Asymmetric 1,3-dipolar cycloaddition reactions of nitrile oxides catalyzed by chiral binaphthyldiimine-Ni(II) complexes

Asymmetric 1,3-Dipolar Cycloaddition Reactions of Nitrile Oxides

Catalyzed by Chiral Binaphthyldiimine-Ni(II) Complexes

Hiroyuki Suga,*^,†Yuki Adachi,^†Kouhei Fujimoto,^†Yasuhisa Furihata,^†Teruko Tsuchida,^†

Akikazu Kakehi,^†and Toshihide Baba^‡

Department of Chemistry and Material Engineering, Faculty of Engineering, Shinshu UniVersity,

Wakasato, Nagano 380-8553, Japan, and Department of EnVironmental Chemistry and Engineering,

Interdisciplinary Graduate School of Science and Engineering, Tokyo Institute of Technology,

G1-14, 4259 Nagatsuta, Midori-ku, Yokohama 226-8503, Japan

sugahio@shinshu-u.ac.jp

ReceiVed October 26, 2008

Asymmetric cycloaddition reactions between several nitrile oxides and 3-(2-alkenoyl)-2-oxazolidinones and

2-(2-alkenoyl)-3-pyrazolidinone derivatives were carried out in the presence of chiral binaphthyldiimine

(BINIM)-Ni(II) complexes as catalysts. Using (R)-BINIM-4(3,5-xylyl)-2QN-Ni(II) complex (30 mol %), good

regioselectivity (4-Me/5-Me ) 85:15) along with high enantioselectivity (96% ee) of the 4-Me adduct were

obtained for the reaction between isolable 2,4,6-trimethylbenzonitrile oxide and 3-crotonoyl-5,5-dimethyl-2-

oxazolidinone. Substituted and unsubstituted benzonitrile oxides and aliphatic nitrile oxides, which were

generated from the corresponding hydroximoyl chloride in the presence of MS 4Å, were reacted with

3-crotonoyl-5,5-dimethyl-2-oxazolidinone, 5,5-dimethyl-3-(2-pentenoyl)-2-oxazolidinone, 5,5-dimethy-3-[3-

(ethoxycarbonyl)propenoyl]-2-oxazolidinone, 1-benzyl-2-crotonoyl-5,5-dimethyl-3-pyrazolidinone, and 1-ben-

zyl-2-[3-(ethoxycarbonyl)propenoyl]-5,5-dimethy-3-pyrazolidinone in the presence of (R)-BINIM-4Ph-2QN-

Ni(II) or (R)-BINIM-4(3,5-xylyl)-2QN-Ni(II) complexes (10-30 mol %) as catalysts to give the corresponding

cycloadducts in high yields, with high regioselectively (4-R/5-R ) 85:15-99:1) and with moderate to high

enantioselectivities (42-95% ee) of the 4-R adducts. Higher enantioselectivities and regioselectivities were

obtained for the reactions using pyrazolidinone derivatives as the dipolarophiles. For the cycloadditions of

2-(2-alkenoyl)-1-benzyl-5,5-dimethyl-3-pyrazolidinones catalyzed by (R)-BINIM-4(3,5-xylyl)-2QN-Ni(II)

complex (30 mol %), the enantioselectivity varied from 75% to 95% ee. The reactions between several nitrile

oxides and 2-acryloyl-1-benzyl-5,5-dimethyl-3-pyrazolidinone in the presence of (R)-BINIM-4(3,5-xylyl)-

2QN-Ni(II) complex (10 mol %) resulted in enantioselectivities (79-91% ee) that exceed those of previously

reported enantioselective cycloadditions of acrylic acid derivatives. Furthermore, studies using a molecular

modeling program using PM3 calculations were carried out to gain insight into the mechanisms of the

asymmetric induction.

Introduction

functionalities in the cycloaddition step, while offering a facile

reductive cleavage of the N-O bond of the cycloadducts.

Accordingly, their use allows the synthesis of biologically

important natural products containing several chiral centers.^1b-e

Classical diastereoselective cycloaddition procedures involving

nitrones and nitrile oxides have been extensively studied and

have resulted in the development of numerous successful

From a synthetic point of view, nitrones and nitrile oxides

can serve as highly useful 1,3-dipoles¹because they allow the

construction of chiral centers that bear nitrogen and oxygen

^†Shinshu University.

^‡Tokyo Institute of Technology.

10.1021/jo802392c CCC: $40.75

Published on Web 12/18/2008

2009 American Chemical Society

J. Org. Chem. 2009, 74, 1099–1113 1099

Suga et al.

methods.^1b-eEfﬁcient syntheses of chiral compounds using such

methodologies, however, require the development of catalytic

asymmetric cycloaddition reactions. For nitrones, numerous

cycloadditions that are catalyzed by chiral Lewis acids have

been developed during the past decade.^1c-e,2-4For nitrile oxides,

Ukaji and Inomata have developed the enantioselective cy-

cloaddition with allylic alcohols using chiral zinc catalysts;

presumably, the reaction involves an active dinuclear zinc

species consisting of an allylic alcohol, a nitrile oxide, and chiral

ligands.⁵To the best of our knowledge, however, only a few

examples have been reported for the cycloaddition between

nitrile oxides and electron-deﬁcient oleﬁns catalyzed by a chiral

Lewis acid.

FIGURE 1. Structures of the BINIM ligands.

SCHEME 1. Reactions of 2,4,6-Trimethylbenzonitrile Oxide

(1a) with Oleﬁns 2, 3, or 4 Catalyzed by (R)-BINIM-Ni(II)

Complexes

Recently, Sibi reported on the successful reaction (79-99%

ee) using (2-alkenoyl)-3-pyrazolidinone derivatives featuring an

aminoindanol-derived bisoxazoline-Mg(II) complex as the chiral

Lewis acid catalyst. Although excellent enantioselectivity was

obtained using 30 mol % of the catalyst,⁶lowering the catalytic

loading from 30 to 10 to 5 mol % reduced both the regio- and

the enantioselectivities of the reaction. For cycloadditions

involving acrylic acid derivative as the dipolarophiles, Yama-

moto was able to obtain good asymmetric induction (87% ee)

for the reaction between benzonitrile oxide and N-acryloyl-2-

imidazolidinone using the (S)-Pybox-i-Pr-Mg(II) complex (1

equiv).⁷More recently, for cycloadditions between nitrile oxides

and methacrolein, Ku¨ndig has reported a highly enantiomeric

reaction (93% ee, 60% yield) using p-triﬂuoromethylbenzonitrile

oxide and a chiral ruthenium Lewis acid catalyst (5 mol %);

unfortunately, other nitrile oxides exhibited only moderate

enantioselectivities (60-76% ee).⁸Difﬁculty in obtaining suc-

cessful asymmetric induction of the chiral Lewis acid catalyzed

nitrile oxide cycloadditions may be owing to the instability of

nitrile oxides, which are generally prepared in situ via treatment

of a basic reagent, and the high donor ability of oxygen atom

of the dipole. Structurally, in contrast to the bent structure of

nitrones, the enantio-face of nitrile oxides is also obscured by

its linear structure in the asymmetric induction step. The

development of an efﬁcient chiral Lewis acid catalyst, therefore,

remains a challenging objective for the asymmetric cycloaddi-

tions of nitrile oxides and other unstable 1,3-dipoles.

Recently, we reported on the effective use of chiral catalysts

consisting of Ni(ClO₄)₂·6H₂O and chiral binaphthyldiimine

(BINIM) ligands in achieving high levels of asymmetric

induction in Diels-Alder reactions;^9a,b1,3-dipolar cycloaddi-

tions of nitrones,^9cazomethine imines,^9dand carbonyl ylides;^9e

and Michael additions of silyloxyfurans.^9fTo extend the scope

of our chiral BINIM-Ni(II) catalysts toward other 1,3-dipolar

cycloaddition reactions, our catalyst system was employed for

the asymmetric cycloadditions of nitrile oxides. Herein, we

describe the successful application of BINIM-Ni(II) complexes

as chiral Lewis acid catalysts for the enantioselective cycload-

dition of nitrile oxides with 3-(2-alkenoyl)-5,5-dimethyl-2-

oxazolidinones and 2-(2-alkenoyl)-1-benzyl-5,5-dimethyl-3-

pyrazolidinones.

(1) (a) 1,3-Dipolar Cycloaddition Chemistry; General heterocyclic chemistry

series; Padwa, A., Ed.; John Wiley and Sons: New York, 1984. (b) Torsell,

K. B. G. Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis; VCH:

Weinheim, 1988. (c) Gothelf, K. V.; Jørgensen, K. A. Chem. ReV. 1998, 98,

863. (d) Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward

Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.; Wiley:

Chichester, 2002. (e) Pellissier, H. Tetrahedron 2007, 63, 3235.

(2) (a) Gothelf, K. V.; Jørgensen, K. A. Chem. Commun. 2000, 1449. (b)

Stanley, L. M.; Sibi, M. P. Chem. ReV. 2008, 108, 2887.

(3) For representative examples, see:(a) Gothelf, K. V.; Thomsen, I.;

Jørgensen, K. A. J. Am. Chem. Soc. 1996, 118, 59. (b) Kobayashi, S.; Kawamura,

M. J. Am. Chem. Soc. 1998, 120, 5840. (c) Kanemasa, S.; Oderaotoshi, Y.;

Tanaka, J.; Wada, E. J. Am. Chem. Soc. 1998, 120, 12355. (d) Simonsen, K. B.;

Rita, P. B.; Hazell, G.; Gothelf, K. V.; Jørgensen, K. A. J. Am. Chem. Soc.

1999, 121, 3845. (e) Desimoni, G.; Faita, G.; Mortoni, A.; Righetti, P.

Tetrahedron Lett. 1999, 40, 2001. (f) Iwasa, S.; Tsushima, S.; Shimada, T.;

Nishiyama, H. Tetrahedron 2002, 58, 227. (g) Hori, K.; Kodama, H.; Ohta, T.;

Furukawa, I. J. Org. Chem. 1999, 64, 5017. (h) Sibi, M. P.; Ma, Z.; Jasperse,

C. P. J. Am. Chem. Soc. 2004, 126, 718. (i) Suga, H.; Nakajima, T.; Itoh, K.;

Kakehi, A. Org. Lett. 2005, 7, 1431.

Results and Discussion

Cycloaddition Reaction of 2,4,6-Trimethylbenzonitrile

Oxide. Initially, the reactions of isolable 2,4,6-trimethylben-

zonitrile oxide (1a) with 3-crotonoyl-2-oxazolidinone (2) in the

presence of complexes consisting of quinoline-based BINIMs

(Figure 1) and Ni(ClO₄)₂·6H₂O were investigated. The com-

plexes were prepared by stirring the BINIM ligands,

Ni(ClO₄)₂·6H₂O, and 4Å molecular sieves (MS 4Å) in CH₂Cl₂

at room temperature for 6 h. The subsequent cycloaddition

reactions between nitrile oxide 1a and oxazolidinone 2 were

carried out by stirring at room temperature (Scheme 1, Table

1, entries 2-4). In contrast to the cycloaddition reaction in the

absence of the Lewis acid catalyst (entry 1), the presence of

(R)-BINIM-4Ph-2QN-Ni(II) complex (10 mol %) (entry 2)

favored the formation of the 4-Me cycloadduct; however, the

resulting regioselectivity was moderate (62:38). Increasing the

catalyst loading to 30 mol % (entry 3) improved the yield and

regioselectivity (91:9), while the enantioselectivity remained

(4) For reactions with R,ꢀ-unsaturated aldehydes, see: (a) Viton, F.; Ber-

nardinelli, G.; Ku¨ndig, E. P. J. Am. Chem. Soc. 2002, 124, 4968. (b) Mita, T.;

Ohtsuki, N.; Ikeno, T.; Yamada, T. Org. Lett. 2002, 4, 2457. (c) Shirahase, M.;

Kamenasa, S.; Oderaotoshi, Y. Org. Lett. 2004, 6, 675. (d) Carmona, D.; Lamata,

M. P.; Viguri, F.; Rodriguez, R.; Oro, L. A.; Balana, A. I.; Lahoz, F. J.; Tejero,

T.; Merino, P.; Franco, S.; Montesa, I. J. Am. Chem. Soc. 2004, 126, 2716. (e)

Kano, T.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2005, 127, 11926.

(5) (a) Ukaji, Y.; Sada, K.; Inomata, K. Chem. Lett. 1993, 1847. (b) Shimizu,

M.; Ukaji, Y.; Inomata, K. Chem. Lett. 1996, 455. (c) Yoshida, Y.; Ukaji, Y.;

Fujinami, S.; Inomata, K. Chem. Lett. 1998, 1023. (d) Tsuji, M.; Ukaji, Y.;

Inomata, K. Chem. Lett. 2002, 1112. See also for antibody catalysis: Toker,

J. D.; Wentworth, P.; Hu, Y.; Houk, K. N.; Janda, K. D. J. Am. Chem. Soc.

2000, 122, 3244.

(6) (a) Sibi, M. P.; Itoh, K.; Jasperse, C. P. J. Am. Chem. Soc. 2004, 126,

5366. (b) Sibi, M. P.; Ma, Z.; Itoh, K.; Prabagaran, N.; Jasperse, C. P. Org.

Lett. 2005, 7, 2349.

(7) Yamamoto, H.; Hayashi, S.; Kubo, M.; Harada, M.; Hasegawa, M.;

Noguchi, M.; Sumimoto, M.; Hori, K. Eur. J. Org. Chem. 2007, 2859.

(8) Brinkmann, Y.; Madhushaw, R. J.; Jazzar, R.; Bernardinelli, G.; Ku¨ndig,

E. P. Tetrahedron 2007, 63, 8413.

1100 J. Org. Chem. Vol. 74, No. 3, 2009

Asymmetric Cycloadditions of Nitrile Oxides

TABLE 1. Reactions of 2,4,6-Trimethylbenzonitrile Oxide (1a) with Oleﬁns 2, 3, or 4 Catalyzed by (R)-BINIM-Ni(II) Complexes^a

entry

mol %^b

X(BINIM ligand)

oleﬁn

time (h)

product

yield (%)

rs^c

ee^d(%)

1

2

3

4

5

6

7

8

none

10

30

10

30

2

3

4

118

64

41

51

48

50

39

5

6

7

74

66

84

81

78

80

78

94

29:71

62:38

91:9

90:10

75:25

85:15

99:1

Ph (BINIM-4Ph-2QN)

62

65

73

79

96

76

92

3,5-xylyl (BINIM-4(3,5-xylyl)-2QN)

Ph (BINIM-4Ph-2QN)

3,5-xylyl (BINIM-4(3,5-xylyl)-2QN)

99:1

^aReactions were carried out by stirring nitrile oxide 1a with oleﬁns 2, 3, or 4 (1 equiv) at rt in CH₂Cl₂in the presence of (R)-BINIM-Ni(II)

complexes. ^bCatalyst loading of (R)-BINIM-Ni(II) complexes. ^cRegioselectivity of cycloadducts (4-Me/5-Me). ^dEnantiomeric excess of the 4-Me

adduct was determined by chiral HPLC after reduction to the corresponding alcohol using NaBH₄.

SCHEME 2. (R)-BINIM-Ni(II)-Catalyzed Reactions of Nitrile Oxides Generated from Hydroximoyl Chlorides with Oleﬁns 3 or 4

unchanged. As a note, the enantioselectivity was determined

by HPLC analysis (Daicel Chiralpak AD-H) after conversion

of the 4-Me cycloadduct to the corresponding alcohol via

reduction using NaBH₄in THF/H₂O (see Experimental Section).

The use of (R)-BINIM-4(3,5-xylyl)-2QN ligand, which pos-

sesses a bulky 3,5-xylyl substituent at the 4-position of the

quinoline rings, exhibited enantioselectivity (73% ee) higher than

that using the 4-Ph ligand (entry 4). In the case of the (R)-

BINIM-4Ph-2QN-Ni(II)-catalyzed reaction of 3-crotonoyl-5,5-

dimethyl-2-oxazolidinone (3) as the dipolarophile (entry 5),

despite the slightly lower regioselectivity, higher enantioselec-

tivity was obtained (entries 3 vs 5). To our delight, the reaction

of oxazolidinone 3 in combination with the (R)-BINIM-4(3,5-

xylyl)-2QN-Ni(II) catalyst resulted in an extremely high enan-

tioselectivity (96% ee) for the 4-Me cycloadduct (entry 6). In

the case of 1-benzyl-2-crotonoyl-5,5-dimethyl-3-pyrazolidinone

(4) as the dipolarophile (entry 8), the reaction under similar

conditions resulted in a slightly lower enantioselectivity (92%

ee), but with high regioselectivity (99:1) of the 4-Me cycload-

duct. Decreasing the catalyst loading to 10 mol % lowered the

enantioselectivity even further (entry 7).

