Fluorium-Initiated Dealkylative Cyanation of Thioethers to Thiocyanates

Article abstract of DOI:10.1021/acs.joc.9b00965

Thioethers are converted to thiocyanates via fluorium-initiated dealkylative cyanation. Selectfluor is used as the oxidant, and trimethylsilyl cyanide is used as the cyanation reagent. The well-streamlined procedure is user-friendly, operationally simple, and step-economical. The current mechanistic studies show that the sulfur radical cation and cyano radical are both involved. They combine to deliver cyanosulfonium, an intermediate toward thiocyanate after dealkylation. Alternatively, a nucleophilic mechanism is also possible. Our dealkyaltive cyanation is also efficient in synthesizing thiocyanates with strongly electrophilic functionalities.

Full text of DOI:10.1021/acs.joc.9b00965

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Article
Fluorium-Initiated Dealkylative Cyanation of Thioethers to Thiocyanates
Yang Chen, Hongyi Qi, Ning Chen, Demin Ren, Jiaxi Xu, and Zhanhui Yang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00965 • Publication Date (Web): 27 Jun 2019
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The Journal of Organic Chemistry
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Fluorium-Initiated Dealkylative Cyanation of Thioethers to
Thiocyanates
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Yang Chen, † Hongyi Qi, ‡ Ning Chen, † Demin Ren, ⊥ Jiaxi Xu,*† and Zhanhui Yang*†
†State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry, Faculty of Science, ‡College
of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing 100029, P. R. China
⊥Hunan Provincial Key Laboratory of Controllable Preparation and Functional Application of Fine Polymers, Hunan
University of Science and Technology, Xiangtan 411201, China
Supporting Information Placeholder
Dealkylative RADICAL cyanation
F
S
TMSCN
S
R
CN
R
RLG
CN
Selectfluor
up to 88%
ABSTRACT: Thioethers are converted to thiocyanates via fluorium-initiated dealkylative cyanation. Selectfluor is used as the
oxidant and trimethylsilyl cyanide as the cyanation reagent. The well streamlined procedure is user-friendly, operationally simple,
and step-economical. The current mechanistic studies show that sulfur radical cation and cyano radical are both involved. They
combine to deliver cyanosulfonium, an intermediate toward thiocyanate after dealkylation. Alternatively, a nucleophilic mechanism
is also possible. Our dealkyaltive cyanation is also efficient in synthesizing thiocyanates with strongly electrophilic functionalities.
In 2015, Shi and co-workers realized the cyanation of
thioethers using an electrophilic cyanation reagent (Scheme
INTRODUCTION
The Pummerer reactions have been widely used to prepare α-
substituted sulfides.1 Recently, to improve the step-economy
of the classical Pummerer reactions, we developed the sulfide
Pummerer reactions (Scheme 1a).2,3 Sulfides were activated
directly by fluorium oxidants to form fluorosulfonium, which
underwent dehydrofluorination in the presence of appropriate
base to deliver alkylidenesulfoniums.2 In our previous studies,
bis(benzenesulfonyl)imide anion was used as the nucleophile
(Scheme 1b).2a Considering the synthetic importance of α-
cyano sulfides,4 we initially planned to synthesize them using
the step-economy sulfide Pummerer protocol by adding
nucleophilic cyano donors (Scheme 1b, up). Beyond our
expectation, trimethylsilyl cyanide (TMSCN) underwent
significantly different reaction pathway from the
bis(benzenesulfonyl)imide anion. Desired α-cyano sulfides
were not observed; thiocyanates, however, were surprisingly
formed in good yields (Scheme 1b, bottom).
1d),11 which was prepared from trimethylsilyl cyanide through
several steps.12 Our discovery provides a novel dealkylative
radical cyanation of thioethers to prepare aryl thiocyanates,
with commercially cheap fluorium oxidant and cyanation
reagent, in a user-friendly, operationally simple, and step-
economical fashion (Scheme 1b).
(a) Sulfide Pummerer Reaction (our previous work):
Nu = N(SO2Ph)2
[F+]
F
base
S
H
S
H
S
H
Ar
S
H
Nu-
Ar
Ar
Ar
F
- H
Nu
(b) This work: Dealkylative cyanation
F
S
R2
CN
- HF
Envisioned
TMSCN
R1
S
R2
S
R2
R1
R1
[F+]
S
R2
H
R1
Observed: TMSCN
S
R1
CN
(c) Two strategies to prepare thiocyanates
Thiocyanation
Cyanation
S
S
R
R
O2Na
S
R
X
CN
R
Y
5
SCN
SCN
CN
]
M
or (
)
[
2
Thiocyanates are important synthetic building blocks and
Y = H, SAr, SO3-, SO2R, Ac, etc.
[CN] = Electrophilic or nucleophilic
cyanation reagents
X = H, N2+, Halogen, B(OH)2, etc;
M = NH4, Na, K, Cu, Zn, etc.
even subunits of
a
number of bioactive structures.6
Thiocyanation of organic partners with inorganic
thiocyanates,7 and cyanation of sulfenyl donors with cyano
reagents,8,9 represent two main strategies (Scheme 1c). By
using thiols, disulfides, sulfinate salts, and the sulfonates,
sulfates, or acetates of thiols as sulfenyl donors, numerous
cyanation processes have been developed.8 These starting
materials are either odorous, or prepared from odorous thiols.
Thioether, which are either commercially available or easily
prepared from odorless sulfur sources,10 are a user-friendly
sulfenyl donor to avoid the strong, repulsive and unpleasant
odors of thiols. However, cyanation of thioethers is quite rare.
(d) Shi's ELECTROPHILIC cyanation of thioethers
ArI(OTf)CN
S
S
R
R2
R
Ar = 3,5-(CF3)2C6H3
CN
Scheme 1. Previous and this work.
RESULTS AND DISCUSSION
Table 1. Optimization of reaction conditions.
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(entry 18) oxidants failed to mediate the demethylative
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TMSCN (x equiv.),
Oxidant (y equiv.)
S
S
CN
1
2
3
4
5
6
7
8
cyanation. Other solvents (chloroform, ethyl acetate, DMSO,
DMF) completely prevented the formation of thiocyanate
(entries 19-22). Low temperature was detrimental (entry 23),
80 oC, solvent, 1 h.
F
F
2a
1a
, 0.1 mmol
o
entry
1
x
Oxidant (y equiv.)
solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
CDCl3
EA
Yield (%)a
and the suitable temperature range was 60-100 C (entries 24
and 25). The highest yield was obtained by using 2.5
equivalents of Selectfluor and by prolonging the time to 4 h
(entry 28).
1.0 Selectfluor (1.5)
1.5 Selectfluor (1.5)
2.5 Selectfluor (1.5)
3.0 Selectfluor (1.5)
3.5 Selectfluor (1.5)
3.0 Selectfluor (1.0)
3.0 Selectfluor (2.0)
3.0 NFSI (2.0)
trace
13
26
38
36
20
52
50
0
2
3
4
Table 2. Reactions of different aryl methyl thioethers.
9
5
TMSCN (3 equiv.),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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44
45
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51
52
53
54
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57
58
59
60
Selectfluor (2.5 equiv.)
