Electrochemical and Scalable Dehydrogenative C(sp3)?H Amination via Remote Hydrogen Atom Transfer in Batch and Continuous Flow

Article abstract of DOI:10.1002/chem.201806092

A hydrogen atom transfer-directed electrochemical intramolecular C?H amination has been developed in which the N-radical species are generated at the anode, and the base required for the reaction is generated at the cathode. A broad range of valuable pyrr

Full text of DOI:10.1002/chem.201806092

A Journal of
Accepted Article
Title: Electrochemical and scalable dehydrogenative C(sp3)-H
amination via remote hydrogen atom transfer in batch and
continuous flow
Authors: Pavlo Nikolaienko, Marc Jentsch, Ajit Prabhakar Kale, and
Magnus Rueping
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To be cited as: Chem. Eur. J. 10.1002/chem.201806092
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Supported by

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3
Electrochemical and scalable dehydrogenative C(sp )-H
amination via remote hydrogen atom transfer in batch and
continuous flow
[
a]
[b]
[a]
[a]
[a],[b]
Pavlo Nikolaienko, Marc Jentsch, Ajit P. Kale, Yunfei Cai, and Magnus Rueping*
Abstract:
A
hydrogen atom transfer-directed electrochemical
the thermal transformation of N-halogenated aliphatic amines to
pyrrolidines in the presence of strong acids, the general strategy
has remained the same; however, many improvements have
been achieved. Recent advances have been reported by Suárez,
who showed that the reaction also proceeds under milder
intramolecular C-H amination has been developed in which the N-
radical species are generated at the anode, and the base required
for the reaction is generated at the cathode. A broad range of
valuable pyrrolidines were prepared in good yields and with high
chemoselectivity. The reaction was easily scaled up in both batch
and continuous flow systems.
neutral conditions with UV light irradiation in the presence of I
2
[9]
[
8]
and lead acetate or a hypervalent iodine reagent I(III).
[
10]
Significant advances were achieved by the Muniz
and
[
11]
Nagib groups who reported improved protocols based on I
2
or
–
–
3
I (I
) and hypervalent iodine I(III) oxidative systems for the light-
Introduction
mediated conversion of sulfonamide-protected amines to the
corresponding pyrrolidines.
The implementation of sustainability principles to organic
synthesis led to the search for new synthetic methods that
require fewer reaction steps, consume less energy and generate
less waste and thus have minimal environmental impact. In this
regard, the direct functionalization of C-H bonds is highly
desirable due to the ubiquity of these bonds in organic
compounds. Over the last decade, hydrogen atom transfer
[
1]
(
HAT) reactions have attracted considerable attraction as a
[
2]
radical-based strategy and as a good alternative to transition-
metal-catalyzed C-H activation methods. HAT reactions typically
proceed under milder reaction conditions, and regio-, chemo-
and stereoselectivity issues are typically solved either by the
presence of N-, O- or C-containing functional groups or by the
[1]
electronic properties of the substrates.
Poly-substituted 5-membered saturated aza-heterocycles,
particularly pyrrolidines, are frequent structural motif in
(Figure 1A) and synthetic biologically active
a
[
3]
natural
compounds
[
4]
(Figure 1B) with a wide range of activities,
including antidiabetic, antitumor and anti HIV properties. For
example, five of the eight anti-infective drugs approved in 2016,
including an antihepatitis C drug, contain a pyrrolidine moiety.
Figure 1. Biologically active pyrrolidines.
[
5]
Therefore, the development of new and efficient methods to
build up these structural entities is of great importance.
Despite these great achievements, most of the reported
protocols
require
halogenated
solvents
and
either
[
6]
The Hofmann-Löffler-Freytag (HLF) reaction is a HAT-
prefunctionalized starting materials or a (super)stoichiometric
oxidant. Organic electrochemistry has attracted increasing
attention over the last few years, mainly due to the replacement
of reducing and oxidizing reagents by “traceless” electrons at the
3
based direct amination of poorly reactive alkyl C(sp )-H bonds.
