An Easy-to-Machine Electrochemical Flow Microreactor: Efficient Synthesis of Isoindolinone and Flow Functionalization

Article abstract of DOI:10.1002/anie.201709717

Flow electrochemistry is an efficient methodology to generate radical intermediates. An electrochemical flow microreactor has been designed and manufactured to improve the efficiency of electrochemical flow reactions. With this device only little or no supporting electrolytes are needed, making processes less costly and enabling easier purification. This is demonstrated by the facile synthesis of amidyl radicals used in intramolecular hydroaminations to produce isoindolinones. The combination with inline mass spectrometry facilitates a much easier combination of chemical steps in a single flow process.

Full text of DOI:10.1002/anie.201709717

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Accepted Article
Title: An easy-to-machine electrochemical flow microreactor: Efficient
isoindolinone synthesis and flow functionalization
Authors: Ana A Folgueiras-Amador, Kai Philipps, Sebastien Guilbaud,
Jarno Poelakker, and Thomas Wirth
This manuscript has been accepted after peer review and appears as an
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201709717
Angew. Chem. 10.1002/ange.201709717
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10.1002/anie.201709717
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An easy-to-machine electrochemical flow microreactor: Efficient
isoindolinone synthesis and flow functionalization
Ana A. Folgueiras-Amador, Kai Philipps, Sébastien Guilbaud, Jarno Poelakker and Thomas Wirth*
Abstract: Flow electrochemistry is an efficient methodology to
generate radical intermediates. An electrochemical flow microreactor
has been designed and manufactured to improve the efficiency of
electrochemical flow reactions. With this device only little or no
supporting electrolytes are needed, making processes less costly
and enabling easier purification. This is demonstrated by the facile
synthesis of amidyl radicals used in intramolecular hydroaminations
to isoindolinones. The combination with inline mass spectrometry
facilitates a much easier telescoping of chemical steps in a single
flow process.
reactor can be made with an aluminum body (Figure 1b), or from
polymers by using additive manufacturing technology (3D
printing, Figure 1c). The latter offers the possibility for the
reactor to be manufactured with lower cost within a few hours
and also offers facile customization if needed according to the
specifications of the reaction. The large electrode area (anode
and cathode: 25 cm2 each) with robust and secure electrode-
wire connection and easily exchangeable electrode materials
leads to more flexibility, but also higher productivity and
efficiency. The two electrodes are separated by a spacer of FEP
(fluorinated ethylene propylene) foil, while the reaction solution
is flowing through a channel cut out in the FEP foil (Figure 1d).
Sealing is achieved through the FEP foil when the two electrode
blocks are screwed together. The flow reactor is shown in Figure
1 and all details of its construction including files for additive
manufacturing (3D printing) can be found in the supporting
information. The distance between the electrodes is defined by
the thickness of the FEP spacer (typically 100 – 500 µm). A
small distance between the electrodes is important and the use
of supporting electrolytes often superfluous.
Over the past decades, organic electrosynthesis has become
recognized as one of the methodologies to perform redox
reactions in an efficient, straightforward and clean way. Anionic
and cationic radical species can be formed from neutral organic
molecules generating
a
wide variety of useful reactive
intermediates.[1] Electrons as reagents can achieve oxidations
and reductions by replacing toxic or dangerous oxidizing or
reducing reagents. As less chemicals are necessary to perform
the reaction, fewer side products are formed. These features
have recently sparked attention in the development of
2
]
equipment[
and in advanced synthetic protocols for
electrochemical reactions.[3]
Organic electrochemistry is a powerful method for organic
synthesis, but there are also limitations for electrochemistry in
batch processes. As common organic solvents have typically
low conductivity, the use and subsequent removal of supporting
electrolytes is necessary. The large distance between electrodes
in batch processes leads to large current gradients. Continuous
flow reactors can address some of these problems.[4] Small
electrode distances avoid large current gradients and reactions
can be performed with small amounts or even without addition of
supporting electrolytes, although modification of electrode
surfaces have also been investigated.[ 5 ] A high electrode
surface-to-reactor volume ratio allows a much-improved mass
transfer on the surface of the electrodes leading to milder
reaction conditions and short reaction times.
a)
c)
b)
d)
Figure 1: Electrochemical flow reactor. a) Schematic diagram; b) Aluminum
reactor; c) Reactor made by additive manufacturing through monomer
polymerization; d) FEP spacer with flow channel.
