Catalyst- and Supporting-Electrolyte-Free Electrosynthesis of Benzothiazoles and Thiazolopyridines in Continuous Flow

Article abstract of DOI:10.1002/chem.201705016

A catalyst- and supporting electrolyte-free method for electrochemical dehydrogenative C?S bond formation in continuous flow has been developed. A broad range of N-arylthioamides have been converted to the corresponding benzothiazoles in good to excellent yields and with high current efficiencies. This transformation is achieved using only electricity and laboratory grade solvent, avoiding degassing or the use of inert atmosphere. This work highlights three advantages of electrochemistry in flow, which is (i) a supporting electrolyte-free reaction, (ii) an easy scale-up of the reaction without the need for a larger reactor and, (iii) the important and effective impact of having a good mixing of the reaction mixture, which can be achieved effectively with the use of flow systems. This clearly improves the reported methods for the synthesis of benzothiazoles.

Full text of DOI:10.1002/chem.201705016

A Journal of
Accepted Article
Title: Catalyst- and Supporting Electrolyte-Free Electrosynthesis of
Benzothiazoles and Thiazolopyridines in Continuous Flow
Authors: Ana A. Folgueiras-Amador, Xiang-Yang Qian, Haichao Xu,
and Thomas Wirth
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To be cited as: Chem. Eur. J. 10.1002/chem.201705016
Link to VoR: http://dx.doi.org/10.1002/chem.201705016
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Catalyst- and Supporting Electrolyte-Free Electrosynthesis of
Benzothiazoles and Thiazolopyridines in Continuous Flow
Ana A. Folgueiras-Amador,†[a] Xiang-Yang Qian,†[b] Hai-Chao Xu*[b] and Thomas Wirth*[a]
Abstract: A catalyst- and supporting electrolyte-free method for
electrochemical dehydrogenative C–S bond formation in continuous
Cl
F
O
flow has been developed. A broad range of N‑arylthioamides have
been converted to the corresponding benzothiazoles in good to
excellent yields and with high current efficiencies. This
transformation is achieved using only electricity and laboratory grade
solvent, avoiding degassing or the use of inert atmosphere. This
work highlights three advantages of electrochemistry in flow, which
is (i) a supporting electrolyte-free reaction, (ii) an easy scale‑up of
the reaction without the need for a larger reactor and, (iii) the
important and effective impact of having a good mixing of the
reaction mixture, which can be achieved effectively with the use of
flow systems. This clearly improves the reported methods for the
synthesis of benzothiazoles.
N
S
N
S
N
S
N
S
Cl
HN
HN
O
NH2
(CH2)4NH2
N
O
HN
O
NH
Frentizole
Antiviral agent
Thioflavin-T
Amyloid Imaging Agent
Phortress
Antitumor agent
(under Phase I in clinical trials)
Halethazole
Antiseptic agent
Figure 1. Benzothiazole based clinically available drugs.
Introduction
The benzothiazole scaffold is part of a large number of bioactive
compounds, including antiviral, antitumor, and antiseptic agents
as well as tracers for ß-amyloid plaques in Alzheimer disease
(Figure 1).[9] Benzothiazoles can be synthesized by oxidative
cyclization of N-arylthioamides. These oxidative cyclizations
have been achieved using iron-based catalysts,[10] with chloranil
as photosensitizer under irradiation,[11] or in a combination of
visible light, oxygen and ruthenium catalysts and a base.[12] The
major disadvantage of these methods is the undesirable
desulfurization of the thioamides to amides as side products.
The formation of benzothiazoles from N-arylthioamides has also
been accomplished by employing hypervalent iodine as the
oxidant[13] and palladium as the catalyst under oxygen
The formation of carbon-carbon and carbon-heteroatom bonds
is one of the most important transformations in organic
chemistry. Direct cross-coupling reactions of C–H and X–H (X =
heteroatom) have been widely studied in the past due to the
simplicity of the method.[1–5] These methods obviate the need to
prefunctionalize the substrate, and thus reduce the number of
steps of a synthetic route. Traditional cross-coupling methods
frequently use precious transition metals or stoichiometric
amounts of organic oxidants, which create waste in the reaction
and make large-scale processes difficult.[6,7] Even if the transition
metals are used in catalytic amounts, there is still a need to
remove residual metal impurities from the products. The removal
of residual metals leads to additional costs.[8]
atmosphere.[14]
A
novel photoredox process employing
ruthenium- and cobalt-based catalysts has been recently
developed by Wu and Lei, where the use of oxidants is avoided
by hydrogen formation from proton reduction.[15] In spite of all the
methods described, the synthesis of 2-alkyl substituted
benzothiazoles and thiazolopyridines is still challenging.
