Cu- And Pd-catalyzed asymmetric one-pot tandem addition-cyclization reaction of 2-(2′,3′-alkadienyl)-β-keto esters, organic halides, and dibenzyl azodicarboxylate: An effective protocol for the enantioselective synthesis of pyrazolidine derivatives

Article abstract of DOI:10.1021/ol0493498

Optically active pyrazolidine derivatives have been constructed by the Cu- and Pd-catalyzed asymmetric one-pot tandem addition-cyclization reaction of 2-(2′,3′-dienyl)-β-ketoesters, organic halides, and dibenzyl azodicarboxylate. The absolute configuratio

Full text of DOI:10.1021/ol0493498

ORGANIC
LETTERS
2004
Vol. 6, No. 13
2193-2196
Cu- and Pd-Catalyzed Asymmetric
One-Pot Tandem Addition−Cyclization
Reaction of 2-(2′,3′-Alkadienyl)-â-keto
Esters, Organic Halides, and Dibenzyl
Azodicarboxylate: An Effective Protocol
for the Enantioselective Synthesis of
Pyrazolidine Derivatives
Shengming Ma,*,†,‡ Ning Jiao,† Zilong Zheng,† Zhichao Ma,‡ Zhan Lu,‡
Longwu Ye,‡ Youqian Deng,‡ and Guofei Chen‡
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, P. R. China, and Department of Chemistry,
Zhejiang UniVersity, Hangzhou 310027, P. R. China
masm@mail.sioc.ac.cn
Received April 9, 2004
ABSTRACT
Optically active pyrazolidine derivatives have been constructed by the Cu- and Pd-catalyzed asymmetric one-pot tandem addition−cyclization
reaction of 2-(2′,3′-dienyl)-â-ketoesters, organic halides, and dibenzyl azodicarboxylate. The absolute configurations of the final products
depend on the structure of the ligand.
The development of new chemical processes for producing
elaborate and important hetereocyclic structures in a rapid,
atom-economic,1 and efficient manner has become an
important area of research in organic chemistry. One of the
major challenges in these areas is the multicomponent
process in which a given target molecule would be assembled
from three or more simple and flexible building blocks in a
practical one-pot operation.2,3
Pyrazolidines are an intensively studied family of hetero-
cycles, which are important subunits in biologically active
naturally occurring compounds.4 This pyrazolidine structural
(2) (a) Tietze, L. F. Chem. ReV. 1996, 96, 115. (b) Parsons, P. J.; Penkett,
C. S.; Shell, A. J. Chem. ReV. 1996, 96, 195. (c) Bunce, R. A. Tetrahedron
1995, 51, 13103.
(3) For recent reviews, see: (a) Hulme, C.; Gore, V. Curr. Med. Chem.
2003, 10, 51. (b) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471. (c)
Zhu, J. Eur. J. Org. Chem. 2003, 1133. (d) Balme, G.; Bossharth, E.;
Monteiro, N. Eur. J. Org. Chem. 2003, 4101. (e) Bienayme´, H.; Hulme,
C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321. (f) Do¨mling, A.;
Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (g) Tietze, L. F.; Modi, A.
Med. Res. ReV. 2000, 20, 304. (h) Weber, L.; Illgen, K.; Almstetter, M.
Synlett 1999, 366. (i) Dax, S. L.; Mcnally, J. J.; Youngman, M. A. Curr.
Med. Chem. 1999, 6, 255.
* Fax: (+86)21-64167510.
† Chinese Academy of Sciences.
‡ Zhejiang University.
(1) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew.
Chem., Int. Ed. Engl. 1995, 34, 259.
10.1021/ol0493498 CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/26/2004

