Asymmetric electrophilic amination of various carbon nucleophiles with enantiomerically pure chiral N-H oxaziridines derived from camphor and fenchone

Article abstract of DOI:10.1021/jo020306j

The first two stable enantiomerically pure chiral N-H oxaziridines, derived from camphor and fenchone, are shown to act as electrophilic sources of nitrogen upon reaction with various carbon nucleophiles. Nitrogen is transferred, together with the camphor

Full text of DOI:10.1021/jo020306j

Asym m etr ic Electr op h ilic Am in a tion of Va r iou s Ca r bon
Nu cleop h iles w ith En a n tiom er ica lly P u r e Ch ir a l N-H Oxa zir id in es
Der ived fr om Ca m p h or a n d F en ch on e
Philip C. Bulman Page,* Corinne Limousin, and Victor L. Murrell
Department of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, England
p.c.b.page@lboro.ac.uk
Received April 30, 2002
The first two stable enantiomerically pure chiral N-H oxaziridines, derived from camphor and
fenchone, are shown to act as electrophilic sources of nitrogen upon reaction with various carbon
nucleophiles. Nitrogen is transferred, together with the camphor/fenchone unit, when deprotonated
esters, malonates, and nitriles are used as nucleophiles. One of the ester or nitrile units in the
substrate usually undergoes hydrolysis; a cyclic mechanism is proposed to account for this
observation.
In tr od u ction
N-alkoxycarbonyloxaziridines, with sulfur, nitrogen, phos-
phorus, and carbon nucleophiles.7
,9-14
However, none of
The synthesis and chemistry of oxaziridines has been
widely studied.1 It has been established that the attack
of a nucleophile occurs at either the oxygen or the
nitrogen atoms of the ring, depending upon the nature
of the nucleophile and the substituents on the oxaziri-
dine, especially at the nitrogen atom. For example,
oxaziridines bearing electron-withdrawing substituents
on the nitrogen atom or on both the nitrogen and the
carbon atoms of the three-membered ring have been
developed for their ability to transfer oxygen atoms to
these electrophilic aminations have been carried out with
enantiomerically pure chiral N-substituted oxaziridines.
To date, only one report of an enantiomerically pure
chiral N-acyloxaziridine has been published.15 Although
the first N-H oxaziridine was reported in the 1960s,
due to their general instability, only a few N-H oxaziri-
-3
1
6,17
dines have been prepared and utilized for their ability
1
8-21
to transfer an amino group to various nucleophiles.
The preparation and derivatization of the first stable
enantiomerically pure chiral N-H oxaziridines has re-
cently been accomplished in our laboratories.2 We report
4
nucleophiles. In particular, N-fluoroalkyloxaziridines,
2
5
6
N-phosphinoyloxaziridines, and N-sulfonyloxaziridines
have proved to be efficient reagents for the oxidation of
sulfides to sulfoxides, the asymmetric hydroxylation of
enolates, and the stereoselective epoxidation of olefins.
(
8) Hanquet, G.; Lusinchi, X.; Millet, P. Tetrahedron Lett. 1988, 29,
2817. Bohe, L.; Lusinchi, M.; Lusinchi, X. Tetrahedron Lett. 1998, 54,
41. Bohe, L.; Lusinchi, M.; Lusinchi, X. Tetrahedron Lett. 1999, 55,
55.
(9) Hata, Y.; Watanabe, M. J . Am. Chem. Soc. 1979, 101, 6671.
(10) Vidal, J .; Damestoy, S.; Guy, L.; Hannachi, J .-C.; Aubry, A.;
Collet, A. Chem. Eur. J . 1997, 3, 1691. Vidal, J .; Guy, L.; Strin, A.;
Collet, A. Tetrahedron Lett. 1993, 34, 6859. Vidal, J .; Damestoy, S.;
Collet, A. Tetrahedron Lett. 1995, 36, 1439. Vidal, J .; Hannachi, J .-C.;
Hourdin, G.; Mulatier, J .-C.; Collet, A. Tetrahedron Lett. 1998, 39,
1
1
Oxygen transfer may also be performed with hindered
oxaziridines and hindered nucleophiles,7 and may be
promoted by acid, forming an N-protonated oxaziridine
that is believed to be the active oxidizing species.8
Nitrogen transfer has also been performed, mainly
using N-H, N-alkyl-, N-aryl-, N-acyl-, N-carboxamido-, or
8
845.
(11) Niederer, D. A.; Kapron, J . T.; Vederas, J . C. Tetrahedron Lett.
1
993, 34, 6859.
(
(
(
(
1) Emmons, W. D. J . Am. Chem. Soc. 1957, 79, 5739.
2) Horner, L.; J rgens, E. Chem. Ber. 1957, 90, 2184.
3) Krimm, H. Chem. Ber. 1958, 91, 1057.
(12) Enders, D.; Poiesz, C.; J oseph, R. Tetrahedron: Asymmetry
1998, 9, 3709.
(13) Foot, O. F.; Knight, D. W. Chem. Commun. 2000, 975.
(14) Armstrong, A.; Atkin, M. A.; Swallow, S. Tetrahedron Lett. 2000,
41, 2247.
(15) Shustov, G. V.; Kadorkina, G. K.; Varlamov, S. V.; Kachanov,
A. V.; Kostyanovsky, R. G.; Rauk, A. J . Am. Chem. Soc. 1992, 114,
1616.
(16) Schmitz, E.; Ohme, R.; Murawski, D. Angew. Chem. 1961, 73,
708.
(17) Schmitz, E.; Ohme, R. Chem. Ber. 1964, 97, 2521.
(18) Hudson, R. F.; Lawson, A. J .; Record, K. A. F. J . Chem. Soc.,
Chem. Commun. 1975, 322.
4) Desmarteau, D. D.; Petrov V. A.; Montanari V.; Pregnolato M.;
Resnati G. J . Org. Chem. 1994, 59, 2762.
5) Boyd, D. R.; Malone, J . F.; McGuckin M. R.; J ennings, W. B.;
(
Rutherford, M.; Saket, B. M. J . Chem. Soc., Perkin Trans. 2 1988, 1145.
Boyd, D. R.; J ennings, W. B.; McGuckin M. R.; Rutherford, M.; Saket,
B. M. J . Chem. Soc., Chem. Commun. 1985, 582. J ennings, W. B.;
Kochanewycz, M. J .; Lovely, C. J .; Boyd, D. R. J . Chem. Soc., Chem.
Commun. 1994, 2569.
(6) Davis, F. A.; Nadir, U. K.; Kluger, E. W. J . Chem. Soc., Chem.
Commun. 1977, 25. Davis, F. A.; Sheppard, A. C. Tetrahedron 1989,
4
1
5, 5703 and references therein. Davis, F. A.; Chen, B. C. Chem. Rev.
992, 919. Davis, F. A.; Towson, J . C.; Weismiller, M. C.; Lal, S.; Caroll,
(19) Andreae, S.; Schmitz, E. Synthesis 1991, 327 and references
therein.
P. C. J . Am. Chem. Soc. 1988, 110, 8477. Page, P. C. B.; Meer, J . P.;
Bethell, E. W.; Collington, E. W.; Andrews, D. M. Tetrahedron:
Asymmetry 1995, 6, 2911. Armstrong, A.; Draffan, A. G. Tetrahedron
Lett. 1999, 40, 4453.
(20) Andreae, S.; Schmitz, E Heterocycles 1994, 37, 379. Andreae,
S.; Schmitz, E.; Wulf, J .-P.; Schulz, B. Liebigs Ann. Chem. 1992, 239.
(21) Choong, I. C.; Ellman, J . A. J . Org. Chem. 1999, 64, 6528.
(22) Page, P. C. B.; Murrell, V. L.; Limousin, C.; Laffan, D. D. P.;
Bethell, D.; Slawin, A. M. Z.; Smith, T. A. D. J . Org. Chem. 2000, 65,
4204.
(7) Hata, Y.; Watanabe, M. J . Org. Chem. 1981, 46, 610 and
references therein.
1
0.1021/jo020306j CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/02/2002
J . Org. Chem. 2002, 67, 7787-7796
7787

Bulman Page et al.
here the first use of these N-H oxaziridines, derived from
1R)-(+)-camphor and (1R)-(-)-fenchone, as asymmetric
SCHEME 1
(
sources of electrophilic nitrogen for the amination of
various ester- and nitrile-containing carbon nucleophiles.
This approach is a potential alternative to the more usual
asymmetric electrophilic amination accomplished by the
use of chiral auxiliary chemistry.2
3,24
Resu lts a n d Discu ssion
Crystalline N-H oxaziridine 1, derived from (1R)-(+)-
camphor, was prepared as previously described by oxida-
tion of the corresponding imine with m-CPBA in 94%
yield.22 It is remarkable for its stability: It can be kept
in its pure form for months at 5 °C, heated under reflux
in THF solution, or submitted to column chromatography
on silica gel without any noticeable decomposition.
Similar oxidation of (1R)-fenchone imine provided, in 86%
yield, the corresponding (1R)-(-)-fenchyl oxaziridine 2 as
an oily liquid stable under reflux in THF or toluene
solutions. It has been proven, by chemical derivatization
coupled with NMR spectroscopy, that 1 and 2 each consist
SCHEME 2
of a pair of diastereoisomers in a ratio of about 60:40,
isomeric at the pyramidal nitrogen atom.22 An unusual
feature of nitrogen-containing three-membered hetero-
cycles is that there is a rather high barrier to inversion
at nitrogen.25
We have tested these N-H oxaziridines as asymmetric
nitrogen transfer agents in reactions with a range of
(23) Recent reviews on electrophilic aminations: Erdik, E.; Ay, M.
Chem. Rev. 1989, 89, 1947. Mulzer, J .; Altenbach, H. J .; Braun, M.;
Krohn, K.; Reissig, H. U. In Organic Synthesis Highlight; VCH
Publishers: Weinheim, Germany, 1991; p 45. Boche, G. In Houben-
Weyl, Methods of Organic Chemistry; Helmchen, G., Hoffmann, R. W.,
Mulzer, J ., Schaumann, E., Eds.; Vol. E, 21e, Stereoselective Synthesis;
Thieme Verlag: Stuttgart, Germany, 1995; p 5133. Greck, C.; Genet,
J .-P. Synlett 1997, 741. See also: Myers, J . K.; J acobsen, E. N. J . Am.
Chem. Soc. 1999, 121, 8959. Erdik, E.; Daskapan, A. J . Chem. Soc.,
Perkin Trans. 1 1999, 3139. Bernardi, P.; Dembech, P.; Fabbri, G.;
Ricci, A.; Seconi, G. J . Org. Chem. 1999, 64, 641. Denmark, S. E.;
Chatani, N.; Pansare, S. V. Tetrahedron 1992, 48, 2191. Gmeiner, P.;
Bollinger, B. Liebigs Ann. Chem. 1992, 273. Du Bois, J .; Hong, J .;
Carreira, E. M.; Day, M. W. J . Am. Chem. Soc. 1996, 118, 915. For
asymmetric versions of electrophilic aminations see: Boche, G.; Schrott,
W. Tetrahedron Lett. 1982, 23, 5403. Gennari, C.; Colombo, L.;
Bertolini, G. J . Am. Chem. Soc. 1986, 108, 6394. Oppolzer, W.; Tamura,
O. Tetrahedron Lett. 1990, 313, 991. Oppolzer, W.; Tamura, O. J . Am.
Chem. Soc. 1992, 114, 5900. Genet, J .-P.; J uge, S.; Mallart, S.
Tetrahedron Lett. 1988, 29, 6765. Carreira, E. M.; Hong, J .; Du Bois,
J .; Tomooka, C. S. Pure Appl. Chem. 1998, 70, 1097. Guanti, G.; Banfi,
L.; Narisano, E. Tetrahedron 1988, 44, 5553. Greck, C.; Bischoff, L.;
Ferreira, F.; Pinel, C.; Piveteau, E.; Genet, J .-P. Synlett 1993, 475.
Seebach, D.; Sting, A. R. Tetrahedron 1996, 52, 279.
enolates, initially using ester enolates as potential pre-
cursors of R-amino acids (Schemes 1 and 2). The rela-
tively stable and unreactive enolate of an unsubstituted
malonate, diethyl malonate, was investigated first. Under
thermodynamic conditions, using a mixture of sodium
ethoxide and the camphor-derived N-H oxaziridine 1 in
ethanolic solution at room temperature, addition of
diethyl malonate provided the (R)-camphor imine of ethyl
glycinate 3 26 in 68% yield after 3 h at room temperature
(Table 1, entry 1). One ester group has thus been lost
during the reaction process. Two geometrical isomers of
1
(24) Evans, D. A.; Britton, T. C.; Ellman, J . A.; Dorow, R. L. J . Am.
