Electrochemical Aziridination of Internal Alkenes with Primary Amines

Article abstract of DOI:10.1016/j.chempr.2020.12.002

An electrochemical approach to prepare aziridines via an oxidative coupling between alkenes and primary alkyl amines was realized. The reaction is carried out in an electrochemical flow reactor, leading to short reaction/residence times (5 min), high yields, and broad scope. At the cathode, hydrogen is generated, which can be used in a second reactor to reduce the aziridine yielding the corresponding hydroaminated product.Aziridines are useful synthetic building blocks, widely employed for the preparation of various nitrogen-containing derivatives. As the current methods require the use of prefunctionalized amines, the development of a synthetic strategy toward aziridines that can establish the union of alkenes and amines would be of great synthetic value. Herein, we report an electrochemical approach, which realizes this concept via an oxidative coupling between alkenes and primary alkylamines. The reaction is carried out in an electrochemical flow reactor leading to short reaction/residence times (5 min), high yields, and broad scope. At the cathode, hydrogen is generated, which can be used in a second reactor to reduce the aziridine, yielding the corresponding hydroaminated product. Mechanistic investigations and DFT calculations revealed that the alkene is first anodically oxidized and subsequently reacted with the amine coupling partner.The central tenet in modern synthetic methodology is to develop new methods only using widely available organic building blocks. As a direct consequence, new activation strategies are required to cajole the coupling partners to react and, subsequently, forge new and useful chemical bonds. Using electrochemical activation, our methodology enables for the first time the direct coupling between olefins and amines to yield aziridines. Aziridines display interesting pharmacological activity and serve as valuable synthetic intermediates to prepare diverse nitrogen-containing derivatives. Interestingly, the sole byproduct generated in this process is hydrogen, which can be subsequently used to reduce the aziridine into the corresponding hydroaminated product. Hence, this electrochemical methodology can be regarded as green and sustainable from the vantage point of upgrading simple and widely available commodity chemicals.

Full text of DOI:10.1016/j.chempr.2020.12.002

ll
Article
Electrochemical Aziridination of Internal
Alkenes with Primary Amines
ꢀ
Maksim Oseka, Gabriele
Laudadio, Nicolaas P. van
Leest, ..., Bas de Bruin, Kleber T.
de Oliveira, Timothy Noel
¨
t.noel@uva.nl
HIGHLIGHTS
Direct electrochemical oxidative
coupling between alkenes and
primary alkylamines
Flow electrochemistry allows to
carry out the aziridination in only
5 min
Using cathodically generated
hydrogen, the aziridine can be
reduced
A combination of experiments
and DFT uncovers details of the
reaction mechanism
An electrochemical approach to prepare aziridines via an oxidative coupling
between alkenes and primary alkyl amines was realized. The reaction is carried out
in an electrochemical flow reactor, leading to short reaction/residence times
(5 min), high yields, and broad scope. At the cathode, hydrogen is generated,
which can be used in a second reactor to reduce the aziridine yielding the
corresponding hydroaminated product.
ꢀ
Oseka et al., Chem 7, 255–266
January 14, 2021 ª 2020 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2020.12.002

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Article
Electrochemical Aziridination of Internal Alkenes with
Primary Amines
Maksim Oseka,1,5 Gabriele Laudadio,1,5,6 Nicolaas P. van Leest,2 Marco Dyga,1,3
ꢀ
Aloisio de A. Bartolomeu,1,4 Lukas J. Gooßen,3 Bas de Bruin,2 Kleber T. de Oliveira,4
and Timothy Noel1,6,7,
*
¨
SUMMARY
The Bigger Picture
The central tenet in modern
synthetic methodology is to
develop new methods only using
widely available organic building
blocks. As a direct consequence,
new activation strategies are
required to cajole the coupling
partners to react and,
Aziridines are useful synthetic building blocks, widely employed for
the preparation of various nitrogen-containing derivatives. As the
current methods require the use of prefunctionalized amines, the
development of a synthetic strategy toward aziridines that can
establish the union of alkenes and amines would be of great syn-
thetic value. Herein, we report an electrochemical approach, which
realizes this concept via an oxidative coupling between alkenes and
primary alkylamines. The reaction is carried out in an electrochemi-
cal flow reactor leading to short reaction/residence times (5 min),
high yields, and broad scope. At the cathode, hydrogen is gener-
ated, which can be used in a second reactor to reduce the aziridine,
yielding the corresponding hydroaminated product. Mechanistic in-
vestigations and DFT calculations revealed that the alkene is first
anodically oxidized and subsequently reacted with the amine
coupling partner.