Microreactors for continuous flow electrosynthesis have already
been developed.[6] We have contributed to that development
with an electrochemical microreactor with a very small inter-elec-
trode gap (100 – 250 µm), which was applied for the synthesis of
diaryl iodonium salts, for the difluoro- and trifluoromethylation of
electron-deficient alkenes and for the electrochemical depro-
tection of iso-nicotinyloxycarbonyl group from carbonates and
thiocarbonates.[7] Here we describe the development of a much
improved, second-generation electrochemical microreactor. This
Nitrogen-containing heterocycles are very important components
in drugs and bioactive natural products. Their synthesis has
been explored with different methodologies, many of them
involving the use of precious transition metals or toxic
reagents.[ 8 ] Using the above-described electrochemical flow
reactor, we use here an alternative method for the synthesis of
N-heterocycles via a nitrogen-centered radical accessed through
electrochemical oxidation and its subsequent addition to alkenes
in an intramolecular cyclization. Such N-centered radicals have
already been used in batch electrochemical processes.[9]
[*]
A. A. Folgueiras-Amador, K. Philipps, S. Guilbaud, J. Poelakker,
Prof. Dr. T. Wirth
O
cathode / anode
N
Ph
School of Chemistry, Cardiff University
Park Place, Main Building, Cardiff CF10 3AT (UK)
E-mail: wirth@cf.ac.uk
NH
Ph
N
MeCN / H2O (19:1)
TEMPO (1.5 eq)
O
O
O
O
Homepage: http://blogs.cardiff.ac.uk/wirth/
2
1
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. Electrochemical cyclization of carbamate 1.
1
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10.1002/anie.201709717
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COMMUNICATION
With the cyclization of carbamate 1 to product 2 (Scheme 1),
general conditions for the electrochemical reaction were
explored such as electrode materials, solvents and bases. In
batch reactions, where NBu4BF4 (0.1 M) is used as supporting
electrolyte, different electrode materials were investigated to
explore the reactivity.
The oxidation potential of 1 after addition of 2,6-lutidine remains
practically unchanged, which explains the similar result with and
without base. The mechanism proposed by Xu et al.[9] (Scheme
2) shows that the cathode-generated hydroxide anion assists in
the deprotonation of the carbamate before forming the nitrogen
radical. With sodium carbonate as base the reaction proceeded
to completion after 3 F mol–1, but the amount of water had to be
increased (50% in acetonitrile) in order to dissolve the base.
This led to poor solubility of the product in the solvent mixture
and to precipitation and blocking of the flow system after 10
minutes of operation, making this base/solvent system inefficient
With platinum as cathode, the reaction behaved very similar with
almost any electrode material used as anode. But the results are
very different when the cathode is not platinum. Only 1 F mol–1
of electricity is theoretically needed for the one-electron
oxidation, but even with 4 F mol–1 the reaction did not go to
completion in most cases (see supporting information for details). for continuous flow.
To accelerate the reaction, benzyltrimethylammonium hydroxide
The counter electrode (cathode) clearly has a larger impact on
the reaction than the working electrode (anode). This is due to
the water reduction reaction taking place at the cathode (see
proposed mechanism in Scheme 2), and the different activation
overpotential for hydrogen evolution on different electrode
materials.[10] The activation overpotential is lower for platinum
(‑0.07 V) than for nickel (‑0.28 V), and much higher for graphite
(‑0.62 V) (all vs Ag/AgCl). As the results obtained for graphite,
platinum and boron doped diamond (BDD) as anode are very
similar, graphite was used as the most inexpensive material.