3 are possible at the imine double bond. The H NMR
Chem. Soc. 1990, 112, 4011. Evans, D. A.; Britton, T. C. J . Am. Chem.
Soc. 1987, 109, 6881. Evans, D. A.; Nelson, S. G. J . Am. Chem. Soc.,
spectrum of the product was however consistent with the
presence of only one isomer, believed to be that with E
configuration. It has been previously reported that the
Z isomer is highly destabilized by a steric interaction with
the C-10 methyl group of the camphor unit.26 When an
R-substituted malonate, diethyl methylmalonate, was
treated with base and 1 under the same conditions,
diastereoisomeric imines 4a /4b were formed as a 1:1
1
997, 119, 6452. Evans, D. A.; J ohnson, D. S. Org. Lett. 1999, 1, 595.
Fioravanti, S.; Loreto, M. A.; Pellacani, L.; Tardella, P. A. Tetrahe-
dron: Asymmetry 1990, 1, 931. Hanessian, S.; Bennani, Y. L. Synthesis
1
994, 1272. Harris, J . M.; McDonald, R.; Vederas, J . C. J . Chem. Soc.,
Perkin Trans. 1 1996, 2669. Zheng, N.; Armstrong, J . D., III; McWil-
liams, C.; Volante, R. P. Tetrahedron Lett. 1997, 38, 2817. Page, P. C.
B.; Allin, S. M.; Collington, E. W.; Carr, R. A. E. Tetrahedron Lett.
1
994, 35, 2427. Page, P. C. B.; McKenzie, M. J .; Allin, S. M.; Collington,
E. W.; Carr, R. A. E. Tetrahedron Lett. 1995, 51, 1285.
25) Bottini, A. T.; Roberts, J . D. J . Am. Chem. Soc., 1958, 80, 5203.
1
(
mixture of isomers ( H NMR) in 89% yield after a 4 h
7
788 J . Org. Chem., Vol. 67, No. 22, 2002

Electrophilic Amination of Various Carbon Nucleophiles
TABLE 1. Ra ea ction s betw een (+)-Ca m p h or yloxa zir id in e
Other stabilized enolates were therefore investigated.
For example, when ethyl acetoacetate was treated with
LHMDS followed by (+)-camphoryloxaziridine 1, the
reaction did not reach completion even after 48 h, a much
slower process than that with diethyl malonate as
substrate. We were surprised to find that the only
1
a n d Ester s
time
yield
entry
substrate
base
(h) products (%)b
1
2
3
4
5
6
7
8
9
0
EtOCOCH2CO2Et
EtOCOCH2CO2Et
EtOCOCH(Me)CO2Et NaOEt
EtOCOCH(Me)CO2Et LHMDS 56
EtOCOCH(Ph)CO2Et LHMDS 60
EtOCOCH(Bu)CO2Et LHMDS 49
NaOEtc
3
6
4
3
3
68
50
89
20
0
14
0
0
LHMDS
c
4a /4b
4a /4b
product isolated was the (R)-camphor imine of ethyl
26
glycinate 3
in a 43% yield, corresponding to loss of
d
acetyl, decarboxylation of the ester not occurring in this
case (Table 1, entry 10). â-Keto esters have, however,
been shown to undergo scission under various conditions
to form decarboxylated compounds, products of retro-
Claisen condensation reactions, or mixtures of both types
of product. In general, under acidic conditions, decar-
boxylation of the free acid form of acetoacetate derivatives
has been shown to be the predominant pathway, whereas
under basic conditions, products of retro-Claisen reaction
5a /5b
d
d
CH3CO2Et
LHMDS
LHMDS
LHMDS 29
LHMDS 48
7.5
5.5
CH3(CH2) 2CO2Et
PhCH2CO2Et
MeCOCH2CO2Et
6a /6b
3
50
43
1
a
All reactions run at -78 °C, then allowed to reach room
b
temperature after addition of 1 unless otherwise noted. Yields
of isolated products after chromatography on silica gel. Reaction
run at room temperature. Only starting materials detected by
TLC and H NMR analysis of the crude reaction mixtures.
c
d
1
2
8
or mixtures of products are commonly formed.
reaction time (entry 3). We were surprised to find that
decarboxylation always occurs under these conditions.
We next investigated the reactivity of camphoryl
oxaziridine 1 toward malonate anions under kinetic
conditions. Reactions were typically carried out by forma-
tion of the enolates at -78 °C with LHMDS in THF
solution, followed by addition of a solution of 1 equiv of
As the initial products of decarboxylation are presum-
ably enolates, then any diastereoisomeric excesses ob-
served in the final products would necessarily arise from
diastereoselective protonation of these enolates induced
by the chiral camphor moiety, or from equilibration
following reaction, and not by an initial enantioselective
amination of the nucleophiles. No diastereoisomeric
1
1
in THF. The reaction mixtures were stirred at -78 °C
excess was observed, however, by H NMR spectroscopy
for the times indicated (Table 1), then allowed to reach
room temperature and quenched with aqueous am-
monium chloride.
of the imine products derived from any of these reactions
with esters: 1:1 mixtures of the two inseparable diaste-
reoisomers 4a /4b, 5a /5b, and 6a /6b were obtained (en-
tries 4, 6, and 9, respectively).
Nitrile derivatives were next investigated, using
both camphoryl oxaziridine 1 and fenchyl oxaziridine 2
(Tables 2 and 3). In a typical experimental procedure,
benzyl cyanide was treated with 1.1 equiv of LHMDS in
THF at -78 °C for 1 h, then 1 equiv of (+)-camphoryl
oxaziridine 1 was added and the reaction mixture was
allowed to reach room temperature. After completion,
Not only were the reaction times much longer than for
the ethoxide/ethanol conditions, even in the case of the
unsubstituted diethyl malonate (entry 2), but the yields
were also lower: 50% and 20% for diethyl malonate and
diethyl methylmalonate respectively (entries 2 and 4).
More bulky R-substituents seemed to hinder the progress
of the reaction; for example, no reaction was observed
after 60 h under these kinetic conditions with diethyl
phenylmalonate as substrate, and only starting materials
were detected by 1H NMR spectroscopy of the crude
reaction mixture (entry 5). Further, when diethyl butyl-
malonate was used as substrate, the yield of the corre-
sponding imine was very low (14%) even after a very long
reaction time (entry 6). For this particular substrate, we
also investigated a different experimental procedure
whereby the malonate was added to a solution of 1 in
THF at -78 °C prior to slow addition of the solution of
LHMDS. No improvement was observed, and after 48 h
the yield was only 13%.
4
washing with saturated aqueous NH Cl, and subsequent
chromatographic purification on silica gel, the two dia-
stereoisomers 8a and 8b , in which the nitrile groups
have been hydrolyzed to primary amide, were isolated
in a 78% yield and with a 25% de (Table 2, entry 1).
Single-crystal X-ray diffraction was carried out on both
isomers, and proved the major one, 8b , to have the
imine bond in an E configuration and to have the S
configuration at the newly created asymmetric carbon
atom. The minor product 8a was shown to be the (E, R)
product.
Monoesters, the enolates of which are less stabilized
and more reactive than those of malonates, were next
investigated, again under kinetic conditions. Neither
ethyl acetate nor ethyl butyrate gave any reaction, and
only starting materials, together with decomposition
products, were present in the reaction mixture after
several hours (entries 7 and 8). In contrast, ethyl phen-
ylacetate afforded surprising results: A 1:1 mixture of
the corresponding acids 6a and 6b could be isolated in a
Similarly, when other aromatic nitriles, including
naphthyl derivatives and 4-chloro- and 4-methoxybenzyl
cyanides (Scheme 3), were treated with 1.1 equiv of
LHMDS followed by (+)-camphoryl oxaziridine 1 in
THF at -78 °C, the corresponding R-imino ethanamides
9-12 were isolated in excellent yields (73-80%) but
moderate de values (5-33%), as indicated in Table 2
(entries 3 to 6).
5
0% yield after 29 h (entry 9). These acids proved to be
(26) McIntosh, J . M.; Mishra, P. Can. J . Chem. 1986, 64, 726.
(27) Roelofsen, D. P.; van Bekkum, H. Recl. Trav. Chim. Pays Bas
unstable even when kept at -30 °C and, like malonates,
undergo decarboxylation to provide the stable (R)-
camphor imine of benzylamine 7 (Scheme 2). 27 The fact
that no reaction took place with ethyl acetate or butyrate
may suggest that the transformation is most successful
with stabilized carbanions.
1
3
973, 91, 605. Mostowicz, D.; Belzecki, C. J . Org. Chem., 1977, 42,
917. Yaozhong, J .; Guilan, L.; J ingen, D. Synth. Commun. 1988, 18,
1291.
(
28) Kutz, W. M.; Adkins, H. J . Am. Chem. Soc. 1930, 52, 4391.
Kaupp, G.; Behmann, G.; Frey, H. Synthesis 1985, 555. Norman, R.;
Coxon, J . M. Principles of Organic Synthesis, 3rd ed.; Blackie Academic
& Professional: Glasgow, 1998; p 238.
J . Org. Chem, Vol. 67, No. 22, 2002 7789

Bulman Page et al.
TABLE 2. Rea ction s betw een (+)-Ca m p h or yl Oxa zir id in e 1 a n d Nitr ilesa
entry
substrate
base
time (h)
products
yield (%)b
de (%)c
1
2
3
4
5
6
7
8
9
0
1
2
3
PhCH2CN
PhCH2CN
LHMDS
LDAd
4.5
3.5
4.5
4.5
5
8a /8b
8a /8b
9a /9b
10a /10b
11a /11b
12a /12b
13
78
62
73
80
80
75
21
36
83, 17
82
45
11
68
25
5
33
33
16
5
2-naphthylacetonitrile
1-naphthylacetonitrile
4-ClC6H4CH2CN
4-MeOC6H4CH2CN
4-O2NC6H4CH2CN
CH3CH2CN
CH3CH2CH2CN
NCCH2CN
CH2dCHCH2CN
EtOCOCH2CN
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
9
6
4.5
6.5
6
26.5
5.5
31
13
e
f
13, 14
15a /15b
16
17a /17b
18a /18b
1
1
1
1
0
0
0
g
EtOCOCH(Ph)CN
a
b
All reactions run at -78 °C, then allowed to reach room temperature after addition of 1. Yields of isolated products after
c
1
chromatography on silica gel. Based on H NMR spectroscopy of the crude product mixture. Compound 8b was the major isomer in
entries 1 and 2. With HMPA (1.1 equiv.). Yield of R-campholenic amide 13.
one (14).
d
e
29,20
f
Yield of 1,8,8-trimethyl-2-azabicyclo[3.2.1]octan-3-
2
9,31
g
9% of a mixture of 8a /8b and 23% of the starting material were also isolated.
TABLE 3. Rea ction s betw een (-)-F en ch yl Oxa zir id in e 2 a n d Nitr ilesa
entry
substrate
base
time (h)
products
yield (%)b
de (%)c
1
2
3
4
PhCH2CN
LHMDS
LHMDS
LHMDS
LHMDS
5
9
4
7
19a /19b
20a /20b
21a /21b
22a /22b
55
31
48
57
50
52
33
23
2-naphthylacetonitrile
1-naphthylacetonitrile
NCCH2CN
a
b
All reactions run at -78 °C, then allowed to reach room temperature after addition of 2. Yields of isolated products after
c
1
chromatography on silica gel. Based on H NMR spectroscopy of the crude product mixture.
SCHEME 3
SCHEME 4
SCHEME 5
Surprisingly, reaction of 4-nitrophenylacetonitrile proved
to be inefficient (entry 7), perhaps due to a stabilizing
effect of the nitro group reducing the reactivity of the
2
9,30
anion. R-Campholenic amide 13
was the only product
isolated, in a 21% yield, presumably through rearrange-
ment induced under the reaction conditions (Scheme 4).
