Copper promoted desulfurization towards the synthesis of isothiocyanates

Article abstract of DOI:10.1016/j.tetlet.2016.11.086

The cheap, readily available and air stable catalyst was used as the desulfurization agent for the conversion of aniline to isothiocyanates in one pot two step reaction under mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2016.11.086

Accepted Manuscript
Copper promoted desulphurization towards the synthesis of isothiocyanates.
UshaRani Mandapati, Srinivasarao Pinapati, RameshRaju Rudraraju
PII:
S0040-4039(16)31567-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.086
TETL 48372
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 September 2016
18 November 2016
19 November 2016
Please cite this article as: Mandapati, U., Pinapati, S., Rudraraju, R., Copper promoted desulphurization towards
the synthesis of isothiocyanates., Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.11.086
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
The cheap, readily available and air stable copper
catalyst was used for the conversion of aniline to
isothiocyanates. Conversion of aniline to
isothiocyanates in one pot two step reaction under
mild reaction conditions.
Copper promoted desulphurization towards
the synthesis of isothiocyanates
UshaRani Mandapati, Srinivasa rao pinapati and Dr.RameshRaju Rudraraju*
Department of chemistry, Acharya Nagarjuna University,Nagarjuna Nagar,Guntur, AP-522510, India.
NH2
NCS
R
1. CS2 (10 eq), Et3N (1 eq), EtOAc/H2O (2:1), rt, 1 h
2. CuSO4.5H2O (50 mol %), Et3N (1 eq), rt, 2 h
(or)
1. CS2 (10 eq), Et3N (1 eq), EtOH/H2O (2:1), rt, 1 h
2. CuSO4.5H2O (50 mol %), Et3N (1 eq), rt, 2 h
R
R = EDG, EWG
Aliphatic aniline
14 examples
Yield 40-98%
EDG-Electron Donating Group
EWG-Electron Withdrawing Group

