Heteroatom transfer to alkenes by N-protected-oxaziridines: New reaction pathways and products

Article abstract of DOI:10.1016/j.tetlet.2005.02.034

N-Alkoxycarbonyl- and N-carboxamido-oxaziridines are shown to react with aromatic alkenes to give epoxide, aziridine or hydro-oxidation products, in ratios depending on the oxaziridine structure. Chiral oxaziridines can effect epoxidation and hydro-oxidation with promising levels of asymmetric induction.

Full text of DOI:10.1016/j.tetlet.2005.02.034

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2207–2210
Heteroatom transfer to alkenes by N-protected-oxaziridines:
new reaction pathways and products
a,
Alan Armstrong, Ian D. Edmonds and Martin E. Swarbrick
a
b
*
a
Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK
b
Neurology and Gastrointestinal Diseases Centre of Excellence for Drug Discovery, GlaxoSmithKline,
New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
Received 22 December 2004; revised 31 January 2005; accepted 7 February 2005
Abstract—N-Alkoxycarbonyl- and N-carboxamido-oxaziridines are shown to react with aromatic alkenes to give epoxide, aziridine
or hydro-oxidation products, in ratios depending on the oxaziridine structure. Chiral oxaziridines can effect epoxidation and hydro-
oxidation with promising levels of asymmetric induction.
Ó 2005 Elsevier Ltd. All rights reserved.
The high levels of asymmetric induction that have been
1
of a new reaction product, and a promising initial
attempt at asymmetric induction.
observed in the reaction of chiral dioxiranes and oxaz-
2
iridinium salts with alkenes suggest that the closely re-
lated oxaziridines may also have considerable potential
for asymmetric heteroatom transfer. The extra stereo-
centre at nitrogen may allow good levels of epoxidation
stereocontrol with a wider range of alkenes than is the
case with dioxiranes. Additionally, there is the intriguing
possibility of effecting alkene aziridination, which we
have recently shown computationally to be a feasible
O NR1
R2
R3
3
1
2
-
1
2
R =H, R , R =-(CH2)5
R =Moc, R =Ph, R =H
1
2
3
3
process. However, while Davis has shown that certain
N-sulfonyloxaziridines can epoxidize alkenes with good
Preliminary experiments indicated that thermal reaction
of aromatic alkenes with N-alkoxycarbonyl- and N-carb-
oxamido-oxaziridines under solvent-free conditions led
to productive reactions (Table 1). Due to the volatility
of the simple alkenes employed, they were generally used
in an excess (3equiv), with isolated yields based on the
more valuable oxaziridine as the limiting reagent. In
an initial study using styrene and the N-carboxamido-
oxaziridine 4a, we obtained two major products (entry
4
levels of enantioselectivity, there are very few other re-
ports of effective heteroatom transfer from oxaziridines
to alkenes. To date, the only report of alkene aziridin-
5
ation by oxaziridines has been by Schmitz, who de-
scribed reaction of NH-oxaziridine 1 with aromatic
alkenes. Transfer of protected nitrogen would be espe-
cially interesting, but in their pioneering studies of the
chemistry of N-alkoxycarbonyloxaziridines, Collet and
co-workers indicated that 2 failed to react with cyclo-
1
). Along with the expected epoxide 6 we obtained a sig-
6
hexene. In this letter, we report preliminary investiga-
nificant and interesting new product, assigned spectro-
scopically (with support from a subsequent crystal-
lographic structure determination—vide infra) as the
imidate 5. We were then able to probe the effect of the
tions on the reaction of a range of N-alkoxycarbonyl-
and N-carboxamido-oxaziridines with alkenes, demon-
strating the first examples of productive heteroatom
transfer to alkenes with this reagent class, identification
8
oxaziridine structure on the product ratio. Staying with
aldehyde-derived oxaziridines, but changing to the N-
Boc series with 4b, the proportion of the aziridine prod-
uct 7 was increased (entry 2), again accompanied by
epoxide 6 and imidate 5. Our mechanistic rationale (vide
infra) required the presence of the oxaziridine ring
Keywords: Oxaziridines; Amination; Aziridines; Epoxides.
*
Corresponding author. Tel.: +44 020 75945876; fax.: +44 020
5945804; e-mail: a.armstrong@imperial.ac.uk
7
0
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.034