Cycloaddition Reaction of Benzonitrile Oxide. Next, reac-

tions between oleﬁn 3 and benzonitrile oxide (1b), which was

generated in situ from the corresponding hydroximoyl chloride

8b, were carried out in the presence of (R)-BINIM-4(3,5-xylyl)-

2QN-Ni(II) complex (30 mol %) (Scheme 2, Table 2). When

an equimolar amount of diisopropylethylamine (DIEA) (relative

to hydroximoyl chloride 8b) was employed during the genera-

tion of benzonitrile oxide 1b, asymmetric induction for the

4-Me-9b cycloadduct was not observed (entry 1). Fortunately,

decreasing the amount of DIEA to 10 or 5 mol % dramatically

favored the formation of 4-Me-9b, with promising enantiose-

lectivity ratios (entries 2 and 3), along with increased yields of

the cycloadducts. Surprisingly, the reaction in the absence of

DIEA (entry 4) also afforded the cycloadduct with similar yields

as that in entry 3, along with high regioselectivity (96:4) and

good enantioselectivity (89% ee). Kim has reported that

molecular sieves, in the presence of dipolarophiles, can convert

hydroximoyl chlorides into nitrile oxides, which then afford the

cycloaddition products in good yields.¹⁰Similarly, the cycload-

dition of crotonoyloxazolidinone 3 in the presence of MS 4Å

(using the same amount as in the preparation of the BINIM-

Ni(II) complex) and in the absence of the BINIM-Ni(II) complex

at room temperature in CH₂Cl₂for 54 h afforded the cycload-

ducts in 84% yield (4-Me/5-Me ) 55:45).

The use of the BINIM-Ni(II) catalyst dramatically improved

the regioselectivity, along with providing a slightly faster

reaction rate. A survey of the BINIM ligands (entries 4-7)

revealed that (R)-BINIM-4Ph-2QN was the most effective in

terms of the enantioselectivity of the 4-Me cycloadduct (90%

ee, entry 7). It is noteworthy that the use of 10 mol % of the

(R)-BINIM-4Ph-2QN-Ni(II) catalyst afforded the cycloadduct

in a high yield, with regioselectivity (93:7) comparable to that

using 30 mol % of the catalyst and without a signiﬁcant loss of

enantioselectivity (89% ee) (entry 9).

In the case of 2-crotonoyl-1-benzyl-5,5-dimethyl-3-pyrazo-

lidinone (4) (entry 10), which has exhibited excellent enanti-

oselectivities in several cycloadditions including those with

nitrile oxide,^6,11the reaction with benzonitrile oxide proceeded

smoothly in the presence of (R)-BINIM-4(3,5-xylyl)-2QN-Ni(II)

(30 mol %) to give the cycloadduct with high regioselectivity

(99:1) and enantioselectivity (95% ee), as compared to those

of oxazolidinone 3. Decreasing the catalyst loading to 10 mol

% (entry 11) did not signiﬁcantly affect the enantioselectivity

(91% ee) nor the regioselectivity (99:1).

Cycloaddition Reactions of Other Nitrile Oxides with

Crotonoyloxazolidinone 3. To investigate the generality of our

(9) (a) Suga, H.; Kakehi, A.; Mitsuda, M. Chem. Lett. 2002, 900. (b) Suga,

H.; Kakehi, A.; Mitsuda, M. Bull. Chem. Soc. Jpn. 2004, 77, 561. (c) Suga, H.;

Nakajima, T.; Itoh, K.; Kakehi, A. Org. Lett. 2005, 7, 1431. (d) Suga, H.; Funyu,

A.; Kakehi, A. Org. Lett. 2007, 9, 97. (e) Suga, H.; Ishimoto, D.; Higuchi, S.;

Ohtsuka, M.; Arikawa, T.; Tsuchida, T.; Kakehi, A.; Baba, T. Org. Lett. 2007,

9, 4359. (f) Suga, H.; Kitamura, T.; Kakehi, A.; Baba, T. Chem. Commun. 2004,

1414.

(10) Kim, J. N.; Ryu, E. K. Heterocycles 1990, 31, 1693.

(11) Sibi, M. P.; Stanley, L. M.; Nie, X.; Venkatraman, L.; Liu, M.; Jasperse,

C. P. J. Am. Chem. Soc. 2007, 129, 395, and references therein.

J. Org. Chem. Vol. 74, No. 3, 2009 1101

Suga et al.

TABLE 2. Reactions of Benzonitrile Oxide (1b) with Oleﬁns 3 or 4 Catalyzed by (R)-BINIM-Ni(II) Complexes^a

entry

DIEA^b(mol %)

X (BINIM ligand)

oleﬁn

temp (°C)

time (h)

yield (%)

rs^c

ee^d(%)

1

2

3

4

5

6

7

8

100

10

5

3,5-xylyl (BINIM-4(3,5-xylyl)-2QN)

H (BINIM-2QN)

Me (BINIM-4Me-2QN)

Ph (BINIM-4Ph-2QN)

3

4

rt

0

rt

14

26

29

24

120

52

24

39

58

70

74

81

95

99

74

93

94

90

96

55:45

93:7

95:5

96:4

91:9

92:8

93:7

96:4

93:7

99:1

0

86

88

89

77

83

90

89

95

91

87

none

9^e

10

11^e

12^e

3,5-xylyl (BINIM-4(3,5-xylyl)-2QN)

Ph (BINIM-4Ph-2QN)

^aReactions were carried out by stirring hydroximoyl chloride 8b (2 equiv) with oleﬁns 3 or 4 at rt in CH₂Cl₂in the presence of (R)-BINIM-Ni(II)

complexes and MS 4Å. ^bThe mol % of DIEA relative to hydroximoyl chloride 8b. ^cRegioselectivity of cycloadducts (4-Me/5-Me). ^dEnantiomeric

excess of the 4-Me adduct was determined by chiral HPLC after reduction to the corresponding alcohol using NaBH₄. ^e10 mol % of catalyst was used.

TABLE 3. Reactions of Hydroximoyl Chloride 8b-8i with Oleﬁn 3 Catalyzed by (R)-BINIM-4Ph-2QN-Ni(II) Complex^a

entry

R

8

mol %

time (h)

product 9

yield (%)

rs^b

ee^c(%)

1

2

3

4

5

6

7

8

Ph

8b

8c

8d

8e

8f

30

10

30

10

30

10

30

10

30

10

30

10

30

10

30

10

24

52

16

43

20

29

24

27

24

22

48

66

48

66

13

48

9b

9c

9d

9e

9f

99

93

91

84

87

88

78

55

quant

48

60

71

82

91

93:7

95:5

88:12

95:5

90:10

86:14

88:12

90:10

86:14

90:10

87:13

90:10

85:15

93:7

90

89

92

83

91

85

84

76

83

75

78

62

73

54

72

51

p-MeOC₆H₄

p-MeC₆H₄

p-ClC₆H₄

o-ClC₆H₄

p-NO₂C₆H₄

p-NCC₆H₄

i-Bu

9

10

11

12

13

14

15

16

8f

9f

8g

8h

8i

9g

9h

9i

i-Bu

8i

9i

87:13

^aReactions were carried out by stirring hydroximoyl chloride 8b-8i (2 equiv) with oleﬁn

3 at rt in CH₂Cl₂in the presence of the

(R)-BINIM-4Ph-2QN-Ni(II) complexes and MS 4Å. ^bRegioselectivity of the cycloadducts (4-Me/5-Me). ^cEnantiomeric excess of the 4-Me adduct was

determined by chiral HPLC after reduction to the corresponding alcohol using NaBH₄.

catalyst toward other nitrile oxides, reactions between several

substituted benzohydroximoyl chlorides and crotonoyloxazoli-

dinone 3 were carried out (Scheme 2, Table 3). Using the (R)-

BINIM-4Ph-2QN-Ni(II) catalyst (30 mol %), the cycloadditions

of the substituted benzonitrile oxides afforded the corresponding

cycloadducts with high regioselectivities (86:14-94:6), along

with moderate to high enantioselectivities (73-92% ee) of the

4-Me cycloadducts (entries 3, 5, 7, 9, 11, and 13). The

enantioselectivities for the benzonitrile oxides with electron-

withdrawing substituents were slightly lower (entries 7-14) than

those for the unsubstituted benzonitrile oxide (entries 1 and 2)

or with electron-releasing substituents (p-methoxy, entries 3 and

4; p-methyl groups, entries 5 and 6). The cycloaddition between

aliphatic nitrile oxide 1i (R ) i-Bu) and oxazolidinone 3 also

1102 J. Org. Chem. Vol. 74, No. 3, 2009

Asymmetric Cycloadditions of Nitrile Oxides

TABLE 4. Reactions of Hydroximoyl Chlorides 8b-8f and 8i-8k with Oleﬁn 4 Catalyzed by (R)-BINIM-4(3,5-xylyl)-2QN-Ni(II) Complex^a

entry

R

8

mol %

time (h)

product 10

yield (%)

rs^b

ee^c(%)

1

2

3

4

5

6

7

8

Ph

8b

8c

8d

8e

8f

8i

8j

30

10

30

10

30

10

30

10

30

10

24

39

17

14

65

18

17

14

61

56

37

72

10b

10c

10d

10e

10f

10i

94

90

97

84

93

81

quant

91

99

91

73

94

86

99:1

98:2

99:1

95

91

92

88

91

79

90

83

87

76

84

77

42

p-MeOC₆H₄

p-MeC₆H₄

p-ClC₆H₄

o-ClC₆H₄

i-Bu

n-Bu

t-Bu

9

10

11

12

13

10i

10j

10k

8k

^aReaction were carried out by stirring hydroximoyl chlorides 8b-8f and 8i-8k (2 equiv) with oleﬁn 4 at rt in CH₂Cl₂in the presence of

(R)-BINIM-4(3,5-xylyl)-2QN-Ni(II) complex and MS 4Å. ^bRegioselectivity of the cycloadducts (4-Me/5-Me). ^cEnantiomeric excess of the 4-Me adduct

was determined by chiral HPLC after reduction to the corresponding alcohol using NaBH₄.

SCHEME 3. Reactions Between Benzonitrile Oxide (1b) and Oleﬁns 11-15 Catalyzed by (R)-BINIM-Ni(II)

proceeded smoothly under similar conditions (30 mol % catalyst)

to preferentially afford the 4-Me cycloadduct (4-Me/5-Me )

93:7) in a high yield with moderate enantioselectivity of the

4-Me adduct (72% ee) (entry 15). Decreasing the catalyst

loading to 10 mol % resulted in lower enantioselectivities and,

to a lesser extent, decreased regioselectivities (entries 4, 6, 8,

10, 12, 14, and 16).

Cycloaddition Reactions of Other Nitrile Oxide with

Crotonylpyrazolidinone 4. The reactions of several nitrile

oxides with pyrazolidinone 4 in the presence of (R)-BINIM-

4(3,5-xylyl)-2QN-Ni(II) complex (10-30 mol %) were also

investigated (Scheme 2, Table 4, entries 3-13). When compared

against those of oxazolidinone 3 (entries 3-10), the cycload-

ditions were highly regioselective (4-Me/5-Me ) 98:2-99:1),

with relatively high enantioselectivities (76-92% ee) of the

4-Me adducts. For the benzonitrile oxides with electron-releasing

p-substituents (entries 3 and 4), the cycloadditions exhibited

satisfactory asymmetric induction (88-92% ee), even with only

10 mol % catalyst. In the cases of electron-deﬁcient p-chloro-

and o-chlorobenzonitrile oxides (entries 5-8), although high

enantioselectivites (90-91% ee) were observed using 30 mol

% catalyst, lowering the catalytic loading from 30 to 10 mol %

reduced the enantioselectivity without affecting the regioselec-

tivity. For aliphatic nitrile oxides (entries 9 and 12), cycload-

dition with pyrazolidinone 4 in the presence of 30 mol % catalyst

was highly regioselective, with good enantioselectivity. It is

noteworthy that the cycloaddition of pentanenitrile oxide (entry

11), a straight-chain aliphatic nitrile oxide that can readily

undergo dimerization, also showed good enantioselectivity (84%

ee) with high regioselectivity (99:1) even with only 10 mol %

catalyst. Among the aliphatic nitrile oxides, the sterically

hindered nitrile oxides exhibited lower enantioselectivities.

Cycloadditon Reactions with 2-Pentenoyl, (Ethoxycarbo-

nyl)propenoyl, and Acryloyl Derivatives. To investigate the

applicability of our methodology to oleﬁnic dipolarophiles, the

cycloadditions of benzonitrile oxide (1b) in the presence of 30

mol % catalyst were carried out using various oxazolidinones

as dipolarophiles (Scheme 3, Table 5, entries 1-3). In the case

of 5,5-dimethyl-3-(2-pentenoyl)-2-oxazolidinone (11, entry 1),

the reaction was highly regio- and enantioselective (90% ee)

and was comparable to that of crotonoyloxazolidinone 3. The

cycloaddition with 3-acryloyl-5,5-dimethyl-2-oxazolidinone (12,

J. Org. Chem. Vol. 74, No. 3, 2009 1103

Suga et al.

ee^c(%)

TABLE 5. (R)-BINIM-Ni(II)-Catalyzed Reactions of Benzonitrile Oxide (1b) with Oleﬁns 11-15^a

entry

R

oleﬁn

X (BINIM ligand)

time (h)

product

yield (%)

rs^b

1^d

2

Et

H

CO₂Et

H

11

12

13

14

15

Ph (BINIM-4Ph-2QN)

48

2

3

2

4

16b

17b

18b

19b

20b

73

86

99

93

90:10

>99:1

85:15

<99:1

99:1

90

74

51

92

75

3,5-xylyl (BINIM-4(3,5-xylyl)-2QN)

3^d

4

5

CO₂Et

^aReactions were carried out by stirring hydroximoyl chloride 8b (2 equiv) with oleﬁns 11-15 at rt in CH₂Cl₂in the presence of (R)-BINIM-Ni(II)

complexes (30 mol %). ^bRegioselectivity of the cycloadducts (4-R/5-R). ^cEnantiomeric excess of the 4-R adduct was determined by chiral HPLC after

reduction to the corresponding alcohol using NaBH₄. ^dThe reaction was carried out under high concentration (0.167 mol/L solution of oleﬁn in CH₂Cl₂).

SCHEME 4. (R)-BINIM-4(3,5-xylyl)-2QN-Ni(II)-Catalyzed Reactions between Nitrile Oxides and 2-Acryloylpyrazolidinone 14

TABLE 6. (R)-BINIM-4(3,5-xylyl)-2QN-Ni(II) Catalyzed Reactions between Nitrile Oxides and 2-Acryloylpyrazolidinone 14^a

entry

R

conditions^b

catalyst (mol %)

time (h)^c

product

yield (%)

rs^d

ee^e(%)

1

2

3

4

5

6

7

8

Ph

A

B

C

D

A

C

D

30

10

2

1

0.5

1

2

0

1

19b

19c

19e

19i

19b

19c

19e

19i

93

95

quant

91

92

90

93

99

90

80

67

78

92

73

92

>99:1

92

87

84

91

87

91

93

77

91

90

79

83

87

86

p-MeOC₆H₄

p-ClC₆H₄

i-Bu

Ph

p-MeOC₆H₄

p-ClC₆H₄

i-Bu

n-Bu

t-Bu

9

10

11

12

13

14

15

19j

19k

^aReactions were carried out under conditions A-D by reacting the corresponding hydroximoyl chloride (2 equiv) with oleﬁn 14 at rt in CH₂Cl₂in

the presence of the (R)-BINIM-4(3,5-xylyl)-2QN-Ni(II) complex. ^bCondition A: oleﬁn 14, hydroximoyl chloride, and CH₂Cl₂were successively added

within 30 s. Condition B: a solution of hydroximoyl chloride in CH₂Cl₂was added to a mixture of oleﬁn 14 and the catalyst. Condition C: a solution of

oleﬁn 14 in CH₂Cl₂was added to a mixture of hydroximoyl chloride and the catalyst. Condition D: a solution of hydroximoyl chloride and oleﬁn 14 in

CH₂Cl₂was added to the catalyst. ^cStirring time after the addition of substrates. ^dRegioselectivity of the cycloadducts. ^eEnantiomeric excess of 4-Me

adduct was determined by chiral HPLC after reduction to the corresponding alcohol using NaBH₄.

entry 2) in the presence of (R)-BINIM-4(3,5-xylyl)-2QN-Ni(II)

complex resulted in a lower enantioselectivity (74% ee) but with

an extremely high regioselectivity (>99:1). Under similar

conditions, only moderate enantioselectivity, with reduced

regioselectivity, was observed for the reaction with 5,5-dimethy-

3-[3-(ethoxycarbonyl)propenoyl]-2-oxazolidinone (13, entry 3).