1
Tetrahedron Letters
Copper promoted desulphurization towards the synthesis of isothiocyanates.
UshaRani Mandapati, Srinivasarao Pinapati and Dr. RameshRaju Rudraraju*
Department of Chemistry, Acharya Nagarjuna University, Nagar,Guntur, AP-522510, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The cheap, readily available and air stable catalyst was used as the desulphurization agent for the
conversion of aniline to isothiocyanates in one pot two step reaction under mild reaction
conditions.
Available online
Keywords:
Copper catalyst
Desulfurization
Isothiocyanates
Room temperature
Substituted anilines
One pot synthesis
1. Introduction
methodology for the preparation of isothiocyanates. In this paper
we report the synthesis of isothiocyanates using cheap and readi-
ly available copper catalyst.
Isothiocyanates is ubiquitary structural functional class in
many biological and pharmaceutical active compounds and it has
been used as versatile important synthetic intermediates for the
synthesis of many natural products and hetero cycles, such as
The optimization of the reaction conditions was carried out with
aniline as model substrate using different bases, solvents and
copper sources at varied temperatures (Table 1). The best result
was obtained when the reaction was pursued at room temperature
using 50 mol % of the copper compounds such as CuI, CuBr,
CuCl, Cu2O, CuSO4∙5H2O, Cu(NO3)2∙3H2O and Cu(OAc)2∙H2O
in the presence of Et3N in Ethylacetate affording the
phenylisothiocyanate in 98% conversion (Scheme 1). Firstly, the
reaction was checked in the presence of different solvents. In
case of polar solvent ethyl acetate could give target product in
quantatative yield (Table 1, entry 2). Other polar solvents like
ethanol, MeOH, DCM and DMF gave final product in high yield.
Unfortunately the greenary solvent H2O couldn’t give target
product. Later we have checked with the non-polar solvents like
n-Hexane and n-Heptane and we could find no target product.
Very interestingly, no recation was occurred in the absence of
solvent. Finally the reaction was checked in the presence of ho-
mogeneous (Ethanol and water) and heterogeneous (Ethyl acetate
and water) solvents. The homogeneous solvent mixtures (Etha-
nol:H2O (1:1 and 2:1)) could give target product in high yield
(Table 1, entries 10 and 12) and another homogeneous mixture
(Ethanol: H2O (1:2)) couldn’t give target product (Table 1, entry
11). The heterogeneous solvent mixtures (Ethyl acetate: H2O (1:1
and 1:2)) didn’t give target product (Table 1, entries 13 and 14).
thiohydantoins,
thiopyrimidones,
thioqui-nazolones,
mercaptoimidizoles, thio-amidazolones, pyridinethiones, pyrroli-
dine and benzothiazine.1 Furthermore, isothiocyanates can be
used as chemoselective electrophiles in bioconugate chemistry.2
Therefore, various methods have been developed for the synthe-
sis of isothiocyanates from amines, in which thiophosagene was
mostly well known.3 Due to the high toxicity of thiophosgene, it
was replaced by other “thiocarbonayl transfer” reagents, such as
thiocarbonylditriazole,
(trichlorome-thyl) carbonate, trichloro methylformats, di-2-
thiocarbonyldiimidazole,
bis-
pyridyl
thionocarbonate
and
bis-(trichloromethyl)
pentathiocarbonate.4 However, most of them are not readily
available and often do not work as desired due to the formation
of thiourea as a side product.
On the other hand, isothiocyanates can also be synthesized by
the desulfurization of dithiocarbomates, which is formed from
the reaction between amine and carbondisulphide in the presence
of base, with diverse reagents, including uranium and
phosphonium-based
peptide
coupling
reagents,5
triphenylphosphine dibromide,6 tosyl chloride,7 dialkyl
dicarbonates,8 hydrogen peroxide,9 Iodine,10 (Diacetocyiodo)
benzene and other harsh reagents,11 and other mild methods are
known.12 The reported methods are really efficient enough, but
most of them possess drawbacks such as rigorous or hazardous
conditions, intractable side reactions, evolved toxic gases (carbon
monoxide), using expensive reagents and longer reaction time.
Thus, there is still need for a commercially available and simple
Scheme 1
NH2
NCS
I. CS2 (10 eq), Et3N (1 eq), EtOAc/H2O (2:1), rt, 1 h
II. CuSO4.5H2O (50 mol %), Et3N (1 eq), rt, 2 h