The reaction from 1 to 2 was carried out in different solvents and
solvent mixtures, such as acetonitrile, methanol, 1,1,1,3,3,3-
hexafluoroisopropyl alcohol (HFIP) and water, and it was found
that acetonitrile/water mixture is the optimum solvent mixture for
this reaction. Although HFIP is known to be efficient for
stabilizing cations and radicals,[11] it led to either recovery of
starting material (< 2 F mol–1) or decomposition (> 3 F mol–1).
The use of a base can be favourable in anodic oxidations if the
compound or its oxidized form can be deprotonated as most
anodic oxidations undergo loss of electrons and protons.[9b,12] Xu
et al.[9] reported the cyclization of carbamates of type 1 in batch
using lithium hydroxide or sodium carbonate as a heterogene-
ous base. The drawback of these bases is their low solubility in
organic solvents which is clearly more problematic for flow than
for batch processes. Different organic bases were investigated
in the flow cyclizations (see supporting information), but
triethylamine inhibited the reaction while with 2,6-lutidine similar
conversions as without base was observed. This was explained
by measuring the cyclic voltammogram of substrate 1 in the
presence of different bases (see supporting information). The
oxidation potential of triethylamine is much lower than of 1, so it
will be oxidized first, and the starting material remains unreacted.
6 was used. Full conversion of 1 after 3 F mol–1 was achieved
and 6 as soluble base was used in further optimization studies.
Cyclic voltammetry endorses this result, as the cyclic
voltammogram in the presence of benzyltrimethylammonium
hydroxide shows a lower oxidation potential (from 1.74 V to 0.27
V, vs Ag/AgCl). This second oxidation potential corresponds to
the deprotonated form of compound 1, which will facilitate the
production of the radical at the anode (see supporting
information). Moeller and co-workers have observed comparable
results where deprotonated sulfonamides exhibit
a lower
oxidation potential than the neutral compounds.[ 13 ] We also
found that under the optimized reaction conditions the thickness
of the spacer can be varied from 250 µm to 500 µm with no
change in the reaction yield.
The optimized conditions were then applied to the synthesis of
isoindolinones in flow. Such isoindolinone motifs are found in
many natural products, pharmaceuticals and biologically active
molecules (Figure 2).[14]
O
O
O
OH
N
F
HO
N
O
O
O
N
O
O
O
N
N
N
N
N
N
N
N
OH
Cl
Cl
Pazinaclone
(sedative and
anxiolytic drug)
Clitocybin
(antioxidant)
Pagoclone
(anxiolytic drug)
(sedative drug)
Figure 2. Biologically active isoindolinone derivatives.
anode
cathode
The cyclization of amide 7 to isoindolinone 8 was investigated in
detail. For this purpose, the electrochemical reactor was
connected to an inline mass spectrometer, which allowed a rapid
assessment of the required amount of electrons. As shown in
Figure 3, at least 3 F mol–1 is necessary in order to achieve full
conversion. Only 0.5 equivalents of the base are needed to
complete the reaction, but with smaller amount of the base full
R1
NH
−OH
+
1/2 H2
N
O
R2
e−
R1
N
e−
N
O
H2O
R2
3
Tol
R1
N
(TEMPO)
O
R1
O
NH
Tol
R2
R2
TEMPO
N
N
Ph
N
O
O
N
4
Ph
N
OH
7
(m/z: 314.5)
8 (m/z: 222.3)
0.1 mL/min
TEMPO (1.5 eq)
BnNMe3OH (0.5 eq)
6
5
MS analysis
Scheme 2. Proposed mechanism.[9]
Scheme 3. Cyclization of amide 7 to 8 with MS analysis.
2
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10.1002/anie.201709717
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COMMUNICATION
conversion cannot be achieved. Here the base can be
considered as an electrolyte, but with much lower loadings than
electrolytes in batch electrochemical reactions and can be
removed easily through aqueous work-up.
was performed for 1.5 h leading to 12 in 96% yield (180 mg).
The same reaction performed in batch required supporting
electrolyte and provided product 12 after 6 h in only 51% yield
(107 mg). This also demonstrates the efficiency of the flow
process allowing a supporting electrolyte-free electrochemical
reaction.