To investigate the applicability of our methodology to

2-alkenoylpirazolidinone derivatives, cycloadditions were carried

out using 2-acryloyl-1-benzyl-5,5-dimethyl-3-pyrazolidinone

(14) and 1-benzyl-2-[3-(ethoxycarbonyl)propenoyl]-5,5-dimethy-

3-pyrazolidinone (15) (Scheme 3, Table 5, entries 4 and 5). In

contrast to that of acryloyloxazolidinone 12, the reaction of

2-acryloylpyrazolidinone 14 (entry 4) using (R)-BINIM-4(3,5-

xylyl)-2QN-Ni(II) complex (30 mol %) was high-yielding while

highly regio- (>99:1) and enantioselective (92% ee). Similarly,

the reaction of [(ethoxycarbonyl)propenoyl]pyrazolidinone 15

(entry 5) exhibited regio- (99:1) and enantioselectivities (75%

ee) higher than those of oxazolidinone 13.

enantioselective asymmetric cycloaddition between benzonitrile

oxide and an acrylic acid derivative (Table 5, entry 4), we

extended our studies using other nitrile oxides while varying

the catalyst loading (Scheme 4, Table 6). The catalyzed

cycloaddition between p-substituted benzonitrile oxides and

2-acryloylpyrazolidinone 14 in the presence of the (R)-BINIM-

4(3,5-xylyl)-2QN-Ni(II) complex (30 mol %), regardless of the

electronic character of p-substituents (entries 2 and 3), proceeded

smoothly to give the corresponding 5-substituted cycloadduct

exclusively in high yields with good enantioselectivity. Simi-

larly, the reaction of 3-methylbutanenitrile oxide (entry 4)

yielded the 5-substituted adduct quantitatively with high enan-

tioselectivity (91% ee). For the reaction between benzonitrile

oxide (1b) and 2-acryloylpyrazolidinone 14 (entry 8), decreasing

the catalyst loading to 10 mol % resulted in lowering the

enantioselectivity (77% ee). To improve the selectivity, the

reaction condition was modiﬁed by the slow addition of

hydroximoyl chloride 8b (Condition B), 2-acryloylpyrazolidi-

none 14 (Condition C), or a mixture of 8b and 14 (Condition

D) over a period of 1 h. Our results showed that conditions C

Cycloaddition Reactions of Several Nitrile Oxides with

2-Acryloylpyrazolidinone 14. On the basis of the highly

1104 J. Org. Chem. Vol. 74, No. 3, 2009

Asymmetric Cycloadditions of Nitrile Oxides

FIGURE 2. ¹H NMR study of (R)-BINIM-4(3,5-xylyl)-2QN complex in CDCl₃(see Supporting Information for good resolution).

and D improved the enantioselectivities to over 90% ee, even

for the reactions using only 10 mol % catalyst (entries 6, 7, 9,

and 10). Under condition D, the reactions between 2-acry-

loylpyrazolidinone 14 and the para-substituted benzonitrile

oxides or aliphatic nitrile oxides using 10 mol % catalyst (entries

11-15) also exhibited good enantioselectivities (79-90% ee)

with high regioselectivities (>99:1).

3, G), in which the H_aand H_bsignals of cycloadduct 4-Me-6

exhibited a signiﬁcant shift to higher ﬁeld with slightly

broadening, as compared to those of 4-Me-6 without the Lewis

acid (Figure 3, H). These results suggest that, as the reaction

proceeds, the BINIM-Ni(II) catalyst coordinates not only with

dipolarophile 3 but also with cycloadduct 4-Me-6, which in turn

deactivates the catalyst. Accordingly, it is difﬁculty to decrease

the catalyst loading in the BINIM-Ni(II)-catalyzed cycloaddition

reactions of some nitrile oxides.

Proposed Mechanism for Asymmetric Induction. Attempts

to form single crystals of the complexes between chiral BINIMs

and Ni(ClO₄)₂·6H₂O for X-ray structure analysis were unsuc-

cessful. Consequently, on the basis of the X-ray structural

analysis of DBFOX/Ph-Ni(ClO₄)₂·3H₂O, as reported by Kane-

masa,¹²the structure of (R)-BINIM-4-(3,5-xylyl)-2QN-Ni(II)·

crotonylpyrazolidinone 4 complex was proposed as a hexa-

coordinated octahedral structure. A similar structure has been

suggested for BINIM-Ni(II)-catalyzed azomithine imine

cycloaddition,^9dby means of a molecular modeling program

using PM3 calculations (Figure 4).¹³Ball-and-spoke models of

the optimized complex are shown in Figure 4. As shown in the

lower side view, the re-face of crotonylpyrazolidinone 4 is

effectively shielded by the 4-(3,5-xylyl)quinoline moiety and

the benzyl group of 4. In contrast, as shown in the top side

view, the si-face is located in a relatively open space. The high

enantioselectvity of the cycloaddition reactions of nitrile oxides

with crotonylpyrazolidinone 4, therefore, is attributable to the

¹H NMR Studies of the Cycloaddition Reaction of

2,4,6-Trimethylbenzonitrile Oxide (1a). To gain insight into

the efﬁcient activation of nitrile oxides under high catalyst

1

loading, H NMR studies were carried out for the reaction

between 2,4,6-trimethylbenzonitrile oxide (1a) and crotonoy-

loxazolidinone 3 catalyzed by the (R)-BINIM-4(3,5-xylyl)-2QN-

Ni(II) complex. The Ni(II) catalyst was prepared by stirring (R)-

BINIM-4(3,5-xylyl)-2QN (28.9 mg, 0.038 mmol), Ni(ClO₄)₂·

6H₂O (13.7 mg, 0.038 mmol), and MS 4Å (95.3 mg) in CDCl₃

(1.5 mL) at room temperature for 6 h. Following removal of

MS 4Å by ﬁltration, the resulting Ni(II) catalyst was washed

1

with CDCl₃(0.75 mL). The H NMR spectrum of the catalyst

(about 0.012 mol dissolved in 0.6 mL CDCl₃) (Figure 2, A)

did not exhibit any signiﬁcant signals, except for those corre-

sponding to hydrocarbon impurities. Upon the addition of

1

oxazolidinone 3 (6.1 mg, 0.13 mmol), the H NMR spectrum

of the resulting solution exhibited signals that correspond to 3

(Figure 2, B) but slightly broader than those without the Lewis

acid (Figure 2, C). Subsequent addition of nitrile oxide 1a (4.4

mg, 0.13 mmol) to the above solution caused the appearance

of sharp signals, which were assigned to nitrile oxide 1a, while

the signals of oxazolinedinone 3 remained broadened (Figure

2, D). The ¹H NMR spectra were also measured after allowing

the mixture to stand for 24 h (Figure 3, F) and 7 days (Figure

(12) Kanemasa, S.; Oderaotoshi, Y.; Sakaguchi, S.; Yamamoto, H.; Tanaka,

J.; Wada, E.; Curran, D. P. J. Am. Chem. Soc. 1998, 120, 3074.

(13) The structure of the complex was optimized by PM3 calculations

(Spartan 04).

J. Org. Chem. Vol. 74, No. 3, 2009 1105

Suga et al.

FIGURE 3. ¹H NMR study for (R)-BINIM-4(3,5-xylyl)-2QN-Ni(II)-catalyzed reaction of 1a with 3 (see Supporting Information for good resolution).

Conclusions

We have developed a novel synthetic scheme featuring

BINIM-Ni(II) complexes as chiral Lewis acid catalysts for the

asymmetric cycloadditions of nitrile oxide. The best result, in

terms of enantioselectivity (96% ee), was achieved for the

reaction of isolable 2,4,6-trimethylbenzonitrile oxide (1a) using

the combination of (R)-BINIM-4(3,5-xylyl)-2QN-Ni(II) catalyst

(30 mol %) and 3-crotonoyl-5,5-dimethyl-2-oxazolidinone (3)

as the dipolarophile. For this reaction, decreasing the catalyst

loading resulted in lower enantioselectivities. For the catalyzed

reactions of substituted and unsubstituted benzonitrile oxides

and aliphatic nitrile oxides, which were generated from the

corresponding hydroximoyl chloride in the presence of MS 4Å,

the enantio- and regioselectivities were higher for 1-benzyl-2-

crotonoyl-5,5-dimethyl-3-pyrazolidinone (4) as the dipolarophile

than those using oxazolidinone 3. For the reactions of benzoni-

trile oxide, para- and ortho-substituted benzonitirile oxides, and

a straight chain aliphatic nitrile oxide, moderate to high

FIGURE 4. Proposed structure of (R)-BINIM-4-(3,5-xylyl)-2QN-

Ni(II)·crotonylpyrazolidinone 4 complex.

enantioselectivities (79-92% ee) were observed for pyrazoli-

dinone 4 as the dipolarophile, even in the presence of only 10

mol % catalyst. For the asymmetric cycloadditions of acrylic

acid derivatives, speciﬁcally, reactions between several nitrile

oxides and 2-acryloyl-1-benzyl-5,5-dimethyl-3-pyrazolidinone

(14), relatively high enantioselectivities (79-91% ee) were

attained with a catalyst loading of 10 mol %. We believe that

our results have contributed toward the development of chiral

Lewis acid catalyzed asymmetric cycloaddition reactions of

unstable 1,3-dipoles.

highly selective approach of the nitrile oxides toward the si-

face of the proposed hexa-coordinated Ni(II) complex (Figure

5). This si-face approach can reasonably explain the selective

formation of (4S,5S)-cycloadducts 4-Me-9b and 4-Me-10b,

which have the same conﬁguration determined by the optical

rotation^5c,6aafter reduction to the corresponding alcohol (see

Experimental Section).

1106 J. Org. Chem. Vol. 74, No. 3, 2009

Asymmetric Cycloadditions of Nitrile Oxides

FIGURE 5. Proposed mechanism for BINIM-Ni(II)-catalyzed asymmetric cycloadditions of nitrile oxides.

ing alcohol (21.3 mg, 99%). Colorless oil; [R]²⁵_D) +191.5 (c 0.13,

Experimental Section

MeOH, 96% ee); IR (neat) 3461, 3220, 2974, 2930, 1520, 1456,

1215, 1033, 929, 852, 769 cm^-1; ¹H NMR (CDCl₃) δ 1.14 (3H, d,

J ) 7.3 Hz), 2.06 (1H, brs), 2.25 (6H, s), 2.29 (3H, s), 3.55 (1H,

dq, J ) 8.1, 7.3 Hz), 3.70-3.76 (1H, m), 3.92-3.97 (1H, m), 4.39

(1H, ddd, J ) 3.2, 4.4, 8.1 Hz), 6.90 (2H, s); ¹³C NMR (CDCl₃) δ

15.8 (CH₃), 20.2 (CH₃), 21.3 (CH₃), 47.4 (CH), 62.8 (CH₂), 87.9

(CH), 125.2 (C), 128.5 (CH), 136.9 (C), 138.4 (C), 161.9 (C); MS

(EI) m/z 233 (M⁺), 202, 172, 159, 146, 119, 91, 77, 57, 28. HRMS

(EI) calcd for C₁₄H₁₉NO₂(M⁺): 233.1416, found 233.1454. The

enantiomeric excess was determined by HPLC analysis (Daicel

Chiralpak AD-H, i-PrOH-hexane (1:39 v/v), detector: UV 254 nm,

ﬂow rate ) 0.5 mL/min, 35 °C. t_minor) 40.4 min, t_major) 62.0

min.

4-[(5,5-Dimethyl-2-oxo-3-oxazolidinyl)carbonyl]-5-methyl-3-

[(2,4,6-trimethyl)phenyl]-4,5-dihydroisoxazole (5-Me-6). Al-

though 5-Me-6 could not be separated by chromatography from a

mixture with major 4-Me-6, it could be characterized by ¹H NMR.

¹H NMR (CDCl₃) δ 1.10 (3H, s), 1.43 (3H, s), 1.55 (3H, d, J )

6.6 Hz), 2.25 (9H, s), 3.52 (1H, d, J ) 11.0 Hz), 3.61 (1H, d, J )

11.0 Hz), 5.27 (1H, dq, J ) 7.1, 6.6 Hz), 5.65 (1H, d, J ) 7.1 Hz),

6.85 (2H, s).

(4S,5S)-4-Methyl-5-[(2-oxo-3-oxazolidinyl)carbonyl]-3-[(2,4,6-

trimethyl)phenyl]-4,5-dihydroisoxazole (4-Me-5). Colorless prisms;

159.5-160.5 °C (CH₂Cl₂-hexane); IR (KBr) 3445, 2982, 1788,

1705, 1610, 1477, 1386, 1317, 1217, 1120, 974, 912, 850, 756

cm^-1; ¹H NMR (CDCl₃) δ 1.31 (3H, d, J ) 7.3 Hz), 2.24 (6H, s),

2.29 (3H, s), 3.81 (1H, dq, J ) 4.2, 7.3 Hz), 4.02-4.16 (2H, m),

4.53 (2H, t, J ) 7.6 Hz), 5.83 (1H, d, J ) 4.2 Hz), 6.89 (2H, s);

¹³C NMR (CDCl₃) δ 16.3 (CH₃), 20.1 (CH₃), 21.2 (CH₃), 42.7

(CH₂), 50.8 (CH), 62.9 (CH₂), 82.9 (CH), 124.0 (C), 128.5 (CH),

137.1 (C), 138.8 (C), 153.2 (C), 160.4 (C), 169.2 (C); MS (EI) m/z

316 (M⁺), 202, 172, 88. HRMS (EI) calcd for C₁₇H₂₀N₂O₄(M⁺):

316.1423, found 316.1421.

For general methods and materials, see Supporting Information.

General Procedure for (R)-BINIM-4(3,5-xylyl)-2QN-Ni(II)-

Catalyzed Reaction of 2,4,6-Trimethylbenzonitrile Oxide (1a)

with 3-Crotonoyl-5,5-dimethyl-2-oxazolidinone (3). A suspension

of (R)-BINIM-4(3,5-xylyl)-2QN (115.7 mg, 0.15 mmol), powdered

MS 4Å (381 mg), and Ni(ClO₄)₂·6H₂O (54.9 mg, 0.15 mmol) in

CH₂Cl₂(6.0 mL) was stirred for 6 h at room temperature.

Oxazolidinone 3 (91.6 mg, 0.50 mmol), nitrile oxide 1a (80.6 mg,

0.50 mmol), and CH₂Cl₂(3.0 mL) were added successively to the

catalyst suspension. After stirring at room temperature for 50 h,

the reaction was quenched with saturated NH₄Cl solution (7.5 mL)

and water (7.5 mL) and then ﬁltered through Celite. The ﬁltrate

was extracted with CH₂Cl₂(5.0 mL × 3). The combined extracts

were dried over MgSO₄and evaporated in vacuo. The residue was

chromatographed on silica gel with hexane-ethyl acetate (7:3 v/v)

as an eluent to give cycloadduct (121.2 mg, 80%). Regioselectivity

was determined to be 4-Me/5-Me ) 85:15 by ¹H NMR (400 MHz)

analysis of the crude mixture. The enantiomeric excess was

determined by HPLC analysis (Daicel Chiralpak AD-H, i-PrOH-

hexane (1:39 v/v), detector: UV 254 nm, ﬂow rate ) 0.5 mL/min,

35 °C) after conversion to the corresponding alcohol by NaBH₄.¹⁴

t_minor) 40.4 min, t_major) 62.0 min.

(4S,5S)-5-[(5,5-Dimethyl-2-oxo-3-oxazolidinyl)carbonyl]-4-

methyl-3-[(2,4,6-trimethyl)phenyl]-4,5-dihydroisoxazole (4-Me-

6). Colorless plates, mp 185.0-186.0 °C (CH₂Cl₂-hexane), IR

(KBr) 3492, 2964, 1770, 1703, 1614, 1462, 1388, 1325, 1292, 1203,

1

1165, 1122, 1093, 1020, 987, 929, 883, 850, 760, 684 cm^-1; H

NMR (CDCl₃) δ 1.31 (3H, d, J ) 7.3 Hz), 1.55 (3H, s), 1.56 (3H,

s), 2.25 (6H, s), 2.29 (3H, s), 3.76 (1H, d, J ) 11.0 Hz), 3.79 (1H,

dq, J ) 4.2, 7.3 Hz), 3.84 (1H, d, J ) 11.0 Hz), 5.83 (1H, d, J )

4.2 Hz), 6.89 (2H, s); ¹³C NMR (CDCl₃) δ 16.3 (CH₃), 20.1 (CH₃),

21.2 (CH₃), 27.3 (CH₃), 27.4 (CH₃), 51.0 (CH), 54.4 (CH₂), 80.0

(C), 83.2 (CH), 124.1 (C), 128.5 (CH), 137.1 (C), 138.7 (C), 152.4

(C), 160.4 (C), 169.5 (C), MS (EI) m/z 344 (M⁺), 316, 202, 172.

HRMS (EI) calcd for C₁₉H₂₄N₂O₄(M⁺): 344.1736, found 344.1725.

Anal. Calcd for C₁₉H₂₄N₂O₄: C, 66.26; H, 7.02; N, 8.13. Found: C,

66.37; H, 7.22; N, 7.83.