subsequently, forge new and
useful chemical bonds. Using
electrochemical activation, our
methodology enables for the first
time the direct coupling between
olefins and amines to yield
aziridines. Aziridines display
interesting pharmacological
activity and serve as valuable
synthetic intermediates to
prepare diverse nitrogen-
INTRODUCTION
Aziridines are a synthetically useful class of three-membered N-containing saturated
heterocycles, which play an essential role in the preparation of different nitrogen-
containing derivatives.1–7 Despite their remarkable reactivity, imparted by the
ring-strain (28 kcal molÀ1), aziridines are also present in many pharmacologically
active natural products, such as antibiotics and anticancer agents.8,9 Consequently,
the development of new methods to prepare aziridine structural motifs remains a
contemporary subject of interest to synthetic organic chemists. Promising results
have been obtained for the synthesis of both racemic and enantiomerically enriched
aziridines,10,11 which can be essentially categorized in three main categories: (1)
addition of a nitrogen-containing moiety to an alkene, (2) addition of substituted car-
benes to a C=N bond, and (3) cyclization of 2-haloamines or 2-amino alcohols.1
Among these different approaches,12–14 the addition of a nitrogen-containing re-
agent to an alkene is the most popular due to its efficiency and versatility.15–17 How-
ever, most of these methodologies require the use of a transition metal catalyst, such
as copper,18–21 rhodium,22 gold,23 cobalt,24–27 iron,28 or palladium,29 in combina-
tion with a suitable and activated nitrene precursor, such as iminoiodinanes and
organic azides (Figure 1A).30,31
containing derivatives.
Interestingly, the sole byproduct
generated in this process is
hydrogen, which can be
subsequently used to reduce the
aziridine into the corresponding
hydroaminated product. Hence,
this electrochemical methodology
can be regarded as green and
sustainable from the vantage
point of upgrading simple and
widely available commodity
chemicals.
In order to foster more sustainable and transition-metal-free alternatives,
new strategies to access aziridines have been devised using electrochemical activa-
tion (Figure 1B).32–35 Yudin and coworkers developed an electrochemical aziridina-
tion, which uses N-amino-phthalimide as the source of electrophilic nitrogen.9,36,37
Chem 7, 255–266, January 14, 2021 ª 2020 Elsevier Inc. 255

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Transition metal-catalyzed aziridination using nitrenes
A
B
R
transition metal catalysis
R
N
+
Y=NR
R
R
R
nitrene
precursor
(with Y = PhI or N2)
Electrochemical approaches towards aziridines
O
Pht
Pt|Pt
R
N
N
NH2
+
+
+
Yudin (2002)
R
R
R
R
R
Et3NH+ OAc-, CH3CN, 3.5-4 h
O
N-amino-phthalimide
(PhtNH2)
O
Pht
GC|Fe
R
N
N
NH2
Zheng/Little (2015)
R
R
Bu4NI as electrocatalyst
K2CO3, LiClO4, CF3CH2OH
O
N-amino-phthalimide
(PhtNH2)
CF3
O
Hfs
F3C
C|C
R
N
O
S
NH2
Cheng (2018)
R
R
O
2,6-lutidine, LiClO4
Sulfamate (HfsNH2)
K2CO3, LiClO4, CH3CN, 5 h
Prefunctionalized
Amines
This work: Electrochemical synthesis of aziridines using primary amines
C
Microflow Electrocell
Commodity chemicals
Mild reaction conditions
Scalable
R
N
R
H2N
+
R
R
R
R
Broad scope
Alkene
Primary
Aziridine
Alkyl Amines
Figure 1. Development of an Electrochemical Synthesis of Aziridines Starting from Alkenes and
Primary Alkyl Amines
(A) Transition-metal-catalyzed aziridination of alkenes with nitrene precursors.
(B) Established synthetic routes for the synthesis of aziridines using electrochemistry.
(C) Electrochemical synthesis of aziridines using primary alkyl amines as aminating reagents.