unit is usually constructed by the [3 + 2] cycloaddition5,6 or
hetero-Diels-Alder reactions.7 Although these methods are
available, there are still some obvious limitations: the starting
material is complex, and the methods for the synthesis of
optically active pyrazolidines are still very limited.
Recently, the direct enantioselective amination of 2-keto-
esters catalyzed by chiral copper(II)-bisoxazoline complexes
was reported.8 On the basis of our past work,9,10 we reasoned
that pyrazolidines 1 with different substitution patterns may
be generally constructed from π-allypalladium intermediate11
2, which in turn, could be generated easily via the carbo-
palladation of intermediate 3 with allene 412,13 (Scheme 1).
three-component asymmetric tandem addition-cyclization
leading to optically active pyrazolidine derivatives with high
selectivity.
Our first approach was based on the reaction of 2-(2′,3′-
dienyl)-â-ketoesters 5a and dibenzyl azodicarboxylate (DBAD)
6 with PhI (7a). First, the enantioselective amination of 5a
with DBAD 6 in CH2Cl2 provided the corresponding
optically active allenic amide 4a (E1 ) COCH3; E2 )
COOEt; R1 ) R2 ) COOBn) in quantitative yield. Then,
the solvent was removed in vacuo and THF was added to
the reaction mixture followed by treatment with PhI,
Pd(PPh3)4 (5% mol), and K2CO3 (2.0 equiv) under reflux
(Scheme 2). The carbopalladation reaction14 of the allenes
afforded a 2-type π-allyl palladium intermediate,11 which can
be further trapped by the intramolecular nitrogen giving the
corresponding pyrazolidine derivative 1aa in good overall
yields with very high enantioselectivity (Scheme 2). On the
Scheme 1
Scheme 2
The optically active allene 4 may be produced from enantio-
selective copper (II)-catalyzed R-amination of R-allenic-
substituted â-keto esters 5 with azodicarboxylates 6 (Scheme
1). Herein, we describe the Cu- and Pd-catalyzed one-pot
(4) (a) Rahman, M. T.; Nishino, H.; Qian, C.-Y. Tetrahedron Lett. 2003,
44, 5225. (b) Chauveau, A.; Martens, T.; Bonin, M.; Micouin, L.; Husson,
H.-P. Synthesis 2002, 1885. (c) Hanessian, S.; Mcnaughton-Smish, G.;
Lombart, H.-G. Tetrahedron 1997, 53, 12798. (d) Kim, H.-O.; Lum, C.;
Lee, M. S. Tetrahedron Lett. 1997, 38, 4935.
(5) (a) For some reviews, see: (a) Huisgen, R.; Grashey, R.; Sauer, J.
In The Chemistry of Alkenes: Cycloaddition Reactions of Alkenes; Patai,
S., Ed.; Interscience: New York, 1964; pp 739-953. (b) Huisgen, R. 1,3-
Dipolar Cycloaddition Chemistry: 1,3-Dipolar Cycloaddition-Introduction,
SurVey, Mechanism; Padwa, A., Ed.; Wiley-Interscience: New York, 1984;
Vol. 1, pp 1-176. (c) Huisgen, R. AdVance in Cycloaddition: Steric Course
and Mechanism of 1,3-Dipolar Cycloaddition; Curran, D. P., Ed.; JAI
Press: Greenwich, CT, 1988; Vol. 1, pp 1-31.
(6) (a) Kobayashi, S.; Hirabayashi, R.; Shimizu, H.; Ishitani, H.;
Yamashita, Y. Tetrahedron Lett. 2003, 44, 3351. (b) Kobayashi, S.; Shimizu,
H.; Yamashita, Y.; Ishitani, H.; Kobayashi, J. J. Am. Chem. Soc. 2002,
124, 13678. (c) Ja¨ger, V.; Bierer, L.; Dong, H.-Q.; Palmer, A. M.; Shaw,
D.; Frey, W. J. Heterocycl. Chem. 2000, 37, 455. (d) Mish, M. R.; Guerra,
F. M.; Carreira, E. M. J. Am. Chem. Soc. 1997, 119, 8379. (e) Gallos, J.
K.; Koumbis, A. E.; Apostolakis, N. E. J. Chem. Soc., Perkin Trans. 1
1997, 2457. (f) Khau, V. V.; Martinelli, M. J. Tetrahedron Lett. 1996, 25,
4323.
(7) Ellis, J. M.; King, S. B. Tetrahedron Lett. 2002, 43, 5833.
(8) (a) Marigo, M.; Juhl, K.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2003, 42, 1367. (b) Juhl, K.; Jørgensen, K. A. J. Am. Chem. Soc. 2002,
124, 2420. (c) Evans, D. A.; Nelson, S. G. J. Am. Chem. Soc. 1997, 119,
6452.
(9) Ma, S.; Jiao, N. Angew. Chem., Int. Ed. 2002, 41, 4737.
(10) For some of our most recent results, see: (a) Ma, S.; Duan, D.;
Shi, Z. Org. Lett. 2000, 2, 1419. (b) Ma, S.; Zhang, J. Chem. Commun.
2000, 117. (c) Ma, S.; Li, L. Org. Lett. 2000, 2, 941. (d) Ma, S.; Xie, H.
Org. Lett. 2000, 2, 3801. (e) Ma, S.; Zhao, S. J. Am. Chem. Soc. 1999,
121, 7943. (f) Ma, S.; Yu, F.; Gao, W. J. Org. Chem. 2003, 68, 5943.
(11) Shimizu, I.; Tsuji, J. Chem. Lett. 1984, 233. Ahmar, M.; Cazes, B.;
Gore, J. Tetrahedron Lett. 1984, 25, 4505.
basis of these results, it is quite obvious that the enantio-
selectivity for the formation of 4a is very high with the abso-
lute configuration depending on the structure of the ligand.
Although the diastereoselectivity is unsatisfactory, the
diastereoisomers differ greatly in terms of molecular polarity
(Rf(R,R)-1aa ) 0.48, Rf(R,S)-1aa ) 0.35; eluent, petroleum ether/
ether ) 1:1) and therefore can be easily separated and
purified by flash chromatography on silica gel. Then, the
four pure isomers (S,S)-, (S,R)-, (R,R)-, and (R,S)-isomer of
1aa can be conveniently obtained in high yield with very
high ee when both enantiomers of Ph-Box were applied as
the ligand.
(12) Schuster, H. F.; Coppola, G. M. Allenes in Organic Synthesis; John
Wiley & Sons: New York, 1984. Patai, S., Ed. The Chemistry of Ketenes,
Allenes, and Related Compounds; John Wiley & Sons: New York, 1980;
Part 1.
(13) (a) Ma, S.; Shi, Z. J. Org. Chem. 1998, 63, 6387. (b) Ma, S.; Zhao,
S. Org. Lett. 2000, 2, 2495. (c) Ma, S.; Jiao, N. Zhao, S.; Hou, H. J. Org.
Chem. 2002, 67, 2837. (d) Ma, S.; Gao, W. Org. Lett. 2002, 4, 2989.
(14) For intermolecular carbopalladation of allenes, see: (a) Cazes, B.
Pure Appl. Chem. 1990, 62, 1867 and references therein. (b) Larock, R.
C.; Berrios-Pena, N. G.; Fried, C. A. J. Org. Chem. 1991, 56, 2615.
2194
Org. Lett., Vol. 6, No. 13, 2004