Conversion to (4S,5S)-5-Hydroxymethyl-4-methyl-3-[(2,4,6-

trimethyl)phenyl]-4,5-dihydroisoxazole.¹⁴To a solution of 4-Me-6

(34.4 mg, 0.10 mmol) in THF (2.0 mL) and water (0.66 mL) was

added NaBH₄(15.1 mg, 0.40 mmol) at 20-25 °C. After stirring

the mixture for 1.5 h, the reaction was quenched with 2 mol/L

hydrochloric acid, and the mixture was extracted with ethyl acetate

(5.0 mL × 3). The organic layer was washed with saturated NaCl

solution (10 mL × 2), and the dried over MgSO₄and evaporated

in vacuo. The residue was chromatographed on silica gel with

hexane-ethyl acetate (3:2 v/v) as an eluent to give the correspond-

5-Methyl-4-[(2-oxo-3-oxazolidinyl)carbonyl]-3-[(2,4,6-trimeth-

yl)phenyl]-4,5-dihydroisoxazole (5-Me-5). Although 5-Me-5 could

not be separated by chromatography from a mixture with major

1

4-Me-5, it could be characterized by H NMR. H NMR (CDCl₃)

δ 1.55 (3H, d, J ) 6.3 Hz), 2.27 (3H, s), 2.28 (6H, s), 3.80-3.87

(1H, m), 3.93-4.00 (1H, m), 4.11-4.16 (1H, m), 4.30-4.36 (1H,

m), 5.19 (1H, dq, J ) 6.6, 6.3 Hz), 5.59 (1H, d, J ) 6.6 Hz), 6.86

(2H, s).

(4S,5S)-5-[(1-Benzyl-5,5-dimethyl-3-oxo-2-pyrazolidinyl)car-

bonyl]-4-methyl-3-[(2,4,6-trimethyl)phenyl]-4,5-dihydroisox-

azole (4-Me-7). Colorless prisms, mp 143 °C (Et₂O-hexane); [R]²⁵

D

) +226.8 (c 0.50, CHCl₃, 92% ee); IR (KBr) 2972, 2930, 1749,

1714, 1455, 1375, 1307, 1234, 853, 699 cm^-1; ¹H NMR (C₆D₆) δ

0.76 (3H, s), 0.77 (3H, s), 0.98 (3H, d, J ) 7.6 Hz), 1.97 (1H, d,

J ) 16.9 Hz), 2.04 (1H, d, J ) 16.9 Hz), 2.04 (3H, s), 2.27 (6H,

s), 3.67 (1H, d, J ) 14.1 Hz), 3.71 (1H, d, J ) 14.1 Hz), 4.01 (1H,

dq, J ) 4.1, 7.6 Hz), 5.93 (1H, d, J ) 4.1 Hz), 6.64 (2H, s),

(14) Prashad, M.; Har, D.; Kim, H.-Y.; Repic, O. Tetrahedron Lett. 1998,

39, 7067.

J. Org. Chem. Vol. 74, No. 3, 2009 1107

Suga et al.

7.03-7.06 (3H, m), 7.50-7.52 (2H, m); ¹³C NMR (CDCl₃) δ 16.2

(CH₃), 20.2 (CH₃), 21.2 (CH₃), 25.8 (CH₃), 26.8 (CH₃), 43.3 (CH₂),

49.5 (CH), 56.9 (CH₂), 61.6 (C), 84.0 (CH), 124.2 (C), 127.6 (CH),

128.3 (CH), 128.4 (CH), 129.4 (CH), 136.8 (C), 137.2 (C), 138.6

(C), 160.6 (C), 166.0 (C), 174.5 (C); MS (EI) m/z 433(M⁺), 204,

189, 113, 91, 37. Anal. Calcd for C₂₆H₃₁N₃O₃: C, 72.03; H, 7.21;

N, 9.69. Found: C, 71.85; H, 6.92; N, 9.57. The enantiomeric excess

was determined by HPLC analysis (Daicel Chiralpak AD-H,

(4S,5S)-5-[(5,5-Dimethyl-2-oxo-3-oxazolidinyl)carbonyl]-3-(p-

methoxyphenyl)-4-methyl-4,5-dihydroisoxazole (4-Me-9c). Col-

orless prisms; mp 154.0-155.0 °C (CH₂Cl₂-hexane); IR (KBr)

3432, 2984, 2937, 1772, 1714, 1608, 1566, 1518, 1450, 1398, 1371,

1296, 1261, 1205, 1188, 1113, 1012, 962, 931, 883, 842 cm^-1; ¹H

NMR (CDCl₃) δ 1.50 (3H, d, J ) 7.3 Hz), 1.54 (6H, s), 3.72 (1H,

d, J ) 11.0 Hz), 3.80 (1H, d, J ) 11.0 Hz), 3.81 (1H, dq, J ) 2.4,

7.3 Hz), 3.84 (3H, s), 5.73 (1H, d, J ) 2.4 Hz), 6.90-6.93 (2H,

m), 7.63-7.67 (2H, m); ¹³C NMR (CDCl₃) δ 18.0 (CH₃), 27.4

(CH₃), 47.6 (CH), 54.3 (CH₂), 55.4 (CH₃), 80.2 (C), 84.6 (CH),

114.1 (CH), 120.2 (C), 128.7 (CH), 152.6 (C), 159.7 (C), 161.0

(C), 169.4 (C); MS (EI) m/z 332 (M⁺), 190, 162, 135, 77, 55, 37.

Anal. Calcd for C₁₇H₂₀N₂O₅: C, 61.44; H, 6.07; N, 8.43. Found: C,

61.35; H, 6.16; N, 8.42.

i-PrOH-hexane (1:39 v/v), detector: UV 254 nm, ﬂow rate ) 0.5

14

mL/min, 35 °C) after reduction to the corresponding alcohol.

) 40.4 min, t_major) 62.0 min.

t

minor

General Procedure for (R)-BINIM-4Ph-2QN-Ni(II)-Cata-

lyzed Reaction of Hydroximyl Chloride with 3-Crotonoyl-5,5-

dimethyl-2-oxazolidione (3) Exempliﬁed by the Reaction of

p-Methylbenzohydroximoyl Chloride (8e). A suspension of (R)-

BINIM-4Ph-2QN (53.6 mg, 0.075 mmol), powdered MS 4Å (190.5

mg), and Ni(ClO₄)₂·6H₂O (27.5 mg, 0.075 mmol) in CH₂Cl₂(3.0

mL) was stirred for 6 h at room temperature. Oxazolidinone 3 (45.8

mg, 0.25 mmol), hyroximoyl chloride 8e (84.8 mg, 0.50 mmol),

and CH₂Cl₂(1.5 mL) were added successively to the catalyst

suspension. After stirring at room temperature for 20 h, the reaction

was quenched with saturated NH₄Cl solution (2.5 mL) and water

(2.5 mL) and then ﬁltered through Celite. The ﬁltrate was extracted

with CH₂Cl₂(5.0 mL × 3). The combined extracts were dried over

MgSO₄and evaporated in vacuo. The residue was chromatographed

on silica gel with hexane-ethyl acetate (73:27 v/v) as an eluent to

give cycloadduct 9e (69.2 mg, 87%). Regioselectivity was deter-

(4S,5S)-5-Hydroxymethyl-3-(p-methoxyphenyl)-4-methyl-4,5-

dihydroisoxazole. Colorless prisms; mp 141.0-142.5 °C

(CH₂Cl₂-hexane); [R]²⁵) +76.2 (c 0.26, CHCl₃, 93% ee); IR

D

(KBr) 3439, 2957, 1653, 1608, 1591, 1516, 1458, 1423, 1386, 1251,

1

1018, 943, 881 cm^-1; H NMR (CDCl₃) δ 1.35 (3H, d, J ) 7.1

Hz), 2.31 (1H, brs), 3.62 (1H, dq, J ) 5.1, 7.1 Hz), 3.66 (1H, dd,

J ) 5.6, 12.2 Hz), 3.75 (1H, dd, J ) 3.7, 12.2 Hz), 3.84 (3H, s),

4.41 (1H, ddd, J ) 3.7, 5.1, 5.6 Hz), 6.90-6.99 (2H, m), 7.59-7.63

(2H, m); ¹³C NMR (CDCl₃) δ 17.8 (CH₃), 43.9 (CH), 55.4 (CH₃),

63.4 (CH₂), 88.3 (CH), 114.1 (CH), 120.8 (C), 128.4 (CH), 160.6

(C), 160.8 (C); MS (EI) m/z 221 (M⁺), 190, 162, 135, 77, 28. Anal.

Calcd for C₁₂H₁₅NO₃: C, 65.14; H, 6.83; N, 6.33. Found: C, 65.41;

H, 6.94; N, 5.96. The enantiomeric excess was determined by HPLC

analysis (Daicel Chiralpak AD-H, i-PrOH-hexane (1:49 v/v),

1

mined to be 4-Me/5-Me ) 95:5 by H NMR (400 MHz) analysis

of the crude mixture. The enantiomeric excess was determined by

detector: UV 254 nm, ﬂow rate ) 0.5 mL/min, 35 °C). t_minor

99.7 min, t_major) 116.3 min.

)

HPLC analysis (Daicel Chiralpak AD-H, i-PrOH-hexane (1:29

v/v), detector: UV 254 nm, ﬂow rate ) 0.5 mL/min, 35 °C) after

4-[(5,5-Dimethyl-2-oxo-3-oxazolidinyl)carbonyl]-3-(p-methox-

yphenyl)-5-methyl-4,5-dihydroisoxazole (5-Me-9c). Although 5-Me-

9c could not be separated by chromatography from a mixture with

14

conversion to the corresponding alcohol by NaBH₄.

min, t_major) 127.0 min.

t

) 97.1

minor

(4S,5S)-5-[(5,5-Dimethyl-2-oxo-3-oxazolidinyl)carbonyl]-4-

methyl-3-phenyl-4,5-dihydroisoxazole (4-Me-9b). Colorless needles;

mp 148.0-149.0 °C (CH₂Cl₂-hexane); IR (KBr) 3460, 3030, 2978,

2935, 2878, 1988, 1778, 1697, 1466, 1379, 1350, 1294, 1209, 1109,

1080, 1037, 979, 937, 873, 852, 760, 698 cm^-1; ¹H NMR (CDCl₃)

δ 1.50 (3H, s), 1.52 (3H, d, J ) 6.3 Hz), 1.54 (3H, s), 3.75 (1H,

d, J ) 11.0 Hz), 3.79 (1H, d, J ) 11.0 Hz), 3.85 (1H, dq, J ) 2.7,

6.3 Hz), 5.76 (1H, d, J ) 2.7 Hz), 7.37-7.42 (3H, m), 7.68-7.73

(2H, m); ¹³C NMR (CDCl₃) δ 17.7 (CH₃), 27.2 (CH₃), 47.2 (CH),

54.1 (CH₂), 80.2 (C), 84.6 (CH), 127.0 (CH), 127.5 (C), 128.5 (CH),

130.0 (CH), 152.5 (C), 160.0 (C), 169.0 (C); MS (EI) m/z 302 (M⁺),

161, 132, 117, 104, 77, 55, 37, 24. Anal. Calcd for C₁₆H₁₈N₂O₄: C,

63.56; H, 6.00; N, 9.27. Found: C, 63.60; H, 6.17; N, 9.06.

(4S,5S)-5-Hydroxymethyl-4-methyl-3-phenyl-4,5-dihydroisox-

1

major 4-Me-9c, it could be characterized by H NMR. H NMR

(CDCl₃) δ 1.50 (3H, d, J ) 6.3 Hz), 1.53 (3H, s), 1.54 (3H, s),

3.73 (1H, d, J ) 11.0 Hz), 3.76 (1H, d, J ) 11.0 Hz), 4.89 (1H,

dq, J ) 4.2, 6.3 Hz), 5.40 (1H, d, J ) 4.2 Hz), 6.89-6.92 (2H,

m), 7.55-7.59 (2H, m).

(4S,5S)-5-[(5,5-Dimethyl-2-oxo-3-oxazolidinyl)carbonyl]-4-

methyl-3-(p-methylphenyl)-4,5-dihydroisoxazole (4-Me-9d). Col-

orless plates; mp 145.0-146.0 °C (CH₂Cl₂-hexane); IR (KBr)

3452, 3042, 2980, 2968, 2930, 1772, 1716, 1606, 1558, 1514, 1460,

1396, 1371, 1313, 1298, 1261, 1209, 1167, 1105, 1020, 960, 843

cm^-1; ¹H NMR (CDCl₃) δ 1.50 (3H, d, J ) 7.1 Hz), 1.54 (6H, s),

2.37 (3H, s), 3.72 (1H, d, J ) 11.0 Hz), 3.80 (1H, d, J ) 11.0 Hz),

3.83 (1H, dq, J ) 2.7, 7.1 Hz), 5.74 (1H, d, J ) 2.7 Hz), 7.20-7.22

(2H, m), 7.58-7.61 (2H, m); ¹³C NMR (CDCl₃) δ 17.9 (CH₃), 21.6

(CH₃), 27.4 (CH₃), 47.5 (CH), 54.2 (CH₂), 80.2 (C), 84.6 (CH),

124.7 (C), 127.0 (CH), 129.3 (CH), 142.5 (C), 152.6 (C), 160.0

(C), 169.3 (C); MS (EI) m/z 316 (M⁺), 301, 174, 146, 118, 91, 59,

37. Anal. Calcd for C₁₇H₂₀N₂O₄: C, 64.54; H, 6.37; N, 8.86. Found:

C, 64.55; H, 6.37; N, 8.85.

azole. Colorless prisms; mp 79.5-80.5 °C (CH₂Cl₂-hexane); [R]²⁵

D

) +76.2 (c 0.31, MeOH, 89% ee); IR (KBr) 3452, 3055, 2966,

2922, 1689, 1620, 1458, 1379, 1350, 1261, 1159, 1078, 1057, 1016,

887, 854, 767 cm^-1; ¹H NMR (CDCl₃) δ 1.35 (3H, d, J ) 7.3 Hz),

2.15 (1H, brs), 3.62 (1H, dq, J ) 5.2, 7.3 Hz), 3.68 (1H, dd, J )

12.0, 5.1 Hz), 3.78 (1H, dd, J ) 12.0, 3.7 Hz), 4.44 (1H, ddd, J )

3.7, 5.1, 5.2 Hz), 7.39-7.43 (3H, m), 7.65-7.69 (2H, m); ¹³C NMR

(CDCl₃) δ 17.8 (CH₃), 43.7 (CH), 63.4 (CH₂), 88.6 (CH), 126.9

(CH), 128.4 (C), 128.7 (CH), 129.9 (CH), 161.0 (C); MS (EI) m/z

191 (M⁺), 146, 77, 39. HRMS (EI) calcd for C₁₁H₁₃NO₂(M⁺):

191.0946, found 191.0964. The enantiomeric excess was determined

by HPLC analysis (Daicel Chiralpak AD-H, i-PrOH-hexane (1:

49 v/v), detector: UV 254 nm, ﬂow rate ) 0.5 mL/min, 35 °C).

t_minor) 116.0 min, t_major) 135.4 min.

(4S,5S)-5-Hydroxymethyl-4-methyl-3-(p-methylphenyl)-4,5-

dihydroisoxazole. Colorless prisms; mp 111.0-112.0 °C

(CH₂Cl₂-hexane); [R]²⁵) +99.3 (c 0.33, CHCl₃, 91% ee); IR

D

(KBr) 3441, 2974, 2943, 2878, 1718, 1608, 1514, 1458, 1410, 1379,

1

1346, 1236, 1076, 993, 941 cm^-1; H NMR (CDCl₃) δ 1.33 (3H,

d, J ) 7.3 Hz), 2.23 (1H, brs), 2.38 (3H, s), 3.60 (1H, dq, J ) 5.1,

7.3 Hz), 3.66 (1H, dd, J ) 5.6, 12.2 Hz), 3.76 (1H, dd, J ) 3.7,

12.2 Hz), 4.42 (1H, ddd, J ) 3.7, 5.1, 5.6 Hz), 7.20-7.22 (2H,

m), 7.54-7.56 (2H, m); ¹³C NMR (CDCl₃) δ 17.8 (CH₃), 21.5

(CH₃), 43.7 (CH), 63.6 (CH₂), 88.4 (CH), 125.4 (C), 127.0 (CH),

129.3 (CH), 140.0 (C), 160.9 (C); MS (EI) m/z 205 (M⁺), 174,

146, 131, 91, 65. Anal. Calcd for C₁₂H₁₅NO₂: C, 70.22; H, 7.37;

N, 6.82. Found: C, 70.29; H, 7.42; N, 6.71. The enantiomeric excess

was determined by HPLC analysis (Daicel Chiralpak AD-H,

i-PrOH-hexane (1:29 v/v), detector: UV 254 nm, ﬂow rate ) 0.5

mL/min, 35 °C). t_minor) 97.1 min, t_major) 127.0 min.