Amide 13 is also the product formed by Beckman or
photochemical rearrangements of camphor oxime.29
Amide 13 was also isolated as the major product when
aliphatic nitriles such as propionitrile or butyronitrile
were submitted to the reaction conditions (entries 8 and
When malonitrile was treated similarly (Scheme 3),
hydrolysis to primary amide of only one nitrile group was
observed, and a 1:1 mixture of the two diastereoisomers
15a and 15b was isolated in 82% yield (entry 10). Allyl
cyanide was observed to be less reactive, 26.5 h being
necessary for the complete consumption of 1 (entry 11).
Enamide 16 was the only product isolated, in a moderate
yield of 45%, in which isomerization of the terminal
double bond to the more stable cross-conjugated position
has occurred (Scheme 5). The Z configuration of the
9
). Indeed, in the latter case, R-campholenic amide 13
29,31
and 1,8,8-trimethyl-2-azabicyclo[3.2.1]octan-3-one 14
were isolated in 83% and 17% yields, respectively (Scheme
), as the only products, corresponding to the complete
rearrangement of camphoryl oxaziridine 1 (entry 9).
6
7
790 J . Org. Chem., Vol. 67, No. 22, 2002

Electrophilic Amination of Various Carbon Nucleophiles
SCHEME 6
SCHEME 8
1
however, a 50% de was observed, determined by H NMR
spectroscopy of the reaction mixture (Table 3, entry 1).
When 2-naphthylacetonitrile was used as the substrate,
the yield of imino compounds 20a /20b was only 31%, but
a 52% de was obtained (entry 2). With 1-naphthylaceto-
nitrile, the yield was slightly better (48%) but with a
lower de (33%) (entry 3). Finally, when malonitrile was
investigated, a 23% de was observed (entry 4), while 0%
de was obtained when 1 was used as the chiral aminating
agent.
SCHEME 7
Although the yields obtained with (-)-fenchyl oxaziri-
dine 2 are more moderate than those with 1, possibly a
result of a lower reactivity of this oxaziridine compared
with 1 due to the steric hindrance generated by the endo-
methyl group, the diastereoisomeric ratios observed are
promising.
The mechanism involved in reaction at the oxaziri-
dine unit may be a stepwise process, as is already
suggested in the literature for the oxidation of nucleo-
philic reagents with sulfonyloxaziridines.32 In this case,
the first step may be nucleophilic attack of the anion at
the nitrogen atom of the oxaziridine ring, causing N-O
bond cleavage and giving a hemiaminal oxyanion as the
intermediate (Scheme 9). Although mild conditions were
used for these reactions, hydrolysis of an ester or nitrile
group normally occurred. This may be rationalized by a
mechanism in which cyclization occurs next by attack of
the oxyanion on an ester or nitrile moiety to give a
heterocyclic intermediate20 which in turn breaks down
to generate a species containing imine and a carboxylate
or derivative. Decarboxylation or simple protonation on
workup, for example to give primary amide, may then
occur, dependent upon the nature of any other substit-
uents.
olefinic double bond was proved by single-crystal X-ray
diffraction.
Reaction between ethyl cyanoacetate and (+)-campho-
ryl oxaziridine 1 (Scheme 6) under the same conditions
gave a mixture of the decarboxylated amido compound
1
7a with its enol tautomer 17b in a poor yield of 11%
(entry 12).
In the nitrile series, the most successful substrates
thus appear to be those containing an aromatic substitu-
ent located R to the nitrile group. Consistent with this
interpretation is the observation that when ethyl phen-
ylcyanoacetate was treated with LHMDS followed by (+)-
camphoryl oxaziridine 1, a long reaction time of 31 h was
necessary for complete consumption of 1, but a good yield
of the two decarboxylated diastereoisomers 18a and 18b
was obtained (68%) together with 9% of a mixture of the
corresponding primary amides 8a and 8b (entry 13)
Presumably as a result of steric factors, the imine bond
in all the products is particularly stable. The best method
found for the generation of the free amino ester from this
2
6,33
type of imines is transimination with hydroxylamine.
(
Scheme 7). Ethyl phenylcyanoacetate was also recovered,
(
29) Suginome, H.; Furukawa, K.; Orito, K. J . Chem. Soc., Perkin
Trans. 1 1991, 917.
30) (a) Krow, G. R.; Szczepanski, S. Tetrahedron Lett. 1980, 21,
593. (b) Goldschmidt, H.; Zurrer, R. Ber. Deutsch. Chem. Ges. 1884,
17, 2071. (c) Ber. Deutsch. Chem. Ges. 1895, 28, 2168.
31) (a) Nakazaki, M.; Naemura, K. Bull. Chem. Soc. J pn. 1964, 37,
32. (b) Satoh, T.; Obase, H. Tetrahedron Lett. 1967, 8, 1633. (c) Satoh,
in 23% yield.
(
In an attempt to improve the diastereoisomeric ex-
cesses in our reactions, we investigated the reactivity of
4
(
(-)-fenchyl oxaziridine 2 toward nitrile anions as nu-
5
cleophiles on the basis that a better diastereoselective
induction might be expected from a higher degree of steric
approach control induced by the presence of the endo-
methyl group adjacent to the carbon atom bearing the
oxaziridine ring (Scheme 8 and Table 3).
T.; Inoue, T.; Yamamoto, K. Bull. Chem. Soc. J pn. 1972, 45, 1176.
(32) Knipe, A. C.; McAuley, I. E.; Kansall, V. K. Tetrahedron Lett.
984, 25, 1411. Evans, D. A.; Morrissey, M. M.; Dorow, R. L. J . Am.
Chem. Soc. 1985, 107, 4346. Davis, F. A.; Wei, J .; Sheppard, A. C.;
Gubernik, S. Tetrahedron Lett. 1987, 28, 5115.
(33) Yamada, S.; Oguri, T.; Shiori, T. J . Chem. Soc., Chem. Commun.
1
1
976, 136. Oguri, T.; Kawai, N.; Shiori, T.; Yamada, S. Chem. Pharm.
When benzyl cyanide was treated with LHMDS fol-
lowed by 2, the yield of imine products 19a /19b was lower
Bull. J pn. 1978, 26, 803. Tatsukawa, A.; Dan, M.; Ohbatake, M.;
Kawatake, K.; Fukata, T.; Wada, E.; Kanemasa, S.; Kakei, S. J . Org.
Chem. 1993, 58, 4221.
(55%) than that obtained with camphoryl oxaziridine 1;
J . Org. Chem, Vol. 67, No. 22, 2002 7791

Bulman Page et al.
SCHEME 9
Con clu sion
solution of lithium bis(trimethylsilyl)amide (1.0 M in THF,
1
.60 mL, 1.60 mmol) in dry THF (5 mL). After 1 h at -78 °C,
The first stable enantiomerically pure chiral N-H
oxaziridines derived from (1R)-(+)-camphor 1 and (1R)-
a solution of dry (+)-camphoryloxaziridine 1 or (-)-fenchyl-
oxaziridine 2 (250 mg, 1.50 mmol) in THF (1 mL) was added
dropwise and the reaction was allowed to reach room tem-
perature over a period of 2 h. The reaction mixture was
stirred at room temperature for the additional time indi-
cated until completion (TLC). Aqueous ammonium chloride (20
mL) was added and the reaction mixture was extracted
with dichloromethane (3 × 35 mL). The combined organic
(-)-fenchone 2 were investigated in the amination of
various carbon nucleophiles such as esters and nitriles.
Yields were moderate to good, especially when 1 was used
with nitriles, but the observed diastereoselectivities were
improved when 2 was employed as chiral electrophilic
aminating reagent. The ready access to these compounds
from the inexpensive commercially available parent
ketones, coupled with their remarkable stability, suggests
that members of this group of compounds may prove to
be effective reagents for asymmetric nitrogen transfer.
4
solution was dried over MgSO and the solvent was removed
in vacuo to give an oil that was purified by column chroma-
tography on silica gel with ethyl acetate/light petroleum as
eluent.
E t h yl-2-{[(1R,4S)-1,7,7-t r im et h ylb icyclo[2.2.1]h ep t -2-
ylid en ]a m in o}eth a n oa te (3).26 Rea ction betw een d ieth yl
m a lon a te a n d (+)-ca m p h or yloxa zir id in e 1:. Diethyl mal-
onate (230 µL, 243 mg, 1.50 mmol) was treated with 1
according to procedure A and the reaction mixture was stirred
for 3 h. After purification, compound 3 was isolated as a
colorless oil (242 mg, 68%).
When procedure B was applied with diethyl malonate as
the substrate, the reaction was quenched after 6 h and gave
product 3 (178 mg, 50%).
Rea ction betw een eth yl a cetoa ceta te a n d (+)-ca m -
p h or yloxa zir id in e 1: Ethyl acetoacetate (191 µL, 195
mg, 1.50 mmol) was treated with 1 according to procedure B
and the reaction mixture was quenched after 48 h. Upon
purification, the starting materials ethyl acetoacetate and
Exp er im en ta l Section
Gen er a l. Thin-layer chromatography was carried out on
aluminum-backed plates coated with silica gel and visualized
by spraying with potassium permanganate solution followed
by heating. Flash column chromatography was performed with
use of 230-400 mesh silica gel. Melting points were deter-
mined with use of an electronic melting point apparatus and
are uncorrected. H NMR spectra and C NMR spectra were
recorded in CDCl at 250 and 400 MHz and at 62.9 and 100.6
MHz, respectively, with TMS as internal standard. In the
1
13
3
1
description of H NMR spectra, the letter A refers to the first
isomer eluted (major) and B to the minor one. Infrared spectra
were recorded from thin films. Mass spectra were obtained by
using the electron impact (EI) ionization technique. Optical
rotations were measured at λ ) 589 nm corresponding to the
sodium (D) line at the temperature indicated.
(
+)-camphoryloxaziridine 1 (85 mg) were first eluted fol-
lowed by the title product 3 isolated as a colorless oil (132 mg,
4
3%).
[R]25
+3° (c 0.62, CHCl
3
); IR νmax (neat)/cm-1 1743, 1686;
) δ 4.18 (q, J ) 7.2 Hz, 2 H), 4.09
D
1
Gen er a l Am in a tion P r oced u r es. P r oced u r e A: Sodium
H NMR (250 MHz, CDCl
3
(
100 mg, 4.35 mmol) was added to dry ethanol (5 mL) and the
(br s, 2 H), 2.38-2.28 (m, 1 H), 1.97 (t, J ) 4.3 Hz, 1 H), 1.93-
1.79 (m, 2 H), 1.70 (dt, J ) 11.2, 3.6 Hz, 1 H), 1.48-1.38 (m,
1 H), 1.27 (t, J ) 7.1 Hz, 3 H), 1.23-1.17 (m, 1 H), 1.03 (s, 3
solution was stirred until the effervescence had ceased and
all of the sodium had reacted. After allowing the solution to
cool to room temperature, a solution of (+)-camphoryloxaziri-
dine 1 (250 mg, 1.50 mmol) in ethanol (1 mL) was added
followed by the corresponding malonate (1.50 mmol). The
reaction mixture was then stirred at room temperature for the
time indicated. When the reaction was complete (TLC), the
reaction mixture was added to saturated aqueous ammonium
chloride (40 mL). The mixture was extracted with dichlo-
romethane (3 × 40 mL), the combined organic extracts were
H), 0.94 (s, 3 H), 0.81 (s, 3 H); 13C NMR (100.6 MHz, CDCl
)
3
δ 188.0 (Cquat), 170.3 (Cquat), 60.8 (CH
47.4 (Cquat), 43.8 (CH), 35.8 (CH ), 32.0 (CH
(CH ), 18.9 (CH ), 11.2 (CH ), 9.3 (CH ); MS m/z 238 (MH ),
237 (M ), 222, 208, 194, 180, 164, 150, 135, 129, 122, 108, 99,
2
), 54.4 (Cquat), 53.9 (CH
2
),
2
2
), 27.4 (CH ), 19.6
2
+
3
3
3
3
+
+
95, 83, 75, 67, 59, 56, 41; HRMS calcd for C14
237.17288, found 237.1726.
2
H23NO (M )
(2R)-E t h yl-2-{[(1R,4S)-1,7,7-t r im e t h ylb icyclo[2.2.1]-
h ep t-2-ylid en ]a m in o}p r op a n oa te (4a ) a n d (2S)-Eth yl-2-
{[(1R ,4S )-1,7,7-t r im e t h ylb icyclo[2.2.1]h e p t -2-ylid e n ]-
a m in o}p r op a n oa te (4b). Diethyl methylmalonate (258 µL,
261 mg, 1.50 mmol) was treated with 1 according to procedure
A and the reaction mixture was stirred at room temperature
4
dried over MgSO , and the solvent was removed in vacuo to
give a pale yellow oil that was purified by column chromatog-
raphy on silica gel with ethyl acetate/light petroleum as eluent.
