First Sustainable Aziridination of Olefins Using Recyclable Copper-Immobilized Magnetic Nanoparticles

Article abstract of DOI:10.1055/s-0037-1611717

The first copper-catalyzed aziridination of olefins using recyclable magnetic nanoparticles is described. Magnetic nanoparticles were modified with dopamine and used as a support to coordinate copper. The methodology was optimized with styrene as olefin a

Full text of DOI:10.1055/s-0037-1611717

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© Georg Thieme Verlag Stuttgart · New York
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M. Khodadadi et al.
Letter
Synlett
First Sustainable Aziridination of Olefins Using Recyclable Copper-
Immobilized Magnetic Nanoparticles
Mohamad Reza Khodadadia
Gwladys Pourceaua
Matthieu Becuweb
Anne Wadouachia
Sylvestre Toumieux*a
a Laboratoire de Glycochimie, des Antimicrobiens et des Agror-
essources (LG2A) CNRS UMR 7378–Institut de Chimie de
Picardie FR 3085, Université de Picardie Jules Verne, 33 Rue
Saint Leu, 80039 Amiens Cedex, France
sylvestre.toumieux@u-picardie.fr
b Laboratoire de Réactivité et Chimie des Solides (LRCS), CNRS
UMR 7314–Institut de Chimie de Picardie FR 3085, Université
de Picardie Jules Verne, 33 Rue Saint Leu, 80039 Amiens
Cedex, France
Received: 22.12.2018
Accepted after revision: 07.01.2018
Published online: 11.02.2019
backs, such as stability, separation, and recovery, which are
not well-suited for sustainable chemistry. Moreover, the
copper counterion could cause dramatic damage or is
DOI: 10.1055/s-0037-1611717; Art ID: st-2018-u0707-l
–
strongly harmful for the environment (i.e., PF6 ). Finally, the
Abstract The first copper-catalyzed aziridination of olefins using re-
cyclable magnetic nanoparticles is described. Magnetic nanoparticles
were modified with dopamine and used as a support to coordinate cop-
per. The methodology was optimized with styrene as olefin and using
[N-(p-toluenesulfonyl)imino]phenyliodinane (PhI=NTs) as nitrene
source. A microwave irradiation decreased the reaction time by 4-fold
compared to conventional heating method. The catalyst was recovered
by simple magnetic extraction and could be reused successfully up to
five times without significant loss of activity. The methodology was
applied to a range of different olefins leading to moderate to excellent
yields in the formation of the expected aziridine.
recycling of the metal is often obscured and only few re-
searches have been engaged toward catalyst recycling. To
circumvent all these concerns, recoverable catalytic sys-
tems had been depicted by supporting the metal on organic
or inorganic materials, such as zeolite, alumina or multi-
walled carbon nanotubes.17 For example, a heterogeneous
catalyst was designed by insertion of copper(II) ligand com-
plex inside Y zeolite pores.18–20 The catalyst may be reused
by filtration and/or centrifugation. Copper supported by
alumina was also used for the aziridination but limitations
such as tedious catalyst preparation, low yields, and long
reaction times reduce its efficiency.21,22 Moreover, the pro-
cedures related to these supported catalysts usually used a
large excess of sometimes hardly obtained olefins toward a
stoichiometric amount of the cheap PhI=NTs as a limiting
reagent.
Otherwise, thanks to their ease of recovery, magnetic
nanoparticles (MNP) have become more and more attrac-
tive to support organic or inorganic catalysts. Examples
with Fe3O4 grafted with the robust and stable dopamine to
coordinate metals23 were successfully reported for oxida-
tion,24 hydrogenation,25 or Suzuki coupling reactions.26
Nevertheless, the use of modified MNP with copper as het-
erogeneous supported catalysts for aziridination was never
reported yet.
Key words sustainable aziridination, magnetic nanoparticle, copper
catalyst, nitrene insertion
Insertion of nitrogen atom to an organic scaffold has
arisen as a fundamental step in organic synthesis. Valuable
tools, such as nitrene insertion onto Csp3–H bonds or
alkenes, via direct C–H amination or through aziridination,
had been developed.1–5 Particularly in the case of aziridine
rings, great biological interest as potential therapeutic and
cytotoxic agents, make them an attractive synthetic tar-
gets.6–8
Originally upon thermic or ultrasonic activation,9,10
alkene aziridination through metal-assisted catalysis has
emerged as the most efficient, selective, and reliable meth-
odology.4,5,11 Copper as metal catalyst12,13 and hypervalent
iodine as oxidant14,15 are the most popular conditions to af-
ford such three-membered rings in good efficiency.16
Nevertheless, there are still weaknesses to spread this
methodology to an industrial scale. A literature survey re-
vealed that copper catalytic charge is generally high while
the tolerance to functional groups remains moderate. Fur-
thermore, homogeneous catalytic systems present draw-
Herein, we report the first use of copper-loaded MNP to
catalyze conversion of alkenes into the corresponding aziri-
dines. Consequently, Cu(OTf)2 or CuPF6complexes were
changed for magnetic Fe3O4-dopamine-Cu, and the as-ob-
tained optimized conditions were used for the conversion
of various olefins.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