4-[(5,5-Dimethyl-2-oxo-3-oxazolidinyl)carbonyl]-5-methyl-3-

phenyl-4,5-dihydroisoxazole (5-Me-9b). Although 5-Me-9b could

not be separated by chromatography from a mixture with major

4-Me-9b, it could be characterized by ¹H NMR. ¹H NMR (CDCl₃)

δ 1.51 (3H, d, J ) 6.6 Hz), 1.54 (3H, s), 1.55 (3H, s), 3.73 (2H,

d, J ) 11.2 Hz), 3.74 (1H, d, J ) 11.2 Hz), 4.93 (1H, dq, J ) 4.1,

6.6 Hz), 5.43 (1H, d, J ) 4.1 Hz), 7.36-7.40 (3H, m), 7.59-7.64

(2H, m).

1108 J. Org. Chem. Vol. 74, No. 3, 2009

Asymmetric Cycloadditions of Nitrile Oxides

4-[(5,5-Dimethyl-2-oxo-3-oxazolidinyl)carbonyl]-5-methyl-3-

(p-methylphenyl)-4,5-dihydroisoxazole (5-Me-9d). Although 5-Me-

9d could not be separated by chromatography from a mixture with

major 4-Me-9d, it could be characterized by H NMR. H NMR

(CDCl₃) δ 1.50 (3H, s), 1.51 (3H, d, J ) 6.3 Hz), 1.54 (3H, s),

2.36 (3H, s), 3.73 (1H, d, J ) 11.0 Hz), 3.76 (1H, d, J ) 11.0 Hz),

4.91 (1H, dq, J ) 4.4, 6.3 Hz), 5.42 (1H, d, J ) 4.4 Hz), 7.07-7.09

(2H, m), 7.50-7.52 (2H, m).

(CH), 132.6 (C), 161.6 (C); MS (EI) m/z 227 (M⁺+2), 225 (M⁺),

194, 166, 131, 102, 75, 28. Anal. Calcd for C₁₁H₁₂ClNO₂: C, 58.54;

H, 5.36; N, 6.21. Found: C, 58.76; H, 5.44; N, 5.92. The

enantiomeric excess was determined by HPLC analysis (Daicel

Chiralpak AD-H, i-PrOH-hexane (1:29 v/v), detector: UV 254 nm,

ﬂow rate ) 0.5 mL/min, 35 °C). t_minor) 76.1 min, t_major) 86.8

min.

1

3-(o-Chlorophenyl)-4-[(5,5-dimethyl-2-oxo-3-oxazolidinyl)car-

bonyl]-5-methyl-4,5-dihydroisoxazole (5-Me-9f). Although 5-Me-

9f could not be separated by chromatography from a mixture with

(4S,5S)-3-(p-Chlorophenyl)-5-[(5,5-dimethyl-2-oxo-3-oxazo-

lidinyl)carbonyl]-4-methyl-4,5-dihydroisoxazole (4-Me-9e). Col-

orless prisms; mp 180.0-181.5 °C (CH₂Cl₂-hexane); IR (KBr)

3457, 3069, 2980, 2947, 1782, 1716, 1593, 1560, 1493, 1464, 1394,

1365, 1317, 1300, 1261, 1209, 1165, 1111, 1012, 962, 933, 889,

854 cm^-1; ¹H NMR (CDCl₃) δ 1.50 (3H, d, J ) 7.1 Hz), 1.54 (3H,

s), 1.55 (3H, s), 3.72 (1H, d, J ) 11.0 Hz), 3.82 (1H, d, J ) 11.0

Hz), 3.83 (1H, dq, J ) 2.7, 7.1 Hz), 5.78 (1H, d, J ) 2.7 Hz),

7.36-7.40 (2H, m), 7.63-7.66 (2H, m); ¹³C NMR (CDCl₃) δ 17.8

(CH₃), 27.4 (CH₃), 47.2 (CH), 54.3 (CH₂), 80.3 (C), 85.0 (CH),

126.2 (C), 128.4 (CH), 129.0 (CH), 136.2 (C), 152.6 (C), 159.3

(C), 169.0 (C); MS (EI) m/z 338 (M⁺+2), 336 (M⁺), 321, 308,

196, 166, 131, 116, 75, 56, 37, 26. Anal. Calcd for C₁₆H₁₇ClN₂O₄:

C, 57.06; H, 5.09; N, 8.32. Found: C, 57.13; H, 5.32; N, 8.03.

(4S,5S)-3-(p-Chlorophenyl)-5-hydroxymethyl-4-methyl-4,5-di-

hydroisoxazole. Colorless prisms; mp 82.0-83.0 °C (CH₂Cl₂-

hexane); [R]²⁵_D) +87.3 (c 0.39, CHCl₃, 84% ee); IR (KBr) 3431,

2978, 2939, 1647, 1595, 1494, 1456, 1381, 1234, 1097, 1012, 993,

941, 883 cm^-1; ¹H NMR (CDCl₃) δ 1.33 (3H, d, J ) 7.1 Hz), 2.11

(1H, brs), 3.60 (1H, dq, J ) 5.1, 7.1 Hz), 3.67 (1H, dd, J ) 5.1,

12.2 Hz), 3.79 (1H, dd, J ) 3.7, 12.2 Hz), 4.44 (1H, dt, J ) 3.7,

5.1 Hz), 7.36-7.40 (2H, m), 7.58-7.61 (2H, m); ¹³C NMR (CDCl₃)

δ 17.6 (CH₃), 43.5 (CH), 63.2 (CH₂), 88.9 (CH), 126.8 (C), 128.1

(CH), 128.9 (CH), 135.8 (C), 160.1 (C); MS (EI) m/z 225 (M⁺),

194, 166, 131, 111, 75, 28. Anal. Calcd for C₁₁H₁₂ClNO₂: C, 58.54;

H, 5.36; N, 6.21. Found: C, 58.54; H, 5.61; N, 5.96. The

enantiomeric excess was determined by HPLC analysis (Daicel

Chiralpak AD-H, i-PrOH-hexane (1:29 v/v), detector: UV 254 nm,

ﬂow rate ) 0.5 mL/min, 35 °C). t_minor) 94.9 min, t_major) 112.9

min.

1

major 4-Me-9f, it could be characterized by H NMR. H NMR

(CDCl₃) δ 1.43 (3H, s), 1.51 (3H, s), 1.60 (3H, d, J ) 6.6 Hz),

3.67 (1H, d, J ) 11.2 Hz), 3.70 (1H, d, J ) 11.2 Hz), 4.97 (1H,

dq, J ) 5.1, 6.6 Hz), 5.67 (1H, d, J ) 5.1 Hz), 7.29-7.40 (3H,

m), 7.74-7.76 (1H, m).

(4S,5S)-5-[(5,5-Dimethyl-2-oxo-3-oxazolidinyl)carbonyl]-4-

methyl-3-(p-nitrophenyl)-4,5-dihydroisoxazole (4-Me-9g). Color-

less prisms; mp 206.0-208.0 °C (CH₂Cl₂-hexane); IR (KBr) 3452,

3113, 2980, 2935, 1776, 1709, 1604, 1575, 1521, 1460, 1377, 1294,

1265, 1207, 1170, 1109, 954, 931 cm^-1; ¹H NMR (CDCl₃) δ 1.52

(3H, d, J ) 7.1 Hz), 1.56 (6H, s), 3.74 (1H, d, J ) 10.7 Hz), 3.89

(1H, d, J ) 10.7 Hz), 3.89 (1H, dq, J ) 2.9, 7.1 Hz), 5.86 (1H, d,

J ) 2.9 Hz), 7.87-7.90 (2H, m), 8.24-8.28 (2H, m); ¹³C NMR

(CDCl₃) δ 17.7 (CH₃), 27.4 (CH₃), 46.7 (CH), 54.2 (CH₂), 80.5

(C), 85.5 (CH), 123.9 (CH), 127.8 (CH), 128.8 (C), 148.3 (C), 152.6

(C), 158.7 (C), 168.6 (C); MS (EI) m/z 347 (M⁺), 332, 149, 105,

77, 57, 37. HRMS (EI) calcd for C₁₆H₁₇N₃O₆(M⁺): 347.1117, found

347.1128.

(4S,5S)-5-Hydroxymethyl-4-methyl-3-(p-nitrophenyl)-4,5-di-

hydroisoxazole. Colorless viscous oil; [R]²⁵) +88.9 (c 0.25,

D

CHCl₃, 78% ee); IR (neat) 3601, 2932, 1722, 1602, 1521, 1456,

1348, 1072, 991, 906, 858 cm^-1; ¹H NMR (CDCl₃) δ 1.37 (3H, d,

J ) 7.3 Hz), 1.97 (1H, brs), 3.70 (1H, dq, J ) 5.4, 7.3 Hz,), 3.71

(1H, dd, J ) 4.9, 12.2 Hz), 3.85 (1H, dd, J ) 3.7, 12.2 Hz), 4.52

(1H, ddd, J ) 3.7, 4.9, 5.4 Hz), 7.82-7.86 (2H, m), 8.25-8.29

(2H, m); ¹³C NMR (CDCl₃) δ 17.7 (CH₃), 43.1 (CH), 63.2 (CH₂),

89.7 (CH), 123.9 (CH), 127.6 (CH), 134.6 (C), 148.2 (C), 159.4

(C); MS (EI) m/z 236 (M⁺), 205, 177, 149, 130, 103, 76, 57, 37.

HRMS (EI) calcd for C₁₁H₁₂N₂O₄(M⁺): 236.0797, found 236.0795.

The enantiomeric excess was determined by HPLC analysis (Daicel

Chiralpak AD-H, i-PrOH-hexane (1:9 v/v), detector: UV 254 nm,

ﬂow rate ) 0.5 mL/min, 35 °C). t_minor) 48.8 min, t_major) 101.0

min.

3-(p-Chlorophenyl)-4-[(5,5-dimethyl-2-oxo-3-oxazolidinyl)car-

bonyl]-5-methyl-4,5-dihydroisoxazole (5-Me-9e). Although 5-Me-

9e could not be separated by chromatography from a mixture with

1

major 4-Me-9e, it could be characterized by H NMR. H NMR

(CDCl₃) δ 1.51 (3H, d, J ) 6.3 Hz), 1.55 (6H, s), 3.73 (1H, d, J

) 11.2 Hz), 3.76 (1H, d, J ) 11.2 Hz), 4.93 (1H, dq, J ) 4.2, 6.3

Hz), 5.38 (1H, d, J ) 4.2 Hz), 7.34-7.38 (2H, m), 7.55-7.58 (2H,

m).

4-[(5,5-Dimethyl-2-oxo-3-oxazolidinyl)carbonyl]-5-methyl-3-

(p-nitrophenyl)-4,5-dihydroisoxazole (5-Me-9g). Although 5-Me-

9g could not be separated by chromatography from a mixture with

1

major 4-Me-9g, it could be characterized by H NMR. H NMR

(CDCl₃) δ 1.55 (3H, s), 1.56 (3H, s), 1.61 (1H, d, J ) 6.8 Hz),

3.76 (1H, d, J ) 11.0 Hz), 3.78 (1H, d, J ) 11.0 Hz), 5.00 (1H,

dq, J ) 4.1, 6.8 Hz), 5.40 (1H, d, J ) 4.1 Hz), 7.79-7.81 (2H,

m), 8.26-8.27 (2H, m).

(4S,5S)-3-(o-Chlorophenyl)-5-[(5,5-dimethyl-2-oxo-3-oxazo-

lidinyl)carbonyl]-4-methyl-4,5-dihydroisoxazole (4-Me-9f). Col-

orless amorphous; IR (KBr) 3446, 2987, 2935, 1776, 1714, 1653,

1591, 1558, 1508, 1475, 1458, 1375, 1265, 1207, 1168, 1109, 1032,

954, 931, 877, 761 cm^-1; ¹H NMR (CDCl₃) δ 1.33 (3H, d, J ) 6.8

Hz), 1.56 (6H, s), 3.78 (1H, d, J ) 11.2 Hz), 3.84 (1H, d, J ) 11.2

Hz), 4.20 (1H, dq, J ) 3.7, 6.8 Hz), 5.84 (1H, d, J ) 3.7 Hz), 7.29

-7.44 (3H, m), 7.54-7.57 (1H, m); ¹³C NMR (CDCl₃) δ 16.8

(CH₃), 27.2 (CH₃), 27.3 (CH₃), 49.2 (CH), 54.3 (CH₂), 80.2 (C),

84.4 (CH), 126.8 (CH), 127.2 (C), 130.1 (CH), 130.9 (CH), 131.3

(CH), 132.8 (C), 152.4 (C), 160.2 (C), 168.8 (C); MS (EI) m/z 338

(M⁺+2), 336 (M⁺), 321, 301, 273, 196, 166, 130, 116, 102, 71,

65, 37, 26. HRMS (EI) calcd for C₁₇H₁₇N₃O₄(M⁺): 336.0877, found

336.0856.

(4S,5S)-3-(p-Cyanophenyl)-5-[(5,5-dimethyl-2-oxo-3-oxazolidi-

nyl)carbonyl]-4-methyl-4,5-dihydroisoxazole (4-Me-9h). Color-

less needles; mp 203.0-204.5 °C (CH₂Cl₂-hexane); IR (KBr) 3422,

2986, 1780, 1714, 1608, 1589, 1508, 1460, 1369, 1300, 1263, 1209,

1168, 1114, 958, 933, 896 cm^-1; ¹H NMR (CDCl₃) δ 1.51 (3H, d,

J ) 7.3 Hz), 1.55 (3H, s), 1.56 (3H, s), 3.73 (1H, d, J ) 11.2 Hz),

3.81 (1H, d, J ) 11.2 Hz), 3.85 (1H, dq, J ) 2.9, 7.3 Hz), 5.84

(1H, d, J ) 2.9 Hz), 7.78-7.86 (4H, m); ¹³C NMR (CDCl₃) δ

17.6 (CH₃), 27.4 (CH₃), 46.6 (CH), 54.2 (CH₂), 80.4 (C), 85.4 (CH),

113.5 (C), 118.0 (C), 127.5 (CH), 132.4 (CH), 152.5 (C), 158.9

(C), 168.6 (C); MS (EI) m/z 327 (M⁺), 312, 185, 157, 130, 116,

102, 56. HRMS (EI) calcd for C₁₇H₁₇N₃O₄(M⁺): 327.1219, found

327.1234.

(4S,5S)-3-(o-Chlorophenyl)-5-hydroxymethyl-4-methyl-4,5-di-

hydroisoxazole. Colorless viscous oil; [R]²⁵) +94.8 (c 0.31,

D

CHCl₃, 83% ee); IR (neat) 3452, 2932, 2361, 1732, 1591, 1456,

1

1217, 1062, 1035, 893, 740 cm^-1; H NMR (CDCl₃) δ 1.16 (3H,

d, J ) 7.3 Hz), 2.30 (1H, brs), 3.78 (1H, dd, J ) 5.1, 12.2 Hz),

3.89 (1H, dd, J ) 3.2, 12.2 Hz), 3.94 (1H, dq, J ) 7.6, 7.3 Hz),

4.44 (1H, ddd, J ) 3.2, 5.1, 7.6 Hz), 7.29-7.39 (2H, m), 7.43-7.49

(2H, m); ¹³C NMR (CDCl₃) δ 16.4 (CH₃), 45.4 (CH), 62.8 (CH₂),

88.8 (CH), 126.8 (CH), 128.1 (C), 130.1 (CH), 130.7 (CH), 131.1

(4S,5S)-3-(p-Cyanophenyl)-5-hydroxymethyl-4-methyl-4,5-di-

hydroisoxazole. Colorless viscous oil; [R]²⁵) +74.9 (c 0.24,

D

CHCl₃, 73% ee); IR (neat) 3406, 2932, 2229, 1736, 1589, 1489,

1

1456, 1348, 1076, 993, 902, 842 cm^-1; H NMR (CDCl₃) δ 1.35

(3H, d, J ) 7.1 Hz), 1.81 (1H, brs), 3.65 (1H, dq, J ) 5.4, 7.1 Hz),

J. Org. Chem. Vol. 74, No. 3, 2009 1109

Suga et al.

3.69 (1H, dd, J ) 4.4, 12.6 Hz), 3.84 (1H, dd, J ) 3.9, 12.6 Hz),

4.50 (1H, ddd, J ) 3.9, 4.4, 5.4 Hz), 7.69-7.72 (2H, m), 7.76-7.79

(2H, m); ¹³C NMR (CDCl₃) δ 17.7 (CH₃), 43.1 (CH), 63.2 (CH₂),

89.5 (CH), 113.3 (C), 118.1 (C), 127.3 (CH), 132.4 (CH), 132.9

(C), 159.7 (C); MS (EI) m/z 216 (M⁺), 185, 157, 142, 102. HRMS

(EI) calcd for C₁₂H₁₂N₂O₂(M⁺): 216.0899, found 216.0898. The

enantiomeric excess was determined by HPLC analysis (Daicel

Chiralpak AD-H, i-PrOH-hexane (1:9 v/v), detector: UV 254 nm,

ﬂow rate ) 0.5 mL/min, 35 °C). t_minor) 55.0 min, t_major) 65.6

min.

