Selectfluor-initiated cyanation of disulfides to thiocyanates

Article abstract of DOI:10.1177/1747519820902670

A Selectfluor-initiated cyanation of disulfides to thiocyanates has been developed. In this process, Selectfluor was employed as the oxidant and trimethylsilyl cyanide was used as the cyanation reagent. It provides an eco-friendly and simple way to synthesize the thiocyanates.

Full text of DOI:10.1177/1747519820902670

902670CHL0010.1177/1747519820902670Journal of Chemical ResearchZhou et al.
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Selectfluor-initiated cyanation of disulfides to
thiocyanates
https://doi.org/10.1177/1747519820902670
DOI: 10.1177/1747519820902670
journals.sagepub.com/home/chl
Pengpeng Zhou, Chuan Chen and Shubai Li
Abstract
A Selectfluor-initiated cyanation of disulfides to thiocyanates has been developed. In this process, Selectfluor was
employed as the oxidant and trimethylsilyl cyanide was used as the cyanation reagent. It provides an eco-friendly and
simple way to synthesize the thiocyanates.
Keywords
cyanation, disulfide, Selectfluor, thiocyanates
Date received: 14 October 2019; accepted: 7 January 2020
A simple, efficient, and green procedure for the synthesis of thiocyanates prompted by Selectfluor was developed.
toxic or expensive. In some cases, metal catalysts or bases
Introduction
were necessary.19,20,23 Moreover, the selective cyanation of
Thiocyanates are very useful synthetic building blocks1
both aromatic and aliphatic thiol derivatives has been
since thiocyano groups widely exist in natural products
rarely reported. Thus, a user-friendly, operationally sim-
and pharmaceutical ingredients.2 Importantly, thiocyano
ple, and efficient procedure for the synthesis of thiocy-
groups can be converted to other useful sulfur-containing
anates is still highly desirable.
functional groups.3–9 Thus, the introduction of thiocyano
Herein, we wish to report a simple, efficient, and user-
groups is of great importance. Much effort has been made
friendly protocol for the synthesis of thiocyanates (Scheme
toward the synthesis of thiocyanates so far. Generally, thi-
1(b)). This reaction proceeded through cyanation of
ocyanates can be synthesized via the following two major
disulfides using Selectfluor as the oxidant and trimethylsi-
routes (Scheme 1(a)): (1) thiocyanation of organic partners
lyl cyanide (TMSCN) as the less toxic cyanation reagent.
(arenes, organic halides, diazonium salts, and arylboronic
Both aromatic and aliphatic disulfides survived the reaction
acids) in the presence of inorganic thiocyanates10–15 and
(2) cyanation of organosulfur compounds including thiols,
conditions.
disulfides, and sulfinates with electrophilic and nucleo-
philic cyanation reagents.16–20 Thiocyanates can also be Results and discussion
prepared via CuCN-mediated direct aerobic oxidative cya-
Initially, we started to optimize the reaction conditions
nation of thiophenols and diaryl disulfides.21 While
using diphenyldisulfide 1a as the model substrate and
acknowledging the pioneering work in this field, the afore-
TMSCN as the cyanating reagent in acetonitrile at 80°C
mentioned methods still have some drawbacks. For exam-
(Table 1). The tentative reaction in the presence of TMSCN
ple, the electrophilic thiocyanation process usually requires
the use of (SCN)2 or XSCN (X=halogen), which is highly
unstable and toxic.22 Although the combination of
School of Chemistry and Material Engineering, Changzhou Vocational
Institute of Engineering, Changzhou, P. R. China
N-chlorosuccinimide (NCS)/NH4SCN was shown to be a
good alternative thiocyanating reagent, the substrate scope
was limited.12 For the cyanation process, the thiol deriva-
tives are usually odorous and some cyanating reagents
such as hypervalent iodine-based reagents20,23 are either
Corresponding author:
Shubai Li, School of Chemistry and Material Engineering, Changzhou
Vocational Institute of Engineering, Changzhou 213164, P. R. China.
Email: lsbcz88@126.com