S
S
6
Ar
2
CN
Ar
80 oC, MeCN, 4 h.
a
1
, yield
7
S
S
S
S
CN
MeO
CN
CN
CN
8
O
O
9
3.0 BAST (2.0)
2a,
2c
2d
55%
, 71%
, 63%
2b
, 63%
10
11
12
13
14
15
16
17
18
19
20
21
22
23b
24c
25d
26
27
28e
29f
3.0 DAST (2.0)
0
S
S
S
CN
CN
CN
O
S
O
3.0 Na2S2O8 (2.0)
3.0 K2S2O8 (2.0)
0
O
Ph
O
O
b
b
2g
, 85%
2f
, 73%
2e
, 45%
0
3.0 Oxone (2.0)
0
S
S
O2N
S
O
CN
CN
CN
3.0 TCCA (2.0)
0
Ph
O
O
b
2j
2h
, 76%
S
, 71%
2i
, 78%
3.0 NCS (2.0)
0
S
S
3.0 NaClO2 (2.0)
3.0 NBS (2.0)
0
S
CN
CN
CN
CN
0
F
Cl
b
2k
, 81%
2l
, 71%
S
2m
, 68%
2n
, 84%
3.0 PhI(OAc)2 (2.0)
3.0 Selectfluor (2.0)
3.0 Selectfluor (2.0)
3.0 Selectfluor (2.0)
3.0 Selectfluor (2.0)
3.0 Selectfluor (2.0)
3.0 Selectfluor (2.0)
3.0 Selectfluor (2.0)
3.0 Selectfluor (2.5)
3.0 Selectfluor (3.0)
3.0 Selectfluor (2.5)
3.0 Selectfluor (2.5)
0
S
S
S
CN
CN
CN
CN
0
MeO2C
OHC
CN
O2N
Br
0
b
c
2q
, 52%
S
2p
2r
, 85%
, 85%
2o
, 69%
DMSO
DMF
0
S
CN
O
N
S
0
CN
S
N
O
N
S
CN
b
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
trace
51
52
59
60
69
67
2s
, 81%
2u
, 44%
2v
, 84%
2t
, 85%
aIsolated yield after column chromatography. bReaction for 2 h.
cReaction for 1 h.
A variety of aryl methyl thioethers were subjected to the
optimal conditions, and the demethylative cyanation occurred
readily (Table 2). In addition to 1a, the reactions of 4-alkoxy
thioanisoles (1b-f) produced corresponding products in 41-
71% yields. The allylic and benzylic C-H bonds were well
tolerated in the reactions of 1e and 1f, as demonstrated by the
GC-MS analysis of the crude reaction mixtures. 4-
(Methylthio)phenyl methanesulfonate (1g) and benzoate (1h)
was demethylatively cyanated into respective thiocyanates 2g
and 2h in 76% and 71% yields, while 4-nitrophenyloxy
thioanisole (1i) was converted to 2i in 77% yield. The
substituted positions on the phenyl rings did not affect the
transformation, as demonstrated by the reactions of 4-methyl
(1j) and 2-methyl (1k) thioanisoles (76% and 81% yields). 4-
tert-Butylphenyl thiocyanate 2l was obtained in 63% yield
from 4-tert-butylthioanisole (1l). The introduction of halogens
at the aryl was also compatible. 4-Fluorophenyl (2m), 4-
chlorophenyl (2n), and 4-bromophenyl (2o) thiocyanates were
easily prepared in 68%, 84%, and 54% yields, respectively.
Thioanisoles with electron-withdrawing functional groups
aObtained from 19F NMR spectra of the crude reaction mixture
with α,α,α- trifluoroacetophenone as an internal standard.
o
c
o
d
o
bReaction at 0 C. Reaction at 60 C. Reaction at 100 C.
eReaction for 4 h. fReaction for 12 h.
Fluorobis(benzenesulfonyl)imide; BAST
methoxyethyl)aminosulfur trifluoride;
NFSI = N-
=
DAST
(bis(2-
=
diethylaminosulfur trifluoride; TCCA = Trichloroisocyanuric
Acid.
The reaction of 4-fluorothioanisole (1a) was used to optimize
the conditions (Table 1). The amount of TMSCN was first
investigated (entries 1-5). In the presence of 1.5 equivalents of
Selectfluor,13 3.0 or more equivalents of TMSCN gave
thiocyanate 2a in greater than 36% (entries 4 and 5). Using 1.0
equivalent of Selectfluor delivered 20% yield (entry 6), while
using 2.0 equivalents increased the yield to 52% (entry 7).
Different oxidants were screened (entries 8-18). NFSI was
almost as efficient as Selectfluor (entry 8). Other fluorium
oxidants (entries 9 and 10), high-valent sulfur oxidants (entries
11-13), chlorium (14-16), brominium (entry 17) and iodium
were evaluated. The demethylative cyanation of 4-
methoxycarbonyl (1p), 4-formy (1q), and 4-nitro
thioanisoles took place readily, affording desired products in
52-85% yields. Under the oxidative conditions, the formyl
group in 2q survived. 4-Phthalimidyl anisole (1s), 2-
methylthionaphthalene (1t), and 2-methylthiopyridine (1u),
12b
(1r)
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The Journal of Organic Chemistry
and 2-(methylthio)benzo[d]thiazole (1v) were also good
scavenger of thioether or TMSCN (Scheme 3a). These results
highly suggested a direct interaction of thioether with
Selectfluor in the dealkylative cyanation process, even though
TMSCN also reacted with Selectfluor when directly mixed in
acetonitrile at 80 C (see Figures S25-29 30 in Supporting
Information).
1
2
3
4
substrates for the demethylative cyanation, and moderate to
good yields (44-85%) were obtained. The low yield of 2u was
attributed to the N-methylation of 2-methylthiopyridine (1u)
and the formation of di(pyridin-2-yl) disulfide (see Figures S1-
S2 in Supporting Information).
o
5
In the above reactions, aryl methyl thioethers were used, and
methyl acted as a leaving group. The thioethers with sterically
and electronically different alkyls (3a-3i) were also applicable
substrates in the dealkylative cyanation, and the thiocyanates
were formed in 34-71% yields (Table 3). In the reactions of 3g,
3h, and 3i, mono- and difluorination of the active methylene,
as well as disulfide formation, were observed (see Figures S3-
S12 in Supporting Information). In addition, the method is
also applicable to dialkyl sulfides (Scheme 2). The reaction of
symmetric dibenzyl sulfide 1w delivered benzyl thiocyanate
(2w) in 78% yield. Good regioselectivity was obtained in the
reaction of unsymmetric sulfide 1x. The dealkylative
cyanation selectivity occurred at the benzyl position, affording
2x in 73% yield and 2w in trace amount (only detected by GC-
MS).
We also explored the evolution of the dissociated alkyl groups
(Scheme 3b). Considering the nucleophilic fluoride and
cyanide anions, fluoroalkanes (R-F) and nitriles (R-CN) had
been regarded as two possible byproducts. The crude reaction
6
7
8
9
1
mixtures of 3a-3f were carefully examined by H NMR, GC-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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44
45
46
47
48
49
50
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59
60
MS, and LC-HRMS. However, no fluoroalkane or nitrile was
observed (Scheme 3b). Instead, 1-(chloromethyl)-4-alkyl-1,4-
diazabicyclo[2.2.2]octane-1,4-diiums (6o, 6a-f) were observed
by HRMS in all cases (Scheme 2b, also see Figures S16-S22
in Supporting Information). In the reaction of 1k, different
1
possible byproducts were probed by H NMR. Gratifyingly,
besides thiocyanate 2k, 1-(chloromethyl)-4-methyl-1,4-
diazabicyclo[2.2.2]octane-1,4-diiums (6), 1-(chloromethyl)-
1,4-diazabicyclo[2.2.2]octane-1-ium (7), and fluorotrimethyl
silane (TMSF) were observed (Scheme 3c, Figures S23 and
S24 in Supporting Information). 16
Table 3. Steric and electronic effects on the dealkylative
cyanation of thioethers.
a
Radical probing
TEMPO (3 equiv.),
TMSCN (3 equiv.),
Selectfluor (2.5 equiv.)
observed
by GC-MS
S
S
NC
N
2k
(0%)
+
+
R
CN
O
4
TMSCN (3 equiv.),
Selectfluor (2.5 equiv.)
