Accepted Manuscript

Copper promoted desulphurization towards the synthesis of isothiocyanates.

UshaRani Mandapati, Srinivasarao Pinapati, RameshRaju Rudraraju
PII:
DOI:
Reference:

S0040-4039(16)31567-2
http://dx.doi.org/10.1016/j.tetlet.2016.11.086
TETL 48372

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Tetrahedron Letters

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

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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
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)
R
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 = EDG, EWG
Aliphatic aniline
14 examples
Yield 40-98%

EDG-Electron Donating Group

EWG-Electron Withdrawing Group

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
Available online

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.

Keywords:
Copper catalyst
Desulfurization
Isothiocyanates
Room temperature
Substituted anilines
One pot synthesis

1. Introduction
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
thiohydantoins,
thiopyrimidones,
thioqui-nazolones,
mercaptoimidizoles, thio-amidazolones, pyridinethiones, pyrrolidine and benzothiazine.1 Furthermore, isothiocyanates can be
used as chemoselective electrophiles in bioconugate chemistry.2
Therefore, various methods have been developed for the synthesis 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,
thiocarbonyldiimidazole,
bis(trichlorome-thyl) carbonate, trichloro methylformats, di-2pyridyl
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
6
7
triphenylphosphine dibromide,
tosyl chloride,
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

methodology for the preparation of isothiocyanates. In this paper

we report the synthesis of isothiocyanates using cheap and readily available copper catalyst.
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, CuSO45H2O, Cu(NO3)23H2O and Cu(OAc)2H2O
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 couldnt 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 homogeneous (Ethanol and water) and heterogeneous (Ethyl acetate
and water) solvents. The homogeneous solvent mixtures (Ethanol: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)) couldnt give target product (Table 1, entry
11). The heterogeneous solvent mixtures (Ethyl acetate: H2O (1:1
and 1:2)) didnt give target product (Table 1, entries 13 and 14).
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

Tetrahedron
Table 1: Solvent optimization

Since CuSO4.5H2O is cheaper than other copper sources, it is

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 absence 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 (%)

Ethanol

85

Ethyl acetate

98

DCM

85

MeOH

85

DMF

80

H2 O

NR

n-Hexane

NR

n-Heptane

NR

Solvent free

NR

CuSO4.5H2O

>98

10

EtOH/H2O (1:1)

90

Cu(NO3)2.3H2O

>98

11

EtOH/H2O (1:2)

NR

12

EtOH/H2O (2:1)

90

EtOAc/H2O (1:1)

NR

Cu(OAc)2.H2O

>98

13
14

EtOAc/H2O (1:2)

NR

CuI

>98

15

EtOAc/H2O (2:1)

98

Acetone

95

CuBr

16

>98

Table 3: Catalyst Standardization

NH2

NCS
CS2 (10 eq), Et3N (2 eq)

Catalyst (50 mol %)

(2 mmol) EtOAc/H2O (2:1), room temp, 3 h
Entry

Catalyst

CuCl

Yield (%)a

Reaction 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.

Table 2: Base optimization

8b

CuSO4.5H2O

65

9c

CuSO4.5H2O

20

NH2

NCS
CS2 (10 eq), base (2 eq)

(2 mmol)

10

CuSO4.5H2O (50 mol %)

EtOAc/H2O (2:1), room temp, 3 h
a

Base

Yield (%)

Et3N

>98

Pyridine

>98

NaOAc

>98

Na3PO4

>98

NaHCO3

>98

>98

NR

Entry

Cu2O

>98

NR

Reaction 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).

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.
b
Catalyst (25 mol%) was used. cCatalyst (10 mol%) was used.
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 various substrates bearing electron donating and electron withdrawing was done under the below shown reaction conditions (Table
4). The phenyl ring having electron donating groups such as 4methyl, 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 4fluoro and 4-chloro substituents gave their final products in 8193% 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 bearing other strong electron withdrawing substituents nitrile and
ester could give their respective target products in 40% yield

3
Table 4: Substrate scope
NH2

NCS

CS2 (10 eq), Et3N (2 eq)

CuSO4.5H2O (50 mol %)
EtOAc/H2O (2:1)
room temp, 3 h

(2 mmol)
Entry

Table5: Substrate scope

phatic isothiocyanates such as n-butyl, cyclohexyl and benzyl
groups from their respective anilines.

Substrate
NH2

NH2

Isolated yield (%)a

Product

EtOH/H2O (2:1)
room temp, 3 h

NCS

(2 mmol)

98

Entry
NH2

NCS

CS2 (10 eq), Et3N (2 eq)

CuSO4.5H2O (50 mol %)

Substrate

Isolated yield (%)a

Product

NCS

NH2

93
Cl

Cl

NCS

NH2

90

NCS

97
MeO

MeO

NH2

NH2

NCS

98
Me

83
Cl

Cl

Me
NH2

NCS

2
NH2

NCS
Me

NCS

3
Me

87
MeO

87

NH2

MeO

NCS

4
NH2
NO2

86
Me

NCS
NO2

Me
NH2

78

NCS
Me

Me

5
NH2

82

NCS

81
F

NH2

F
NH2

NCS
Me

NCS
NO2

NO2

NH2

NCS

84

7
Me
NH2

NCS

NH2

78
F

Me

F
NH2

92

80
Me

NCS

NH2

Me

NH2

11

40
NC

NC
NH2

NH2

NCS

83

Reaction 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.

NCS

14

40
MeOOC

85

NCS

13

85

NCS

10

93
Me

NCS

90

NCS

12

Me
NH2

9
NH2

Me

8
89

NH2

NCS
Me

NCS

10
11

72

Me

MeOOC

Reaction 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).
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. Following similar methodology, we have successfully obtained ali-

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 using 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 intermediate 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 converted into sulfide) via intermediate E.
In conclusion, the reactions were neat, clean and efficient.
During the reaction process we couldnt observe any other byproducts. The reactions are rapid and facile and accomplished at
room temperature. All the substrates could obtain their target
products in good to excellent yields.

Tetrahedron
NH2
C
NCS
N

S NHEt3

Et3N H
N

S
[CuS]

Cu

S
S

S NHEt3
H
N

S
Cu

S NHEt3
S

B
H
N

CuI +e CuII

S NHEt3
S

Cu

Scheme 2: proposed mechanism

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 fellowship and the authors are grateful to Icon Pharmaceutical Lab
for providing instrumental support.
References and notes
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2.

3.
4.

5.

6.
7.
8.

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References and notes

Tetrahedron

Highlights

The reactions are neat, clean and

efficient.
Methodology for the synthesis of
isothiocyanates has been developed.
Desulfurization is developed by
cheap, available and air stable
Copper catalyst.
The reactions are rapid, facile
and accomplished at room temperature.
All the substrates could obtain
their target products in good to
excellent yields.