2208
A. Armstrong et al. / Tetrahedron Letters 46 (2005) 2207–2210
7
Table 1. Reaction of aromatic alkenes with oxaziridines
O
R1
O
N
X
R1
O
N
O
R1
R1
O
Y
4
Ph
O
N
X
R2
R2
R2
Z
Ph
R2
Y
X
Ph
Ph
typically:
3
neat, 50°C, 50 h
5
6
7
1
R
2
R
d
e
e
e
Entry
3
4
X
Y
Z
5:6:7
% 5
% 6
% 7
f
1
2
3a
H
H
4a
4b
4c
4d
4a
4b
4c
4a
4b
4c
NEt
2
p-ClC
6
H
4
H
H
46:46:8
40
25
—
—
39
49
—
27
23
—
21
32
17
nd
t
O Bu
p-CNC
6
H
4
24:41:35
0:32:68
0:13:87
50:50:0
47:53:0
0:100:0
36:64:0
23:73:4
0:96:4
23
24
52
—
—
—
—
a
t
O Bu
t
O Bu
3
2
CO Et
Ph
CO
CO
H
2
Et
Me
b
f
4
c
2
nd
5
3b
3c
Ph
H
H
NEt
2
p-ClC
p-CNC
CO Et
6
H
4
50
50
82
34
57
79
t
O Bu
6
6
H
4
H
a
t
O Bu
7
2
CO
H
2
Et
t
O Bu
8
CH
3
p-CNC
p-CNC
6
H
H
4
4
t
O Bu
f
9
6
H
nd
c
t
O Bu
f
1
0
CO Et
2
CO
2
Et
nd
a
b
c
d
e
f
Reaction at room temperature for 96 h.
Reaction at room temperature for 3weeks.
1
equiv alkene employed.
Measured by integration of peaks in the H NMR spectrum of the crude product.
1
Isolated yields.
nd = not determined.
proton for formation of 5, so we reasoned that use of
3
dations and aziridinations, computational and experi-
mental studies favour an asynchronous concerted
process, at least for N-sulfonyl and N–H oxaziri-
,3-disubstituted oxaziridines should prevent this. Addi-
tionally, we reasoned that developing interactions be-
tween the N-Boc-substituent and the C3-substituent in
the imine co-product should disfavour oxygen transfer.
This strategy previously proved successful for control-
3
,10
dines.
In order to determine whether the N-carbonyl
oxaziridines studied here were also effecting concerted
heteroatom transfer, the stereospecificity was probed
by reaction of cis- and trans-stilbene with oxaziridine
4c. cis-Stilbene (96% purity) reacted at room tempera-
ture over 114 h to afford a 20:2:1 mixture of cis-epox-
9
ling sulfide amination versus oxidation. In accord with
these ideas, the use of ketone-derived oxaziridine 4c led
to the aziridine for the first time being the major reac-
tion product (entry 3), although the isolated yield was
low. An alternative 3,3-disubstituted oxaziridine 4d led
to an acceptable yield of aziridine (entry 4), albeit after
a long reaction time. In future studies, incorporation of
further electron withdrawing substituents might be
expected to provide increased reactivity.
1
ide:cis-aziridine:trans-epoxide according to H NMR
analysis. trans-Stilbene gave only ꢀ10% conversion un-
der the same conditions and only the trans-epoxide
product could be detected. These results suggested that
the epoxidation and aziridination reactions are syn-ste-
reospecific and therefore likely to be concerted. For
the formation of the imidates 5, a possible mechanism
involves homolytic cleavage of the oxaziridine N–O
bond, subsequent addition of the oxygen-centred radical
to the alkene to give a stabilised benzylic radical, and
final hydrogen radical abstraction to generate the
carbon–nitrogen double bond (Scheme 1). Control
experiments established that 5 is not derived from open-
ing of epoxide 6 under the reaction conditions.
We then probed the effect of alkene structure. In line
with previous findings that steric hindrance in the nucleo-
6
,9
phile disfavours nitrogen transfer, we did not observe
any aziridine product with a-phenylstyrene 3b (entries 5–
7
). With aldehyde-derived oxaziridines 4a and 4b, this alk-
ene again gave a mixture of imidate 5 and epoxide 6
entries 5 and 6). 3,3-Disubstituted oxaziridine 4c now
(
effected epoxidation exclusively, providing a good yield
of 6 (entry 7). Similar results were obtained when a b-
substituted aromatic alkene, E-b-methylstyrene 3c, was
used (entries 8–10). Preliminary attempts at using alk-
enes without an aromatic substituent in reactions with
Finally, we decided to investigate the possibility of
asymmetric induction in these reactions by employing
enantiomerically pure, chiral oxaziridines. We employed
the diastereomeric N-carboxamido-oxaziridines 8a and
8b, the synthesis and configurational assignment of
4
a so far have led to complex product mixtures. Never-
theless, the reactions of these aromatic alkenes provided
good yields of epoxide in some cases, as well as access to
the novel product 5, a process, which can be viewed as
an alternative to hydroboration/oxidation. The first
examples of aziridination by this class of oxaziridine
have also been revealed.
COX
COX
COX
O
N
N
N
O
O
Ar
Ar
Ar
H
H
H
Ar
Ar
Ar
Interesting mechanistic questions arise regarding all
three of the observed reaction products. For the epoxi-
Scheme 1. Potential mechanisms of hydro-oxidation.