A tandem cyclization reaction was then attempted with a
vinylphenyl substituent on the nitrogen, but only monocyclized
product 18 was obtained (Scheme 4). This compound now bears
With the optimized reaction conditions (3 F / mol–1, 24 mA, 1-2
V) in hand, different substrates were examined as shown in
Figure 4. While aromatic moieties on the amide nitrogen are
required to stabilize the nitrogen radical, the substituents on the
alkene moiety can be varied widely.
a
functionalized styrene moiety which could be used in
subsequent reactions. NMR characterization of 18 was difficult
due to the appearance of broad peaks, which could only be
slightly improved at high temperature NMR. After separation of
the diastereomers, the oxygen – nitrogen bond was cleaved with
zinc and acetic acid and the structures of the two
diastereoisomers 23a and 23b were determined by X-ray
analysis (see supporting information).[15]
O
Figure 3. Inline mass spectrometric analysis of the electrochemical flow
reaction 7 → 8.
N
H
OH
O
Ph
Only with the 4-OMe functionality present in the aromatic ring
next to the double bond, the reaction results in a complex
mixture leading to a low yield of the desired products (15 and
16). Due to the radical pathway of the cyclization, the
diastereoselectivities are low and were dictated only by steric
effects. The stereochemistry of the substrate was also found not
to affect the selectivity, thus when pure E- or Z-isomers are used
for the reaction the same diastereomeric ratios are obtained for
compound 12. The (R,S)/(S,R) diastereomer is always favored
as confirmed by X-ray crystallographic analysis of compound 12
Zn
N
23a, 42%
THF/AcOH/H2O
(1:3:1 v:v:v)
50 ºC, 3 h
O
N
Ph
O
N
H
18 d.r. 2.25:1
OH
Ph
23b, 30%
Scheme 4. N–O-bond cleavage of compound 18.
]
(see supporting information).[ 15 When electron-withdrawing
The isoindolinone products were then used for subsequent
functionalization, including elimination of the TEMPO moiety and
reduction of the nitrogen-oxygen bond. The elimination reaction
was performed using the same base as used in the cyclization to
yield alkenes such as 24,[16] which can be employed in further
reactions. Furthermore, the electrochemical cyclization and the
elimination were coupled in a single flow system as shown in
Scheme 5.
substituents such as chloride are attached to the aromatic ring
adjacent to the double bond, the reduced product 20 is observed
in addition to 19. Such reduced compounds are the only
products with a 3-nitrophenyl substituent (21 and 22), where no
TEMPO addition is observed. In these reactions no gas
evolution is observed, which implies that there is no gaseous
hydrogen formed from proton reduction. Since TEMPO is not
being consumed here as is not added to the final product, the
redox cycle can be completed by reducing the oxoammonium
cation to the free radical. A flow reaction on slightly larger scale
3 F/mol
O
85 ºC
2.8 bar
R
N
H
O
8 R = 4-MeC6H4, R' = Ph, 78%, d.r. 1.24:1
9 R = 4-ClC6H4, R' = Ph, 56%, d.r. 1.06:1
10 R = R' = Ph, 72%, d.r. 1.14:1
11 R = n-C4H9, R' = Ph, 0% (no reaction)
12 R = Ph, R' = i-Pr, 96%, d.r. 3:1
BPR
N
R'
R'
O
R
BnNMe3OH (2 eq)
TEMPO (1.5 eq)
0.1 mL/min
R
N
24–29
O
13 R = Ph, R' = n-Pr, 75%, d.r. 1.65:1
24 R = Ph, R' = i-Pr, 75%, E/Z : 9/1
25 R = 4-MeC6H4, R' = Ph, 68%, E/Z : 19/1
26 R = R' = Ph, 62%, E/Z : 19/1
27 R = Ph, R' = 4-MeC6H4, 71%, E/Z : 9/1
28 R = Ph, R' = 4-ClC6H4, 73%, E/Z : 7/1
29 R = 4-ClC6H4, R' = Ph, 66%, E/Z : 5/1
N
14 R = Ph, R' = 4-MeC6H4, 62%, d.r. 1.15:1
15 R = 4-MeC6H4, R' = 4-MeOC6H4, 21%, d.r. 1.27:1
16 R = Ph, R' = 4-MeOC6H4, 18%, d.r. 1.21:1
17 R = 4-MeC6H4, R' = 1-naphth, 79%, d.r. 1.57:1
18 R = 2-(H2C=CH)C6H4, R' = Ph, 85%, d.r. 2.25:1
R'
O
O
Scheme 5. Two-step flow reaction: cyclization and elimination. BPR: back
pressure regulator.