Ref [10]: [Fe] (10 mol%), [O] (1 eq.), base
Previous work:
Ref [11]: chloranil (PS, 1 eq.), hν, N2 atm., 80 ºC
Ref [12]: [Ru] (1 mol%), hν, base (1 eq.), O2
Ref [13]: DMP (1 eq.);
Ref [14]: [Pd] (10-20 mol%), O2, 100-140 ºC
S
N
[a]
A. A. Folgueiras-Amador, Prof. Dr. T. Wirth
School of Chemistry, Cardiff University
Park Place, Main Building, Cardiff CF10 3AT (UK)
E-mail: wirth@cf.ac.uk
S
R'
R
R
N
R'
Ref [15]: [Ru] (3 mol%), [Co] (8 mol%), hν
H
Ref [34a]: div. cell, controlled potential, 0.1 M SE
Ref [34b]: undiv. cell, base (2 eq.), SE (6 eq.), 70 ºC
Ref [35]: undiv. cell, TEMPO (5-10 mol%),
SE (20 mol%), Ar atmosphere
Homepage: http://blogs.cardiff.ac.uk/wirth/
[b]
X.-Y. Qian, Prof. H.-C. Xu
College of Chemistry and Chemical Engineering, Xiamen University
Xiamen, 361005, P. R. China
Email: Haichao.xu@xmu.edu.cn
Homepage: http://chem.xmu.edu.cn/groupweb/hcxu/index.asp
These authors contributed equally to this work.
This work:
S
S
flow undivided cell
R'
R
-
R'
only e
N
N
R
†
H
PS = photosensitizer; DMP = Dess-Martin periodinane; SE = supporting electrolyte
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. Aromatic dehydrogenative C–S bond formation.
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Organic electrosynthesis is known as an alternative method to
perform redox processes, where toxic or dangerous oxidizing or
reducing reagents are replaced by electrons, making such
processes more environmentally friendly than traditional
methods employing stoichiometric redox reagents.[16–21] There
are a number of examples of electrochemical methods to
achieve C–H functionalization.[22–28] We have recently developed
electrochemical reactions to synthesize N-heterocycles through
creating new C–N bonds,[29,30] and some of these methods use a
mediator such as 2,2,6,6-tetramethylpiperidine-N-oxyl radical
(TEMPO)[31] or ferrocene[32,33] to perform the oxidation of the
substrate.
flow rate. The amount of electricity used in the reaction could be
decreased to 2.5 F mol–1 without affecting the conversion (Table
1, entry 8). However, a further reduction to 2.0 F mol–1 led to the
drop of the conversion to 90% (Table 1, entry 9). With the
optimized conditions (entry 8), a larger scale reaction was
performed leading to the formation of the product 2 in 97%
isolated yield (121 mg).
Table 1. Optimization of the reaction conditions.
The electrosynthesis of benzothiazoles from N-arylthioamides
was firstly reported in 1979 and lately by Lei.[34] We have
recently developed
a versatile method for synthesis of
benzothiazoles and thiazolopyridines through mediated
electrochemical oxidation of N‑arylthioamides.[35] For all of these
methods, supporting electrolytes are employed to increase the
conductivity of the solution. On the other hand, flow
electrochemistry offers many advantages over batch
electrochemistry.[18,36–43] For example, a large ratio of electrode
surface to reactor volume reduces the reaction time. In addition,
the short distance between electrodes enables a more efficient
mass transfer and allows the use of low concentrations of
supporting electrolyte or even no supporting electrolyte at all.
We have also developed such systems for efficient flow
electrolysis.[44–47] Electrolyte-free solvent systems with a residual
conductivity such as acetonitrile/water was recently described by
Waldvogel et al.,[48] and provides significant advantages in
downstream processing. Herein, we report the first catalyst-free
and supporting electrolyte-free electrochemical synthesis of
Concentr
ation
Flow rate
[mL min–1
Current
density
Current
[F mol–1
1H NMR
conversion
Entry
]
]
[mol L–1
]
[mA cm–2
]
1[a]
2[a]
3[a]
4
0.49
0.98
1.46
1.46
2.93
5.85
11.71
4.88
3.90
2.0
4.0
6.0
33%
0.025
0.05
50%
98%
0.05
0.1
>99%
>99%
>99%
>99%
>99%
90%
5
0.025
6.0
6
0.2
7
6.0
2.5
2.0
8[b]
9
0.05
0.2
benzothiazoles
and
thiazolopyridines
from
N-
(hetero)arylthioamides using a flow electrochemical reactor.[47]
[a] 5 mol% of TEMPO. [b] 97% isolated yield.
