Palladium(II)-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition of Nitrones to 3-Alkenoyl-1,3-oxazolidin-2-ones

Article abstract of DOI:10.1021/jo981483g

Chiral phosphinepalladium(II)-catalyzed asymmetric 1,3-dipolar cycloaddition of nitrones to α,β-unsaturated carboxylic acid derivatives has been investigated. In the presence of a catalytic amount of [Pd(NCMe)₂{(S)-tolbinap}](BF₄)₂ [TolBINAP = 2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl], the reaction of 3-alkenoyl-1,3-oxazolidin-2-ones as dipolarophiles and N-substituted N-benzylidenenitrones has been successfully performed to give isoxazolidine derivatives in high yields with high enantioselectivities. For example, 3-((2,5-dimethyl-3-phenylisoxazolidin-4-yl)carbonyl)-1,3-oxazolidin-2-one was obtained from the reaction of N-benzylidenemethylamine N-oxide and 3-crotonoyl-1,3-oxazolidin-2-one in 89% yield with 60% endo selectivity and 91% ee of the endo isomer. The cycloaddition of N-benzylidenebenzylamine N-oxide and 3-crotonoyl-1,3-oxazolidin-2-one afforded 3-((2-benzyl-5-methyl-3-phenylisoxazolidin-4-yl)carbonyl)-1,3-oxazolidin-2-one in 94% yield with 93% endo selectivity and 89% ee of the endo isomer. Remarkably, the endo/exo selectivity of the products depended on the N-substituent group of the nitrones. These selectivities were explained using molecular modeling.

Full text of DOI:10.1021/jo981483g

J . Org. Chem. 1999, 64, 5017-5023
5017
P a lla d iu m (II)-Ca ta lyzed Asym m etr ic 1,3-Dip ola r Cycloa d d ition of
Nitr on es to 3-Alk en oyl-1,3-oxa zolid in -2-on es
Kazushige Hori, Hidehiko Kodama, Tetsuo Ohta, and Isao Furukawa*
Department of Molecular Science and Technology, Faculty of Engineering, Doshisha University,
Kyotanabe, Kyoto 610-0394, J apan
Received J uly 27, 1998
Chiral phosphinepalladium(II)-catalyzed asymmetric 1,3-dipolar cycloaddition of nitrones to R,â-
unsaturated carboxylic acid derivatives has been investigated. In the presence of a catalytic amount
of [Pd(NCMe)2{(S)-tolbinap}](BF4)2 [TolBINAP ) 2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl], the
reaction of 3-alkenoyl-1,3-oxazolidin-2-ones as dipolarophiles and N-substituted N-benzylideneni-
trones has been successfully performed to give isoxazolidine derivatives in high yields with high
enantioselectivities. For example, 3-((2,5-dimethyl-3-phenylisoxazolidin-4-yl)carbonyl)-1,3-oxazolidin-
2-one was obtained from the reaction of N-benzylidenemethylamine N-oxide and 3-crotonoyl-1,3-
oxazolidin-2-one in 89% yield with 60% endo selectivity and 91% ee of the endo isomer. The
cycloaddition of N-benzylidenebenzylamine N-oxide and 3-crotonoyl-1,3-oxazolidin-2-one afforded
3-((2-benzyl-5-methyl-3-phenylisoxazolidin-4-yl)carbonyl)-1,3-oxazolidin-2-one in 94% yield with 93%
endo selectivity and 89% ee of the endo isomer. Remarkably, the endo/exo selectivity of the products
depended on the N-substituent group of the nitrones. These selectivities were explained using
molecular modeling.
In tr od u ction
by J ørgensen,6 Scheeren,7 and Inomata8 using chiral
Lewis acids as catalysts under stringently anhydrous
conditions. Recently, J ørgensen and Kobayashi reported
the same reaction catalyzed by chiral magnesium(II)9 or
ytterbium(III)10 complexes as stable catalysts in moisture;
however, the enantioselectivity depended on the amount
of water or the structure of the nitrone. In contrast, late
transition metal complexes11 such as palladium or ru-
Optically active heterocyclic compounds are not only
useful in themselves but are also widely employable
intermediates for preparing chiral acyclic compounds.1
In particular, isoxazolidines can be converted to γ-amino
alcohols, which are precursors to biologically active
compounds such as alkaloids and â-lactam antibiotics2
(eq 1).
(3) (a) Brandi, A.; Cicchi, S.; Goti, A.; Pietrusiewicz, K. M.; Zablocka,
M.; Wieniewski, W. J . Org. Chem. 1991, 56, 4383-4388. (b) Takahashi,
T.; Fujii, A.; Sugita, J .; Hagi, T.; Kitano, K.; Arai, Y.; Koizumi, T.