P r oced u r e B: A solution of ester or nitrile (1.50 mmol) in
THF (1 mL) was added dropwise to a cooled (-78 °C), stirred
7
792 J . Org. Chem., Vol. 67, No. 22, 2002

Electrophilic Amination of Various Carbon Nucleophiles
1
1
for 4 h. After purification, imines 4a /4b were isolated (335 mg,
6b: colorless oil; IR νmax (neat)/cm- 2958, 1771, 1683; H
NMR (250 MHz, CDCl ) δ 9.08 (br s, 1 H), 7.35-7.23 (m, 5 H),
4.89 (s, 1 H), 2.00-1.71 (m, 5 H), 1.48-1.36 (m, 1 H), 1.30-
8
9%). The products 4a /4b were found to be present in a 1:1
3
1
ratio by H NMR spectroscopy.
1
3
When procedure B was applied, the reaction was quenched
after an additional 54 h of stirring at room temperature and
gave 4a /4b (75.3 mg, 20%).
1.20 (m, 1 H), 1.09 (s, 3 H), 0.92 (s, 3 H), 0.50 (s, 3 H);
NMR (100.6 MHz, CDCl ) δ 184.0 (Cquat), 172.2 (Cquat), 137.0
(Cquat), 128.7 (CH), 128.3 (CH), 128.0 (CH), 127.3 (CH), 126.4
(CH), 66.4 (CH), 54.1 (Cquat), 47.2 (Cquat), 43.8 (CH), 35.9 (CH ),
2.2 (CH ), 27.5 (CH ), 19.5 (CH ), 18.9 (CH ), 11.4 (CH ).
7: colorless oil; IR νmax (neat)/cm-1 1685; 1H NMR (250
MHz, CDCl ) δ 7.34-7.17 (m, 5 H), 4.47 (qab, J ) 15.2 Hz, 2
H), 2.41 (dt, J ) 16.6, 3.5 Hz, 1 H), 1.96 (t, J ) 4.4 Hz, 1 H),
1.92 (d, J ) 17.3 Hz, 1 H), 1.86-1.80 (m, 1 H), 1.70 (dt, J )
16.2, 3.6 Hz, 1 H), 1.48-1.37 (m, 1 H), 1.26-1.16 (m, 1 H),
1.04 (s, 3 H), 0.95 (s, 3 H), 0.77 (s, 3 H); 13C NMR (100.6 MHz,
) δ 183.5 (Cquat), 140.6 (Cquat), 128.3 (2 CH), 127.4 (2 CH),
126.4 (CH), 55.6 (CH ), 54.0 (Cquat), 47.1 (Cquat), 43.9 (CH), 35.8
), 19.8 (CH
(CH ); HRMS calcd for C17H23N (M
41.18286.
(2R)-2-P h en yl-2-{[(1R,4S)-1,7,7-tr im eth ylbicyclo[2.2.1]-
h ep t-2-ylid en ]a m in o}eth a n a m id e (8a ) a n d (2S)-2-P h en yl-
2-{[(1R,4S)-1,7,7-t r im et h ylb icyclo[2.2.1]h ep t -2-ylid en ]-
a m in o}eth a n a m id e (8b). Benzyl cyanide (174 µL, 176 mg,
1.50 mmol) was treated with 1 according to procedure B and
the reaction mixture was stirred for 2.5 h. Upon purification,
(2R)-2-phenyl-2-{[(1R,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-
yliden]amino}ethanamide (8a , 137 mg, 32%) was first eluted
followed by (2S)-2-phenyl-2-{[(1R,4S)-1,7,7-trimethylbicyclo-
[2.2.1]hept-2-yliden]amino}ethanamide (8b, 196 mg, 46%).
C
3
-
1
1
2
4
a /4b: IR ν max (neat)/cm 1740, 1683; H NMR (250 MHz,
CDCl ) δ 4.27-3.99 (m, 2 HA+B), 4.04 (q, J ) 6.8 Hz, 1 H ),
.03 (q, J ) 6.8 Hz, 1 H ), 2.47-2.29 (m, 1 HA+B), 1.97-1.80
m, 2 HA+B), 1.68 (dt, J ) 12.5, 3.8 Hz, 1 HA+B), 1.41 (d, J )
3
2
2
3
3
3
3
A
2
6
4
(
6
1
B
3
.6 Hz, 3 H
A
), 1.40 (d, J ) 6.8 Hz, 3 H
.00 (s, 6 HA+B), 0.93 (s, 6 HA+B), 0.81 (s, 3 H
B
), 1.31-1.16 (m, 3 HA+B),
), 0.76 (s, 3 H );
A
B
1
3
C NMR (62.9 MHz, CDCl ) δ 184.3, 184.2, 172.89, 172.86,
3
6
3
1
1
0.6, 59.34, 59.27, 53.8, 47.2, 46.8, 43.7, 35.6, 35.5, 35.3, 35.2,
1.9, 31.8, 31.7, 27.4, 27.3, 27.2, 19.4, 18.9, 18.8, 18.6, 18.5,
8.4, 14.0, 13.9, 11.3; MS m/z 252 (MH ), 251 (M ), 236, 222,
CDCl
3
+
+
2
79, 178, 162, 152, 150, 135, 122, 109, 95, 83, 70, 55; HRMS
(CH
2
), 32.3 (CH
2
), 27.5 (CH
2
3 3
), 19.2 (CH ), 11.5
) 241.18305, found
+
+
calcd for C15
H
25NO
2
(M ) 251.18853, found 251.18836.
3
2
(
2R)-E t h yl-2-{[(1R,4S)-1,7,7-t r im e t h ylb icyclo[2.2.1]-
h ep t-2-ylid en ]a m in o}h exa n oa te (5a ) a n d (2S)-Eth yl-2-
[(1R ,4S )-1,7,7-t r im e t h ylb icyclo[2.2.1]h e p t -2-ylid e n ]-
{
a m in o}h exa n oa te (5b). Diethyl butylmalonate (330 µL, 324
mg, 1.50 mmol) was treated with 1 according to procedure B
and the reaction mixture was stirred at room temperature for
4
7 h. After purification, (2R)-ethyl-2-{[(1R,4S)-1,7,7-trimethylbi-
cyclo[2.2.1]hept-2-yliden]amino}hexanoate (5a ) and (2S)-ethyl-
-{[(1R,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yliden]amino}-
2
hexanoate (5b), a mixture of inseparable diastereoisomers in
a 1:1 ratio, were isolated as a colorless oil (62 mg, 14%). The
starting materials diethyl butylmalonate (259 mg, 1.197 mmol)
and (+)-camphoryloxaziridine 1 (150 mg, 0.898 mmol) were
also isolated.
2
5
8a : colorless needles, mp 131-133 °C; [R]
D
-87° (c 0.85,
-
1
1
CHCl
3
); IR νmax (neat)/cm 3438, 3170, 1696, 1651; H NMR
) δ 7.48 (br s, 1 H), 7.43-7.20 (m, 5 H), 6.26
(400 MHz, CDCl
3
a /5b: IR νmax (neat)/cm-1 1741, 1684; H NMR (250 MHz,
CDCl ) δ 4.17-4.11 (m, 2 HA+B), 3.88 (dd, J ) 8.8, 5.3 Hz, 1
), 3.86 (dd, J ) 8.8, 5.1 Hz, 1 H ), 2.46-2.32 (m, 1 H ), 2.38-
.26 (m, 1 H ), 1.98-1.13 (m, 15 HA+B), 1.00 (s, 6 HA+B), 0.94
s, 3 H ), 0.93 (s, 3 H
100.6 MHz, CDCl ) δ 184.8 (2 Cquat), 172.64 (Cquat), 172.60
quat), 64.5 (CH), 64.4 (CH), 60.6 (2 CH ), 54.2 (Cquat), 54.1
quat), 47.4 (Cquat), 46.7 (Cquat), 44.0 (CH), 43.9 (CH), 36.2 (CH
1
(br s, 1 H), 4.78 (br s, 1 H), 2.42 (d, J ) 17.3 Hz, 1 H), 1.91 (t,
J ) 4.4 Hz, 1 H), 1.81-1.71 (m, 1 H), 1.65 (dt, J ) 12.1, 3.9
Hz, 1 H), 1.56 (d, J ) 17.3 Hz, 1 H), 1.27-1.21 (m, 1 H), 1.04
5
3
H
A
B
A
1
3
2
B
(s, 3 H), 0.98-0.89 (m, 1 H), 0.93 (s, 3 H), 0.77 (s, 3 H);
C
1
3
NMR (100.6 MHz, CDCl ) δ 185.5 (C ), 176.0 (Cquat), 139.9
(
(
(
(
A
B
), 0.79 (s, 3 H
A
), 0.75 (s, 3 H
B
); C NMR
3
quat
(Cquat), 128.8 (CH), 128.7 (CH), 127.8 (CH), 127.6 (CH), 126.6
(CH), 68.3 (CH), 54.9 (Cquat), 47.5 (Cquat), 44.2 (CH), 36.3 (CH ),
32.1 (CH ), 27.5 (CH ), 19.9 (CH ), 19.3 (CH ), 11.6 (CH ); MS
m/z 285 (MH ), 241, 224, 212, 198, 184, 172, 135, 118, 106,
3
C
C
2
2
2
),
),
2
2
3
3
3
+
3
2
5.9 (CH
8.2 (CH
), 19.5 (CH
), 11.5 (CH
2
), 32.7 (2 CH
), 27.6 (CH ), 27.4 (CH
), 19.1 (CH ), 18.9 (CH
), 11.4 (CH ); MS m/z 294 (MH ), 293 (M ),
2
), 32.4 (CH
2
), 31.9 (CH
2
), 28.4 (CH
), 22.4 (CH
2
+
2
2
2
), 22.7 (CH
2
2
), 19.6
91, 79, 69, 55, 41; HRMS calcd for C18
found 284.18987. Anal. Calcd for C18
H
24 2
N
O (M ) 284.18942,
O: C, 76.02; H, 8.51;
(CH
3
3
3
3
3
), 14.2 (2 CH
3
), 14.0 (2
H
24
N
2
+
+
N, 9.85. Found: C, 76.02; H, 8.48; N, 9.60.
CH
3
3
2
8
78, 265, 250, 237, 220, 208, 192, 178, 163, 150, 135, 112, 95,
8b: colorless crystals, mp 173-177 °C; [R]25
D
+111° (c 1.03,
+
-1
1
3, 73, 69, 55, 41; HRMS calcd for C18
H
31NO
2
(M ) 293.23548,
CHCl
3
); IR νmax (neat)/cm 3435, 3200, 1700, 1654; H NMR
found 293.23568.
(400 MHz, CDCl ) δ 7.53 (br s, 1 H), 7.43-7.37 (m, 2 H), 7.30-
3
(
2R)-2-P h en yl-2-{[(1R,4S)-1,7,7-tr im eth ylbicyclo[2.2.1]-
7.18 (m, 3 H), 6.30 (br s, 1 H), 4.80 (br s, 1 H), 2.00 (dt, J )
17.4, 3.4 Hz, 1 H), 1.93-1.83 (m, 3 H), 1.74-1.70 (m, 1 H),
1.36-1.32 (m, 1 H), 1.26-1.21 (m, 1 H), 1.04 (s, 3 H), 0.90 (s,
h ep t -2-ylid en ]a m in o}et h a n oic Acid (6a ) a n d (2S)-2-
P h en yl-2-{[(1R,4S)-1,7,7-t r im et h ylb icyclo[2.2.1]h ep t -2-
ylid en ]a m in o}eth a n oic Acid (6b). Ethyl phenylacetate (239
µL, 246 mg, 1.50 mmol) was treated with 1 according to
procedure B. After addition of (+)-camphoryloxaziridine 1, the
reaction mixture was stirred for 29 h then quenched and
purified as described. (2R)-2-Phenyl-2-{[(1R,4S)-1,7,7-trimethyl-
bicyclo[2.2.1]hept-2-yliden]amino}ethanoic acid (6a ) and (2S)-
3 H), 0.50 (s, 3 H); 13C NMR (100.6 MHz, CDCl
) δ 185.4 (Cquat),
3
175.5 (Cquat), 139.2 (Cquat), 128.4 (CH), 128.3 (CH), 127.6 (CH),
127.4 (CH), 127.2 (CH), 68.5 (CH), 54.3 (Cquat), 47.7 (Cquat), 43.7
(CH), 36.2 (CH
11.3 (CH ); MS m/z 284 (M ), 241, 224, 211, 198, 184, 172,
135, 118, 106, 91, 79, 69, 55, 41; HRMS calcd for C18
2 2 2 3 3
), 31.9 (CH ), 27.2 (CH ), 19.2 (CH ), 18.9 (CH ),
+
3
H
24
N
2
O
O:
+
2
-phenyl-2-{[(1R,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yliden]-
(M ) 284.18942, found 284.18917. Anal. Calcd for C18
H
24
N
2
amino}ethanoic acid (6b) were isolated as a mixture of
diastereoisomers in a 1:1 ratio (210 mg, 50%). These acids were
not stable and decarboxylated after a few hours even when
kept at -30 °C to give the imine N-[(1R,4S)-1,7,7-trimethylbi-
cyclo[2.2.1]hept-2-yliden]phenylmethanamide (7).
