The synthesis of highly functionalized morpholine N-oxides from ephedrine and pseudoephedrine utilizing a tandem Cope elimination/reverse Cope elimination protocol

Article abstract of DOI:10.1016/j.tetlet.2007.01.047

Highly functionalized monocyclic morpholine N-oxides can be prepared in three steps starting from ephedrine and pseudoephedrine utlizing a tandem Cope elimination/reverse Cope elimination.

Full text of DOI:10.1016/j.tetlet.2007.01.047

Tetrahedron Letters 48 (2007) 1691–1694
The synthesis of highly functionalized morpholine N-oxides
from ephedrine and pseudoephedrine utilizing a tandem
Cope elimination/reverse Cope elimination protocol
Neil Henry and Ian A. O’Neil*
Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Crown St, Liverpool L69 7ZD, UK
Received 11 July 2006; revised 2 January 2007; accepted 10 January 2007
Available online 14 January 2007
Abstract—Highly functionalized monocyclic morpholine N-oxides can be prepared in three steps starting from ephedrine and pseu-
doephedrine utlizing a tandem Cope elimination/reverse Cope elimination.
Ó 2007 Published by Elsevier Ltd.
The reverse Cope elimination is emerging as a power-
ful method for the synthesis of a wide variety of
heterocyclic systems.1 The synthesis of simple pyrroli-
dine and piperidine based derivatives using this meth-
odology was established by Black and Doyle in 1978.2
Recently the work of Ciganek et al.,3 our group,4 and
Palmer and Ja¨ger5 have demonstrated the scope and
limitations of this reaction in the synthesis of chiral
functionalized pyrrolidines. Elegant use of this meth-
odology in the total syntheses of several alkaloids
has been demonstrated by Oppolzer et al.,6 Holmes
and co-workers7 and Knight and Salter.8 The synthesis
of piperidine based compounds is less well docu-
mented, but is equally as viable as demonstrated first
by House and Lee9 and later by O’Neil et al.10 In this
Letter we report the synthesis of monocyclic function-
alized, homochiral, morpholine amine N-oxides using
the tandem Cope elimination/reverse Cope reaction.
The synthesis of chiral morpholine derivatives is of
interest due to their extensive potential as therapeutic
agents.11 Morpholine amine N-oxides with up to four
contiguous chiral centres can be prepared utilizing our
methodology.
Treatment of pseudoephedrine 1 with acrylonitrile
gave the corresponding N-cyanoethyl derivative 2,
which was O-alkylated with allyl bromide to give 3.
Treatment of 3 with purified (ꢀ95%) meta-chloro-
perbenzoic acid in CH2Cl2 yielded the intermediate
N-oxide 4, which underwent Cope elimination in situ
to give hydroxylamine 5. On heating in CH2Cl2,
hydroxylamine 5 underwent reverse Cope elimination
to give morpholine amine N-oxide 6 as a single
diastereoisomer in 32% yield (Scheme 1). This tandem
Cope/reverse Cope methodology has been established
within our group and has been demonstrated in the
synthesis of bicyclic chiral morpholine derivatives,12
however, this is the first example of the synthesis of a
monocyclic morpholine N-oxide using the reverse Cope
elimination.
All attempts to isolate pure hydroxylamine 5 by chro-
matography met with failure. In order to investigate
the effect of solvent on the reaction, after consumption
of the N-cyanoethyl derivative 3, the reaction mixture
was filtered, the dichloromethane removed, and the resi-
due taken up in methanol and heated to reflux for 3
days. This gave the two diastereoisomeric N-oxides 6
and 7 in a 3:2 ratio, in a combined yield of 82%. It is
likely that hydrogen bonding solvents such as MeOH
stabilize the N-oxide products. Conclusive determina-
tion of the stereochemistry of these compounds required
a further transformation. Treatment of N-oxide 6 with
BH3ÆTHF gave the parent tertiary amine 8 in 62% along
with the borane complex of the parent tertiary amine 9
(Scheme 2).
The synthesis of morpholine amine N-oxides 6 and 7
begins with the known b-amino alcohol (1S,2S)-(+)-
pseudoephedrine 1, and is shown in Scheme 1.
*
Corresponding author. Tel.: +44 (0) 151 794 3485; fax: +44 (0) 151
794 3588; e-mail: ion@liv.ac.uk
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.01.047

