A general and facile one-pot process of isothiocyanates from amines under aqueous conditions

Article abstract of DOI:10.3762/bjoc.8.6

A general and facile one-pot protocol for the preparation of a broad range of alkyl and aryl isothiocyanates has been developed from their corresponding primary amines under aqueous conditions. This synthetic process involves an in situ generation of a dithiocarbamate salt from the amine substrate by reacting with CS₂ followed by elimination to form the isothiocyanate product with cyanuric acid as the desulfurylation reagent. The choice of solvent is of decisive importance for the successful formation of the dithiocarbamate salt particularly for highly electron-deficient substrates. This novel and economical method is suitable for scale-up activities.

Full text of DOI:10.3762/bjoc.8.6

A general and facile one-pot process
of isothiocyanates from amines
under aqueous conditions
Nan Sun1, Bin Li1, Jianping Shao1, Weimin Mo*1, Baoxiang Hu1,
Zhenlu Shen1 and Xinquan Hu*1,2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 61–70.
1College of Chemical Engineering and Materials Science, Zhejiang
University of Technology, Hangzhou 310014, China and 2State Key
Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou
Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou 730000, China
doi:10.3762/bjoc.8.6
Received: 04 November 2011
Accepted: 18 December 2011
Published: 10 January 2012
Email:
Associate Editor: D. Y.-K. Chen
Weimin Mo* - mowm@zjut.edu.cn; Xinquan Hu* -
xinquan@zjut.edu.cn
© 2012 Sun et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
aqueous conditions; cyanuric acid; isothiocyanates; one-pot process;
organic synthesis; primary amines
Abstract
A general and facile one-pot protocol for the preparation of a broad range of alkyl and aryl isothiocyanates has been developed
from their corresponding primary amines under aqueous conditions. This synthetic process involves an in situ generation of a
dithiocarbamate salt from the amine substrate by reacting with CS2 followed by elimination to form the isothiocyanate product with
cyanuric acid as the desulfurylation reagent. The choice of solvent is of decisive importance for the successful formation of the
dithiocarbamate salt particularly for highly electron-deficient substrates. This novel and economical method is suitable for scale-up
activities.
Introduction
Isothiocyanates are a class of heteroallenic compounds which medical applications [3-6]. Morevoer, isothiocyanates are
are abundant in many cruciferous vegetables. Recently, it has pivotal intermediates in organic synthesis, especially in the syn-
been found that naturally occurring isothiocyanates play a thesis of various heterocyclic compounds [7,8] and unsym-
significant role in the cancer chemopreventive activity of these metric thioureas [9-12]. Although many synthetic methods for
plant species [1,2], and thus, many of such analogues containing the preparation of isothiocyanates have been reported to date
the isothiocyanate motif have been synthesized for potential [13-33], most methods suffer from the employment of highly
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Beilstein J. Org. Chem. 2012, 8, 61–70.
toxic reagents such as thiophosgene and its analogs, the avail-
ability of non-commercialized reagents, or from a narrow sub-
strate scope. Recently, a two-step approach, which was named
reagent-promoted desulfurylation of dithiocarbamates strategy,
has attracted much attention. In the context of this method, an
amine is typically converted into a corresponding dithiocarba-
mate by reacting with CS2 in the presence of a base; and a
subsequent desulfurylation affords the desired isothiocyanate
with proper desulfurylation reagent. Although many desul-
furylating reagents for this strategy were developed [34-59],
most of them were efficient only for alkyl and electron-rich aryl
isothiocyanates. Few efficient methods were reported for those
substrates with highly electron-withdrawing groups (such as,
CF3, CN, CH3CO or NO2). Therefore, the development of a
more efficient method for the synthesis of isothiocyanates –
particularly highly electron-deficient aryl isothiocyanates – is
still a challenge in organic chemistry.
Scheme 1: The proposed process for the formation of N-phenyl isoth-
iocyanate from aniline.
Results and Discussion
Previously, Furumoto reported the application of cyanuric chlo- Because inorganic bases were more efficient during the conver-
ride (2,4,6-trichloro-1,3,5-triazine, TCT) as a desulfurylation sion of arylamines to N-aryl dithiocarbamates in aqueous
reagent in the synthesis of carbodiimides from thioureas under systems [54-59], we chose inorganic bases to screen the optimal
mild conditions [60]. In that reaction, the S-nucleophiles first reaction conditions for the one-pot synthesis of 4. Following the
reacted with TCT and then decomposed to release the product literature procedure, N-phenyl dithiocarbamate was generated
carbodiimides and by-product 2,4,6-trimercapto-1,3,5-triazine by mixing aniline and 2.0 equiv of CS2 (based on aniline) in
(TMT) [61]. Considering that TCT is an efficient desulfuryla- water with 1.0 equiv of NaOH at room temperature. After the
tion reagent of thioureas to synthesize carbodiimides and that it complete disappearance of the aniline, the mixture was cooled
is affordable in large scale, we speculated that it could also be to 0 °C and a solution of TCT (0.5 equiv) in CH2Cl2 was added.
effective and practical in the desulfurylation of dithiocarba- Then the biphasic mixture was stirred for 0.5 h and basified by
mates to form isothiocyanates.
addition of 6 N NaOH to form a clear solution. A usual work-up
afforded the phenyl isothiocyanate in 61% isolated yield along
Our initial study started with aniline (1, Scheme 1) to prepare with a small amount of N,N’-diphenylthiourea (Table 1,
phenyl isothiocyanate (4, Scheme 1) via N-phenyl dithiocarba- entry 1). We proposed that the overall reaction proceeded as
mate (2-1, Scheme 1) followed by desulfurylation with TCT. described in Scheme 1.
