Synthesis of O-alkylhydroxylamines by electrophilic amination of alkoxides

Article abstract of DOI:10.1039/b002388o

The 3-trichloromethyloxaziridine 7 reacts smoothly with lithium alkoxides, derived from a representative range of alcohols, transferring an NHBoc function to the oxygen to provide good to excellent yields of N-Boc-O- alkylhydroxylamines 8-16 by this new O-amination protocol.

Full text of DOI:10.1039/b002388o

Synthesis of O-alkylhydroxylamines by electrophilic amination of alkoxides
Oliver F. Foot and David W. Knight*
Chemistry Department, Cardiff University, PO Box 912, Cardiff, UK CF10 3TB. E-mail: knightdw@cf.ac.uk
Received (in Liverpool, UK) 21st March 2000, Accepted 27th April 2000
The 3-trichloromethyloxaziridine 7 reacts smoothly with
lithium alkoxides, derived from a representative range of
alcohols, transferring an NHBoc function to the oxygen to
provide good to excellent yields of N-Boc-O-alkylhydroxyl-
amines 8–16 by this new O-amination protocol.
In pursuance of our studies of various electrophile-driven
5-endo cyclisation processes,1 we required access to the
hydroxylamines represented by structures 2 and 6 and sought to
obtain these by a Mitsunobu displacement2 using the corre-
sponding and readily available alcohols 1 and 5, as this seemed
Scheme 2
the best of a relatively limited number of options.3 Un-
fortunately, both approaches suffered from serious drawbacks.
isoxazolidines and isoxazolines, respectively.6 We were there-
For the allylic alcohol 1, the Mitsunobu method using N-
hydroxyphthalimide,4 under standard conditions delivered good
yields of the required substrate 2a; in contrast, when N-
(4-toluenesulfonyl)hydroxylamine (TsNHOH)5 was used as the
nucleophile, yields were very poor (Scheme 1). However, when
fore prompted to find an alternative and more efficient approach
to these classes of compounds (2–4 and 6), both for this reason
and also because approaches to hydroxylamines in general are
somewhat lacking.7 We were attracted by recent reports from
the Vidal–Collet group8 that various electron-deficient oxazir-
idines could behave as positive nitrogen sources (+NHBoc),
rather than as the more familiar positive oxygen sources (+OH),
popularized by the work of Davis and his colleagues.9 However,
while such species were reported to react efficiently with
various amines and enolates and both sulfur and phosphorus
nucleophiles, there was no report of similar reactions with
alcohols or the derived alkoxides.8 Such a transformation has
been achieved using chloramine, but only with a large excess of
alkoxide and in relatively poor yields,10 and it was not until a
very recent report that 3,3A-di-tert-butyloxaziridine reacts with a
range of potassium alkoxides in DMPU and in the presence of
18-crown-6 to provide O-alkylhydroxylamines in 10–86%
yields that such a process had synthetic value.11 We report
herein, that the highly electron deficient oxaziridine 7 reacts
Scheme 1
applied to unsymmetrical substrates, both the SN2 and SN2A
pathways were followed (Fig. 1) to give both possible products
smoothly with lithium alkoxides using very practical condi-
tions, despite our fears that it would simply act as a proton
source for these basic species.
Oxaziridine 7 was prepared as previously described8 starting
from tert-butyl carbazate, diazotization of which provided tert-
butyl azide. This potentially dangerous material was not
isolated but only handled in solution and was immediately
treated with triphenylphosphine in wet ether to give the imine
Ph3PNNBoc; subsequent aza-Wittig reaction with chloral and
oxone® oxidation gave the oxaziridine 7, as previously
reported.8 The compound was purified by column chromatog-
raphy8 and, in our hands, was sufficiently stable for use for ca.
two months if stored below 0 °C, after which repurification was
necessary. We were delighted to find that generation of the
lithium alkoxide of benzyl alcohol using lithium hexamethyldi-
silazide (LHMDS) in tetrahydrofuran at 278 °C followed by
the addition of oxaziridine 7 and slow warming to ambient
temperature delivered an essentially quantitative yield of the O-
benzyl-N-Boc-hydroxylamine 8 after a simple aqueous work-
up.8 Using the same method, we tested its viability with a range
of other alcohols of varying structure and the results are
collected in Table 1. A primary saturated alcohol, phenethanol,
Fig. 1
(i.e. hydroxylamines 3 and 4). For propargylic alcohols 5,
Mitsunobu displacement with either nucleophile (R1R2NOH)
gave very variable, precursor dependent yields of the required
products 6 (Scheme 2). Despite these problems, and the
additional necessity of converting the phthalimides (e.g. 2a, 6a),
into the corresponding N-tosylates (e.g. 2b, 6b)we were able to
access the latter substrates in sufficient quantities to demon-
strate that the projected 5-endo-trig and 5-endo-dig cyclisations
generally work extremely well to provide a new entry into
DOI: 10.1039/b002388o
Chem. Commun., 2000, 975–976
This journal is © The Royal Society of Chemistry 2000
975