80 oC, MeCN, 4 h.
S
Br
2o
Br
1o 3a-i
,
80 oC, MeCN, 4 h.
entry
R
1
2
3
4
5
1k
observed
by GC-MS
S
N
O
Me Et
1o 3a
yield (%)a 69b 51
n-Bu
3b
47
8
Bn
3c
42
9
CH2Bn
3d
5
80 oC, MeCN, 1 h
thioether
1k
+ TEMPO
3 equiv.
5
1k
(1 equiv.)
then
71%
10
80 oC, MeCN, 1 h
N
5
Selectfluor + TEMPO
1 equiv. 3 equiv.
entry
R
6
7
O
80 oC, 1 h
i-Pr t-Bu CH2CN CH2CO2Et CH2COPh
TMSCN (1 equiv.)
Detection of dissociated alkyls
80 oC, 1 h
R = Me,
4
thioether
3e
3f
3g
3h
3i
b
yield (%)a 65
59
34
39
45
6o
6a
6b
6c
Cl
R = Et,
R = Bu,
R = Bn,
R = CH2Bn,
R = i-Pr,
R = t-Bu,
aYield of 2o based on 1H NMR with 4-nitroiodobenzene as an
R
CN
R F
N
-
internal standard. bIsolated yield after 1 h.
2BF4
Not observed by
GC-MS or 1H NMR;
6d
N
R
Observed
by HRMS
6
6e
6f
TMSCN (3 equiv.),
Ph
Selectfluor (2.5 equiv.)
S
Ph
S
Ph
CN
CN
c
Byproduct probing
TMSF (observed
by 1H NMR)
S
80 oC, MeCN, 4 h.
CN
1w
2w
, 78%
2k
1k,
, 41%
37% recovery
Cl
As above
TMSCN (3 equiv.),
Selectfluor (1.5 equiv.)
S
S
Ph
2w
+
Ph
Ph
S
Cl
trace
Me
2x
, 73%
1x
80 oC, CD3CN, 4 h.
N
N
N
1k
-
-
Scheme 2. Reactions of dialkyl sulfides
2BF4
6o
BF4
Note: 4-iodonitrobenzene (1.5 equiv. )
was used as an internal standard, and
N
, 20%
, 49%
1k
the yield and recovery was based on
.
7
Me
The mechanistic studies were shown in Scheme 3. Addition of
3 equivalents of radical scavenger TEMPO into the reaction of
1k under standard conditions completely prevented the
formation of thiocyanate 2k (Scheme 3a). Instead, 1-cyanato-
2,2,6,6-tetramethylpiperidine (4) and methyl((2,2,6,6-
tetramethylpiperidin-1-yl)oxy)(o-tolyl)sulfonium (5) were
clearly observed by GC-MS (see Figures S13-S15, Schemes
S1-S3 in Supporting Information), probably indicating the
involvement of cyano radical and sulfur radical cation.13b,14
Scheme 3. (a) Radical probing experiment, (b) detection of
dissociated alkyls, and (c) byproduct probing.
Based on the above results, we prefer a radical mechanism
(Scheme 4). Single electron transfer (SET) from the sulfur
center of thioethers 1 to the fluorium center of Selectfluor
reagent delivers sulfur radical cations 8, nitrogen radical
cation 9, and fluoride anion.13,14 The resulting fluoride
facilitates the dissociation of TMSCN into a cyanide anion, by
releasing volatile TMSF.17 A second SET from cyanide anion
o
However, direct heating 1k and TEMPO at 80 C in MeCN
did not give 5 (Scheme 3a). Oxidation of TEMPO with
Selectfluor led to TEMPO cation,15 which did not serve as a
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Page 4 of 8
to nitrogen radical cation 9 generates cyano radical and tertiary
amine 7. The formation of 7 was observed by both HRMS and
1H NMR (see Figures S23 and
S24 in Supporting
Information). Combination of sulfur radical cations 8 and
cyano radical leads to cyano sulfoniums 10 as key
Scheme 5. Synthetic applications of dealkylative cyanation.
1
2
3
4
5
6
7
8
CONCLUTION
In summary, we have developed an efficient, operationally
simple, and step-economical dealkylative radical cyanation
protocol to convert thioethers to thiocyanates in moderate to
good yields. Selectfluor is used as the oxidant and
trimethylsilyl cyanide as the cyanation reagent. Aryl thioethers
with sterically and electronically different alkyls are applicable
substrates. Mechanistically, sulfur radical cations and cyano
radical are both involved, and cyanosulfoniums are the key
intermediates that undergo dealkylation to form thiocyantes.
Our dealkyaltive cyanation is applicable to synthesis of
thiocyanates bearing strongly electrophilic functionalities,
which have been demonstrated synthetically useful in
structural modification of natural products.
intermediates. Alternatively, a nucleophilic mechanism is also
13b,16
possible,
which cannot be eliminated by the current
evidence. Nucleophilic attack at the fluorine of Selectfluor
renders fluorosulfonium 11, which subsequently reacted with
TMSCN, possibly via 12, to yield 10 and release TMSF. The
arylcyanosulfonium moiety of 10 acts as a good leaving group
to initiate the dealkylation. An SN2 (for primary alkyls) or SN1
(for tertiary alkyls) or both (for tertiary alkyls) mechanism is
suggested for the dealkylation of 10 with amine 7, and N-alkyl
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
-
ammonium salts 6 (BF4 as a counterion) and thiocyanates 2
are produced. The chemoselectivity toward dealkylative
cyanation rather than Pummerer-type cyanation is presumably
indicative of (1) the strong affinity of the nucleophilic cyano
radical (or anion) with electrophilic sulfur radical cation (or
fluorosulfonium cation), (2) the strong nucleophilicity instead
of basicity of tertiary amine 7, (3) and the good leaving ability
of arylcyanosulfonium moiety of 10.
EXPERIMENTAL SECTION
General Information
All the dealkylative cyanation reactions were performed in dry
solvents under nitrogen atmosphere, and the reaction tubes were
flame-dried prior to use. Acetonitrile and ethyl acetate were
refluxed over calcium hydride, and freshly distilled prior to use.
Dry DMSO, CDCl3, and DMF were commercially available.
Column chromatography was performed on silica gel (200–300
mesh) from Qingdao Haiyang Chemical, and petroleum ether
(PE, b.p. 60–90 oC) and ethyl acetate (EA, commercially
received) were used as eluents. Reactions were monitored by
thin-layer chromatography on silica gel from Yantai Chemical
-
2 BF4
N
N F
Radical
proposal
Cl
S
S
Ar
R
Ar
R1
dealkylation
1
8
CN
7
F-
+
S
N
N
S
CN
Ar
R
Ar
Cl
CN
2
1
10
Industry Institute. The plates were visualized under UV light. H
9
and 13C NMR spectra were recorded on a Bruker 400 MHz
spectrometer in CDCl3 or CD3CN with TMS as an internal
standard, and the chemical shifts (δ) were reported in part(s) per
million (ppm). The IR spectra (film on KBr pellets, v [cm−1]) were
taken on a Nicolet 5700 FTIR spectrometer. The high-resolution
mass analyses were performed under ESI ionization using an
LC/MSD TOF mass spectrometer. The GC-MS analyses were
performed on a Thermo Scientific equipment.
CN
TMS
CN
Trapped radical
species
TMS
F
N
N
R
N
N
Cl
- TMSF
6
Cl
Nucleophilic proposal
7
NC
F
R1
F
S
CN
TMS
S
N
N
F
Ar
Ar
R1
Cl
12
11
All thioethers are known compounds. Thioethers 3f and 1w
7
S
Ar
R
19a
19b
were prepared according to Feringa’s
and McCaleb’s
1
procedures, respectively. The rest were either commercially
available or prepared by our previous methods in quantitative
yields.2a Their purity and structures were identified by GC-MS.