Table 1: Reaction of aniline with CS2 in aqueous base solutionsa.
aniline/CS2/base
(equiv)
selectb (%)
2-1:2-2
TCTc
(equiv)
yieldd
(%)
entry
base
time (h)
convb (%)
1
2
3
4
5
6
7
NaOH
KOH
1:2:1
1:2:1
1:2:1
1:2:1
1:2:1
1:2:1
1:2:2
3
3
5
5
5
5
3
94
93
63:35
72:26
95:2
90:6
89:2
97:1
99:0
0.5
0.5
–
61
63
–
NH4OHe
Na2CO3
NaHCO3
K2CO3
K2CO3
70
86
–
–
57
–
–
86
–
–
>99
0.5
97
0.5
0.35
98
89
8
K2CO3
1:1.2:2
3
>99
99:0
aReaction conditions: 20 mmol of aniline was used in the reaction of the formation of N-phenyl dithiocarbamate at room temperature. The desulfuryla-
tion of in situ generated N-phenyl dithiocarbamate was carried out by dropwise addition of a solution of TCT in CH2Cl2 at 0 °C and then, the mixture
was stirred for another 0.5 h followed by basification to pH >11 with 6 N NaOH. bDetermined by HPLC. cThe amount of TCT was based on aniline.
dIsolated yield. e28% aqueous NH4OH was used.
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Beilstein J. Org. Chem. 2012, 8, 61–70.
The success observed in our preliminary study encouraged us to ammonium salt was almost insoluble and difficult to stir.
further optimize the conditions for better yields. Our immediate Although the isolation of intermediate 3 was not successful
effort was to enhance the selectivity of N-phenyl dithiocarba- (Scheme 1), the fact that the formation of the side product TMT
mate over 1,3-diphenylthiourea (2-2) at the first stage. Although was observed strongly indicated the presence of this interme-
the formation of N-phenyl dithiocarbamate by reaction of diacy.
aniline and CS2 in the presence of inorganic base under aqueous
conditions has already been reported, the conversion of aniline To further study the substrate scope of this newly developed
and the selection of N-phenyl dithiocarbamate have not been method, various amines were subjected to the treatment with
disclosed before. Thus, with the help of HPLC analysis, the CS2 in aqueous K2CO3 solution followed by desulfurylation
selectivity of N-phenyl dithiocarbamate (2-1 in Scheme 1) was with TCT under optimal conditions (1.2 equiv of CS2, 2.0 equiv
first studied by testing the base effect. The results of the selec- of K2CO3 at room temperature, and 0.5 equiv of TCT in
tivity of 2-1 with various bases are summarized in Table 1. As CH2Cl2 at 0 °C). The results are summarized in Table 2. As can
can be seen from Table 1, the conversion and the selectivity be seen from Table 2, all tested alkylamines and electron-rich
were influenced by the strength of the bases. When strong bases arylamines afforded their corresponding isothiocyanates in
– such as NaOH and KOH – were employed, a significant excellent yields (Table 2, entries 1–13). Compared to
amount of 1,3-diphenylthiourea (2-2) was formed; this resulted arylamines, alkylamines can generally be converted into their
in the low selectivity for N-phenyl dithiocarbamate (2-1) (Ta- corresponding dithiocarbamates in a relative short time. This
ble 1, entry 1 and 2) despite a high conversion observed for the rate difference could be originated from the different basicities
anilines. When weaker bases – such as NH4OH, Na2CO3 and and their differences in water solubility. Once the dithiocarba-
NaHCO3 – were used, the selectivity of N-phenyl dithiocarba- mate was generated, the desulfurylation step using TCT
mate was obviously improved but the conversion of aniline proceeded smoothly for all amines. The branched alkylamines,
decreased even at elongated reaction time (Table 1, entries 3–5). cyclic alkylamines and benzylamines showed similar activity as
A high selectivity for 2-1 (97:1) along with high conversion linear alkylamines (Table 2, entries 1–9). The relative low
(86%) was achieved (Table 1, entry 6) when K2CO3 was used. yields of isopropyl isothiocyanate and tert-butyl isothiocyanate
When the reaction was carried out with 2 equiv of K2CO3, a were ascribed to their volatility loss associated with isolation
complete conversion was observed. More importantly, the (Table 2, entries 1 and 3). The substituent pattern on the phenyl
selectivity of 2-1 over 2-2 was almost exclusive (Table 1, entry ring of arylamines exhibited no different activity. This also
7). Further studies indicated that only a slight excess of CS2 is illustrated the tolerance of some steric bulk in the synthesis of
needed for a high conversion (Table 1, entry 8).
isothiocyanate (Table 2, entries 11–13). Under similar reaction
conditions, we then tested some electron-deficient arylamines.