O
O
Ph
Ph
Ph
N
N
N
N
O
In order to achieve full conversion to compound 24, the reaction
conditions were investigated and a residence time of 25 minutes
at 85 ºC / 2.8 bar were found to be optimal (see supporting
information, Table S2). Compound 24 was obtained as a mixture
of E- and Z-isomers, with excess of the E-isomer (up to 9:1 in
entry 6 for compound 24, and up to 19:1 for compounds 25 and
N
+
O2N
22, 91%
O2N
Cl
20, 21%
Cl
19, 56%, d.r. 1.29:1
21, 94%
Figure 4. Substrate Scope for the cyclization reaction.
3
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10.1002/anie.201709717
Angewandte Chemie International Edition
COMMUNICATION
26). The configuration was determined by NOE NMR (see
supporting information).
University, for helpful discussions and Dr. S. Cattaneo, CCI at
Cardiff University, for assistance with the 3D printing. We also
thank the EPSRC National Mass Spectrometry Facility,
Swansea, for mass spectrometric data. We thank Cardiff
University and the Erasmus program (K.P.) for financial support.
The nitrogen-oxygen bond reduction in flow was performed
using a Zn cartridge[17] and acetic acid, as shown in Scheme
6.[ 18 ] The cartridge was heated to 40 ºC to achieve full
conversion to the corresponding alcohols (Scheme 6).
Compounds 30–32 were prepared in 54–80% overall yield.
Keywords: flow electrochemistry • cyclizations • isoindolinones •
microreactors • tandem reactions
AcOH, H2O
3 F/mol
O
R
N
[1] a) B. A. Frontana-Uribe, R. D. Little, J. G. Ibanez, A. Palma, R. Vasquez-
Medrano, Green Chem. 2010, 12, 2099–2119; b) O. Hammerich, B.
Speiser, Organic Electrochemistry, CRC Press, Boca Raton, 2016; c) E. J.
Horn, B. R. Rosen, P. S. Baran, ACS Cent. Sci. 2016, 2, 302–308.
[2] M. Yan, Y. Kawamata, P. S. Baran, Angew. Chem. Int. Ed. 2017, 56, in
press. DOI: 10.1002/anie.201707584
[3] a) E. J. Horn, B. R. Rosen, Y. Chen, J. Tang, K. Chen, M. D. Eastgate, P.
S. Baran, Nature 2016, 533, 77; b) R. Hayashi, A. Shimizu, J. Yoshida, J.
Am. Chem. Soc. 2016, 138, 8400; c) L. Schulz, M. Enders, B. Elsler, D.
Schollmeyer, K. M. Dyballa, R. Franke, S. R. Waldvogel, Angew. Chem.
Int. Ed. 2017, 56, 4877; d) N. Fu, G. S. Sauer, A. Saha, A. Loo, S. Lin,
Science 2017, 357, 575; e) R. Feng, J. A. Smith, K. D. Moeller, Acc.
Chem. Res. 2017, 50, 2346–2352.
H
40 ˚C
Zn
cartridge
O
N
R'
N
R'
R
0.1 mL/min
OH
BnNMe3OH (2 eq)
TEMPO (1.5 eq)
30–32
O
O
OH
Ph
N
N
O
OH
OH
O
Ph
30, 80%
31, 54%
32, 66%
[4] a) J. Yoshida, Electrochem. Soc. Interface 2009, 40–45; b) K. Watts, A.
Baker, T. Wirth, J. Flow Chem. 2014, 4, 2–11; c) A. Folgueiras-Amador, T.
Wirth, J. Flow Chem. 2017, in press; d) M. Atobe, H. Tateno, Y.