Most of the synthesized thiocyanates are known compounds,
and their spectra are identical with those reported.
Scheme 4. Two mechanistic proposals.
The thiocyanates bearing strongly electrophilic functionalities
are rarely accessed by precedented nucleophilic thiocyanation
or nucleophilic cyanation, due to the poor functionality
tolerance. In addition, the self-nucleophilicity of thiols also
make it difficult to obtain starting materials with electrophilic
groups. In this study, 4-bromomethylthioanisole (1y), with an
electrophilically active benzyl bromide moiety, was
successfully converted to desired thiocyanate 2y in 40% yield.
As our interests in steroid structure modification,18 we
converted estrone 13 into 14 using 2y (Scheme 5).
General Procedure for the Dealkylative Cyanation
To a reaction tube was sequentially added thioether 1 (0.2
mmol), TMSCN (74 μL, 0.6 mmol, 3 equiv), Selectfluor
reagent (177 mg, 0.5 mmol; 2.5 equiv). The tube was
evacuated and backfilled with nitrogen for three times. Then 1
ml of dry acetonitrile added via a syringe, and the resulting
o
solution was stirred in an 80 C oil bath. When the reaction
was completed (monitored by TLC), the solvent was removed
by distillation under reduced pressure. The crude residue was
purified by silica gel column chromatography to give desired
thiocyanate 2.
TMSCN (3 equiv.),
Selectfluor (2.5 equiv.)
S
S
CN
Br
S
Br
80 oC, MeCN, 4 h.
2y
, 40%
1y
, 1 mmol
O
CN
O
2y
, K2CO3,
O
MeCN, 80 oC, 2 h
Thiocyanatobenzene (2a) [CAS No.: 5285-87-0] 8a
H
H
H
H
Yield: 14.7 mg (55%); yellowish liquid; Rf = 0.55 (PE:EA =
20:1, v:v). 1H NMR (400 MHz, CDCl3) δ 7.56–7.50 (m, 2H),
7.47–7.40 (m, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
H
H
HO
13
14
, 98%
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130.2, 130.02, 129.5, 124.4, 110.5. MS (EI): m/z calcd for
C7H5NS: 135.01; found: 134.96.
4-Thiocyanatophenyl benzoate (2h) [CAS No.: 1821240-59-8]
20b
1
2
3
4
5
6
7
8
9
Yield: 36.0 mg (71%); yellowish solid; m.p.: 76-78 oC; Rf =
0.2 (PE:EA = 5:1, v:v). 1H NMR (400 MHz, CDCl3) δ 8.22 (m,
2H), 7.75 – 7.62 (m, 3H), 7.56 (m, 2H), 7.36 (m, 2H). 13C{1H}
NMR (101 MHz, CDCl3) δ 164.7, 152.2, 134.0, 131.9, 130.3,
128.9, 128.7, 123.8, 121.3, 110.4. MS (EI): m/z calcd for
C14H9NO2S: 255.04; found: 254.97.
1-Methoxy-4-thiocyanatobenzene (2b) [CAS: 5285-90-5] 8g
Yield: 25.7 mg (63%); yellowish liquid; Rf = 0.35 (PE:EA =
1
10:1, v:v). H NMR (400 MHz, CDCl3) δ 7.5 – 7.47 (m, 2H),
6.9 – 6.92 (m, 2H), 3.82 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 161.3, 133.8, 115.88, 113.8, 111.6, 55.5. MS (EI):
m/z calcd for C8H7NOS: 165.02; found: 165.11.
1-Nitro-4-(4-thiocyanatophenoxy)benzene (2i)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Yield: 39.0 mg (78%); yellowish solid; m.p.: 90-92 oC; Rf =
0.3 (PE:DCM = 1:1, v:v). H NMR (400 MHz, CDCl3) δ 8.30
1-Ethoxy-4-thiocyanatobenzene (2c) [CAS No.: 5286-01-1] 20a
1
Yield: 24.0 mg (71%); yellowish liquid; Rf = 0.35 (PE:EA =
10:1, v:v). 1H NMR (400 MHz, CDCl3) δ 7.53 – 7.45 (m, 2H),
6.95 – 6.90 (m, 2H), 4.05 (q, J = 7.0 Hz, 2H), 1.43 (t, J = 7.0
Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.7, 133.8,
116.3, 113.5, 63.9, 14.6. MS (EI): m/z calcd for C9H9NOS:
179.04; found: 179.00.
– 8.21 (m, 2H), 7.67 – 7.51 (m, 2H), 7.20 – 7.13 (m, 2H), 7.11
– 7.02 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 161.9,
156.7, 143.5, 133.1, 126.1, 121.7, 120.1, 118.1, 110.5. IR
(film): v (cm−1) 2157, 1609, 1595, 1581, 1507, 1485, 1343,
1249, 1169, 1107, 840.HRMS (ESI): m/z calcd for [M+H]+
C13H9N2O3S: 273.0329; found: 273.0320.
1-Butoxy-4-thiocyanatobenzene (2d) [CAS No.: 14372-50-0]
1-Methyl-4-thiocyanatobenzene (2j) [CAS: 5285-74-5] 8g
20a
Yield: 22.6 mg (76%); yellowish liquid; Rf = 0.40 (PE:DCM =
Yield: 26.0 mg (63%); yellowish liquid; Rf = 0.40 (PE:EA =
20:1, v:v). 1H NMR (400 MHz, CDCl3) δ 7.57 – 7.43 (m, 2H),
6.98–6.87 (m, 2H), 3.97 (t, J = 6.5 Hz, 2H), 1.82 1.72 (m, 2H),
1.54–1.43 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 160.9, 134.9, 116.39, 113.4, 111.7, 68.1,
31.1, 19.1, 13.8. MS (EI): m/z calcd for C11H13NOS: 207.07;
found: 207.00.
1
5:1, v:v). H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.3 Hz,
2H), 7.16 (d, J = 8.1 Hz, 2H), 2.30 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 140.3, 130.9, 130.7, 120.6, 111.1, 21.2.
MS (EI): m/z calcd for C8H7NS: 149.03; found: 149.00.
1-Methyl-2-thiocyanatobenzene (2k) [CAS No.: 5285-88-1] 20c
Yield: 24.1 mg (81%); yellowish liquid; Rf = 0.40 (PE:DCM =
1
5:1, v:v). H NMR (400 MHz, CDCl3) δ 7.59 – 7.51 (m, 1H),
1-(Allyloxy)-4-thiocyanatobenzene (2e)
7.33 – 7.15 (m, 3H), 2.41 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 139.3, 132.0, 131.5, 130.2, 127.8, 123.6, 110.5, 20.4.
MS (EI): m/z calcd for C8H7NS: 149.03; found: 149.00.
Yield: 17.0 mg (45%); yellowish liquid; Rf = 0.40 (PE:EA =
1
10:1, v:v). H NMR (400 MHz, CDCl3) δ 7.52 –7.47 (m, 2H),
7.00 – 6.92 (m, 2H), 6.03 (ddt, J = 17.2, 10.5, 5.3 Hz, 1H),
5.42 (ddd, J = 17.3, 3.0, 1.5 Hz, 1H), 5.32 (ddd, J = 10.5, 2.6,
1.3 Hz, 1H), 4.56 (dt, J = 5.3, 1.5 Hz, 2H). 13C{1H} NMR (101
MHz, CDCl3) δ 160.3, 133.7, 132.4, 118.3, 116.6, 113.9,
111.6, 69.0. IR (film): v (cm−1) 2154, 1654, 1590, 1491, 1460,
1418, 1293, 1251, 1227, 1175, 825. HRMS (ESI): m/z calcd
for [M+H]+ C10H9NOS: 192.0478; found: 192.0476.