With an efficient method for the formation of 2-1 in hand, we The difficulty in the formation of their potassium salts of dithio-
then continued our research on the synthesis of phenyl isothio- carbamate was not surprising. The reaction required a slightly
cyanate by the desulfurylation of 2-1 with TCT. We found out higher temperature and a larger excess of CS2 to complete the
that the reaction between N-phenyl dithiocarbamate and TCT conversion of substrate amines. For example, 3 equiv of CS2
proceeded rather fast, even at a lower temperature (0 °C), and was needed for the conversion of 4-fluoroaniline at 40 °C in 12
0.5 equiv of TCT was proved to be necessary for a complete h during the first step. When N-(4-fluorophenyl)dithiocarba-
conversion of N-phenyl dithiocarbamate. It turned out that the mate was formed, 4-fluorophenyl isothiocyanate could be
decomposition of the adduct formed between N-phenyl dithio- smoothly obtained in reasonable yield after treatment with TCT.
carbamate and TCT to release phenyl isothiocyanate was However, under the same reaction conditions as 4-fluoroaniline,
incomplete under neutral to weak basic conditions. However, the reaction rate of 4-chloroaniline was much slower and a
when the reaction mixture was basified to pH >11 with 6 N longer reaction time was needed. Increasing the amount of CS2
NaOH, a complete decomposition of the adduct was observed. did not improve the conversion. Increasing the reaction
Moreover, under this conditions, the by-product TMT was temperature to 60 °C did improve the conversion of
easily soluble in water to form a clear solution and thus, con- 4-chloroaniline but generated a lot of impurities. With 3 equiv
venient to the layers separation during the workup. Under of CS2 at 40 °C for 20 h, about 80% conversion of 4-chloroani-
optimal conditions, an overall yield of phenyl isothiocyanate line with 92% selectivity of dithiocarbamate was observed.
from aniline was obtained up to 98% (Table 1, entry 8). It However, only 70% yield of 4-chlorophenyl isothiocyanate was
should be noted that choosing K2CO3 as the reaction base was obtained (Table 2, entry 15). The more electron-deficient aryl-
crucial. It was found out that only the potassium salt of N-phe- amines, such as 4-trifluoromethyl- and 4-cyanoaniline, failed to
nyl dithiocarbamate could form a clear aqueous solution, while convert into their corresponding isothiocyanates when the same
the corresponding sodium salt was much less soluble and the procedure as described for 4-chloroaniline was applied.
63

Beilstein J. Org. Chem. 2012, 8, 61–70.
Table 2: Preparation of isothiocyanatesa.
entry
1
substrate
product
timeb (h)
1
yieldc (%)
85
2
3
4
1
1
1
94
80
95
5
6
7
1
1
1
98
95
99
8
1
99
9
3
3
3
98 (94)
86
10
11
93
12
13
3
3
95
98
14
15
12
20
81d
70d
aReaction conditions: 20 mmol of amine substrate, 24 mmol of CS2, 40 mmol of K2CO3, room temperature. HPLC monitored the conversion. After the
amine was totally consumed, the mixture was cooled to 0 °C, and 10 mmol of TCT in CH2Cl2 was added dropwise. The mixture was stirred for
another 0.5 h and basified to pH >11 with 6 N NaOH. bThe reaction time for the first step. cIsolated yield. Data in the parenthesis is the isolated yield
in 1-mol scale. d3.0 equiv of CS2 was used and the reaction temperature was 40 °C.
Moreover, to evaluate the procedure for the potential scaling-up isothiocyanate could be conveniently isolated via vacuum distil-
capability, we used aniline as test substrate to scale up the syn- lation (Table 2, entry 9). This experiment demonstrated its
thesis in 1.0 mol scale. It became clear that the desired phenyl potential for a larger-scale application.
64

Beilstein J. Org. Chem. 2012, 8, 61–70.
The inefficiency observed for the highly electron-deficient which could smoothly afford high yield of their corresponding
arylamines drove us to further optimize the process. We specu- isothiocyanates by further treatment with TCT (Table 4, entries
lated that the inefficiency for those strongly electron-deficient 5–7). To our surprise, in the case of 4-nitroaniline as the sub-
arylamines could be ascribed to the difficulty in the generation strate, only 13% of 4-nitrophenyl isothiocyanate was obtained
of dithiocarbamates between amines and CS2 in aqueous along with up to 50% of 1,4-diisothiocyanatobenzene (Table 4,
K2CO3 solution. This prompted us to seek new reaction condi- entry 8). This probably resulted from the partial reduction of
tions. It was reported that C2H5OH was a beneficial solvent in 4-nitroaniline to 1,4-diaminobenzene by CS2 in aqueous K2CO3
the conversion of electron-deficient arylamines to their corres- solution.
ponding dithiocarbamates with concentrated NH4OH [54]. The
effect of C2H5OH in reaction media might facilitate the solu- Conclusion
bility of arylamines in water and thus, accelerate the reaction. In summary, we have successfully developed a facile and
Unfortunately, we found that CS2 would react with C2H5OH to general method to synthesize isothiocyanates from amines. In
form insoluble solid when it was charged into the reaction mix- the context of this method, the amines reacted with CS2 in
ture. This solid was separated and confirmed to be potassium aqueous K2CO3 solutions to afford dithiocarbamate intermedi-
ethylxanthate formed between CS2 and C2H5OH in aqueous ates, which were further desulfurylized with TCT at 0 °C to
basic solution [62]. On the other hand, much better results were provide the corresponding isothiocyanates. The newly devel-
observed when acetonitrile, DMF or DMAc was employed. For oped method could convert a wide range of primary alkyl and
example, with 4-chloroaniline as the substrate (Table 3), the arylamines into their corresponding isothiocyanates in excel-
results showed that the reaction rate of 4-chloroaniline with CS2 lent yields and provides promise for further scale-up activities.
in the aqueous K2CO3 solution was significantly improved with Morevover, this method is advantageous over many other
acetonitrile, DMF or DMAc, and best conversion was obtained methods for the synthesis of highly electron-deficient aromatic
with DMF as co-solvent (Table 3). The optimized result showed isothiocyanates.
that a solvent mixture of DMF/water (1:4) is suitable for elec-
Experimental
tron-deficient arylamines (Table 3, entry 5).