1Micro Flow Chemistry and Synthetic
Methodology, Department of Chemical
Engineering and Chemistry, Eindhoven University
of Technology, Het Kranenveld, Bldg 14 – Helix,
5600 MB Eindhoven, the Netherlands
2Homogeneous, Supramolecular and
An iodide-mediated electrocatalytic variant of this protocol was realized by Little,
Zheng, and coworkers.38 Recently, Cheng et al. established an electrochemical strat-
egy, which utilizes a trifluoromethylated sulfamate as a coupling partner.39 Despite
the synthetic value of these electrochemical and other approaches toward aziridines,
the scope of the nitrogen-containing coupling partners remains restricted to a
limited set of prefunctionalized amines, either PhtNH2 or HfsNH2 (Figure 1B). It is,
however, manifest that an electrochemical coupling between olefins and amines
would be of significant value given the broad availability and the low cost of these
building blocks (Figure 1C). Such a strategy would also remove the requirement
for substrate prefunctionalization, thereby increasing the atom efficiency of the
transformation while expanding the scope of available molecular fragments.40
Based on recent work from our lab involving the electrochemical synthesis of sulfon-
amides41 and sulfonyl fluorides,42,43 we surmised that direct electrochemical activa-
tion of either olefins or amines via anodic oxidation might enable the
expedient formation of a carbon-nitrogen bond, eventually leading to the targeted
aziridines. Herein, we report on our efforts to develop such an approach, enabling
Bio-Inspired Catalysis Group (HomKat), van ’t
Hoff Institute for Molecular Sciences (HIMS),
Universiteit van Amsterdam (UvA), Science Park
904, 1098 XH Amsterdam, the Netherlands
3Evonik Chair of Organic Chemistry, Fakultat fur
Chemie und Biochemie, Ruhr-Universitat
Bochum Universitatsstr. 150, ZEMOS, 44801
¨
Bochum, Germany
¨
¨
¨
4Departamento de Quımica, Universidade
´
Federal de Sao Carlos, Sao Carlos, SP 13565-905,
˜
˜
Brazil
5These authors contributed equally
6Present address: Flow Chemistry Group, van ’t
Hoff Institute for Molecular Sciences (HIMS),
Universiteit van Amsterdam (UvA), Science Park
904, 1098 XH Amsterdam, the Netherlands
7Lead Contact
*Correspondence: t.noel@uva.nl
https://doi.org/10.1016/j.chempr.2020.12.002
256 Chem 7, 255–266, January 14, 2021

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Table 1. Optimization of the Electrochemical Aziridination between Alkenes and Primary Amines
Variation from the
Standard Conditions
Entry
Yield (%)b
1a
2
3
4
5
6
7
8
none
88 (72)c
Traces
75
neat HFIP
2.5 equiv amine
no g-terpinene
graphite cathode
p-TsOH (1 equiv)
no electricity
batch (16 h)
78
59
32
0
14d
aReaction Conditions: anethole (2 mmol), g-terpinene (0.5 equiv), cyclohexylamine (5 equiv), HFIP (5
equiv), CH3CN (0.1 M), C anode/Fe cathode, 2.5–5 mA cmÀ2
bYield determined by GC-FID with biphenyl as an internal standard
cIsolated yield
dBatch reaction conditions: Electrasyn, 3.1 mA cmÀ2, 3.5 F, C anode/Fe cathode, 0.5 mmol scale
for the first time the union of olefins and amines, as convenient and widely available
starting materials, to prepare aziridines.
RESULTS AND DISCUSSION
Initial Experiments and Optimization
Our investigation into this aziridination protocol began with the introduction of
trans-anethole and cyclohexylamine into an electrochemical microflow reactor with
a small interelectrode gap (250 mm) between the carbon anode and stainless steel
cathode (Table 1).44 After an extensive optimization of the different reaction vari-
ables (see Section S2), a good isolated yield (72% yield) could be obtained in only
5 min of reaction/residence time under galvanostatic conditions using an excess of
amine (5 equiv) in CH3CN (Table 1, entry 1). Addition of 5 equiv of hexafluoroisopro-
panol (HFIP) proved beneficial for the targeted transformation and serves as a
radical-stabilizing cosolvent and as a proton source for the cathodic half-reaction,
generating hydrogen as a useful byproduct (Table 1, entries 1 and 2).45–47 Reducing
the amount of amine resulted in lower yields (Table 1, entry 3). Interestingly, the pres-
ence of a substoichiometric amount of g-terpinene proved beneficial to prevent
overoxidation of the starting material (Table 1, entry 4). Other electrode combina-
tions did not lead to improved results or were less effective for different substrate
combinations (Table 1, entry 5; see also Section S2.6). HFIP was the optimal proton
source for the electrochemical aziridination, while other acids proved less effective
(Table 1, entry 6; see also Section S2.4). As expected, the reaction was electrochem-
ical in nature as no conversion was observed in the absence of electricity (Table 1,
Chem 7, 255–266, January 14, 2021 257

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Microflow Electrocell
(C|Fe)
Br
Br
(1.2 equiv.)