2
Tetrahedron
Since CuSO4.5H2O is cheaper than other copper sources, it is
Table 1: Solvent optimization
used for examples table 4 and 5. The reactions with other organic
base pyridine and inorganic bases sodiumbicarbonate, sodium
acetate and sodium phosphate showed similar effect like Et3N
(Table 3). Similarly, lowering of the reaction temperature (10
°C) or base (1 equiv) led to the formation of a target product in
fewer yields. The control experiment confirmed that in the ab-
sence of the copper source (table 3, entry 10) and base (Table 2,
entry 6) no reaction was occurred. We have also tried the reaction
with 25 mol% and 10 mol% catalyst and they gave target product
in 65% and 20% yield, respectively (Table 3, entries 8-9).
Entry
Solvent
Yield (%)
1
Ethanol
85
Table 3: Catalyst Standardization
2
Ethyl acetate
DCM
98
NH2
NCS
3
85
CS2 (10 eq), Et3N (2 eq)
4
MeOH
85
Catalyst (50 mol %)
5
DMF
80
EtOAc/H2O (2:1), room temp, 3 h
(2 mmol)
Entry
6
H2O
NR
NR
NR
NR
90
Catalyst
Yield (%)a
>98
7
n-Hexane
8
n-Heptane
CuSO4.5H2O
9
Solvent free
EtOH/H2O (1:1)
EtOH/H2O (1:2)
EtOH/H2O (2:1)
EtOAc/H2O (1:1)
EtOAc/H2O (1:2)
EtOAc/H2O (2:1)
Acetone
1
2
10
11
12
13
14
15
16
>98
Cu(NO3)2.3H2O
NR
90
3
4
>98
>98
Cu(OAc)2.H2O
CuI
NR
NR
98
CuBr
>98
>98
5
6
95
aReaction conditions: Anline (2 mmol), CS2 (10 eq), Et3N (2
eq), CuSO4.5H2O (50 mol%) were stirred at room temperature in
the presence of respective solvent for 3 h.. NR=No reaction.
CuCl
Cu2O
7
>98
65
Table 2: Base optimization
8b
CuSO4.5H2O
CuSO4.5H2O
-
NH2
9c
20
NCS
CS2 (10 eq), base (2 eq)
CuSO4.5H2O (50 mol %)
10
NR
EtOAc/H2O (2:1), room temp, 3 h
(2 mmol)
a Reaction conditions: Aniline (2 mmol), CS2 (10 eq), Et3N (2
eq), catalyst (50 mol %) were stirred at room temperature in the
presence of respective solvent for 3 h. NR = No reaction.
bCatalyst (25 mol%) was used. cCatalyst (10 mol%) was used.
Entry
1
Base
Yield (%)a
>98
Et3N
Having the optimal conditions in hand, we explored the scope
of this procedure for the substrates having electron donating and
electron withdrawing substituents on the aryl rings. As we shown
in above solvent standardization table, EtoAC/H2O (2:1) could
give the target product in quantitative yield. Therefore, the vari-
ous substrates bearing electron donating and electron withdraw-
ing was done under the below shown reaction conditions (Table
4). The phenyl ring having electron donating groups such as 4-
methyl, 4-methoxy could give their respective aromatic
isothiocyanates (Table 4, entries 3,4) in high yield. The
unsubstited phenyl ring also gave target product in quantitative
yield (table 4, entry 1). Electron withdrawing groups such as 4-
fluoro and 4-chloro substituents gave their final products in 81-
93% yields (Table 4, entries 2 and 7). The aryl ring having strong
electron withdrawing group –NO2 on second position gave their
final product in moderate yield (table 4, entry 6). Aryl ring bear-
ing other strong electron withdrawing substituent’s nitrile and
ester could give their respective target products in 40% yield
Pyridine
NaOAc
Na3PO4
>98
>98
>98
>98
NR
2
3
4
5
6
NaHCO3
-
aReaction conditions: Anline (2 mmol), CS2 (10 eq), Base (2
eq), CuSO4.5H2O (50 mol%) were stirred at room temperature in
the presence of respective solvent for 3 h.
on the other hand, another heterogeneous reaction mixture ratio
(EA:H2O (2:1)) could give target product in quantitative yield
(Table 1, entry 15). Both copper (I) and copper (II) sources
showed similar effect to affording the target product (Table 2).