Through a C-H halogenation-nucleophilic substitution sequence,
primary and secondary aliphatic amines are converted into
[
7]
[12]
valuable pyrrolidines in a single step. Since the initial reports of
cathode and holes at the anode. From a practical perspective,
organic electrosynthesis can minimize total energy losses and
reduce waste formation, and as a result, these techniques will
decrease the overall costs of industrial synthesis. Because N-
[
[
a]
b]
Dr. P. Nikolaienko, Dr. A. P. Kale, Dr. Y. Cai, Prof. Dr. M. Rueping
KAUST Catalysis Center (KCC)
King Abdullah University of Science and Technology (KAUST)
Thuwal 23955-6900, Saudi Arabia
M.Sc. M. Jentsch, Prof. Dr. M. Rueping
Institute of Organic Chemistry, RWTH-Aachen University
Landoltweg 1, 52074 Aachen (Germany)
[13]
radicals can be produced electrochemically, as has been
[
14]
demonstrated by Shono and others
we aimed to combine
such a strategy with a subsequent 1,5-HAT (1,5-hydrogen atom
3
transfer) to circumvent known obstacles related to C(sp )-H
amination (HLF reaction) and make the developed protocol
applicable to large-scale synthetic applications (Scheme 1).
E-mail: Magnus.Rueping@rwth-aachen.de
Supporting information for this article is given via a link at the end of
the document.
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Electrodes such as graphite, RVC and platinum (for reference)
2
with a wide range of current densities (0.5–50 mA/cm ) did not
generate the desired product with various anode/cathode
combinations (see SI). Either recovered starting material or
inseparable mixtures of decomposition products were observed
in these cases. Among the various tested additives (see SI),
bases had a strong impact on the reaction, and the desired
product 1b was finally obtained in decent yield. Encouraged by
these findings, we performed extensive screenings of a variety
of additives, bases, substrate concentrations, electrode
materials and current densities (see SI). To our delight, a
0.025 M solution of 1a in methanol with 5 equivalents of sodium
3
methoxide, a graphite electrode couple and a current density of
Scheme 1. Regioselective intramolecular C(sp )-H bond amination.
2
10 mA/cm gave the best result. The desired pyrrolidine 1b was
isolated in 71% yield (Table 1, entry 1), with the deaminated
aliphatic aldehyde as the only major byproduct. Not surprisingly,
when various graphite sources were tested to evaluate the
reproducibility, a strong dependence on the graphite source was
observed. The yield of 1b varied from 40 to 75% under identical
reaction conditions. Less absorbing glassy carbon and RVC did
not provide reproducible results.
Results and Discussion
For initial optimization experiments, the use of precious metal
electrodes, such as platinum and gold, as well as the
construction of complicated divided cells were not considered
due to our intention to scale-up the reaction. Additionally, only
methanol and acetonitrile were considered as potential solvents
due to industrial green chemistry concerns and proper
To get an insight into the reaction and understand the
reactivity, the electrochemical behavior of the reactants and
reagents was investigated. Based on cyclic voltammetry (CV),
the redox-potentials of starting materials similar to 1a were
found to be controlled by the outer-sphere oxidation of the
nitrogen centered lone pair (see SI) and are all of ERed = 2.0 V vs
[
15]
electrochemical windows.
Substrate 1a was chosen as a
model compound and was subjected to direct oxidation in
acetonitrile with different tetraalkylammonium salts as the
supporting electrolyte (see SI for details).
+
Ag/Ag and higher. Only substrates possessing electron-rich
aromatic substituents showed oxidation peaks from ERed = 1.5 V
to ERed = 1.9 V vs Ag/Ag most likely due to oxidation of the
Table 1. Optimization of the reaction conditions.
+
benzylic C-H bonds. The ERed of the corresponding product 1b
was found to be very similar to that of the corresponding starting
+
+
material 1a [ERed1a = 1.9 V vs Ag/Ag ; ERed1b = 2.2 V vs Ag/Ag ]
Figure 2). This observation support the failed attempts on direct
(
[
a]
[b]
amination either due to poor reactivity or by overoxidation.
Entry
Deviation of the reaction conditions
no mediator, MeONa (5 equiv.)
Pyridine (2 equiv.)
Yield
[
c]
1
2
3
4
5
6
7
8
9
71
17
11
TFA (10 equiv.)