HS
S
BF3·Et2O (10 mol%)
N
H2N
+
CH3CN
room temperature
HN
(Product B)
Aziridine
(Product A)
Alkene
Amine
2.5 - 5.0 mA cm-2
HFIP (5 equiv.)
-terpinene (0.5 equiv.)
CH3CN (0.1 M)
room temperature, tR = 5 min
Amine Scope
Me
Me
Me
Me
Me
Me
H
Me
N
N
N
N
N
Me
Me
Me
Me
Me
MeO
MeO
MeO
MeO
MeO
1-A, decomp.
1-B, 19%
2-A, decomp.
2-B, 48%
3-A, 50%
3-B, 72%
4-A, 71%
4-B, 80%
5-A, 41%
5-B, 69%
N
N
N
N
N
Me
Me
Me
Me
Me
MeO
MeO
MeO
Cl
MeO
MeO
9-A, 72% (66%)a
9-B, 82%
6-A, 45%
6-B, 65%
7-A, traces
7-B, 23%
8-A, 53%
8-B, 64%
10-A, traces
10-B, 25%
Me
EtOOC
MeOOC
N
N
N
N
N
Me
Me
Me
Me
Me
MeO
MeO
MeO
MeO
MeO
11-A, 62%
11-B, 77%
12-A, 57%
12-B, 78%
13-A, 70%
13-B, 94%
14-A, decomp.
14-B, 63%
15-A, decomp.
15-B, 84%
Alkene Scope
N
N
N
N
N
Me
MeO
MeO
Me
MeO
Me
OMe
O
MeO
19-A, 25%, (26%)b
16-A, 58%
17-A, decomp.
17-B, 72%
18-A, decomp.
18-B, 72%
20-A, 59%
N
N
N
N
N
Me
S
Me
Me
Me
F3CO
F
MeO
O
MeO
21-A, 29%
22-A, 33%
23-A, 30%
24-A, 93%
25-A, 78%
H
N
N
N
(NH3, 7 M in MeOH)
51%
(NH3, 40% w/w in H2O) 61%
26-A, 88%
27-A, 27%
28-A
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Figure 2. Substrate Scope for the Electrochemical Aziridine Synthesis
(A) Reaction Conditions: alkene (1 mmol), amine (5 equiv), HFIP (5 equiv), g-terpinene (0.5 equiv), CH3CN (0.1 M), C anode/Fe cathode, 2.5–5 mA cmÀ2
.
Decomposition refers to the instability of the product making isolation of the compound impossible.
(B) Reaction Conditions: isolated yields refer to the ring-opened product. The nucleophilic quenching was carried out in the collection vial with 4-
bromothiophenol (1.2 equiv) in the presence of BF3.OEt2 (10 mol %). Decomposition indicates full decomposition of the aziridine during the reaction or
workup. Traces denote an inseparable mixture in which small amounts of aziridine (<5%) are still apparent.a10 mmol scale reaction.bcis-Stilbene used as
a substrate.
entry 7). Finally, the reaction was less effective in a batch reactor, requiring longer
reaction times, which resulted in an increased generation of byproducts (Table 1, en-
try 8).48 The difference in efficacy between a microflow electrochemical cell and a
batch cell to enable the aziridination reaction is significant (Table 1, entry 1 versus
entry 8). This can be attributed to the high electrode surface-to-volume ratio, the
short diffusion distances (250 mm interelectrode gap) between anode and cathode,
and the reduced Ohmic drop observed in the flow reactor. Hence, reaction/resi-
dence times are significantly reduced (5 min in flow versus 16 h in batch), which min-
imizes effectively the extent to which these degradation-sensitive compounds are
exposed to the electrochemical conditions. In addition, due to the continuous oper-
ation of the flow reactor, less deposition of organic residue was observed at the elec-
trodes in flow compared to batch. Such a deposition leads to faster passivation of the
electroactive surface, which further prolongs the required reaction times in batch.
