Intramolecular epoxidation of unsaturated oxaziridines

Article abstract of DOI:10.1055/s-1998-1733

Treatment of unsaturated oxaziridines with MeOTf results in intramolecular epoxidation, presumably via oxaziridinium salts. The method has been used to effect regioselective epoxidation of a nonconjugated diene.

Full text of DOI:10.1055/s-1998-1733

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SYNLETT
Intramolecular Epoxidation of Unsaturated Oxaziridines
Alan Armstrong,* Alistair G. Draffan
Department of Chemistry, University of Nottingham, Nottingham NG7 2RD, UK
Fax +44 115 9513564; E-mail Alan.Armstrong@nottingham.ac.uk
Received 14 March 1998
Abstract: Treatment of unsaturated oxaziridines with MeOTf results in
intramolecular epoxidation, presumably via oxaziridinium salts. The
method has been used to effect regioselective epoxidation of a non-
conjugated diene.
in CH Cl with MeOTf followed by brief exposure to aqueous NaHCO
2 2 3
afforded the epoxyaldehyde 4a in moderate yield as the only isolated
13
product. A crossover experiment was then performed to demonstrate
that the epoxidation process was indeed intramolecular: an equimolar
mixture of 3a and benzyl ether 5 in CH Cl was treated with MeOTf
2
2
followed by aqueous NaHCO . The benzyl ether 5 was recovered in
3
Reactions in which regio- and stereoselectivity are controlled by
”internal delivery” of reagent are of great importance in organic
good yield (73%), with no evidence of the corresponding epoxide, while
4a was again the major product (39%). Since 5 would be expected to
undergo intermolecular electrophilic epoxidation as least as quickly as
3a or the unsaturated oxaziridinium salt derived from it (and probably
faster than the latter due to the –I inductive effect of the oxaziridinium
group), this suggests that the selective epoxidation of 3a in this
experiment is due to an intramolecular epoxidation process.
1
synthesis. In the area of alkene epoxidation, high selectivity has been
1
accomplished by hydroxyl-directed processes. As an alternative
approach, we have been interested in the possibility of intramolecular
2
oxygen delivery from carbonyl groups and we have also begun an
investigation of the possibility of intramolecular epoxidation with
unsaturated oxaziridines. Oxaziridines have rarely been used for alkene
3
epoxidation: indeed, N-unsubstituted oxaziridines are reported to
4
transfer nitrogen rather than oxygen to olefins. However, introduction
3b
5
of electron withdrawing N-sulfonyl or N-phosphinoyl groups does
result in active epoxidants, and perfluorooxaziridines are also capable of
6
oxygen transfer to olefins. As a first stage in our investigations of
The homologue 1b, with an extra carbon atom in the linking tether and
potentially an eventual precursor to a tetrahydropyran rather than a
tetrahydrofuran product, was investigated next (Table 1, entry 2).
Application of the same reagent sequence again provided the
epoxyaldehyde (4b, 41%), and a crossover experiment as described
above again suggested that the epoxidation process was indeed
intramolecular. Having established the feasibility of the process, a range
of substrates of varying alkene substitution pattern were examined
(Table 1). As well as trisubstituted alkenes (2a and 2b, entries 1 and 2),
1,1-disubstituted (2c, entry 3), and E- or Z- 1,2-disubstituted olefins
intramolecular oxaziridine epoxidation, we were particularly attracted to
7
the pioneering work of Hanquet and Luscini and co-workers who
demonstrated that N-quaternisation of oxaziridines leads to
8
oxaziridinium salts which can efficiently transfer oxygen to alkenes.
We wondered whether an intramolecular version of this process
(Scheme 1) might allow regio- and/or stereoselective alkene
epoxidation, providing, after iminium hydrolysis, a stereocontrolled
route to epoxycarbonyl compounds as precursors to oxygen
9
heterocycles via rearrangement. Here we report the realisation of the
concept of intramolecular oxaziridinium epoxidation and demonstrate
its use for the regioselective epoxidation of a non-conjugated diene.