[
d]
Bu
4
NPF
6
0.1 M, N- or O-mediators (1 equiv.)
< 10
< 5
Bu NPF
4
6
0.1 M, ferrocene (1.0 equiv.)
no light or 18W CFL
71 / 74
70 / 72
62 / 69
19
under argon or under air
–10 °C or 50 °C
Pt anode
10
Cu cathode
< 5
11
0.1 M KCl
54
1
2
3
0.1 M KI
14
44
1
CH
3
CN/H
2
O, NaOH (5 equiv.)
[
e]
14
CH
3
CN/H
2
O, 0.1 M KBr
68
[
a] Reactions were conducted on a 0.2 mmol scale; [b] Yields are based on
NMR or GC; [c] Yields strongly vary due to graphite source; [d]
Triethylamine, quinuclidine, DABCO, TEMPO, NHPI and HOBt. [e] 8 F/mol.
Figure 2. Cyclic voltammetry of the 1a (solid line) and 1b (dashed line) (5 mM
2
in 0.1 M of Bu NPF6 in CH CN); Work. el.: glassy carbon, 8 mm ; Ref. el.: Ag-
4
3
wire in 10 mM AgNO
3
4 6 3
/ 0.1 M Bu NPF in CH CN.
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According to our design, the desired C-H amination is expected
to be initiated by the formation of N-centered radicals. Thus, the
effect of different protecting groups was tested. When an
unprotected amine was subjected to the reaction conditions, the
corresponding deaminated aldehyde was isolated as the sole
product. Acetyl-based protecting groups such as trifluoroacetyl
and benzoyl as well as phosphamide did not provide any
product over the course of the reaction. Only tosyl-protected
amines were able to provide the desired product. Subsequently,
CV-studies were performed with amine 26A which bears
different protecting groups and has no aromatic residue on the
aliphatic chain (Figure 3). As expected, the ERed potential was
found to be dependent on the nature of the protecting group and
only substrates with protecting groups incorporating aromatic
Despite similarities in the redox-potential of benzoyl, phosphoryl
and tosyl-protected amines, only the latter was converted into
the corresponding product under the given conditions, most
probably due to much higher acidity of the N-H bond. Indeed,
the redox-potential of deprotonated 1a is almost 1.5 V lower
(ERed1a K = 0.3 V vs Ag/Ag ) and clearly originates from the N-
radical generation (Figure 4). However, the decrease of ERed of
the amine 1a upon deprotonation is not sufficient for practical
reaction rates. Direct anodic oxidation is still sensitive to the
electrode material due to substrate-electrode surface
physisorbtive interactions over the outer-sphere oxidation
pathway.
−
+
+
Therefore, we switched to the mediated anodic oxidation
+
and electrosynthetic mediators with ERed up to 0.9 V vs Ag/Ag
[
16]
[17]
rings (Ts, Bz, PO(OPh)
2
+
) featured a redox-potential ERed in the
were tested. All tertiary amines tested, aminoxyl mediators,
[18]
range of 2.0 V vs Ag/Ag .
and ferrocene failed to support the reaction (Table 1, entries 4
and 5). Noteworthy, mediators such as TEMPO inhibited the
formation of the desired product, pointing towards the radical
nature of the reaction initialization. Finally, simple halide salts,
also known as redox mediators, were successfully tested (see
SI). To be noted, electrochemical oxidations with the help of
halides are known to proceed via an inner-sphere path, which is
typically of several orders faster when compared to the outer-
sphere one. While chloride and iodide salts led to a complex
mixture of products or poor current efficiencies due to concurrent
oxidation/reduction, bromide anions were found to be good
mediators for the electrochemical amination in undivided cells.
[
19]
[
19]
−
Based on CV, the bromide (Br ) has two ERed potentials
detectable in acetonitrile on graphite, glassy carbon and
platinum electrodes (Figure 5). First anodic peak is attributed to
−
the formation of Br
of Br
3
while the second represents the formation
2
. Despite same scan rates and same geometrical surface
Figure 3. Protection group effect on 26A (5 mM in 0.1 M of Bu
4
NPF
CN); Work. el.: glassy carbon, 8 mm ; Ref. el.: Ag-wire in 10 mM AgNO
.1 M Bu NPF in CH CN; scan rate = 100 mV/s.
6
in
3
/
area of electrodes, the bromide oxidation current on graphite is
three-fold higher due to higher active surface area. While the
2
CH
3
0
4
6
3
+
oxidation peak at 0.8 V vs Ag/Ag shows some reversibility, the
+
peak at ERed = 0.5 V vs Ag/Ag has no reductive half-wave due
−
to fast diffusion of Br
3
into the bulk solution.