Tetrahedron: Asymmetry 1991, 2, 1379-1390. (c) Iyo, M.; Maeda, M.;
Kibayashi, C. Tetrahedron Lett. 1992, 33, 3765-3768. (d) Bravo, P.;
Bruche, L.; Farina, A.; Fronza, G.; Meille, S. V.; Merli, A. Tetrahe-
dron: Asymmetry 1993, 4, 2131-2134. (e) Murahashi, S.-I.; Imada,
Y.; Kohno, M.; Kawakami, T. Synlett 1993, 395-396. (f) Saito, S.;
Ishikawa, T.; Moriwake, T. Synlett 1994, 279-281. (g) Louis, C.;
Hootele´, C. Tetrahedron: Asymmetry 1995, 6, 2149-2152. (h) Ina, H.;
Ito, M.; Kibayashi, C. J . Org. Chem. 1996, 61, 1023-1029.
(4) (a) Mukai, C.; Kim, I. J .; Cho, W. J .; Kido, M.; Hanaoka, M. J .
Chem. Soc., Perkin Trans. 1 1993, 2495-2503. (b) Saito, S.; Ishikawa,
T.; Kishimoto, K.; Kohara, T.; Moriwake, T. Synlett 1994, 282-284.
(c) Brandi, A.; Cicchi, S.; Goti, A. J . Org. Chem. 1994, 59, 1315-1318.
(d) van den Broek, L. A. G. M. Tetrahedron 1995, 52, 4467-4478. (e)
Broggini, G.; Folcio, F.; Sardone, N.; Sonzogni, M.; Zecchi, G. Tetra-
hedron: Asymmetry 1996, 7, 797-806.
(5) The review of asymmetric 1,3-dipolar cycloaddition: (a) Gothelf,
K. V.; J ørgensen, K. A. Acta Chem. Scand. 1996, 50, 652-660. (b)
Frederickson, M. Tetrahedron 1997, 53, 403-425. (c) Gothelf, K. V.;
J ørgensen, K. A. Chem. Rev. 1998, 98, 863-909.
(6) (a) Gothelf, K. V.; J ørgensen, K. A. J . Org. Chem. 1994, 59, 5687-
5691. (b) Gothelf, K. V.; Hazell, R. G.; J ørgensen, K. A. J . Am. Chem.
Soc. 1995, 117, 4435-4436. (c) Gothelf, K. V.; Thomsen, I.; J ørgensen,
K. A. J . Am. Chem. Soc. 1996, 118, 59-64. (d) J ensen, K. B.; Gothelf,
K. V.; J ørgensen, K. A. Helv. Chim. Acta 1997, 80, 2039-2046.
(7) (a) Seerden, J .-P. G.; Scholte op Reimer, A. W. A.; Scheeren, H.
W. Tetrahedron Lett. 1994, 35, 4419-4422. (b) Seerden, J .-P. G.;
Kuypers, M. M. M.; Scheeren, H. W. Tetrahedron: Asymmetry 1995,
6, 1441-1450. (c) Seerden, J .-P. G.; Boeren, M. M. M.; Scheeren, H.
W. Tetrahedron 1997, 53, 11843-11852.
These heterocycles traditionally are prepared from the
1,3-dipolar cycloaddition of nitrones to olefins.2 Over the
past few years, the use of chiral olefins3 and nitrones4
has provided for the asymmetric synthesis of isoxazoli-
dine.5 However, only a few catalytic asymmetric 1,3-
dipolar cycloadditions have been reported so far.5a Since
1994, very good asymmetric induction has been achieved
* To whom correspondence should be addressed. Phone: 81 (J apan)-
774-65-6623. Fax: 81 (J apan)-774-65-6794. E-mail: ifurukaw@
mail.doshisha.ac.jp
(1) (a) Comprehensive Organic Chemistry; Sammes, P. G., Ed.;
Pergamon: Oxford, 1979; Vol. 4. (b) Comprehensive Heterocyclic
Chemistry; Katritzky, A. R.; Rees, C. W.; Eds.; Pergamon: Oxford;
1984; Vols. 1-8.
(2) (a) 1,3-Dipolar Cycloaddition Chemistry, Vol. 2; Padwa, A., Ed.;
Wiley: New York, 1984; Chapter 9, pp 83-168. (b) Torssell, K. B. G.
Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis; VCH:
New York, 1988. (c) Confalone, P. N.; Huie, E. M. Org. React. 1988,
36, 1-173.
(8) (a) Ukaji, Y.; Sada, K.; Inomata, K. Chem. Lett. 1993, 1847-
1850. (b) Shimizu, M.; Ukaji, Y.; Inomata, K. Chem. Lett. 1996, 455-
456. (c) Ukaji, Y.; Taniguchi, K.; Sada, K.; Inomata, K. Chem. Lett.