1692
N. Henry, I. A. O’Neil / Tetrahedron Letters 48 (2007) 1691–1694
OH
O
OH
Me
1. NaH, THF, 0oC
Me
CN
Ph
Me
Ph
Ph
NMe
MeOH, 100%
2. Allyl bromide, 97%
NMe
NC
NHMe
NC
2
1
3
m-CPBA, CH2Cl2, K2CO3
-78 oC 3 hrs then RT
Ph
Me
Ph
O
Solvent 6
:
7
6
CH2Cl2
MeOH
1
3
:
:
0
2
N
Me
O
O
Me
O
Cope
elimination
Me
Me
OH
Reverse Cope
+
Ph
Ph
O
elimination
Δ, solvent
N
MeN
Me
O
NC
7
Me
N
Me
4
5
Me
O
Scheme 1.
Ph
O
N
Ph
O
Ph
O
.
BH3 THF (1.5 eq.)
+
Me
Me
Me
N
Me
Me
N
Me
Me
Me
O
Me
BH3
6
8 (62%)
9 (28%)
Scheme 2.
dichloromethane solvent was removed and the crude
hydroxylamine taken up and heated to reflux in metha-
nol for 3 days, the yield of N-oxide 12 was increased to
45%. Once again all attempts to isolate the intermediate
hydroxylamine by chromatography met with failure.
The stereochemistry of 12 was determined by NOE
analysis.
In order to incorporate further functionality in the mole-
cule, we prepared the substituted alkene 14. The pres-
ence of an allylic oxygen has been reported to favour
the reverse Cope elimination.8 The allylic bromide deriv-
ative 13 (Scheme 4) was synthesized in two steps using a
reported procedure.14 When the previously described
methodology was used to synthesize the reverse Cope
elimination precursor 14, the yield for the O-allylation,
was significantly lower than expected. This could be pos-
sibly explained by the fact that the allylic bromide 13 ap-
peared to be somewhat unstable. Selective N-oxidation
of 14 followed by in situ Cope elimination gave a
hydroxylamine. Again no attempt was made to isolate
this species. On heating the intermediate hydroxylamine
to reflux in methanol, reverse Cope elimination gave the
morpholine N-oxides 15 and 16 in a 67% yield as a 5:2
mixture of diasteroisomers. These could be separated
Figure 1.
The stereochemistry of compound 6 was determined by
the X-ray crystallographic analysis of the borane salt 9
(Fig. 1).13 This was supported by NOESY experiments
on the parent compound 6.
The same methodology was also applied to (1R,2S)-(À)-
ephedrine 10 (Scheme 3). The precursor for the tandem
Cope elimination/reverse Cope elimination 11 was made
in 88% yield over two steps. Oxidation of amine 11 with
m-CPBA gave an intermediate N-oxide, which then
underwent Cope elimination in situ. The resulting
hydroxylamine was not isolated but after heating to re-
flux in CH2Cl2 yielded the morpholine amine N-oxide 12
in 36% yield as a single diastereoisomer. When the