General
Under optimal conditions, various electron-deficient arylamines All solvents and reagents were purchased from commercial
were converted into the desired isothiocyanates in high yield sources and used without further purification. Melting points
and the results were listed in Table 4. With the help of DMF, were measured without correction. Proton NMR spectra were
more CS2 and longer reaction time, those strong electron-defi- recorded on a 500 MHz spectrometer in CDCl3 with tetram-
cient arylamines, for examples, CF3, CN, CH3CO-substituted ethylsilane (TMS) as internal standard. IR spectra were
arylamines, could be also converted into their dithiocarbamates, performed on a FTIR instrument. GC–MS analyses were
Table 3: Preparation of 4-chlorophenyl isothiocyanate in different solventsa.
entry
solvent (v/v)b
time (h)c
conversion (%)d
yield (%)e
1
2
3
4
5
6
H2O
20
20
6
56
80
91
98
98
90
50
64
86
91
92
80
CH3CN:H2O (1:2)
DMAc:H2O (1:2)
DMF:H2O (1:2)
DMF:H2O (1:4)
DMF:H2O (1:6)
6
6
10
aReaction conditions: 20 mmol of 4-chloroaniline was used in the reaction of the formation of N-(4-chlorophenyl)dithiocarbamate at 40 °C. The desul-
furylation of in situ generated N-(4-chlorophenyl)dithiocarbamate was carried out by dropwise addition of a solution of TCT in CH2Cl2 at 0 °C and then
the mixture was stirred another 0.5 h followed by basification to pH >11 with 6 N NaOH. DMAc = N,N-dimethyl acetamide. b20 mL of H2O used. cThe
reaction time for the conversion of 4-chloroaniline to potassium N-(4-chlorophenyl)dithiocarbamate. dDetermined by HPLC. eIsolated yield.
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Beilstein J. Org. Chem. 2012, 8, 61–70.
Table 4: Preparation of electron-deficient aryl isothiocyanatesa.
Entry
Substrate
Product
CS2 (equiv)
Time b (h)
Yield c (%)
1
2
1.2
2
3
6
94
92
3
4
2
2
6
6
90
89
5
6
7
5
5
5
7
89
86
10
10
91
13
50
8
10
72
aReaction conditions: The substrate (20 mmol) was treated with excess of CS2 and 2 equiv of K2CO3 in the mixture of 5 mL of DMF and 20 mL of
H2O at 40 °C. After the conversion of the substrate was complete, the mixture was cooled to 0 °C and 10 mmol of TCT in CH2Cl2 was added drop-
wise. The mixture was stirred for another 0.5 h and basified to pH >11 with 6 N NaOH. bThe reaction time for the conversion of amine to the corres-
ponding dithiocarbamate. cIsolated yield.
performed in EI mode. HPLC analyses were performed using a Typical procedure for the preparation of alkyl and
Atlantis ODS column (150 × 4.6 mm (i.d.), 3.5 μm) with a UV aryl isothiocyanates
detector (280 nm) at room temperature and mobile phase (60:40 To a mixture of amine (20 mmol) and K2CO3 (5.52 g, 40
CH3CN/5 mmol/L K2HPO4 water solution) with a flow rate of mmol) in 20 mL of water 1.82 g of CS2 (24 mmol) was added
0.8 mL/min. GC analyses were performed with a FID detector dropwise in a period of 20–30 min at room temperature. After
using a HP-5 capillary column (30 m × 0.25 mm (i.d.), 0.25 μm the addition was complete, the mixture was stirred for several
film thickness). The flow rate of carrier gas (N2) was 1.0 mL/ hours until complete conversion was determined by HPLC
min with a split ratio of 50:1. The column temperature was (arylamine) or GC (alkylamine). Then, the reaction mixture was
increased from an initial temperature of 100 to 280 °C at 10 °C/ cooled to 0 °C and a solution of 1.85 g of TCT (10 mmol) in 15
min and maintained at this temperature for 10 min. The FID mL of CH2Cl2 was added dropwise. After the addition was
detector temperature was kept at 280 °C. All operations were complete, the mixture was stirred for another 0.5 h to finish the
carried out under atmospheric conditions and all synthesized reaction. The reaction mixture was then basified to pH >11 with
isothiocyanates were stable under the operational conditions. 6 N NaOH to obtain a clear solution. The organic layer was sep-
66

Beilstein J. Org. Chem. 2012, 8, 61–70.
arated and the aqueous phase was extracted with CH2Cl2 (2 × 1H NMR (CDCl3) δ 7.20–7.35 (m, 5H); GC–EIMS m/z: 135
10 mL). The combined organic layers were dried over anhy- [M+, 100%].
drous Na2SO4, filtered and the solvent was removed in vacuo.
The residual was purified by flash chromatography through a 4-Methoxyphenyl isothiocyanate (CAS No: 2284-20-0,
short silica column using petroleum ether as eluent.
