The first stable enantiomerically chiral pure N-H oxaziridines: Synthesis and reactivity

Full text of DOI:10.1021/jo000176j

4204
J . Org. Chem. 2000, 65, 4204-4207
only one report of a chiral enantiomerically pure N-
Th e F ir st Sta ble En a n tiom er ica lly P u r e
5
acyloxaziridine.4 Most N-acyl- and N-alkoxycarbonyl-
Ch ir a l N-H Oxa zir id in es: Syn th esis a n d
oxaziridines have been prepared by oxidation of N-pro-
tected imines of benzaldehydes.6 N-Sulfonyl-7 and N-phos-
phinoyloxaziridines,8 useful oxygen transfer agents, are
prepared in the same way. This method is efficient for
the oxidation of N-sulfonylimines, which are commonly
easily prepared and stable, but is less satisfactory for the
oxidation of N-phosphinoylimines, which are more prone
to hydrolysis. N-Acylimines are even less stable and are
commonly only available when prepared from a ketone
that is nonenolizable and contains R-electron-withdraw-
ing groups.9
Rea ctivity
Philip C. Bulman Page,* Victor L. Murrell,
Corinne Limousin, David D. P. Laffan,† Donald Bethell,‡
Alexandra M. Z. Slawin, and Timothy A. D. Smith
Department of Chemistry, Loughborough University,
Loughborough, Leicestershire, LE11 3TU, England,
Astra Zeneca Pharmaceuticals, Silk Road Business Park,
Macclesfield, Cheshire, SK10 2NA, U.K., Robert Robinson
Laboratories, Department of Chemistry, University of
Liverpool, Oxford Street, Liverpool L69 3BX, U.K.
Derivatization at the nitrogen atom of an oxaziridine,
as opposed to oxidation of the derivatized imine, could
therefore provide a useful alternative method of prepara-
tion of N-functionalized oxaziridines, if the corresponding
N-H oxaziridines can themselves be readily prepared.
Indeed, some examples of acyl derivatives have been
prepared in situ by use of solutions of unstable N-H
oxaziridines.4,10
Received February 8, 2000
N-H oxaziridines, first reported in the early 1960s,
induce amination of nitrogen, oxygen, sulfur and carbon
nucleophiles,1 including aziridination of alkenes and
amination of enolates. To date, of the very few N-H
oxaziridines that are known, no chiral nonracemic N-H
oxaziridine has been isolated. We report here the prepa-
ration of the first stable enantiomerically pure chiral
N-H oxaziridines 1 and 2 together with a brief survey
of their derivatization and chemical reactivity. Also
reported is the first example of an N-sulfenyloxaziridine,
the first enantiomerically pure chiral N-alkoxycarbonyl-
oxaziridine, and the first enantiomerically pure N-
phosphinoyloxaziridine chirally functionalized at carbon.
Due to their instability, N-H oxaziridines must gener-
ally be prepared and used in dilute solution. The only
one that has been isolated as a stable compound in pure
form is compound 3,2 and the chemical reactivity of only
one has been thoroughly investigated (compound 4).1
Their instability no doubt accounts for the dearth of
knowledge and awareness of N-H oxaziridines. Never-
theless, this functional group appears to offer an intrigu-
ing alternative potential solution to the problem of
asymmetric electrophilic nitrogen transfer, usually ac-
complished by use of chiral auxiliary chemistry.3 For this
reason we turned our attention to the synthesis and
chemistry of chiral, nonracemic N-H oxaziridines 1 and
2, derived from camphor and fenchone, respectively.
N-H oxaziridines have been prepared from ketones
by treatment with hydroxylamine-O-sulfonic acid or
precursors of chloramine.1 Neither of these two tech-
niques proved successful for camphor or fenchone, pos-
sibly due to the steric hindrance about the ketone moiety.
We therefore sought an alternative and selected oxidation
of the primary (N-H) imine with peracid, a method used
in the preparation of N-H oxaziridines 3 and 5, derived
respectively from di-tert-butyl ketone and benzophenone.6
Preparation of primary imines by simple condensation
of ammonia with ketones is problematic, as primary
imines are commonly unstable above room temperature.