B
M. Khodadadi et al.
Letter
Synlett
MNP-supported Cu catalyst (Fe3O4-Dopa-Cu) were read-
ily prepared from inexpensive starting materials via a sim-
ple method as a heterogeneous magnetic catalyst.27 For this,
dopamine hydrochloride was added to an aqueous solution
of Fe3O4 by sonicating for 2 h. Expected MNP were obtained
through addition of 10 wt% of CuCl2 in the presence of
hydrazine and sodium borohydride (NaBH4) as reducing
agents. Characterization of the materials were performed
using transmission electron microscopy (TEM), atomic ab-
sorption spectroscopy (AAS), X-ray diffraction (XRD), and
FT-IR spectroscopy. As shown by TEM images and con-
firmed by XRD (see Supporting Information), 11 nm sized
spherical highly cystalline Fe3O4 nanoparticles were ob-
tained by coprecipitation of iron salts. Anchoring of dopa-
mine, proved by FT-IR, and subsequent complexation with
copper did not affect the morphology, size, and crystallinity
of the magnetic nanoparticles. Copper loading was mea-
sured by AAS as 10%. Copper particles were not visible nei-
ther in TEM images nor in XRD analyses that tend to prove
that atomic copper was deposited. Efficiency of the as-ob-
tained catalyst was evaluated in classical conditions for the
aziridination of styrene (Table 1). As a reference, Cu(OTf)2
was tested using two different oxidants. Portionwise addi-
tion of PhI=O resulted in good conversion (monitored by
TLC) and yield whereas PhI(OAc)2gave poor results (Table 1,
entries 1 and 2).14,16 CuPF6 was also tested (result not
shown) and, as expected, gave similar yield to Cu(OTf)2.
Copper complexes were substituted with Fe3O4-Dopa-Cu.
First attempt was realized by mixing PhI=O with tosylamine
in dry acetonitrile with 4 Å molecular sieves (Table 1, entry
3). The reaction succeeded in the formation of the expected
aziridine but the yield was low (27%) because of a problem-
atic recovering of magnetic catalyst. According to Koloti-
lov,28 a covalent bonding between Fe3O4 and silica from mo-
lecular sieves could happen, causing hard recoverability
and low activity of catalyst. To overcome this side interac-
tion, we changed the oxidant by the preformed intermedi-
ate [N-(p-toluenesulfonyl)imino]phenyliodinane (PhI=NTs)29
that does not require molecular sieves. We were pleased to
obtain the expected product but flanked with a low yield of
18% under these conditions (Table 1, entry 4). Hopefully, we
succeeded in easily recovering the catalyst using an exter-
nal magnet.
Table 1 Alkene Aziridination Using MNP Catalyst
NTs
Cu cat., CH3CN
1
1 equiv.
Entry
Oxidant
Copper
sourcea
Time
(h)
Temp
(°C)
Yield
(%)b
1
2
PhI(OAc)2
1.4 equiv.c
Cu(OTf)2
Cu(OTf)2
Cu-MNP
Cu-MNP
Cu-MNP
Cu-MNP
Cu-MNP
Cu-MNP
Cu-MNP
Cu-MNP
Cu-MNP
18
6
0
0
21
93
27
18
70
82
86
90
64
91
87
PhI=O
1.4 equiv.c
3
PhI=O
6
0
1.4 equiv.c
4
PhI=NTs
1.4 equiv.
0.5
0.5
1
40
70
70
70
70
70
70
70
5
PhI=NTs
1.4 equiv.
6
PhI=NTs
1.4 equiv.
7
PhI=NTs
1.4 equiv.
2
8
PhI=NTs
1.2 equiv.
2
9
PhI=NTs
1 equiv.
2
10
11
PhI=NTs
1.2 equiv.
2d
0.5d
PhI=NTs
1.2 equiv.
a 0.1 equiv. of 10% Fe3O4-Dopa-Cu catalyst.
b Determined after purification on silica gel.
c TsNH2(1.4 equiv.) was added.
d MW irradiation.
(Table 1, entries 8 and 9). At least, we were able to obtain a
comparable yield with our recyclable catalyst (90%, Table 1,
entry 8) than those obtain in literature under classical con-
ditions (PhINTs, CuOTf2).16
We also investigated different optimization parameters
such as solvent, copper loading on MNP, and catalyst charge
in the media and MW irradiation.30,31 Changing acetonitrile
to other common solvent (water, acetone, dichloromethane,
THF) resulted in a large decrease or a total lack of reactivity
(see Supportihng Information). Modifying copper amount
on MNP (from 10% to 1%) or catalytic charge (from 10% to
1%) did not change reaction behaviors and leaching (see
Supporting Information). Fortunately, under microwave ir-
radiation (MW), we were pleased to observe full conversion
and 91% yield in 2 h (Table 1, entry 10). Moreover, MW irra-
diation could reduce by four times the reaction duration
compared to CH, and 87% of aziridine were achieved in 30
min (Table 1, entry 11). Nevertheless, an atomic absorption
spectroscopy (AAS) analysis revealed a copper leaching of
20% during the experimentation carried out using the best
found conditions. We postulated that competitive interac-
In view of this promising result, we investigated several
parameters such as temperature, time, equivalent of re-
agent, and amount of catalyst in order to optimize the reac-
tion conditions and enhance catalytic activity.
Under conventional heating (CH), a simple change of the
temperature from 40 °C to 70 °C allowed a threefold in-
crease of the yield, from 18% to 70% (Table 1, entry 5). Lon-
ger reaction time resulted also in an improvement of the
aziridination outcome to 82% and 86% after 1 h and 2 h
(Table 1, entries 6 and 7). We also tried to reduce the
amount of PhINTs from 1.4 equiv. to 1.2 equiv. and 1 equiv.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