Table 2, entry 10): Yield: 86%; colorless oil; IR (neat): 2109
cm−1; 1H NMR (CDCl3) δ 3.81 (s, 3H), 6.84–7.18 (m, 4H);
Isopropyl isothiocyanate (CAS No: 2253-73-8, Table 2, GC–EIMS m/z: 165 [M+, 100%].
entry 1): Yield: 85%; colorless oil; IR (neat): 2079 cm−1;
1H NMR (CDCl3) δ 1.37 (d, J = 7.0 Hz, 6H), 3.88–3.95 (m, 4-Methylphenyl isothiocyanate (CAS No: 622-59-3, Table 2,
1H); GC–EIMS m/z: 101 [M+, 100%].
entry 11): Yield: 93%; colorless oil; IR (neat): 2100 cm−1;
1H NMR (CDCl3) δ 2.34 (s, 3H), 7.10–7.15 (m, 4H); GC–EIMS
n-Butyl isothiocyanate (CAS No: 592-82-5, Table 2, entry 2): m/z: 149 [M+, 100%].
Yield: 94%; colorless oil; IR (neat): 2099 cm−1; 1H NMR
(CDCl3) δ 0.94–0.97 (t, J = 7.0 Hz, 3H), 1.42–1.50 (m, 2H), 2-Methylphenyl isothiocyanate (CAS No: 614-69-7, Table 2,
1.66–1.72 (m, 2H), 3.53 (t, J = 6.5 Hz, 2H); GC–EIMS m/z: 115 entry 12): Yield: 95%; colorless oil; IR (neat): 2083 cm−1;
[M+, 100%].
1H NMR (CDCl3) δ 2.38 (s, 3H), 7.16–7.22 (m, 4H); GC–EIMS
m/z: 149 [M+, 100%].
tert-Butyl isothiocyanate (CAS No: 590-42-1, Table 2, entry
3): Yield: 80%; colorless oil; IR (neat): 2074 cm−1; 1H NMR 3-Methylphenyl isothiocyanate (CAS No: 621-30-7, Table 2,
(CDCl3) δ 1.44 (s, 9H); GC–EIMS m/z: 115 [M+, 100%].
entry 13): Yield: 98%; colorless oil; IR (neat): 2106 cm−1;
1H NMR (CDCl3) δ 2.34 (s, 3H), 7.02–7.24 (m, 4H); GC–EIMS
n-Octyl isothiocyanate (CAS No: 4430-45-9, Table 2, entry 4): m/z: 149 [M+, 100%].
Yield: 95%; colorless oil; IR (neat): 2102 cm−1; 1H NMR
(CDCl3) δ 0.89 (t, J = 7.0 Hz, 3H), 1.28–1.32 (m, 8H), Synthetic procedure for phenyl isothiocyanate in
1.39–1.42 (m, 2H), 1.67–1.72 (m, 2H), 3.51 (t, J = 7.0 Hz, 2H); 1-mol scale
GC–EIMS m/z: 171 [M+, 0%], 115 (100%).
Into a 2-L jacketed flask, 91.2 g of CS2 (1.2 mol) was dropwise
added to a mixture of aniline (93.0 g, 1.0 mol) and K2CO3
2-Ethyl-1-hexyl isothiocyanate (CAS No: 21663-56-9, (276.0 g, 2.0 mol) in 700 mL of water at room temperature
Table 2, entry 5): Yield: 98%; colorless oil; IR (neat): 2095 within a period of 2.5 h. After the addition was complete, the
cm−1; 1H NMR (CDCl3) δ 0.90–0.93 (m, 6H), 1.25–1.44 (m, mixture was stirred another 2 h. Then, the mixture was cooled
8H), 1.56–1.61 (m, 1H), 3.47–3.49 (m, 2H); GC–EIMS m/z: to 0 °C, and a solution of 92.3 g of TCT (0.5 mol) in 450 mL of
171 [M+, 4%], 57 (100%).
CH2Cl2 was dropwise added within 4 h. After the addition was
complete, the mixture was stirred another 1 h to complete the
Cyclohexyl isothiocyanate (CAS No: 1122-82-3, Table 2, conversion. The resulting mixture was basified to pH >11 with
entry 6): Yield: 95%; colorless oil; IR (neat): 2103 cm−1; 250 mL of 6 N NaOH and yielded a clear solution. The organic
1H NMR (CDCl3) δ 1.38–1.90 (m, 10H), 3.67–3.71 (m, 1H); layer was separated and the aqueous layer was extracted with
GC–EIMS m/z: 141 [M+, 90%], 55 (100%).
150 mL of CH2Cl2. The combined organic layers were dried
over anhydrous Na2SO4, filtered, and the solvent of filtrate was
Benzyl isothiocyanate (CAS No: 622-78-6, Table 2, entry 7): removed via distillation under atmospheric pressure with a
Yield: 99%; colorless oil; IR (neat): 2091 cm−1; 1H NMR 25-cm Vigreux column. The residue was vacuum distilled and
(CDCl3) δ 4.71 (s, 2H), 7.31–7.41 (m, 5H); GC–EIMS m/z: 149 the desired product fraction was collected at 72–74 °C/1 mmHg.
[M+, 30%], 91 (100%).
Finally, 127.0 g of colorless liquid (94%) was obtained.
1-Phenylethyl isothiocyanate (CAS No: 4478-92-6, Table 2, Typical procedure for the preparation of electron-
entry 8): Yield: 99%; colorless oil; IR (neat): 2090 cm−1; deficient aryl isothiocyanates
1H NMR (CDCl3) δ 1.67 (d, J = 6.5 Hz, 3H), 4.91 (q, J = 6.5 A certain amount of CS2 and arylamine (20 mmol) was added
Hz, 1H), 7.31–7.40 (m, 5H); GC–EIMS m/z: 163 [M+, 6%], 105 to a solution of K2CO3 (5.52 g, 40 mmol) in 20 mL of water
(100%).
and 5 mL of DMF. The mixture was warmed to 40 °C for
several hours to a constant conversion based on HPLC
Phenyl isothiocyanate (CAS No: 103-72-0, Table 2, entry 9): determination. The following operation was the same as the
Yield: 98%; colorless oil; IR (neat): 2079 cm−1; experimental procedure described above.
