A facile and highly diastereoselective aziridination of chiral camphor N-enoylpyrazolidinones with N-aminophthalimide

Article abstract of DOI:10.1021/jo005621p

Reaction of various chiral camphor N-enoylpyrazolidinones 2a-g with N-aminophthalimide in the presence of lead tetraacetate in CH₂Cl₂ proceed smoothly afford the corresponding N-phthalimidoaziridines (3a-e, 4f-g) with excellent material yields (86-95%) at room temperature in 5 min. High levels of diastereoselectivities (up to >95:5 dr) were obtained. The solvent effect was investigated, and the auxiliary can be easily recovered in high yields under mild reaction conditions.

Full text of DOI:10.1021/jo005621p

1676
J . Org. Chem. 2001, 66, 1676-1679
A F a cile a n d High ly Dia ster eoselective Azir id in a tion of Ch ir a l
Ca m p h or N-En oylp yr a zolid in on es w ith N-Am in op h th a lim id e
Kung-Shuo Yang and Kwunmin Chen*
Department of Chemistry, National Taiwan Normal University, 88 Sec. 4 TingChow Road,
Taipei, Taiwan 116, ROC
kchen@scc.ntnu.edu.tw
Received August 24, 2000
Reaction of various chiral camphor N-enoylpyrazolidinones 2a -g with N-aminophthalimide in the
presence of lead tetraacetate in CH2Cl2 proceed smoothly afford the corresponding N-phthalimi-
doaziridines (3a -e, 4f-g) with excellent material yields (86-95%) at room temperature in 5 min.
High levels of diastereoselectivities (up to >95:5 dr) were obtained. The solvent effect was
investigated, and the auxiliary can be easily recovered in high yields under mild reaction conditions.
The synthesis of aziridine derivatives has received
much attention in recent years, for they are versatile
building blocks for the synthesis of a wide range of
nitrogen-containing substances.1 Many biologically active
substances such as amino acids, â-lactam antibiotics, and
alkaloids were derived from aziridines. The regiospecific
reductive cleavage of aziridine-2-carboxylates providing
R- or â-amino acids has been reported with excellent
yield.2 The use of metal-mediated chiral aziridines for
asymmetric transformations has been reported.3 It is not
surprising that many efforts have been devoted to an
efficient construction of the constrained three-membered
ring system.3,4 Diastereoselective addition of a nitrogen
source to chiral R,â-unsaturated carboxylic acid deriva-
tives is a conventional approach and has not yet been
fully explored.5 In continuation of our work on the
stoichiometric reagent controller strategy in asymmetric
synthesis, we were intrigued by the potential of the
synthetic utility toward the preparation of aziridines from
R,â-unsaturated carbonyl substrates 2a -g derived from
camphor pyrazolidinone 1. Herein, we disclose high
diastereofacial selectivities (up to >95:5 dr) of N-phthal-
imidoaziridine 3a -e, 4f-g can be obtained by treatment
of the corresponding chiral N-enoylpyrazolidinones 2a -g
with N-aminophthalimide in the presence of lead tet-
raacetate.
Resu lts a n d Discu ssion
A novel camphor pyrazolidinone auxiliary 1 has been
developed in this laboratory and has proved to be
(4) (a) Boivin, S.; Outurquin, F.; Paulmier, C. Tetrahedron Lett.
2000, 41, 663. (b) Ali, S. I.; Nikalje, M. D.; Sudalai, A. Org. Lett. 1999,
1, 705. (c) Gontcharov, A. V.; Liu, H.; Sharpless, K. B. Org. Lett. 1999,
1, 783. (d) McLaren, A. B.; Sweeney, J . B. Org. Lett. 1999, 1, 1339. (e)
Dauben, P.; Dodd, R. H. J . Org. Chem. 1999, 64, 5304. (f) J eong, J . U.;
Tao, B.; Sagasser, I.; Henniges, H.; Sharpless, K. B. J . Am. Chem. Soc.
1998, 120, 6844. (g) Filigheddu, S. N.; Taddei, M. Tetrahedron Lett.
1998, 39, 3857. (h) So¨dergren, M.; Alonso, D. A.; Bedekar, A. V.;
Andersson, P. G. Tetrahedron Lett. 1997, 38, 6897. (i) Muller, P.; Baud,
C.; J acquier, Y. Tetrahedron 1996, 52, 1543. (j) Ha, H.-J .; J ang, K.-H.;
Suh, J . M.; Ahn, Y. G. Tetrahedron Lett. 1996, 37, 7069. (k) Garner,
P.; Dogan, O.; Pillai, S. Tetrahedron Lett. 1994, 35, 1653. (l) Michida,
T.; Sayo, H. Chem. Pharm. Bull. 1994, 42, 27. (m) Evans, D. A.; Faul,
M. M.; Bilodeau, M. T. J . Org. Chem. 1991, 56, 6744. (n) Mansuy, D.;
Mahy, J .-P.; Dureault, A.; Bedi, G.; Battioni, P. J . Chem. Soc., Chem.
