Scalable electrochemical oxidant-and metal-free dehydrogenative coupling of S-H/N-H

Article abstract of DOI:10.1039/C8OB03211D

A practical and scalable electrochemical oxidation of S-H and N-H was developed. This oxidant- and catalyst-free electrochemical process enables S-N bond formation with inexpensive nickel electrodes in an undivided cell. This procedure exhibits broad substrate scopes and good functional-group compatibility. A 50 g scale oxidative coupling augurs well for industrial applications.

Full text of DOI:10.1039/C8OB03211D

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Scalable electrochemical oxidant-and metal-free
dehydrogenative coupling of S–H/N–H†
Cite this: DOI: 10.1039/c8ob03211d
Shanyu Tang,a Yan Liu,b Longjia Li,a Xuanhe Ren,a Jiao Li,a Guanyu Yang,a
Received 27th December 2018,
Accepted 9th January 2019
a
Heng Li *a and Bingxin Yuan
*
DOI: 10.1039/c8ob03211d
rsc.li/obc
A practical and scalable electrochemical oxidation of S–H and sulfoximines and aniline with hydroperoxide as the oxidant.23
N–H was developed. This oxidant- and catalyst-free electrochemical TEMPO was also an efficient catalyst for the aerobic metal-free
process enables S–N bond formation with inexpensive nickel elec- synthesis of sulfenamides.24 However, these methods still
trodes in an undivided cell. This procedure exhibits broad substrate suffer from some drawbacks, such as a limited substrate
scopes and good functional-group compatibility. A 50 g scale oxi- scope, toxic metal complexes, over-oxidation, and excess of oxi-
dative coupling augurs well for industrial applications.
dants. In this context, the development of novel synthetic tools
to fulfill the criteria of green chemistry, atom economy, and
great efficiency is highly desired.
Sulfenamides, a class of organosulfur compounds containing
sulfur–nitrogen bonds, have drawn much interest in diverse
fields due to their vital applications in organic synthesis,
photoliable therapy, materials chemistry, and food science,
The electrochemical oxidation process has emerged as a
highly efficient and environmentally benign synthetic tool.25–36
Lei et al. reported electrochemical oxidant-free cross coupling
reactions of S–H along with hydrogen evolution.37,38 Thiol
could be oxidized at the anode to generate the sulfur radical.
Inspired by these aspects and our continuous interest in green
processes,21,24,39–41 a catalyst-free electrochemical oxidation of
S–H and N–H was investigated as a scalable and sustainable
strategy to produce sulfenamides.
particularly
in
pharmaceuticals
and
industrial
manufacturing.1–5 For instance, the sulfenamide derivatives of
mercaptobenzothiazole (MBT), such as TBBS, CBS and NOBS,
are widely applied rubber vulcanization accelerators with
highest economical and technological importance (Fig. 1).6,7
Euparen-CM, Captan and Phaltanare are also commercially
important sulfenamides (Fig. 1).8 Sulfenamide derivatives have
been proved to show in vivo antitumor and antiviral activities
(Fig. 1).8,9
Despite classical methods described in the literature
studies,10–18 the direct synthesis of sulfenamides via the oxi-
dative coupling of thiols and amines shows an example of
green transformation, since such substrates require no pre-
functionalization. The copper-catalyzed aerobic cross-dehydro-
genative coupling of arylthiols and primary amines was first
reported by Taniguchi,19 and Jang et al. modified the reaction
system to be able to deal with electron-deficient amides.20
Recently, our group has reported a cobalt catalyzed aerobic
dehydrogenative coupling of thiols and amines with water as
the sole solvent.21 A hypervalent iodine promoted metal-free
protocol was disclosed by Wacharasindhu and co-workers.22
Zeng et al. developed an iodine-catalyzed oxidative coupling of
aDepartment of Chemistry and Molecular Engineering, Zhengzhou University,
Zhengzhou, Henan, China 450001. E-mail: hengli@zzu.edu.cn, bxyuan@zzu.edu.cn
bSchool of Life Science, Zhengzhou University, Zhengzhou, Henan, China 450001
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8ob03211d
Fig. 1 Representative significant sulfenamides.
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2-Mercaptobenzothiazole 1a and t-butylamine 2a were (entry 16). A control experiment was performed under air, and
chosen as model substrates to screen various reaction con- a good reaction yield was still obtained (entry 17). Thus, the
ditions for the envisioned electrochemical S–H/N–H coupling. following reactions were conducted in a test tube without pre-
The reaction was conducted at room temperature in a simple cautions to exclude air or moisture. The elimination of electric
undivided test tube under a constant current (5 mA). We current led to no product under an air or a nitrogen
intended to avoid the usage of noble electrode materials at the atmosphere.
start of this study. Nickel foam was purchased in a large piece
With the optimal reaction conditions in hand, the versati-
and cut into a desired size to be used as an anode and a lity of this electrochemical S–H/N–H coupling reaction was
cathode ($0.02 per electrode). The choice of electrolytes clearly explored. Generally, aliphatic and benzyl amines were
has a substantial effect on the reaction outcome. The usage of smoothly converted within the cross-coupling regime.
