A novel synthesis of isothiocyanates from amines and phenyl isothiocyanate via replacement reaction

Article abstract of DOI:10.1007/s11696-021-01692-x

A new efficient method for the synthesis of isothiocyanates has been developed via the replacement reaction of phenyl isothiocyanate and the corresponding amines (the amino group of these amines was linked to tertiary carbon or secondary carbon) with dimethylbenzene as solvent. This reaction was carried out under the protection of nitrogen and mild condition. In addition, the yields of some products could be more than 90%. More importantly, this method has advantages with low toxicity, low cost, safety, less by-products and simple to operate. It has the potential to realize the industrial production of some complicated isothiocyanates.

Full text of DOI:10.1007/s11696-021-01692-x

Chemical Papers
https://doi.org/10.1007/s11696-021-01692-x
ORIGINAL PAPER
A novel synthesis of isothiocyanates from amines and phenyl
isothiocyanate via replacement reaction
Shou‑ji Zhu1 · Jin‑feng Li1
Received: 5 March 2021 / Accepted: 30 April 2021
© Institute of Chemistry, Slovak Academy of Sciences 2021
Abstract
A new efcient method for the synthesis of isothiocyanates has been developed via the replacement reaction of phenyl
isothiocyanate and the corresponding amines (the amino group of these amines was linked to tertiary carbon or secondary
carbon) with dimethylbenzene as solvent. This reaction was carried out under the protection of nitrogen and mild condition.
In addition, the yields of some products could be more than 90%. More importantly, this method has advantages with low
toxicity, low cost, safety, less by-products and simple to operate. It has the potential to realize the industrial production of
some complicated isothiocyanates.
Keywords Isothiocyanates · Phenyl isothiocyanate · Amines · Replacement reaction · One-pot synthesis
Introduction
lots of isothiocyanates cannot be obtained by this method.
In addition, carbon disulfde is volatile liquid and readily
explosive. The third method, the synthesis of isothiocyanates
is achieved through the reactions of phenyl chlorothiono-
formate with various primary amines (Fig. 3) (Zhang et al.
2000; Chen et al. 2011; Li et al. 2013). In our previous inves-
tigation, it was also found that isothiocyanate derivative of
p-menth-3-en-1-amine could be synthesized via this reac-
tion and the result had been published in Natural Product
Research (Zhu et al. 2021). However, the price of phenyl
chlorothionoformate is expensive and the production rate is
low. Although the previous methods are efcient, we were
eager to develop a synthetic method for isothiocyanates with
low toxicity, safety, low cost and high output rate.
Isothiocyanates are considered to be the most biologically
active degradation products of glucosinolates-secondary
metabolites of some plants, mainly from Brassicaceae fam-
ily (Pilipczuk et al. 2017; Fechner et al. 2018; Sarah et al.
2015). Meanwhile, isothiocyanates are a class of important
organic synthetic intermediates and are widely applied as
chemoselective electrophiles in bioconjugate chemistry due
to their tolerance toward aqueous reaction conditions (Yella
et al. 2010; Xiao et al. 2008; Márquez et al. 2008; Srisa
et al. 2019). Therefore, various methods have been devel-
oped to synthesize isothiocyanates. There are three common
methods for synthesis of isothiocyanates. The frst method,
isothiocyanates are prepared from amines and thiophosgene
(Fig. 1) (Li et al. 2015; Banert et al. 2001). However, thi-
ophosgene is an extremely poisonous and volatile liquid. Its
production, transportation and storage will not be secure.
The second method, isothiocyanates are synthesized from
the corresponding amines with carbon disulfde using di-
tert-butyl dicarbonate and DMAP or DABCO as catalyst
(Fig. 2) (Zhang et al. 2019; Sun et al. 2012). Nevertheless,
As we know that aromatic isothiocyanates can be easy to
react with amines to give corresponding thioureas (Murata
et al. 2018; Yildiz et al. 2017; Vagapova et al. 2015). How-
ever, in our investigation, it was found that thioureas could
be broken down into isothiocyanates and amine at high
temperatures. Based on the above points, thioureas were
designed to synthesize from a highly reactive isothiocy-
anate (phenyl isothiocyanate) and amines, then thioureas are
degraded to another isothiocyanate together with a less reac-
tive amine. For this method, there were many advantages,
such as inexpensive and commercially available material
(phenyl isothiocyanate), mild reaction conditions and high
security (normal pressure), simple work-up procedure and
good potential of industrial application.