2
Journal of Chemical Research 00(0)
Scheme 1. Synthetic methods for the synthesis of thiocyanates.
Table 1. Optimization of reaction conditions.a
Entry
TMSCN (equiv.)
Oxidant (equiv.)
Solvent
MeCN
Temperature (°C)
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1.0
2.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
Selectfluor (1.5)
Selectfluor (1.5)
Selectfluor (1.5)
Selectfluor (1.0)
Selectfluor (2.0)
NFSI (2.0)
DAST (2.0)
Oxone (2.0)
K2S2O8 (2.0)
NCS (2.0)
PhI(OAc)2 (2.0)
Selectfluor (2.0)
Selectfluor (2.0)
Selectfluor (2.0)
Selectfluor (2.0)
Selectfluor (2.0)
Selectfluor (2.0)
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
60
100
24
67
85
74
93
86
0
0
0
0
0
16
Trace
Trace
Trace
81
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
DMSO
EtOAc
1,4-dioxane
MeCN
MeCN
94
TMSCN: trimethylsilyl cyanide; NFSI: N-fluorobis(benzenesulfonyl)imide; DAST: diethylaminosulfur trifluoride; NCS: N-chlorosuccinimide.
aReaction conditions: 1a (0.2mmol), TMSCN, oxidant, solvent (2mL), 4h.
bIsolated yield.
(1.0equiv.) and Selectfluor (1.5equiv.) gave the desired reaction temperature was checked. It was found that the
product 2a in 24% yield (entry 1). The amount of TMSCN reaction at lower temperature (60°C) gave a lower yield
and Selectfluor significantly affect the yield. Further study (81%), while raising the temperature to 100°C had little
showed that a 93% yield was obtained while using 3.0equiv. effect on the reaction.
of TMSCN and 2.0equiv. of Selectfluor (entry 5). Different
To evaluate the scope and limitations of this protocol,
oxidants were then evaluated (entries 6–11). The results a series of disulfides were tested under the optimized
showed that N-fluorobis(benzenesulfonyl)imide (NFSI) reaction conditions. The results are summarized in
was as efficient as Selectfluor (entry 6, 86%). However, the Table 2. In general, all the reactions proceeded smoothly
use of other oxidants such as diethylaminosulfur trifluoride to give the corresponding products in good yields (65%–
(DAST), oxone, K2S2O8, NCS, and PhI(OAc)2 failed to 93%). Aromatic disulfides bearing both electron-with-
provide the desired product. The solvent also had a signifi- drawing and electron-donating groups showed good
cant influence on the reaction (entries 12–15). The reaction activities. Steric hindrance was also examined and
in dimethylformamide (DMF) delivered 2a in 16% yield. ortho-substituted disulfides gave slightly lower yields.
However, only trace amount of the desired product was Notably, 4,4′-disulfanediyldiphenol (1d) survived the
observed when reaction was carried out either in dimethyl- reaction conditions to give the desired product 2d in
sulfoxide (DMSO), EtOAc, or 1,4-dioxane. Finally, the moderate yield (entry 4). Nitro-substituted disulfides 1h