Commun., 1984, 1161. For enatioselective aziridination, see: (o)
Minakata, S.; Ando, T.; Nishimura, M.; Ryu, I.; Komatsu, M. Angew.
Chem. Int. Ed. 1998, 37, 3392. (p) So¨dergren, M.; Alonso, D. A.;
Andersson, P. G. Tetrahedron: Asymmetry 1997, 8, 3563. (q) Nishikori,
H.; Katsuki, T. Tetrahedron Lett. 1996, 37, 9245. (r) Harm, A. M.;
Knight, J . G.; Stemp, G. Tetrahedron Lett. 1996, 37, 6189. (s) Li, Z.;
Quan, R. W.; J acobsen, E. N. J . Am. Chem. Soc. 1995, 117, 5889. (t)
Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J . Am. Chem. Soc. 1994,
116, 2742. (u) Li, Z.; Conser, K. R.; J acobsen, E. N. J . Am. Chem. Soc.
1993, 115, 5326. (v) Aires-de Sousa, J .; Lobo, A. M.; Prabhakar, S.
Tetrahedron Lett. 1996, 37, 3183. (w) Carducci, M.; Eioravanti, S.;
Loreto, M. A.; Pellacani, L.; Tardella, P. A. Tetrahedron Lett. 1996,
37, 3777.
* To whom correspondence should be addressed. Tel: 886(2)-
89315831. Fax: 886(2)29324249.
(1) (a) Pearson, W. H.; Lain, B. W.; Bergmeier, S. C. In Compre-
hensive Heterocyclic Chemistry II; Padwa, A., Ed.; Pergamon Press:
New York, 1996; Vol. 1A, pp 1-60. (b) Rai, K. M. L.; Hassner, A. In
Comprehensive Heterocyclic Chemistry II; Padwa, A., Ed.; Pergamon
Press: New York, 1996; Vol. 1A, pp 61-96.
(2) (a) Wu, J .; Hou, X.-L.; Dai, L.-X. J . Org. Chem. 2000, 65, 1344.
(b) Chandrasekhar, S.; Ajmed, M. Tetrahedron Lett. 1999, 40, 9325.
(c) Pak, C. S.; Kim, T. H.; Ha, S. J . J . Org. Chem. 1998, 63, 10006. (d)
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G. A.; Stengel, P. J . Tetrahedron 1997, 53, 8887. (f) Choi, S.-K.; Lee,
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J . E.; Farthing, C. N.; Russell, A. T.; Schofield, C. J .; Spivey, A. C.
Tetrahedron 1996, 52, 3761.
(3) For recent reviews for the preparation of aziridines and use of
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Rev. 1997, 97, 2341. (d) Tanner, D. Angew. Chem., Int. Ed. Engl. 994,
33, 599.
10.1021/jo005621p CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/03/2001

Diastereoselective Aziridination
J . Org. Chem., Vol. 66, No. 5, 2001 1677
Ta ble 1. Azir id in a tion of a Va r iety of
N-En oylp yr a zolid in on es (2a -g) w ith
N-Am in op h th a lim id e in th e P r esen ce of Lea d
Tetr a a ceta tea
synthetically useful for asymmetric reactions in several
reaction types to achieve high stereoselection.6 N-
Enoylpyrazolidinones 2a -g can be easily prepared from
1 with high chemical yields following standard acylation
procedures. Vederas et al. have reported the oxidation
of N-aminophthalimide with lead tetraacetate in the
presence of N-enoylbornane[10,2]sultams resulting in
stereospecific syn addition to afford the corresponding
N-phthalimidoaziridines with 33-95% de.5g The analo-
gous process was carried out with 2a in CH2Cl2 for 5 min
to give aziridine 3a as the major product (entry 1). The
structure of 3a was initially assigned by 1H and 13C NMR
and HRMS analyses, and the absolute stereochemistry
was confirmed by single-crystal X-ray analysis.
% yieldb
drc
(3:4)
entry
substrate
solvent
t (min)
(3 + 4)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2d
2f
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
5
5
5
5
5
5
5
5
5
94
90
95
86
92
88
90
91
89
>95:5
>95:5
>95:5
61:39
>95:5
20:80
<5:95
95:5
CHCl3
20:80
a
b
All reactions were carried out at room temperature. Isolated
yield. c Ratio determined by 200 MHz 1H NMR and/or HPLC
analyses with J apan Spectroscopic Co., LTD Finepak SIL NH2
column (4.6 × 250 mm, 10 µm); flow rate: 1.0 mL/min, n-hexane/
2-propanol, 70/30 (v/v).