Table 1. Cu and Pd-Catalyzed Three-Component Asymmetric Tandem Addition-Cyclization Reactions of
2-(2′,3′-Dienyl)-â-keto-esters 5a and Dibenzyl Azodicarboxylate (DBAD) 6 with PhI 7a in Different Solventsa
entry
solvent (1)
t (1), °C
time(1), h
solvent (2)
t (2), °C
time (2), h
yield (%)
dr (% ee) (R,R)/(R,S)
1
2
3
4
5
6
7
8
9
CH2Cl2
THF
CH2Cl2
CH2Cl2
CH2Cl2/Bb
CH2Cl2
CH2Cl2/Bb
CH2Cl2/Cb
CH2Cl2/Db
0
3
57
3
3
3
1.5
10
20
20
THF
THF
reflux
reflux
reflux
100
100
100
100
100
100
4
4
4
4
4
4
4
4
4
92
66
92
85
95
100
90
19
0
36:64 (98;98)
48:52 (99;96)
40:60 (98;98)
33:67 (98;98)
32:68 (95;95)
37:63 (97;97)
36:64 (97;98)
76:24 (13;8)
0
0-rt
0
0
rt
rt
0
0
0
CH2Cl2/Ab
CH2Cl2/Bb
CH2Cl2/Bb
CH2Cl2/Bb
CH2Cl2/Bb
CH2Cl2/Cb
CH2Cl2/Db
a DBAD (1.2 equiv), Ph-Box (1.1 equiv of Cu), PhI (1.2 equiv), and K2CO3 (2.0 equiv) were applied. b A ) THF; B ) 1,4-dioxane; C ) DMSO; D )
DMF. The solvent ratio was 1:2.
To identify a more convenient operation for the reaction,
we tested the effect of the solvents of the two steps on the
Table 2. Cu- and Pd-Catalyzed Three-Component Asymmetric
reaction. The results are summarized in Table 1. When both
Tandem Addition-Cyclization Reactions of
2-(2′,3′-Dienyl)-â-keto-esters 5a and Dibenzyl Azodicarboxylate
steps were carried out in THF, high enantioselectivity was
achieved; however, the yield and diastereoselectivity were
unsatisfactory (entry 2, Table 1). When a mixture of CH2Cl2/
1,4-dioxane (1:2) was used as the solvent in both steps, the
results were better (entry 7, Table 1), but the first step was
slow (compare entry 7 with entry 4, Table 1). The reaction
gave poor results in the mixed solvent of DMSO or DMF
and CH2Cl2 (entries 8 and 9, Table 1). The temperature in
the first step is important to the enantioselectivity (compare
entry 4 with entry 6 and entry 5 with entry 7, Table 1). On
the basis of these results, CH2Cl2 was chosen as the solvent
at 0 °C in the first step followed by the direct addition of
1,4-dioxane (double volume of CH2Cl2) to the reaction
mixture to conduct the second step at 100 °C.
(DBAD) 6 with Different Organohalides
The results of the Cu- and Pd-catalyzed three-component
asymmetric tandem addition-cyclization reactions of 2-(2′,3′-
dienyl)-â-ketoesters 5a and dibenzyl azodicarboxylate (DBAD)
6 with different organohalides are summarized in Table 2.
From these results, it should be noted that (1) the yield and
the enantioselectivity of these reactions are high and (2) the
configuration of the CdC bond in 1-alkenyl iodide remained
unchanged during the reaction (entries 7-9, Table 2). To
determine the absolute structure of the pyrazolidine deriva-
tive, we studied the reaction of 5a, 6, and 1-bromo-4-
iodobenzene 7e, which afforded the solid pyrazolidine
derivative 1ae with a bromine atom in the structure,
indicating that the C-I bond was chemoselectively cleaved.
The absolute configurations of 1ae were determined by X-ray
diffraction studies,15,16 which led to the tentative assignment
Org. Lett., Vol. 6, No. 13, 2004
2195