A. Armstrong et al. / Tetrahedron Letters 46 (2005) 2207–2210
2209
1
1
which we have previously reported, and examined
their reaction with trans-b-methylstyrene. The chemose-
lectivity was consistent with the trends observed for the
achiral oxaziridines, with epoxidation predominating
Ph
N
Ph
H
N
O
(
Table 2). Promising diastereoselectivities were ob-
tained: the benzimidate 9 was formed with 70% de and
the epoxide 6 with 47 or 56% ee. The absolute configu-
ration of 9 was assigned by X-ray crystallography of
the major diastereomer ((R)-9) derived from reaction
O
Cl
1
2
of oxaziridine 8a (Fig. 1). It is interesting to note that
a and 8b gave opposite and approximately equal stereo-
selectivity in formation of 9 and 6. This reinforces the
Figure 1. X-ray crystal structure of benzimidate (R)-9.
8
observation made in the previous diastereoselective sulf-
for oxaziridine 8a. Both planar and spiro transition state
models are shown, that minimise steric interactions or
maximise p–p interactions.
1
1
imidation with these oxaziridines, that the ring carbon
stereocentre has greater influence than the N-substituent
over the stereoselectivity. In addition, it is of note that
for a given oxaziridine, the epoxide and imidate prod-
ucts have opposite configurations of the newly formed
In conclusion, we have demonstrated for the first time
that N-alkoxycarbonyl- and N-carboxamido-oxazir-
idines can react productively with alkenes. We have also
assessed the effect of oxaziridine structural modifications
on product ratios, and shown that promising levels of
stereocontrol are possible. While the yields of the reac-
tion products are currently moderate-to-low, the studies
suggest synthetic targets for new oxaziridine reagents
offering higher levels of chemo- and stereoselectivity,
as well as improving our understanding of the factors
affecting these.
1
0b
stereocentre. Possible models that can rationalise
the observed stereoselectivity are shown in Figure 2
Table 2. Asymmetric reaction of enantiopure oxaziridines with trans-
b-methylstyrene
O
Ph
O
Ph
N
N
N
N
O
O
Ph
Ph
8b
N
Cl
8a
Cl
Ph
Acknowledgements
8
a or 8b
neat, 50°C, 48 h
O
O
O
We are grateful to the EPSRC (GR/R54668) and GSK
(CASE award to I.D.E.) for their support of this work.
We thank Dr. N. Treweeke for performing some control
experiments.
Ph
+
Ph
Ar
NR2
3
c
6
9
Ar=p-ClC6H4
R=N(CH(CH3)Ph)2
a
b
% 9 9 dr
a
b
% 6 % ee 6
c
Entry Oxaziridine 9:6
References and notes
1
2
8a
8b
30:70 30
33:67 30
85:15 (R) 25
85:15 (S)
47 (S,S)
4 5 R6 , (R )
3
1
. Shi, Y. Acc. Chem. Res. 2004, 37, 488–496; Yang, D. Acc.
Chem. Res. 2004, 37, 497–505; Armstrong, A. Angew.
Chem., Int. Ed. 2004, 43, 1460–1462.
2. Bulman Page, P. C.; Buckley, B. R.; Blacker, A. J. Org.
Lett. 2004, 6, 1543–1546.
a
1
Measured by integration of the H NMR spectrum of the crude
product.
Isolated yields.
b
c
1
Determined by H NMR in the presence of Eu(hfc)
3
.
H
Ar
CONR2
N
CONR2
N
O
Ar
O
Me
O H
H
Ph
Ph
H
H
Me
Ph
H
(
S,S)
Me
Asynchronous spiro transition state
with attractive π-stacking interaction
and steric repulsion of oxaziridine H.
Synchronous planar transition state
with minimisation of steric
interactions.
CONR2
N
CONR2
H
Ar
N
Ar
H
O
O
N
O
O
Ph
Ph
H
H
Me
Ph
H
H
Me
Ar
R)-9
NR2
(
Stepwise 'spiro' transition
state with minimisation of
steric interactions.
Stepwise 'planar' transition
state with attractive π-
stacking interaction.
Figure 2. Possible models of stereoselectivity for oxaziridine 8a.