Figure 4. Cyclic voltammetry of the protonated 1a (dashed line), deprotonated
a (potassium salt; dash-dotted red line) and of the slurry of potassium hydride
dash-dotted line green). All substances of 5 mM in 0.1 M of Bu NPF in
CN); Work. el.: glassy carbon, 8 mm ; Ref. el.: Ag-wire in 10 mM AgNO
NPF in CH CN; scan rates = 100 mV/s.
Figure 5. Cyclic voltammetry of the tetrabutylammonium bromide (5 mM in
2
1
(
CH
0.1 M of Bu
4
NPF
6
in CH
3
CN); Work. el. 8 mm ; Ref. el.: Ag-wire in 10 mM
CN; scan rate = 100 mV/s.
4
6
AgNO / 0.1 M Bu
3
4
NPF in CH
6
3
2
3
3
/
0.1 M Bu
4
6
3
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When similar measurements were performed in methanol
Figure 6) the only on-set potential Eonset = 0.8 V vs Ag/Ag was
the current density (Figure 7) upon addition of the starting
material as well as broader current fluctuations (red line) when
compared to the only bromide oxidation (black line) is a clear
evidence for the mediated electrochemical process.
+
(
detected due to the existing base and fast formation of methyl
−
hypobromite (MeOBr). Nevertheless, both Br
3
and MeOBr are
sufficiently reactive to oxidize the deprotonated starting material
and also inert enough to prevent undesired overoxidation and
Csp -H bromination.
Due to the price and availability, the corresponding alkali
bromides were used as both mediator and supporting electrolyte.
Subsequent variation of the reaction atmosphere, temperature
and amount of light (Table 1, Entries 6-8) did not affect the
reaction, and 1b was obtained in comparable yields in all cases.
Among the cathodes tested, stainless steel 316 performed the
best. Various metals provided reaction outcome similar to that
achieved with steel; however, titanium gave only moderate
yields. Surprisingly, the pure copper cathode (Table 1, Entry 10)
completely inhibited the reaction, most likely due to the high
hydrogen reduction overpotential. No reaction was detected
even when up to 15 F/mol of electricity was used due to the
dynamic bromide oxidation/reduction equilibrium on the copper
cathode. Indeed, when we recorded several cyclic
voltammograms of the 1a N-bromo-derivative (Figure 8) on
different electrodes a high reduction peak was clearly visible,
particularly on the copper working electrode.
2
Figure 6. Cyclic voltammetry of the reaction mixture under the optimized
conditions, without starting material (solid line) and with 1a (dashed line).
(
50 mM in 100 mM of KBr and 25 mM of MeONa in CH
3
OH); Work. el.:
2
Graphite, 8 mm ; Ref. el.: Ag-wire in 10 mM AgNO
CH CN; scan rate = 100 mV/s.
3
/ 0.1 M Bu NPF in
4
6
3
Figure 8. Cyclic voltammetry of the N-bromo-derivative of 1a (5 mM in 0.1 M
2
of Bu
4
NPF
NPF
6
in CH
3
CN); Work. el. 8 mm ; Ref. el.: Ag-wire in 10 mM AgNO
3
/
0.1 M Bu
4
6
in CH
3
CN; scan rate = 100 mV/s.
In addition to the methanol reaction system, an
acetonitrile/water mixture can also be used (Table 1, Entry 14).
However, double amount of electricity (8 F/mol) was needed to
obtain the desired product 1b in decent yield.
With the optimized reaction conditions in hand, the scope
of Ts-protected aliphatic amines was evaluated (Figure 9). First,
various substrates 1a - 25a, 28a, and 29a bearing aromatic and
heteroaromatic groups in the δ-position were subjected to the
reaction conditions. Starting materials bearing both electron-
donating and electron-withdrawing substituents on the aromatic
ring were converted into the desired products in good yields.
Pyrrolidine 11b was isolated in only moderate yield, most likely
due to the electronic effects of the ortho-fluoro substituent.