Sealed tube methods have been used,11 but they are
unreliable. The primary imines 6 and 7, derived from
camphor and fenchone, respectively, are, however, both
stable up to ca. 30 °C and were prepared via the
nitrimines 8 and 9.12 Nitrosation/rearrangement of the
corresponding oximes 10 and 11 followed by ammonolysis
of the resulting nitrimines in THF13 gave the primary
imines in quantitative yields. Oxidation of each imine
with 1 equiv of m-CPBA at -30 to -40 °C in dichloro-
methane took place to give the N-H oxaziridines 1 and
(4) Shustov, G. V.; Kadorkina, G. K.; Varlamov, S. V.; Kachanov,
A. V.; Kostyanovsky, R. G.; Rauk, A. J . Am. Chem. Soc. 1992, 114,
1616.
(5) Schmitz, E.; Schramm, S. Chem. Ber. 1967, 100, 2593.
(6) Vidal, J .; Damestoy, S.; Guy, L.; Hannachi, J .-C.; Aubry, A.;
Collet, A. Chem.: A Eur. J . 1997, 1691, and references contained
therein.
(7) Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45, 5703. Davis,
F. A.; Chen, B. C. Chem. Rev. 1992, 92, 919. Page, P. C. B.; Heer, J .
P.; Bethell, D.; Collington, E. W.; Andrews, D. M. Tetrahedron:
Asymmetry 1995, 6, 2911.
N-Acyl- and N-alkoxycarbonyloxaziridines have been
shown to transfer their nitrogen moiety to a number of
sulfur, nitrogen, phosphorus, and carbon nucleophiles
and tend to be more stable. There has, however, been
† Astra Zeneca Pharmaceuticals.
(8) J ennings, W. B.; Kochanewycz, M. J .; Lovely, C. J .; Boyd, D. R.
J . Chem. Soc., Chem. Commun. 1994, 2569.
‡ University of Liverpool.
(1) Schmitz, E.; Andreae, S. Synthesis 1991, 327, and references
therein.
(2) Hudson, R. F.; Lawson, A. J .; Record, K. A. F. J . Chem. Soc.,
Chem. Commun. 1975, 322.
(9) Lasne, M.-C.; Ripoll, J .-L.; Thuillier, A. J . Chem. Res., Synop.
1982, 214.
(10) Niederer, D. A.; Kapron, J . T.; Vederas, J . C. Tetrahedron Lett.
1993, 6859.
(3) Evans, D. A.; Britton, T. C.; Ellman, J . A.; Dorow, R. L. J . Am.
Chem. Soc. 1990, 112, 4011. Evans, D. A.; Britton, T. C. J . Am. Chem.
Soc. 1987, 109, 6881. Page, P. C. B.; Allin, S. M.; Collington, E. W.;
Carr, R. A. E. Tetrahedron Lett., 1994, 35, 2427. Page, P. C. B.;
McKenzie, M. J .; S. M.; Collington, E. W.; Carr, R. A. E. Tetrahedron
1995, 51, 1285.
(11) Rupe, H.; Tommasi di Vignano, A. Helv. Chim. Acta 1937, 20,
1078.
(12) Brooks, S. G.; Evans, R. M.; Green, G. F. H.; Hunt, J . S.; Long,
A. G.; Mooney, B.; Wyman, L. J . J . Chem. Soc. 1958, 4614. Bondavalli,
F.; Schienone, P.; Ranise, A. Synthesis 1979, 830.
(13) Guziec, F. S.; Russo, J . M. Synthesis 1984, 479.
10.1021/jo000176j CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/06/2000

Notes
J . Org. Chem., Vol. 65, No. 13, 2000 4205
Sch em e 1
line width and chemical shift, the N-H NMR signals of
1 (δ 4.97 and 4.83 at 25 °C) showed no significant change
in their appearance over the temperature range -70 to
+50 °C. The data suggest a Gibbs free energy of activa-
tion for nitrogen inversion of greater than 16 kcal mol-1
.
We reasoned that the identity of the isomers of 1 might
be proven by efficient derivatization at the nitrogen atom
(eq 1). Reactions of 1 with acetyl chloride, tosyl chloride,
2, in 94% and 86% yields respectively, on a 20 g scale
(Scheme 1).
