Electrochemical intramolecular dehydrogenative C-S bond formation for the synthesis of benzothiazoles

Article abstract of DOI:10.1039/c7gc00468k

An external oxidant-free intramolecular dehydrogenative C-S cross-coupling has been developed under undivided electrolytic conditions. Various 2-aminobenzothiazoles could be synthesized with up to 99% yield from the direct combination of aryl isothiocyanates with amines. In the presence of a base, this reaction protocol is also applicable for the synthesis of benzothiazoles from N-aryl thioamides.

Full text of DOI:10.1039/c7gc00468k

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Electrochemical Intramolecular Dehydrogenative C-S Bond
Formation for the Synthesis of Benzothiazoles
Pan Wang,‡a Shan Tang,‡a and Aiwen Lei*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An external oxidant-free intramolecular dehydrogenative C-S oxidation of sulfur compounds.10 Herein, we would like to
cross-coupling has been developed under undivided electrolytic communicate our recent progress on an electrochemical
conditions. Various 2-aminobenzothiazoles could be synthesized dehydrogenative C-S cross-coupling under metal- and oxidant-
with up to 99% yield from the direct combination of aryl free conditions (Scheme 1). This reaction protocol provides an
isothiocyanates with amines. In the presence of base, this reaction atom-economical and sustainable way for the synthesis of
protocol is also applicable for the synthesis of benzothiazoles from benzothiazoles with up to 99% yield.
N-aryl thioamides.
S
C
Oxidative R1−H/R2−H cross-coupling has been recognized as
one of the most atom economical and efficient ways to
construct new chemical bonds.1 Great progresses have been
made in the construction of C-C,2 C-N3 and C-O4 bonds. In
comparison, selective oxidative C-S cross-coupling has received
much less developments because of the facile over-oxidation
of sulfur compounds under oxidative conditions.5 For example,
intramolecular dehydrogenative C-S cross-coupling of N-aryl
thioureas or N-aryl thioamides has been developed as one of
the most efficient and widely used approaches to access
benzothiazoles.6 However, these transformations require the
use of external chemical oxidants to facilitate the
dehydrogenation process, which generally face the problem of
over-oxidation to afford ureas or amides. Thus, the developed
methods usually suffer from limited substrate scope and low
reaction efficiency. To deal with these problems, it is highly
desirable to develop external oxidant-free dehydrogenative C-
S bond formation protocols.7
N
N
S
electricity
+
H
N
H2↑
+
N
R
R
oxidant-free
catalyst-free
H
Scheme 1. Oxidant-free dehydrogenative C-S bond formation.
2-Aminobenzothiazoles and benzothiazoles
structure motifs in many agrochemicals and pharmaceuticals.11
are key
The dehydrogenative C-S bond formation of N-phenyl thiourea
4a generated in situ upon mixing phenyl isothiocyanate (1a
)
and morpholine (2a) was chosen as the model reaction for
testing the reaction conditions in the synthesis of 2-
aminobenzothiazoles. Cyclic voltammetry (CV) experiments of
the substrates in acetonitrile were conducted. No obvious
oxidation peak could be observed below 2.0 V for 1a (see ESI,
Fig. S1a) while an oxidation peak of 2a could be observed at
n
1.24V (see ESI, Fig. S1b). Utilizing Bu4NBF4 as the electrolyte
and acetonitrile as the solvent, 2-aminobenzothiazole 3aa
could be obtained from the mixing of 1a and 2a in 22% yield
under 7 mA constant current for 4 h in an undivided cell (Table
1, entry 1). The choice of co-solvent was important for
achieving a high reaction efficiency. Alcohols such as methanol,
isopropanol and hexafluoroisopropanol (HFIP) could not
promote this transformation (Table 1, entries 2-4). However,
an increased reaction yield could be obtained when water was
used as the co-solvent (Table 1, entry 5). Attempt on
decreasing and increasing the current density both led to
Electrosynthesis is recognized as
a
versatile and
environmentally friendly synthetic tool and has attracted
continuous interests.8 Electrochemical anodic oxidation
represents an ideal choice for replacing external chemical
oxidants in oxidative R1−H/R2−H cross-coupling reactions.9
Since the operating voltage and current can be controlled in
electrochemical reactions, it is possible to avoid the over-
decreased reaction yields (Table 1, entries
6 and 7).