Bu4N·Br or Bu4N·ClO4 resulted in no product formation Primary and secondary aliphatic amines gave the desired
(Table 1, entries 1 and 2). LiClO4 and Bu4N·BF4 led to the product in modest to excellent yields (3a–3j). The cross-coup-
target compound in 40% and 82% yields (entries 3 and 4), ling of linear primary amines with 1a occurred preferentially
respectively. After considerable experimentation, acetonitrile compared to cyclic systems, as illustrated by 3a–d. A similar
turned out to be the optimal solvent, while attempts to use trend was observed with secondary amines (3e–j). The reac-
other polar solvents such as DMF, EtOH, MeOH, and THF tion time was extended to 10 h for cyclohexayl scaffolds to
were much less effective (entries 4–8). Copper and iron foams achieve good yields (3g–j). We speculated that the steric
were tested (entries 9 and 10), however, the electrode surface effect might be responsible for the lower yield of 3g com-
turned black during the reaction, indicating severe electrode pared to that of 3f. Thus, diisopropylamine 2k and 2,2,6,6-
corrosion. With the vitreous carbon electrode as the anode tetramethylpiperidine 2l were tested, and low yields of 3k
and nickel foam as the cathode, 30% yield was achieved (entry and 3l confirmed the hypothesis. This electrochemical cross-
11). By extending the reaction time to 6 h, the yield increased coupling protocol exhibited compatibility with benzyl
slightly (entry 12). However, at the end of the reaction, some amines as well (3m–o). Unexpectedly, the cross-coupling of
black spots appeared on the surface of the nickel electrode. 2-pyridinethiol with tert-butylamine produced 3p instead of
The electrochemical performance could be further improved the monosulfurated product. Morpholine, as a representative
by increasing the ratio of 2a against 1a to 10 : 1, while the elec- of secondary amine scaffolds, was used and furnished the
trode would retain the initial appearance unchanged (entries desired product 3q in modest yield. Other heteroaryl thiols,
13–15). Delightfully, the electrodes could be reused. Compared 4-mercaptopyridine, 2-mercaptopyrimidine, and 2-mercapto-
to nickel, the platinum electrode was almost equally effective benzoxazole (3r–t), were also suitable for this transform-
ation. Unfortunately, no aryl amines furnished the desired
sulfenamides (Table 2).
The robustness and feasibility of the scalable electrocataly-
sis were reflected by a large-scale synthesis of 3a. The reaction
was conducted in a glass tank open to air, using two Ni foam
sheets as electrodes. 3a was produced in 94% yield on a 50 g
scale while the Ni sheets could be reused (Fig. S1, see the
ESI†). The highlights of this large-scale test include oper-
ational simplicity, safe procedure, simple workup and ease of
product isolation.
To understand dehydrogenative coupling’s electrochemical
mode of action, cyclic voltammetry experiments were carried
out to study the anodic oxidation of the substrates (Fig. 2). An
oxidation peak of 1a in CH3CN was observed at 1.22 V, while
the oxidation peak of 2m was observed at 1.55 V. The combi-
nation of 1a and 2m resulted in two oxidation peaks at 0.8 V
and 1.23 V, respectively. Since the operating voltage was round
2 V, the oxidation of thiols and amines was feasible under the
optimal reaction conditions.
To gain some insights into the reaction mechanism, we
conducted several control experiments. One equivalent of 2,
2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), a
typical free radical inhibitor, was added to the reaction of 1a
with 2a under standard conditions. The product yield was
lowered to 65%, suggesting that radical intermediates might
be involved (Scheme 1, reaction a). In the absence of amine,
thiol 1a accomplished dehydrogenative homo-coupling to
Table 1 Reaction condition screeninga
Entry Electrolyte (+)/(−) Solvent 1a/2a Time (h) Yieldb (%)
1
2
3
4
5
6
7
8
Bu4N·Br
Bu4N·ClO4 Ni/Ni
LiClO4
Ni/Ni
CH3CN 1/5
CH3CN 1/5
CH3CN 1/5
CH3CN 1/5
DMF
EtOH
MeOH
THF
5
5
5
5
5
5
5
5
0.5
5
5
6
6
6
6
6
6
6
n.p.
n.p.
40
82
20
15
30
15
20
Trace
30
86
94
95
97
87
93
n.p.