These N-H oxaziridines are remarkably stable in their
pure form in comparison to their simpler analogues and
can be kept at 5 °C for at least 6 months without
decomposition. They are stable to silica gel chromatog-
raphy. The camphor-derived oxaziridine 1 is crystalline
and can be heated under reflux in THF solution for at
least 6 h without decomposition, although it is unstable
under reflux in toluene. In this context, it is interesting
to note that 1 has been implicated as a reactive inter-
mediate in the thermal rearrangement of camphor oxime.14
The fenchone-derived oxaziridine 2, an oily liquid, is
stable under reflux overnight in THF and toluene solu-
tions.
N-H oxaziridines 1 and 2 were each shown by 1H
NMR spectroscopy to consist of a pair of diastereoisomers
in a ratio of about 60:40. It is possible in principle to form
both endo and exo isomers of the oxaziridine ring,
depending upon the direction of attack of the oxidant.
An unusual feature of nitrogen-containing three-mem-
bered heterocycles is that there is a rather high barrier
to inversion at nitrogen.15 It is therefore possible that
oxidation of imines 6 and 7 could give rise to four
different diastereoisomers each. We believe, on the basis
of chemical derivatization coupled with NMR spectro-
scopic evidence, that the diastereoisomers observed in
this case arise from the two configurations at the nitrogen
atom, the result of endo delivery of the oxygen atom to
the camphor system to give 1, and exo delivery to the
fenchone system to give 2.
ethyl chloroformate, or diphenyl phosphinic chloride in
the absence of base gave none of the desired derivatized
oxaziridines. A new material, an oxidant capable of
oxidizing thioanisole, was isolated in low yields from all
of these reactions and was proven by single-crystal X-ray
crystallography to be the N-chlorooxaziridine 12, with the
oxygen atom of the oxaziridine moiety endo as expected
and the chlorine atom pointing away from the bridgehead
methyl group. Compound 12 was also formed in 31% yield
in a few seconds as a single diastereoisomer, together
with camphor in 35% yield, by treating 1 with anhydrous
hydrogen chloride in 1,4-dioxane at -40 °C. It is possible
that one molecule of the N-H oxaziridine (or N-proto-
nated oxaziridinium species) oxidizes the hydrogen chlo-
ride to an electrophilic chlorine species, which then
chlorinates another molecule of the oxaziridine, so ac-
counting for the approximately 1:1 mixture of camphor
to N-chlorooxaziridine in the product. Compound 12 was
indeed produced in 85% yield, again as a single diaste-
reoisomer, by treatment of 1 with the electrophilic
chlorine reagent tert-butyl hypochlorite in ether at -78
°C. The barrier to inversion at nitrogen in the related
spirocyclohexane N-chlorooxaziridine 13 is known to be
high from studies on the resolved material,21 suggesting
that the stereocontrol observed in the formation of 12 is
kinetically controlled.
Although there have been no reports of the barrier to
inversion of nitrogen atoms in N-H oxaziridines, studies
on the related N-alkyl/aryl-,1,16 N-acyl-,1,17 N-alkoxycar-
bonyl-,1 N-sulfonyl-,18 and N-phosphinoyloxaziridines19
show that the barrier to N-inversion appears to be
lowered in oxaziridines where the nitrogen atom is
conjugated with an electron-withdrawing subtituent, in
comparison to N-alkyloxaziridines.20 N-Alkyl and N-
chlorooxaziridines21 are, however, configurationally stable
at room temperature. Apart from some small changes in
Chiral N-sulfonyloxaziridines are useful asymmetric
oxidants, and a number have been prepared previously
by Davis, ourselves, and others.7 In each case, these
oxaziridines were prepared by oxidation of the corre-
sponding imines. We have been able to prepare the
known N-phenylsulfonyloxaziridine 14 as a single dias-
tereoisomer in 62% yield by treatment of 1 with benzene
sulfonyl chloride in the presence of DMAP in dichloro-
methane.22
(14) Suginome, H.; Furukawa, K.; Orito, K. J . Chem. Soc., Perkin
Trans. 1 1991, 917.