Delightfully, heating the reaction mixture could improve the
reaction efficiency (Table 1, entries 8 and 9). An excellent yield
o
of 3aa could be obtained at 70 C (Table 1, entry 9). As was
expected, large amount of H2 could be detected by GC under
the optimized conditions. No desired product could be
obtained without electricity either under nitrogen or
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atmospheric conditions (Table 1, entries 10 and 11). The isothiocyanatonaphthalene were able to furnish the desired
reactions didn’t required deoxygenation. However, a slightly products in good yields 3la and 3ma). Then different
(
decreased reaction yield was obtained when the reaction was secondary amines were applied as substrates in synthesizing
directly carried out under air atmosphere (Table 1, entry 12). It benzothiazoles. Six-membered cyclic amines including
is possible to replace platinum plate cathode by cheaper electrodes thiomorpholine, 1,4-dioxa-8-azaspiro[4.5]decane and 1-
(Table 1, entries 13-15)
.
Table 1. Condition optimizationa
phenylpiperazine were all showed excellent reactivity in the
synthesis of 2-aminobenzothiazoles (3ab-3ac). Saturated cyclic
amines without other heteroatom afforded the desired
product in slightly decreased yields
(3ae-3ag). Acyclic
secondary amines were also suitable in this transformation,
furnishing corresponding 2-aminobenzothiazoles in good to
high yields (3ah-3aj). At this moment, primary amines could
undergo addition to aryl isothiocyanates while no cyclization
product could be obtained under the standard conditions.
Temperat
Entry
Solvents
Current density
ure
Yieldb
1
2
CH3CN
11.7 mA/cm2
11.7 mA/cm2
11.7 mA/cm2
11.7 mA/cm2
11.7 mA/cm2
8.3 mA/cm2
15.0 mA/cm2
11.7 mA/cm2
11.7 mA/cm2
0
r.t.
r.t
r.t
r.t
r.t
r.t
r.t
22%
22%
15%
10%
48%
18%
13%
58%
95%
n.d.
CH3CN/MeOHc
CH3CN/iPrOHc
CH3CN/HFIPc
CH3CN/H2Oc
CH3CN/H2Oc
CH3CN/H2Oc
CH3CN/H2Oc
CH3CN/H2Oc
CH3CN/H2Oc
CH3CN/H2Oc
3
Table 2. Synthesis of benzothiazoles from different aryl
isothiocyanates and aminesa
4
S
C
N
5d
6e
7
N
C (+) Pt (-)
+
H
N
N
R
R
nBu4NBF4, CH3CN/H2O
undivided cell
S
H
1
2
3
N
S
N
N
N
O
O
N
O
O
N
O
8
50 o
C
S
S
9
70 oC
70 oC
70 oC
70 oC
70 oC
70 oC
70 oC
3aa, 92%
3ba, 77%
3ca, 77%
N
N
10
11f
N
N
S
N
O
N
S
S
MeO
X
0
n.d.
3fa, X= F, 90%
3ga, X= Cl, 95%
3ha, X= Br, 92%
3ia, X= I, 80%
12f
13g
14h
15i
CH3CN/H2Oc
CH3CN/H2Oc
CH3CN/H2Oc
CH3CN/H2Oc
11.7 mA/cm2
11.7 mA/cm2
11.7 mA/cm2
11.7 mA/cm2
75%
89%
82%
86%
3da, 70%
3ea, 76%
N
S
N
N
O
N
O
N
N
S
S
Ac
F3C
O
3ja, 99%
3ka, 99%
3la, 82%
a
N
Standard conditions: graphite rod anode (ф 6 mm), platinum plate
N
O
N
N
S
N
N
S
O
cathode (15 mm×15 mm×0.3 mm), constant current = 7 mA, 1a (0.50
mmol), 2a (1.0 mmol), nBu4NBF4 (3.0 mmol), solvents (10.0 mL),
S
S
O
3ma, 93%
b
undivided cell, N2, 4 h (2.1 F). Yields were determined by GC analysis
3ab, 93%
3ac, 99%
c
with biphenyl as the internal standard, n.d. = not detected. Co-
N
N
S
N
N
S
N
N
S
N
Ph
e
solvent (1.0 mL) was used. d Constant current = 5 mA, 5.6 h (2.1 F).