67

Beilstein J. Org. Chem. 2012, 8, 61–70.
4-Fluorophenyl isothiocyanate (CAS No: 1544-68-9, Table 4,
entry 1): Yield: 94%; colorless oil; IR (neat): 2079 cm−1;
1H NMR (CDCl3) δ 7.04–7.08 (m, 2H), 7.21–7.24 (m, 2H);
GC–EIMS m/z: 153 [M+, 100%].
Supporting Information
Supporting Information File 1
Proton NMR and GC–MS spectra.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-6-S1.pdf]
4-Chlorophenyl isothiocyanate (CAS No: 2131-55-7, Table 4,
entry 2): Yield: 92%; white solid; mp 45–46 °C (lit. [57]: mp
44–45 °C); IR (KBr): 2037 cm−1; 1H NMR (CDCl3) δ
7.15–7.18 (m, 2H), 7.31–7.33 (m, 2H); GC–EIMS m/z: 169
[M+, 100%], 171 [M + 2, 44%].
Acknowledgements
The authors gratefully acknowledge the financial support of the
National Natural Science Foundation of China (NSFC,
20772111, 20876149), the project of Science and Technology
Department of Zhejiang Province (2009C21013) and the
Natural Science Foundation of Zhejiang Province (Y407193).
Hu would like to thank Dr. Tony Y. Zhang and Prof. Wenjun
Tang for their helpful discussions and comments.
2-Chlorophenyl isothiocyanate (CAS No: 2740-81-0, Table 4,
entry 3): Yield: 90%; colorless oil; IR (neat): 2075 cm−1;
1H NMR (CDCl3) δ 7.19–7.25 (m, 3H), 7.41–7.43 (m, 1H);
GC–EIMS m/z: 169 [M+, 100%], 171 [M + 2, 37%].
3-Chlorophenyl isothiocyanate (CAS No: 2392-68-9, Table 4,
entry 4): Yield: 89%; colorless oil; IR (neat): 2097 cm−1;
1H NMR (CDCl3) δ 7.10–7.13 (m, 1H), 7.22–7.30 (m, 3H);
GC–EIMS m/z: 169 [M+, 100%], 171 [M + 2, 34%].
References
1. Fahey, J. W.; Zalcmann, A. T.; Talalay, P. Phytochemistry 2001, 56,
5–51. doi:10.1016/S0031-9422(00)00316-2
2. Nakamura, Y.; Miyoshi, N. Biosci., Biotechnol., Biochem. 2010, 74,
242–255. doi:10.1271/bbb.90731
4-Trifluoromethylphenyl isothiocyanate (CAS No: 1645-65-
4, Table 4, entry 5): Yield: 89%; White solid; mp 40–41 °C (lit.
[52]: mp 43 °C); IR (KBr): 2091 cm−1; 1H NMR (CDCl3) δ
7.31–7.34 (m, 2H), 7.62–7.63 (m, 2H); GC–EIMS m/z: 203
[M+, 100%].
3. Pedras, M. S. C.; Zheng, Q.-A.; Gadagi, R. S. Chem. Commun. 2007,
368–370. doi:10.1039/b615424g
4. Munday, R.; Zhang, Y.; Munday, C. M.; Bapardekar, M. V.;
Paonessa, J. D. Pharm. Res. 2008, 25, 2164–2170.
doi:10.1007/s11095-008-9595-2
5. Tian, X.; Huters, A. D.; Douglas, C. J.; Garg, N. K. Org. Lett. 2009, 11,
2349–2351. doi:10.1021/ol9007684
4-Acetophenyl isothiocyanate (CAS No: 2131-57-9, Table 4,
entry 6): Yield: 86%; white solid; mp 73–74 °C (lit. [63]: mp
75–76 °C); IR (KBr): 2125, 1680 cm−1; 1H NMR (CDCl3) δ
2.61 (s, 3H), 7.30–7.32 (m, 2H), 7.96–7.98 (m, 2H); GC–EIMS
m/z: 177 [M+, 70%], 162 (100%).
6. Adsule, S.; Banerjee, S.; Ahmed, F.; Padhye, S.; Sarkar, F. H.
Bioorg. Med. Chem. Lett. 2010, 20, 1247–1251.
doi:10.1016/j.bmcl.2009.11.128
7. Mukerjee, A. K.; Ashare, R. Chem. Rev. 1991, 91, 1–24.
doi:10.1021/cr00001a001
8. Sommen, G. Synlett 2004, 1323–1324. doi:10.1055/s-2004-825608
9. Li, J.; Tan, Z.; Tang, S.; Hewlett, I.; Pang, R.; He, M.; He, S.; Tian, B.;
Chen, K.; Yang, M. Bioorg. Med. Chem. 2009, 17, 3177–3188.
doi:10.1016/j.bmc.2009.02.051
4-Cyanophenyl isothiocyanate (CAS No: 2719-32-6, Table 4,
entry 7): Yield: 91%; white solid; mp 121–122 °C (lit. [63]: mp
119–120 °C); IR (KBr): 2138 cm−1; 1H NMR (CDCl3) δ
7.30–7.32 (m, 2H), 7.65–7.67 (m, 2H); GC–EIMS m/z: 160
[M+, 100%].