1997, 547-548.
(9) (a) Gothelf, K. V.; Hazell, R. G.; J ørgensen, K. A. J . Org. Chem.
1996, 61, 346-355. (b) Gothelf, K. V.; Hazell, R. G.; J ørgensen, K. A.
J . Org. Chem. 1998, 63, 5483-5488.
10.1021/jo981483g CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/16/1999

5018 J . Org. Chem., Vol. 64, No. 14, 1999
Hori et al.
Ta ble 2. Liga n d Effect on P a lla d iu m (II)-Ca ta lyzed
Ta ble 1. Asym m etr ic 1,3-Dip ola r Cycloa d d ition of 1a to
2a Ca ta lyzed by Tr a n sition Meta l-BINAP Com p lexesa
1,3-Dip ola r Cycloa d d ition of Nitr on e 1a a n d
3-Cr oton oyl-1,3-oxa zolid in e-2-on e (2a )a
yield, endo/ % ee of % ee of
b
entry catalyst solvent temp
%
exoc endo-3a d exo-3a d
% ee of
% ee of
entry
ligand
yield, %b
endo/exoc
endo-3a d
exo-3a d
1
2
3
4
5
6
7
8
9
10
11
12
13
none CHCl3 reflux 17
8:92
5:95
4
5
5
5
5
5
5
6
6
7
7
7
CHCl3 reflux 78
CHCl3 reflux 61 45:55
CH2Cl2 rt 10:90
CH2Cl2 reflux 34 23:77
C6H6 reflux 50 40:60
CH3CN rt 13 7:93
5
91
12
79
71
3
1
23
1
4
25
5
9
31
1
11
1
13
24
7
1
2
3
4
5
6
8
9
10
11
12
13
61
59
61
88
65
76
27:73
12:88
45:55
57:43
62:38
50:50
9
50
91
89
25
71
1
34
25
60
72
48
9
CH3CN reflux 27 26:74
CH2Cl2 reflux 24 11:89
a
Reaction conditions: nitrone 1a (1.0 mmol), olefin 2a (1.0
mmol), AgBF4 (0.2 mmol), and PdCl2(ligand) (0.1 mmol) were
dissolved in CHCl3 (10 mL), and then the resulting mixture was
C6H6
CHCl3 reflux 63 47:53
C6H6 reflux 90 27:73
CH3CN reflux 48 15:85
reflux 80 10:90
91
66
15
b
stirred for 48 h under reflux. Based on olefin 2a . c Determined
d
by 1H NMR spectroscopy of the reaction mixture. Determined
1
by chiral HPLC using Daicel Chiralcel OJ -R.
a
Reaction conditions: nitrone 1a (1.0 mmol), olefin 2a (1.0
exo selectivity in only 17% yield (Table 1, entry 1). When
the complex 4 was used as a catalyst, 3a was obtained
in 78% yield with exo selectivity but without enantiose-
lectivities of both isomers (Table 1, entry 2). Next, the
palladium(II) complex 5 was prepared by the reaction of
4 and AgBF4 in an organic solvent, and then the nitrone
1a and the olefin 2a were added to the catalyst solution.
When chloroform was used as a solvent, 3a was obtained
in 61% yield and the enantioselectivity of endo-3a drasti-
cally increased to 91% ee (Table 1, entry 3). This reaction
did not proceed efficiently using CH2Cl2 as a solvent at
room temperature (Table 1, entry 4). However, at reflux,
the yield of 3a was increased with higher endo selectivity
and with 79% enantiomeric excess of the endo isomer
than at room temperature (Table 1, entry 5). In refluxing
benzene, the enantioselectivity of the endo isomer de-
creased slightly compared to the reaction in chloroform
(Table 1, entry 6). In acetonitrile, neither the yield nor
the enantioselectivity was favored at either room tem-
perature or under reflux.
mmol), and catalyst (0.1 mmol) were dissolved in a solvent (10
b
mL), and then the resulting mixture was stirred for 48 h. Based
on olefin 2a . c Determined by 1H NMR spectroscopy of the reaction
d
mixture. Determined by chiral HPLC using Daicel Chiralcel OJ -
R.
thenium can be used even in the presence of water.
Herein, we wish to describe the asymmetric 1,3-dipolar
cycloaddition of nitrones with R,â-unsaturated carbonyl
compounds catalyzed by palladium(II) complexes coor-
dinated with chiral phosphine ligands. A preliminary
account of this work has appeared.12
Resu lts a n d Discu ssion
Ca ta lysts a n d Rea ction Con d ition s. The late tran-
sition metal-catalyzed 1,3-dipolar cycloaddition of N-
benzylidenemethylamine N-oxide (1a ) and 3-crotonoyl-
1,3-oxazolidin-2-one (2a ) was first investigated because
this bidentate olefinic substrate is often used for highly
selective asymmetric reactions such as the Diels-Alder
reaction13 (eq 2, Table 1).