3
Table 4: Substrate scope
Table5: Substrate scope
NH2
NCS
phatic isothiocyanates such as n-butyl, cyclohexyl and benzyl
groups from their respective anilines.
CS2 (10 eq), Et3N (2 eq)
CuSO4.5H2O (50 mol %)
EtOAc/H2O (2:1)
room temp, 3 h
(2 mmol)
NH2
NCS
CS2 (10 eq), Et3N (2 eq)
CuSO4.5H2O (50 mol %)
Entry
Substrate
NH2
Product
NCS
Isolated yield (%)a
EtOH/H2O (2:1)
room temp, 3 h
(2 mmol)
1
98
Entry
Substrate
NH2
Product
NCS
Isolated yield (%)a
NH2
NCS
2
3
4
93
97
98
Cl
Cl
1
90
NH2
NH2
NCS
NCS
NH2
MeO
Me
NCS
MeO
Me
2
83
Cl
Cl
NH2
NH2
NCS
NCS
NH2
NH2
NCS
NCS
3
4
87
86
Me
Me
MeO
Me
MeO
Me
5
87
NH2
NH2
NCS
NCS
NO2
NH2
NO2
6
7
78
81
Me
Me
5
82
NCS
F
F
NO2
NH2
NO2
6
7
72
78
NH2
NCS
Me
Me
8
9
84
92
NCS
F
Me
F
Me
NH2
NCS
NH2
NCS
Me
Me
8
9
80
85
NH2
NCS
10
11
89
90
Me
Me
NH2
NCS
NH2
NCS
NH2
NCS
NH2
NCS
10
11
85
83
93
12
Me
Me
NCS
NH2
NCS
aReaction conditions: Substrate (2 mmol), CS2 (10 eq), Et3N
(2 eq), CuSO4.5H2O (50 mol%) were stirred at room temperature
in the presence of respective solvent for 3 h.
NH2
13
14
40
40
NC
NC
NH2
NCS
The mechanism of formation for phenyl isothiocyante from
anilines is shown in above scheme 2. The experimental evidence
and from the literature reports the mechanism is proposed. As we
shown in below figure Aniline reacts with carbon disulphide us-
ing triethyl amine as base and in the presence of solvent to give
thiocarbomate salt B. It may help to reduce the Copper (II) salt to
Copper (I) active species, which may co-ordinate with
thiocarbomate salt B13 and followed by the removal of proton to
afford the intermediate D via another intermediate C. The inter-
mediate D may give the target product along with byproduct
copper sulfide, which was confirmed by powder XRD analysis
(Figure 1)14 and poly sulfide (the extra sulfur might have con-
verted into sulfide) via intermediate E.
MeOOC
MeOOC
aReaction conditions: Substrate (2 mmol), CS2 (10 eq), Et3N
(2 eq), CuSO4.5H2O (50 mol %) were stirred at room temperature
in the presence of respective EtOAc/H2O (2:1) for 3 h.
(Table 4, entries 13-14). Disubstituted and 2- substituted aryl
rings could give their respective isothiocyanates in good yield
(Table 4, entries 5 and 8). Finally we have also studied about
aliphatic anilines. The aliphatic substrates readily underwent the
reaction to produce the target products in high yields (Table 4,
entries 9-11). To explore the substrate scope we have also tried
the reaction with m-toluidine. It gave respective target product in
93% yield (Table 4, entry 12).
In conclusion, the reactions were neat, clean and efficient.
During the reaction process we couldn’t observe any other by-
products. The reactions are rapid and facile and accomplished at
room temperature. All the substrates could obtain their target
products in good to excellent yields.
The substrate scope was also developed using another optimal
reaction EtOH/H2O (2:1) (Table 5). As we shown in Table 5,
both electron donating and electron with drawing substituents on
aryl ring could give their target products in 72-90% yields. Fol-
lowing similar methodology, we have successfully obtained ali-