Results and Discussion
The cyclization of N-(quinolin-3-yl)butanethioamide
1
to
The substrate scope was explored as shown in Table 2 and
Figure 2. Results obtained in a batch reactor are provided for
comparison. Alkyl and aryl thioamides reacted smoothly with
good yields (3-6, 9-17, 20, 22). Many functional groups were
tolerated in the electrochemical oxidation, such as free alcohols
(14, 21), silyl ethers (15), esters (16, 20), carbamates (17),
sulfonamides (17, 22) and phosphine oxides (24). The
cyclization to benzothiazole could also be obtained with other 2-
substituents, such as heteroaryl (29) and electron-rich arenes
(6).
thiazolo[4,5-c]quinoline 2 was initially studied using reaction
conditions similar to those previously employed in batch.[35] This
substrate was chosen because the product 2 (Table 1) was an
intermediate in the synthesis of CL075 (a TLR8 receptor
agonist).[49] The electrolysis in flow employed platinum as the
cathode, graphite as the anode (working electrode surface: 8.2
cm2 each), a solvent mixture of acetonitrile and methanol, and a
catalytic amount of TEMPO (5 mol%). Initial reaction
optimization used a low current density of 0.49 mA cm−2 (Table 1,
entry 1), and product 2 was obtained in 33% conversion with the
consumption of 2 F mol–1 of charge. With a low concentration
and flow rate, 6 F mol–1 was needed to achieve full conversion
(entry 3). Further experiments showed that TEMPO was not
required for the electrolysis of thioamide 1 in flow (entry 4). To
increase the throughput, higher flow rates (entries 5 and 6) and
substrate concentrations were investigated (entry 7). Under
these conditions, similarly high conversions (>99%) were
obtained demonstrating that higher production rates can be
achieved through increasing the substrate concentration and
Table 2. Substrate scope.
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AcO
20
21
PG = H
N
Flow:
Batch:
Product
S
N
PG = MeCO
H
Yield [%]
(Current [F mol–
1])
Yield [%]
(Current
mol–1])
H
[F
Flow: 72% (2.3 F) 33% (2.0 F)
H
OPG
N
H
AcO
Batch:
nd
nd
H
(from cholic acid)
R1 = Ph
Ms
N
3, R2 = H
96 (2.6) [a]
77 (2.6) [a]
57 (2.9) [a]
92 (4.0) [a]
95 (3.2)
92 (3.3)
68 (4.6)
90 (3.2)
O
P
Ph
Cl
S
S
N
PMP
S
N
4, R2 = OCF3
5, R2 = SMe
nPr
N
Ph
R1
6, R2 = OMe
23
24
22
40% (3.0 F)[a]
73% (2.6 F)
67% (3.1 F)
74% (3.3 F)
nd
Flow:
S
N
R1 = nPr
nd
Batch:
7, R2 = CN
58 (2.6)
70 (2.6)
75 (5.6)
60 (5.3)
8, R2 = OMe
CF3
S
S
N
R2
S
Ph
N
nBu
F3C
R2 = H
nBu
N
9, R1 = Cy
65 (2.0)
81 (2.5)
64 (4.0)
82 (5.6)
86 (3.5)
-
10, R1 = nBu
11, R1 = Bn
26
27
25
Flow:
80% (2.5 F)
73% (4.0 F)
nd
67% (4.0 F)
Batch:
nd
CF3
S
nd
N
12, R = Ph
13, R = nBu
97 (2.5)
93 (3.0)
-
-
S
N
N
N
N
Ph
S
N
F3C
2
29
28
86% (2.6 F)
80% (3.3 F)
97% (2.5 F) (r.r. > 20:1)
92% (3.2 F) (r.r. > 20:1)
Flow:
76% (3.0 F)
nd
Batch:
14, R = OH
66 (2.6)
83 (3.0)
83 (3.0)
36 (3.0)
48 (4.0)
80 (3.5)
92 (3.9)
56 (4.8)
Figure 2. Substrate scope.
15, R = OTBDPS
16, R = CO2tBu
17, R = TsNBoc
[a] 3% H2O was added to the solvent mixture. nd = not determined, PMP =
4‑methoxyphenyl, Ms = methanesulfonyl.