* Shou-ji Zhu
zsj82633829@126.com
1
Guangdong Province, College of Chemical
and Environmental Engineering, Hanshan Normal
University, Chaozhou 521041, China
Vol.:(0123456789)
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Chemical Papers
boiling point was 137–140 °C) were added into a fask.
Then, the reaction mixture was heated to refux for 5 h
under the protection of nitrogen. After this, the solvent
was removed by vacuum rotatory evaporator. The crude
was purifed by column chromatography on silica gel to
aford the corresponding isothiocyanates. All of the prod-
uct yields had been reported in molar units.
Fig. 1 The synthesis of isothiocyanate from amines and thiophosgene
1-isopropyl-4-isothiocyanato-4-methylcyclohex-1-ene,
3a (a racemate), was recovered in 90.0% yield as a color-
less transparent liquid, b.p. : 245.6–247.3 °C. Purity,
1
99.2%. H NMR (DMSO-d6, 500 MHz), δH 5.34 (1H, t,
Fig. 2 The synthesis of isothiocyanate from the corresponding
amines with carbon disulfde
3-Ha), 2.30–2.35 (1H, m, 5-Ha), 2.17–2.27 (3H, m, 2-Ha,
5-He, 8-H), 2.05–2.09 (1H, m, 2-He), 1.95–2.00 (1H,
m, 6-Ha), 1.69–1.75 (1H, m, 6-He), 1.41 (3H, s, 7-H),
1.04 (6H, d, J = 7.5, 9-H, 10-H). 13C NMR (DMSO-d6,
125 MHz), δC 142.8 (4-C), 130.9 (1-N = C = S), 114.9
(3-C), 59.9 (1-C), 38.9 (6-C), 35.3 (2-C), 34.8 (8-C),
28.0 (7-C), 23.4 (5-C), 21.89 (10-C), 21.5 (9-C). FT-IR
(cm−1): 3060 (w, ν=C–H); 2961, 2931 (s, νC-H); 2095, 2067
(s, ν-N=C=S); 1661 (w, νC=C); 1381 (m, δC-H); 813 (m,
ν
-C=CH). GC–MS, m/z 195.1, 162.1, 136.1, 107.1, 81.1,
53.1. Elem. Anal. calcd. for C11H17NS: C, 67.64; H, 8.77;
N, 7.17; S,16.42. Found: C, 67.68; H, 8.80; N, 7.13; S,
16.39. Spectroscopic data are according to the literature
(Zhu et al. 2021).
Fig. 3 The synthesis of isothiocyanate from phenyl chlorothionofor-
mate with various primary amines
1-isothiocyanato-4-(2-isothiocyanatopropan-2-yl)-
1-methylcyclohexane, 3b (a new compound), was recovered
in 94.6% yield as a white solid, m.p. 85.7–86.2 °C. Purity,
Experimental
1
99.0%. H NMR (DMSO-d6, 500 MHz), δH 2.00 (2H, d,
Materials and instrumentation
J = 12.8 Hz, 3-Ha, 5-Ha), 1.80 (2H, d, J = 12.2 Hz, 2-Ha,
6-Ha), 1.53–1.60 (3H, m, 2-He, 4-H, 6-He), 1.42 (6H, s, 9-H,
10-H), 1.41 (3H, s, 7-H), 1.31–1.39 (2H, m, 3-He, 5-He).
13C NMR (DMSO-d6, 125 MHz), δC 130.8 (1-N=C=S),
130.0 (8-N=C=S), 64.7 (8-C), 62.0 (1-C), 46.2 (4-C), 38.2
(2-C, 6-C), 29.4 (7-C), 26.9 (9-C, 10-C), 23.4 (3-C, 5-C).
FT-IR (cm−1): 2978, 2937 (s, νC-H); 2127, 2095 (s, ν-N=C=S);
1386 (m, δC-H). GC–MS, m/z 254.1, 195.1, 137.2, 112.0,
81.1, 55.1. Elem. Anal. calcd. for C12H18N2S2: C, 56.65; H,
7.13; N, 11.01; S, 25.1. Found: C, 56.62; H, 7.17; N, 10.98;
S, 24.99.