Matsumura, Chem. Rev. 2017, 117, in press. DOI:
Scheme 6. Two-step flow reaction: cyclization and reduction.
Two additional transformations performed in the electrochemical
flow reactor without supporting electrolyte are shown in Scheme
7. The electrolysis of thioacetic acid generates the correspon-
ding radical. Unlike carboxylic acids, which decarboxylate and
react in Kolbe reactions, the thioacetyl radical is stable and adds
smoothly to terminal alkynes to yield products such as 33. The
use of hexafluoroisopropanol (HFIP) to stabilize the formed
radical is crucial as with other solvents dimerization of thioacetic
acid is observed. An intramolecular C–H thiolation of N-
arylthioamides to form benzothiazoles such as 34 can also be
performed with superior yields than the batch process, which
needs TEMPO and a supporting electrolyte to operate.[19]
10.1021/acs.chemrev.7b00353
[5] S. J. Yoo, L.-J. Li, C.-C. Zeng, R. D. Little, Angew. Chem. Int. Ed. 2015,
54, 3744–3747.
[6] a) D. Horii, M. Atobe, T. Fuchigami, F. Marken, Electrochem. Commun.
2005, 7, 35–39; b) R. Horcajada, M. Okajima, S. Suga, J. Yoshida, Chem.
Commun. 2005, 1303–1305; c) P. He, P. Watts, F. Marken, S. J. Haswell,
Angew. Chem. Int. Ed. 2006, 45, 4146–4149; d) J. Kuleshova, J. T. Hill-
Cousins, P. R. Birkin, R. C. D. Brown, D. Pletcher, T. J. Underwood,
Electrochim. Acta 2011, 56, 4322–4326; e) A. Attour, P. Dirrenberger, S.
Rode, A. Ziogas, M. Matlosz, F. Lapicque, Chem. Eng. Sci. 2011, 66,
480–489; f) T. Kashiwagi, B. Elsler, S. R. Waldvogel, T. Fuchigami, M.
Atobe, J. Electrochem. Soc. 2013, 160, G3058–G3061; g) M. A.
Kabeshov, B. Musio, P. R. D. Murray, D. L. Browne, S. V. Ley, Org. Lett.
2014, 16, 4618–4621; h) M. R. Chapman, Y. M. Shafi, N. Kapur, B. N.
Nguyen, C. E. Willans, Chem. Commun. 2015, 51, 1282–1284; i) R. A.
Green, R. C. D. Brown, D. Pletcher, B. Harji, Org. Process Res. Dev.
2015, 19, 1424–1427; j) C. Gütz, M. Bänziger, C. Bucher, T. R. Galvão, S.
R. Waldvogel, Org. Process Res. Dev. 2015, 19, 1428–1433; k) R. A.
Green, D. Pletcher, S. G. Leach, R. C. D. Brown, Org. Lett. 2015, 17,
3290–3293; l) R. A. Green, R. C. D. Brown, D. Pletcher, B. Harji,
Electrochem. Commun. 2016, 73, 63–66; m) C. Gütz, A. Stenglein, S. R.
Waldvogel, Org. Process Res. Dev. 2017, 21, 771–778.
Pt cathode / Graphite anode
1 F mol–1
O
a)
CH3COSH (2 eq.)
S
HFIP
33, 49%
[7] a) K. Watts, W. Gattrell, T. Wirth, Beilstein J. Org. Chem. 2011, 7, 1108–
1114; b) K. Arai, K. Watts, T. Wirth, Chem. Open 2014, 3, 23–28; c) K.
Arai, T. Wirth, Org. Process Res. Dev. 2014, 18, 1377–1381.
[8] a) T. J. Donohoe, C. K. A. Callens, A. Flores, A. R. Lacy, Chem. Eur. J.
2011, 17, 58–76; b) P. H. Fuller, J. Kim, S. R. Chemler, J. Am. Chem. Soc.
2008, 130, 17638–17639; c) G. Yang, W. Zhang, Org. Lett. 2012, 14,
268–271.