In the presence of the ruthenium(II) complex 6, which
was efficient for the asymmetric hydrogenation of ole-
fins,14 the reaction proceeded with exo selectivity, but the
enantioselectivities of the products were poor (Table 1,
entries 9 and 10).
On the basis of the above results, cationic (S)-BINAP-
palladium(II) complex 7, which can be easily prepared
by the method in eq 3 and has two acetonitriles as labile
ligands, was selected as a catalyst for the asymmetric
1,3-dipolar cycloaddition of 1a and 2a (Table 1, entries
11-13). Previously, a chiral phosphinepalladium(II)-
nitrile complex such as 7 has been used for the synthesis
of chiral alternating R-olefin-carbon monoxide copoly-
mers.15 Significantly, complex 7 is stable in air and shows
excellent solubility in a variety of solvents with the
exception of diethyl ether and hexane. Therefore, the
catalyst can be conveniently recovered simply by pre-
cipitation from the reaction mixture by adding hexane
or diethyl ether. When this reaction was performed in
chloroform as solvent at refluxing temperature, 3a was
obtained in 63% yield and the enantiomeric excess of
endo-3a was 91% ee, the same as when the catalyst 5
prepared in situ was used (Table 1, entry 11).
The 1,3-dipolar cycloaddition of the nitrone 1a and the
olefin 2a without catalyst gave the isoxazolidine 3a with
(10) (a) Sanchez-Blanco, A. I.; Gothelf, K. V.; J ørgensen, K. A.
Tetrahedron Lett. 1997, 38, 7923-7926. (b) Kobayashi, S.; Akiyama,
R.; Kawamura, M.; Ishitani, H. Chem. Lett. 1997, 1039-1040. (c)
Kobayashi, S.; Kawamura, M. J . Am. Chem. Soc. 1998, 120, 5840-
5841.
(11) For the chiral phosphine ligands used and their abbreviations,
see: (a) Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New
York, 1993. (b) Chiral Auxiliaries and Ligands in Asymmetric Syn-
thesis; Seyden-Penne, J ., Ed.; Wiley: New York, 1995.
(12) Hori, K.; Kodama, H.; Ohta, T.; Furukawa, I. Tetrahedron Lett.
1996, 37, 5947-5950.
(13) The review of catalytic asymmetric Diels-Alder reactions: (a)
Kagan, H. B.; Riant, O. Chem. Rev. 1992, 92, 1007-1019. (b) Dias, L.
C. J . Braz. Chem. Soc. 1997, 8, 289-332.
Interestingly, the enantioselectivity of the exo product
is considerably smaller compared to the enantioselectivity
(14) Ohta, T.; Takaya, H.; Noyori, R. Inorg. Chem. 1988, 27, 566-
569.
(15) (a) Xu, F. Y.; Zhao, A. X.; Chien, J . C. W. Makromol. Chem.
1993, 194, 2579-2603. (b) J iang, Z.; Adams, S. E.; Sen, A. Macromol-
ecules 1994, 27, 2694-2700.

Pd(II)-Catalyzed Asymmetric 1,3-Dipolar Cycloadditions
J . Org. Chem., Vol. 64, No. 14, 1999 5019
Ta ble 3. Asym m etr ic 1,3-Dip ola r Cycloa d d ition of
Va r iou s Nitr on es 1 a n d Olefin s 2 Ca ta lyzed by
P a lla d iu m (II) Com p lex 14a
of the endo product in most cases. Thermal reaction of
nitrone 1a and 2a proceeds with exo selectivity. Conse-
quently, endo product was mainly formed from the
catalytic reaction by palladium, while exo product was
produced by both thermal and catalytic reactions. That
could be the reason for the difference between both
isomers in enantioselectivities, though it cannot be
excluded that the enantioselectivities of the catalytic
reactions giving both isomers are basically different.
% ee
% ee
yield, endo/ of endo
%
of exo
b
entry nitrone olefin product
exoc productd productd
1
1a
1b
1c
1d
1e
1a
1b
2a
2a
2a
2a
2a
2b
2b
3a
3b
3c
3d
3e
3f
89
94
94
trace
trace
trace
f
60:40
93:7
28:72
91
89
54
34
93
48
2
3e
4
5
6
7
3g
a
Reaction conditions: nitrone 1 (1.2 mmol), olefin 2 (1.0 mmol),
and 14 (0.1 mmol) were dissolved in CHCl3 (10 mL), and then the
b
resulting mixture was stirred for 48 h under reflux. Based on
olefin 2. c Determined by 1H NMR spectroscopy of the reaction
d
mixture. Determined by chiral HPLC using Daicel Chiralcel
OJ -R or Daicel Chiralcel OD-H (see Experimental Section). e This
reaction was performed in CH2Cl2 (10 mL), and then the resulting
mixture was stirred for 48 h under reflux. f No reaction.
increased both the yield (88%) and the endo selectivity
of 3a , in which reaction the enantiomeric excess of the
endo isomer was 89% and that of the exo isomer was
improved to 60% ee (entry 4). Other BINAP derivatives
were used as a ligand, but the stereo- and enantioselec-
tivies of the products were not improved (Table 2, entries
5 and 6).