Figure 7. Chronoamperometry of the reaction mixture with 1a (50 mM in
00 mM of KBr and 25 mM of MeONa in CH OH); Ref. el.: Ag-wire in 10 mM
AgNO / 0.1 M Bu NPF in CH CN; Stirring rate = 500 rpm.
1
3
3
4
6
3
Chronoamperometry (CA) at the given constant potential
2
revealed that the optimal current densities are 9.5 mA/cm for
2
the solvent/supporting electrolyte system and 11.5 mA/cm for
the reaction mixture (Figure 7) which are in good agreement with
2
the optimized current density of 10 mA/cm . A slight increase in
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Figure 9. Scope of the Electrochemical HLF reaction of aliphatic N-tosyl-protected amines. [a] Reaction conditions: methanolic 0.1 M KBr, 0.025 M MeONa,
2
0
.05 M substrate, graphite anode, stainless steel cathode, J = 10 mA/cm , Q = 3 to 35 F/mol, isolated yields. [b] For the results in brackets, the reaction conditions
2
are as follows: methanolic 0.125 M MeONa, 0.025 M substrate, graphite anode and cathode, J = 10 mA/cm , Q = 3 to 35 F/mol, isolated yields. [c] Isolated as a
mixture of diastereomers (ratio is close to 1:1). [d] Yields are based on recovered starting material.
Steric hindrance does not affect the reaction, as
methylated products 2b and 3b were obtained in similar yields.
Substrates bearing sensitive functional groups, such as
methylenedioxy (5a), triple bond (7a) and even ferrocene (8a)
moieties, were smoothly converted into the corresponding
pyrrolidines in good yields. The reaction conditions were also
suitable for substrates bearing heterocyclic groups such as
indole (9a), pyrazole (14a) and thiophene (25a). In addition to
secondary C-H bonds, tertiary bonds also underwent the
electrochemical amination reaction and lead to tetra-substituted
pyrrolidines 16b and 17b in good yields. Aza-spirocyclic
10 F/mol electricity was required to produce the desired
products in moderate yields. Furthermore, azabicyclic pyrrolidine
29b, which is of interest in medicinal chemistry, was prepared.
Such scaffolds are used as NMDA, 5HT3, and neuronal nicotinic
[
21]
receptor antagonists.
Interestingly, starting material 29a was
subjected to the reaction as a cis/trans mixture, and due to the
expected conformational restrictions, only the cis-isomer
underwent the reaction to give the desired product, and the
trans-isomer was successfully recovered.
Mechanistically, based on CV studies and experiments, in the
–
bromide-mediated reaction, electro-oxidation of bromide (Br )
[
20]
compounds are valuable scaffolds in drug discovery. Notably,
we were able to prepare number of saturated spiro-
pyrrolidines, 18b - 24b, including oxygen-containing derivative
3b, by the same strategy. Interestingly, the size of the spiro-
leads to the formation of bromine (Br
immediately trapped by excess bromide to generate Br
and consequently converted to methyl hypobromite (MeOBr).
2
) active species, which is
–
a
3
anion
[
22]
+
2
Due to the low potential (0.3–0.8 V vs Ag/Ag ), only N-bromo
species B can be generated at the electrode, which forms N-
centered radical A either by light-supported homolytic cleavage
or by a SET event on the cathode (Scheme 2). Compound A is
converted to C–centered radical C via a 1,5-HAT process
through a 6-membered cyclic transition state.
ring did not affect the success of the reaction, and the desired
pyrrolidines were obtained in good yields. Nonactivated C-H
bonds reacted successfully, although a much higher amount of
electricity was required. For example, during the preparation of
di- and trisubstituted pyrrolidines 26b, 27b and 30b, 6 to
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3
Scheme 2. Proposed mechanism for the electrochemical C(sp )-H amination.