C
M. Khodadadi et al.
Letter
Synlett
tion between Cu-dopamine immobilized on the surface of
catalyst and other nitrogen sources such as excess of PhINTs
or even the product itself could occurred and potentially
can be a reason of Cu leaching from Fe3O4-Dopa-Cu sys-
tem.32
The lifetime of the catalyst and its level of reusability
were tested by carrying out turnover reactions on the same
batch of catalyst in aziridination reaction of styrene
(Scheme 1). All reactions were performed under the same
conditions. The results showed that the Fe3O4-Dopa-Cu
magnetic catalyst could be reused up to five times with full
conversion of styrene, good yield, and slight loss of activity.
Also, it should be mentioned that after five runs, no loss of
magnetic responsiveness or morphological change was de-
tectable.
ceeded sluggishly and required more than 2 h for comple-
tion but afforded the expected product in 78% yield (Table 2,
entry 9). This result confirms our suspicions and could ex-
plain copper leaching. Indeed, a detrimental interaction
with a Lewis base present in the media (i.e., aniline) could
be at play and interferes with coordination between the
copper and the MNP (generating the leaching by this way).
When nitrogen reactivity was reduced using a deactivating
protecting group, aziridination took place normally and full
conversion was obtained. More functionalized olefin like
Table 2 MW-Assisted Aziridination of Olefins Using Fe3O4-Dopa-Cu
Catalysta
Entry
1
Substrate
Yield (%)b,c
70
Conv.(%)d
>95
2
3
2
78
>95
4
3
4
83
>95
40
32 (80)
5
Ph
6
5
40 (50)
80
Scheme 1 Reusability of Cu-MNP for styrene aziridination
O
6
7
8
9
96
91
0
100
>95
>95
>95
Metal leaching has been measured by AAS analysis after
each experience and finally after five runs. Analysis showed
there was a leaching of copper from 10 wt % to 4.4 wt % af-
ter five reactions. Deeper investigations showed that, after
extraction of the catalyst with the magnet, copper traces
were detected with the product in the corresponding pro-
portion that has been lost by the catalyst.
A range of olefins was tested toward aziridination using
Fe3O4-Dopa-Cu catalyst. In general, products were obtained
in good to excellent yields (Table 2). Vinyl toluene deriva-
tives gave very good results (Table 2, entries 1–3), especially
for the ortho substituted. trans-Stilbene or trans-chalcone
suffer from low conversion since 40% and 80% of starting
materials were converted (Table 2, entries 4 and 5) but they
gave relatively good selectivity (80% and 50%, respectively).
When an electron-withdrawing group (EWG), such as chlo-
rine or a nitro group, were added, olefins provided the cor-
responding aziridines in excellent yields (96% and 91%), re-
spectively (Table 2, entries 6 and 7). Interestingly, in the
case of 4-aminostyrene, aziridination did not undergo,
probably due to side interactions with catalyst (Table 2, en-
try 8). However, reaction of protected amine group pro-
7
Cl
8
9
O2N
H2N
78
10
AcHN
O
10
11
0
>30
O
11
O
32 (80)
40
OMe
7
7
12
a Conditions: substrate (1 equiv.), PhI=NTs (1.2 equiv.), Cu-MNP (0.1
equiv.), MeCN, 2 h, 70 °C.
b Recovered by column chromatography.
c Selectivity is given in bracket.
d Determined with respect to the crude NMR.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