of the absolute configurations of other products. It is obvious
that the reaction favors the formation of trans-pyrazolidine
derivative.
reaction of 2-(2′,3′-dienyl)-â-keto esters, organic halides, and
dibenzyl azodicarboxylate leading to pyrazolidine derivatives
with high enantioselectivity. The advantages of this method
are the easy availability and diversity of the starting
compounds. Although the diastereoselectivity needs further
attention, this study will open a new area for the transition
metal-catalyzed chemistry of allenes. Further studies on the
scope and synthetic applications of this reaction are being
pursued in our laboratory.
In the reaction, it is valuable to note the following: (1)
The reaction that allows a great increase in complexity is
atom economic. (2) Although two different metals were used
to catalyze the reaction, the operation is convenient with a
one-pot operation and the yield is very high. (3) Two
diastereomers were easily separated with high ee.
In conclusion, we have demonstrated the Cu- and Pd-
catalyzed asymmetric one-pot tandem addition-cyclization
Acknowledgment. Financial support from the Major
State Basic Research Development Program (Grant G20000-
77500), the National Natural Science Foundation of China,
and Shanghai Municipal Committee of Science and Technol-
ogy are greatly appreciated.
(15) CCDC 232606. Crystal data for compound cis-1ae (3R,5R): C32-
H31N2O7Br, MW ) 635.50, crystal system, space group orthorhombic,
P2(1)2(1)2(1), Mo KR, final R indices [I > 2σ(I)], R1 ) 0.0469, wR2 )
0.0813, a ) 8.9635 (9) Å, b ) 10.2834 (11) Å, c ) 32.786 (4) Å, R ) 90°,
â ) 90°, γ ) 90°, V ) 3022.1 (6) Å3, T ) 293 (2) K, Z ) 4, reflections
collected/unique: 18 496/7023 (Rint ) 0.0975), no observation [I > 2σ(I)]
3265, parameters 425, absolute structure parameter: -0.001 (7).
(16) CCDC 232607. Crystal data for compound trans-1ae (3R,5S):
C32H31N2O7Br, MW ) 635.50, crystal system, space group orthorhombic,
P2(1)2(1)2(1), Mo KR, final R indices [I > 2σ(I)], R1 ) 0.0629, wR2 )
0.1517, a ) 9.0453 (7) Å, b ) 9.5125 (8) Å, c ) 35.549 (3) Å, R ) 90°,
â ) 90°, γ ) 90°, V ) 3058.7 (4) Å3, T ) 293 (2) K, Z ) 4, reflections
collected/unique: 18 653/7107 (Rint ) 0.0710), no observation [I > 2σ(I)]
2796, parameters 357, absolute structure parameter: 0.014 (14).
Supporting Information Available: Typical experimen-
tal procedure and analytical data for all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0493498
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Org. Lett., Vol. 6, No. 13, 2004