6
C, 76.02; H, 8.51; N, 9.85. Found: C, 75.71; H, 8.45; N, 9.72.
(2R )-2-Na p h t h a le n -2-yl-2-{[(1R ,4S )-1,7,7-t r im e t h yl-
bicyclo[2.2.1]h ep t-2-ylid en ]a m in o}eth a n a m id e (9a ) a n d
(2S)-2-Naph th alen -2-yl-2-{[(1R,4S)-1,7,7-tr im eth ylbicyclo-
[2.2.1]h ep t -2-ylid en ]a m in o}et h a n a m id e (9b ). 2-Naph-
thylacetonitrile (251 mg, 1.50 mmol) was treated with 1
according to procedure B and the reaction mixture was
stirred for 2.5 h. Upon purification, (2R)-2-naphthalen-2-yl-
2-{[(1R,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yliden]amino}-
ethanamide (9a , 135 mg, 27%) was first eluted followed by
(2S)-2-naphthalen-2-yl-2-{[(1R,4S)-1,7,7-trimethylbicyclo[2.2.1]-
hept-2-yliden]amino}ethanamide (9b, 234 mg, 47%).
2
6
-
1
1
a : colorless oil; IR νmax (neat)/cm 2958, 1771, 1683; H
NMR (250 MHz, CDCl ) δ 9.07 (br s, 1H), 7.36-7.28 (m, 5 H),
3
4
1
1
3
1
1
.93 (s, 1 H), 2.52-2.42 (m, 1 H), 1.96 (t, J ) 4.2 Hz, 1 H),
.93-1.83 (m, 1 H), 1.82-1.68 (m, 1 H), 1.56 (d, J ) 17.9 Hz,
H), 1.48-1.32 (m, 1 H), 1.11 (s, 3 H), 0.97 (m, 1 H), 0.95 (s,
H), 0.78 (s, 3 H); 13C NMR (100.6 MHz, CDCl
) δ 184.0 (Cquat),
3
72.2 (Cquat), 137.5 (Cquat), 128.8 (CH), 128.1 (CH), 127.4 (CH),
27.2 (CH), 124.8 (CH), 67.3 (CH), 55.4 (Cquat), 48.0 (Cquat), 43.9
2
5
9a : colorless solid, mp 159-162 °C; [R]
D
-91° (c 0.92,
-
1
1
(
1
CH), 37.2 (CH
1.1 (CH
2
), 31.8 (CH
2
), 27.0 (CH
2
), 19.6 (CH
3
), 19.3 (CH
3
),
CHCl
3
); IR νmax (neat)/cm 3428, 1692, 1652; H NMR (250
3
).
MHz, CDCl
3
) δ 7.83-7.76 (m, 4 H), 7.58-7.54 (m, 2 H), 7.45-
J . Org. Chem, Vol. 67, No. 22, 2002 7793

Bulman Page et al.
7
1
)
1
.42 (m, 2 H), 6.18 (br s, 1 H), 4.93 (br s, 1 H), 2.51-2.42 (m,
H), 1.89 (t, J ) 4.2 Hz, 1 H), 1.76-1.71 (m, 1 H), 1.67 (dd, J
[2.2.1]h ep t -2-ylid en ]a m in o}et h a n a m id e (11b ). 4-Chlo-
robenzyl cyanide (178 µL, 228 mg, 1.50 mmol) was treated with
1 according to procedure B and the reaction mixture was
stirred for 3 h. Upon purification, (2R)-2-(4-chlorophenyl)-2-
{[(1R,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yliden]amino}-
ethanamide (11a , 165 mg, 34%) was first eluted followed by
(2S)-2-(4-chlorophenyl)-2-{[(1R,4S)-1,7,7-trimethylbicyclo[2.2.1]-
hept-2-yliden]amino}ethanamide (11b, 218 mg, 46%).
12.1, 3.1 Hz, 1 H), 1.56 (d, J ) 17.5 Hz, 1 H), 1.28-1.18 (m,
H), 1.07 (s, 3 H), 0.92 (s, 3 H), 0.92-0.88 (m, 1 H), 0.77 (s, 3
1
3
H); C NMR (100.6 MHz, CDCl ) δ 186.1 (Cquat), 176.0 (Cquat),
3
1
1
6
36.9 (Cquat), 133.3 (Cquat), 133.0 (Cquat), 128.3 (CH), 128.1 (CH),
27.7 (CH), 126.4 (CH), 126.1 (CH), 126.0 (CH), 125.2 (CH),
8.1 (CH), 54.5 (Cquat), 47.2 (Cquat), 43.9 (CH), 36.0 (CH ), 31.8
), 27.2 (CH ), 19.7 (CH ), 19.0 (CH ), 11.4 (CH ); MS m/z
34 (M ), 305, 291, 290, 265, 222, 199, 185, 172, 155, 141, 127,
2
2
5
(CH
2
2
3
3
3
11a : pale yellow oil; [R]
-113° (c 1.02, CHCl ); IR ν
D
3
max
+
-1
1
3
1
3
(neat)/cm 3429, 3200, 1694; H NMR (250 MHz, CDCl ) δ
3
7.46 (br s, 1 H), 7.38-7.32 (m, 2 H), 7.29-7.25 (m, 2 H), 6.13
(br s, 1 H), 4.73 (s, 1 H), 2.47-2.35 (m, 1 H), 1.92 (t, J ) 4.3
Hz, 1 H), 1.87-1.61 (m, 2 H), 1.52 (d, J ) 17.2 Hz, 1 H), 1.29-
1.14 (m, 1 H), 1.04 (s, 3 H), 0.93 (s, 3 H), 0.96-0.84 (m, 1 H),
+
08, 95, 81, 69, 55, 43; HRMS calcd for C22
H
26
N
2
O (M )
34.20451, found 334.20367.
2
5
9
b: colorless solid, mp 145-150 °C; [R]
3
D
+115° (c 1.01,
-
1
1
CHCl
MHz, CDCl
); IR νmax (neat)/cm 3429, 1694, 1651; H NMR (250
) δ 7.86-7.75 (m, 4 H), 7.62 (br s, 1 H), 7.56 (dd,
0.75 (s, 3 H); 13C NMR (62.9 MHz, CDCl
) δ 185.3 (Cquat), 174.9
(Cquat), 137.1 (Cquat), 133.2 (Cquat), 128.5 (2 CH), 128.4 (2 CH),
67.1 (CH), 54.5 (Cquat), 47.0 (Cquat), 43.7 (CH), 35.9 (CH ), 31.6
(CH ), 27.0 (CH ), 19.4 (CH ), 18.8 (CH ), 11.1 (CH ).
11b: colorless needles, mp 145-146 °C; [R] +146° (c 1.04,
3
3
J ) 8.7, 1.7 Hz, 1 H), 7.48-7.40 (m, 2 H), 5.68 (br s, 1 H), 4.96
(
(
(
1
1
br s, 1 H), 2.04-1.65 (m, 5 H), 1.44-1.34 (m, 1 H), 1.29-1.19
2
m, 1 H), 1.09 (s, 3 H), 0.89 (s, 3 H), 0.47 (s, 3 H); 13C NMR
2
2
3
3
3
2
5
100.6 MHz, CDCl
3
) δ 186.1 (Cquat), 175.9 (Cquat), 136.5 (Cquat),
33.4 (Cquat), 133.0 (Cquat), 128.3 (CH), 128.1 (CH), 127.7 (CH),
26.3 (CH), 126.1 (CH), 126.0 (CH), 125.1 (CH), 68.7 (CH), 54.5
quat), 47.9 (Cquat), 43.9 (CH), 36.0 (CH ), 32.1 (CH ), 27.4
CH ), 19.4 (CH ), 19.1 (CH ), 11.6 (CH ); MS m/z 335 (MH ),
34 (M ), 291, 274, 261, 246, 234, 222, 206, 193, 185, 168, 156,
41, 128, 109, 95, 81, 69, 55, 41; HRMS calcd for C22
D
-
1
1
CHCl ); IR ν
3
max
(neat)/cm 3430, 3200, 1694; H NMR (250
MHz, CDCl ) δ 7.53 (br s, 1 H), 7.37-7.34 (m, 2 H), 7.29-7.23
3
(C
2
2
(m, 2 H), 5.61 (br s, 1 H), 4.76 (br s, 1 H), 2.00-1.85 (m, 3 H),
1.84-1.67 (m, 2 H), 1.41-1.30 (m, 1 H), 1.29-1.16 (m, 1 H),
+
(
3
1
2
3
3
3
+
13
1.04 (s, 3 H), 0.91 (s, 3 H), 0.51 (s, 3 H); C NMR (62.9 MHz,
H
26
N
2
O
O:
CDCl ) δ 185.4 (Cquat), 173.2 (Cquat), 135.9 (Cquat), 131.2 (Cquat),
3
+
(
M ) 334.20451, found 334.20384. Anal. Calcd for C22
C, 79.01; H, 7.84; N, 8.38. Found: C, 79.12; H, 7.85; N, 8.36.
2R )-2-Na p h t h a le n -1-yl-2-{[(1R ,4S )-1,7,7-t r im e t h yl-
bicyclo[2.2.1]h ep t-2-ylid en ]a m in o}eth a n a m id e (10a ) a n d
H
26
N
2
128.43 (2 CH), 128.40 (2 CH), 67.7 (CH), 54.2 (Cquat), 47.6
(Cquat), 43.7 (CH), 36.2 (CH ), 31.8 (CH ), 27.2 (CH ), 19.3
2
2
2
+
(
(CH
3 3 3
), 18.9 (CH ), 11.3 (CH ); MS m/z 318 (M ), 303, 277, 260,
239, 232, 218, 206, 192, 171, 169, 152, 140, 133, 125, 109, 95,
+
(
[
2S)-2-Naph th alen -1-yl-2-{[(1R,4S)-1,7,7-tr im eth ylbicyclo-
2.2.1]h ep t -2-ylid en ]a m in o}et h a n a m id e (10b). 1-Naph-
89, 83, 77, 69, 55, 43, 41; HRMS calcd for C18
H
23
N
2
OCl (M )
318.14987, found 318.15068. Anal. Calcd for C18
H
N OCl: C,
23 2
thylacetonitrile (251 mg, 1.50 mmol) was treated with 1
according to procedure B and the reaction mixture was
stirred for 2.5 h. Upon purification, (2R)-2-naphthalen-1-yl-
67.81; H, 7.27; N, 8.79. Found: C, 67.86; H, 7.19; N, 8.75.
(2R)-2-(4-Met h oxyp h en yl)-2-{[(1R,4S)-1,7,7-t r im et h -
ylbicyclo[2.2.1]h ep t-2-ylid en ]a m in o}eth a n a m id e (12a )
a n d (2S)-2-(4-Meth oxyp h en yl)-2-{[(1R,4S)-1,7,7-tr im eth -
ylbicyclo[2.2.1]h ep t -2-ylid en ]a m in o}et h a n a m id e (12b).
4-Methoxybenzyl cyanide (203 µL, 221 mg, 1.50 mmol) was
treated with 1 according to procedure B and the reaction mix-
ture was stirred for 7 h. Upon purification, (2R)-2-(4-meth-
oxyphenyl)-2-{[(1R,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yli-
den]amino}ethanamide (12a ) and (2S)-2-(4-methoxyphenyl)-
2-{[(1R,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yliden]amino}-
ethanamide (12b) were isolated by column chromatography
on silica gel as an oily mixture of inseparable diastereoisomers
in a 1:1 ratio (355 mg, 75%).