Th e Rea ction of Va r iou s Nitr on es a n d 3-Alk en -
oyl-1,3-oxa zolid in -2-on es. On the basis of these results,
cationic (S)-TolBINAP-palladium(II) nitrile complex 14
was prepared and used as a catalyst for this asymmetric
1,3-dipolar cycloaddition. The results of the asymmetric
1,3-dipolar cycloaddition of various nitrones 1a -e and
olefins 2a -b (eq 4) are presented in Table 3.
Liga n d Effect. Using chloroform as an optimal sol-
vent, to improve the stereoselectivity and the enantiose-
lectivity, the influence of the bidentated chiral-phosphine
ligand on this reaction was studied (Table 2). When
BCPM (8) and (+)-DIOP (9) were used instead of (S)-
BINAP, the product yields were moderate and the
enantioselectivities were not satisfactory (Table 2, entries
1 and 2). Employing (S)-TolBINAP (11) as a ligand
When the reaction of 1a and 2a was catalyzed by
preformed 14, isoxazolidine 3a was obtained in a higher
yield than in the reaction using the catalyst prepared in
situ. In the reaction of N-benzyl nitrone 1b and 2a , the
isoxazolidine 3b was obtained in 94% yield with high
endo selectivity and with excellent enantioselectivity for
both isomers. The absolute configuration of endo-3b was

5020 J . Org. Chem., Vol. 64, No. 14, 1999
Hori et al.
F igu r e 1. 1H NMR spectra (400 MHz, CDCl3) of a mixture of nitrone 1a , palladium(II) complex 7, and olefin 2a . (a) The nitrone
1a (0.05 mmol) was dissolved in 0.5 mL of CDCl3. (b) The complex 7 (0.005 mmol) was added to a mixture in (a). (c) The olefin
2a (0.05 mmol) was added to a mixture in (b).
determined as 3R,4S,5R.16 On the other hand, the reac-
tion of N-phenyl nitrone 1c proceeded with high exo
quickly with the complex. Interestingly, by addition of
nitrone 1a to the above mixture broad signals of the olefin
became sharp, like the signals of the olefin alone. These
observations show that both substrates can coordinate
to the palladium center and the nitrone 1a coordinates
to the complex 7 more strongly than the olefin 2a . That
is to say, most of the palladium species could be formu-
lated as A at room temperature. At room temperature,
the palladium complex showed virtually no catalytic
activity as mentioned above (Figure 3). If elevated
temperature accelerates the transformation between A
and B, B therefore must react with nitrone more smoothly
than the free olefin. For obtaining some evidence for this
prediction, an 1H NMR study at elevated temperature
was attempted. But all signals including TMS became
broadened at 40-60 °C. The structure B cannot be
confirmed by any experimental way, but there are several
examples in which Lewis acids are thought to activate
olefins such as 2a through bidentate coordination in 1,3-
dipolar cycloaddition reactions.9a,18
selectivity and with moderate enantioselectivity for both
exo and endo isomers. The absolute configuration of exo-
3c could not be determined, and that of endo-3c was
determined as 3R,4S,5R.17 Using the larger N-tert-butyl
nitrone 1d or N-trityl nitrone 1e, only small amounts of
the isoxazolidines 3d and 3e were obtained. Similarly,
the use of 3-cinnamoyl-1,3-oxazolidin-2-one (2b) resulted
in only trace amounts of cycloaddition product.