Although such radicals are believed to be quenched by N-
Br or MeOBr species, similar to the reported photoredox
The essential role of the cathodically generated base for
the reported transformation was confirmed by divided cell
experiments (see SI) along with the visual observation of the
[
23]
processes,
we could neither detect nor isolate the
step. In the
corresponding alkyl bromide due to the rapid S
N
2
evolution of molecular hydrogen (H ). Although the starting
direct halogen-free, oxidative process, radical C is believed to be
oxidized to a carbocation while it is physisorbed onto the surface
of the electrode. In both cases, the formation of pyrrolidine is
achieved by nucleophilic substitution with the N-H group. In
addition to the 1,5-HAT reaction, α-deprotonation of N-Br
intermediate B is observed with formation of the corresponding
aldimine (RCH=NTs) followed by hydrolysis to the corresponding
aldehyde. The chemoselectivity is typically dependent on the
material can be deprotonated directly at the cathode, methanol
or residual water are considered the main source of the base
due to the matching of the pKa value to the acidic N-H bond of
the starting material. Most of the reactions to explore the
substrate scope were performed in a two-electrode cell with a
loading of 1-2 mmol. However, to further extend the utility of the
electrochemical HLF reaction, additional scalability tests were
conducted (Figure 10).
[
25]
molecular conformation and BDE of the reacting C-H bond.
batch 15a: 25 mmol
Yield 15b: 6.47 g (75%)
batch 35a: 25 mmol
Yield 35b: 5.78 g (72 %)
0.5 L MeOH
Anode: 128 cm2
time: 5 h (S1)
batch 31 (33)a: 150 mmol
Yield 31 (33)b: 30.3 g
[68 (70)%]
3 L MeOH, Anode 260 cm2
time: 32 h (S2)
0
.5 L MeOH
2
Anode 128 cm
time: 2 h (S1)
batch 15a: 0.3 mmol
batch 14a: 2.25 mmol
Yield 14b: 0.57 g (64%)
45 mL MeOH, Anode: 5 cm2
time: 3 h (P1)
Yield 15b: 75 mg (73%)
6
mL MeOH, Anode: 1.1 cm2
time: 3 h (ES-2.0)
Figure 10. Scaling up of the HLF reaction. (S1/S2) Scaling up of the HLF reaction with 15a, 31a, 33a and 35a in batch reactions (up to 50 g loading); (ES-2.0) test
of reproducibility with an IKA ElectroSynth system; (P1) Employment of a photovoltaic-powered setup
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Thus, benzylic substrate 15a and menthol-derivative 35a were
converted into the desired pyrrolidines in 75 and 72% yields
after 2 and 5 hours, respectively. Almost no differences, except
for a much lower current efficiency, were observed even in the
The flow setup contains methanolic electrolyte solution feed
followed by the sample loop connected to the reagent injector.
The electrochemical cell with a graphite anode and an SS 316
cathode equipped with a Teflon® separating gasket has an
2
50-g scale cyclizations of protected amino acids such as leucine
internal volume of 225 µL and 12 cm of total surface area. Over
and isoleucine to the corresponding 4- and 3-methyl proline
carboxylates (Figure 10 S1/S2). To our delight, desired products
the course of the reaction, due to release of hydrogen and the
closed system the general liquid flow was unevenly cut into
small slugs of different size. Such phenomenon significantly
increases the overall flow rate due to the difference in viscosity
and at normal pressure we completely failed to achieve
conversions above 20% even at the slowest flow rate possible
(10 µL/min). The usage of other cathodes which might produce
less hydrogen such as graphite or tin didn’t solve the problem
either. Decreasing the temperature usually increases the
solubility of the gases, however, in our case it decreased also
the reaction rate and the conversions were again low. Finally,
the general pressure in the system was increased with the help
of a back pressure regulator. To our delight, the conversion as
31b and 33b were isolated in 68 and 70% yield, while unreacted
starting material and pyrrolidinin-2-one-carboxylates accounted
for the remaining mass balance. Concerning the amount of
electricity used, the solvent and the chemicals (isoleucine: 2 $/g,
Acros), the production cost of highly valuable enantiopure
methyl N-tosyl-3-methyl-proline carboxylate (33b, 705 $/g,
Acros) from the corresponding protected amino acid can be
estimated as only 100 $ per 1 mol.