10.Kang, I.-J.; Wang, L.-W.; Yeh, T.-K.; Lee, C.-C.; Lee, Y.-C.; Hsu, S.-J.;
Wu, Y.-S.; Wang, J.-C.; Chao, Y.-S.; Yueh, A.; Chern, J.-H.
Bioorg. Med. Chem. 2010, 18, 6414–6421.
doi:10.1016/j.bmc.2010.07.002
11.Peng, H.; Liang, Y.; Chen, L.; Fu, L.; Wang, H.; He, H.
Bioorg. Med. Chem. Lett. 2011, 21, 1102–1104.
doi:10.1016/j.bmcl.2010.12.130
4-Nitrophenyl isothiocyanate (CAS No: 2131-61-5, Table 4,
entry 8): Yield: 13%; white solid; mp 107–108 °C (lit. [63]: mp
108–110 °C); IR (KBr): 2120 cm−1; 1H NMR (CDCl3) δ
7.36–7.38 (m, 2H), 8.26–8.27 (m, 2H); GC–EIMS m/z: 180
[M+, 100%].
12.Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–5743.
doi:10.1021/cr068373r
13.Toshimitsu, A.; Uemura, S.; Okano, M.; Watanabe, N. J. Org. Chem.
1983, 48, 5246–5251. doi:10.1021/jo00174a018
14.Albanese, D.; Penso, M. Synthesis 1991, 1001–1002.
doi:10.1055/s-1991-26629
1,4-Diisothiocyanatobenzene (CAS No: 4044-65-9, Table 4,
entry 8): Yield: 50%; white solid; mp 129–130 °C (lit. [64]: mp
132 °C); IR (KBr): 2072 cm−1; 1H NMR (CDCl3) δ 7.22 (s,
4H); GC–EIMS m/z: 192 [M+, 100%].
15.Shan, W. G.; Bian, G. F.; Su, W. K.; Liang, X. R. Org. Prep. Proced. Int.
2004, 36, 283–286. doi:10.1080/00304940409355967
16.Kim, J. N.; Ryu, E. K. Tetrahedron Lett. 1993, 34, 8283–8284.
doi:10.1016/S0040-4039(00)61411-9
68

Beilstein J. Org. Chem. 2012, 8, 61–70.
17.Kim, J. N.; Jung, K. S.; Lee, H. J.; Son, J. S. Tetrahedron Lett. 1997,
38, 1597–1598. doi:10.1016/S0040-4039(97)00121-4
18.Adam, W.; Bargon, R. M.; Bosio, S. G.; Schenk, W. A.; Stalke, D.
J. Org. Chem. 2002, 67, 7037–7041. doi:10.1021/jo026042i
19.Arisawa, M.; Ashikawa, M.; Suwa, A.; Yamaguchi, M. Tetrahedron Lett.
2005, 46, 1727–1729. doi:10.1016/j.tetlet.2005.01.069
20.Valette, L.; Poulain, S.; Fernandez, X.; Lizzani-Cuvelier, L.
J. Sulfur Chem. 2005, 26, 155–161. doi:10.1080/17415990500070144
21.Isoda, T.; Hayashi, K.; Tamai, S.; Kumagai, T.; Nagao, Y.
Chem. Pharm. Bull. 2006, 54, 1616–1619. doi:10.1248/cpb.54.1616
22.Zhong, B.; Al-Awar, R. S.; Shih, C.; Grimes, J. H., Jr.; Vieth, M.;
Hamdouchi, C. Tetrahedron Lett. 2006, 47, 2161–2164.
doi:10.1016/j.tetlet.2006.01.119
46.Wong, R.; Dolman, S. J. J. Org. Chem. 2007, 72, 3969–3971.
doi:10.1021/jo070246n
47.Bian, G.; Qiu, H.; Jiang, J.; Wu, J.; Lai, G.
Phosphorus, Sulfur Silicon Relat. Elem. 2007, 182, 503–508.
doi:10.1080/10426500600977379
48.Ghosh, H.; Yella, R.; Nath, J.; Patel, B. K. Eur. J. Org. Chem. 2008,
6189–6196. doi:10.1002/ejoc.200800901
49.Munch, H.; Hansen, J. S.; Pittelkow, M.; Christensen, J. B.; Boas, U.
Tetrahedron Lett. 2008, 49, 3117–3119.
doi:10.1016/j.tetlet.2008.03.045
50.Chaskar, A. C.; Bandgar, B. P.; Modhave, R. K.; Patil, A. B.; Yewale, S.
Synth. Commun. 2009, 39, 992–1001.
doi:10.1080/00397910802448481
23.Neely, W. J. Aust. J. Chem. 1960, 13, 341–346.
doi:10.1071/CH9600341
51.Nath, J.; Ghosh, H.; Yella, R.; Patel, B. K. Eur. J. Org. Chem. 2009,
1849–1851. doi:10.1002/ejoc.200801270
24.Bollini, M.; Casal, J. J.; Alvarez, D. E.; Boiani, L.; González, M.;
Cerecetto, H.; Bruno, A. M. Bioorg. Med. Chem. 2009, 17, 1437–1444.
doi:10.1016/j.bmc.2009.01.011
52.Jamir, L.; Ali, A. R.; Ghosh, H.; Chipem, F. A. S.; Patel, B. K.
