The stereospecific addition of hydroxylamines to α,β-unsaturated sulfones, nitriles and nitro compounds

Article abstract of DOI:10.1016/S0040-4039(01)01746-4

N-Alkyl hydroxylamines have been shown to undergo a highly stereospecific cis addition to α,β-unsaturated sulfones, nitriles and nitro compounds.

Full text of DOI:10.1016/S0040-4039(01)01746-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8251–8254
The stereospecific addition of hydroxylamines
to a,b-unsaturated sulfones, nitriles and nitro compounds
Ian A. O’Neil,a,* Ed Cleator,a J. Mike Southern,a Jamie F. Bickleya and David J. Tapolczayb
aDepartment of Chemistry, University of Liverpool, Crown St, Liverpool L69 7ZD, UK
bMillennium Pharmaceuticals, The Merryfield Centre, Rosemary Lane, Cambridge CB1 3LQ, UK
Received 1 August 2001; accepted 14 September 2001
Abstract—N-Alkyl hydroxylamines have been shown to undergo a highly stereospecific cis addition to a,b-unsaturated sulfones,
nitriles and nitro compounds. © 2001 Published by Elsevier Science Ltd.
a,b-unsaturated ketones, lactones and esters is well
documented in the literature,2 however the analogous
addition to other Michael acceptors such as a,b-unsatu-
rated sulfones, nitriles and nitro compounds has not been
previously investigated in any detail.3 We wish to disclose
that these reactions proceed smoothly giving the addition
products in high yield and with very high diastereoselec-
tivity (Scheme 2).
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 reaction
is regioselective and gives access to the desired substrates
for the subsequent reverse-Cope cyclisations.1
In order to extend the methodology, we wished to
prepare a range of hydroxylamines, which possessed an
electron-withdrawing group b to the hydroxylamine
nitrogen so that further functionalisation was possible.
The conjugate addition of N-alkylhydroxylamines to
The substrates were prepared according to standard
literature methods. We initially examined the addition of
N-benzylhydroxylamine to simple activated trans b-sub-
stituted styrenes.
As expected, the hydroxylamine underwent rapid addi-
tion to the nitrostyrene, the reaction being complete in
five minutes. Addition to the a,b-unsaturated sulfone was
complete in 12 h, however it took 7 days for addition to
the a,b-unsaturated nitrile.
Scheme 1.
Scheme 2.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)01746-4

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Table 1. Addition of N-alkylhydroxylamines to Michael acceptors
Zhao and others have2 recently shown that the addition
of hydroxylamines to a,b-unsaturated esters and lac-
tones proceeds with high stereospecificity. In order to
ascertain if such high selectivity was observed with our
substrates we prepared a number of geometrically
defined trisubstitued nitroalkenes,4 two a,b-unsaturated
sulfones5 and an a,b-unsaturated nitrile.6 The results
are shown in Table 1. Addition of N-benzylhydroxyl-
amine to the four trisubstituted nitroalkenes was high
yielding, rapid and complete within 1 h. In all cases a
single diastereoisomer was formed as indicated by H
1
NMR analysis, which indicated that addition had
occurred in a stereospecific syn fashion. The structures
of two of these derivatives were confirmed by X-ray
analysis (Fig. 1) and both showed that the N-benzylhy-
droxylamine had added in a syn stereospecific fashion
to the nitroalkene.
Addition to two a,b-unsaturated sulfones was exam-
ined. The bromosulfone (entry 5) underwent clean and

I. A. O’Neil et al. / Tetrahedron Letters 42 (2001) 8251–8254
8253
Figure 1. ORTEP view of the molecular structure of the hydroxylamine (Table 1, entry 1) and the hydroxylamine (Table 1, entry 2).
Scheme 3.
rapid addition to give a single diasteroisomeric hydroxyl-
amine, again consistent with a stereospecific syn addi-
tion. The reaction of cyclohexene sulfone (entries 5 and
6) with two hydroxylamines was investigated. Addition
with the N-benzylhydroxylamine was found to be very
sluggish and gave only 5% of the desired product, as a
single diastereoisomer after 7 days at reflux. However,
use of N-methylhydroxylamine gave the addition
product again as a single diastereoisomer in 65% after 1
day.
by subjecting a 5:1 mixture of the nitroalkenes shown
in Scheme 3 to the addition reaction. The two
diastereoisomeric products were formed in a matching
5:1 ratio.
Finally, addition to the bromonitrile (entry 7) gave a
modest yield of the product as a single diastereoisomer.
The stereospecificity of the addition was also illustrated
Scheme 4.

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I. A. O’Neil et al. / Tetrahedron Letters 42 (2001) 8251–8254
Scheme 5.
The potential utility of this diastereoselective addition
reaction is shown in Scheme 4. Hydrogenation of the
b-nitro hydroxylamine gave racemic trans-cyclohexane-
1,2-diamine in quantitative yield, highlighting the syn-
thetic potential of this addition reaction. We are
currently examining asymmetric examples of this
stereospecific reaction, which will be reported in due
course.
References
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1998, 39, 9089–9092; (b) O’Neil, I. A.; Cleator, E.;
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2000, 695–697; (c) O’Neil, I. A.; Cleator, E.; Southern,
J. M.; Hone, N.; Tapolczay, D. J. Synlett. 2000, 1408–
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The stereospecific addition of hydroxylamines to these
a,b-unsaturated systems are consistent with a concerted
mechansim and the reaction could be viewed as an
intermolecular reverse-Cope cyclisation (Scheme 5).
3. Kliegel, W.; Lubkowitz, G.; Rettig, S. J.; Trotter, J.
Can. J. Chem. 1992, 70, 2027–2032.
Acknowledgements
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This work was supported by the EPSRC grant GR/
M13558. I.O.N. would like to thank Millennium Phar-
maceuticals for their generous financial support.
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