Under the optimum conditions, treatment of 2b with
N-aminophthalimide in CH2Cl2 in the presence of lead
tetraacetate provided 90% chemical yield with a ratio of
>95:5 in favor the formation of 3b (entry 2). The relative
configuration of the aziridine moiety was initially as-
1
signed by H NMR analysis (3J trans ) 5.0 Hz),7 and the
at the aziridine nitrogen atom to the thermodynamically
preferred cis-3a . Thus, the isolated pure (flash column
chromatography, E. Merck silica gel 60, Rf ) 0.2, hexane/
ethyl acetate ) 2:1) trans-3a slowly converts into its
N-invertomer (Rf ) 0.5, hexane/ethyl acetate ) 2:1) and
reached an equilibrium to give an 1:1 ratio of trans-3a
and cis-3a after 18 h at room temperature. Several
attempts to crystallize both isomers for absolute stere-
ochemistry assignment failed. Finally, the single-crystal
structure of trans-3a and co-crystal structures of trans-
3a and cis-3a were obtained separately, which allowed
for X-ray crystallographic analyses.9 The inversion bar-
rier at the aziridine nitrogen atom, as can be expected,
is larger with the presence of R- and/or â-substituents
and has a retarding effect on the rate of N-interconver-
sion in the aziridine adducts.10 Thus, the major aziridine
3b (the phthalimido group and the CdO is cis-disposed)
gives only detectable amounts of the corresponding
absolute stereochemistry was again confirmed by X-ray
analysis of a single crystal. The use of N-2-pentenoyl
pyrazolidinone (2c) gave a very high diastereoselectivity
(entry 3). The electron-rich N-cinnamoylpyrazolidinone
(2d ) was investigated, and the desired products were
isolated with low stereoselectivity (entry 4). The use of
â,â-dimethyl substituent (2e) affords aziridine 3e with
high stereoselectivity (entry 5). The stereoselectivity
drops significantly if an R-substituent is present. Thus,
the use of N-methacryloyl pyrazolidinone (2f) to give
moderate stereoselectivity (3f/4f ) 20:80) (entry 6).
Interestingly, the selectivity rebounds with the presence
of an additional â-substituent (entry 7). The major
isomeric product was assigned to be 4g. The absolute
stereochemistry assignments of 4f and 4g are based on
the conformational analysis of 2f and 2g in the solid
state, but studies are in progress to confirm these
assignments.
1
isomer (TLC and H NMR analyses) at room temperature
over 18 h under the same operation conditions. To
complete one cycle of the chiral auxiliary the initial
adduct was subject to deacylation conditions.11 Exposure
of 3a in MeOH to DMAP at 40 °C provided the desired
2-carboxyl aziridine derivatives 5a without incident
(82%). The auxiliary 1 was recovered in 94% yield.
The stereochemical outcome of the present study can
be rationalized as reported previously.6b,12 Preference for
the planar s-cis conformation in N-enoylpyrazolidinones
2a -e has been attributed to the presence of significant
steric interactions in the s-trans between the CR sub-
stituent and the camphor nucleus (Figure 1). The X-ray
The solvent effect was studied to improve the diaste-
reoselectivity of 2d and 2f. A wide variety of solvents
(THF, CH3CN, toluene, DMSO, PhCF3) were screened
without success. To our surprise, high stereoselectivity
(3d /4d ) 95:5) was obtained when 2d was treated with
N-aminophthalimide in CHCl3 (entry 8). However, for 2f
the selectivity was still moderate under the same reaction
conditions (entry 9).
An interesting N-interconversion phenomena was ob-
served for 3a .8 The kinetically formed trans-3a inverts
(5) (a) Cardillo, G.; Gentilucci, L.; Bastardas, I. R.; Tolomelli, A.
Tetraderon 1998, 54, 8217. (b) Fioravanti, S.; Pellacani, L.; Tabanella,
S.; Tardella, P. A. Tetrahedron 1998, 54, 14105. (c) Atkinson, R. S.;
Ulukanli, S. J . Chem. Soc., Perkin Trans. 2 1999, 771. (d) Atkinson,
R. S.; Barker, E.; Ulukanli, S. J . Chem. Soc., Perkin Trans. 1 1998,
583. (e) Cardillo, G.; Gentilucci, L.; Tomasini, C.; Castejon-Bordas, M.
P. V. Tetrahedron: Asymmetry 1996, 7, 755. (f) Cardillo, G.; Casolari,
S.; Gentilucci, L.; Tomasini, C. Angew. Chem., Int. Ed. Engl. 1996,
35, 1848. (g) Kapron, J . T.; Santarsiero, B. D.; Vederas, J . C. J . Chem.
Soc., Chem. Commun. 1993, 1074. (h) Atkinson, R. S.; Kelly, B. J .;
Williams, J . Tetrahedron 1992, 48, 7713.
(9) For the X-ray ORTEP drawings of trans-3a and cis-3a , see the
Supporting Information.
(10) The reaction of monoethyl fumaroyl N-enoylpyrazolidinone 2h
(R1 ) R2 ) H R3 ) COOEt) with N-aminophthalimide affords the
corresponding aziridines with 93% yield. However, the 1H NMR
spectrum as well as TLC analyses indicates a mixture of 1:1 N-
invertomers were present. In addition to the steric repulsion (camphor
nucleus and the phthalimido group), the dipole moment interaction
between the ester functionality and the phthalimido group may play
an important role for the rapid interconversion.