All the chemicals were purchased from Shanghai Jingchun
Biochemical Technology Co., Ltd (Shanghai, China) and
were used without further purifcation. The NMR spec-
tra were recorded on a Bruker AV-500 (Bruker, Switzer-
land) spectrometer with TMS as the internal reference and
dimethylsulfoxide (DMSO-d6) as solvent. The IR spectra
were carried out on a Thermo Nicolte IS10 spectrometer
(Thermo, USA) connected to an OMNIC operating system.
GC analysis was carried out on an Agilent 6890 N/5973 N
spectrometer and used to confrm the purity of the com-
pounds. The ESI+-MS were recorded on a TSQ Quantum
Ultra AM mass spectrometer (Finnigan, USA). The ele-
ment analysis was carried out on a Vario EL cube (Ele-
mantar, Germany). Melting points were determined on a
WRS-1B digital melting point apparatus. Column chro-
matography was carried out on silica gel (200–300 mesh).
Isothiocyanatocyclohexane, 3c, was recovered in 53.6%
yield as a colorless transparent liquid, b.p. 217.7–218.8 °C.
1
Purity, 99.1%. H NMR (DMSO-d6, 500 MHz), δH 3.58
(1H, m, 1-H), 3.29 (s, H2O), 1.87–1.92 (2H, m, 2-Ha, 6-Ha),
1.59–1.64 (4H, m, 2-He, 3-Ha, 5-Ha, 6-He), 1.36–1.48
(4H, m, 3-He, 4-Ha, 4-He, 5-He). 13C NMR (DMSO-d6,
125 MHz), δC 129.11 (1-N=C=S), 55.5 (1-C), 33.0 (2-C,
6-C), 25.0 (3-C, 5-C), 23.2 (4-C). FT-IR (cm−1): 2936, 2857
(s, νC-H); 2178, 2102 (s, ν-N=C=S); 1361 (m, δC-H). GC–MS,
m/z 141.1, 113.0, 98.0, 83.1, 55.1. Elem. Anal. calcd. for
C7H11NS: C, 59.53; H, 7.85; N, 9.92; S, 22.70. Found: C,
59.56; H, 7.89; N, 9.88; S, 22.67. Spectroscopic data are
according to the literature (Li et al. 2015).
General reaction procedure
16 mmol amine (except for entry 2, 8 mmol), 16 mmol
phenyl isothiocyanate and 30 mL dimethylbenzene (the
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Chemical Papers
1-isothiocyanato-4-methylbenzene, 3d, was recov-
ered in 45.6% yield as a colorless transparent, liquid b.p.
aromatic isothiocyanates could not be obtained from the
reaction between the corresponding aromatic amines and
phenyl isothiocyanate, and the main product of the reaction
was thiourea. The reason we speculated is that the electron
of the group (N=C=S) of aromatic isothiocyanate could be
dispersed to the benzene, making the electrophilic ability
of the isothiocyanate stronger. As a result, the isothiocy-
anate was easier to react with nucleophilic reagent (amine)
and the direction of the reaction moved toward the inter-
mediate (thiourea). Based on the above consideration, we
planned to introduce an electron-donating group into aniline
as the reaction substrate. It was found that 1-isothiocyanato-
4-methoxybenzene and 1-isothiocyanato-4-trifuorometh-
oxybenzene could not be acquired from the reaction between
the corresponding amines and phenyl isothiocyanate due to
the fact that the steric hindrance of the groups (methoxy and
trifuoromethoxy) was not enough low (entries 8 and 9). To
our delight, 1-isothiocyanato-4-methylbenzene (compound
3d) could be obtained from the reaction between 4-Methyl-
aniline (introduction of a strong electron-donating group into
aniline, entry 4) and phenyl isothiocyanate in 45.6% yield.
4-Methylaniline had not been converted to other materials
except for compound 3d and the corresponding thiourea. The
thiourea could be degraded continuously to give the product
compound 3d.