To further demonstrate the synthetic potential of the method
herein described, a larger scale reaction (13 mmol) was
performed as shown in Scheme 2, using the same flow
electrochemical reactor. Compound 3 was obtained in 87% yield
(2.4 g). A higher flow rate and higher concentration than the one
described in the general procedure were used, which allowed
the reaction time to be shortened. This led to a lower yield (87%
instead of 96%), but it is still a good sacrifice to obtain a large
amount of product in a short time. These results showcased the
advantage of flow electrochemistry in reaction scale up. Here
the substrate was pumped through the same reactor for a longer
time.
81 (3.0)
(r.r. = 19:1)
87 (3.5)
18, R = Ph
-
-
19, R = nBu
(r.r. = 19:1)
[a] 3% H2O was added to the solvent mixture.
TBDPS tert-butyldiphenylsilyl, Ts 4-toluenesulfonyl, Boc
butoxycarbonyl.
=
=
=
tert-
Different N-aryl groups were also investigated in the
electrochemical cyclization. Substrates bearing electron-
donating groups (5, 6, 8, 25, 27), electron-withdrawing groups (4,
7, 26, 28) and halogens (23) underwent successful cyclization.
With the same methodology, aminopyridine-derived thioamides
were cyclized to thiazolopyridines (18–21, 23). As previously
reported, the 3-aminopyridine-derived thioamides showed high
regioselectivity for the α-position of the pyridyl ring (18 and 19).
Scheme 2. Large scale benzothiazole synthesis.
When a 2-cyano substituent was attached to the N-aryl moiety
(31), the dimer 7b was obtained in 13% yield in addition to
compound 7. A similar product has been previously reported in
the oxidation of electron-deficient N-arylthioamides with 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).[50] To investigate
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if TEMPO-mediated thioamide oxidation could stabilize the
radical formed and avoid the formation of the dimer 7b, the
oxidation reaction of 31 was performed with catalytic amounts of
TEMPO (1 or 10 mol%), but this led to a significant decrease in
the conversion of the starting material 31 as the amount of
TEMPO was increased. The isolated yields of both
benzothiazole 7 and dimer 7b were not improved by varying the
current density (see the Supporting Information for details). The
formation of the dimer 7b pointed to a radical-based mechanism
for the formation of the benzothiazoles.
In conclusion, a novel flow electrochemical method has been
developed for the formation of benzothiazoles from N-
arylthioamides. In this method, there is no need for any catalyst
or supporting electrolyte. An inert atmosphere is also not
necessary and laboratory grade solvents can be used without
degassing. A gram-scale reaction showed the potential to scale
up flow electrochemical processes. This work clearly highlights
the advantages of flow electrochemistry and largely improves
the reported methods for the formation of benzothiazoles.
Based on the results described above, a possible mechanism for
the electrosynthesis was proposed using thioamide 31 (Scheme
3). The thioamide substrate is oxidized at the anode to form a
thioamidyl radical. This radical intermediate can cyclize onto the
aryl group to give benzothiazole 7 after rearomatization (path a)
and react with a second radical molecule to form the dimer 7
(path b). For most substrates tested in this study, the
dimerization product was not observed suggesting the
cyclization being predominant in most cases. In our previous
manuscript we reported mechanistic investigations of this
transformation in batch, and proved that the thioamidyl radical
was involved.[35]
Experimental Section
A solution of the thioamide (0.6 mmol) in methanol/acetonitrile (12 mL,
1:1 v/v) was pumped in the electrochemical reactor (0.205 mL inner
volume) via syringe pump (0.2 mL min-1), using the corresponding
amount of electricity (F mol–1). After reaching the steady state, the
solution was collected for 55 min. The solvent was evaporated under
reduced pressure, and the crude mixture was purified by flash column
chromatography.
Acknowledgements
We thank the EPSRC National Mass Spectrometry Facility,
Swansea, for mass spectrometric data. We thank Cardiff
University and Xiamen University for financial support.
Keywords: flow electrosynthesis • cyclization • supporting
electrolyte-free • benzothiazoles
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10.1002/chem.201705016
Chemistry - A European Journal
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Ana A. Folgueiras-Amador, Xiang-Yang
Qian, Hai-Chao Xu* and Thomas Wirth*
Page No. – Page No.
Catalyst- and supporting electrolyte-
free electrosynthesis of
benzothiazoles and thiazolopyridines
in continuous flow
No catalyst and no supporting electrolyte are needed for the formation of
benzothiazoles from N-arylthioamides. Electrons and a flow reactor for
electrochemistry are sufficient.
This article is protected by copyright. All rights reserved.