2
-{[(1R,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yliden]amino}-
ethanamide (10a , 154 mg, 31%) was first eluted followed by
2S)-2-naphthalen-1-yl-2-{[(1R,4S)-1,7,7-trimethylbicyclo[2.2.1]-
hept-2-yliden]amino}ethanamide (10b, 266 mg, 53%).
(
2
5
1
0a : colorless powder, mp 156-158 °C; [R]
3
D
-127° (c 1.04,
-
1
1
CHCl
MHz, CDCl
); IR νmax (neat)/cm 3420, 1696, 1653; H NMR (250
) δ 8.42 (d, J ) 8.4 Hz, 1 H), 7.83-7.72 (m, 2 H),
.63 (br s, 1 H), 7.56-7.36 (m, 4 H), 6.39 (br s, 1 H), 5.45 (s, 1
H), 2.46-2.37 (m, 1 H), 1.81 (t, J ) 4.4 Hz, 1 H), 1.73-1.62
m, 1 H), 1.55 (dt, J ) 11.5, 3.7 Hz, 1 H), 1.33 (d, J ) 17.3 Hz,
H), 1.20-1.08 (m, 1 H), 1.05 (s, 3 H), 0.89 (s, 3 H), 0.77 (s, 3
3
7
(
1
1
3
Mixture of 12a /12b: IR νmax (neat)/cm-1 3430, 3269, 1686,
H), 0.76-0.70 (m, 1 H); C NMR (62.9 MHz, CDCl
quat), 175.6 (Cquat), 136.5 (Cquat), 134.1 (Cquat), 131.6 (Cquat),
3
) δ 185.3
+
(C
1654; MS m/z 314 (M ), 271, 227, 214, 202, 175, 164, 148, 136,
1
1
28.7 (CH), 128.2 (CH), 126.4 (CH), 126.2 (CH), 125.7 (CH),
25.3 (CH), 125.0 (CH), 65.2 (CH), 54.6 (Cquat), 47.1 (Cquat), 43.9
121, 109, 93, 91, 81, 77, 69, 67, 55; HRMS calcd for C19
H
26
N
2
O
2
+
(M ) 314.19940, found 314.19907.
2
), 31.4 (CH
2 2 3 3
), 27.0 (CH ), 19.6 (CH ), 18.9 (CH ),
12a : 1H NMR (250 MHz, CDCl ) δ 7.51 (br s, 1 H), 7.34-
3
(CH), 36.1 (CH
+
1
1
3
7
1.4 (CH
27, 115, 95, 69, 55, 41; HRMS calcd for C22
34.20451, found 334.20483. Anal. Calcd for C22
3
); MS m/z 334 (M ), 290, 222, 185, 172, 155, 141,
7.30 (m, 2 H), 6.86-6.82 (m, 2 H), 6.09 (br s, 1 H), 4.71 (s, 1
H), 3.78 (s, 3 H), 2.45-2.35 (m, 1 H), 1.91 (t, J ) 4.3 Hz, 1 H),
1.80-1.63 (m, 2 H), 1.55 (d, J ) 17.2 Hz, 1 H), 1.25-1.15 (m,
+
H
26
N
2
O (M )
H
N O: C,
26 2
9.01; H, 7.84; N, 8.38. Found: C, 78.94; H, 7.89; N, 8.39.
1 H), 1.03 (s, 3 H), 0.98-0.93 (m, 1 H), 0.93 (s, 3 H), 0.75 (s, 3
2
5
13
1
0b: colorless powder, mp 190-191.5 °C; [R]
D
+133° (c
3
H); C NMR (100.6 MHz, CDCl ) δ 184.9 (Cquat), 175.9 (Cquat),
-
1
1
1
.01, CHCl
3
); IR νmax (neat)/cm 3429, 3196, 1697, 1651; H
) δ 8.42 (d, J ) 8.4 Hz, 1 H), 7.82-7.71
m, 3 H), 7.56-7.34 (m, 4 H), 6.26 (br s, 1 H), 5.46 (s, 1 H),
158.9 (Cquat), 131.8 (Cquat), 128.1 (2 CH), 113.9 (2 CH), 67.3
(CH), 55.4 (CH ), 54.2 (Cquat), 47.0 (Cquat), 43.9 (CH), 35.8 (CH ),
31.7 (CH ), 27.3 (CH ), 19.5 (CH ), 19.0 (CH ), 11.2 (CH ).
12b: 1H NMR (250 MHz, CDCl
) δ 7.52 (br s, 1 H), 7.34-
NMR (250 MHz, CDCl
(
3
3
2
2
2
3
3
3
1
.92-1.63 (m, 5 H), 1.40 (dt, J ) 12.5, 3.9 Hz, 1 H), 1.26-1.15
3
(
(
m, 1 H), 1.04 (s, 3 H), 0.83 (s, 3 H), 0.25 (s, 3 H); 13C NMR
7.29 (m, 2 H), 6.86-6.79 (m, 2 H), 6.65 (br s, 1 H), 4.71 (s, 1
H), 3.75 (s, 3 H), 2.00-1.95 (m, 1 H), 1.92-1.59 (m, 4 H), 1.38-
62.9 MHz, CDCl
3
) δ 186.1 (Cquat), 175.8 (Cquat), 136.4 (Cquat),
34.2 (Cquat), 131.8 (Cquat), 128.9 (CH), 128.4 (CH), 126.5 (CH),
26.2 (CH), 125.9 (CH), 125.5 (CH), 125.3 (CH), 65.9 (CH), 54.7
quat), 48.2 (Cquat), 44.1 (CH), 37.0 (CH ), 32.3 (CH ), 27.6
); MS m/z 335 (MH ),
1
3
1
1
1.14 (m, 2 H), 1.01 (s, 3 H), 0.89 (s, 3 H), 0.49 (s, 3 H);
NMR (100.6 MHz, CDCl
(Cquat), 131.4 (Cquat), 128.1 (2 CH), 113.7 (2 CH), 67.8 (CH),
55.2 (CH ), 54.7 (Cquat), 47.9 (Cquat), 43.7 (CH), 36.2 (CH ), 31.6
(CH ), 27.1 (CH ), 19.3 (CH ), 18.8 (CH ), 11.4 (CH ).
C
3
) δ 184.8 (Cquat), 176.0 (Cquat), 158.6
(C
2
2
+
(CH
2
), 19.4 (CH
3
), 19.3 (CH
3
), 11.8 (CH
3
3
2
+
3
9
34 (M ), 291, 262, 234, 222, 206, 185, 168, 156, 141, 129, 109,
5, 81, 69, 55, 41; HRMS calcd for C22
2
2
3
3
3
+
H
26
N
2
O (M ) 334.20451,
Tr im eth ylcyclopen t-3-en yl)eth an am ide (R-Cam ph olen -
found 334.20420. Anal. Calcd for C22
H
26
N
2
O: C, 79.01; H, 7.84;
31,32
ic Am id e) (13)
a n d 1,8,8-Tr im eth yl-2-a za bicyclo[3.2.1]-
N, 8.38. Found: C, 78.64; H, 7.80; N, 8.40.
2R)-2-(4-Ch lor op h en yl)-2-{[(1R,4S)-1,7,7-t r im et h yl-
bicyclo[2.2.1]h ep t-2-ylid en ]a m in o}eth a n a m id e (11a ) a n d
2S)-2-(4-Ch lor oph en yl)-2-{[(1R,4S)-1,7,7-tr im eth ylbicyclo-
31,33
octa n -3-on e (14).
Rea ction betw een 4-n itr op h en yla c-
(
eton itr ile a n d (+)-ca m p h or yloxa zir id in e 1: 4-Nitrophenyl-
acetonitrile (245 mg, 1.513 mmol) was treated with 1 according
to procedure B and the reaction mixture was stirred for 4 h at
(
7
794 J . Org. Chem., Vol. 67, No. 22, 2002

Electrophilic Amination of Various Carbon Nucleophiles
room temperature until complete disappearance of the cam-
phoryloxaziridine was observed by TLC analysis. 2-(2,2,3-
Trimethylcyclopent-3-enyl)ethanamide (R-campholenic amide)
B and the reaction mixture was stirred for 24.5 h. Upon
purification, (Z)-2-{[(1R,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-
2-yliden]amino}but-2-enamide (16) was isolated as pale yellow
crystals (157 mg, 45%). The Z configuration of the double bond
of the lateral chain was proved by single-crystal X-ray diffrac-
tion.
(13) was isolated as a colorless solid (52 mg, 21%).
Rea ction betw een p r op ion itr ile a n d (+)-ca m p h or yl-
oxa zir id in e 1: Propionitrile (83.3 mg, 108 µL, 1.513 mmol)
was treated with 1 according to procedure B and the reaction
mixture was stirred for 2 h at room temperature until complete
disappearance of the camphoryloxaziridine was observed by
TLC analysis. 2-(2,2,3-Trimethylcyclopent-3-enyl)ethanamide
16: mp 115.5-116.5 °C; IR νmax (neat)/cm- 3466, 3315,
1
1
2957, 1676, 1630; H NMR (400 MHz, CDCl
3
) δ 6.19 (br s, 1H),
6.14 (q, J ) 7.2 Hz, 1 H), 6.04 (br s, 1 H), 2.27-2.16 (m, 1 H),
1.97 (t, J ) 4.0 Hz, 1 H), 1.94-1.78 (m, 2 H), 1.74 (d, J ) 18.0
Hz, 1 H), 1.56 (d, J ) 7.2 Hz, 3 H), 1.48-1.36 (m, 1 H), 1.29-
(13) was isolated as a colorless solid (91 mg, 36%).
1
3
Rea ction betw een bu tyr on itr ile a n d (+)-ca m p h or yl-
1.18 (m, 1 H), 1.07 (s, 3 H), 0.97 (s, 3 H), 0.81 (s, 3 H);
NMR (100.6 MHz, CDCl ) δ 189.0 (Cquat), 167.1 (Cquat), 141.7
(Cquat), 116.6 (CH), 54.8 (Cquat), 47.6 (Cquat), 43.7 (CH), 38.1
C
oxa zir id in e 1: Butyronitrile (104.6 mg, 132 µL, 1.513 mmol)
was treated with 1 according to procedure B and the reaction
mixture was stirred for 4 h at room temperature until complete
disappearance of the camphoryloxaziridine was observed by
TLC analysis. 2-(2,2,3-Trimethylcyclopent-3-enyl)ethanamide
3
(CH
(CH
2
), 32.5 (CH
), 11.1 (CH
2
), 27.2 (CH
); MS m/z 234 (M ), 219, 206, 189, 174, 152,
2 3 3
), 19.9 (CH ), 19.0 (CH ), 12.5
+
3
3
146, 135, 124, 108, 93, 81, 77, 67, 59, 55, 41; HRMS calcd for
+
(
13) was first eluted as a colorless solid (210 mg, 83%) followed
by 1,8,8-trimethyl-2-azabicyclo[3.2.1]octan-3-one (14, 43 mg,
7%).
C
18
H
24
N
2
O (M ) 234.17321, found 234.17307.
2-{[(1R,4S)-1,7,7-Tr im eth ylbicyclo[2.2.1]h ep t-2-ylid en ]-
1
a m in o}eth a n a m id e (17a ) a n d 1-Am in o-2-{[(1R,4S)-1,7,7-
t r im et h ylb icyclo[2.2.1]h ep t -2-ylid en ]a m in o}et h -1-en -1-
ol (17b ). Ethyl cyanoacetate (161 µL, 171 mg, 1.51 mmol)
was treated with 1 according to procedure B and the re-
action mixture was stirred for 2.5 h. Upon purification, 2-
{[(1R,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yliden]amino}-
ethanamide (17a ) and 1-amino-2-{[(1R,4S)-1,7,7-trimethylbi-
cyclo[2.2.1]hept-2-yliden]amino}eth-1-en-1-ol (17b) were iso-
lated as an inseparable mixture of isomers (35 mg, 11%).