(6) (a) Yang, K.-S.; Chen, K. Org. Lett. 2000, 2, 729. (b) Yang, K.-S.;
Lain, J .-C.; Lin, C.-H.; Chen, K. Tetrahedron Lett. 2000, 41, 1453. (c)
Lin, C.-H.; Yang, K.-S.; Pan, J .-F.; Chen, K. Tetrahedron Lett. 2000,
41, 6815.
(11) Wang, Y.-C.; Su, D.-W.; Lin, S.-M.; Tseng, H.-L.; Li, C.-L.; Yan,
T.-H. J . Org. Chem. 1999, 64, 6495.
(12) For the conformational analyses and results of nonchelate model
for cycloaddition of N-enoylcamphor sultams reacted with Me3SiCHN2
and nitrile oxides, see: (a) Mish, M. R.; Guerra, F. M.; Carreira, E. M.
J . Am. Chem. Soc. 1997, 119, 8379. (b) Kim, K. S.; Kim, B. H.; Park,
W. M.; Cho, S. J .; Mhin, B. J . J . Am. Chem. Soc. 1993, 115, 7472. (c)
Kim, B. H.; Curran, D. P. Tetrahedron 1993, 49, 293. (d) Curran, D.
P.; Heffner, T. A. J . Org. Chem. 1990, 55, 4585. (e) Curran, D. P.; Kim,
B. H.; Daugherty, J .; Heffner, T. A. Tetrahedron Lett. 1988, 29, 3555.
3
(7) Typical coupling constants of such aziridines: J cis ) 8.2-8.5
Hz, 3J trans ) 4.8-5.1 Hz see: Chilmonczyk, Z.; Egli, M.; Behringer, C.;
Dreiding, A. S. Helv. Chim. Acta 1989, 72, 1095.
(8) (a) Atkinson, R. S.; Ayscough, A. P.; Gattrell, W. T.; Raynham,
T. M. J . Chem. Soc., Perkin Trans. 1 1998, 2783. (b) Atkinson, R. S.;
Gattrell, W. T.; Ayscough, A. P.; Raynham, T. M. J . Chem. Soc., Perkin
Trans. 1 1996, 1935.

1678 J . Org. Chem., Vol. 66, No. 5, 2001
Yang and Chen
2b: 1H NMR (CDCl3, 200 MHz) δ 7.33-7.26 (m, 4H), 7.30-
7.10 (m, 1H), 7.08 (qd, 1H, J ) 15.2, 6.8 Hz), 5.95 (dd, 1H, J
) 15.2, 1.8 Hz), 4.09 (dd, 1H, J ) 7.8, 4.8 Hz), 2.70 (ddd, 1H,
J ) 9.8, 6.6, 3.4 Hz), 2.36-1.92 (m, 4H), 1.84 (dd, 3H, J ) 6.8,
1.6 Hz), 1.52-1.25 (m, 2H), 1.13 (s, 3H), 1.10 (s, 3H); 13C NMR
(CDCl3, 50 MHz) δ 170.54, 165.68, 144.09, 138.95, 128.46,
128.42, 125.41, 122.03, 120.98, 66.49, 59.11, 53.37, 46.37,
38.99, 28.22, 26.77, 20.14, 20.09, 18.22; HRMS m/z 324.1838
(calcd for C20H24N2O2 324.1838). Anal. Calcd for C20H24N2O2:
C, 74.04; H, 7.26; N, 8.64. Found: C, 74.09; H, 7.30; N, 8.64.
2d : 1H NMR (CDCl3, 200 MHz) δ 7.66 (d, 1H, J ) 15.6 Hz),
7.47-7.35 (m, 9H), 7.17-7.04 (m, 1H), 6.55 (d, 1H, J ) 15.6
Hz), 4.20 (dd, 1H, 8.0, 4.8 Hz), 2.82 (ddd, 1H, J ) 6.8, 5.6, 3.2
Hz), 2.35-2.26 (m, 2H), 2.08-2.04 (m, 2H), 1.55-1.48 (m, 2H),
1.18 (s, 3H), 1.14 (s, 3H); 13C NMR (CDCl3, 50 MHz) δ 170.64,
165.50, 143.85, 139.01, 134.61, 130.32, 128.93, 128.63, 128.02,
125.64, 121.21, 117.49, 66.93, 59.17, 53.32, 46.53, 38.81, 28.31,
26.80, 20.20, 20.14; HRMS m/z 386.1976 (calcd for C25H26N2O2
386.1994).
F igu r e 1. Proposed mechanism of the diastereoselective
aziridination.
crystal structures of 2a ,c-e reveal this conformation in
the solid state. On the other hand, for R-substituted
N-methacryloylpyrazolidinone 2f and N-tigloylpyrazoli-
dinone 2g the s-trans conformation predominates (X-ray
crystallographic analyses) with the â-olefinic hydrogen
toward the C3 (camphor numbering) orientation in these
two structures. For 2a -e, the syn attack of an N-
acetoxyaminophthalimide intermediate is from the CR
re face while from the si face for 2f and 2g to afford the
observed diastereoselectivity. The difference in stereo-
selectivity between 2f and 2g may be due to conforma-
tional changes induced by the presence of an additional
â-methyl group in a congested area.