Reaction Scope
Having established optimal reaction conditions, we next investigated the generality
of this electrochemical aziridination reaction. As shown in Figure 2, a wide variety of
structurally and electronically diverse primary alkyl amines and alkenes can be
readily engaged in this transformation. In most cases, the targeted aziridines could
be isolated as pure compounds (product A) in good isolated yields, while other com-
pounds proved to be too fragile to be isolated via standard workup and chromato-
graphic procedures. This non-productive degradation is especially problematic for
aziridines bearing small N-alkyl substituents and for very electron-rich aziridines,
where nucleophilic ring-opening reactions with excess amine or HFIP can occur.
We opted to isolate those compounds after subsequent ring opening with a suitable
nucleophile, i.e., 4-bromothiophenol as the corresponding 1,2-amino thioether
(product B).49 Interestingly, unprotected N–H aziridines (1 and 28) can be prepared
by using ammonia in either water (40% w/w) or methanol (7 M). It should be noted
that these N–H aziridines are extremely challenging to make and only recently a
method toward these compounds using rhodium catalysis and O-(2,4-dinitro-
phenyl)hydroxylamine, as an electrophilic nitrogen reagent, was reported.22
Furthermore, a variety of primary amines are competent coupling partners in this
electrochemical aziridination protocol, including methylamine (2), butylamine (3),
isopropylamine (4), tert-butylamine (5), cyclopropanemethylamine (6), cyclobutyl-
amine (7), cyclopentylamine (8) and cyclohexylamine (9), furnishing the targeted
products in good isolated yields. The use of a narrow-gap flow cell allows us to
readily scale the reaction conditions without the need for reoptimization48,50,51; by
pumping the reagents continuously into the reactor for a prolonged amount of
time, compound 9 was isolated on a 10 mmol scale. Also activated amines, such
as propargylamine (10), benzylamine (11–12), and a-methylbenzylamine (13) are
effective in this transformation. Finally, the esters of amino acids glycine (14) and
phenylalanine (15) can be readily engaged in this aziridination protocol, providing
opportunities for peptide modification. Notably, no racemization of the chiral center
occurs under the electrochemical reaction conditions.
Chem 7, 255–266, January 14, 2021 259

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Similarly, we investigated the variability of the alkene reaction partner that is
compatible with the reaction conditions. Both electro-neutral and electron-
rich internal alkenes can be effectively reacted with cyclohexylamine. For instance,
(E)-1-methoxy-2-(prop-1-en-1-yl)benzene (16) and (E)-1,2-dimethoxy-4-(prop-1-
enyl)benzene (17) delivered the desired functionalized product in good yield.
When the substrate contained two double bonds, the terminal double
bond remained intact providing exclusively the internal trans-aziridine (18). This
site specificity may be exploited for the selective aziridination of other polyene com-
pounds. Next, a variety of stilbenes (19–22) were subjected to the reaction condi-
tions, highlighting the breadth of our transformation in comparison with previous
electrochemical aziridination strategies. Both cis- and trans-stilbene led to the
same trans-aziridine (19-A). In addition, heterocyclic moieties like thiophene (23-A)
are compatible with the electrochemical conditions, yielding synthetically useful
quantities of the targeted aziridine. The cyclic alkene of precocene I (24-A), a natural
chromene, was found to be an adequate reaction partner and furnished the targeted
product in excellent yield. Next, we moved our attention to the functionalization of
trisubstituted alkenes. Even for such sterically congested double bonds, the tar-
geted product can be obtained in good to excellent yields for both electron-rich
(25-A) and electron-neutral (26-A) alkenes. Notably, a spirocyclic aziridine (27-A)
could be accessed as well using this electrochemical aziridination strategy.
Formal Hydroamination
All single electron transfer events relevant for the electrochemical aziridination occur
at the anode, while the other half-reaction generates hydrogen as a useful yet hazard-
ous byproduct at the cathode. We wondered if this hydrogen could be productively
used in a follow-up hydrogenation step to form the corresponding hydroaminated
product (Figure 3A). Indeed, by connecting a packed-bed reactor filled with Pd/C
to the electrochemical flow reactor, the gas-liquid flow (Figure 3D) exiting the first
reactor can be directed over the Pd/C bed without intermediate isolation (Figure 3C).