Table 1
Scheme 3 Reagents and conditions: NaH, Et2O, 20 °C, > 95% yield or
BuLi, THF, 278 °C for 1 h then warming to 20 °C, > 90% yield.
diethyl ether at ambient temperature followed by addition of the
oxaziridine 7 again gave an excellent yield of the hydrox-
ylamine 8 as did the use of butyllithium as base. Finally, we
have succeeded in preparing suitable substrates for the 5-endo-
dig cyclisations by a very direct, ‘one-pot’ method (Scheme 4).
Thus, condensation of hex-1-yne 18, after deprotonation using
butyllithium, with phenylacetaldehyde, addition of the oxazir-
idine 7 to the resulting alkoxide and warming to ambient
temperature gave a 55% yield of the desired hydroxylamine 19.
These results suggest that there could well be a number of
(substrate-dependent) modifications which could usefully be
applied to this type of chemistry. Further studies along these
lines are underway, along with work on the 5-endo cyclisations,
which is now viable in the light of the foregoing results.
Scheme 4
We are very grateful for some helpful referees comments and
to the EPSRC mass Spectrometry Centre (University College,
Swansea) for the provision of mass spectral data and to the
EPSRC for financial support.
Notes and references
1 A. D. Jones and D. W. Knight, Chem. Commun., 1996, 915; S. P. Bew
and D. W. Knight, Chem. Commun., 1996, 1007; A. D. Jones, D. W.
Knight, A. L. Redfern and J. Gilmore, Tetrahedron Lett., 1999, 40,
3267; S. B. Bedford, K. E. Bell, F. Bennett, C. J. Hayes, D. W. Knight
and D. E. Shaw, J. Chem. Soc., Perkin Trans. 1, 1999, 2143.
2 O. Mitsunobu, Synthesis, 1981, 1; O. Mitsunobu, Comp. Org. Synth,
1991, 6, 1; O. Mitsunobu, Comp. Org. Synth, 1991, 6, 65; D. L. Hughes,
Org. React., 1992, 42, 335; D. L. Hughes, Org. Prep. Proced. Int., 1996,
28, 127.
3 E. Breuer, H. G. Aurich and A. Nielsen, Nitrones, Nitronates and
Nitroxides, ed. S. Patai and Z. Rappoport, John Wiley and Sons,
Chichester, 1989.
4 E. Grochowski and J. Jurczak, Synthesis, 1976, 682. We found that ethyl
acetate was a superior solvent for this reaction; see: H. Iwagami, M.
Yatagi, M. Nakazawa, H. Orita, Y. Honda, T. Ohnuki and T. Yukawa,
Bull. Chem. Soc. Jpn., 1991, 64, 175.
reacted slightly less efficiently giving the hydroxylamine
derivative 9 in 80% yield. Two secondary alcohols, cyclohex-
anol and cholesterol, similarly gave the hydroxylamines 10 and
11 in 85 and 70% yields, respectively. Even the tertiary alcohol
group in a-terpineol reacted reasonably efficiently to give the
derivative 12 in 50% yield. This contrasts with the use of 3,3A-
di-tert-butyloxaziridine,11 which delivered only a 10% yield
from a similar tertiary alcohol. However, it should be noted that
this latter method leads directly to O-alkylhydroxylamines as
the free bases, which could be useful in some contexts.
Returning to our original substrates, we were glad to find that
yields were again viable, the allylic alcohol derivative 13 being
isolated in almost quantitative yield while the relatively
sensitive propargylic derivative 14 was isolated in 50% yield,
with the material balance being largely unreacted alcohol.
Hence, it appears that the present method is especially efficient
when applied to benzylic or allylic alcohols. Other oxygen-
based nucleophiles also react successfully. Thus, under the
same conditions, (E)-hex-3-enoic acid was converted into the
O-acylhydroxylamine 15 and 4-methoxyphenol into the O-
arylhydroxylamine 16, both in excellent yields. In general, all of
the foregoing derivatives appeared rather sensitive to chroma-
tography over silica gel; Grade II alumina was more suitable but
its use still often resulted in losses of some 10–20%12
deprotection to give the corresponding O-alkylhydroxylamines
(i.e. 2, 6; R1 = R2 = H) has ample literature precedent,13 which
we have confirmed during the present work, during which we
have also been able to exchange the N-protecting group from
Boc to TS (e.g. 13 ? 2b) in an efficient manner.
5 M. Fujimoto and M. Sakai, Chem. Pharm. Bull., 1965, 13, 248.
6 O. F. Foot and D.W. Knight, in preparation.
7 For recent notable contributions, see: S. D. Bull, S. G. Davies, S. Jones,
J. V. A. Ouzman, A. J. Price and D. J. Watkin, Chem. Commun., 1999,
2079; Y.-M. Lin and M. J. Miller, J. Org. Chem., 1999, 64, 7451.
8 J. Vidal, S. Damestoy, L. Guy, J.-C. Hannachi, A. Aubry and A. Collet,
Chem. Eur. J., 1997, 3, 1691; J. Vidal, J.-C. Hannachi, G. Hourdin, J.-C.
Mulatier and A. Collet, Tetrahedron Lett., 1998, 39, 8845 and
references cited therein.
9 F. A. Davis and A. C. Sheppard, Tetrahedron, 1989, 45, 5703; F. A.
Davis and B.-C Chen, Chem. Rev., 1992, 92, 912.
10 W. Theilacker and K. Ebke, Angew. Chem., 1956, 68, 303. For a review
of electrophilic amination in general, see: S. Andreae and E. Schmitz,
Synthesis, 1991, 327.
11 I. C. Choong and J. A. Ellman, J. Org. Chem., 1999, 64, 6528.
12 Satisfactory spectroscopic and analytic data have been obtained for all
compounds reported herein.
13 For examples of Boc hydrolysis in such hydroxylamine derivates, see,
for example, L. A. Carpino, C. A. Giza and B. A. Carpino, J. Am. Chem.
Soc., 1959, 81, 955; T. Sheradsky, G. Salemnick and Z. Nir,
Tetrahedron, 1972, 28, 3833; C. Baloli, P. D. Buttero, E. Licandro and
S. Mairona, Synthesis, 1988, 344.
The ease with which alkoxides in general can be formed led
us to briefly investigate some alternative protocols, using
benzyl alcohol 17 as a test substrate. As outlined in Scheme 3,
generation of the sodium alkoxide using sodium hydride in
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Chem. Commun., 2000, 975–976