In summary, an efficient method has been developed
for the synthesis of high to excellent stereoselectivity of
N-phthalimidoaziridine adducts. Our procedure repre-
sents a simple and effective alternative to enantiopure
2-carboxylaziridine derivatives. This extends the syn-
thetic application to the versatile and general utility of
chiral auxiliary 1. Further investigations on the enanti-
oselective version of aziridination are currently undergo-
ing.
2e: 1H NMR (CDCl3, 200 MHz) δ 7.39-7.29 (m, 4H), 7.18-
7.10 (m, 1H), 5.73 (s, 1H), 4.02-3.95 (dd, 1H, J ) 8.0, 4.8 Hz),
2.77-2.68 (m, 2H), 2.33-2.23 (m, 1H), 2.14-1.99 (m, 3H), 2.07
(s, 3H), 1.85 (s, 3H), 1.52-1.36 (m, 1H), 1.13 (s, 3H), 1.10 (s,
3H); 13C NMR (CDCl3, 50 MHz) δ 170.49, 167.55, 156.21,
139.19, 128.42, 125.19, 120.77, 116.10, 66.46, 59.13, 53.64,
46.26, 39.10, 28.21, 27.62, 26.81, 20.48, 20.12; HRMS m/z
338.1996 (calcd for C21H26N2O2 338.1994). Anal. Calcd for
C
21H26N2O2: C, 74.52; H, 7.74; N, 8.28. Found: C, 74.20; H,
7.61; N, 8.10.
2f: 1H NMR (CDCl3, 200 MHz) δ 7.39-7.30 (m, 4H), 7.20-
7.11 (m, 1H), 5.55 (qd, 1H, J ) 1.6, 0.4 Hz), 5.52 (qd, 1H, J )
1.6, 0.8 Hz), 4.25 (dd, 1H, J ) 8.0, 5.2 Hz), 2.29 (m, 2H), 2.01-
1.92 (m, 3 H), 1.93 (dd, 3H, J ) 0.8, 0.4 Hz), 1.41 (m, 2H),
1.14 (s, 6H); 13C NMR (CDCl3, 50 MHz) δ 169.77, 167.89,
140.31, 138.00, 128.61, 125.70, 121.02, 120.95, 69.47, 59.35,
51.78, 46.91, 39.43, 28.65, 26.47, 20.54, 19.84, 18.55; HRMS
m/z 324.1842 (calcd for C20H24N2O2 324.1838). Anal. Calcd for
C
20H24N2O2: C, 74.04; H, 7.46. Found: C, 73.71; H, 7.28.
Exp er im en ta l Section
Meth od B. A solution of thionyl chloride (7.3 mL, 100 mmol)
and trans-2,3-dimethylacrylic acid (5.0 g, 50.0 mmol) was
heated to 60 °C for 2 h. The excess thionyl chloride was
removed in vacuo and the residue dried under a high vacuum
pump line for 10 min. To this was then added CH2Cl2 (156
mL), and a solution of camphor pyrazolidinone 1 (1.5 g, 5.8
mmol) in CH2Cl2 was added dropwise at 25 °C under N2
atmosphere. This was followed by the addition of Et3N (7.5
mL, 55 mmol). The reaction was quenched with H2O (15 mL)
and extracted with CH2Cl2 (1 × 50 mL). The organic layer was
washed (brine), dried (Na2SO4), filtered, and concentrated in
vacuo. The crude product was purified by flash column
chromatography, using hexane/ethyl acetate (4:1) as eluent to
give 1.82 g (92%) of 2g as a white solid: 1H NMR (CDCl3, 200
MHz) δ 7.36-7.27 (m, 4H), 7.19-7.10 (m, 1H), 6.25 (q, 1H, J
) 6.2 Hz), 4.24-4.17 (dd, 1H, J ) 7.8, 5.0 Hz), 2.38-2.23 (m,
2H), 2.06-1.87 (m, 3H), 1.81 (d, 3H, J ) 6.2 Hz), 1.59 (s, 3H),
1.50-1.26 (m, 2H), 1.14 (s, 6H); 13C NMR (CDCl3, 50 MHz) δ
169.67, 169.61, 138.13, 132.91, 132.48, 128.59, 125.54, 120.86,
69.58, 59.34, 51.77, 46.88, 38.95, 28.69, 26.51, 20.53, 19.91,
Gen er a l Meth od s. All reactions were carried out in flame-
or oven-dried glassware under a positive pressure of nitrogen.
Air- and moisture-sensitive compounds were introduced by the
use of a cannula through a rubber septum. Most reagents were
commercially available and of synthetic grade. Tetrahydrofu-
ran was distilled from sodium/benzophenone ketyl. Dichlo-
romethane and toluene were dried over CaH2 and distilled
before use. Analytical thin-layer chromatography was per-
formed with E. Merck silica gel 60F glass plates and flash
column chromatography by the use of E. Merck silica gel 60
(230-400 mesh). HRMS values were measured by Finingan
Mat TSQ-46C GC/MS/MS/DS spectrometer. Elemental analy-
ses were performed by a Perkin-Elmer 2400 or 2400II Elemen-
tal Analyzer. 1H and 13C NMR spectra were recorded routinely
in CDCl3 on a Varian Gemini 2000 spectrometer.
