The synthesis of chiral functionalised morpholine N-oxides using a tandem Cope elimination/reverse-Cope elimination protocol

Article abstract of DOI:10.1016/j.tetlet.2004.03.040

Hydroxylamine derivatives of (S)-prolinol have been generated using a Cope elimination. These undergo reverse-Cope elimination onto a pendant double bond to give morpholine N-oxides containing three contiguous chiral centres.

Full text of DOI:10.1016/j.tetlet.2004.03.040

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3655–3658
The synthesis of chiral functionalised morpholine N-oxides using a
tandem Cope elimination/reverse-Cope elimination protocol
Ian A. O’Neil,a,* Ed Cleator,a V. Elena Ramos,a Alan P. Chorltonb
and David J. Tapolczayb
aRobert Robinson Laboratories, Department of Chemistry, University of Liverpool, Crown Street, Liverpool L69 7ZD, UK
bMillennium Pharmaceuticals, 75, Sidney Street, Cambridge, MA, USA
Received 26 January 2004; revised 27 February 2004; accepted 5 March 2004
Abstract—Hydroxylamine derivatives of (S)-prolinol have been generated using a Cope elimination. These undergo reverse-Cope
elimination onto a pendant double bond to give morpholine N-oxides containing three contiguous chiral centres.
Ó 2004 Published by Elsevier Ltd.
The reverse-Cope elimination is emerging as a powerful
method for the synthesis of a range of heterocyclic sys-
onto a suitably positioned alkene, generating two new
chiral centres in the process. Thus, prolinol 5 was treated
with acrylonitrile in methanol to give the cyanoethyl
adduct 6 in 96% yield. Allylation of the alcohol gave
tertiary amine 7 in 90% yield. Upon treatment with
1 equiv of mCPBA the amine 7 was selectively oxidised
to give the N-oxide 8. The N-oxide 8 underwent Cope
elimination under the reaction conditions2p to generate
the hydroxylamine 9 in 92% yield. This could be purified
by flash chromatography, but 1H NMR indicated that it
had started to undergo reverse-Cope elimination to give
the morpholine N-oxide 10 at room temperature. This
process was facilitated simply by heating the hydroxyl-
amine 9 in methanol under a nitrogen atmosphere to
4
tems.1;2 We3 and Jager and Palmer have recently
€
reported the synthesis of a highly functionalised chiral
pyrrolidine derivative via the regioselective ring opening
of a chiral epoxide 1 with N-benzylhydroxylamine. The
intermediate hydroxylamine 2 underwent reverse-Cope
elimination at room temperature to give the pyrrolidine
N-oxide 3 as a single stereoisomer (Scheme 1).
We now wish to report the synthesis of highly func-
tionalised chiral morpholine N-oxides, which utilises a
Cope elimination to generate an intermediate hydrox-
ylamine; this then undergoes reverse-Cope elimination
HO
OH
Bn
HO
OH
OH
Reverse-Cope
Elimination
BnNHOH.HCl
72%
O
N
N
3
NaOMe, MeOH
72h, r.t.
H3C
H
O
O
2
Bn
1
HO
OH
H2, Pd/C
MeOH, 100%
4
N
H3C
H
Scheme 1.
Keywords: Cope elimination; Reverse-Cope elimination; Amine oxides.
* Corresponding author. Tel.: +44-151-794-3485; fax: +44-151-794-3588; e-mail: ion@liv.ac.uk
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.03.040

