Thiocyanation of aromatic and heteroaromatic compounds with 1-Chloro-1,2-benziodoxol-3-(1H)-one and (Trimethylsilyl)isothiocyanate

Article abstract of DOI:10.1248/cpb.c19-00352

Thiocyanation of aromatic compounds has been investigated using the combination of 1-chloro-1,2-benziodoxol-3-(1H)-one (1) and (trimethylsilyl)isothiocyanate (TMSNCS). The reaction with electron rich aromatic compounds proceeded smoothly to provide the th

Full text of DOI:10.1248/cpb.c19-00352

Vol. 67, No. 9
Chem. Pharm. Bull. 67, 1015–1018 (2019)
1015
Note
Thiocyanation of Aromatic and Heteroaromatic Compounds with
1-Chloro-1,2-benziodoxol-3-(1H)-one and (Trimethylsilyl)isothiocyanate
Yuta Ito, Akihiro Touyama, Minako Uku, Hiromichi Egami,* and Yoshitaka Hamashima*
School of Pharmaceutical Sciences, University of Shizuoka; 52–1 Yada, Suruga-ku, Shizuoka 422–8526, Japan.
Received April 26, 2019; accepted June 7, 2019
Thiocyanation of aromatic compounds has been investigated using the combination of 1-chloro-1,2-
benziodoxol-3-(1H)-one (1) and (trimethylsilyl)isothiocyanate (TMSNCS). The reaction with electron rich
aromatic compounds proceeded smoothly to provide the thiocyanated products in high yield, while electron
deficient heteroaromatic compounds were not suitable for this reaction. In these reactions, the regioselectiv-
ity was generally high. Transformations of the products were also investigated to demonstrate the utility of
the reaction. Based on NMR experiments, we propose that thiocyanogen chloride is generated in situ as an
active species.
Key words thiocyanation; thiocyanogen chloride; aromatic electrophilic substitution; hypervalent iodine
Table 1. Screening of the Reaction Conditionsa)
Aromatic compounds having a thiocyanate unit have been
used as a substructure of bioactive molecules and building
blocks in organic synthesis.1) For example, phenols, anilides
and heteroaromatic compounds with a thiocyanate group are
known to show herbicidal acitivity,2) hypolipidemic activity,3)
anti-cancer activity,4) antifungal activity,5) and antimicrobial
activity.6,7) Aryl thiocyanate unit can be not only transformed
to sulfide,8–10) disulfide,11) tetrazole,12) and thiocarbamate13,14)
but also act as cyanate and/or thiolate sources in cross cou-
pling reactions and difunctionalization of alkyne deriva-
tives.15–20) In this context, several efficient methodologies for
thiocyanation of aromatic compounds have been reported.
The major strategy for the purpose is to use the combination
of oxidant and inorganic thiocyanate salts, in which either the
generation of electrophilic thiocyanium ion equivalent or oxi-
dation of aromatic compounds is the key step.1,21–46)
During the course of our reaction development with hy-
pervalent iodine reagents,47–51) we recently reported several
difunctionalizations of alkenes using 1-chloro-1,2-benziodox-
ol-3-(1H)-one (1).52) Among them, the chlorothiocyanation
of alkenes was achieved, in which thiocyanogen chloride
(Cl–SCN) was proposed as an active species52) (Chart 1a). Al-
though Cl–SCN is considered to be a highly reactive thiocya-
nation reagent, there have been only a few reports regarding
Entry
SCN source
Solvent
Yield of 3 [%]b)
1
2
TMSNCS
TMSNCS
TMSNCS
TMSNCS
KSCN
CH2Cl2
Acetone
MeCN
MeOH
CH2Cl2
Acetone
MeCN
MeOH
CH2Cl2
Acetone
MeCN
MeOH
92
33
36
6
3
4
5
n.r.
4
6
KSCN
7
KSCN
6
8
KSCN
52
64
41
44
48
9
NH4SCN
NH4SCN
NH4SCN
NH4SCN
10
11
12
a) The reactions were carried out with
1
(1equiv.) and thiocyanate source
(1equiv.) on a 0.2mmol scale at room temperature for 1h. b) Isolated yield.
Chart 1. Thiocyanation Using 1 and TMSNCS
Fig. 1. 13C-NMR Analyses
*To whom correspondence should be addressed. e-mail: hegami@u-shizuoka-ken.ac.jp; hamashima@u-shizuoka-ken.ac.jp
© 2019 The Pharmaceutical Society of Japan