(15) Bottinim, A. T.; Roberts, J . D. J . Am. Chem. Soc. 1958, 80, 5203.
(16) Montanari, F.; Moretti, I.; Torre, G. J . Chem. Soc., Chem.
Commun. 1969, 1086. Ono, H.; Splitter, J . S.; Calvin, M. Tetrahedron
Lett. 1973, 4107. Bjorgo, J .; Boyd, D. R. J . Chem. Soc., Perkin Trans.
2 1973, 1575.
(17) J ennings, W. B.; Watson, S. P.; Boyd, D. R. J . Chem. Soc., Chem.
Commun. 1992, 1078.
(18) J ennings, W. B.; Watson, S. P.; Boyd, D. R. J . Chem. Soc., Chem.
Commun. 1988, 931.
(19) J ennings, W. B.; Watson, S. P.; Boyd, D. R. Tetrahedron Lett.
1989, 235.
(21) Shustov, G. V.; Varlamov, S. V.; Chervin, I. I.; Aliev, A. E.;
Kostyanovsky, R. G.; Kim, D.; Rauk, A. J . Am. Chem. Soc. 1989, 111,
4210.
(22) Davis, F. A.; Reddy, R. T.; Han, W.; Carroll, P. J . J . Am. Chem.
Soc. 1992, 114, 1428.
(20) Typical values in kcal mol-1
: N-alkyl, 25-34; N-chloro, 32;
N-sulfonyl, 20-21; N-alkoxycarbonyl, 18; N-acyl, 11-12; N-phosphi-
noyl, 13. See refs 1, 16-19, and 21.

4206 J . Org. Chem., Vol. 65, No. 13, 2000
Notes
Sch em e 2
Sch em e 3a
N-Phosphinoyloxaziridines are also useful oxidants.8
Although asymmetric reactions have been carried out
using this type of oxaziridine in enantiomerically en-
riched form, the asymmetric center was in these cases
the phosphorus atom, and not the carbon atom of the
oxaziridine moiety. We have been able to prepare the first
example of an enantiomerically pure N-phosphinoyloxa-
ziridine chirally functionalized at the carbon atom.
Reaction of 1 with diphenyl phosphinic chloride in the
presence of DMAP gave 15 in 37% yield, again as a single
diastereoisomer. N-Phosphinoyloxaziridines are known
to be somewhat less reactive than their N-sulfonyl
counterparts,23 and indeed 15 is a poor oxidant: it reacts
only very sluggishly with sulfides at room temperature.
It has been reported that N-acyloxaziridines are more
stable than their analogous N-H oxaziridines.1 As yet,
however, we have not been able to achieve an effective
acylation of N-H oxaziridine 1. Attempted acylation of
1 with p-nitrobenzoyl chloride in the presence of DMAP,
gave two new compounds, one with oxidizing properties
(presumed to be N-acyloxaziridine),24 and the second, in
trace amount, not an oxidant. Workup followed by
attempted chromatographic purification gave only the
latter product, and in much larger yield (63%) than
expected from TLC analysis of the reaction mixture. This
product was shown by 1H NMR spectroscopy to be a
mixture of two diastereoisomeric products in about a 1:1
ratio, both also isomers of the expected N-acyl oxaziridine
16a . The data are consistent with dihydrodioxazoles 17a
and 18a , which could arise from N-acyloxaziridine by
rearrangement (Scheme 2). Acylation of 1 using acetic
anhydride proceeded more cleanly, only N-acyl oxaziri-
ing conclusion that the rearrangement is not concerted,
but must take place through an intermediate in which
the oxaziridine carbon atom has lost its stereogenicity.
Efficient functionalization of the nitrogen atom of 1 was
finally achieved by reaction of the N-H oxaziridine with
various derivatizing agents in the presence of base.
Formation of N-methoxycarbonyl 19 and N-ethoxycar-
bonyl 20 derivatives was effected in 95% and 89% yields,
respectively, by the reaction of 1 with methyl or ethyl
chloroformate and pyridine in dichloromethane solution.