Rea ction Mech a n ism . For mechanistic consider-
Or igin of Ster eo- a n d En a n tioselectivity. The endo
adduct 3b was selectively obtained in the reaction of
N-benzyl nitrone 1b and 2a . On the other hand, exo-3c
was the major product from 1c. Such differences in
selectivity could be explained by the steric effect in the
transition state between the intermediate B and the two
nitrones (Figures 4-6). From the model the Si face of
the olefin’s R-carbon in B is not covered by any atoms or
groups in B, while the Re face of the olefin’s R-carbon in
B is partially shaded by the aryl substituent on phos-
phorus atom of TolBINAP. That is to say, the Si face of
the coordinated olefin’s R-carbon is less sterically hin-
dered (top view) than the Re face (bottom view). For
N-benzyl nitrone 1b, endo approach to the Si face of
olefin’s R-carbon in B seems to be the most favored, and
the exo approach to the Si face creates some steric
repulsion between the aryl moiety on phosphorus atom
1
ations, two series of H NMR analyses were presented
in Figures 1 and 2. In Figure 1, aromatic and methine
protons (8.18-8.26 ppm) of nitrone 1a became broader
in the presence of 10 mol % catalyst 7 (b) than in the
absence of complex (a). This broadening indicates that
some interaction occurred between the nitrone 1a and
the complex. Addition of olefin 2a to the above mixture
of 1a and 7 in CDCl3 did not make any change in their
signals. Next, to a solution of olefin 2a was added the
complex in three portions, and then the nitrone 1a was
added to this mixture successively. The results are listed
in Figure 2. All proton signals of the olefin 2a became
broad by adding complex (Figure 2a-d). These broaden-
ings also indicate that the olefinic substrate interacted
(16) The optical rotation of (+)-endo-3b was reported as [R]D ) +5.5
(51% ee), and the absolute configuration of the isoxazolidine ring of
(+)-endo-3b was assigned as 3S,4R,5S in the literature (see ref 6c).
(17) The optical rotation of (-)-endo-3c was reported as [R]D ) -13.1
(75% ee), and the absolute configuration of the isoxazolidine ring of
(-)-endo-3c was assigned as 3S,4R,5S in the literature (see ref 9a).
(18) Kanemasa, S.; Uemura, T.; Wada, E. Tetrahedron Lett. 1992,
33, 7889-7892.

Pd(II)-Catalyzed Asymmetric 1,3-Dipolar Cycloadditions
J . Org. Chem., Vol. 64, No. 14, 1999 5021
F igu r e 2. 1H NMR spectra (400 MHz, CDCl3) of a mixture of olefin 2a , palladium(II) complex 7, and nitrone 1a . (a) The olefin
2a (0.05 mmol) was dissolved in 0.5 mL of CDCl3. (b) The complex 7 (0.0015 mmol) was added to a mixture in (a). (c) The complex
7 (0.0015 mmol) was further added to a mixture in (b). (d) The complex 7 (0.0020 mmol) was further added to a mixture in (c).
(e) The nitrone 1a (0.05 mmol) was added to a mixture in (d).
internal standard for 1H and 85% H3PO4 as an external
and the benzyl group on nitrone (dotted atoms in Figure
standard for 31P. Melting points were not corrected. Solvents
5). Meanwhile, the phenyl substituent of N-phenyl ni-
trone 1c prevents the endo contact on the Si face of the
olefin’s R-carbon in B (dotted atoms in Figure 6). Con-
sequently, the exo attack for the Si face of the olefin’s
R-carbon in B is thought to be the most preferential.
were dried using standard procedures19 and distilled under
Ar. Nitrones 1a ,20 1b,21 1c,22 and 1d 23 and 3-alkenoyl-1,3-
oxazolidin-2-ones 2a 24 and 2b24 were prepared according to the
procedures in published literature. Nitrone 1e was used as
supplied without further purification.
P r ep a r a tion of (S)-TolBINAP -P a lla d iu m (II) Nitr ile
Com p lex 14. Silver tetrafluoroborate (1.23 g, 6.3 mmol) under
argon atmosphere was added to a solution of (S)-TolBINAP-
palladium dichloride25 (2.56 g, 3 mmol) in acetonitrile (60 mL).
The solution was stirred at room temperature. After being
stirred for 30 min, the resulting mixture was filtered and
concentrated to ca. 5 mL, and then the solution was slowly
Con clu sion
In conclusion, the 1,3-dipolar cycloaddition of nitrone
1 to olefin 2 was catalyzed by a cationic TolBINAP-
palladium(II) complex 14 resulting in moderate to excel-
lent yields and good enantioselectivities for the resulting
isoxazolidine derivatives. To the best of our knowledge,
this is the first example of a late transition metal-
catalyzed asymmetric 1,3-dipolar cycloaddition. Further
investigation of this catalytic system is currently in
progress.
(19) Perrin, D. D.; Armarego, W. L. F. In Purification of Laboratory
Chemicals, 3rd ed.; Pergamon: Oxford, 1988.
(20) Chan, K. S.; Yeung, M. L.; Chan, W.-K.; Wang, R.-J .; Mak, T.
C. W. J . Org. Chem. 1995, 60, 1741-1747.
(21) Murahashi, S.-I.; Mitsui, H.; Shiota, T.; Tsuda, T.; Watanabe,
S. J . Org. Chem. 1990, 55, 1736-1744.
(22) Wheeler, O. H.; Gore, P. H. J . Am. Chem. Soc. 1956, 78, 3363-
3366.