1697, 1375, 1031, 1238, 1199, 1110, 881 cm^-1; ¹H NMR (CDCl₃)

δ 1.05 (3H, t, J ) 7.3 Hz), 1.49 (3H, s), 1.54 (3H, s), 1.82-1.89

(2H, m), 3.73 (1H, d, J ) 11.5 Hz), 3.76 (1H, d, J ) 11.5 Hz),

4.78 (1H, ddd, J ) 4.8, 5.6, 11.7 Hz), 5.62 (1H, d, J ) 4.8 Hz),

7.36-7.41 (3H, m), 7.62-7.64 (2H, m); ¹³C NMR (CDCl₃) δ 14.2

(CH₃), 27.1 (CH₃), 27.2 (CH₃), 54.5 (CH₂), 55.8 (CH), 62.4 (CH₂),

79.8 (C), 83.0 (CH), 127.0 (CH) 128.8 (CH), 130.5 (CH), 152.4

(C), 154.7 (C), 167.8 (C), 168.1 (C); MS (EI) m/z 316 (M⁺), 243,

184, 172, 144, 116, 98, 77, 35. Anal. Calcd for C₁₇H₂₀N₂O₄: C,

64.54; H, 6.37; N, 8.86. Found: C, 64.42; H, 6.50; N, 8.57.

(5S)-5-[(5,5-Dimethyl-2-oxo-3-oxazolidinyl)carbonyl]-3-phenyl-

4,5-dihydroisoxazole (17b). Colorless prisms; mp 196.0 °C (Et₂O);

3-(p-Cyanophenyl)-4-[(5,5-dimethyl-2-oxo-3-oxazolidinyl)car-

bonyl]-5-methyl-4,5-dihydroisoxazole (5-Me-9h). Although 5-Me-

9h could not be separated by chromatography from a mixture with

[R]²⁵) +55.2 (c 0.5, CHCl₃, 62% ee); IR (KBr) 2981, 1774,

D

1

major 4-Me-9h, it could be characterized by H NMR. H NMR

(CDCl₃) δ 1.48 (3H, d, J ) 3.2 Hz), 1.54 (3H, s), 1.56 (3H, s),

3.75 (1H, d, J ) 6.6 Hz), 3.77 (1H, d, J ) 6.6 Hz), 4.98 (1H, dq,

J ) 3.7, 3.2 Hz), 5.37 (1H, d, J ) 3.7 Hz), 7.73-7.45 (2H, m),

7.95-7.98 (2H, m).

1713, 1374, 1294, 1107, 921, 760, 687 cm^-1; ¹H NMR (CDCl₃) δ

1.55 (6H, s), 3.58 (1H, dd, J ) 6.1, 16.8 Hz), 3.76 (1H, d, J )

10.7 Hz), 3.83 (1H, d, J ) 10.7 Hz), 3.83 (1H, dd, J ) 11.7, 16.8

Hz), 6.14 (1H, dd, J ) 11.7, 6.1 Hz), 7.38-7.43 (3H, m), 7.67-7.70

(2H, m); ¹³C NMR (CDCl₃) δ 27.3 (CH₃), 39.1 (CH₂), 54.5 (CH₂),

78.3 (CH), 80.6 (C), 127.4 (CH), 129.1 (C), 129.2 (CH), 130.9

(CH), 153.0 (C), 156.4 (C), 170.1 (C); MS (EI) m/z 288 (M⁺), 260,

146, 118, 104, 91, 77, 35. Anal. Calcd for C₁₅H₁₆N₂O₄: C, 62.49;

H, 5.59; N, 9.72. Found: C, 62.61; H, 5.43; N, 9.76. The

enantiomeric excess was determined by HPLC analysis (Daicel

Chiralpak AD-H, i-PrOH-hexane (1:19 v/v), detector: UV 254 nm,

ﬂow rate ) 0.5 mL/min, 35 °C) after reduction to the corresponding

alcohol.¹⁴t_minor) 53.9 min, t_major) 62.8 min.

(4S,5S)-5-[(5,5-Dimethyl-2-oxo-3-oxazolidinyl)carbonyl]-4-

methyl-3-(2-methylpropyl)-4,5-dihydroisoxazole (4-Me-9i). Col-

orless prisms; mp 126.0-127.0 °C (Et₂O-hexane); [R]²⁵

)

D

+103.4 (c 0.50, CHCl₃, 67% ee); IR (KBr) 2965, 2872, 1778, 1705,

1390, 1370, 1294, 1107, 958 cm^-1; ¹H NMR (CDCl₃) δ 0.91 (3H,

d, J ) 6.6 Hz), 1.00 (3H, d, J ) 6.6 Hz), 1.36 (3H, d, J ) 7.3 Hz),

1.53 (6H, s), 1.87-2.02 (1H, m), 2.14-2.29 (2H, m), 3.28-3.41

(1H, m), 3.71 (1H, d, J ) 11.0 Hz), 3.79 (1H, d, J ) 11.0 Hz),

5.61 (1H, d, J ) 3.7 Hz); ¹³C NMR (CDCl₃) δ 16.6 (CH₃), 22.0

(CH₃), 22.2 (CH₃), 26.4 (CH), 27.4 (CH₃), 34.3 (CH₂), 49.2 (CH),

54.3 (CH₂), 79.9 (C), 82.8 (CH), 152.4 (C), 161.3 (C), 169.7 (C);

MS (EI) m/z 282 (M⁺), 267, 209, 152, 112, 98, 72, 38. HRMS

(EI) calcd for C₁₄H₂₂N₂O₄(M⁺): 282.1596, found 282.1610. The

enantiomeric excess was determined by HPLC analysis (Daicel

Chiralpak AD-H, i-PrOH-hexane (1:19 v/v), detector: UV 254 nm,

ﬂow rate ) 0.5 mL/min, 35 °C). t_minor) 57.1 min, t_major) 85.9

min.

(4S,5S)-5-[(5,5-Dimethyl-2-oxo-3-oxazolidinyl)carbonyl]-4-

ethoxycarbonyl-3-phenyl-4,5-dihydroisoxazole (4-CO₂Et-18b).

Colorless prisms; mp 121.0 °C (Et₂O-hexane); [R]²⁵) +81.4

D

(c 0.4, CHCl₃, 51% ee); IR (KBr) 2977, 1764, 1739, 1375, 1297,

1263, 1238, 1177, 1111, 755 cm^-1; ¹H NMR (CDCl₃) δ 1.20 (3H,

t, J ) 7.1 Hz), 1.55 (3H, s), 1.56 (3H, s), 3.75 (1H, d, J ) 11.0

Hz), 3.81 (1H, d, J ) 11.0 Hz), 4.20 (1H, dq, J ) 11.7, 7.1 Hz),

4.23 (1H, dq, J ) 11.7, 7.1 Hz),, 4.76 (1H, d, J ) 4.6 Hz), 6.40

(1H, d, J ) 4.6 Hz), 7.36-7.42 (3H, m), 7.77-7.86 (2H, m); ¹³C

NMR (CDCl₃) δ 14.0 (CH₃), 27.3 (CH₃), 27.4 (CH₃), 54.2 (CH₂),

57.0 (CH), 62.5 (CH₂), 80.4 (C), 82.3 (CH), 127.3 (CH), 127.4

(C), 128.5 (CH), 130.5 (CH), 152.2 (C), 153.6 (C), 167.5 (C), 167.6

(C); MS (EI) m/z 360 (M⁺), 332, 218, 190, 172, 144, 77, 55, 37.

Anal. Calcd for C₁₈H₂₀N₂O₆: C, 59.99; H, 5.59; N, 7.77. Found: C,

59.96; H, 5.67; N, 7.73. The enantiomeric excess was determined

by HPLC analysis (Daicel Chiralpak AD-H, i-PrOH-hexane (1:

19 v/v), detector: UV 254 nm, ﬂow rate ) 0.5 mL/min, 35 °C)

after reduction to the corresponding alcohol.¹⁴t_minor) 54.9 min,

t_major) 68.5 min.

4-[(5,5-Dimethyl-2-oxo-3-oxazolidinyl)carbonyl]-5-methyl-3-

(2-methylpropyl)-4,5-dihydroisoxazole (5-Me-9i). Colorless prisms;

mp 80.0-82.0 °C (Et₂O-hexane); IR (KBr) 2962, 2870, 1775,

1694, 1467, 1376, 1294, 1107 cm^-1; ¹H NMR (CDCl₃) δ 0.95 (3H,

d, J ) 6.8 Hz), 1.00 (3H, d, J ) 6.3 Hz), 1.42 (3H, d, J ) 6.3 Hz),

1.54 (6H, s), 1.85-2.01 (1H, m), 2.18 (1H, dd, J ) 5.6, 15.1 Hz),

2.29 (1H, dd, J ) 9.0, 15.1 Hz), 3.78 (2H, s), 4.74-7.85 (1H, m),

4.90 (1H, d, J ) 5.6 Hz); ¹³C NMR (CDCl₃) δ 20.5 (CH₃), 22.2

(CH₃), 23.1(CH₃), 26.2 (CH), 27.3 (CH₃), 27.3 (CH₃), 36.1 (CH₂),

54.6 (CH₂), 60.3 (CH), 79.4 (C), 81.2 (CH), 152.4 (C), 155.1 (C),

169.1 (C); MS (EI) m/z 282 (M⁺), 267, 209, 152, 112, 98, 72, 38.

Anal. Calcd for C₁₄H₂₂N₂O₄: C, 59.56; H, 7.85; N, 9.92. Found: C,

59.75; H, 7.94; N, 9.65.

4-[(5,5-Dimethyl-2-oxo-3-oxazolidinyl)carbonyl]-5-ethoxycar-

bonyl-3-phenyl-4,5-dihydroisoxazole (5-CO₂Et-18b). Colorless

prisms; mp 165.5-166.5 °C (Et₂O-hexane) IR (KBr) 1768, 1743,

1697, 1376, 1338, 1332, 1238, 1199, 1110, 881, 768 cm^-1; ¹H NMR

(CDCl₃) δ 1.33 (3H, t, J ) 7.1 Hz), 1.47 (3H, s), 1.55 (3H, s),

3.72 (1H, d, J ) 11.0 Hz), 3.76 (1H, d, J ) 11.0 Hz), 4.29 (1H,

dq, J ) 14.1, 7.1 Hz), 4.30 (1H, dq, J ) 14.1, 7.1 Hz), 5.22 (1H,

d, J ) 5.4 Hz), 6.20 (1H, d, J ) 5.4 Hz), 7.36-7.42 (3H, m),

7.63-7.67 (2H, m); ¹³C NMR (CDCl₃) δ 14.4 (CH₃), 27.1 (CH₃),

27.2 (CH₃), 54.4 (CH₂), 55.8 (CH), 62.4 (CH₂), 79.8 (C), 83.2 (CH),

127.0 (CH), 127.7 (C), 128.8 (CH), 130.5 (CH), 152.4 (C), 154.8

(C), 167.8 (C), 168.1 (C); MS (EI) m/z 360 (M⁺), 287, 218, 184,

172, 116, 98, 77. HRMS (EI) calcd for C₁₈H₂₀N₂O₆(M⁺): 360.1321,

found 360.1341.

General Procedure for the (R)-BINIM-4(3,5-xylyl)-2QN-

Ni(II)-Catalyzed Reaction of Hydroximyl Chloride with 1-Ben-

zyl-2-crotonoyl-5,5-dimethyl-3-pyrazolidinone (4) Exempliﬁed

by the Reaction of Benzohydroximoyl Chloride (8b). A suspen-

sion of (R)-BINIM-4(3,5-xylyl)-2QN (19.3 mg, 0.025 mmol),

powdered MS 4Å (190.5 mg), and Ni(ClO₄)₂·6H₂O (9.2 mg, 0.025

mmol) in CH₂Cl₂(3.0 mL) was stirred for 6 h at room temperature.

Pyrazolidinone 4 (68.1 mg, 0.25 mmol), hyroximoyl chloride 8b

(77.8 mg, 0.50 mmol), and CH₂Cl₂(1.5 mL) were added succes-

sively to the catalyst suspension. After stirring at room temperature

(4S,5S)-5-[(5,5-Dimethyl-2-oxo-3-oxazolidinyl)carbonyl]-4-

ethyl-3-phenyl-4,5-dihydroisoxazole (4-Et-16b). Colorless prisms;

mp 141.0 °C (Et₂O-hexane); [R]²⁵) +124.5 (c 0.22, CHCl₃,

D

88% ee); IR (KBr) 2973, 2935, 1775, 1708, 1375, 1295, 1207, 1109,

761, 695 cm^-1; ¹H NMR (CDCl₃) δ 0.94 (3H, t, J ) 7.3 Hz), 1.55

(3H, s), 1.55 (3H, s), 1.76-1.84 (1H, m), 1.96-2.05 (1H, m), 3.74

(1H, d, J ) 11.2 Hz), 3.80 (1H, d, J ) 11.2 Hz), 3.99 (1H, ddd, J

) 3.2, 4.1, 7.3 Hz), 5.93 (1H, d, J ) 3.2 Hz), 7.39-7.42 (3H, m),

7.70-7.73 (2H, m); ¹³C NMR (CDCl₃) δ 9.9 (CH₃), 23.8 (CH₂),

27.3 (CH₃), 27.4 (CH₃), 52.5 (CH), 54.4 (CH₂), 80.1 (C), 82.3 (CH),

127.1 (CH), 127.9 (C), 128.7 (CH), 130.2 (CH), 152.4 (C), 158.7

(C), 169.5 (C); MS (EI) m/z 316 (M⁺), 219, 175, 117, 104, 91, 71,

55, 38. Anal. Calcd for C₁₇H₂₀N₂O₄: C, 64.54; H, 6.37; N, 8.86.

Found: C, 64.76; H, 6.33; N, 8.68. The enantiomeric excess was

determined by HPLC analysis (Daicel Chiralpak AD-H,

i-PrOH-hexane (3:97 v/v), detector: UV 254 nm, ﬂow rate ) 0.5

mL/min, 35 °C) after reduction to the corresponding alcohol. t_minor

) 78.7 min, t_major) 90.3 min.

4-[(5,5-Dimethyl-2-oxo-3-oxazolidinyl)carbonyl]-5-ethyl-3-(2-

methylpropyl)-4,5-dihydroisoxazole (5-Et-16b). Colorless prisms;

mp 105.0-106.0 °C (Et₂O-hexane); IR (KBr) 2972, 1770, 1743,

1110 J. Org. Chem. Vol. 74, No. 3, 2009

Asymmetric Cycloadditions of Nitrile Oxides

for 24 h, the reaction was quenched with saturated NH₄Cl solution

(2.5 mL) and water (2.5 mL) and then ﬁltered through Celite. The

ﬁltrate was extracted with CH₂Cl₂(5.0 mL × 3). The combined

extracts were dried over MgSO₄and evaporated in vacuo. The

residue was chromatographed on silica gel with hexane-ethyl

acetate (73:27 v/v) as an eluent to give cycloadduct 10b (88.0 mg,

90%). Regioselectivity was determined to be 4-Me/5-Me ) 99:1

by ¹H NMR (400 MHz) analysis of the crude mixture. The

enantiomeric excess was determined by HPLC analysis (Daicel

Chiralpak AD-H, i-PrOH-hexane (1:19 v/v), detector: UV 254 nm,

ﬂow rate ) 0.5 mL/min, 35 °C) after reduction to the corresponding

alcohol by NaBH₄.¹⁴t_minor) 41.6 min, t_major) 49.5 min.

(4S,5S)-5-[(1-Benzyl-5,5-dimethyl-3-oxo-2-pyrazolidinyl)car-

bonyl]-3-(p-chlorophenyl)-4-methyl-4,5-dihydroisoxazole (4-Me-

10e).⁶Colorless prisms; mp 154.5-155.0 °C (Et₂O-hexane); [R]²⁵

D

) +100.8 (c 0.59, CHCl₃, 79% ee); IR (KBr) 2981, 2938, 1751,

1722, 1496, 1304, 1217, 1093, 929, 887, 834, 694 cm^-1; ¹H NMR

(C₆D₆) δ 0.75 (3H, s), 0.77 (3H, s), 0.99 (3H, d, J ) 7.3 Hz), 2.02

(2H, s), 3.65 (2H, s), 3.85 (1H, dq, J ) 2.9, 7.3 Hz), 5.81 (1H, d,

J ) 2.9 Hz), 6.93-7.02 (3H, m), 7.09-7.19 (2H, m), 7.27-7.30

(2H, m), 7.44-7.46 (2H, m); ¹³C NMR (CDCl₃) δ 17.5 (CH₃), 26.4

(CH₃), 26.4 (CH₃), 43.2 (CH₂), 45.6 (CH), 57.0 (CH₂), 61.7 (C),

85.5 (CH), 126.3 (C), 127.4 (CH), 128.2 (CH), 128.3 (CH), 128.8

(CH), 129.1 (CH), 136.0 (C), 136.7 (C), 159.4 (C), 165.6 (C) 174.6

(C); MS (EI) m/z 425 (M⁺), 205, 189, 131, 111, 92. Anal. Calcd

for C₂₃H₂₄N₃O₃Cl: C, 64.86; H, 5.68; N, 9.87. Found: C, 64.96; H,

5.39; N, 9.68. The enantiomeric excess was determined by HPLC

analysis (Daicel Chiralpak AD-H, i-PrOH-hexane (1:19 v/v),

detector: UV 254 nm, ﬂow rate ) 0.5 mL/min, 35 °C) after

reduction to the corresponding alcohol.¹⁴t_minor) 55.9 min, t_major

) 67.5 min.