2
9,30
30a
1
3:
colorless crystals, mp 130 °C (lit. mp 127-128 °C;
29
3
0b
-1
lit. mp 124 °C; lit. mp 130.5-131 °C); IR νmax (neat)/cm
1
3
(
373, 3196, 1662, and 1628; H NMR (250 MHz, CDCl
br s, 1 H), 5.78 (br s, 1 H), 5.23 (br s, 1 H), 2.44-2.07 (m, 4
H), 1.97-1.86 (m, 1 H), 1.61 (q, J ) 1.5 Hz, 3 H), 1.01 (s, 3 H),
3
) δ 6.20
1
3
0
1
3
(
(
.78 (s, 3 H); C NMR (100.6 MHz, CDCl
48.0 (Cquat), 121.7 (CH), 47.0 (Cquat), 46.8 (CH), 37.0 (CH
5.3 (CH ), 25.5 (CH ), 19.9 (CH ), 12.6 (CH ); MS m/z 167
3
) δ 176.2 (Cquat),
2
),
2
3
3
3
+
M ), 152, 134, 108, 93, 79, 67, 41; HRMS calcd for C10
M ) 167.13101, found 167.13112.
H
17NO
17a /17b : colorless solid, mp 159-166 °C; IR ν
max
(neat)/
+
-1
1
cm 3627, 3418, 1668, 1652, 1645, 1634; H NMR (400 MHz,
CDCl ) δ 7.65 (br s, 1 H ), 5.56 (br s, 1 H ), 4.96 (s, 1 H ),
), 2.31-2.21 (m, 1 H ), 2.13 (d, J ) 16.9
), 1.95 (t, J ) 4.3 Hz, 1 HA+B), 1.90-1.78 (m, 1 HA+B
), 1.75-1.61 (m, 1 HA+B), 1.45-1.12 (m, 2 HA+B, 2 H
2
9,31
1
4:
colorless crystals (ethyl acetate, light petroleum); mp
3
A
A
B
2
9
31a
-1
1
1
1
84-187 °C (lit. mp 197-198 °C in a sealed tube; lit. mp
2.75-2.65 (m, 1 H
B
A
3
1b,c
56-160 °C; lit.
mp 133-136 °C); IR νmax (neat)/cm 3318,
Hz, 1 H
and 1 H
A
1
652; H NMR (250 MHz, CDCl ) δ 6.59 (br s, 1 H), 2.60 (ddd,
3
B
A
,
J ) 18.0, 4.5, 2.6 Hz, 1 H), 2.17 (dd, J ) 18.0, 1.6 Hz, 1 H),
3 H
B
), 1.00 (s, 3 H), 0.98 (s, 3 H), 0.93 (s, 3 H), 0.92 (s, 3 H),
1
3
2
3
6
.10-1.89 (m, 4 H), 1.56-1.45 (m, 1 H), 1.13 (s, 3 H), 1.02 (s,
H), 0.97 (s, 3 H); 13C NMR (100.6 MHz, CDCl
) δ 172.8 (Cquat),
3.6 (Cquat), 43.4 (Cquat), 42.9 (CH), 40.1 (CH ), 39.5 (CH ), 27.8
); HRMS calcd for
17NO (M ) 167.13101, found 167.13087.
0.82 (s, 3 H), 0.75 (s, 3 H); C NMR (100.6 MHz, CDCl ) δ
3
3
197.5 (Cquat), 186.7 (Cquat), 186.6 (Cquat), 173.5 (Cquat), 78.3 (CH),
54.5 (2 Cquat), 47.5 (Cquat), 47.1 (Cquat), 44.04 (CH), 43.96 (CH),
2
2
(CH
2
), 23.4 (CH
3
), 18.3 (CH
3
), 18.0 (CH
3
37.0 (CH
2
), 36.4 (CH
), 27.2 (CH ), 19.6 (CH
), 11.5 (CH ), 11.4 (CH
3
2
), 32.1 (CH
), 19.5 (CH
); MS m/z 208 (M ), 207, 191, 162,
2
), 32.0 (CH
2
), 29.7 (CH
2
), 27.6
+
C
10
H
(CH
(CH
2
2
3
3
), 19.01 (CH
3
), 18.96
+
(
2R)-2-Cya n o-2-{[(1R,4S)-1,7,7-tr im eth ylbicyclo[2.2.1]-
3
3
h ep t-2-ylid en ]a m in o}eth a n a m id e (15a ) a n d (2S)-2-Cy-
an o-2-{[(1R,4S)-1,7,7-tr im eth ylbicyclo[2.2.1]h ept-2-yliden ]-
a m in o}eth a n a m id e (15b). Malonitrile (94 µL, 99 mg, 1.50
mmol) was treated with 1 according to procedure B and the
reaction mixture was stirred for 4 h. Upon purification, (2R)-
152, 136, 123, 108, 95, 81, 69, 55, 41; HRMS calcd for
+
C
12
H
20
N
2
O (M ) 208.15756, found 208.15709.
(R)-1-P h en yl-1-{[(1R,4S)-1,7,7-tr im eth ylbicyclo[2.2.1]-
h ep t-2-ylid en ]a m in o}m eth yl Cya n id e (18a ) a n d (S)-1-
P h en yl-1-{[(1R,4S)-1,7,7-t r im et h ylb icyclo[2.2.1]h ep t -2-
ylid en ]a m in o}m eth yl Cya n id e (18b). Ethyl phenylcyano-
acetate (260 µL, 284 mg, 1.50 mmol) was treated with 1
according to procedure B and the reaction mixture was stirred
for 29 h. Upon purification, (R)-1-phenyl-1-{[(1R,4S)-1,7,7-
trimethylbicyclo[2.2.1]hept-2-yliden]amino}methyl cyanide (18a)
and (S)-1-phenyl-1-{[(1R,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-
2-yliden]amino}methyl cyanide (18b) were isolated as an
inseparable mixture of diastereoisomers in a 1:1 ratio (271 mg,
68%). The starting material, ethyl phenylcyanoacetate (64 mg,
0.338 mmol), and a mixture of the diastereoisomers (2R)-2-
phenyl-2-{[(1R,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yliden]-
amino}ethanamide (8a ) and (2S)-2-phenyl-2-{[(1R,4S)-1,7,7-
trimethylbicyclo[2.2.1]hept-2-yliden]amino}ethanamide (8b, 38
mg, 0.134 mmol) were also isolated in 23% and 9% yields,
respectively.
2
-cyano-2-{[(1R,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yliden]-
amino}ethanamide (15a ) and (2S)-2-cyano-2-{[(1R,4S)-1,7,7-
trimethylbicyclo[2.2.1]hept-2-yliden]amino}ethanamide (15b)
were isolated by column chromatography on silica gel as an
oily mixture of inseparable diastereoisomers in a 1:1 ratio (288
mg, 82%).
1
5a /15b : colorless solid, mp 139-140 °C; IR νmax (neat)/
-
1
1
cm 3413, 3165, 2254, 1704, 1675; H NMR (250 MHz, CDCl
δ 7.50 (br s, 1 HA+B), 6.11 (br s, 1 HA+B), 4.65 (s, 1 H ), 4.64 (s,
), 2.17 (d, J )
), 2.10 (t, J ) 4.3 Hz, 1 HA+B), 1.99-1.85 (m, 1
), 1.84-1.70 (m, 1 HA+B), 1.47-1.21 (m, 2 HA+B),
.01 (s, 3 HA+B), 0.98 (s, 3 HA+B), 0.82 (s, 3 H ), 0.74 (s, 3 H );
) δ 193.5 (Cquat), 193.1 (Cquat), 167.2
2 Cquat), 115.1 (Cquat), 114.6 (Cquat), 55.7 (Cquat), 55.6 (Cquat),
3.8 (CH), 53.7 (CH), 48.8 (Cquat), 47.6 (Cquat), 44.0 (2 CH), 37.1
3
)
A
1
1
H
H
B
), 2.82-2.70 (m, 1 H
A
), 2.47-2.36 (m, 1 H
B
8.0 Hz, 1 H
A+B and 1 H
A
B
1
A
B
1
3
C NMR (62.9 MHz, CDCl
3
(
5
18a /18b: colorless oil; IR νmax (neat)/cm- 2239, 1674; H
1
1
(
(
(
CH
CH
CH
2
3
3
), 36.5 (CH
), 19.5 (CH
); MS m/z 234 (MH ), 233 (M ), 218, 207, 189, 175, 162,
2
), 31.9 (CH
2
), 31.4 (CH
2
), 27.1 (2 CH
2
), 19.6
), 11.0
NMR (250 MHz, CDCl ) δ 7.49-7.31 (m, 10 H), 5.29 (s, 1 H ),
5.28 (s, 1 H ), 2.69-2.59 (m, 1 H ), 2.41-2.32 (m, 1 H ), 2.13-
3
A
3
), 19.0 (CH
3
), 18.9 (CH
3
), 11.2 (CH
3
B
A
B
+
+
1.98 (m, 1 HA and 1 H ), 1.94-1.64 (m, 1 H
B
A+B
, 1 H and 2
A
1
C
C
50, 133, 121, 108, 95, 77, 69, 55, 41; HRMS calcd for
H ), 1.53-1.40 (m, 1 H ), 1.40-1.08 (m, 1 H
and 1 H ),
B
A
A+B
B
+
13
H
H
19
N
N
3
O (M ) 233.15281, found 233.15326. Anal. Calcd for
O: C, 66.92; H, 8.21; N, 18.01. Found: C, 66.91; H,
1.04 (s, 3 H), 1.02 (s, 3 H), 0.96 (s, 3 H), 0.94 (s, 3 H), 0.93-
1
3
13
19
3
0.88 (m, 1 H ), 0.83 (s, 3 H), 0.66 (s, 3 H); C NMR (100.6
A
8
.13; N, 17.82.
Z)-2-{[(1R ,4S )-1,7,7-Tr im e t h ylb icyclo[2.2.1]h e p t -2-
ylid en ]a m in o}bu t-2-en a m id e (16). Allyl cyanide (121 µL,
01 mg, 1.50 mmol) was treated with 1 according to procedure
MHz, CDCl ) δ 189.6 (Cquat), 189.2 (Cquat), 135.8 (2 Cquat), 129.0
3
(
(2 CH), 128.9 (2 CH), 128.6 (2 CH), 127.2 (2 CH), 127.1 (2 CH),
118.8 (Cquat), 118.5 (Cquat), 55.1 (Cquat), 55.0 (Cquat), 54.8 (CH),
1
54.6 (CH), 47.9 (Cquat), 47.4 (Cquat), 44.0 (2 CH), 36.3 (CH
2
),
J . Org. Chem, Vol. 67, No. 22, 2002 7795

Bulman Page et al.
+
3
6.1 (CH
2
), 31.9 (CH
), 19.49 (CH ), 19.0 (CH
); MS m/z 267 (MH ), 266 (M ), 240, 209, 150, 123, 117,
2
), 31.6 (CH
2
), 27.3 (CH
2
), 27.2 (CH
2
), 19.54
), 11.15
(CH
184, 156, 141, 129, 107; HRMS calcd for C22
335.21234, found 335.21228. Anal. Calcd for C22
3 3
), 18.0 (CH ); MS m/z 335 (MH ), 291, 290, 246, 208, 185,
+
(
(
CH
CH
3
3
3
), 18.9 (CH
3
), 11.19 (CH
3
H
27
N
H
2
O (MH )
O: C,
+
+
3
26
N
2
+
1
2
09, 91, 89, 81, 77, 67, 55, 41; HRMS calcd for C18
66.17830, found 266.17851.
(
H
22
N
2
(M )
79.01; H, 7.84; N, 8.38. Found: C, 78.37; H, 7.76; N, 8.22.
2R )-2-N a p h t h a le n -1-y l-2-{[(1R ,4S )-1,3,3-t r im e t h -
ylbicyclo[2.2.1]h ept-2-yliden ]am in o}eth an am ide an d (2S)-
-Naph th alen -1-yl-2-{[(1R,4S)-1,3,3-tr im eth ylbicyclo[2.2.1]-
h ep t-2-ylid en ]a m in o}eth a n a m id e (21a /21b). 1-Naphthy-
lacetonitrile (253 mg, 1.513 mmol) was treated with 2 according
to procedure B and the reaction mixture was stirred for 2 h.