®
(2d-f, entries 4-6) underwent the selective Oxone oxidation and
subsequent epoxidation. In all cases, the epoxyaldehydes 4 were
obtained in moderate yields; this may be partly due to product volatility
1
since analysis of the TLC and crude H NMR spectrum did not indicate
the formation of significant by-products. The low yields do not appear
to be due to the presence of triflic acid (from hydrolysis of MeOTf),
since addition of 2,6-di-tert-butylpyridine (4 eq relative to oxaziridine)
to the reaction mixture did not improve yields.
Scheme 1
The first substrate to be examined was the unsaturated imine 2a,
10
prepared from the corresponding aldehyde 1a (Scheme 2 and Table 1).
As a key requirement of the proposed sequence, selective oxidation of
the imine in the presence of the alkene was necessary. There was
surprisingly little precedent for this, although scattered examples of the
use of mCPBA, usually at low temperature, were to be found in the
11
®
literature. We were pleased to find that Oxone in CH CN / H O
3
2
12, 13
effected this transformation cleanly (Scheme 2, Table 1).
Scheme 2
Moreover, treatment of a 42 mM solution of the resulting oxaziridine 3a

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SYNLETT
647
York, 1985; vol. 42, Chapter 3. (b) Davis, F.A.; Sheppard, A.C.
Tetrahedron 1989, 45, 5703.
(4) Andreae, S.; Schmitz, E. Synthesis 1991, 327.
(5) Boyd, D.R.; Jennings, W.B.; McGuckin, R.M.; Rutherford, M.;
Saket, B.M. J. Chem. Soc., Chem. Commun. 1985, 582.
(6) Arnone, A.; DesMarteau, D.D.; Novo, B.; Petrov, V.A.;
Pregnolato, M.; Resnati, G. J. Org. Chem. 1996, 61, 8805. Petrov,
V.A.; Resnati, G. Chem. Rev. 1996, 96, 1809.
(7) (a) Hanquet, G.; Lusinchi, X.; Milliet, P. Tetrahedron Lett. 1988,
29, 3941. (b) Hanquet, H.; Lusinchi, X.; Milliet, P. C.R. Acad. Sci.
Paris 1991, 313, 625. (c) Bohé, L.; Hanquet, G.; Lusinchi, M.;
Lusinchi, X. Tetrahedron Lett. 1993, 34, 7271. Lusinchi, X;
Hanquet, G. Tetrahedron 1997, 40, 13727.
Finally, the application of the method to the regioselective epoxidation
of a polyene was investigated. We were pleased to find that treatment of
unsaturated oxaziridine derived from aldehyde 6 with MeOTf then
10
(8) Aggarwal, V.K.; Wang, M.F. Chem. Commun. 1996, 191.
Armstrong, A.; Ahmed, G.; Goacolou, K.; Garnett, I. Synlett
1997, 1075. Page, P.C.B.; Rassias, G.A.; Bethell, D.; Schilling,
M.B., in the press.
aqueous NaHCO resulted solely in epoxidation at the disubstituted
3
olefin, leading to 7 (48%) (Scheme 3). In contrast, epoxidation of the
corresponding alcohol 8 with mCPBA (1 eq) led to the regioisomeric
epoxide 9 as the sole product (75%) via epoxidation of the more
electron rich alkene (Scheme 4).
(9) Wasserman, H.H.; Barber, E.H. J. Am. Chem. Soc. 1969, 91, 3674.