Ni/Ni
Ni/Ni
Ni/Ni
Ni/Ni
Ni/Ni
Ni/Ni
Bu4N·BF4
Bu4N·BF4
Bu4N·BF4
Bu4N·BF4
Bu4N·BF4
Bu4N·BF4
Bu4N·BF4
Bu4N·BF4
Bu4N·BF4
Bu4N·BF4
Bu4N·BF4
Bu4N·BF4
Bu4N·BF4
Bu4N·BF4
Bu4N·BF4
1/5
1/5
1/5
1/5
9
Cu/Cu CH3CN 1/5
Fe/Fe
C/Ni
Ni/Ni
Ni/Ni
Ni/Ni
Ni/Ni
Pt/Pt
Ni/Ni
Ni/Ni
10
11
12
13
14
15
16
17c
18d
CH3CN 1/5
CH3CN 1/5
CH3CN 1/5
CH3CN 1/7
CH3CN 1/10
CH3CN 1/12
CH3CN 1/10
CH3CN 1/10
CH3CN 1/10
a Unless otherwise noted, reaction conditions are as follows: Ni anode,
Ni cathode, constant current = 5 mA, 1a (0.30 mmol), Bu4N·BF4
(0.5 mmol), MeCN (5 mL), room temperature, seal tube N2, 6 h.
b Isolated yield. c In air. d No current.
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Table 2 Substrate scopea
a Reaction conditions: 1 (0.3 mmol), 2 (3 mmol), Bu4N·BF4 (0.1 mol L−1), Ni anode/Ni cathode, CH3CN (5 ml), constant current = 5 mA, air, room
temperature, 6 h. b t = 10 h.
Fig. 2 Cyclic voltammetry of 1a and 2m in CH3CN with Bu4N·BF4 (0.1
M) under nitrogen at a platinum-wire electrode and a platinum counter
electrode at a scan rate of v = 0.1 V s−1
.
Scheme 1 Mechanistic studies by experiments.
form disulfide 4a in fair yield. To be noticed, the control dethiolation. Actually, disulfide 4a was also observed during
experiment (Scheme 1, reaction b) was conducted by using the reaction of 1a with 2a under the optimal reaction con-
platinum electrodes. The electrolysis of thiols with no amines ditions at room temperature. When the temperature was
added caused severe Ni electrode corrosion, furnishing benzo increased to 30 °C, no disulfide 4a was detected during the
[d]thiazole as the main product. The microscopic observation reaction while the product was formed much more rapidly. In
of Ni electrodes showed some yellow particles attached to the fact, the reaction could be completed in 2 h at 30 °C with 95%
surface of the Ni foam (both the anode and the cathode), yield. However, a trace amount of benzo[d]thiazole was pro-
which presumably were sulfur particles formed owing to the duced due to the dethiolation of substrate 1a. By adopting di-
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Conclusions
In summary, an electrochemical oxidant- and metal-free dehy-
drogenative S–H/N–H cross-coupling protocol is developed.
The practical procedure enables the formation of sulfenamides
in a simple fashion through the electrochemical process and
utilizes inexpensive nickel foam as electrodes. Our method is
further highlighted by its easy scalability, zero-precaution on
setup, room temperature conditions, and reusability of nickel
foam electrodes. Thus, the mild S–H/N–H coupling in the
absence of catalysts and oxidants has the high potential to
facilitate the synthesis of sulfenamide in industrial
manufacturing.
Scheme 2 Mechanistic studies by HRMS.
sulfide 4a as a substrate, 3a was formed in quantitative yield
(Scheme 1, Reaction c). In the absence of thiol, benzylamine
2m underwent electrochemical dehydrogenative coupling, fur-
nishing N-benzyl-1-phenylmethanimine (N-BB) 5a in excellent
yield (Scheme 1, Reaction d). Previous studies suggested that
N-BB was formed with a nitrogen-centered radical inter-
mediated participated.42–44 Thus, we proposed that a nitrogen-
centered radical generated from the amine should also be
involved in the electrochemical coupling reaction.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Furthermore,
a radical scavenger 5,5-dimethyl-1-pyrroline-
The authors would thank the National Natural Science
Foundation of China (No. 21801229 and 21502174) for the
funding support.
noxide (DMPO) was added to the electrolysis of 1a and 2m
under the standard conditions, respectively (Scheme 2). The
corresponding adduct of radicals with DMPO was observed by
HRMS analysis (Fig. S2 and S3, see the ESI†), demonstrating
that the thiyl radical and the aminyl radical might be the key
intermediates in the reaction.
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cathode to produce the corresponding radical anion. The clea-
vage of the radical anion reproduces the thiyl radical and a
thiyl anion.
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