1-(tert-Butyl)-4-thiocyanatobenzene (2l) [CAS No.: 16255-53-
1] 8g
Yield: 27.0 mg (71%); yellow oil; Rf = 0.70 (PE:EA = 10:1,
1
v:v). H NMR (400 MHz, CDCl3) δ 7.50 – 7.42 (m, 4H), 1.32
(s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 153.4, 130.5,
127.4, 120.6, 111.0, 34.8, 32.9. MS (EI): m/z calcd for
C11H13NS: 191.08; found: 191.03.
1-(Benzyloxy)-4-thiocyanatobenzene (2f)
Yield: 29.0 mg (73%); yellow liquid; Rf = 0.30 (PE:EA = 20:1,
1
v:v). H NMR (400 MHz, CDCl3) δ 7.52 – 7.48 (m, 2H), 7.43
1-Fluoro-4-thiocyanatobenzene (2m) [CAS No.: 2924-02-9] 8g
– 7.39 (m, 4H), 7.39 – 7.32 (m, 1H), 7.04 – 7.00 (m, 2H), 5.09
(s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.4, 136.0,
133.7, 128.7, 128.3, 127.4, 116.7, 114.1, 111.5, 70.3. IR (film):
v (cm−1) 2154, 1589, 1491, 1457, 1382, 1291, 1247, 1174,
1014, 856, 738, 695. HRMS (ESI): m/z calcd for [M+H]+
C14H12NOS: 242.0635; found: 242.0638.
Yield: 20.8 mg (68%); yellowish liquid; Rf =0.45 (PE:EA =
10:1, v:v).
1H NMR (400 MHz, CDCl3) δ 7.60 – 7.50 (m, 2H), 7.20 –
7.09 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 163.7 (d,
JC-F = 252.0 Hz), 133.3 (d, JC-F = 8.7 Hz), 117.7 (d, JC-F = 22.7
Hz), 114.9 (d, JC-F = 871.9 Hz). MS (EI): m/z calcd for
C7H4FNS: 153.00; found: 152.95.
4-Thiocyanatophenyl methanesulfonate (2g)
Yield: 40.8 mg (85%); yellowish liquid; Rf = 0.2 (PE:EA = 5:1,
1-Chloro-4-thiocyanatobenzene (2n) [CAS No.: 3226-37-7] 8g
1
v:v). H NMR (400 MHz, CDCl3) δ 7.63 – 7.57 (m, 2H), 7.40
Yield: 28.4 mg (84%); yellowish liquid; Rf = 0.45 (PE:EA =
10:1, v:v). 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.36 (m, 2H),
7.36 – 7.30 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ
136.2, 131.5, 130.5, 122.8, 110.0. MS (EI): m/z calcd for
C7H4ClNS: 168.98; found: 168.93.
– 7.35 (m, 2H), 3.20 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 149.8, 131.8, 123.9, 123.6, 109.8, 37.9. IR (film): v (cm−1)
2158, 1632, 1585, 1485, 1412, 1365, 1203, 1177, 1156, 865.
HRMS (ESI): m/z calcd for [M+H]+ C8H8NO3S2: 229.9941;
found: 229.9946.
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1-Bromo-4-thiocyanatobenzene (2o) [CAS No.: 3226-41-3] 8g
2-Thiocyanatobenzo[d]thiazole (2v) [CAS No.: 6011-99-0] 8g
1
2
3
4
5
6
Yield: 30.7 mg (84%); white solid; m.p.: 51 – 53 oC; Rf = 0.33
Yield: 32.0 mg (84%); white solid; m.p.: 85 – 87 oC; Rf = 0.35
(PE:DCM = 5:1, v:v) 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J
= 8.1 Hz, 1H), 7.89 – 7.85 (m, 1H), 7.56 – 7.50 (m, 1H), 7.50
– 7.42 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 153.4,
153.0, 136.5, 127.2, 126.4, 123.2, 121.4, 107.0. MS (EI): m/z
calcd for C8H5NOS: 191.98; found: 191.93.
1
(PE:DCM = 5:1, v:v). H NMR (400 MHz, CDCl3) δ 7.55 –
7.45 (m, 2H), 7.36 – 7.30 (m, 2H). 13C{1H} NMR (101 MHz,
CDCl3) δ 132.4, 130.5, 123.1, 122.5, 108.8. MS (EI): m/z
calcd for C7H4BrNS: 212.92; found: 212.98.
7
8
9
Methyl 4-thiocyanatobenzoate (2p) [CAS No.: 1879-22-7] 20c
o
(Thiocyanatomethyl)benzene (2w) [CAS No.: 3012-37-1] 8g
Yield: 33.0 mg (85%); white solid; m.p.: 64-66 C; Rf =0.33
1
o
(PE:EA = 20:1, v:v). H NMR (400 MHz, CDCl3) δ 8.13 –
Yield: 23.5 mg (78%); yellowish solid; m.p.: 39-41 C; Rf =
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8.03 (m, 2H), 7.59 – 7.51 (m, 2H), 3.93 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 165.8, 131.2, 130.9, 130.4, 128.4, 109.1,
52.5. MS (EI): m/z calcd for C9H7NO2S: 193.02; found:
192.95.
1
0.41 (PE:EA = 20:1, v:v). H NMR (400 MHz, CDCl3) δ
7.43 – 7.25 (m, 5H), 4.16 (s, 2H). 13C{1H} NMR (101 MHz,
CDCl3) δ 134.3, 129.0, 128.9, 128.8, 111.9, 38.2. MS (EI):
m/z calcd for C8H7NS: 149.03; found: 149.03.
4-Thiocyanatobenzaldehyde (2q) [CAS No.: 89898-72-6] 20d
(2-Thiocyanatoethyl)benzene (2x) [CAS No.: 5654-72-8] 8a
Yield: 16.8 mg (52%); yellowish liquid; Rf = 0.20 (PE:DCM =
Yield: 24 mg (73%); colorless liquid; Rf = 0.35 (PE:EA = 20:1,
1
1:1, v:v). H NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 8.00 –
1
v:v). H NMR (400 MHz, CDCl3) δ 7.52 – 7.22 (m, 5H),
7.90 (m, 2H), 7.70 – 7.61 (m, 2H). 13C{1H} NMR (101 MHz,
CDCl3) δ 190.6, 136.4, 132.3, 130.9, 128.7, 108.7. MS (EI):
m/z calcd for C8H5NOS: 163.01; found: 163.01. (These two
data are occasionally identical)
3.13 (ttd, J = 9.1, 6.0, 2.6 Hz, 4H). 13C{1H} NMR (101 MHz,
CDCl3) δ 137.6, 128.8, 128.6, 127.2, 112.0, 36.0, 35.1. MS
(EI): m/z calcd for C9H9NS: 163.04; found: 163.05.
1-(Bromomethyl)-4-thiocyanatobenzene (2y) [CAS No.:
1-Nitro-4-thiocyanatobenzene (2r) [CAS No.: 2137-92-0] 8g
55796-77-5] 20e
o
Yield: 30.6 mg (85%); white solid; m.p.: 128 – 130 C; Rf =
Reaction performed on 1 mmol scale. Yield: 92.3 mg (40%);
yellowish solid, m.p.: 80-82 oC; Rf = 0.50 (PE:EA = 10:1, v:v).
1H NMR (400 MHz, CDCl3) δ 7.53 – 7.48 (m, 2H), 7.48 –
7.43 (m, 2H), 4.47 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3)
δ 139.5, 130.8, 130.2, 124.6, 110.1, 31.7. MS (EI): m/z calcd
for C8H6BrNS: 226.89; found: 226.94.