Wasserman, H.H.; Wolff, S.; Oku, T. Tetrahedron Lett. 1986, 27,
4909. Wasserman, H.H.; Oku, T. Tetrahedron Lett. 1986, 27,
4913. Fotsch, C.H.; Chamberlin, A.R. J. Org. Chem. 1991, 56,
4141. Kotsuki, H. Synlett 1992, 97.
(10) The unsaturated aldehydes 1 and 6 are literature compounds. 1a:
Marfat, A.; McGuirk, P.R.; Helquist, P. J. Org. Chem. 1979, 44,
3888. 1b: Hudson, C.M.; Marzabadi, M.R.; Moeller, K.D.; New,
D.G. J. Am. Chem. Soc. 1991, 113, 7372. 1c: Taura, Y.; Tanaka,
M.; Wu, X.; Funakoshi, K.; Sakai, K. Tetrahedron 1991, 47, 4879.
1d-f: Bestmann, H.J.; Koschatzky, K.H.; Schätzke, W.; Süβ, J.;
Vostrowsky, O. Liebigs Ann. Chem. 1981, 1705. 6: Takigawa, T.;
Mori, K.; Matsui, M. Agric. Biol. Chem. 1975, 39, 249.
Scheme 3
(11) For example: Aubé, J.; Wang, Y.; Hammond, M.; Tanol, M.;
Takusagawa, F.; Vander Velde, D. J. Am. Chem. Soc. 1990, 112,
4879. Aubé, J.; Gülgeze, B.; Peng, X. Bioorg. Med. Chem. Lett.
1994, 4, 2461.
®
(12) Oxidation of imines by Oxone has been reported previously:
Scheme 4
Hajipour, A.R.; Pyne, S.G. J. Chem. Res. (S) 1992, 388.
(13) General procedure for preparation of unsaturated imines 2:
To a stirred solution of unsaturated aldehyde 1 (5.0 mmol) in
We have demonstrated that intramolecular epoxidation via unsaturated
oxaziridinium salts is feasible, and that this method allows
regioselective epoxidation of a polyene. We are currently investigating
the use of the reaction sequence for acyclic stereocontrol, as well as
using the unsaturated oxaziridine substrates to develop alternative
methods (e.g. metal catalysis) to activate oxaziridines for oxygen
transfer.
CH Cl (5 ml) under nitrogen was added benzylamine (536 mg,
2
2
5.0 mmol) followed by powdered 4Å molecular sieves (500 mg).
The reaction was stirred for 15 hours, filtered and the sieves
washed with CH Cl . The solvent was removed under reduced
2
2
pressure to yield the crude imine 2 as a yellow oil which was
1
carried on to the next stage without purification. In all cases, H
NMR showed a single imine, presumed to be the E-isomer.
General procedure for preparation of unsaturated oxaziridines 3:
To a stirred solution of imine 2 (4.0 mmol) in acetonitrile (60 ml)
Acknowledgements. We thank the EPSRC for ther support of this
work. We also thank Dr. J.A. Ballantine and the EPSRC mass
spectrometry service for accurate mass measurements. This work
was added deionised water (40 ml). To this homogeneous solution
®
was added a mixture of Oxone (1.48 g, 4.8 mmol KHSO ) and
14
5
benefitted from access to the EPSRC Chemical Database Service.
NaHCO (627 mg, 7.46 mmol). The reaction was stirred for 30
3
minutes, poured into water (100 ml) and extracted with CH Cl (3
2
2
References and Notes
x 50 ml). The combined organic extracts were dried (MgSO ),
4
filtered and the solvent removed under reduced pressure to give a
yellow oil. Flash column chromatography (petrol/ethyl acetate
(1) Hoveyda, A.H.; Evans, D.A.; Fu, G.C. Chem. Rev. 1993, 93, 1307.
(2) Armstrong, A.; Barsanti, P.A.; Clarke, P.A.; Wood, A.
Tetrahedron Lett. 1994, 35, 6155; J. Chem. Soc., Perkin Trans. 1
1996, 1373.