Gen er a l P r oced u r e for th e P r ep a r a tion of N-En oyl
P yr a zolid in on es 2a -g. Meth od A. To a solution of 1 (4.00
g, 15.55 mmol) in CH2Cl2 was added Et3N (3.2 mL, 23.33
mmol) at 0 °C under N2 atmosphere. This was followed by the
addition of acryloyl chloride (1.54 mL, 18.66 mmol) dropwise,
and the mixture was stirred for 30 min. The mixture was
quenched with H2O (15 mL) and extracted with CH2Cl2 (50
mL × 2). The layers were separated, and the organic layer
was washed with brine and dried over Na2SO4. The solvent
was removed in vacuo, and the product was crystallized from
hexane/ethyl acetate (6:1) to give 4.66 g (96%) of 2a as a
colorless crystal: 1H NMR (CDCl3, 200 MHz) δ 7.39-7.29 (m,
4H), 7.18-7.12 (m, 1H), 6.38 (dd, 1H, J ) 16.8, 2.6 Hz), 6.25
(dd, 1H, J ) 16.8, 9.4 Hz), 5.68 (dd, 1H, J ) 9.4, 2.6 Hz), 4.15
(dd, 1H, J ) 7.8, 5.0 Hz), 2.75-2.65 (m, 1H), 2.36-2.24 (m,
1H), 2.16-2.06 (m, 1H), 2.03-1.95 (m, 2H), 1.48-1.26 (m, 2H),
1.14 (s, 3H), 1.11 (s, 3H); 13C NMR (CDCl3, 50 MHz) δ 170.60,
164.57, 138.78, 129.77, 128.54, 127.57, 125.63, 121.14, 66.73,
59.10, 53.18, 46.46, 38.66, 28.24, 26.72, 20.15, 20.01; HRMS
m/z 310.1682 (calcd for C19H22N2O2 310.1681).
13.93, 12.67; HRMS m/z 338.1992 (calcd for
C21H26N2O2
338.1994). Anal. Calcd for C21H26N2O2: C, 74.52; H, 7.74; N,
8.28. Found: C, 74.45; H, 7.79; N, 8.18.
2c: 1H NMR (CDCl3, 200 MHz) δ 7.33 (m, 4H), 7.20-7.16
(m, 1H), 7.05 (td, 1H, J ) 15.2, 6.4 Hz), 5.92 (dd, 1H, J ) 15.2,
1.8 Hz), 4.06 (dd, 1H, J ) 8.2, 4.8 Hz), 2.71 (ddd, 1H, J ) 8.2,
7.8, 3.4 Hz), 2.22 (m, 6H), 1.55-1.48 (m, 2H), 1.14 (s, 3H), 1.11
(s, 3H), 0.98 (t, 3H, J ) 7.4 Hz); 13C NMR (CDCl3, 50 MHz) δ
170.57, 165.95, 150.16, 139.01, 128.54, 128.49, 125.43, 121.09,
119.66, 66.61, 59.10, 53.36, 46.39, 38.95, 28.25, 26.78, 25.40,
20.17, 20.11, 11.96; HRMS m/z 338.1991 (calcd for C21H26N2O2
338.1994).
2h : 1H NMR (CDCl3, 200 MHz) δ 7.40-7.14 (m, 5H), 7.05
(d, 1H, J ) 15.4 Hz), 6.79 (d, 1H, J ) 15.4 Hz), 4.23 (dd, 1H,
J ) 8.0, 4.0 Hz), 4.23 (t, 2H, J ) 7.2 Hz), 2.68-2.56 (m, 1H),
2.38-1.98 (m, 4H), 1.54-1.35 (m, 2H), 1.28 (t, 3H, J ) 7.2
Hz), 1.14 (s, 3H), 1.13 (s, 3H); 13C NMR (CDCl3, 50 MHz) δ

Diastereoselective Aziridination
J . Org. Chem., Vol. 66, No. 5, 2001 1679
170.37, 165.12, 161.45, 138.20, 132.89, 132.32, 128.63, 126.05,
121.50, 67.06, 61.24, 59.19, 53.00, 46.63, 38.58, 28.25, 26.61,
20.15, 19.97, 13.96; HRMS m/z 382.1913 (calcd for C22H26N2O4
382.1893). Anal. Calcd for C22H26N2O4: C, 69.09; H, 6.85.
Found: C, 68.89; H, 6.64
7.14 (m, 5H), 4.46 (dd, 1H, J ) 8.0, 4.8 Hz), 3.26 (s, 1H), 3.06-
3.00 (m, 1H), 2.29-2.22 (m, 1H), 2.21-1.94 (m, 4H), 1.45 (s,
3H), 1.44-1.39 (m, 1H), 1.22 (s, 3H), 1.20 (s, 3H), 1.15 (s, 3H);
13C NMR (CDCl3, 50 MHz) δ 172.92 (x2), 165.20, 163.18,
139.77, 134.00 (x2), 130.25, 129.00 (x2), 126.36, 122.90 (x2),
121.39 (x2), 69.69, 58.98, 51.77, 50.78, 49.89, 47.10, 35.10,
28.56, 26.69, 20.41, 20.21, 18.82, 17.75; HRMS m/z 498.2291
(calcd for C29H30N4O4 498.2267). Anal. Calcd for C29H30N4O4:
C, 69.86; H, 6.06; N, 11.24. Found: C, 69.68; H, 6.21; N, 10.89.
