Direct conversion of epoxides into aziridines with N-arylphosphoramidates

Article abstract of DOI:10.1016/j.tetlet.2014.08.009

Treatment of terminal epoxides with N-arylphosphoramidate anions leads directly to N-aryl aziridines. Existing methods for this transformation employ either multi-step syntheses or an iminophosphorane in conjunction with a Lewis acid. The described method therefore presents an advantage in terms of brevity and atom economy.

Full text of DOI:10.1016/j.tetlet.2014.08.009

Tetrahedron Letters 55 (2014) 5890–5891
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct conversion of epoxides into aziridines
with N-arylphosphoramidates
Fabrizio Minicone, Wendy J. Rogers, James F. J. Green, Mommna Khan, Geoffrey M. T. Smith,
⇑
Christopher D. Bray
School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of terminal epoxides with N-arylphosphoramidate anions leads directly to N-aryl aziridines.
Existing methods for this transformation employ either multi-step syntheses or an iminophosphorane
in conjunction with a Lewis acid. The described method therefore presents an advantage in terms of brev-
ity and atom economy.
Received 10 July 2013
Revised 27 June 2014
Accepted 6 August 2014
Available online 13 August 2014
Ó 2014 Published by Elsevier Ltd.
Keywords:
Aziridine
Epoxide
Phosphoramidate
Ring-opening
Anion-relay
Despite being labelled the ‘ugly cousins’ of epoxides,1 aziridines
are valuable intermediates which undergo a variety of useful reac-
tions,2 most notably stereospecific and often regioselective ring-
opening with a variety of nucleophiles.3 They also act as precursors
to azomethine ylides for use in cycloaddition reactions,4 undergo
palladium-mediated annulations5 and arylations on nitrogen6
and carbon,7 as well as base-induced cyclopropanation, dimeriza-
tion and reductive alkylation.8 Furthermore, they are the key motif
within the azinomycin9 and mitomycin10 families of anticancer
natural products. The synthesis of aziridines is thus of interest
and can be achieved in a concerted process either by the addition
of a nitrene or carbene (or their equivalents) to either an alkene
or imine, respectively.11 Such processes often require the use of
metal catalysts in combination with chiral ligands in order to
achieve the desired regio and stereocontrol. The development
and optimization of such reactions are further complicated by var-
iation of the group on nitrogen. Stepwise approaches to the synthe-
sis of aziridines are therefore also popular. This can begin from
amino alcohols, which themselves are readily available from
chiral pool sources as well as through aminohydroxylation or
dihydroxylation/amination reactions of alkenes.1,2,11 Alternatively,
such a process can begin from an epoxide via a ring-opening with
azide followed in a separate step by Ph3P-mediated ring-closure.12
The increasing commercial availability of a range of enantiopure
epoxides thus renders their direct conversion into aziridines an
attractive process. Jørgensen and co-workers have reported that
the use of iminophosphoranes in the presence of Zn(II)-Lewis acids
facilitated this conversion.13 As part of our ongoing interest in the
synthesis of small rings,14 it struck us that, as one might intuitively
expect, the triethylphosphonoacetate anion is considerably more
reactive towards epoxides than the corresponding phosphorany-
lidene, and leads to much improved yields of the same cyclopro-
pane (Scheme 1).15 We therefore hypothesized that reaction of
an epoxide with a phosphoramidate anion might be more facile
than with an analogous iminophosphorane and that in fact, such
a reaction might proceed even in the absence of a Lewis acid.
We began by reacting ( )-styrene oxide with the anion of com-
mercially available diethyl N-phenylphosphoramidate. Different
temperatures, bases and solvents were screened whereupon it
was found that heating one equivalent of the lithiated phosphor-
amidate with the epoxide in dimethoxyethane (DME) at 70 °C gave
1,2-diphenylaziridine in 70% yield (Table 1, entry 1). Higher tem-
peratures and/or alternative counterions led to the formation of
Ph3P
CO2Et
Ph3P=NPh, 10% ZnCl2
210 °C, 21%
NR
O
80 °C, 72%
CO2Et
Ph
Ph
Ph
this work
110 °C, 64%
O
O
CO2Et
(EtO)2P
(EtO)2P-NR, no Lewis acid
needed
⇑
Corresponding author. Tel.: +44 (0)20 7882 3271; fax: +44 (0)20 7882 7427.
E-mail address: c.bray@qmul.ac.uk (C. D. Bray).
Scheme 1. Making cyclopropanes and aziridines from epoxides.
http://dx.doi.org/10.1016/j.tetlet.2014.08.009
0040-4039/Ó 2014 Published by Elsevier Ltd.