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M. Khodadadi et al.
Letter
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cinnamic derivative was also tested and led to degradation
(Table 2, entry 10). Finally, inactivated olefin such as methyl
oleate gave promising results since 32% yield was observed
with only 40% conversion (80% based on recovered starting
materials, Table 2, entry 11).
We have developed an eco-friendly protocol for aziridi-
nation reaction using a magnetically recoverable Fe3O4-do-
pamine-Cu catalyst.33 Optimization led us to use PhINTs
under microwave irradiation to give high yield of aziridine.
The easy recyclability of the catalyst with a simple magnet
allowed it to be reused for five times without significant
loss of conversion and yield. Finally, a range of olefins were
examined resulting in a medium to excellent yields. Cur-
rently, we are investigating the use of different linkers for a
better anchoring and chelation of the copper to decrease
leaching during the reaction.
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Funding Information
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This work was supported by the KouhShekan SA Co. and the CNRS.()
Acknowledgment
Prof. Dominique Larcher (LRCS) and Dr. Christine Cézard (LG2A) are
greatly acknowledged for fruitful discussions.
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Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611717.
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References and Notes
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(33) General Synthetic Procedure for Aziridination
To a mixture of olefin substrates (0.4 mmol), 10% Fe3O4-Dopa-
Cu catalyst (0.04 mmol, 0.1 equiv.) in dry acetonitrile was added
PhI=NTs (0.48 mmol, 1.2 equiv.) portionwise in 5 times in
microwave at 70 °C under argon atmosphere, and the whole
mixture was stirred until TLC showed a complete conversion
(10 min to 3 h). The catalyst was removed with an external
magnet and washed with dried MeCN. The solvent was
removed under reduce pressure. The crude was purified by
flash chromatography on silica gel using a Reveleris™ Flash
System.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D