6528
J . Org. Chem. 1999, 64, 6528-6529
Communications
Syn th esis of Alk oxyla m in es by Alk oxid e
Am in a tion w ith 3,3′-Di-ter t-bu tyloxa zir id in e
Ingrid C. Choong and J onathan A. Ellman*
Department of Chemistry, University of California,
Berkeley, California 94720
Received March 19, 1999
F igu r e 1. Representative O-alkyl oxime drugs.
O-Alkyl oximes have become increasingly important in
chemical biology and medicinal chemistry research. Chemose-
lective ligation to provide the oxime linkage is the key step
in the synthesis of numerous semisynthetic biopolymers
and biomolecules1-6 and the O-alkyl oxime functionality is
present in many drugs and drug candidates (Figure 1).7 The
O-alkyl oxime functionality is prepared in near-quantitative
yields and with almost complete functional group compat-
ibility by the condensation of alkoxylamines with aldehydes
and ketones. However, the potential applications of O-alkyl
oximes are compromised by the narrow range of methods
that have been developed to prepare the alkoxylamine
precursors. Generally, these methods rely on a specific two-
step sequence consisting of (1) nucleophilic attack of an
N-protected hydroxylamine nucleophile upon an electrophilic
carbon and (2) deprotection to provide the alkoxylamine
product.8,9 The direct electrophilic amination of alcohols
would provide a more powerful and efficient approach.
However, in the only report of the direct electrophilic
amination of alcohols, chloroamine was used to aminate
simple alkoxides in low yields (30-40%). Moreover, 40-fold
excess of the alkoxide was required.10 Indeed, in a prior
report on the reaction of chloroamine with stoichiometric
alkoxides, less than 5% yields were observed.11
Herein, we report the first high-yielding, single-step
procedure for the preparation of alkoxylamines through the
direct electrophilic amination of a wide range of alkoxide
nucleophiles. Because this reported method relies upon a
completely different disconnection than the standard meth-
ods, previously inaccessible alkoxylamines can now readily
be prepared in high yields. We further report use of this
method for the high-yielding, one-pot preparation of O-alkyl
oximes from alcohols.
In contrast to the amination of alkoxides, there have been
numerous reports of electrophilic aminations of the less basic
phenoxides to generate phenoxyamines. These methods
involve an amine exchange reaction where a phenoxide
acceptor attacks an amine donor, XNH2. Reagents reported
for the amination of phenoxides include O-(mesitylene-
sulfonyl)hydroxylamine,12 hydroxylamine O-sulfonic acid,13
chloroamine,14-16 and (2,4-dinitrophenoxy)amine.17 The re-
activity of these aminating reagents with phenoxides is due
to the electron-deficient nature of the leaving group, which
unfortunately also results in competitive deprotonation and
rapid decomposition of the reagents upon treatment with
electron-releasing phenoxide nucleophiles. Clearly, the ami-
nation of the significantly more basic alkoxide nucleophiles
is even more problematic.
To eliminate competitive deprotonation and reagent de-
composition, we chose to focus on the development of the
less acidic oxaziridine-based aminating reagents, since ring
strain rather than leaving group electronegativity provides
the necessary reactivity. Cyclohexanespiro-3′-oxaziridine,
1,18 is the only oxaziridine unsubstituted on nitrogen to have
previously been explored as an aminating agent, in particu-
lar for the amination of carbon, sulfur, and nitrogen nucleo-
philes.19 While the amination of oxygen nucleophiles with 1
has received little attention,20 oxaziridine 1 is known to
decompose to cyclohexanone and nitrogen gas upon treat-
ment with hydroxide.21
On the basis of these prior reports, we concluded that
oxaziridine 1 is not an acceptable reagent for the amination
of alcohols. Not only is oxaziridine 1 unstable and must be
used without purification, but the cyclohexanone byproduct
can undergo serious competing side reactions, including
competitive cyclohexanone deprotonation and rapid conden-
sation with amination products (eq 1). We instead focused
on the previously unexplored 3,3′-di-tert-butyl oxaziridine,
3,22 since we believed that this reagent would not have the
inherent limitations of oxaziridine 1. First, due to increased
steric hindrance, we hoped that oxaziridine 3 would be stable
and isolable in pure form. Second, the steric hindrance of
the 2,2,4,4-tetramethyl-3-pentanone byproduct should sig-
nificantly retard condensation with the desired alkoxylamine
product. Finally, competitive deprotonation of the ketone
byproduct would clearly not be possible.
(12) Tamura, Y.; Minamikawa, J .; Sumoto, K.; Fujii, S.; Ikeda, M. J . Org.
Chem. 1973, 38, 1239.
* To whom correspondence should be addressed. Tel: (510) 642-4488.
Fax: (510) 642-8369. E-mail: jellman@uclink4.berkeley.edu.
(1) Tuchscherer, G. Tetrahedron Lett. 1993, 34, 8419.
(2) Rose, K. J . Am. Chem. Soc. 1994, 116, 30.
(3) Shao, J .; Tam, J . P. J . Am. Chem. Soc. 1995, 117, 3893.
(4) Canne, L. E.; Ferre´-D′Amare´, A. R.; Burley, S. K.; Kent, S. B. H. J .
Am. Chem. Soc. 1995, 117, 2998.
(5) Cornish, V. W.; Hahn, K. M.; Schultz, P. G. J . Am. Chem. Soc. 1996,
118, 8150.
(6) Rodriguez, E. C.; Marcaurelle, L. A.; Bertozzi, C. R. J . Org. Chem.
1998, 63, 7134.
(13) Sheradsky, T. J . Heterocycl. Chem. 1967, 4, 413.
(14) Paquette, L. A. J . Am. Chem. Soc. 1963, 85, 3288.
(15) Theilacker, W. Angew. Chem. 1960, 72, 498.
(16) Theilacker, W.; Ebke, K.; Seidl, L.; Schwerin, S. Angew. Chem. 1963,
75, 208.
(17) Castellino, A. J .; Rapoport, H. J . Org. Chem. 1983, 49, 1348.
(18) Schmitz, E.; Ohme, R.; Schramm, S.; Striegler, H.; Heyne, H.-U.;
Rusche, J . J . Prakt. Chem. 1977, 319, 195.
(19) Andreae, S.; Schmitz, E. Synthesis 1991, 327.
(20) Amination of methanol by 1 under acid catalysis has been reported
to give cyclohexanone oxime O-methyl ether in 40% yield. No experimental
details were provided. Schmitz, E. Dreiringe mit zwei Heteroatomen;
Springer-Verlag: Berlin, 1967.
(7) MDL Drug Data Report, MDL Information Systems, Inc., San
Leandro, CA.
(8) Grochowski, E.; J urczak, J . Synthesis 1976, 682.
(9) Kim, J . N.; Kim, K. M.; Ryu, E. K. Synth. Commun. 1992, 22, 1427.
(10) Theilacker, W.; Ebke, K. Angew. Chem. 1956, 68, 303.
(11) Truitt, P.; Long, L. M.; Mattison, M. J . Am. Chem. Soc. 1948, 70, 9.
(21) Schmitz, E.; Ohme, R.; Schramm, S. Liebigs Ann. Chem. 1967, 702,
131.
(22) Hudson, R. F.; Lawson, A. J .; Record, K. A. F. J . Chem. Soc., Chem.
Commun. 1975, 322.
10.1021/jo990490h CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/18/1999