3656
I. A. O’Neil et al. / Tetrahedron Letters 45 (2004) 3655–3658
Br
CN
N
H
N
N
MeOH, 96%
NC
NaH, THF, 90%
O
OH
OH
NC
5
6
7
mCPBA
CH2Cl2
Reverse-Cope
Elimination
Cope
Elimination
MeOH, N2, ∆, 95%
N
N
N
O
O
O
O
O
OH
CN
NC
H3C
8
9
10
92%
Scheme 2.
give a 95% yield of the morpholine N-oxide 10 con-
taining three contiguous chiral centres, as a single dia-
stereoisomer (Scheme 2).
CHCl3, N2, ∆, 24h
N
N
N
O
O
O
O
O
OH
H3C
H3C
Reduction of the morpholine N-oxide 10 by catalytic
hydrogenation gave the morpholine 11 (Scheme 3).
13 (30%)
10 (51%)
9
Scheme 5.
The structure of the reverse-Cope elimination product
was established by NOE experiments on the morpholine
11 (Fig. 1). There was a clear NOE between the methyl
group at C-4 and the H-9 proton.
By changing the solvent to refluxing CHCl3 it was found
that a second diastereoisomeric N-oxide 13 was also
formed as the minor component in the reaction (Scheme
5). The two diastereoisomers were separable by flash
chromatography.
Interestingly, reoxidation of the amine 11 with mCPBA
gave a 3.5:1 mixture of the parent amine oxide 10 and its
diastereoisomer 12 (Scheme 4).
We next examined the effect of substituents on the ter-
minus of the double bond. In most cases such substit-
uents slow down the rate of the reverse-Cope
elimination.2g We prepared the hydroxylamine sub-
strates 16 and 17 bearing an additional methyl and a
phenyl substituent, respectively, using a modification of
the earlier procedure. It was found that on heating the
hydroxylamine 16 bearing a methyl group on the double
bond in methanol under nitrogen, no reverse-Cope
elimination occurred. However, with a phenyl sub-
stituent present the reverse-Cope product 19 was iso-
lated in a 40% yield along with recovered starting
material. To the best of our knowledge this is the first
example of a reverse-Cope elimination on a double bond
with a terminal substituent that generates a six mem-
bered ring product (Scheme 6).
H2, Pd/C
MeOH, 100%
N
N
O
O
O
H3C
H
3C
10
11
Scheme 3.
7
8
O
9
6
1
N
5
H
CH3
n.O.e
O
2
N
4
H3C
3
Figure 1. NOE between the C-9 proton and the C-4 methyl group in
morpholine 11.
We also examined the effect of ring size on the reaction.
Thus, racemic piperidinol was subjected to a similar
reaction sequence to generate the tertiary amine 21 in
87% over two steps. Oxidation of 21 with mCPBA gave
the hydroxylamine 23 in 63% yield. On heating in
MeOH a 2:3 ratio of the diastereoisomeric N-oxides 24
and 25 was formed in a combined 93% yield. Again a
solvent dependence was observed; when CHCl3 was
used as the solvent the ratio of 24–25 changed to a 1:4
(Scheme 7). Assignments of the structures 24 and 25
were made by NOE measurements.
mCPBA (1eq)
N
N
N
O
O
O
O
O
CH2Cl2
H3C
H3C
H3C
12 (20%)
11
10 (76%)
Scheme 4.

I. A. O’Neil et al. / Tetrahedron Letters 45 (2004) 3655–3658
3657
mCPBA
CH2Cl2
R
Br
N
N
N
NaH, THF
O
R
O
O
R
OH
NC
NC
R = Me 14, 83%
R = Ph 15, 77%
6
CN
Cope
Elimination
Reverse-Cope
Elimination
CN
MeOH, N2, ∆
N
N
O
O
R = Me 16, 97%
R = Ph 17, 74%
O
OH
R = Me 18, 0%
R = Ph 19, 40%
R
R
Scheme 6.
1. MeOH,100%
CN
mCPBA, CH2Cl2
N
2. NaH, THF, 0o,
TBAI, 87%
N
N
H
OH
O
NC
O
O
Br
CN
22
21
20
Cope
Elimination
63%
∆, N2, solvent, 36h,
90-95%
N
N
N
OH
O
O
H3C
O
O
O
25
24
H3C
23
2
1
:
:
3
4
MeOH
CHCl3
Scheme 7.
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In summary, we have demonstrated that the novel tan-
dem Cope elimination/reverse-Cope elimination proto-
col is a powerful method for the high yielding synthesis
of homochiral morpholine derivatives.
Acknowledgements
I.O.N. would like to thank Millennium Pharmaceuticals
for their continued support of this work and Manuel
Perez for the NOE measurements.
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€
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