Exp er im en ta l Section
(23) Buehler, E. J . Org. Chem. 1967, 32, 261-265.
(24) Evans, D. A.; Chapman, K. T.; Bisaha, J . J . Am. Chem. Soc.
1988, 110, 1238-1256.
(25) Sodeoka, M.; Tokunoh, R.; Miyazaki, F.; Hagiwara, E.; Shiba-
saki, M. Synlett 1997, 463-466.
Gen er a l Meth od s. The 1H and 31P NMR spectra were
recorded at 400 and 160 MHz, respectively. Chemical shifts
for NMR are reported in ppm downfield from TMS as an

5022 J . Org. Chem., Vol. 64, No. 14, 1999
Hori et al.
48 h. The yields of the isoxazolidines 3 were determined by
1H NMR spectroscopy of the reaction mixture using the ratio
of the integral value between the signal of 2a (δ 1.97 (dd, J )
6.2, 1.0 Hz, 3H, Me)) and 5-Me of endo- and exo-3 (see below).
After addition of silica gel (ca. 1 g) to the solution and
concentration of the mixture in vacuo, the residue was
extracted with diethyl ether (20 mL) by Soxhlet extractor for
6 h. Removal of the solvent followed by silica gel column
chromatography gave endo-3 and exo-3. The results of 1,3-
dipolar cycloaddition of 1a -c with 2a and 2b are given in
Table 3. Spectral and analytical data of 3a -c are listed below.
3-((2,5-Dim eth yl-3-p h en ylisoxa zolid in -4-yl)ca r bon yl)-
1,3-oxa zolid in -2-on e (3a ).26 Yield: 89%. endo-3a : viscous
colorless liquid; [R]20D ) +10.0 (c 1.0, CHCl3, ee 87%); 1H NMR
(CDCl3) δ 1.53 (d, J ) 6.0 Hz, 3H, 5-Me), 2.59 (s, 3H, N-Me),
3.88-3.99 (m, 2H), 4.10 (d, J ) 7.6 Hz, 1H), 4.22-4.34 (m,
3H), 4.54 (dd, J ) 4.8, 7.6 Hz, 1H), 7.20-7.33 (m, 5H). Anal.
Calcd for C15H18N2O4: C, 62.06; H, 6.25; N, 9.65. Found: C,
62.00; H, 6.26; N, 9.61. exo-3a : white crystal; mp 125.2-133.5
1
°C; [R]20 ) -20.0 (c 1.0, CHCl3, ee 34%); H NMR (CDCl3) δ
D
1.30 (d, J ) 6.0 Hz, 3H, 5-Me), 2.54 (s, 3H, N-Me), 2.98-3.04
(m, 1H), 3.50-3.65 (m, 2H), 3.95 (d, J ) 10.8 Hz, 1H), 4.03
(dt, J ) 4.8, 8.4 Hz, 1H), 4.33 (dd, J ) 4.8, 10.8 Hz, 1H), 4.85
(qd, J ) 6.0, 8.4 Hz, 1H), 7.21-7.28 (m, 5H). Anal. Calcd for
C15H18N2O4: C, 62.06; H, 6.25; N, 9.65. Found: C, 61.88; H,
1
6.25; N, 9.61. The endo/exo ratio was determined by H NMR
spectroscopy using the integral ratio of each 5-Me protons of
3a in the reaction mixture. Enantiomeric excesses were
determined by HPLC analysis using a chiral column (Daicel
Chiralcel OJ -R, mobile phase: methanol/water ) 60:40, detec-
tor: UV 220 nm, flow rate: 0.5 mL/min, endo-3a : tR ) 64.4
(minor) and 72.6 min (major), exo-3a : tR ) 24.0 (major) and
28.5 min (minor)).
F igu r e 3. Plausible mechanism.
3-((2-Ben zyl-5-m eth yl-3-p h en ylisoxa zolid in -4-yl)ca r bo-
n yl)-1,3-oxa zolid in -2-on e (3b). Yield: 94%. These products
were identified by comparison of their 1H NMR signals with
those in the literature.6a endo-(3R,4S,5R)-3b: viscous colorless
liquid; [R]20 ) -11.0 (c 1.0, CHCl3, ee 83%) (lit.6c [R]D ) +5.5
D
(c 1.0, CHCl3, ee 51%)). exo-3b: white crystal; mp 105.0-112.1
°C; [R]20D ) -33.0 (c 1.0, CHCl3, ee 89%) (lit.6a [R]D ) +15.0 (c
1.0, CHCl3, ee 27%)). The endo/exo ratio was determined by
1H NMR spectroscopy using the integral ratio of each 5-Me
protons (endo-3b: 1.59 (d, J ) 6.0 Hz, 3H), exo-3b: 1.33 (d, J
) 6.0 Hz, 3H)) of 3b in the reaction mixture. Enantiomeric
excesses were determined by HPLC analysis using a chiral
column (Daicel Chiralcel OD-H; endo-3b: mobile phase: n-hex-
ane/2-propanol ) 80:20, detector: UV 220 nm, flow rate: 0.3
mL/min, tR ) 39.6 (3S,4R,5S) and 59.8 min (3R,4S,5R); exo-
3b: mobile phase: n-hexane/2-propanol ) 85:15, detector: UV
220 nm, flow rate: 0.3 mL/min, tR ) 29.9 (major) and 34.3
min (minor)).