n
f
Constant current = 9 mA, 3.1 h (2.1 F). Under air atmosphere.
h
Graphite rod anode was used. Graphite rod cathode was used.
g
i
3ae, n = 1, 79%b
3af, n = 2, 82%b
3ag, n = 3, 86%
3ad, 99%b
3ah, 75%
Nickel plate cathode was used. j Stainless steel plate cathode was used.
N
N
S
N
N
S
Since the optimized condition has been obtained, efforts
were then paid to the substrate scope of this transformation
(Table 2). Firstly, different aryl isothiocyanates were applied as
substrates to react with morpholine for the synthesis of 2-
aminobenzothiazoles. Simple phenyl isothiocyanate could
furnish the desired benzothiazole in an excellent yield (3aa).
Phenyl isothiocyanates bearing electron donating substituents
such as methyl group and methoxyl group gave slightly
3ai, 87%
3aj, 86%
a
Reaction conditions: graphite rod anode (ф 6 mm), platinum plate
cathode (15 mm×15 mm×0.3 mm), constant current = 7 mA (janode
≈
11.7 mA/cm2),
1
(0.50 mmol), 2a (1.0 mmol), nBu4NBF4 (3.0 mmol),
MeCN (9.0 mL), H2O (1.0 mL), 70 oC, N2, 4 h (2.1 F). Isolated yields were
shown. b PhCOONa (1.0 mmol) was added.
The scalability of this electrochemical dehydrogenative C-S
cross-coupling was then evaluated by performing a 5 mmol
scale reaction. With almost the same ratio of F/mol of
electricity, the reaction of 1a and 2a smoothly furnished the
desired product in 82% yield (Scheme 2, 3aa, 0.9 g). This result
highlights the potential of this electrochemical hydrogen-
evolution reaction in future applications.
decreased reaction yields
including F, Cl, Br and
(
3ba-3ea). Halide substituents
I
were well tolerated under
electrochemical
conditions,
furnishing
corresponding
benzothiazoles in good to high yields
(
3fa-3ia). Strong
electron-deficient phenyl isothiocyanates showed excellent
reactivity in this transformation (3ja and 3ka). Moreover, both
1-isothiocyanatonaphthalene
and
2-
2 | J. Name., 2012, 00, 1-3
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a
Reaction conditions: graphite rod anode (ф 6 mm), platinum plate
≈
cathode (15 mm×15 mm×0.3 mm), constant current = 7 mA (janode
11.7 mA/cm2),
1
(0.50 mmol), 2a (1.0 mmol), nBu4NBF4 (3.0 mmol),
MeCN (9.0 mL), H2O (1.0 mL), 70 oC, N2, 4 h (2.1 F). Isolated yields were
shown. b PhCOONa (1.0 mmol) was added.
In the next step, the intramolecular dehydrogenative C-S
cross-coupling of N-aryl thioamides was explored to further
demonstrate the utility of this electrochemical method (Table
3). In the presence of 2 equiv of sodium benzoate, N-phenyl
Scheme 2. Gram scale synthesis.
Since thiourea was observed to be generated during the
reaction, the intramolecular dehydrogenative C-S cross-
coupling of thiourea 4aa was directly tested under electrolysis
conditions (Scheme 3). A very low reaction yield could be
obtained under the standard conditions. By adding sodium
benzoate as a base into the reaction system, a high reaction
yield of benzothiozole 3aa could be obtained. To clarify the
requirement of base, CV experiments of 4aa were carried out.