10:1) on base-washed silica (1% Et N in eluent) yielded the
3
1
oxaziridine as a colourless oil. In all cases, H NMR indicated that
a single oxaziridine diastereomer was present. All products
1
13
(3) For reviews of oxaziridine chemistry, see: (a) Haddadin, M.S.;
Freeman, J.P. in The Chemistry of Heterocyclic Compounds:
Small Ring Heterocycles - Part 3. Hassner, A., ed., Wiley: New
displayed satisfactory
H
and
C NMR, IR, MS and
microanalytical or accurate mass data. Characteristic resonances
1
for the oxaziridine were at ca. 3.9 ppm (t) in the H NMR

648
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SYNLETT
13
spectrum (HC(O)N), and at 81-83 ppm in the
C NMR
vigorously for 20 minutes before separation and extraction of the
(oxaziridine ring carbon).
aqueous layer with CH Cl (3 x 5 ml). The combined organic
2
2
Data for 3a: colourless oil, ν
(film) 2916, 1640, 1496, 1453,
extracts were dried (MgSO ), filtered and the solvent removed
max
4
-1
737, 697 cm ; δ (270 MHz, CDCl ) 7.37-7.29 (5H, m, Ar-H),
under reduced pressure to yield a yellow oil. Flash column
chromatography (petrol/ethyl acetate 5:1) yielded the epoxy
aldehyde as a colourless oil. All products displayed satisfactory
H
3
5.11-5.05 (1H, m, HC=C(CH ) ), 3.90 (1H, t, 5.0 Hz, HCN(O)),
3 2
3.83 (2H, s, PhCH N), 2.14-2.06 (2H, m, CH ), 1.74-1.67 (2H, m,
2
2
1
13
CH ), 1.67 (3H, s, CH ), 1.58 (3H, s, CH ); δ (68 MHz, CDCl )
2
3
3
C
3
H and C NMR, IR, MS and microanalytical or accurate mass
135.5 (s), 132.7 (s), 128.8 (d), 128.6 (d), 127.8 (d), 122.7 (d), 81.8
(d), 65.6 (t), 32.3 (t), 25.6 (q), 22.7 (t), 17.6 (q); m/z (CI) 218
(M+H, 100%), 200, 146, 132, 126, 106, 91. (Observed MH
data.
Data for 4a: colourless oil, ν
(film) 2965, 2728, 1724, 1458,
max
+
-1
1380, 1252, 1124, 916 cm ; δ (270 MHz, CDCl ) 9.83 (1H, t,
H
3
218.1544. C
H NO requires 218.1545).
14 20
1.5 Hz, HC=O), 2.77 (1H, dd, 7.5, 5.0 Hz, HC(O)C(CH ) ), 2.69-
3 3
General procedure for methylation of oxaziridines
hydrolysis to epoxy aldehydes 4: To a stirred solution of
oxaziridine 3 (0.25 mmol) in freshly distilled CH Cl (6 ml) under
3
and
2.63 (2H, m, CH C(H)=O), 2.03-1.90 (1H, m, CHHCH(O)), 1.80-
2
1.67 (1H, m, CHHCH(O)), 1.32 (3H, s, CH ), 1.30 (3H, s, CH );
3
3
2
2
δ
(68 MHz, CDCl ) 201.6 (d), 63.4 (d), 59.2 (s), 41.1 (t), 25.0
3
C
nitrogen was added methyltrifluoromethanesulfonate (0.056 ml,
0.5 mmol) dropwise. The reaction was followed by TLC with a
further amount of methyltrifluoromethanesulfonate (0.5 mmol)
added every 90 minutes until reaction was complete. Saturated
(q), 21.8 (t), 19.0 (q); m/z (EI) 129 (M+H, 100%), 111, 95, 85, 71.
+
(Observed MH 129.0911. C H O requires 129.0915).
7
13 2
(14) Fletcher, D.A.; McMeeking, R.F.; Parkin, D. J. Chem. Inf.
Comput. Sci. 1996, 36, 746.
aqueous NaHCO (3 ml) was added and the reaction stirred
3