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Chem. Pharm. Bull.
Vol. 67, No. 9 (2019)
Table 2. Thiocyanation of Various Aromatic and Heteroaromatic Com-
poundsa)
use of lead compounds should be avoided due to their toxicity.
Therefore, we envisioned that our previous method would be
an alternative protocol for the reaction with Cl–SCN. In this
report, the thiocyanation of aromatic and heteroaromatic com-
pounds using 1 and (trimethylsilyl)isothiocyanate (TMSNCS)
is disclosed (Chart 1b).
Initially, the reaction conditions were screened with phenol
2a as a test substrate (Table 1). To our delight, TMSNCS was
found to be a good thiocyanate source. The reaction in CH2Cl2
occurred at the para-position to give the corresponding prod-
uct 3a in 92% yield (entry 1). In contrast, low yields were
observed in polar solvents (entries 2–4). Potassium thiocya-
nate could work only in MeOH, albeit in modest yield (entries
5–8). Irrespective of the solvents, thiocyanation product 3a
was obtained in modest yields when the reaction was carried
out with ammonium thiocyanate (NH4SCN) (entries 9–12).
These results suggest that the solubility of the thiocyanate
source is important for this thiocyanation.
We next tried to confirm the in-situ generated reactive
species under the reaction conditions. As seen in our previ-
ous report,52) 1H-NMR measurements suggested that Cl–SCN
would be generated, because the formation of trimethyl-
silyl 2-iodobenzoate was observed upon treatment of 1 with
1equiv. of TMSNCS. In order to obtain more direct evidence,
13C-NMR analysis was carried out56) (Fig. 1). When 1 was
reacted with TMSNCS, the peak of TMSNCS disappeared
and new peaks were observed at 109.1ppm (Fig. 1b). The peak
of 109.1ppm was clearly different from thiocyanogen (NCS–
SCN, 106.8ppm), which was prepared according to the litera-
1
ture.26,55) Coupled with the previous H-NMR analysis,52) these
results strongly indicate that the peak of 109.1ppm comes
from the nitrile carbon of Cl–SCN. After addition of phenol to
the mixture, the peak of 109.1ppm disapperared,56) suggesting
Cl–SCN was an active species.
Having established the optimized reaction conditions, the
substrate scope was examined (Table 2). Other poly-substitut-
ed phenols were good substrates for this reaction and excel-
lent yields were obtained with high para-selectivity (3b–3f).
When para-position was substituted by an alkyl group, other
positions were thiocyanated. For example, the reaction of
4-tert-butylphenol afforded ortho-thiocyanated product 3g
in 69% yield. Interestingly, 3g was relatively unstable even
after purification and was gradually converted to cyclized
product 3g′.57) Anisole 2h was found to be a good substrate,
suggesting that the hydroxyl group is not essential for this
reaction. Subsequently, the thiocyanation of aniline deriva-
tives was investigated under the same reaction conditions. As
expected, not only anilines but also anilides underwent the
reaction smoothly (5a–5d). However, the yield of 5e was only
7%, probably because of the reduced nucleophilicity of 4e.
Electron-rich heteroaromatic compounds were also available.
Indole gave 3-thiocyanato-1H-indole 7a in 73% yield. The
reaction of 2-substituted pyrrole 6b provided 4-thiocyanated
product 7b in 61% yield selectively. In contrast to electron-
rich aromatic rings, electron-poor aromatic compounds such
a) The reactions were carried out with 1 (1equiv.) and TMSNCS (1equiv.) in
CH2Cl2 for 1h on a 0.2mmol scale.
thiocyanation of aromatic compounds with Cl–SCN.53,54) This as quinoline were not reactive at all. Tyrosine derivative 8 was
is probably because its preparation is technically unfavor- also thiocyanated under the standard conditions. As expected,
able. In general, Cl–SCN can be prepared by using dangerous ortho-substitution of the phenol moiety occurred selectively
chlorine gas (Cl2). Another example employed iodobenzene as in the case of 3g, and the product 9 gradually underwent
dichloride (Ph–ICl2) and lead(II) thiocyanate (Pb(SCN)2).54,55) intramolecular cyclization to 9′.57)
Although the reagent is generated under mild conditions, the
To confirm the utility of this protocol, further transforma-

Vol. 67, No. 9 (2019)
Chem. Pharm. Bull.
1017
Chart 2. One-Pot Transformations via Thiocyanation
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