To our delight, the corresponding hydroaminated products (Figure 3B) could be
promptly obtained in good overall yield.52 Furthermore, we observed a single-phase
exiting the packed-bed reactor indicating that nearly all hydrogen gas was
consumed. In contrast, when this experiment was conducted in batch, additional
hydrogen to compensate for leakage to the headspace was required to obtain a
full conversion, albeit at a lower isolated yield (For 9-C: 50% for the batch hydroge-
nation versus 58% for the two-step flow protocol). It should be further noted that
this paired reaction sequence in flow not only increases the yield and the atom effi-
ciency of the process but also allows for facile reuse and recycling of the Pd/C bed
and it reduces the risks associated with the handling of combustible hydrogen gas
due to its immediate consumption in a follow-up reaction.48,53,54
Mechanistic Investigation
To obtain insights into the underlying mechanism, we performed additional experiments
and studied possible mechanistic pathways by means of density functional theory (DFT)
calculations (Figure 4). Cyclic voltammetry (CV) experiments revealed two subsequent
oxidations of the alkene moiety (Figure 4A). The first oxidation results in the formation
of a radical cation while the second oxidation leads to oxidative cleavage of the olefin.
Small quantities of the corresponding Schiff base could be found in the reaction mixture
confirming this hypothesis (Figure 4B).55,56 We anticipated that this overoxidation could
be countered by adding a suitable donor of hydrogens and electrons. Indeed, 0.5 equiv-
alents 1,4-cyclohexadiene (1,4-CHD) allowed for the reduction in the amount of imine
significantly. Also, g-terpinene, which is a more stable, non-toxic, and a cheaper alterna-
tive for 1,4-CHD, enabled the suppression of the overoxidation of the alkene as shown in
260 Chem 7, 255–266, January 14, 2021

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Schematic representation of the two-step hydroamination protocol
A
Microflow Electrocell
(C|Fe)
H
N
H2N
Pd/C
+
HN
Alkene
Amine
Aziridine
(Product A)
Hydroaminated product
2.5 - 5.0 mA cm-2
HFIP (5 equiv.)
(Product C)
-terpinene (0.2 equiv.)
CH3CN (0.1 M)
room temperature, tR = 5 min
Representative examples
B
H
H
H
Me
Me
Me
Me
HN
Me
HN
HN
MeO
MeO
MeO
4-C
9-Ca
11-C
42%
58%
51%
H
H
H
H
N
H
N
Me
Me
Me
NH2
Me
Me
Me
Me
MeO
MeO
O
MeO
O
31-Cb
24-Cb
29-C
60%
54%
28%
C
D
Segmented gas-liquid flow emerging the
electrochemical reactor
Continuous-flow setup
v
iv
iii
ii
i
Figure 3. Two-Step Hydroamination Protocol by Combining the Electrochemical Aziridine
Synthesis and a Subsequent Hydrogenation
(A) Schematic representation of the two-step protocol.
(B) Representative examples. Yields denote the overall yield over two steps.
(C) Picture of the two-step flow protocol: (i) syringe pump, (ii) potentiostat, (iii) electrochemical flow
reactor, (iv) packed bed filled with Pd/C, and (v) collection vessel.
(D) Hydrogen gas bubbles exiting the electrochemical flow reactor.
Reaction conditions (C): alkene (1 mmol), amine (5 equiv), HFIP (5 equiv), g-terpinene (0.2 equiv),
CH3CN (0.1 M), C anode/Fe cathode, 2.7 mA cmÀ2. Flow conditions: Pd/C (150 mg
cartridge).aBatch conditions: Pd/C (5 mol %), H2 (1 bar) resulted in 50% isolated yield.bNo full
conversion was observed upon exiting the Pd-cartridge for these compounds (31-c: 43 % H-NMR
yield; 24-c: 44 % H-NMR yield). Additional hydrogenation in batch was carried out to achieve full
conversion.
the CV (Figure 4A).57,58 While our experimental results indicate that oxidation of the
alkene is most likely the first step, CV analysis showed that a competitive activation of
cyclohexylamine couldoccuraswell(SeeSectionS3). However, duetothe irreversiblena-
ture of the oxidation of both reaction partners and the similar set-off potentials, it is diffi-
cult to predict the first anodic event in this aziridination protocol. Hence, we decided to
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A
C
1200
900
600
300
0
Anethole
Anethole+Terpinene+HFIP
Anethole+CyNH2
Reaction Mixture
0
1
2
3
Potential (V vs SCE)
B
D
Figure 4. Mechanistic Investigation
(A) Cyclic voltammetry experiments.
(B) Addition of a reducing agent to suppress overoxidation of the alkene.
(C) Proposed mechanism.