N. Henry, I. A. O’Neil / Tetrahedron Letters 48 (2007) 1691–1694
1693
O
OH
Ph
O
N
1. m-CPBA, CH2Cl2, K2CO3
1. acrylonitrile,
MeOH, 97%
Me
-78 oC 3 h then RT
Me
Ph
Ph
2. NaH, THF, 0 oC
3. allyl bromide,
TBAI, 91%
Me
Me
2. Solvent, Δ, 72 h
NMe
NHMe
NC
Me
O
CH2Cl2 = 36%
MeOH = 45%
11
12
10
Scheme 3.
Ph
O
15
OH
Me
N
1. m-CPBA, CH2Cl2, K2CO3
O
1. acrylonitrile,
MeOH, 100%
-78 oC 3 h then RT
O
Me
Me
Me
OTBDMS
2. MeOH, Δ, 5 d, 67%
Ph
OTBDMS
+
Ph
2. NaH, THF, 0 oC
3. TBAI, 42%
Br
NHMe
Ph
O
NMe
CN
1
15/16 = 5:2
14
16
Me
N
13
Me
O
OTBDMS
OTBDMS
Scheme 4.
Ph
O
O
Ph
Ph
O
Me
Ph
Me
N
Me
N
NMe
O
Me
O
Me
NC
OH
OH
19
17
18
Figure 2.
by using rapid flash chromatography (Scheme 4). Pro-
longed exposure of this mixture to silica gel resulted in
the loss of the TBDMS protecting group to give com-
pounds 17 and 18 (Fig. 2).
ther, and investigating the wide variety of further trans-
formations possible from amine N-oxides.
Acknowledgements
We also prepared the phenyl substituted alkene 19
(Fig. 2) using the methodology described above, but
after oxidation and Cope elimination, the resulting
hydroxylamine failed to undergo reverse Cope elimina-
tion in either refluxing dichloromethane or methanol.
This was attempted with both ephedrine and pseudo-
ephedrine substrates. This result highlights the activating
effect of the allylic oxygen.8
We would like to thank Mr. Mehdi Mobli and Mr.
Jamie Bickley, Department of Chemistry, University
of Liverpool, for NMR and X-ray crystallographic
analysis, respectively. Dr. J. M. Southern is thanked
for his useful discussions. This work was supported by
the EPSRC.
In summary, we have reported new syntheses of highly
functionalized chiral, monocyclic morpholine amine N-
oxides utilizing the reverse Cope elimination. Out future
efforts will focus around adapting this methodology fur-
Supplementary data
The following supplementary data is available: (1) de-
tailed descriptions of experimental procedures, (2) H
1

1694
N. Henry, I. A. O’Neil / Tetrahedron Letters 48 (2007) 1691–1694
6. Oppolzer, W.; Bochet, C. G.; Spivey, A. C. J. Am. Chem.
Soc. 1994, 116, 3139–3140.
7. Williams, G. M.; Roughly, S. D.; Davies, J. E.; Holmes,
A. B. J. Am. Chem. Soc. 1999, 121, 4900–4901.
8. Knight, D. W.; Salter, R. Tetrahedron Lett. 1999, 40,
5915–5918.
NMR spectra. Supplementary data associated with this
article can be found, in the online version, at
doi:10.1016/j.tetlet.2007.01.047.
References and notes
9. House, H. O.; Lee, L. F. J. Org. Chem. 1976, 41, 863–
869.
1. Cooper, N. J.; Knight, D. W. Tetrahedron 2004, 60, 243–
269.
2. Black, D. St. C.; Doyle, J. Aust. J. Chem. 1978, 31, 2317–
2322.
3. (a) Ciganek, E. J. Org. Chem. 1990, 55, 3007–3009; (b)
Ciganek, E.; Read, J. M., Jr.; Calabrese, J. C. J. Org.
Chem. 1995, 60, 5795–5802, and 5803–5807.
4. (a) O’Neil, I. A.; Cleator, E.; Southern, J. M.; Hone, N.;
Tapolczay, D. J. Synlett 2000, 1408–1410; (b) O’Neil, I.
A.; Woolley, J. C.; Southern, M. J.; Hobbs, H. Tetra-
hedron Lett. 2001, 42, 8243–8245.
10. (a) O’Neil, I. A.; Southern, J. M. Tetrahedron Lett. 1998,
39, 9089; (b) O’Neil, I. A.; Cleator, E.; Southern, J. M.;
Hone, N.; Tapolczay, D. J. Synlett 2000, 695–697.
11. Lanman, B. A.; Myers, A. G. Org. Lett. 2004, 6, 1045–
1047.
12. O’Neil, I. A.; Cleator, E.; Ramos, V. E.; Chorlton, A. P.;
Tapolczay, D. J. Tetrahedron Lett. 2004, 45, 3655–3658.
13. The crystal structure has been deposited at the Cambridge
Crystallographic Data Centre and allocated the deposition
number CCDC 629517.
14. Ziegler, F. E.; Lim, H. J. Org. Chem. 1984, 49, 3278–
3281.
5. Palmer, A.; Ja¨ger, V. Synlett 2000, 1405–1406.