F. Minicone et al. / Tetrahedron Letters 55 (2014) 5890–5891
5891
Table 1
phosphoramidate anions still requires the use of a mild Lewis acid.
Finally, in an attempt to expand the scope of this reaction, we
treated styrene oxide with diethyl N-benzylphosphoramidate. TLC
analysis of this reaction revealed the epoxide was consumed, but
no aziridine was observed with the formation of only baseline mate-
rial. This would indicate that ring-opening had occurred but that
phosphonate transfer, to give intermediate 4, did not take place. This
observation is consistent with those of Wadsworth and Emmons
who noted the requirement during cyclopropane formation for an
anion-stabilizing group to assist in phosphonate transfer.16
In conclusion a simple method for the conversion of alkyl epox-
ides into N-arylaziridines that does not require the use of a Lewis
acid has been discovered using N-arylphosphoramidates.
1,2-Diphenylaziridine (2a): To a solution of diethyl N-phenyl
phosphoramidate (684 mg, 3.00 mmol) in DME (4.0 ml) was added
n-butyllithium (2.5 M; 1.23 ml, 3.00 mmol) at 23 °C. Styrene oxide
O
(EtO)2P-NAr
O
NAr
R
R
DME, 70 °C
Entry Epoxide
Ar
Aziridine
Yield (%)
70
O
NPh
1
2
1a Ph
1b Ph
2a
2b
Ph
Ph
Me
O
NPh
53
Me
O
O
O
O
O
NPh
NPh
NPh
NPh
3
4
5
6
1c Ph
1d Ph
1e Ph
2c
2d
2e
2f
48
53
20
20
BnO
BnO
F
F
1f
Ph
(342 ll, 3.00 mmol) was added in one portion. The reaction was
MeO
MeO
BnO
heated to 70 °C for 18 h. After cooling to 23 °C, the mixture was dis-
solved in CH2Cl2 (50 ml) and washed with saturated aqueous
NaHCO3 (50 ml) and brine (50 ml) before the organic layer was dried
over MgSO4. Once filtered, the solvent was removed in vacuo. The
residue was purified by flash column chromatography [Al2O3
(Brockmann-I), 10% Et2O in light petrol] to give the title compound
7
1c
2g
40
N
BnO
O
O
Ph
8
9
1a
1c
2h 71a
N
F
F
F
F
2a (410 mg, 70%) as a colourless oil; IR (cmÀ1
) mmax 3059, 3028,
Ph
2981, 1595, 1488, 1297; 1H NMR (400 MHz, CDCl3) d 7.51–7.42 (m,
4H), 7.41–7.32 (m, 3H), 7.17–7.13 (m, 2H), 7.11–7.06 (m, 1H), 3.19
(dd, J = 6.4 and 3.3 Hz, 1H), 2.55 (dd, J = 6.4 and 1.1 Hz, 1H) and
2.49 (dd, J = 3.3 and 1.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) d
154.6, 139.5, 129.1, 127.4, 126.3, 122.6, 120.6, 41.6, 37.6. These data
are in accord with those reported previously in the literature.17
BnO
2i
59a
N
BnO
a
CuI (1 equiv) added.
O
O
O
Acknowledgments
(EtO)2P-NAr
O
P(OEt)2
N
(EtO)2PO
O
NAr
N
R
R
Ar
R
Ar
R
We thank the EPSRC for a studentship (to F.M.) under a research
Grant (EP/G041431/1) and EPSRC/Syngenta for a CASE studentship
(to G.M.T.S). Mass spectrometry data were acquired at the EPSRC
UK National Mass Spectrometry Facility at Swansea University.
3
4
Scheme 2. Proposed reaction pathway.
greater amounts of intractable polymeric material. Reactions car-
ried out at lower temperature failed to go to completion in less
than 24 h. Reaction of lithium N-phenylphosphoramidate with a
range of simple alkyl epoxides led to the expected aziridines albeit
in moderate yields (entries 2–4). The diminished yields can be
explained by considering the proposed reaction pathway
(Scheme 2) where the final ring-closure event can occur at benzylic
position for styrene oxide rather than at a simple secondary alkyl
centre. It is noteworthy that the use of (R)-benzylglycidyl ether
(1c) led to an aziridine product (S)-2c in which there was complete
conservation of enantiomeric excess. Reaction with epifluorohy-
drin was low yielding (entry 5), which is likely due to eliminative
processes rather than ring-closure occurring for intermediate 4
(Scheme 2). This observation is in keeping with our findings seen
during cyclopropane formation with this substrate.14a This simi-
larly explains why vinyl oxirane was converted into the corre-
sponding aziridine in 20% yield (entry 6). Phosphoramidates
derived from electron-rich anilines such as m-anisidine reacted
with styrene oxide to give complete conversion, however isolation
of the resultant aziridines was difficult on account of their instabil-
ity towards column chromatography. It was possible however to
isolate aziridine 2g, which was marginally more tolerant of the
purification procedure. A more electron-deficient phosphorami-
date anion such as that derived from o-fluoroaniline, did not affect
the initial epoxide ring-opening with the starting materials being
returned unreacted. However, it was found that the addition of a
Cu(I)-salt enabled the reactions to proceed as intended (entries 8
and 9), which suggests that aziridination with electron-deficient
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
08.009.
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