In the absence of base, an obvious oxidation peak of 4aa was
observed at 0.98 V (see ESI, Fig. S1c, Epa). When 1 equiv of
sodium hydroxide was added, a new oxidation peak could be
observed at 0.43V (see ESI, Fig. S1d, Epb). The reaction results
in Scheme 3 and cyclic voltammogram in Figure S1 suggested
that single electron transfer with sulfur anion intermediate
generated in situ from the acid−base equilibrium would be
much more favorable than the direct single electron transfer
benzothioamide (5a) could furnish 2-phenyl benzothiazole (6a
)
in 91% yield. N-Phenyl benzothioamides bearing methyl group
or bromide on the ortho position of the N-aryl moiety could
both furnish the desired benzothiazoles in excellent yields (6b
and 6c). Notably, iodide could be well tolerated under the
undivided electrolysis conditions
(
6d). Strong electron-
6j was
donating substituents such as methoxyl group
(
)
beneficial for achieving a good reaction yield while strong
electron-withdrawing groups such as trifluoromethyl group led
to decreased reaction yields (6e). The reaction with N-
naphthalene substituted benzothioamide could give an
excellent yield in this transformation (6f). Moreover, chloride,
methoxyl group and ester group at the 2-aryl moiety of N-
phenyl benzothioamide were all tolerated under the
electrolysis conditions (6g-6i). N-phenyl alkylthioamides were
also tested under standard conditions (6j-6l). It is worthy of
noting that α-hydrogen atoms had evident effects on the
reaction efficiency. N-Phenyl tert-butylthioamide could afford
corresponding benzothiazole in a moderate yield (6k) while
only a low yield in the case of N-phenyl cyclohexylthioamide
with N-phenylbenzothioamide 4aa
.
(
6l).
Based on the experimental results and literature reports,6c, 7
a plausible mechanism of the reaction between 1a and 2a is
proposed in Scheme 4. In situ nucleophilic addition of amine
2a to isothiocyanates 1a generates thiourea 4a. Following
deprotonation by hydroxide generated from cathodic
Scheme 3. Direct intramolecular dehydrogenative C-S cross-coupling of
thiourea.
Table 3. Synthesis of benzothiazoles from different N-aryl thioamidesa
reduction of water can give a sulfur ion intermediate
I. Single-
electron-transfer (SET) oxidation of I by anode leads to the
formation of a sulfur radical II. Alternatively, the sulfur radical
II is also possible to be generated from the direct anodic
oxidation of 4a. The sulfur radical will then undergo quick
intramolecular radical addition to generate III. Following
anodic oxidation and deprotonation of III by base (excess
amount of 1a or PhCOONa) can furnish the final product 3aa
.
At the same time, concomitant cathodic reduction of water
can release hydrogen gas during the reaction.
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Scheme 4. Proposed mechanism.
Conclusions
In conclusion, an environmentally friendly electrochemical
reaction protocol was developed to achieve intramolecular
dehydrogenative C-S bond formation. Neither metal catalysts
nor chemical oxidants were needed in this transformation.
Under undivided electrolysis conditions,
a series of 2-
aminobenzothiazoles could be synthesized from the direct
combination of aryl isothiocyanates with aliphatic amines.
Importantly, this reaction could be conducted in gram scale,
which is important for future application. By adding base into
the reaction system, intramolecular dehydrogenative C-S bond
formation of N-aryl thioamides could also be achieved to
furnish benzothiazoles in good to high yields. This study
provides
a good example of electrochemical hydrogen-
evolution cross-coupling, which will inspire people to replace
external chemical oxidants by electrochemical anodic
oxidation in more dehydrogenative cross-coupling reactions.
10. P. Wang, S. Tang, P. Huang and A. Lei, Angew. Chem. Int. Ed.,
2017, 56, 3009.
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This work was supported by the National Natural Science
Foundation of China (21390402, 21520102003), the Ministry of
Science and Technology of China (2012YQ120060), the
Fundamental Research Funds for the Central Universities and
the Program of Introducing Talents of Discipline to Universities
of China (111 Program)
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4 | J. Name., 2012, 00, 1-3
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