3-((5-Meth yl-2,3-d ip h en ylisoxa zolid in -4-yl)ca r bon yl)-
1,3-oxa zolid in -2-on e (3c). Yield: 94%. These products were
identified by comparison of their 1H NMR signals with those
in the literature.6a endo-(3R,4S,5R)-3c: viscous light yellow
liquid; [R]20 ) +9.0 (c 1.0, CHCl3, ee 54%) (lit.9a [R]D ) -13.1
D
(c 1.0, CHCl3, ee 75%)). exo-3c: viscous light yellow liquid;
[R]20 ) -10.0 (c 1.0, CHCl3, ee 39%) (lit.6a [R]D ) +11.9 (c
F igu r e 4. Space-filling model of (S)-TolBINAP-Pd(II)-2a
complex (olefinic carbons as dark areas).
D
1.0, CHCl3, ee 60%)). The endo/exo ratio was determined by
1H NMR spectroscopy using the integral ratio of each 5-Me
proton (endo-3c: 1.54 (d, J ) 6.0 Hz, 3H), exo-3c: 1.45 (d, J
) 6.0 Hz, 3H)) of 3c in the reaction mixture. Enantiomeric
excesses were determined by HPLC analysis using a chiral
column (Daicel Chiralcel OD-H; endo-3c: mobile phase: n-hex-
ane/2-propanol ) 90:10, detector: UV 220 nm, flow rate: 0.3
mL/min, tR ) 98.9 (3R,4S,5R) and 130.7 min (3S,4R,5S); exo-
3c: mobile phase: n-hexane/2-propanol ) 90:10, detector: UV
254 nm, flow rate: 0.3 mL/min, tR ) 41.7 (major) and 44.1
min (minor)).
added into ether (50 mL). The light yellow precipitate was
filtered and dried in vacuo. The obtained yellow solid was
identified as 4 by NMR and used directly as a catalyst: yield
1
of 14 2.30 g (63%); mp 123.0 °C dec; H NMR (CDCl3) δ 2.05
(s, 6H), 2.41 (s, 6H), 3.25 (br, 6H), 6.70 (d, J ) 8.4 Hz, 4H),
7.17-7.73 (m, 24H); 31P NMR (CDCl3) δ 32.52 (s).
Gen er a l P r oced u r e for P a lla d iu m (II)-Ca ta lyzed Asym -
m etr ic 1,3-Dip ola r Cycloa d d ition of Nitr on es 1 w ith
Olefin s 2. In a 50 mL three-necked reaction vessel equipped
with a condenser and a magnetic stirring bar were placed 1
(1.2 mmol), 2 (1.0 mmol), and 4 (104 mg, 0.1 mmol) under
argon atmosphere. To this was added CHCl3 (10 mL) by
syringe. The resulting mixture was stirred under reflux for
(26) Identification of the endo/exo isomers was performed on the
basis of their 1H NMR spectra by coupling constants as well as NOE
analysis (see ref 12).

Pd(II)-Catalyzed Asymmetric 1,3-Dipolar Cycloadditions
J . Org. Chem., Vol. 64, No. 14, 1999 5023
F igu r e 5. Proposed exo and endo approach of nitrone 1b for intermediate B.
F igu r e 6. Proposed exo and endo approach of nitrone 1c for intermediate B.
Ack n ow led gm en t. We thank Dr. Takayuki Ya-
mashita for his helpful discussions and also the under-
graduate project students J unji Ito, Mitsuru Kawazome,
Noriteru Maeda, Akiko Fujii, Masamiti Okamura,
Takeshi Inoue, Takashi Okamoto, Daisuke Kobayashi,
and Hiroyuki Kamizono. This work was partially sup-
ported by a grant to RCAST at Doshisha University
from the Ministry of Education, J apan and Doshisha
University’s Reserch Promotion Fund.
Su p p or tin g In for m a tion Ava ila ble: HPLC charts of
1
racemates and reaction mixtures and H NMR and IR spectra
of both endo and exo isomers of 3a -c. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O981483G