Zhou et al.
3
and 1l also reacted with TMSCN smoothly, affording the was added to the reaction, no desired product was detected.
corresponding products in good yields. 2,2′-Dipyridyl Instead, 1-cyanato-2,2,6,6-tetramethylpiperidine (3) was
disulfide (1n) worked well under the standard conditions observed by gas chromatography–mass spectrometry (GC-
to provide 2n in 71% yield. Particularly, alkyl disulfides MS), indicating a radical pathway might be involved (Scheme
also reacted well, and good yields were obtained (entries 2, equation (2)). Considering that disulfide might be attacked
15 and 16).
by CN anion, 1equiv. of KF was used alone, however, only
Some control experiments were then conducted to gain trace amount of the desired product was observed (Scheme 2,
some insight into the reaction (Scheme 2). No product 2a was equation (3)).
observed when the reaction was carried out in the absence of
Based on the above results, a mechanism is tenta-
Selectfluor (Scheme 2, equation (1)). When 3equiv. of the radi- tively proposed (Scheme 3). Initially, Selectfluor obtains
cal scavenger 2,2,6,6-tetramethylpiperidinyl-1-oxy (TEMPO) an electron from the disulfide to release the sulfur radi-
cal 4, nitrogen radical cation 5, and the fluoride anion.24,25
The resulting fluoride anion can promote the generation
of the CN− nucleophile from TMSCN.21 Next, the CN
anion can be oxidized by the nitrogen radical cation 5 to
deliver a CN radical and 6. The CN radical then attacks
the sulfur radical 4 to give the cyano sulfoniums 7, which
reacts with 6 to provide the final product 3 and com-
pound 8.
Table 2. Reaction scope.a
Entry
R
Product
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
C6H5
4-CH3C6H4
4-CH3OC6H4
4-OHC6H4
4-ClC6H4
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
93
86
84
65
88
85
86
84
81
78
83
82
89
71
79
72
Conclusion
In summary, we have developed a simple and efficient pro-
cedure for cyanation of disulfides to thiocyanates. In this
process, Selectfluor was employed as the oxidant and tri-
methylsilyl cyanide was used as the green cyanation rea-
gent. A series of aromatic disulfides survived the reaction
conditions to give the corresponding products in good
yields. Notably, alkyl disulfides are tolerated well. The con-
trol experiments also showed that a radical pathway might
be involved in this reaction.
4-BrC6H4
4-MeO2CC6H4
4-NO2C6H4
2-CH3C6H4
2-ClC6H4
3-ClC6H4
3-NO2C6H4
2-Naphthyl
2-Pyridinyl
Benzyl
Experiment
General
Cyclohexyl
All of the reagents and solvents are commercially available
and were used without further purification. Disulfides 1f,
1j, and 1k were purchased from Hubei Jusheng Technology
aReaction conditions: 1 (0.2mmol), TMSCN (3.0equiv.), Selectfluor
(2.0equiv.), MeCN (2mL), 80°C, 4h.
bIsolated yield.
Scheme 2. Control experiments.

