A convenient synthesis of secondary hydroxylamines

Article abstract of DOI:10.1016/S0040-4039(01)01745-2

The oxidation of a range of β-cyanoethyl tertiary amines with mCPBA gives the corresponding N-oxides, which can be isolated or undergo Cope-elimination to give secondary hydroxylamines in excellent yield.

Full text of DOI:10.1016/S0040-4039(01)01745-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8247–8249
A convenient synthesis of secondary hydroxylamines
Ian A. O’Neil,a,* Ed Cleatora and David J. Tapolczayb
aDepartment of Chemistry, University of Liverpool, Crown St, Liverpool L69 7ZD, UK
bMillennium Pharmaceuticals, The Merrifield Centre, Rosemary Lane, Cambridge CB1 3LQ, UK
Received 1 August 2001; accepted 14 August 2001
Abstract—The oxidation of a range of b-cyanoethyl tertiary amines with mCPBA gives the corresponding N-oxides, which can
be isolated or undergo Cope-elimination to give secondary hydroxylamines in excellent yield. © 2001 Published by Elsevier
Science Ltd.
As part of our studies on the use of the reverse-Cope
cyclisation in the synthesis of nitrogen heterocycles we
have shown that functionalised hydroxylamines can be
readily prepared by the ring opening of epoxides with
simple N-alkylhydroxylamines (Scheme 1). The reac-
tion is regioselective and gives access to the desired
tioned b-electron withdrawing nitrile allows the elimi-
nation to occur at significantly lower temperatures. In
their system, proline (1) was treated with acrylonitrile
to give the corresponding tertiary amine (2). This was
then oxidised with mCPBA in methanol to give the
N-oxide as a single diastereoisomer. The stereochem-
istry of the product was assigned on the basis of IR as
the isomer (3) in which the N-oxide and the carboxylic
acid were trans. This is in contrast to our earlier work
on related systems and it is more probable that the
product is the cis isomer (4).10
substrates
for
the
subsequent
reverse-Cope
cyclisations.1
Various other methods are available for the synthesis of
secondary hydroxylamines, but most have serious limi-
tations. These include the oxidation of secondary
amines,2 reduction or addition of an appropriate nucleo-
phile to a nitrone,3 addition of organometallic reagents
to nitro or nitroso compounds,4 the addition of hydrox-
ylamines to a,b-unsaturated systems,5 the reverse Cope
cyclisation,6 use of the Mitsunobu reaction7 and the
Cope elimination of suitable tertiary amine N-oxides.8
This latter method has generally not been widely
exploited due to the high temperatures required and the
problems associated with regiochemistry of the elimina-
tion in many cases. There have been isolated reports of
the use of electron withdrawing groups placed b to the
N-oxide facilitating the elimination. Nagasawa et al.9
have reported that the use of an appropriately posi-
The N-oxide (3) was reported to undergo Cope elimina-
tion on warming in acetone to give the hydroxylamine
(5) in a moderate 50% yield (Scheme 2).
We recently required a number of chiral hydroxyl-
amines and have examined this reaction in more detail.
We have found that it is an excellent method for the
synthesis of a range of secondary hydroxylamines. The
parent secondary amines (6) were treated with acryloni-
trile in methanol to give the tertiary b-cyanoethyl
amines (7) in excellent yield. Oxidation of these com-
pounds with mCPBA gave the corresponding N-oxides
(8). If the reaction was carried out in methanol as the
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)01745-2

8248
I. A. O’Neil et al. / Tetrahedron Letters 42 (2001) 8247–8249
solvent the N-oxides could be isolated and character-
ised, although they slowly decomposed on standing.
The reaction works for both cyclic and acyclic sys-
tems (Table 1). Apart from entries 3 and 4 in Table
1, all of the secondary hydroxylamines reported are
new compounds.
This is presumably a consequence of the methanol
hydrogen bonding to the N-oxide. However, if the
oxidation was performed in a non hydrogen bonding
solvent such as CH2Cl2 then the intermediate N-oxide
(8) underwent Cope elimination in situ to generate
the hydroxylamine (9) in excellent yield (Scheme 3).
We are currently exploring the use of these chiral
hydroxylamines in asymmetric transformations and
their scope in the synthesis of a range of nitrogen
based heterocycles.
Table 1. Synthesis of secondary hydroxylamines via Cope elimination of b-cyanoethylamines (see Scheme 3)

I. A. O’Neil et al. / Tetrahedron Letters 42 (2001) 8247–8249
8249
Scheme 2.
Scheme 3.
Acknowledgements
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I.O’N. would like to thank Millennium Pharmaceuti-
cals for their continued generous financial support and
Dr. Tom Gilchrist (Liverpool) for helpful discussions.
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