1
235.7–236.9 °C. Purity, 99.1%. H NMR (DMSO-d6,
500 MHz), δH 7.28 (2H, d, J=8.5 Hz, 3-H, 5-H), 7.24 (2H,
d, J = 8.4 Hz, 2-H, 6-H), 2.33 (3H, s, 4-CH3). 13C NMR
(DMSO-d6, 125 MHz), δC 138.19 (4-C), 133.57 (1-N=C=S),
130.7 (3-C, 5-C), 127.8 (1-C), 126.1 (2-C, 6-C), 21.2
(4-CH3). FT-IR (cm−1): 3032 (w, ν=C-H); 2922, 2854 (m,
νC-H); 2175, 2092 (s, ν-N=C=S); 1607, 1578 (w, νC=C); 1503
(s, νC=C); 813 (m, ν-C–CH). GC–MS, m/z 149.0, 121.0, 91.1,
65.0. Elem. Anal. calcd. for C8H7NS: C, 64.39; H, 4.73; N,
9.39; S, 21.49. Found: C, 64.42; H, 4.77; N, 9.35; S, 21.47.
Spectroscopic data are according to the literature (Li et al.
2015).
Results and discussion
Phenyl isothiocyanate was a good electrophilic reagent due
to the fact that the electrons of the group (N=C=S) could
be spread over the benzene, and it was highly reactive with
various amines. Furthermore, it was very cheap comparing
with phenyl chlorothionoformate. So phenyl isothiocyanate
was selected as the reaction substrate in this investigation.
A competitive experiment in which 16 mmol phenyl iso-
thiocyanate was reacted with 16 mmol amine (except for
cis-1,8-p-menthane-diamine) was undertaken in our experi-
ment (Fig. 4). Dimethylbenzene or methylbenzene was used
as solvent and nitrogen was used to prevent oxidization of
the amine. The result is listed in Table 1. It was found that
most of the aliphatic amines were easy to react with phenyl
isothiocyanate to provide relevant aliphatic isothiocyanates
(53.6–94.6% yield) and aniline (entries 1–4). However, some
Conclusions
In conclusion, it was speculated that isothiocyanates could
be synthesized from phenyl isothiocyanate and various
amines (the amino group of these amines was linked to
tertiary carbon or secondary carbon) via replacement
Fig. 4 Proposed mechanism
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Chemical Papers
Table 1 The synthesis of isothiocyanates from amines and phenyl isothiocyanate via replacement reaction
Entry
1
1 (amine)
nisothiocyanate: namine
1:1
Product
Yield/%
90.0
2
2:1
94.6
3
4
1:1
1:1
53.6
45.6
5
1:1
No reaction
–
6
7
1:1
1:1
No reaction
No reaction
–
–
8
1:1
1:1
1:1
No reaction
No reaction
No reaction
–
–
–
9
10
CH3(CH2)5 N=C=S
Acknowledgements This work was supported by Science and Tech-
nology Project of Chaozhou (grant No. 2019ZC01), PhD Startup
Project of Hanshan Normal University (grant No. QD20181008), and
The Program of Basic Capability Improvement Project of Young and
Middle-aged Teachers in GuangXi Colleges and Universities (grant
No. 2018KY0697).
reaction. Although some aromatic isothiocyanates could
not be prepared through this reaction, the characteristics
(low toxicity, safety, low cost, less by-products and simple
to operate) of this method are still attractive for isothiocy-
anate preparation in many cases.
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Chemical Papers
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25:4549–4552. https://doi.org/10.1016/j.bmcl.2015.08.065
Srisa J, Tankam T, Sukwattanasinitt M, Wacharasindhu S (2019)
Micelle-enabled one-pot guanidine synthesis in water directly
from isothiocyanate using hypervalent iodine(III) reagents under
mild conditions. Chem Asian J 14:3335–3343. https://doi.org/10.
1002/asia.201900982
Declaration
Conflict of interest A patent fling on the practice of this reaction
[Faming Zhuanli Shenqing (2020), CN 111635345 A 20200908] has
been initiated by Shouji Zhu.
Sun N, Li B, Shao J, Mo W, Hu B, Shen Z, Hu X (2012) A general
and facile one-pot process of isothiocyanates from amines under
aqueous conditions. Beilstein J Org Chem 8:61–70. https://doi.
org/10.3762/bjoc.8.6
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