4
Tetrahedron
NH2
9.
Li, G.; Tajima, H.; Ohtani, T. J. Org. Chem. 1997, 62, 4539-4540.
S
S
C
10. Nath, J.; Jamir, L.; Patel, B. K. Green Chemistry Letters and Re-
views 2011, 4, 1-34.
NCS
H
N
Et3N
11. Ghosh, H.; Yella, R.; Nath, J.; Patel, B.K. Eur. J. Org. Chem.
2008, 6189-6196.
N
S
NHEt3
S
NHEt3
H
S
S
N
S
NHEt3
12. (a)Yella, R.; Ghosh, H.; Murru, S.; Sahoo, S. K.; Patel, B. K.
Synth Comm 2010, 40, 2083. (b) Ghosh, H.; Yell, R.; Ali, A. R.;
Sahoo, S. K.; Patel, B. K. Tetrahedron Lett. 2009, 50, 2407. (c)
Ali, A. R.; Ghosh, H.; Patel, B. K. Tetrahedron Lett. 2010, 8,
1674. (d) Zhang, Z.; Wu, H. H.; Ya-Jun Tan, Y. J. RSC Adv
2013, 3, 16940. (e) Zhu, J.; Han, L.; Diao, Y.; Ren, X.; Xu, M.;
Xu, L.; Li, S.; Li, Q.; Dong, D.; Huang, J.; Liu, X.; Zhao,
Z.; Wang, R.; Zhu, L.; Xu, Y.; Qian, X.; Li, H. J. Med. Chem.
2015, 58, 1123. (f) Wong, R.; Dolman, S. J. J. Org. Chem 2007,
72, 3969. (g) Chen, Y.; Su, L.; Yang, X.; Pan, W.; Fang, H. Tetra-
hedron 2015, 71, 9234.
Cu
Cu
E
D
[CuS]
S
+e
CuI
CuII
B
H
N
S
NHEt3
S
Cu
C
13. For the reduction of copper(II) salts to copper(I) species, see:
Bowmaker, G. A.; Hanna, J. V.; Pakawatchai, C.; Skelton, B. W.;
Thanyasirikul, Y.; White, A. H. Inorg. Chem. 2009, 48, 350–368.
(b) Ramana, T.; Saha, P.; Das, M.; Punniyamurthy, T. Org. Lett.
2010, 12, 84.
Scheme 2: proposed mechanism
14. (a) Batey, R. A.; Powell, D. A. Org. Lett. 2000, 2, 3237. (b)
Ramana. T.; Punniyamurthy, T. Chem. Eur. J. 2012, 18, 13279.
Figure 1: Powder XRD plot of isolated CuS
Acknowledgements
The authors thankful to Department of Chemistry, Acharya
Nagarjuna University, Nagarjuna Nagar, Guntur for providing
work space and thanks to UGC-BSR for providing research fel-
lowship and the authors are grateful to Icon Pharmaceutical Lab
for providing instrumental support.
References and notes
1.
2.
(a) Mukerjee, A.K.; Ashare, R. Chem. Rev. 1991, 91, 1-24. (b)
Stephensen, H.; Zaragosa, F. J. Org. Chem. 1997, 62, 6096–6097.
(a) Fernandez, J.M.G.; Mellet, C.O.; Blanco, J.L.J.; Mota, J.F.;
Gadelle, A.; Coste Sarguet, A.; Defaye, J. Carbohydr. Res. 1995,
268, 57_71. (b) Nastruzzi, C.; Cotesi, R.; Eaposito, E.; Menegatti,
E.; Leoni, O.; Iori, R.; Palmier, S. J. Agric. Food. Chem.2000, 48,
3572-3575.
3.
4.
Dyer, E.; Johnson, T.B. J. Am. Chem. Soc. 1932, 54, 777-787.
(a) Larsen, C.; Stelliou, K.; Harpp, D.N. J. Org. Chem. 1978, 43,
337-339. (b) Larsen, C.; Harpp, D.N. J. Org. Chem. 1981, 46,
2465-2466. (c) Kim, S.; Yi, K.Y. Tetrahedron Lett. 1985, 26,
1661-1664. (d) Gottfried, R. Angew. Chem. Int. Ed 1966, 5, 963-
964.
5.
(a) Boas, U.; Jakobsen, M. H. J. Chem. Soc., Chem. Commun.
1995, 1995–1996. (b). Boas, U.; Pedersen, B.; Christensen, J. B.
Synth. Commun. 1998, 28, 1223–1228. (c) Boas, U.; Pedersen, H.
G.; Christensen, J. B.; Heegaard, P. M. H. Tetrahedron Lett. 2004,
45, 269–272.
6.
7.
8.
Molina, P.; Alajarin, M.; Tamiaki, H. Synthesis 1982, 596–597.
Stephensen, H.; Zaragosa, F. J. Org. Chem. 1997, 62, 6096–6097
(a) Munch, H.; Hansen, J.S.; Pittelkow, M.; Christensen, J.B.; Bo-
as, U. Tetrahedron Lett. 2008, 49, 3117-3119. (b) Hodgkins, J.E.;
Reeves, W.P. J. Org. Chem. 1964, 29, 3098-3099.

5
References and notes

6
Tetrahedron
Highlights
 The reactions are neat, clean and
efficient.
 Methodology for the synthesis of
isothiocyanates has been devel-
oped.
 Desulfurization is developed by
cheap, available and air stable
Copper catalyst.
 The reactions are rapid, facile
and accomplished at room tem-
perature.
 All the substrates could obtain
their target products in good to
excellent yields.