An inseparable mixture of 3f and 4f (1:4) was isolated, and
selected data are presented.
3f (minor): 1H NMR (CDCl3, 200 MHz) δ 4.24 (dd, 1H, J )
8.0, 5.2 Hz), 1.69 (s, 3H), 1.08 (s, 3H), 1.06 (s, 3H). 4f (major):
1H NMR (CDCl3, 200 MHz) δ 4.49 (dd, 1H, J ) 8.0. 5.0 Hz),
1.65 (s, 3H), 1.20 (s, 3H), 1.12 (s, 3H); HRMS m/z 484.2126
(calcd for C28H28N4O4 484.2111).
4g: 1H NMR (CDCl3, 200 MHz) δ 7.61-7.51 (m, 4H), 7.26-
7.09 (m, 4H), 7.01-6.93 (m, 1H), 4.24 (dd, 1H, J ) 8.0, 5.0
Hz), 4.01 (q, 1H, J ) 6.0 Hz), 2.61-2.52 (m, 1H), 2.30-1.97
(m, 5H), 1.68 (s, 3H), 1.52-1.37 (m, 1H), 1.30 (d, 3H, J ) 6.0
Hz), 1.08 (s, 3H), 1.04 (s, 3H); 13C NMR (CDCl3, 50 MHz) δ
169.84, 169.61, 165.06 (×2), 137.81, 133.55 (×2), 130.30, 128.27
(×2), 125.13, 122.70 (×2), 120.89 (×2), 68.00, 59.51, 52.60,
48.04, 46.60, 46.20, 38.80, 28.33, 26.51, 20.11, 20.07, 15.13,
12.72; HRMS m/z 498.2287 (calcd for C29H30N4O4 498.2267).
Anal. Calcd for C29H30N4O4: C, 69.86; H, 6.06; N, 11.24.
Found: C, 69.82; H, 6.47.
P r ep a r a tion of Ch ir a l 2-Ca r boxyla zir id in es 5a . A solu-
tion of 3a (0.10 g, 0.21 mmol) and DMAP (13 mg, 0.11 mmol)
in MeOH (2 mL) was brought to 40 °C for 4 h. The mixture
was filtered and concentrated. The crude product was purified
by flash column chromatography, using hexane/ethyl acetate
(6:1) as eluent to give 43 mg (82%) of 5a as a white solid and
the auxiliary 1 was recovered with 50 mg (94%): 1H NMR
(CDCl3, 200 MHz) δ 7.78-7.66 (m, 4H), δ 3.81 (s, 3H), 3.21-
3.14 (dd, 1H, J ) 7.6, 5.8 Hz), 2.85-2.80 (dd, 1H, J ) 7.6, 1.6
Hz), 2.85-2.80 (dd, 1H, J ) 5.8, 1.6 Hz); 13C NMR (CDCl3, 50
MHz) δ 168.47, 164.45, 134.32, 129.94, 123.28, 52.65, 39.71,
36.42; HRMS m/z 246.0641 (calcd for C12H10N2O4 246.0624).
Anal. Calcd for C12H10N2O4: C, 58.54; H, 4.09; N, 11.38.
Found: C, 58.31; H, 4.32; N, 11.12.
Gen er a l P r oced u r e for th e P r ep a r a tion of Azir id in es
3a -e a n d 4f-g. To a solution of 2c (0.20 g, 0.59 mmol) and
N-aminophthalimide (0.16 g, 0.89 mmol) in CH2Cl2 (6.0 mL)
was added lead tetraacetate (0.44 g, 0.95 mmol) at room
temperature under N2 atmosphere for 5 min. The mixture was
filtered and concentrated. The crude product was purified by
flash column chromatography, using hexane/ethyl acetate (3:
1) as eluent to give 0.28 g (95%) of 3c as a white solid: 1H
NMR (CDCl3, 200 MHz) δ 7.69-7.56 (m, 4H), 7.37-7.23 (m,
4H), 7.12-7.03 (m, 1H), 4.90 (dd, 1H, J ) 7.4, 5.0 Hz), 3.45
(td, 1H, J ) 6.8, 5.0 Hz), 3.00 (d, 1H, J ) 5.0 Hz), 2.74-2.64
(m, 1H), 2.40-2.29 (m, 2H), 2.15-2.03 (m, 2H), 1.86-1.68 (m,
3H), 1.58-1.47 (m, 1H), 1.16 (d, 3H, J ) 7.0 Hz), 1.15 (s, 3H),
1.12 (s, 3H); 13C NMR (CDCl3, 50 MHz) δ 170.13 (x2), 164.79,
164.71, 138.27, 133.70 (×2), 129.97, 128.07 (×2), 125.10, 122.73
(×2), 120.59 (×2), 65.21, 58.90, 54.17, 49.16, 45.93, 42.92,
39.71, 27.74, 26.60, 23.94, 20.07, 19.76, 9.99; HRMS m/z
498.2267 (calcd for C29H30N4O4 498.2267). Anal. Calcd for
C
29H30N4O4: C, 69.86; H, 6.06; N, 11.24. Found: C, 69.67; H,
6.07; N, 11.14.