Upon purification, (2R)-2-naphthalen-1-yl-2-{[(1R,4S)-1,3,3-
trimethylbicyclo[2.2.1]hept-2-yliden]amino}ethanamide and
(
2R)-2-P h en yl-2-{[(1R,4S)-1,3,3-tr im eth ylbicyclo[2.2.1]-
h ep t -2-ylid en ]a m in o}et h a n a m id e a n d (2S)-2-P h en yl-2-
[(1R ,4S )-1,3,3-t r im e t h ylb icyclo[2.2.1]h e p t -2-ylid e n ]-
2
{
a m in o}eth a n a m id e (19a /19b). Benzyl cyanide (174 µL, 176
mg, 1.50 mmol) was treated with 2 according to procedure B
and the reaction mixture was stirred for 3 h. Upon purification,
(2R)-2-phenyl-2-{[(1R,4S)-1,3,3-trimethylbicyclo[2.2.1]hept-2-
yliden]amino}ethanamide and (2S)-2-phenyl-2-{[(1R,4S)-1,3,3-
trimethylbicyclo[2.2.1]hept-2-yliden]amino}ethanamide (19a /
1
first diastereoisomer eluted was the major one and could be
purified by recrystallization, allowing the assignment of the
NMR spectra for both diastereoisomers.
(
2S)-2-naphthalen-1-yl-2-{[(1R,4S)-1,3,3-trimethylbicyclo[2.2.1]-
hept-2-yliden]amino}ethanamide (21a /21b) were isolated as
an inseparable mixture (218 mg, 48%) of 33% de.
9b, 234 mg, 55%) were isolated as a mixture of 50% de. The
2
1a /21b: pale yellow solid, mp 136-140 °C; IR νmax (neat)/
-1
1
cm 3433, 1690; H NMR (400 MHz, CDCl
.4 Hz, 1 H ), 8.58 (d, J ) 8.4 Hz, 1 H ), 7.84 (d, J ) 7.9, 1
A+B), 7.75 (d, J ) 7.7, 2 HA+B), 7.61-7.57 (m, 1 HA+B), 7.50-
.41 (m, 2 HA+B), 7.28 (br s, 1 H ), 7.03 (br s, 1 H ), 6.20 (s, 1
), 6.11 (s, 1 H ), 5.98 (br s, 1 H ), 5.94 (br s, 1 H ), 1.82-
.76 (m, 2 HA+B), 1.57-1.51 (m, 2 HA+B), 1.45-1.42 (m, 1 HA+B),
.36 (s, 3 HA+B), 1.35 (s, 3 H ), 1.34 (s, 3 H ), 1.29-1.25 (m, 1
), 0.77 (s, 3 H
) δ 187.3 (Cquat), 187.0 (Cquat), 175.7
3
) δ 8.62 (d, J )
8
A
B
Mixture of 19a /19b: colorless solid, mp 162-170 °C; IR νmax
H
-
1
+
(neat)/cm 3431, 3284, 1693; MS m/z 285 (MH ), 240, 152,
7
A
B
+
1
2
34, 106; HRMS calcd for C18
85.19755.
25 2
H N O (MH ) 285.19725, found
H
B
A
B
A
1
1
1
9a : major diastereoisomer; colorless crystals, mp 170-178
A
B
1
°
C; H NMR (250 MHz, CDCl
3
) δ 7.52-7.47 (m, 2 H), 7.34-
.23 (m, 3 H), 7.18 (br s, 1 H), 5.78 (br s, 1 H), 5.32 (s, 1 H),
.84 (br s, 1 H), 1.78-1.53 (m, 5 H), 1.43 (dd, J ) 10.4, 1.6 Hz,
13
H
A+B), 1.19-1.16 (m, 1 HA+B), 0.80 (s, 3 H
A
B
); C
7
1
1
NMR (100.6 MHz, CDCl
3
(C
quat), 175.4 (Cquat), 137.8 (Cquat), 137.7 (Cquat), 134.39 (Cquat),
34.35 (Cquat), 131.5 (Cquat), 131.4 (Cquat), 129.0 (CH), 128.9
CH), 128.33 (CH), 128.25 (CH), 126.7 (CH), 126.6 (CH), 125.9
CH), 125.8 (CH), 125.7 (CH), 125.6 (CH), 125.2 (CH), 125.1
CH), 125.0 (CH), 124.5 (CH), 63.34 (CH), 63.27 (CH), 53.8
1
3
H), 1.30 (s, 3 H), 1.25 (s, 3 H), 1.00 (s, 3 H); C NMR (100.6
) δ 187.2 (Cquat), 175.9 (Cquat), 140.7 (Cquat), 129.1
CH), 128.7 (CH), 127.7 (CH), 127.0 (CH), 126.9 (CH), 67.2
CH), 53.5 (Cquat), 50.1 (CH), 44.9 (Cquat), 42.5 (CH ), 34.0 (CH ),
). Anal. Calcd
1
MHz, CDCl
(
(
3
(
(
(
(
(
(
(
2
2
2
5.43 (CH
for C18
H, 8.51; N, 9.83.
2
), 25.41 (CH
3
3 3
), 24.6 (CH ), 17.9 (CH
C
C
CH
CH
quat), 53.6 (Cquat), 50.2 (CH), 50.1 (CH), 44.93 (Cquat), 44.85
24 2
H N O: C, 76.02; H, 8.51; N, 9.85. Found: C, 76.00;
quat), 42.53 (CH
2
), 42.46 (CH
2
), 34.0 (CH
2
), 33.8 (CH
), 24.0 (2 CH
2
), 25.7
), 18.2
2
), 25.5 (CH
), 18.0 (CH
3
), 25.4 (CH ), 25.1 (CH
2
3
3
1
1
9b: minor diastereoisomer; H NMR (250 MHz, CDCl
3
) δ
+
3
3
); MS m/z 334 (M ), 185, 156, 141, 129, 115,
7
.55-7.50 (m, 2 H), 7.34-7.23 (m, 3 H), 6.96 (br s, 1 H), 5.78
+
9
1, 84, 69, 47; HRMS calcd for C22
found 334.20466.
2R)-2-Cya n o-2-{[(1R,4S)-1,3,3-tr im eth ylbicyclo[2.2.1]-
h ep t -2-ylid en ]a m in o}et h a n a m id e a n d (2S)-2-Cya n o-2-
[(1R ,4S )-1,3,3-t r im e t h ylb icyclo[2.2.1]h e p t -2-ylid e n ]-
a m in o}eth a n a m id e (22a /22b). Malonitrile (94 µL, 99 mg,
.50 mmol) was treated with 2 according to procedure B and
the reaction mixture was stirred for 5 h. Upon purification,
2R)-2-cyano-2-{[(1R,4S)-1,3,3-trimethylbicyclo[2.2.1]hept-2-
yliden]amino}ethanamide and (2S)-2-cyano-2-{[(1R,4S)-1,3,3-
trimethylbicyclo[2.2.1]hept-2-yliden]amino}ethanamide (22a /
2b) were isolated by column chromatography on silica gel as
an inseparable oily mixture of diastereoisomers (200 mg, 57%)
of 23% de.
26 2
H N O (M ) 334.20451,
(br s, 1 H), 5.33 (s, 1 H), 1.79 (br s, 1 H), 1.78-1.53 (m, 5 H),
1
1
1
.43-1.38 (m, 1 H), 1.31 (s, 3 H), 1.29 (s, 3 H), 0.96 (s, 3 H);
3C NMR (100.6 MHz, CDCl ) δ 187.4 (Cquat), 175.6 (Cquat),
40.9 (Cquat), 128.73 (CH), 128.67 (CH), 127.8 (CH), 126.9 (2
),
(
3
{
CH), 67.3 (CH), 53.7 (Cquat), 50.0 (CH), 45.0 (Cquat), 42.6 (CH
3.9 (CH ), 25.7 (CH ), 25.4 (CH ), 24.6 (CH ), 18.2 (CH ).
2R )-2-N a p h t h a le n -2-y l-2-{[(1R ,4S )-1,3,3-t r im e t h -
ylbicyclo[2.2.1]h ept-2-yliden ]am in o}eth an am ide an d (2S)-
-Naph th alen -2-yl-2-{[(1R,4S)-1,3,3-tr im eth ylbicyclo[2.2.1]-
2
3
2
2
3
3
3
1
(
(
2
h ep t-2-ylid en ]a m in o} eth a n a m id e (20a /20b). 2-Naphthy-
lacetonitrile (253 mg, 1.513 mmol) was treated with 2 according
to procedure B and the reaction mixture was stirred for 7 h.
Upon purification, (2R)-2-naphthalen-2-yl-2-{[(1R,4S)-1,3,3-
trimethylbicyclo[2.2.1]hept-2-yliden]amino}ethanamide and
2
2
2a /22b : colorless solid, mp 130-131 °C; IR νmax (neat)/
(2S)-2-naphthalen-2-yl-2-{[(1R,4S)-1,3,3-trimethylbicyclo[2.2.1]-
-
1
1
3
cm 3432, 3239, 2257, 1712, 1671; H NMR (400 MHz, CDCl )
hept-2-yliden]amino}ethanamide (20a /20b) were isolated as
an inseparable mixture (141 mg, 31%) of 52% de.
δ 7.16 (br s, 1 H
s, 1 H ), 5.14 (s, 1 H
s, 1 H ), 1.84-1.41 (m, 6 H
A
), 6.96 (br s, 1 H
B
), 6.73 (br s, 1 H
), 2.02 (br s, 1 H
), 1.36 (s, 3 H ), 1.29 (s, 3 H ),
B
), 6.70 (br
A
B
), 5.08 (s, 1 H
A
B
), 1.93 (br
2
0a /20b: pale yellow solid, mp 175-182 °C; IR νmax (neat)/
-
1
1
cm 3433, 1690; H NMR (400 MHz, CDCl
7
7
3
) δ 7.97 (s, 1 H
), 7.83-7.79 (m, 3 HA+B), 7.73-7.67 (m, 1 HA+B),
.48-7.41 (m, 2 HA+B), 7.26 (br s, 1 H ), 7.03 (br s, 1 H ), 6.01
), 5.48 (s, 1 H ), 1.95-1.75 (m, 2
A+B), 1.68-1.51 (m, 3 HA+B), 1.47-1.40 (m, 1 HA+B), 1.35 (s,
), 1.34 (s, 3 HA+B), 1.29 (s, 3 H ), 1.27-1.16 (m, 1 HA+B),
); C NMR (100.6 MHz, CDCl ) δ
A
),
A
A+B
A
B
3
1
1
.24 (s, 3 H
B
), 1.20 (s, 3 H
A
), 1.19 (s, 3 H
A
), 1.09 (s, 3 H
B
);
C
.92 (s, 1 H
B
NMR (100.6 MHz, CDCl
3
) δ 195.8 (Cquat), 195.7 (Cquat), 167.4
quat), 167.2 (Cquat), 116.4 (Cquat), 116.0 (Cquat), 54.52 (Cquat),
4.50 (Cquat), 54.3 (2 CH), 50.2 (CH), 50.1 (CH), 45.9 (Cquat),
5.8 (Cquat), 42.5 (CH ), 42.4 (CH ), 33.9 (CH ), 33.8 (CH ),
A
B
(C
(br s, 1 HA+B), 5.51 (s, 1 H
A
B
5
4
H
3
1
1
H
A
B
2
2
2
2
1
3
25.42 (CH ), 25.38 (CH ), 24.6 (CH ), 24.5 (2 CH ), 24.1 (CH ),
.01 (s, 3 H
B
), 0.97 (s, 3 H
A
3
2
2
3
3
3
+
1
1
7.7 (CH
3
3
), 17.4 (CH ); MS m/z 234 (MH ), 207, 189, 176, 154,
87.8 (Cquat), 187.6 (Cquat), 175.8 (Cquat), 175.5 (Cquat), 138.4
quat), 138.2 (Cquat), 133.72 (Cquat), 133.70 (Cquat), 133.34 (Cquat),
33.28 (Cquat), 128.48 (CH), 128.46 (CH), 128.43 (CH), 128.36
+
36, 123, 107; HRMS calcd for C13
20 3
H N O (MH ) 234.16064,
(C
found 234.16061.
1
(CH), 128.0 (2 CH), 126.30 (CH), 126.29 (CH), 126.13 (2 CH),
1
5
4
25.9 (CH), 125.7 (CH), 125.2 (2 CH), 67.4 (CH), 67.3 (CH),
3.8 (Cquat), 53.6 (Cquat), 50.1 (CH), 50.0 (CH), 45.0 (2 Cquat),
Ack n ow led gm en t. This investigation has enjoyed
the support of the EPSRC.
2.7 (CH
2
), 42.5 (CH
2
), 34.1 (CH
2
), 33.9 (CH
2
), 25.7 (CH
), 24.6 (CH
2
), 25.5
), 18.3
(CH
3
), 25.42 (CH
2
), 25.36 (CH
3
), 24.7 (CH
3
3
J O020306J
7
796 J . Org. Chem., Vol. 67, No. 22, 2002