) meso-tetrakis(2,6-
dichlorophenyl)porphyrin] was employed (entry 3). However,
II
with [Ru (TDMPP)(CO)] [H TDMPP ) meso-tetrakis(2,6-
2
2
dimethoxyphenyl) porphyrin], the cycloaddition furnished a
lower product yield of 61% (entry 4).
With [Ru (TDCPP)(CO)] (0.1 mol %) as catalyst, we
found that using 1.5 and 4 equiv of acrylate 3 gave similar
II
1
2
6 4
C H
1
2
6 4
H
results for the azomethine ylide cycloadditon, and cycload-
1
2
6 4
H
substrate, no cycloadduct was isolated. We attribute this
finding to the steric bulkiness of 1j and 1i, and the Ru-
catalyzed cycloaddition would proceed via a highly organized
transition state involving three reaction components.
In this work, we have studied the Ru-catalyzed azomethine
ylide cycloaddition with various dipolarophiles. We first
examined the reactions with a series of monosubstituted
alkenes 3a-c as dipolarphiles. Reactions of 1b (1.1 equiv),
(
9) (a) Zhou, C.-Y.; Yu, W.-Y.; Che, C.-M. Org. Lett. 2002, 4, 3235.
(
b) Zhang, J.-L.; Che, C.-M. Org. Lett. 2002, 4, 1911. (c) Zheng, S.-L.;
Yu, W.-Y.; Che, C.-M. Org. Lett. 2002, 4, 889. (d) Li, Y.; Huang, J.-S.;
Zhou, Z.-Y. J. Am. Chem. Soc. 2001, 123, 4843. (e) Che, C.-M.; Huang,
J.-S.; Lee, F.-W.; Li, Y.; Lai, T.-S.; Kwong, H.-L.; Teng, P.-F.; Lee,
W.-S.; Lo, W.-C.; Peng, S.-M.; Zhou, Z.-Y. J. Am. Chem. Soc. 2001, 123,
4
119. (f) Lo, W.-C.; Che, C.-M.; Cheng, K.-F.; Mak, T. C.-W. J. Chem.
Soc., Chem. Commun. 1997, 1205.
10) For works by others, see for example: (a) Mirafzal, G. A.; Cheng,
(
G.; Woo, L. K. J. Am. Chem. Soc. 2002, 124, 176. (b) Hamaker, C. H.;
Djukic, J.-P.; Smith, D. A.; Woo, L. K. Organometallics 2001, 20, 5189.
c) Galardon, E.; Maux, P. L.; Simonneaux, G. Tetrahedron 2000, 56, 615.
d) Gross, Z.; Galili, N.; Simkhovich, L. Tetrahedron Lett. 1999, 40, 1571.
e) Galardon, E.; Rou e´ , S.; Maux, P. L.; Simonneaux, G. Tetrahedron Lett.
(
(
(
2 2
2c (1 equiv), and the alkenes (1.5 equiv) in CH Cl in the
II
presence of [Ru (TDCPP)(CO)] (0.1 mol %) afforded
cycloadducts 4d, 4e, and 4f in 63, 57, and 61%, respectively
(Table 6, entries 1-3).
1
998, 39, 2333. (f) Galardon, E.; Maux, P. L.; Simonneaux, G. J. Chem.
Soc., Perkin Trans. 1 1997, 2455. (g) Frauenkron, M.; Berkessel, A.
Tetrahedron Lett. 1997, 38, 7175. (h) Galardon, E.; Maux, P. L.;
Simonneaux, G. Chem. Commun. 1997, 927. (i) Smith, D. A.; Reynolds,
D. N.; Woo, L. K. J. Am. Chem. Soc. 1993, 115, 2511.
Similarly disubstituted alkenes 3d,f such as R-methyl
acrylate, cinnamophenone, and N-phenylmaleimide also
Org. Lett., Vol. 5, No. 12, 2003
2155

alkenes as dipolarophiles could be ascribed to the increased
steric bulkiness of the alkenes. When dimethyl acetylene-
dicarboxylate was used as dipolarophile, the reaction with
Table 6. Cycloaddition with Various Dipolarophilesa
1
b and 2c proceeded effectively to give the expected
cycloadduct in 84% yield.
Previous studies showed that ruthenium(II) porphyrins
reacted with diazo compounds to give ruthenium-carbene
9
c-f
complexes.
We postulate that the cycloaddition is medi-
ated by an azomethine ylide intermediate, which is generated
by the reaction of ruthenium-carbene complexes with imine.
The azomethine ylide (which can be a free or metal-bound
species) undergoes 1,3-dipolar cycloaddition with alkenes
to give the functionalized prolines as products.
In conclusion, ruthenium porphyrin complexes are excel-
lent catalysts for the azomethine ylide-mediated cycloaddition
reaction involving N-benzylidene imine, diazo esters, and
alkenes to form functionalized pyrrolidines with remarkable
stereoselectivity. Such a one-pot, three-component coupling
system provides a convenient entry to functionalized nitrogen
heterocycles that are of interest in organic synthesis.
Acknowledgment. We are thankful for the financial
support of The University of Hong Kong (Generic Drugs
Research Program), the Area of Excellence Scheme (AoE
1
(
7
0/01P), administered by the University Grants Council
HKSAR), and Hong Kong Research Grants Council (HKU
099/01P). We acknowledge Drs. Nian-Yong Zhu (HKU)
and Jie Sun (SIOC) for performing the X-ray crystallographic
analyses of 4d and 5a, respectively. L.G.Y. thanks the
Croucher Foundation of Hong Kong for the postgraduate
studentship.
a
Reaction conditions: Ru catalyst/1a/2c/3 ) 0.001:2.0:1.0:4. b Reaction
Supporting Information Available: Detailed descrip-
tions of experimental procedures, characterization data, and
detailed description of the X-ray crystallographic determi-
nation of 4d and 5a. This material is available free of charge
via the Internet at http://pubs.acs.org.
c
was undertaken at room temperature. Reaction was undertaken at 50°C.
reacted with 1b and 2c under the Ru-catalyzed conditions
to afford the cycloadducts 4g-i in ca. 50% yield. The
moderate yields observed for the reactions with disubstituted
OL034614V
2156
Org. Lett., Vol. 5, No. 12, 2003