trans-3a : 1H NMR (CDCl3, 200 MHz) δ 7.80-7.68 (m, 4H),
7.37-7.32 (m, 4H), 7.16-7.08 (m, 1H), 4.72 (broad, 1H), 3.13
(dd, 1H, J ) 7.4, 5.3 Hz), 2.85-2.65 (m, 3H), 2.40-2.26 (m,
1H), 2.19-2.01 (m, 3H), 1.68-1.40 (m, 2H), 1.25 (s, 3H), 1.14
(s, 3H); 13C NMR (CDCl3, 50 MHz) δ 170.17, 164.89 (×2),
164.68, 134.40 (×2), 133.96, 129.97 (×2), 128.68, 128.21, 125.84
(×2), 123.09 (×2), 66.56, 59.14, 53.36, 46.58, 46.03, 39.60,
36.32, 28.24, 27.84, 26.77, 20.23; HRMS m/z 470.1944 (calcd
for C27H26N4O4 470.1954). Anal. Calcd for C27H26N4O4: C,
68.92; H, 5.57; N, 11.91. Found: C, 68.86; H, 5.42; N, 12.05.
3b: 1H NMR (CDCl3, 200 MHz) δ 7.67-7.55 (m, 4H), 7.37-
7.25 (m, 4H), 7.13-7.02 (m, 1H), 4.92 (broad, 1H), 3.40 (qd,
1H, J ) 5.6, 5.0 Hz), 2.94 (d, 1H, J ) 5.0 Hz), 2.74-2.68 (m,
1H), 2.39-2.28 (m, 2H), 2.13-2.02 (m, 2H), 1.81-1.72 (m, 1H),
1.56-1.42 (m, 1H), 1.48 (d, 3H, J ) 5.6), 1.14 (s, 3H), 1.11 (s,
3H); 13C NMR (CDCl3, 50 MHz) δ 170.20, 164.85, 164.76 (×2),
138.31, 133.80 (×2), 130.12, 128.18 (×2), 125.20, 122.91 (×2),
120.65 (×2), 66.12, 58.99, 54.41, 45.96, 44.40, 44.18, 39.80,
27.77, 26.70, 20.18, 19.83, 16.18; HRMS m/z 484.2116 (calcd
for C28H28N4O4 484.2111). Anal. Calcd for C28H28N4O4: C,
69.41; H, 5.82; N, 11.56. Found: C, 69.12; H, 5.82; N, 11.73.
3d : 1H NMR (CDCl3, 200 MHz) δ 7.73-7.61 (m, 5H), 7.42-
7.36 (m, 4H), 7.32-7.22 (m, 4H), 7.13-7.04 (m, 1H), 5.02 (dd,
1H, J ) 7.8, 5.0 Hz), 4.42 (d, 1H, J ) 5.0 Hz), 3.46 (d, 1H, J
) 5.0 Hz), 2.75-2.67 (m, 1H), 2.44-2.33 (m, 2H), 2.16-2.05
(m, 2H), 1.87-1.76 (m, 1H), 1.62-1.51 (m, 1H), 1.15 (s, 3H),
1.13 (s, 3H); 13C NMR (CDCl3, 50 MHz) δ 170.26, 164.73 (×2),
164.07, 138.34, 134.78, 134.00 (×2), 130.27, 128.75 (×2), 128.72
(×2), 128.32 (×2), 127.22, 125.46, 123.15 (×2), 120.91 (×2),
65.36, 59.14, 54.56, 49.08, 46.17, 45.67, 40.07, 27.96, 26.84,
Ack n ow led gm en t. Financial support by the Na-
tional Science Council of the Republic of China and the
collection and processing of X-ray crystal data by the
Taipei Instrumentation Center, College of Science (Na-
tional Taiwan University), and Professor C.-H. Ueng
(National Taiwan Normal University) are gratefully
acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR specta for compounds 2a -h , 3a -e,g and X-ray crystal-
lographic data (tables of experimental details, bond lengths
and angles and ORTEP diagrams) for structures 2a ,c-g,
trans-3a , cis-3a , and 3b,d ,e. This material is available free of
charge via the Internet at http://pubs.acs.org.
20.30, 19.94; HRMS m/z 546.2285 (calcd for
C33H30N4O4
546.2267). Anal. Calcd for C33H30N4O4: C, 72.51; H, 5.53; N,
10.25. Found: C, 71.96; H, 5.36; N, 10.19.
3e: 1H NMR (CDCl3, 200 MHz) δ 7.73-7.59 (m, 4H), 7.40-
J O005621P