(4S,5S)-5-[(1-Benzyl-5,5-dimethyl-3-oxo-2-pyrazolidinyl)car-

bonyl]-4-methyl-3-phenyl-4,5-dihydroisoxazole (4-Me-10b).⁶Col-

orless prisms; mp 111.0-112.0 °C (Et₂O-hexane); [R]²⁵

)

D

+115.4 (c 0.51, CHCl₃, 95% ee); IR (KBr) 2977, 2933, 1749, 1709,

1455, 1346, 1305, 1233, 925, 881, 768, 696 cm^-1; ¹H NMR (C₆D₆)

δ 0.75 (3H, s), 0.77 (3H, s), 1.09 (3H, d, J ) 7.3 Hz), 2.04 (2H,

s), 3.66 (2H, s), 3.99 (1H, dq, J ) 2.7, 7.3 Hz), 5.83 (1H, d, J )

2.7 Hz), 6.97-7.18 (6H, m), 7.44-7.47 (2H, m), 7.59-7.63 (2H,

m); ¹³C NMR (CDCl₃) δ 17.6 (CH₃), 26.3 (CH₃), 26.4 (CH₃), 43.3

(CH₂), 45.8 (CH), 56.9 (CH₂), 61.7 (C), 85.3 (CH), 127.1 (CH),

127.4 (CH), 127.8 (C), 128.2 (CH), 128.6 (CH), 129.1 (CH), 130.0

(CH), 136.8 (C), 160.3 (C), 165.8 (C), 174.6 (C); MS (EI) m/z 391

(M⁺), 204, 189, 113, 91, 77, 37. Anal. Calcd for C₂₃H₂₅N₃O₃: C,

70.57; H, 6.44; N, 10.73. Found: C, 70.53; H, 6.38; N, 10.72. The

enantiomeric excess was determined by HPLC analysis (Daicel

Chiralpak AD-H, i-PrOH-hexane (1:19 v/v), detector: UV 254 nm,

ﬂow rate ) 0.5 mL/min, 35 °C) after reduction to the corresponding

alcohol by NaBH₄.¹⁴t_minor) 41.6 min, t_major) 49.5 min.

(4S,5S)-5-[(1-Benzyl-5,5-dimethyl-3-oxo-2-pyrazolidinyl)car-

bonyl]-3-(o-chlorophenyl)-4-methyl-4,5-dihydroisoxazole (4-Me-

10f).⁶Colorless prisms; mp 53.0 °C (Et₂O-hexane); [R]²⁵

)

D

+100.3 (c 0.34, CHCl₃, 83% ee); IR (KBr) 3061, 3028, 2975, 2935,

1747, 1714, 1455, 1313, 1235, 874, 759, 698 cm^-1; ¹H NMR (C₆D₆)

δ 0.77 (3H, s), 0.78 (3H, s), 1.02 (3H, d, J ) 6.8 Hz), 1.99 (1H,

d, J ) 16.8 Hz), 2.05 (1H, d, J ) 16.8 Hz), 3.68 (1H, d, J ) 13.9

Hz), 3.72 (1H, d, J ) 13.9 Hz), 4.45-4.53 (1H, m), 5.90 (1H, d,

J ) 4.1 Hz), 6.66-6.74 (2H, m), 6.98-7.13 (4H, m), 7.38-7.41

(1H, m), 7.50-7.53 (2H, m); ¹³C NMR (CDCl₃) δ 16.6 (CH₃), 26.0

(CH₃), 26.7 (CH₃), 43.3 (CH₂), 47.9 (CH), 56.8 (CH₂), 61.6 (C),

85.2 (CH), 126.7 (CH), 127.3 (C), 127.4 (CH), 128.3 (CH), 129.1

(CH), 130.1 (CH), 130.8, (CH) 131.2 (CH), 132.9 (C), 137.0 (C),

160.3 (C), 165.4 (C), 174.5 (C); MS (EI) m/z 425 (M⁺), 205, 189,

130, 111, 92, 77. HRMS (EI) calcd for C₂₃H₂₄N₃O₃Cl (M⁺):

425.1502, found 425.1512. The enantiomeric excess was determined

by HPLC analysis (Daicel Chiralpak AD-H, i-PrOH-hexane (1:

19 v/v), detector: UV 254 nm, ﬂow rate ) 0.5 mL/min, 35 °C)

after reduction to the corresponding alcohol.¹⁴t_minor) 48.5 min,

t_major) 54.4 min.

(4S,5S)-5-[(1-Benzyl-5,5-dimethyl-3-oxo-2-pyrazolidinyl)car-

bonyl]-3-(p-methoxyphenyl)-4-methyl-4,5-dihydroisoxazole (4-

Me-10c).⁶Colorless prisms; mp 121.0-121.5 °C (Et₂O-hexane);

[R]²⁵) +111.6 (c 0.51, CHCl₃, 92% ee); IR (KBr) 2973, 2937,

D

1753, 1709, 1604, 1515, 1261, 1229, 1176, 925, 886, 840, 699

cm^-1; ¹H NMR (C₆D₆) δ 0.76 (3H, s), 0.78 (3H, s), 1.15 (3H, d, J

) 7.3 Hz), 2.04 (2H, s), 3.19 (3H, s), 3.67 (2H, s), 4.02 (1H, dq,

J ) 2.9, 7.3 Hz), 5.85 (1H, d, J ) 2.9 Hz), 6.61-6.64 (2H, m),

7.00-7.04 (1H, m), 7.11-7.19 (2H, m), 7.47-7.49 (2H, m),

7.57-7.61 (2H, m); ¹³C NMR (CDCl₃) δ 17.7 (CH₃), 26.3 (CH₃),

26.4 (CH₃), 43.3 (CH₂), 46.1 (CH), 55.4 (CH₃), 56.9 (CH₂), 61.7

(C), 85.1 (CH), 114.0 (CH), 120.2 (C), 127.4 (CH), 128.2 (CH),

128.6 (CH), 129.1 (CH), 136.8 (C), 159.9 (C), 160.8 (C), 166.0

(C), 174.6 (C); MS (EI) m/z 421 (M⁺), 204, 190, 133, 113, 92, 77.

Anal. Calcd for C₂₄H₂₇N₃O₄: C, 68.39; H, 6.46; N, 9.97. Found: C,

68.17; H, 6.16; N, 9.84. The enantiomeric excess was determined

by HPLC analysis (Daicel Chiralpak AD-H, i-PrOH-hexane (1:

19 v/v), detector: UV 254 nm, ﬂow rate ) 0.5 mL/min, 35 °C)

after reduction to the corresponding alcohol.¹⁴t_minor) 51.9 min,

t_major) 69.1 min.

(4S,5S)-5-[(1-Benzyl-5,5-Dimethyl-3-oxo-2-pyrazolidinyl)car-

bonyl]-4-methyl-3-(2-methylpropyl)-4,5-dihydroisoxazole (4-Me-

10i).⁶Colorless needles; mp 88.0-89.0 °C (Et₂O-hexane); [R]²⁵

D

) +135.3 (c 0.57, CHCl₃, 76% ee); IR (KBr) 2957, 2933, 2872,

1

1750, 1709, 1471, 1265, 1237, 1204, 716 cm^-1; H NMR (C₆D₆)

δ 0.75 (3H, s), 0.78 (3H, s), 0.80 (3H, d, J ) 6.6 Hz), 0.86 (3H,

d, J ) 6.6 Hz), 0.90 (3H, d, J ) 7.3 Hz), 1.73-1.87 (2H, m),

1.97-2.07 (3H, m), 3.46 (1H, dq, J ) 4.1, 7.3 Hz), 3.68 (2H, s),

5.70 (1H, d, J ) 4.1 Hz), 7.03-7.19 (3H, m), 7.47-7.49 (2H, m);

¹³C NMR (CDCl₃) δ 16.2 (CH₃), 22.0 (CH₃), 23.2 (CH₂), 26.0

(CH₃), 26.2 (CH₃), 26.6 (CH₃), 34.4 (CH₂), 43.3 (CH), 47.6 (CH),

56.9 (CH₂), 61.6 (C), 83.5 (CH), 127.5 (CH), 128.2 (CH), 129.3

(CH), 136.8 (C), 161.5 (C), 166.2 (C), 174.4 (C); MS (EI) m/z 371

(M⁺), 356, 205, 189, 113, 92, 77, 65. Anal. Calcd for C₂₁H₂₉N₃O₃:

C, 67.90; H, 7.87; N, 11.31. Found: C, 67.97; H, 7.87; N, 11.25.

The enantiomeric excess was determined by HPLC analysis (Daicel

Chiralpak OJ, i-PrOH-hexane (1:9 v/v), detector: UV 254 nm, ﬂow

rate ) 0.5 mL/min, 35 °C). t_minor) 26.6 min, t_major) 30.6 min.

(4S,5S)-5-[(1-Benzyl-5,5-dimethyl-3-oxo-2-pyrazolidinyl)car-

bonyl]-3-butyl-4-methyl-4,5-dihydroisoxazole (4-Me-10j). Color-

(4S,5S)-5-[(1-Benzyl-5,5-dimethyl-3-oxo-2-pyrazolidinyl)car-

bonyl]-4-methyl-3-p-tolyl-4,5-dihydroisoxazole (4-Me-10d). Col-

orless prisms; mp 170.0-171.0 °C (Et₂O-hexane); [R]²⁵

)

D

+121.2 (c 0.5, CHCl₃, 88% ee); IR (KBr) 2995, 2971, 2930, 1754,

1

1705, 1304, 1235, 1210, 952, 883, 817 cm^-1; H NMR (C₆D₆) δ

0.76 (3H, s), 0.79 (3H, s), 1.14 (3H, d, J ) 7.3 Hz), 2.00 (3H, s),

2.06 (2H, s), 3.67 (2H, s), 4.02 (1H, dq, J ) 7.3, 2.9 Hz), 5.84

(1H, d, J ) 2.9 Hz), 6.85-6.87 (2H, m), 7.01-7.04 (1H, m),

7.10-7.19 (2H, m), 7.45-7.49 (2H, m), 7.57-7.62 (2H, m); ¹³C

NMR (CDCl₃) δ 17.7 (CH₃), 21.5 (CH₃), 26.3 (CH₃), 26.4 (CH₃),

43.3 (CH₂), 46.0 (CH), 56.9 (CH₂), 61.7 (C), 85.2 (CH), 124.9 (C),

127.0 (CH), 127.4 (CH), 128.2 (CH), 129.1 (CH), 129.2 (CH), 136.8

(C), 140.3 (C), 160.2 (C), 165.9 (C), 174.5 (C); MS (EI) m/z 405

(M⁺), 204, 189, 174, 146, 113, 92, 77. Anal. Calcd for C₂₄H₂₇N₃O₃:

C, 71.09; H, 6.71; N, 10.36. Found: C, 71.29; H, 6.34; N, 10.22.

The enantiomeric excess was determined by HPLC analysis (Daicel

Chiralpak AD-H, i-PrOH-hexane (1:19 v/v), detector: UV 254 nm,

ﬂow rate ) 0.5 mL/min, 35 °C) after reduction to the corresponding

alcohol.¹⁴t_minor) 56.7 min, t_major) 75.0 min.

less cottonlike needles; mp 88.0-89.0 °C (Et₂O-hexane); [R]²⁵

D

) +53.5 (c 0.51, CDCl₃, 84% ee); IR (KBr) 2969, 2933, 2872,

1

1750, 1705, 1463, 1370, 1314, 1257, 1237, 1213, 772 cm^-1; H

NMR (C₆D₆) δ 0.76 (3H, t, J ) 7.3 Hz), 0.77 (3H, s), 0.79 (3H, s),

0.90 (3H, d, J ) 7.1 Hz), 1.11-1.27 (2H, m), 1.38-1.45 (2H, m),

1.86 (1H, dt, J ) 15.4, 7.8 Hz), 2.04 (2H, s), 2.16 (1H, dt, J )

15.4, 7.8 Hz), 3.47 (1H, dq, J ) 4.4, 7.1 Hz), 3.69 (2H, s), 5.69

(1H, d, J ) 4.4 Hz), 7.03-7.72 (1H, m), 7.13-7.19 (2H, m),

7.46-7.51 (2H, m); ¹³C NMR (CDCl₃) δ 13.8 (CH₃), 16.3 (CH₃),

22.5 (CH₂), 25.4 (CH₂), 26.1 (CH₃), 26.5 (CH₃), 28.3 (CH₂), 43.3

J. Org. Chem. Vol. 74, No. 3, 2009 1111

Suga et al.

(CH₂), 47.4, (CH) 57.0 (CH₂), 61.6 (C), 83.7 (CH), 127.5 (CH),

128.2 (CH), 129.3 (CH), 136.9 (C), 162.2 (C), 166.1 (C), 174.4

(C); MS (EI) m/z 371 (M⁺), 204, 189, 113, 91, 57. Anal. Calcd for

C₂₁H₂₉N₃O₃: C, 67.90; H, 7.87; N, 11.31. Found: C, 67.82; H, 8.04;

N, 11.36. The enantiomeric excess was determined by HPLC

analysis (Daicel Chiralpak AD-H, i-PrOH-hexane (1:19 v/v),

reduction to the corresponding alcohol by NaBH₄.¹⁴t_minor) 53.9

min, t_major) 62.8 min.

(5S)-5-[(1-Benzyl-5,5-dimethyl-3-oxo-2-pyrazolidinyl)carbo-

nyl]-3-(p-methoxyphenyl)-4,5-dihydroisoxazole (19c). Colorless

needles; mp 121.0-121.5 °C (Et₂O-hexane); [R]²⁵_D) +148.5 (c

0.40, CHCl₃, 91% ee); IR (KBr) 2966, 2928, 1755, 1698, 1607,

1

detector: UV 254 nm, ﬂow rate ) 0.5 mL/min, 35 °C). t_minor

60.8 min, t_major) 68.2 min.

)

1515, 1362, 1246, 1227, 1179, 1025, 838, 723 cm^-1; H NMR

(CDCl₃) δ 1.30 (3H, s), 1.32 (3H, s), 2.61 (1H, d, J ) 17.1 Hz),

2.67 (1H, d, J ) 17.1 Hz), 3.42 (2H, d, J ) 7.3 Hz), 3.83 (3H, s),

4.06 (1H, d, J ) 13.7 Hz), 4.11 (1H, d, J ) 13.7 Hz), 5.81 (1H,

brt, J ) 7.3 Hz), 6.88-6.92 (2H, m), 7.18-7.29 (3H, m), 7.40-7.44

(2H, m), 7.53-7.60 (2H, m); ¹³C NMR (CDCl₃) δ 26.1 (CH₃), 26.4

(CH₃), 38.1 (CH₂), 43.2 (CH₂), 55.4 (CH₃), 57.0 (CH₂), 61.6 (C),

78.1 (CH), 113.9 (CH), 121.2 (C), 127.5 (CH), 128.2 (CH), 128.3

(CH), 129.2 (CH), 136.7 (C), 155.2 (C), 160.9 (C), 166.1 (C), 174.3

(C); MS (EI) m/z 407 (M⁺), 204, 189, 113, 91, 77, 56. Anal. Calcd

for C₂₃H₂₅N₃O₄: C, 67.80; H, 6.18; N, 10.31. Found: C, 67.75; H,

6.16; N, 10.38. The enantiomeric excess was determined by HPLC

analysis (Daicel Chiralpak AD-H, i-PrOH-hexane (1:19 v/v),

(4S,5S)-5-[(1-Benzyl-5,5-dimethyl-3-oxo-2-pyrazolidinyl)car-

bonyl]-3-tert-butyl-4-methyl-4,5-dihydroisoxazole (4-Me-10k).⁶

Colorless cottonlike needles; mp 155.0-156.0 °C (Et₂O-hexane);

[R]²⁵) +67.1 (c 0.5, CDCl₃, 42% ee); IR (KBr) 2969, 2933,

D

1753, 1697, 1467, 1374, 1318, 1224, 881, 724, 696 cm^-1; ¹H NMR

(CDCl₃) δ 0.64 (3H, s), 0.67 (3H, s), 0.95 (3H, d, J ) 7.3 Hz),

0.99 (9H, s), 1.88 (1H, d, J ) 17.1 Hz), 1.92 (1H, d, J ) 17.1 Hz),

3.35-3.43 (1H, m), 3.55 (1H, d, J ) 14.1 Hz), 3.59 (1H, d, J )

14.1 Hz), 5.54 (1H, d, J ) 2.0 Hz), 6.92-6.95 (1H, m), 7.00-7.08

(2H, m), 7.34-7.39 (2H, m); ¹³C NMR (CDCl₃) δ 18.2 (CH₃), 25.9

(CH₃), 26.7 (CH₃), 29.1 (CH₃), 33.5 (C), 43.3 (CH₂), 46.1 (CH),

56.9 (CH₂), 61.6 (C), 85.1 (CH), 127.4 (CH), 128.3 (CH), 129.2

(CH), 136.9 (C), 166.0 (C), 169.0 (C), 174.4 (C); MS (EI) m/z 371

(M⁺), 356, 204, 189, 113, 91, 69, 57. Anal. Calcd for C₂₁H₂₉N₃O₃:

C, 67.90; H, 7.87; N, 11.31. Found: C, 68.04; H, 7.73; N, 11.31.