A
recently
launched
commercially
available
[
24]
electrosynthesizer (by IKA, Figure 4, ES-2.0)
was applied to
evaluate the reproducibility of the reaction. Products 7b, 15b,
and 23b were all obtained in similar chemical and faradaic yields. well as the yield gradually increased with the pressure applied in
Photovoltaic panels were tested as an alternative source of
electricity in the synthesis of 14b (Figure 4, P1). The reaction
outcome did not change compared to that achieved using the
conventional electrical network. Notably, due to the outdoor
ambient temperature, the reaction mixture was heated to 50 °C
regardless of if it was exposed to direct sunlight or kept in
shadow. Nevertheless, the desired pyrazole-substituted
pyrrolidine was isolated in 64% yield.
the range from 1 to 5 bars (Table 2, Entries 1-5). Nevertheless,
fluidic slugs of hydrogen gas were still detectable, but the
number of bubbles was drastically reduced providing quasi-even
flow over the channels in the cell. Eventually, tuning of the flow
rate and the applied voltage provided us the optimal conditions
for the electrochemical C(sp )-H amination under continuous
flow conditions (Table 2, Entries 5 and 6) for both constant
voltage and constant current modes.
3
Further scaling up of the reaction by employing
a
Finally, 250 mL of the methanolic stock solution of
butylamine 15a was pumped through the flow cell over 34 h
without significant changes in the reactivity. The desired
pyrrolidine 15b was isolated in 76% yield with 16% of the
starting material being recovered.
continuous flow setup (Table 2) was also examined. For the
optimization of the reaction conditions the Asia Syrris® flow
reactor was employed.
[
a]
Table 2. Optimization of the reaction conditions under continuous flow.
Sample loop
Syrris Asia FLUX® Module
Graphite anode
Reagent injector
SSE storage
Conclusions
In conclusion, we have developed a sustainable and
environmentally benign protocol for an electrochemically driven,
intramolecular direct C(sp )-H amination.
catalysts and/or (super)stoichiometric
BPR
3
26
Transition-metal
oxidants were
Sample collector
SS316 cathode
Washing syringe pump
successfully replaced by “traceless” anodic oxidation. The
electrochemical reaction utilizes an industrially acceptable
solvent-supporting electrolyte system and inexpensive graphite
and stainless-steel electrodes. Furthermore, we applied this
method to both direct and mediated electrochemical reactions.
The developed reaction conditions were compatible with a wide
variety of functional groups, and the desired pyrrolidines were
obtained with great regioselectivity, good yields and reasonable
current efficiency. The amount of electricity required was
[
b]
Entry
Mode
Flow rate
Back pressure
(bar)
Conversion/
Yield (%)
[
c]
(µL/min)
1
2
3
CV (3.5 V)
CV (3.5 V)
CV (3.0 V)
250
1
2
3
28/24
250
36/31
250
54/48
4
5
CV (2.8 V)
CV (2.8 V)
125
125
125
4
5
5
67/60
[
d]
84/76
2
6
CC (5 mA/cm )
85/75
3
correlated with the BDE of the corresponding C(sp )-H bonds.
[
a] Reactions were conducted with stock solution of 0.025 M KBr, 0.0125 M
The anodic transformations of Ts-isoLeu-OMe and Ts-Leu-OMe
to the methyl-substituted proline methyl esters were efficiently
performed on a 50-g scale; therefore, the protocol can be
implemented for large-scale synthetic applications.
MeONa, and 0.05 M starting material in methanol, SSE is
a
solvent/supporting electrolyte, BPR – back pressure regulator. [b] Mode
refers to the constant voltage (CV) in volts or constant current (CC) and
current density (J) respectively. [c] Conversion and yields are based on
GC-FID. [d] Conversion is based on recovered starting material; Yield is
isolated after column chromatography.
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Chemistry - A European Journal
10.1002/chem.201806092
FULL PAPER
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6
Stirring too quickly must be avoided to prevent vortex formation, which
may change the actual surface area of the electrodes. For the halogen-
free reaction, 2 graphite plates were used as electrodes and 4 mL of
0.125 M NaOMe in methanol solution were used for 0.1 mmol of starting
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2
electrolyzed under a constant current (J = 10 mA/cm ). The reaction
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1
F/mol until full conversion was reached. After the reaction was
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were removed in vacuo. The residue was redissolved in DCM, 4 g of
silica was added, and the solvent was carefully removed again to afford a
free-flowing powder, which was directly purified by column
chromatography. Additional experimental details are provided in the
Supplemental Information.
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Chemistry - A European Journal
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Layout 2:
FULL PAPER
Pavlo Nikolaienko, Marc Jentsch, Ajit P.
Kale and Magnus Rueping*
Page No. – Page No.
Electrochemical and scalable
3
dehydrogenative C(sp )-H amination
via remote hydrogen atom transfer in
batch and continuous flow
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