1
0.25 (PE:EA = 10:1, v:v). H NMR (400 MHz, CDCl3) δ 8.37
– 8.26 (m, 2H), 7.72 – 7.64 (m, 2H). 13C{1H} NMR (101 MHz,
CDCl3) δ 133.4, 128.7, 125.1, 124.5, 108.1. MS (EI): m/z
calcd for C8H5NOS: 180.00; found: 180.00. (These two data
are occasionally identical).
2-(4-Thiocyanatophenyl)isoindoline-1,3-dione (2s)
(8R,9S,13S,14S)-13-Methyl-3-((4-thiocyanatobenzyl)oxy)-
6,7,8,9,11,12,13,14,15,16-decahydro-17H-
cyclopenta[a]phenanthren-17-one (14)
Yield: 45.0 mg (81%); white solid; m.p.: 198-200 oC; Rf = 0.40
(PE:EA = 3:1, v:v). 1H NMR (400 MHz, CDCl3) δ 7.98 (dd, J
= 5.5, 3.1 Hz, 2H), 7.83 (dd, J = 5.5, 3.1 Hz, 2H), 7.70 – 7.65
(m, 2H), 7.63 – 7.58 (m, 2H). 13C{1H} NMR (101 MHz,
CDCl3) δ 166.7, 134.8, 133.1, 131.5, 130.6, 127.8, 124.0,
123.9, 109.9. IR (film): v (cm−1) 2153, 1743, 1712, 1501, 1466,
1400, 1279, 1174, 1124, 1098, 885, 789. HRMS (ESI): m/z
calcd for [M+H]+ C15H9N2O2S: 281.0380; found: 281.0385.
Under a nitrogen atmosphere, a mixture of 11 (0.27 mg, 0.1
mmol), 1y (29 mg, 0.13 mmol), and K2CO3 (36 mg, 0.26
mmol) in 1 ml of acetonitrile was stirred in a reaction tube in
o
an 80 C oil bath for 2 h. After cooling to room temperature
and removing the solvent under reduced pressure, 5 ml of
water was added, and the mixture was extracted with
dichloromethane (5 ml × 3). The organic phase was dried over
anhydrous magnesium sulfate, concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography to give 14.
Yield: 41.4 mg (98%); white solid; m.p.: 138-140 oC; Rf = 0.50
(PE:EA = 3:1). 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.4
Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.6 Hz, 1H),
6.78 (dd, J = 8.6, 2.5 Hz, 1H), 6.73 (m, 1H), 5.09 (s,2H), 2.92
(m, 2H), 2.53 (dd, J = 18.8, 8.6 Hz, 1H), 2.42 (m, 1H), 2.28
(m, 1H), 2.08 m, 4H), 1.71 – 1.41 (m, 6H), 0.94 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 220.9, 156.4, 139.4, 138.0,
132.8, 130.4, 128.9, 126.5, 123.6, 114.9, 112.3, 110.5, 68.9,
50.4, 48.0, 44.0, 38.3, 35.9, 31.6, 29.7, 26.5, 25.9, 21.6, 13.9.
IR (film): v (cm−1) 2160, 1733, 1607, 1570, 1497, 1460, 1407,
1249, 1375, 1307, 1280, 1248, 1160, 1084, 1055, 1009, 847.
HRMS (ESI): m/z [M+H]+ calcd for C26H28NO2S: 418.1835
found: 418.1832.
2-Thiocyanatonaphthalene (2t) [CAS No.: 2645-24-1] 8g
Yield:43.5 mg (85%);white solid; m.p.:33 – 35 oC; Rf = 0.50
(PE:DCM = 1:1, v:v). 1H NMR (400 MHz, CDCl3) δ 7.91 (m,
1H), 7.83 – 7.68 (m, 3H), 7.52 – 7.40 (m, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 132.6, 132.0, 129.2, 128.8, 126.9, 126.9
126.5, 126.4, 125.2, 120.2, 109.6. MS (EI): m/z calcd for
C11H7NS: 185.03; found: 184.98.
2-Thiocyanatopyridine (2u) [CAS No. 2637-3-6] 8a
Yield:12.5 mg (45%);colorless liquid; Rf =0.20 (PE:EA = 20:1,
1
v:v). H NMR (400 MHz, CDCl3) δ 8.54 (dd, J = 4.8, 0.9 Hz,
1H), 7.79 (td, J = 7.9, 1.9 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H),
7.30 (ddd, J = 7.4, 4.8, 0.8 Hz, 1H). 13C{1H} NMR (101 MHz,
CDCl3) δ 150.6, 150.0, 138.5, 122.8, 122.0, 109.0. MS (EI):
m/z calcd for C6H4N2S: 136.01; found: 136.03.
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The Journal of Organic Chemistry
Chem. Sci. 2017, 8, 7047–7051. (c) Pawliczek, M.; Garve, L. K.
ASSOCIATED CONTENT
Supporting Information
Copies of NMR (1H, 13C), MS, and HRMS spectra. These
material is available free of charge via the Internet at
http://pubs.acs.org.
B.; Werz, D. B. Activation of Aryl Thiocyanates Followed by
Aryne Insertion: Access to 1,2-Thiobenzonitriles. Org. Lett.
2015, 17, 1716–1719. (d) Exner, B.; Bayarmagnai, B.; Jia, F.;
1
2
3
4
5
6
7
8
Goossen, L. J.
Iron-Catalyzed Decarboxylation of
Trifluoroacetate and Its Application to the Synthesis of
Trifluoromethyl Thioethers. Chem. Eur. J. 2015, 21, 17220–
17223. (e) Lee, Y. T.; Choi, S. Y.; Chung, Y. K. Microwave-
Assisted Palladium-Catalyzed Regioselective Cyanothiolation of
Alkynes with Thiocyanates. Tetrahedron Lett. 2007, 48, 5673–
5677.
AUTHOR INFORMATION
Corresponding Author
9
* zhyang@mail.buct.edu.cn (Z.Y.)
* jxxu@mail.buct.edu.cn (J.X.)
6. (a) Dutta, S.; Abe, H.; Aoyagi, S.; Kibayashi, C.; Gates, K. S. J.
Am. Chem. Soc. 2005, 127, 15004–15005. (b) Taylor, M. G.;
Massey, V. 6-Mercapto-FAD and 6-Thiocyanato-FAD as Active
Site Probes of Phenol Hydroxylase. J. Biolog. Chem. 1991, 266,
8281–90. (c) Jin, Y.; Sui, D.; Li, X.; Yu, X.; Gui, M. Use of
Flavone and Flavanone Derivatives in Preparation of Sedative
and Hypnotic Drugs. PCT Int. Appl. 2013, WO 2013185301. (d)
Sheng, Y.; You, Y.; Cao, Z.; Liu, L.; Wu, H. Rapid and
Selective DNA-based Detection of Melamine Using α-
Hemolysin Nanopores. Analyst 2018, 143, 2411-2415.