Ph
Pt cathode / Graphite anode
Ph
1.25 F mol–1
HN
S
N
b)
S
MeCN/H2O (1:1)
[9] a) H. C. Xu, J. M. Campbell, K. D. Moeller, J. Org. Chem. 2014, 79, 379–
391; b) F. Xu, L. Zhu, S. Zhu, X. Yan, H. C. Xu, Chem. Eur. J. 2014, 20,
12740–12744; b) L. Zhu, P. Xiong, Z. Y. Mao, Y. H. Wang, X. Yan, X. Lu,
H. C. Xu, Angew. Chem. Int. Ed. 2016, 55, 2226–2229; c) Z. W. Hou, Z. Y.
Mao, H. B. Zhao, Y. Y. Melcamu, X. Lu, J. Song, H. C. Xu, Angew. Chem.
Int. Ed. 2016, 55, 9168–9172; d) P. Xiong, H. H. Xu, H. C. Xu, J. Am.
Chem. Soc. 2017, 139, 2956–2959.
[10] E. W. Washburn, International Critical Tables of Numerical Data, Physics,
Chemistry and Technology. National Academy of Sciences, McGraw Hill,
New York, 1926.
[11] a) L. Eberson, O. Persson, M. P. Hartshorn, Angew. Chem. Int. Ed. 1995,
34, 2268–2269; b) L. Eberson, M. P. Hartshorn, O. Persson, J. Chem.
Soc., Perkin Trans. 2 1995, 1735–1744.
[12] H. C. Xu, K. D. Moeller, J. Am. Chem. Soc. 2010, 132, 2839–2844.
[13] J. M. Campbell, H. C. Xu, K. D. Moeller, J. Am. Chem. Soc. 2012, 134,
18338–18344.
34, 97%
Scheme 7. a) Electrochemical addition of thioacetic acid to phenyl acetylene;
b) Electrochemical C–H thiolation of an N-arylthioamide to benzothiazole 34.
In conclusion,
a new and efficient flow electrochemical
microreactor has been designed and manufactured which was
used to generate nitrogen and sulfur-based radical intermediates
for syntheses with no or little supporting electrolyte. In addition,
one of the first combinations of an electrochemical reaction with
a second one in a single flow system is demonstrated.[20]
[14] R. Manoharan, M. Jeganmohan, Chem. Commun. 2015, 51, 2929–2932.
[15] CCDC-1569516 (12), CCDC-1569515 (23a) and CCDC-1569517 (23b)
contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
[16] J. Gui, H. Tian, W. Tian, Org. Lett. 2013, 15, 4802–4805.
[17] The Zn cartridge was prepared using silica as support (60 – 100 mesh,
50% in weight). This was required to reduce the backpressure produced
due to the small size of the Zn dust particles (<10 µm).
We thank the workshop staff from Cardiff School of Chemistry
for helping in the reactor manufacturing and Prof. S. Waldvogel,
Mainz University, for enabling the electrode and solvent
screening in his laboratory. We thank Dr. D. L. Browne, Cardiff
[18] a) P. G. M. Wuts, Y. W. Jung, J. Org. Chem. 1988, 53, 1957–1965; b) D.
A. Dias, M. A. Kerr, Org. Lett. 2009, 11, 3694–3697.
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10.1002/anie.201709717
Angewandte Chemie International Edition
COMMUNICATION
[19] X.-Y. Quian, S.-Q. Li, J. Song, H.-C. Xu, ACS Catal. 2017, 7, 2730–2734.
[20] a) R. A. Green, D. Pletcher, S. G. Leach, R. C. D. Brown, Org. Lett. 2016,
18, 1198–1201; b) R. Stalder, G. P. Roth, ACS Med. Chem. Lett. 2013, 4,
1119–1123.
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10.1002/anie.201709717
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
None or little supporting electrolyte
needed in flow electrochemistry:
Recycling and waste problems are
eliminated as cyclization products are
obtained in a fast and clean process.
Ana A. Folgueiras-Amador, Kai Philipps,
Sébastien Guilbaud, Jarno Poelakker
and Thomas Wirth*
Page No. – Page No.
An easy-to-machine electrochemical
flow microreactor: Efficient
isoindolinone synthesis and flow
functionalization
6
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