Inspection of the 1H NMR spectra of the products
suggests that each of these reactions gave the product
as a single diastereoisomer; taken in conjunction with
the high yields, this demonstrates that 1 is indeed a
mixture of two isomers differing in the configuration at
the pyramidal nitrogen atom and not at the carbon atom
of the three-membered ring, none of the stereoisomers
at that carbon atom being observed in either case.
We have also prepared the first N-sulfenyloxaziridine
21, a previously unreported class of oxaziridine derivative
and also an oxidant,24 again as a single diastereoisomer,
in 41% yield, by treatment of 1 with pentafluorobenzene
sulfenyl chloride and pyridine in dichloromethane at
room temperature. The thiooxime was also isolated in
10% yield together with bis(pentafluorophenyl) disulfide
(20%) and camphor (28%).
We have identified conditions under which nitrogen
transfer takes place to enolates and related carbanions:
for example, deprotonation of phenylacetonitrile and
treatment with 1 provides a 78% yield of 22a /b as a ca.
1.5:1 mixture of diastereoisomers at the new stereogenic
center. During this reaction, the nitrogen atom has been
transferred together with the camphor moiety, water has
been eliminated to generate an imine unit, and the nitrile
group has been hydrolyzed to a primary amide, we
believe via a cyclic intermediate (Scheme 3).
In summary, preparation of the first stable enantio-
merically pure chiral N-H oxaziridines is reported
together with a brief survey of their derivatization and
chemical reactivity. These N-H oxaziridines exist as
mixtures of diastereoisomers at the pyramidal nitrogen
atom. Also reported are the first example of an N-
sulfenyloxaziridine, the second enantiomerically pure
chiral N-acyloxaziridine, the first enantiomerically pure
N-alkoxycarbonyloxaziridine, and the first enantiomeri-
cally pure N-phosphinoyloxaziridine chirally functional-
ized at carbon. NMR spectroscopy suggests that all
N-substituted oxaziridines were isolated as single dias-
tereoisomers with the N-substituent oriented in thermo-
dynamically most favored position away from the bridge-
head methyl group, or perhaps as rapidly inverting
isomers, irrespective of the stereochemistry of the N-H
oxaziridine starting material. Were the barrier to nitro-
gen inversion high in the products, this outcome would
presumably result from much faster reaction of the less
stable isomer of the NH oxaziridine; if, as seems likely,
1
dine 16b being observed in the product mixture by H
NMR spectroscopy before attempted purification. Treat-
ment of this material with silica gel at room-temperature
overnight induced complete transformation into the
dihydrodioxazoles 17b/18b; the two diastereoisomers
were isolated in ca. 90% yield overall, and again in a 1:1
ratio. Such rearrangements, for example, of cyclohexa-
none N-acetyloxaziridine25 and N-acylaziridines,26 have
previously been observed, although they generally re-
quire heating of the reaction mixture.
A related
dihydrodioxazole has been shown to undergo reductive
cleavage to give the parent ketone and benzamide.27
Hydrogenolysis of 17c/18c, obtained from the reaction
of 1 with benzoyl chloride, over palladium at room
temperature indeed gives camphor and benzamide as
products. The fact that we observe formation of two
isomers during the rearrangement leads to the interest-
(23) J ennings, W. B. Personal communication.
(24) Potassium iodide/sodium hydroxide test.
(25) Schmitz, E.; Ohme, R.; Schramm, S. Tetrahedron Lett. 1965,
1857.
(26) Ferraris, D.; Drury, W. J .; Cox, C.; Lectka, T. J . Org. Chem.
1998, 63, 4568.
(27) Mackay, D.; Dao, L. H.; Dust, J . M. J . Chem. Soc., Perkin Trans.
1 1980, 2408.

Notes
J . Org. Chem., Vol. 65, No. 13, 2000 4207
Su p p or tin g In for m a tion Ava ila ble: Full experimental
details; A4 photocopies of 1H and 13C NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
the barrier to inversion is low in the products, this
outcome would arise from inversion at nitrogen and
formation of a thermodynamic mixture of isomers.
Ack n ow led gm en t. This investigation has enjoyed
the support of the EPSRC and Astra Zeneca Pharma-
ceuticals.
J O000176J