7. For a review, see: (a) Erian, A. W.; Sherif, S. M. The Chemistry
of Thiocyanic Esters. Tetrahedron 1999, 55, 7957–8024. For
selected recent examples, see: (b) Venkanna, P.; Rajanna, K. C.;
Kumar, M. S.; Venkateswarlu, M.; Ali, M. M. An Efficient
Method for Thiocyanation of Aromatic and Heteroaromatic
Compounds using Cyanuric Chloride and Ammonium
Thiocyanate under Conventional and Nonconventional
Conditions. Synlett 2016, 27, 237–240. (c) Sun, N.; Zhang, H.;
Mo, W.; Hu, B.; Shen Z.; Hu X. Synthesis of Aryl Thiocyanates
via Copper-Catalyzed Aerobic Oxidative Cross-coupling
Between Arylboronic Acids and KSCN. Synlett, 2013, 24, 1443–
1447. (d) Akhlaghinia, B.; Pourali, A.-R.; Rahmani, M. Efficient
and Novel Method for Thiocyanation of Aromatic Compounds
Using Trichloroisocyanuric Acid/ammonium Thiocyanate/wet
SiO2. Synth. Commun. 2012, 42, 1184–1191. (e) Vaddula, B. R.;
Varma, R. S.; Leazer, J. One-Pot Catalyst-free Synthesis of β-
and γ-Hydroxy Sulfides Using Diaryliodonium Salts and
Microwave Irradiation. Eur. J. Org. Chem. 2012, 6852–6855. (f)
Wang, Y.-F.; Zhou, Y.; Wang, J.-R.; Liu, L.; Guo, Q.-X. CuI-
Catalyzed Synthesis of Aryl Thiocyanates From Aryl Iodides.
Chin. Chem. Lett. 2006, 17, 1283–1286.
8. (a) Guo, W.; Tan, W.; Zhao, M.; Zheng, L.; Tao, K.; Chen, D.;
Fan, X. Direct Photocatalytic S−H Bond Cyanation with Green
“CN” Source. J. Org. Chem. 2018, 83, 6580−6588. (b) Frei, R.;
Courant, T.; Wodrich, M. D.; Waser, J. General and Practical
Formation of Thiocyanates from Thiols. Chem. Eur. J. 2015, 21,
2662–2668. (c) Castanheiro, T.; Gulea, M.; Donnard, M.; Suffert,
J. Practical Access to Aromatic Thiocyanates by CuCN-
Mediated Direct Aerobic Oxidative Cyanation of Thiophenols
and Diaryl Disulfides. Eur. J. Org. Chem. 2014, 7814–7817. (d)
Yamaguchi, K.; Sakagami, K.; Miyamoto, Y.; Jin, X.; Mizuno,
N. Oxidative Nucleophilic Strategy for Synthesis of
Thiocyanates and Trifluoromethyl Sulfides from Thiols. Org.
Biomol. Chem. 2014, 12, 9200–9206. (e) Kim, J.-J.; Kweon, D.-
H.; Cho, S.-D.; Kim, H.-K.; Jung, E.-Y.; Lee, S.-G.; Falck, J. R.;
Yoon, Y.-J. 2-Cyanopyridazin-3(2H)-ones: Effective and
Chemoselective Electrophilic Cyanating Agents. Tetrahedron
2005, 61, 5889–5894. (f) Wu, Y.-Q.; Limburg, D. C.; Wilkinson,
D. E.; Hamilton, G. S. 1-Cyanoimidazole as a Mild and Efficient
Electrophilic Cyanating Agent. Org. Lett. 2000, 2, 795–797. For
an example with in situ generated cyano reagent, see: (g) Wang,
Z.-H.; Ji, X.-M.; Hu, M.-L.; Tang, R.-Y. Nitromethane as a
Cyanating Reagent for the Synthesis of Thiocyanates.
Tetrahedron Lett. 2015, 56, 5067–5070. For cyanation of in situ
generated thiols or thiol derivatives, see: (h) Feng, C.; Peng, Y.;
Ding, G; Li, X.; Cui C.; Yan Y. Catalyst and Additive-Free
Regioselective Oxidative C–H Thio/selenocyanation of Arenes
and Heteroarenes with Elemental Sulfur/selenium and TMSCN.
Chem. Commun. 2018, 54, 13367–13370.
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ORCID
Zhanhui Yang: 0000-0001-7050-8780
Jiaxi Xu: 0000-0002-9039-4933
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work is financially supported by the National Natural
Science Foundation of China (No. 21602010 to Z.Y.), and the
Fundamental Research Funds for the Central Universities (No.
XK1802-6 to Z.Y. and J.X.; No. 12060093063 to Z.Y.).
REFERENCES
1. For selected reviews on Pummerer reactions, see: (a) Bur, S. K.;
Padwa, A. The Pummerer Reaction: Methodology and Strategy
for the Synthesis of Heterocyclic Compounds. Chem. Rev. 2004,
104, 2401–2432. (b) Feldman, K. S. Modern Pummerer-type
reactions. Tetrahedron 2006, 62, 5003–5034. (c) Akai, S.; Kita,
Y. Recent advances in Pummerer reactions. Top Curr Chem.
2007, 274, 35–76; (d) Smith, L. H. S.; Coote, S. C.; Sneddon, H.
F.; Procter, D. J. Beyond the Pummerer Reaction: Recent
Developments in Thionium Ion Chemistry. Angew Chem., Int Ed.
2010, 49, 5832–5844.
2. (a) Yang, Z. H.; Yang, S. Y.; Xu, J. X. Sulfur-Directed Metal-
free and Regiospecific Methyl C(sp3)-H Imidation of
Thioanisoles. Tetrahedron 2017, 73, 3240–3248. (b) Yang, Z.
H.; Yang, S. Y.; Haroone, M. S.; Xu, J. X. Sulfur-Mediated
C(sp2)-H Imidation and 1,2-Imidofluorination of Vinyl sulfides.
Tetrahedron 2017, 73, 3338–3346.
3. For our recent work on development of new reactions from
oxidation of low-valent sulfur, see: (a) Fu, Z. H.; Yuan, W. H.;
Ning Chen, N.; Yang, Z. H.; Xu, J. X. Na2S2O8-Mediated
Efficient Synthesis of Isothiocyanates From Primary Amines in
Water. Green Chem., 2018, 20, 4484–4491. (b) Yang, Z. H.; Xu,
W.; Wu, Q. Y.; Xu, J. X. Aminoxidation of Arenethiols to N-
Chloro-N-sulfonyl Sulfinamides. J. Org. Chem., 2016, 81, 3051–
3057.
4. For selected references, see: (a) Stevenart-De Mesmaeker, N.;
Merenyi, R.; Viehe, H. G. Synthesis of Dienes with 1,1-
Captodative Substitution. Tetrahedron Lett. 1987, 28, 2591–
2594. (b) Takeda, T.; Kaneko, Y.; Nakagawa, H.; Fujiwara, T. A
Convenient Method for the Transformation of Alkenyl Sulfides
to 2-(Phenylthio)alkanenitriles, Homoallyl Sulfides, and
Thioacetals. Chem. Lett. 1987, 1963–1966. (c) Coldham, I.;
Burrell, A. J. M. Watson, L.; Oram, N.; Martin, N. G. Synthesis
of Fused Tricyclic Heterocycles by Condensation, Cyclization,
Dipolar Cycloaddition Cascade of α-Benzenesulfonyl and α-
Phenylthio Substituted Aldehydes. Heterocycles 2012, 84, 597–
613.
5. For a review, see: (a) Castanheiro, T.; Suffert, J.; Donnard, M.;
Gulea, M. Recent Advances in the Chemistry of Organic
ThioCyanates. Chem. Soc. Rev. 2016, 45, 494–505. For recent
examples, see: (b) Huang, Y.; Li, X.; Wang, X.; Yu, Y.; Zheng,
J.; Wu, W.; Jiang, H. Copper-Catalyzed Cyanothiolation to
Incorporate a Sulfur-substituted Quaternary Carbon Center.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 8
9. For recent synthesis of alkenyl thiocyanates, see: (a) Lu, L.-H.;
of Radical Cation in Electrophilic Fluorination by ESI-MS. Org.
Lett. 2005, 7, 3877–3880.