The enantiomeric excess was determined by HPLC analysis (Daicel

Chiralpak AD-H, i-PrOH-hexane (1:19 v/v), detector: UV 254 nm,

ﬂow rate ) 0.5 mL/min, 35 °C). t_minor) 41.2 min, t_major) 52.3

min.

detector: UV 254 nm, ﬂow rate ) 0.5 mL/min, 35 °C) after

14

reduction to the corresponding alcohol by NaBH₄.

min, t_major) 124.2 min.

t

) 111.4

minor

(5S)-5-[(1-Benzyl-5,5-dimethyl-3-oxo-2-pyrazolidinyl)carbo-

nyl]-3-(p-chlorophenyl)-4,5-dihydroisoxazole (19e). Colorless

needles; mp 128.0-129.0 °C (Et₂O-hexane); [R]²⁵) +82.4 (c

D

0.50, CDCl₃, 79% ee); IR (KBr) 3034, 2977, 1757, 1701, 1491,

1

1349, 1240, 1216, 825, 720 cm^-1; H NMR (CDCl₃) δ 1.30 (3H,

s), 1.33 (3H, s), 2.62 (1H, d, J ) 17.1 Hz), 2.69 (1H, d, J ) 17.1

Hz), 3.41 (2H, d, J ) 7.1 Hz), 4.05 (1H, d, J ) 13.2 Hz), 4.11

(1H, d, J ) 13.2 Hz), 5.84 (1H, brt, J ) 7.1 Hz), 7.18-7.29 (3H,

m), 7.33-7.44 (4H, m), 7.53-7.61 (2H, m); ¹³C NMR (CDCl₃) δ

26.4 (CH₃), 26.1 (CH₃), 37.6 (CH₂), 43.2 (CH₂), 57.1 (CH₂), 61.7

(C), 78.5 (CH), 127.1 (C), 127.5 (CH), 128.0 (CH), 128.3 (CH),

128.8 (CH), 129.3 (CH), 136.1 (C), 136.6 (C), 154.8 (C), 165.7

(C), 174.3 (C); MS (EI) m/z 411 (M⁺), 204, 189, 113, 91, 75, 56.

Anal. Calcd for C₂₂H₂₂N₃O₃Cl: C, 64.15; H, 5.38; N, 10.20. Found:

C, 64.23; H, 5.24; N, 10.27. The enantiomeric excess was

determined by HPLC analysis (Daicel Chiralpak AD-H,

i-PrOH-hexane (1:19 v/v), detector: UV 254 nm, ﬂow rate ) 0.5

mL/min, 35 °C) after reduction to the corresponding alcohol by

NaBH₄.¹⁴t_minor) 72.0 min, t_major) 83.7 min.

General Procedure for (R)-BINIM-4(3,5-xylyl)-2QN-Ni(II)-

Catalyzed Reaction of Hydroximyl Chloride with 2-Acryloyl-

1-benzyl-5,5-dimethyl-3-pyrazolidinone (14) Exempliﬁed by

the Reaction of Benzohydroximoyl Chloride (8b). A suspension

of (R)-BINIM-4(3,5-xylyl)-2QN (19.3 mg, 0.025 mmol), powdered

MS 4Å (190.5 mg), and Ni(ClO₄)₂·6H₂O (9.2 mg, 0.025 mmol) in

CH₂Cl₂(3.0 mL) was stirred for 6 h at room temperature. A solution

of pyrazolidinone 14 (63.5 mg, 0.25 mmol) and hyroximoyl chloride

8b (77.8 mg, 0.50 mmol) in CH₂Cl₂(1.0 mL) were added to the

catalyst suspension over a period of 1 h by syringe pump. The

syringe was washed with CH₂Cl₂(0.5 mL). After stirring the

mixture at room temperature for 1 h, the reaction mixture was

quenched with saturated NH₄Cl solution (2.5 mL) and water (2.5

mL) and then ﬁltered through Celite. The ﬁltrate was extracted with

CH₂Cl₂(5.0 mL × 3). The combined extracts were dried over

MgSO₄and evaporated in vacuo. The residue was chromatographed

on silica gel with hexane-ethyl acetate (72: 28 v/v) as an eluent

to give cycloadduct 19b (75.6 mg, 80%). Regioselectivity was

(5S)-5-[(1-Benzyl-5,5-dimethyl-3-oxo-2-pyrazolidinyl)carbo-

nyl]-3-(2-methylpropyl)-4,5-dihydroisoxazole (19i). Colorless cot-

tonlike needles; mp 77.0-78.0 °C (Et₂O-hexane); [R]²⁵_D) +118.5

(c 0.50, CHCl₃, 83% ee); IR (KBr) 2957, 2876, 1757, 1693, 1390,

1

1224, 886, 833, 716 cm^-1; H NMR (CDCl₃) δ 0.93 (3H, d, J )

1

determined to be 4-Me/5-Me ) >99:1 by H NMR (400 MHz)

6.8 Hz), 0.95 (3H, d, J ) 6.8 Hz), 1.28 (3H, s), 1.31 (3H, s), 1.87

(1H, quint, J ) 6.8 Hz), 2.20 (2H, d, J ) 7.3 Hz), 2.56 (1H, d, J

) 17.1 Hz), 2.66 (1H, d, J ) 17.1 Hz), 2.90-3.08 (2H, m), 4.03

(1H, d, J ) 13.7 Hz), 4.11 (1H, d, J ) 13.7 Hz), 5.65 (1H, brt, J

) 7.3 Hz), 7.24-7.32 (3H, m), 7.41-7.43 (2H, m); ¹³C NMR

(CDCl₃) δ 22.5 (CH₃), 22.6 (CH₃), 26.0 (CH₃), 26.3 (CH), 26.5

(CH₃), 36.1 (CH₂), 39.8 (CH₂), 43.2 (CH₂), 57.0 (CH₂), 61.5 (C),

76.8 (CH), 127.5 (CH), 128.2 (CH), 129.3 (CH), 136.7 (C), 157.5

(C), 166.3 (C), 174.2 (C); MS (EI) m/z 357 (M⁺), 204, 189, 113,

91, 57. Anal. Calcd for C₂₀H₂₇N₃O₃: C, 67.20; H, 7.61; N, 11.76.

Found: C, 67.18; H, 7.62; N, 11.72. The enantiomeric excess was

determined by HPLC analysis (Daicel Chiralpak AD-H,

i-PrOH-hexane (1:19 v/v), detector: UV 254 nm, ﬂow rate ) 0.5

mL/min, 35 °C). t_minor) 92.1 min, t_major) 99.70. min.

analysis of the crude mixture. The enantiomeric excess was

determined by HPLC analysis (Daicel Chiralpak AD-H,

i-PrOH-hexane (1:19 v/v), detector: UV 254 nm, ﬂow rate ) 0.5

mL/min, 35 °C) after reduction to the corresponding alcohol by

NaBH₄.¹⁴t_minor) 53.9 min, t_major) 62.8 min.

(5S)-5-[(1-Benzyl-5,5-dimethyl-3-oxo-2-pyrazolidinyl)carbo-

nyl]-3-phenyl-4,5-dihydroisoxazole (19b). Colorless prisms; mp

195.0-196.0 °C (Et₂O-hexane); [R]²⁵_D) +165.5 (c 0.50, CHCl₃,

90% ee); IR (KBr) 2981, 2696, 1753, 1693, 1353, 1233, 881, 768,

1

700 cm^-1; H NMR (CDCl₃) δ 1.30 (3H, s), 1.33 (3H, s), 2.60

(1H, d, J ) 17.1 Hz), 2.68 (1H, d, J ) 17.1 Hz), 3.45 (2H, d, J )

7.1 Hz), 4.06 (1H, d, J ) 13.7 Hz), 4.11 (1H, d, J ) 13.7 Hz),

5.84 (1H, brt, J ) 7.1 Hz), 7.14-7.31 (3H, m), 7.34-7.47 (5H,

m), 5.84-7.63 (2H, m); ¹³C NMR (CDCl₃) δ 26.1 (CH₃), 26.4

(CH₃), 37.8 (CH₂), 43.2 (CH₂), 57.0 (CH₂), 61.7 (C), 78.3 (CH),

126.8 (CH), 127.5 (CH), 128.3 (CH), 128.5 (CH), 128.7 (C), 129.3

(CH), 130.1 (CH), 136.7 (C), 155.7 (C), 165.9 (C), 174.3 (C); MS

(EI) m/z 377 (M⁺), 205, 189, 146, 118, 92, 77, 65. Anal. Calcd for

C₂₂H₂₃N₃O₃: C, 70.01; H, 6.14; N, 11.13. Found: C, 69.95; H, 6.10;

N, 11.24. The enantiomeric excess was determined by HPLC

analysis (Daicel Chiralpak AD-H, i-PrOH-hexane (1:19 v/v),

detector: UV 254 nm, ﬂow rate ) 0.5 mL/min, 35 °C) after

(5S)-5-[(1-Benzyl-5,5-dimethyl-3-oxo-2-pyrazolidinyl)carbo-

nyl]-3-butyl-4,5-dihydroisoxazole (19j). Colorless oil; [R]²⁵

)

D

+72.8 (c 0.50, CHCl₃, 87% ee); IR (neat) 2962, 2934, 1684, 1585,

1

1454, 1373, 1219, 754, 700 cm^-1; H NMR (CDCl₃) δ 0.91 (3H,

t, J ) 7.3 Hz), 1.28 (3H, s), 1.31 (3H, s), 1.32-1.39 (2H, m),

1.48-1.59 (2H, m), 2.31 (2H, t, J ) 7.3 Hz), 2.56 (1H, d, J )

17.3 Hz), 2.65 (1H, d, J ) 17.3 Hz), 2.96-3.08 (2H, m), 4.04

(1H, d, J ) 13.7 Hz), 4.11 (1H, d, J ) 13.7 Hz), 5.66 (1H, brdd,

J ) 6.3, 7.8 Hz), 7.23-7.33 (3H, m), 7.42-7.44 (2H, m); ¹³C NMR

1112 J. Org. Chem. Vol. 74, No. 3, 2009

Asymmetric Cycloadditions of Nitrile Oxides

(CDCl₃) δ 14.1 (CH₃), 22.6 (CH₂), 26.3 (CH₃), 26.7 (CH₃), 27.3

(CH₂), 28.7 (CH₂), 40.0 (CH₂), 43.5 (CH₂), 57.3 (CH₂), 61.9 (C),

77.2 (CH), 127.7 (CH), 128.5 (CH), 129.5 (CH), 137.0 (C), 158.5

(C), 166.6 (C), 174.5 (C); MS (EI) m/z 357 (M⁺), 204, 189, 119,

92, 82, 65. HRMS (EI) calcd for C₂₀H₂₇N₃O₃(M⁺): 357.2052, found

357.2017. The enantiomeric excess was determined by HPLC

analysis (Daicel Chiralpak AD-H, i-PrOH-hexane (1:19 v/v),

20b). Colorless oil; [R]²⁵_D) +143.8 (c 0.40, CHCl₃, 75% ee); IR

(neat) 2988, 2971, 2938, 1763, 1734, 1701, 1337, 1235, 890, 694

cm^-1; ¹H NMR (C₆D₆) δ 0.70 (3H, s), 0.74 (3H, s), 0.74 (3H, t, J

) 7.1 Hz), 1.92-2.03 (2H, m), 3.58 (2H, s), 3.70-3.86 (2H, m),

5.09 (1H, d, J ) 4.4 Hz), 6.23 (1H, br), 6.95-7.18 (6H, m),

7.44-7.46 (2H, m), 7.85-7.87 (2H, m); ¹³C NMR (CDCl₃) δ 14.0

(CH₃), 25.2 (CH₃), 43.2 (CH₂), 56.8 (CH₂), 56.9 (CH₃), 62.5 (CH₂),

62.8 (C), 82.0 (CH), 126.8 (CH), 127.3 (CH), 127.5 (C), 127.8

(CH), 128.5 (CH), 128.5 (CH), 129.1 (CH), 130.5 (CH), 135.9 (C),

135.9 (C), 167.6 (C), 171.4 (C), 174.4 (C); MS (EI) m/z 449 (M⁺),

204, 189, 144, 113, 91, 77. HRMS (EI) calcd for C₂₅H₂₇N₃O₅(M⁺):

449.1950, found 449.1925. The enantiomeric excess was determined

by HPLC analysis (Daicel Chiralpak AD-H, i-PrOH-hexane (1:

19 v/v), detector: UV 254 nm, ﬂow rate ) 0.5 mL/min, 35 °C)

detector: UV 254 nm, ﬂow rate ) 0.5 mL/min, 35 °C). t_minor

92.6 min, t_major) 101.8 min.

)

(5S)-5-[(1-Benzyl-5,5-dimethyl-3-oxo-2-pyrazolidinyl)carbo-

nyl]-3-tert-butyl-4,5-dihydroisoxazole (19k). Colorless cottonlike

needles; mp 148.0-149.0 °C (Et₂O-hexane); [R]²⁵_D) +130.4 (c

0.50, CHCl₃, 86% ee); IR (KBr) 2971, 2870, 1751, 1712, 1251,

1232, 1213, 929, 863, 771 cm^-1; ¹H NMR (CDCl₃) δ 1.18 (9H, s),

1.26 (3H, s), 1.31 (3H, s), 2.56 (1H, d, J ) 17.1 Hz), 2.66 (1H, d,

J ) 17.1 Hz), 3.00 (1H, dd, J ) 10.0, 16.6 Hz), 3.10 (1H, dd, J )

6.3, 16.6 Hz), 4.03 (1H, d, J ) 13.4 Hz), 4.11 (1H, d, J ) 13.4

Hz), 5.63 (1H, brdd, J ) 6.3, 10.0 Hz), 7.24-7.33 (3H, m),

7.41-7.44 (2H, m); ¹³C NMR (CDCl₃) δ 26.0 (CH₃), 26.5 (CH₃),

28.1 (CH₃), 33.0 (C), 36.9 (CH₂), 43.2 (CH₂), 57.1 (CH₂), 61.6

(C), 77.3 (CH), 127.5 (CH), 128.3 (CH), 129.3 (CH), 136.8 (C),

165.1 (C), 166.2, (C) 174.1 (C); MS (EI) m/z 357 (M⁺), 205, 190,

113, 92, 77, 65. Anal. Calcd for C₂₀H₂₇N₃O₃: C, 67.20; H, 7.61; N,

11.76. Found: C, 67.19; H, 7.64; N, 11.74. The enantiomeric excess

was determined by HPLC analysis (Daicel Chiralpak AD-H, i-PrOH-

hexane (1:19 v/v), detector: UV 254 nm, ﬂow rate ) 0.5 mL/min,

35 °C). t_minor) 56.2 min, t_major) 63.0 min.

after reduction to the corresponding alcohol by NaBH₄.¹⁴t_minor

54.9 min, t_major) 68.5 min.

)

Acknowledgment. This work was supported in part by a

Grant-in-Aid for Scientiﬁc Research (nos. 17550097, 20550094,

and 20200052) from the Ministry of Education, Science and

Culture, Japan.

Supporting Information Available: General methods and

materials for experimental section and spectroscopic data of the

products. This material is available free of charge via the Internet

at http://pubs.acs.org.

(4S,5S)-5-[((1-Benzyl-5,5-dimethyl-3-oxo-2-pyrazolidinyl)car-

bonyl]-4-ethoxycarbonyl-3-phenyl-4,5-dihydroisoxazole (4-CO₂Et-

JO802392C

J. Org. Chem. Vol. 74, No. 3, 2009 1113

Article Doi

Asymmetric 1,3-dipolar cycloaddition reactions of nitrile oxides catalyzed by chiral binaphthyldiimine-Ni(II) complexes

DOI: 10.1021/jo802392c

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Article abstract of DOI:10.1021/jo802392c

Full text of DOI:10.1021/jo802392c

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