4
Journal of Chemical Research 00(0)
Scheme 3. Proposed mechanism.
Co., Ltd. Disulfides 1g and 1i were supplied by Jiangsu
1-Chloro-4-thiocyanatobenzene (2e). Yield: 30mg (88%);
Aikon Biopharmaceutical R&D Co., Ltd. Other disulfides yellowish liquid.21 1H NMR (400Hz, CDCl3): δ 7.46–7.48
were purchased from SigmaAldrich Corporation (Shanghai, (m, 2H), 7.40–7.43 (m, 2H).13C NMR (CDCl3, 100MHz) δ
China). Melting points were determined with a WRS-1B 110.0, 122.7, 130.4, 131.4, 136.2. MS (EI) m/z: 169 [M+].
1
apparatus and were uncorrected. H NMR spectra were
recorded in CDCl3 using a Bruker Avance III 400-MHz
1-Bromo-4-thiocyanatobenzene
(2f). Yield:
36mg
spectrometer. The GC-MS analyses were performed on a (85%); yellowish liquid.23 1H NMR (400Hz, CDCl3): δ
Thermo Scientific equipment. All the products are known 7.48–7.52 (m, 2H), 7.31–7.35 (m, 2H).13C NMR (CDCl3,
compounds and their spectroscopic data are in accordance 100MHz) δ 109.8, 123.4, 124.1, 131.4, 133.4. MS (EI)
with those previously presented.
m/z: 213 [M+].
Methyl 4-thiocyanatobenzoate (2g). Yield: 33mg (86%);
Typical procedure for the synthesis of 2a
white solid; m.p.: 65–66°C.24 1H NMR (400Hz, CDCl3):
A mixture of disulfide 1a (44mg, 0.2mmol), TMSCN δ 8.07−8.12 (m, 2H), 7.55–7.58 (m, 2H), 3.93 (s, 3H).13C
(74μL, 0.6mmol), Selectfluor (142mg, 0.4mmol) was NMR (CDCl3, 100MHz) δ 52.6, 109.1, 128.4, 130.4, 131.0,
added to acetonitrile (2mL). The mixture was stirred at 131.2, 165.7. MS (EI) m/z: 193 [M+].
80°C for 4h. After completion of the reaction, the reaction
mixture was cooled to room temperature and extracted with
1-Nitro-4-thiocyanatobenzene (2h). Yield: 30mg (84%);
EtOAc (3×5mL). The organic layer was concentrated and white solid; m.p.: 127–129°C.21 1H NMR (400Hz, CDCl3):
the resulting crude product was further purified by silica δ 8.30 (d, J=8.9Hz, 2H), 7.67 (d, J=8.9Hz, 2H).13C NMR
gel column chromatography to provide 2a in 93% (25mg) (CDCl3, 100MHz) δ 108.0, 125.0, 128.7, 133.3, 147.9. MS
yield.
(EI) m/z: 180 [M+].
Characterization data
1-Methyl-2-thiocyanatobenzene (2i). Yield: 24mg (81%);
Thiocyanatobenzene (2a). Yield: 25mg (93%); yellow- yellowish liquid.23 1H NMR (400Hz, CDCl3): δ 7.54–7.56
ish liquid.20 1H NMR (400Hz, CDCl3): δ 7.41–7.46 (m, (m, 1H), 7.18–7.29 (m, 3H), 2.41 (s, 3H).13C NMR (CDCl3,
3H), 7.52–7.55 (m, 2H).13C NMR (CDCl3, 100MHz) δ 100MHz) δ 20.4, 110.4, 123.6, 127.8, 130.2, 131.5, 132.0,
110.5, 124.3, 129.5, 130.0, 130.2. MS (EI) m/z: 135 [M+]. 139.3. MS (EI) m/z: 149 [M+].
1-Methyl-4-thiocyanatobenzene
(2b). Yield:
26mg
1-Chloro-2-thiocyanatobenzene (2j). Yield: 26mg (78%);
(86%); yellowish liquid.20 1H NMR (400Hz, CDCl3): δ colorless liquid.26 1H NMR (400Hz, CDCl3): δ 7.67–7.69
7.41–7.43 (m, 2H), 7.24 (d, J=8.4Hz, 2H), 2.38 (s, 3H).13C (m, 1H), 7.32–7.44 (m, 3H).13C NMR (CDCl3, 100MHz)
NMR (CDCl3, 100MHz) δ 21.1, 111.0, 120.5, 130.7, 130.9, δ 108.1, 123.8, 127.4, 128.8, 129.2, 129.3, 131.7. MS (EI)
140.2. MS (EI) m/z: 149 [M+].
m/z: 169 [M+].
1-Methoxy-4-thiocyanatobenzene (2c). Yield: 28mg
1-Chloro-3-thiocyanatobenzene (2k). Yield: 28mg (83%);
(84%); yellowish liquid.20 1H NMR (400Hz, CDCl3): δ colorless liquid.26 1H NMR (400Hz, CDCl3): δ 7.51 (d,
7.47–7.51 (m, 2H), 6.92–6.97 (m, 2H), 3.82 (s, 3H).13C J=1.2Hz, 1H), 7.35–7.41 (m, 3H).13C NMR (CDCl3,
NMR (CDCl3, 100MHz) δ 55.5, 111.6, 113.7, 115.8, 133.8, 100MHz) δ 109.5, 126.2, 127.7, 129.4, 129.8, 131.2,
161.2. MS (EI) m/z: 165 [M+].
136.0. MS (EI) m/z: 169 [M+].
4-Thiocyanatophenol (2d). Yield: 20mg (65%); red liq-
1-Nitro-3-thiocyanatobenzene (2l). Yield: 30mg (82%);
uid.21 1H NMR (400Hz, CDCl3): δ 7.42–7.47 (m, 2H), white solid; m.p.: 52–55°C.26 1H NMR (400Hz, CDCl3):
6.86–6.91 (m, 2H).13C NMR (CDCl3, 100MHz) δ 112.1, δ 8.36 (s, 1H), 8.26 (d, J=8.0Hz, 1H), 7.87 (d, J=8.0Hz,
113.4, 117.4, 134.2, 158.0. MS (EI) m/z: 151 [M+].
1H), 7.69 (t, J=8.0Hz, 1H).13C NMR (CDCl3, 100MHz)

Zhou et al.
5
δ 108.6, 124.2 (2C), 127.2, 131.2, 134.9, 148.8. MS (EI) References
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Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect
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The author(s) disclosed receipt of the following financial support for
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ORCID iD
Shubai Li
https://orcid.org/0000-0003-4417-5745
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Supplemental material
The 1H NMR and 13C NMR spectra of the compounds are given
in the Support Information.
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