Org. Biomol. Chem. 2010, 8, 1674–1678. doi:10.1039/b923336a
53.Yella, R.; Ghosh, H.; Murru, S.; Sahoo, S. K.; Patel, B. K.
Synth. Commun. 2010, 40, 2083–2096.
25.Dyer, E.; Johnson, T. B. J. Am. Chem. Soc. 1932, 54, 777–787.
doi:10.1021/ja01341a048
doi:10.1080/00397910903219476
26.Dyson, G. M.; Harrington, T. J. Chem. Soc. 1942, 374–375.
doi:10.1039/jr9420000374
54.Dains, F. B.; Brewster, R. G.; Olander, C. P. Organic Syntheses; John
Wiley & Sons: New York, NY, 1941; Vol. 1, p 447.
55.Moore, M. L.; Crossley, F. S. Organic Syntheses; John Wiley & Sons:
New York, NY, 1955; Vol. 3, p 599.
27.Jochims, J. C.; Seeliger, A. Tetrahedron 1965, 21, 2611–2616.
doi:10.1016/S0040-4020(01)93917-1
28.Gottfried, R. Angew. Chem., Int. Ed. Engl. 1966, 5, 963–964.
doi:10.1002/anie.196609632
56.Li, Z.; Qian, X.; Liu, Z.; Li, Z.; Song, G. Org. Prep. Proced. Int. 2000,
32, 571–573. doi:10.1080/00304940009355953
29.Larsen, C.; Steliou, K.; Harpp, D. N. J. Org. Chem. 1978, 43, 337–339.
doi:10.1021/jo00396a035
57.van der Kerk, G. J. M.; Pluygers, C. W.; de Vries, G. Organic
Syntheses; John Wiley & Sons: New York, NY, 1973; Vol. 5, p 223.
58.Heusenstamm, G. G.; Schreyer, G.; Vanheertum, R. U.S. Patent
4,089,887, May 16, 1978.
30.Larsen, C.; Harpp, D. N. J. Org. Chem. 1981, 46, 2465–2466.
doi:10.1021/jo00325a007
31.Kim, S.; Yi, K. Y. J. Org. Chem. 1986, 51, 2613–2615.
doi:10.1021/jo00363a046
59.Mesheram, H. M.; Dale, S.; Yadav, J. S. Tetrahedron Lett. 1997, 38,
8743–8744. doi:10.1016/S0040-4039(97)10158-7
60.Furumoto, S. Nippon Kagaku Zasshi 1971, 92, 1005–1007.
doi:10.1246/nikkashi1948.92.1005
32.Kim, S.; Yi, K. Y. Tetrahedron Lett. 1985, 26, 1661–1664.
doi:10.1016/S0040-4039(00)98578-2
33.Grayson, J. I. Org. Process Res. Dev. 1997, 1, 240–246.
doi:10.1021/op970002c
61.Henke, K. R.; Hutchison, A. R.; Krepps, M. K.; Parkin, S.; Atwood, D. A.
Inorg. Chem. 2001, 40, 4443–4447. doi:10.1021/ic0103188
62.Xiao, W.-J.; Alper, H. J. Org. Chem. 1999, 64, 9646–9652.
doi:10.1021/jo9913098
34.Hodgkins, J. E.; Ettlinger, M. G. J. Org. Chem. 1956, 21, 404–405.
doi:10.1021/jo01110a006
35.Hodgkins, J. E.; Reeves, W. P. J. Org. Chem. 1964, 29, 3098–3099.
doi:10.1021/jo01033a524
63.Sayigh, A. A. R.; Ulrich, H.; Potts, J. S. J. Org. Chem. 1965, 30,
2465–2466. doi:10.1021/jo01018a511
36.Shibanuma, T.; Shiono, M.; Mukaiyama, T. Chem. Lett. 1977, 6,
573–574. doi:10.1246/cl.1977.573
64.Lieber, E.; Slutkin, R. J. Org. Chem. 1962, 27, 2214–2217.
doi:10.1021/jo01053a509
37.Kondo, K.; Komamura, C.; Murakami, M.; Takemoto, K.
Synth. Commun. 1985, 15, 171–177. doi:10.1080/00397918508063784
38.Yamamoto, T.; Terada, A.; Muramatsu, T.; Ikeda, K.
Org. Prep. Proced. Int. 1994, 26, 555–557.
doi:10.1080/00304949409458055
39.Boas, U.; Jakobsen, M. H. J. Chem. Soc., Chem. Commun. 1995,
1995–1996. doi:10.1039/C39950001995
40.Boas, U.; Pedersen, B.; Christensen, J. B. Synth. Commun. 1998, 28,
1223–1231. doi:10.1080/00397919808005964
41.Boas, U.; Gertz, H.; Christensen, J. B.; Heegaard, P. M. H.
Tetrahedron Lett. 2004, 45, 269–272. doi:10.1016/j.tetlet.2003.10.182
42.Li, G.; Tajima, H.; Ohtani, T. J. Org. Chem. 1997, 62, 4539–4540.
doi:10.1021/jo970100w
43.Isobe, T. J. Org. Chem. 1999, 64, 6984–6988. doi:10.1021/jo990210y
44.Bian, G.; Shan, W.; Su, W. J. Chem. Res. 2005, 585–586.
doi:10.3184/030823405774308862
45.Chaskar, A. C.; Yewale, S.; Bhagat, R.; Langi, B. P. Synth. Commun.
2008, 38, 1972–1975. doi:10.1080/00397910801997744
69

Beilstein J. Org. Chem. 2012, 8, 61–70.
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