Zhou, S.-J.; Sun, M.; Chen, J.-L.; Xia, W.; Yu, X.; Xu, X.; He,
W.-M. Metal- and Solvent-Free Ultrasonic Multicomponent
Synthesis of (Z)-β-Iodo Vinylthiocyanates. ACS Sustainable
Chem. Eng. 2019, 7, 1574–1579. (b) Lu, L.-H.; Zhou, S.-J.; He,
W.-B.; Xia, W.; Chen, P.; Yu, X.; Xu, X.; He, W.-M. Metal-Free
Difunctionalization of Alkynes Leading to Alkenyl
Dithiocyanates and Alkenyl Diselenocyanates at Room
Temperature. Org. Biomol. Chem. 2018, 16, 9064–9068. (c) Wu,
C.; Lu, L.-H.; Peng, A.-Z.; Jia, G.-K.; Peng, C.; Cao, Z.; Tang,
Z.; He, W.-M.; Xu, X. Ultrasound-Promoted Brønsted Acid
Ionic Liquid-Catalyzed Hydrothiocyanation of Activated
Alkynes under Minimal Solvent Conditions. Green Chem. 2018,
20, 3683–3688.
1
2
3
4
5
6
7
8
15. For TEMPO cation generation, see: Montanari, F., Quici, S.,
Henry-Riyad, H., Tidwell, T. T., Studer, A., Vogler, T. 2,2,6,6-
Tetramethylpiperidin-1-oxyl. Encyclopedia of Reagents for
Organic Synthesis. 2007, doi:10.1002/047084289x.rt069.pub3.
16. For 1H NMR spectrum of 6o, see: Yang, K.; Zhang, H.; Niu, B.;
Tang, T.; Ge, H. Benzisothiazol-3-ones through a Metal-Free
Intramolecular N–S Bond Formation. Eur. J. Org. Chem. 2018,
5520–5523.
17. For 1H and 19F NMR data and physical properties of TMSF, see:
Levin, V. V.; Dilman, A. D.; Belyakov, P. A.; Struchkova, M. I.;
Tartakovsky, V. A. Reaction of the Ruppert-Prakash Reagent
with Perfluorosulfonic Acids. J. Fluor. Chem. 2009, 130,
667−670.
18. (a) Yang, S.; Tang, W.; Yang, Z.; Xu, J. Iridium-Catalyzed
Highly Efficient and Site-Selective Deoxygenation of Alcohols.
ACS Catal. 2018, 8, 9320−9326. (b) Li, J.; Tang, W.; Ren, D.;
Xu, J.; Yang, Z. Iridium-catalysed Highly Selective Reduction-
Elimination of Steroidal 4-En-3-ones to 3,5-Dienes in Water.
Green Chem. 2019, 21, 2088−2094.
19. (a) Pijper, T. C.; Robertus, J.; Browne, W. R.; Feringa, B. L.
Mild Ti-Mediated Transformation of t-Butyl Thioethers into
Thioacetates. Org. Biomol. Chem. 2015, 13, 265-268. (b) Kees,
K. L.; Fitzgerald, J. J., Jr.; Steiner, K. E.; Mattes, J. F.; Mihan,
B.; Tosi, T.; Mondoro, D.; McCaleb, M. L. New Potent
Antihyperglycemic Agents in db/db Mice: Synthesis and
Structure-Activity Relationship Studies of (4-Substituted
benzyl)(trifluoromethyl)pyrazoles and –Pyrazolones. J. Med.
Chem. 1996, 39, 3920−3928.
20. (a) Hueller, H.; Luess, K. D.; Wollmann, H.; Pohloudek-Fabini,
R. Organic Thiocyanogen Compounds. XXXII. Fungistatic
Properties and Skin tolerance of Some Thicyanophenols,
Thiocyanophenol Ethers, and Thiocyanophenol Ketones.
Pharmazie 1968, 23, 188-191. (b) Benjamin, E.; Bilguun, B.;
Fan, J.; Lukas, J. G. Iron-Catalyzed Decarboxylation of
Trifluoroacetate and Its Application to the Synthesis of
Trifluoromethyl Thioethers. Chem. Eur. J. 2015, 21, 17220-
17223. (c) Exner, B.; Bayarmagnai, B.; Matheis, C.; Goossen, L.
J. Synthesis of Perfluoroalkyl Thioethers from Aromatic
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10. Li, Y.; Pu, J.; Jiang, X. A Highly Efficient Cu-Catalyzed S-
Transfer Reaction: From Amine to Sulfide. Org. Lett. 2014, 16,
2692–2695.
11. (a) Zhu, D.; Chang, D.; Shi, L. Transition-Metal-Free Cross-
Coupling of Thioethers with Aryl(cyano)iodonium Triflates: a
Facile and Efficient Method for the One-pot Synthesis of
Thiocyanates. Chem. Commun. 2015, 51, 7180–7183. For
thiocyanate formation through C-S bond cleavage, see: (b)
Testaferri, L.; Tingoli, M.; Tiecco, M.; Chianelli, D.;
Montanucci, M. Synthesis of Aryl Thiocyanates From Aryl
Alkyl Sulfides. Conversion of Unactivated Aryl Halides into
Aryl Thiocyanates. Phosphorus Sulfur Relat. Elem. 1983, 15,
263-268. Also see ref 5b.
12. (a) Shu, Z.; Ji, W.; Wang, X.; Zhou, Y.; Zhang, Y.; Wang, J.
Iron(II)-Catalyzed Direct Cyanation of Arenes with
Aryl(cyano)-iodonium Triflates. Angew. Chem., Int. Ed. 2014,
53, 2186 –2189. (b) Peng, L.; Hu, Z.; Tang, Z.; Jiao, Y.; Xu, X..
Recent Progress in Transition Metal Catalyzed Cross Coupling
of Nitroarenes, 2019, DOI: 10.1016/j.cclet.2019.04.008.
13. For reviews on Selectfluor-mediated reactions, see: (a) Singh, R.
P.; Shreeve, J. M.
Fluorination with
Recent Highlights in Electrophilic
1-Chloromethyl-4-fluoro- 1,4-
diazoniabicyclo[2.2.2]octane Bis(tetrafluoroborate). Acc. Chem.
Res. 2004, 37, 31–44. (b) Nyffeler, P. T.; Duron, S. G.; Burkart,
M. D.; Vincent, S. P.; Wong, C.-H. Selectfluor: Mechanistic
Insight and Applications. Angew. Chem. Int. Ed. 2005, 44, 192 –
212. (c) Stavber, S. Recent Advances in the Application of
Selectfluor F-TEDA-BF4 as a Versatile Mediator or Catalyst in
Organic Synthesis. Molecules 2011, 16, 6432–6464. For a recent
related example, see: (d) Xie, L.-Y.; Peng, S.; Liu, F.; Yi, J.-Y.;
Wang, M.; Tang, Z.; Xu, X.; He, W.-M. Metal-free
Deoxygenative 2-Amidation of Quinoline N-oxides with Nitriles
via a Radical Activation Pathway. Adv. Synth. Catal. 2018, 360,
4259–4264.
Thiocyanates
by
Iron-catalysed
Decarboxylative
Perfluoroalkylation. J. Fluor. Chem. 2017, 198, 89–93. (d)
Gryko, D. T.; Clausen, C.; Lindsey, J. S.; Thiol-Derivatized
Porphyrins for Attachment to Electroactive Surfaces. J. Org.
Chem. 1999, 64, 8635−8647. (e) Jart, A. Infrared Spectra of
Carboxylic Acid Derivatives. VI. Equivalent Weight
Determination. Quantitative Aspects of the Pressed Halide Disk
Technique. Acta Polytechnica Scandinavica: Chemistry
Including Metallurgy Series 1974, 121, 118.
14. For a study on a radical process mediated by Selectfluor, see:
Zhang, X.; Liao, Y.; Qian, R.; Wang, H.; Guo, Y. Investigation
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