(D) DFT Gibbs free energy profile at 298 K (in kcal molÀ1). Calculations were performed at the B3LYP/def2-TZVP//B3LYP/def2-TZVP(COSMO) level of
theory on an m4 grid with disp3 dispersion corrections.
obtain further insights via DFT calculations. These computational studies revealed that
the anodic oxidation of anethole is indeed the first step in the electrochemical aziridina-
tion (DGo298K = +28.3 kcal molÀ1 and +1.226 V versus saturated calomel electrode [SCE])
(Figure 4D). An alternative pathway starting from the oxidation of the amine coupling
partner, yielding the aminium radical, is energetically disfavored due to the higher
requiredenergyinput(DGo298K = +38.4 kcalmolÀ1 and+1.665VversusSCE)(seeSection
S4.2). However, we cannot exclude that for some substrate combinations, the reaction
can be initiated via the formation of the aminium radical. Once the radical cation of
262 Chem 7, 255–266, January 14, 2021

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anethole is formed, it readily reacts with an amine coupling partner yielding intermediate
C(Figure4D)viaalow-barriertransitionstate. Afterdeprotonationandsubsequentsingle
electron transfer, acarbocation (E) isformed, whichcan undergo a rapid barrier-lessintra-
molecularringclosure anddeprotonationtoyieldthetargetaziridine(F).59 The reactionis
exergonic after the initial oxidation (DGo
= ‒11.7 kcal molÀ1) but endergonic with
298K
respect to the starting materials, which is consistent with the required energy input in
the form of electrons during the reaction. Further, the conversion of both cis- and
trans-alkenes to the same trans-aziridine supports this stepwise mechanistic proposal
(Figure 2, 19-A).
Finally, this mechanistic rationale also explains the observed scope and limitations.
The protocol is currently limited to electron-rich b-substituted styrenes, which can be
attributed to a combination of their accessible oxidation potential and the steric pro-
tection of the radical cation intermediate. Alkenes with higher oxidation potentials
(e.g., styrene or trans-b-methylstyrene, see Section S8) did not afford the desired
aziridines, likely due to excessive amine oxidation at the electrode prior to alkene
oxidation. 4-Methoxystyrene, as a terminal alkene substrate, has an accessible
oxidation potential (see Table S11), but lacks steric protection of the b-substituent,
therefore making it prone to degradative side-reactions after anodic oxidation. With
regard to the amine coupling partner, a broad scope of nucleophilic alkyl amines was
compatible with the reaction conditions (Figure 2). In contrast, less-nucleophilic aryl
amines were not able to react with the radical cation B (Figure 4D).
Conclusion
The electrochemical approach reported herein demonstrates the possibility to
directly convert olefins and primary alkyl amines into synthetically useful aziridines.
We expect that the operational simplicity of this protocol and its potential to use
common and broadly available starting materials will find widespread use among
organic chemistry practitioners both in academia and industry.
EXPERIMENTAL PROCEDURES
Resource Availability
Lead Contact
Further information and requests for resources should be directed to and will be ful-
filled by the Lead Contact, Timothy Noel (t.noel@uva.nl).
¨
Materials Availability
Unique and stable reagents generated in this study will be made available on
request, but we might require a payment and/or a completed materials transfer
agreement if there is potential for commercial application.
Data and Code Availability
There is no dataset and code associated with the paper. Full experimental proced-
ures are provided in the Supplemental Information.
General Procedure for Electrochemical Aziridination in Flow
Procedure A
Alkene (1.0 equiv, 2.0 mmol), together with amine (5.0 equiv, 10.0 mmol), hexafluor-
oisopropanol (HFIP, 5.0 equiv, 10.0 mmol, 1.05 mL), and g-terpinene (0.5 equiv,
1.0 mmol, 0.16 mL) were dissolved in acetonitrile using a 20 mL volumetric flask
(0.1 M). The mixture was swirled until homogeneous and taken up in a 20 ml dispos-
able syringe. The solution was pumped through the electrochemical setup with a
fixed flowrate of 0.15 mL/min to give a residence time of 5 min in the active part
Chem 7, 255–266, January 14, 2021 263

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of the electrochemical flow reactor, equipped with a graphite anode, a steel cath-
ode, and distanced by a 0.25 mm thick Teflon gasket. The first fraction was discarded
to ensure steady-state data collection, after which a constant current (selected on
the basis of the voltammograms recorded) was applied. The reaction mixture was
collected in a vial cooled at 0ꢀC for 67 min, which corresponds to 1.0 mmol scale.
The crude mixture was concentrated under vacuum at room temperature to prevent
decomposition of the product and directly purified by flash column chromatography
on silica gel.