2210
A. Armstrong et al. / Tetrahedron Letters 46 (2005) 2207–2210
3
. Washington, I.; Houk, K. N.; Armstrong, A. J. Org.
Chem. 2003, 68, 6497–6501.
. Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45, 5703–
126.5 (CH), 67.5 (CH
2
), 42.4 (CH
2
), 40.5 (CH
2
), 35.0
) 3 59
359.1531.
(CH
([M+H] ,
2
), 13.8 (CH
3
), 13.0 (CH
100%); Found:
20 24 2 2
C H N O Cl requires: [M+H] 359.1526.
3
); m/z (CI, NH
3
+
+
4
[M+H] ,
5742; Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919–
934.
8. Oxaziridines 4a (Armstrong, A.; Atkin, M. A.; Swallow, S.
Tetrahedron Lett. 2000, 41, 2247–2251), 4b (Ref. 6) and 4c
(Ref. 9) were prepared as described previously. Oxaziri-
dine 4d was prepared from N-Boc-phenylalanine by
5
6
. Andreae, S.; Schmitz, E. Synthesis 1991, 327–341.
. Vidal, J.; Damestoy, S.; Guy, L.; Hannachi, J.; Aubry, A.;
Collet, A. Chem. Eur. J. 1997, 3, 1691–1709.
7
. Typical procedure: Reaction between styrene and oxazir-
idine 4a. A mixture of the oxaziridine 4a (100 mg,
bromination/elimination (NBS, CCl
by imine oxidation (mCPBA, K CO , CH Cl /H O; 91%).
4
, hm; 63%) followed
2
3
2
2
2
0
.39 mmol) and styrene (140 lL, 1.22 mmol) was stirred
9. Armstrong, A.; Cooke, R. Chem. Commun. 2002, 904–905.
10. (a) Anderson, D. R.; Woods, K. W.; Beak, P. Org. Lett.
1999, 1, 1415–1417; (b) Houk, K. N.; Liu, J.; DeMello, N.
C.; Condroski, K. R. J. Am. Chem. Soc. 1997, 119, 10147–
10152.
at 50 °C under nitrogen for 50 h to afford a 46:8:46 crude
ratio of 5:6:7. Purification by flash chromatography (5–
30% EtOAc in petrol) afforded epoxide 6 (10 mg, 21%)
and imidate 5 (56 mg, 40%), isolated as a yellow oil, mmax
cm 3029, 2974, 2934, 1664, 1644, 1472, 1425, 1267, 1109,
/
À1
11. Armstrong, A.; Edmonds, I. D.; Swarbrick, M. E.
Tetrahedron Lett. 2003, 44, 5335–5338.
1
015, 836, 700; d
Ar–H), 7.35–7.25 (7H, m, Ar–H), 4.48 (2H, t, J 7.1,
OCH ), 3.39 (2H, q, J 7.0, NCH CH ), 3.19 (2H, q, J 7.0,
NCH CH ), 3.09 (2H, t, J 7.1, PhCH ), 1.13( 3H , t, J 7.0,
NCH CH ), 1.03( 3H , t, J 7.0, NCH CH ); d (75.4 MHz,
H 3
(250 MHz, CDCl ) 7.59 (2H, d, J 8.5,
12. We are grateful to Dr. A. J. P. White, Dept. of Chemistry,
Imperial College London, for this structure determination.
Crystallographic data for 9 (excluding structure factors)
have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication number CCDC
258891.
2
2
3
2
3
2
2
3
2
3
C
CDCl ) 160.7 (C), 158.5 (C), 137.9 (C), 137.4 (C), 131.0
(
3
C), 129.6 (CH), 128.9 (CH), 128.5 (CH), 128.5 (CH),