Procedure B
Alkene (1.0 equiv, 2.0 mmol), together with amine (5.0 equiv, 10.0 mmol), hexafluor-
oisopropanol (HFIP, 5.0 equiv, 10.0 mmol, 1.05 mL), and g-terpinene (0.5 equiv,
1.0 mmol, 0.16 mL) were dissolved in acetonitrile using a 20 mL volumetric flask
(0.1 M). The mixture was swirled until homogeneous and taken up in a 20 ml dispos-
able syringe. The solution was pumped through the electrochemical setup with a
fixed flowrate of 0.15 mL/min to give a residence time of 5 min in the active part
of the electrochemical flow reactor, equipped with a graphite anode, a steel cath-
ode, and distanced by a 0.25-mm thick Teflon gasket. The first fraction was dis-
carded to ensure steady-state data collection, after which a constant current
(selected on the basis of the voltammograms recorded) was applied. The reaction
mixture was collected in a vial containing a stirred solution of 4-bromothiophenol
(1.2 mmol, 227 mg) and BF3,Et2O (0.1 mmol, 12.7 mL) in acetonitrile (5 mL) for
67 min, which corresponds to 1.0 mmol scale. The crude mixture was concentrated
under vacuum and dissolved in methanol (5 mL). Subsequently, NaBH4 (0.26 mmol,
10 mg) was added and the solution was stirred for 1 h at room temperature. The
crude mixture was concentrated under vacuum and purified by flash column chroma-
tography on silica gel.
General Procedure for Formal Electrochemical Hydroamination in Flow
Alkene (1.0 equiv, 2.0 mmol), together with amine (5.0 equiv, 10.0 mmol), hexafluor-
oisopropanol (HFIP, 5.0 equiv, 10.0 mmol, 1.05 mL), and g-terpinene (0.2 equiv,
0.4 mmol, 64 mL) were dissolved in acetonitrile using a 20 mL volumetric flask (0.1
M). The mixture was swirled until homogeneous and taken up in a 20 ml disposable
syringe. The solution was pumped through the electrochemical setup with a fixed
flowrate of 0.15 mL/min to give a residence time of 5 min in the active part of the
electrochemical flow reactor, equipped with a graphite anode, a steel cathode
and distanced by a 0.25-mm thick Teflon gasket. A self-made packed bed reactor
(1 mL), filled with Pd/C (200 mg) and glass beads (500 mg), was connected to the
outlet of the electrochemical reactor. The first fraction was discarded to ensure
steady-state data collection, after which a constant current (selected on the basis
of the voltammograms recorded) was applied. The reaction mixture was collected
in a vial for 67 min, which corresponds to a 1.0 mmol scale. The crude mixture was
concentrated under vacuum and purified by flash column chromatography on silica
gel.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2020.12.002.
ACKNOWLEDGMENTS
We acknowledge financial support from the Dutch Science Foundation (NWO) for a
VIDI grant for T.N. (SensPhotoFlow, no. 14150) and the Estonian Research Council
264 Chem 7, 255–266, January 14, 2021

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Article
(ETAG) for a PUT post-doctoral grant for M.O. (PUTJD821). A.A.B. and K.T.O. thank
the Sa˜o Paulo Research Foundation for a FAPESP Fellowship Grant (2018/08772-6).
The Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under
Germany´s Excellence Strategy – EXC 2033 – 390677874 – RESOLV, is kindly
acknowledged for funding the research of M.D. and L.J.G. Finally, we also would
like to thank Ing. Jan Goeman (Ghent University) for recording the HRMS and M.
Kimm and D. Trubitso˜ n (Tallinn University of Technology) for chiral HPLC analysis.
AUTHOR CONTRIBUTIONS
T.N. coordinated the project and secured the project funding. T.N., M.O., and G.L.
wrote the manuscript with the help of all co-authors. T.N., M.O., and G.L. conceived
the initial project idea. M.O. and G.L. designed and carried out the majority of the
experiments. N.P.L. and B.d.B. carried out the DFT calculations. M.D. contributed
to the synthesis of some substrates and electrochemical aziridination. M.O., G.L.,
and A.A.B. carried out the optimization reactions and demonstrated the feasibility
of the transformation. All authors discussed the project progress together at regular
intervals and provided input for future experiments.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: August 26, 2020
Revised: November 9, 2020
Accepted: December 2, 2020
Published: December 31, 2020
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