Cobalt mediated by desulfurization toward the synthesis of isothiocyanates

Article abstract of DOI:10.1080/00397911.2016.1224351

A highly efficient and simple protocol for the construction of aromatic and aliphatic isothiocyanates from their respective amines in the presence of cheap, readily available, and air-stable cobalt catalyst is described. All reactions were carried out under optimized reaction conditions and gave target products in good to excellent yields within shorter reaction time.

Full text of DOI:10.1080/00397911.2016.1224351

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Cobalt mediated by desulfurization toward the
synthesis of isothiocyanates
Mohan Seelam, Bajivali Shaik & Prasada Rao Kammela
To cite this article: Mohan Seelam, Bajivali Shaik & Prasada Rao Kammela (2016)
Cobalt mediated by desulfurization toward the synthesis of isothiocyanates, Synthetic
Communications, 46:21, 1759-1765, DOI: 10.1080/00397911.2016.1224351
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1224351
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Date: 21 October 2016, At: 12:48

SYNTHETIC COMMUNICATIONS®
2016, VOL. 46, NO. 21, 1759–1765
http://dx.doi.org/10.1080/00397911.2016.1224351
Cobalt mediated by desulfurization toward the synthesis of
isothiocyanates
Mohan Seelam, Bajivali Shaik, and Prasada Rao Kammela
Department of Chemistry, Bapatla Engineering College, Acharya Nagarjuna University, Bapatla, India
ABSTRACT
ARTICLE HISTORY
Received 10 June 2016
A highly efficient and simple protocol for the construction of aromatic
and aliphatic isothiocyanates from their respective amines in the
presence of cheap, readily available, and air-stable cobalt catalyst is
described. All reactions were carried out under optimized reaction
conditions and gave target products in good to excellent yields within
shorter reaction time.
KEYWORDS
C-N bond formation; cobalt
catalyst; desulfurization;
isothiocyanates; room
temperature
GRAPHICAL ABSTRACT
Introduction
Isothiocyanates have been used as versatile important synthetic intermediates for the synthesis
of a number of natural products and heterocycles, such as thiohydantoins, thiopyrimidones,
thioqui-nazolones, merca-ptoimidizoles, thio-amidazolones, pyrid-inethiones, pyrrolidine,
and benzothiazine.[1] It is a ubiquitous structural functional class in many biologically and
pharmaceutically active compounds.[2] Furthermore, isothiocyanates can be used as chemose-
lective electrophiles in bioconugate chemistry.[3] Therefore, various methods have been
developed for the synthesis of isothiocyanates from amines, in which thiophosagene is mostly
well known.[4] Because of the high toxicity of thiophosgene, it was replaced by other
thiocarbonayl transfer reagents, such as thiocarbonylditriazole, thiocarbonyldiimid-azole, bis-
(trichlorome-thyl) carbonate, trichloromethylformats, di-2-pyridyl thionocarbonate, and bis-
(trichloromethyl) pentathiocarbonate.[5] However, most of them are not readily available
and often do not work as desired because of 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 carbondisulfide
in the presence of a base, with diverse reagents, including uranium- and phosphonium-based
CONTACT Prasada Rao Kammela
prasad17467@gmail.com
Department of Chemistry, Bapatla Engineering College,
Acharya Nagarjuna University, Bapatla 522101, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental material for this article can be accessed on the publisher’s website.
© 2016 Taylor & Francis

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M. SEELAM ET AL.
peptide coupling reagents,[6] triphenylphosphine dibromide,[7] tosyl chloride,[8] dialkyl
dicarbonates,[9] hydrogen peroxide,[10] iodine,[11] diacetoxy iodobenzene, other harsh
reagents,[12] and other mild methods are also known.[13] The reported methods are really
efficient, but most of them possess drawbacks such as rigorous or hazardous conditions,
intractable side reactions, and evolved toxic gases. Thus, there is still need for a commercially
available and environmentally acceptable methodology for the preparation of isothiocya-
nates. In this connection we report the synthesis of isothiocyanates using cheap and readily
available cobalt catalyst.
Results and discussion
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 cobalt salts such as CoCl2·6H2O and CoSO4·H2O in the presence of Et3N
in ethyl acetate, affording the phenyl isothiocyanate 1a in 95% conversion (conversion
was confirmed by thin-layer chromatography, TLC, as well as gas chromatography, GC).
First, the reaction was checked in the presence of different solvents. In the case of polar
solvent, ethyl acetate could give target product 1a in quantatative yield (Table 1, entry 2).
Other polar solvents such as ethanol gave the final product 1a in good yield (Table 1,
entry 1). The reaction could give expected product 1a in lower yields in the presence of
MeOH (Table 1, entry 4) or dichloromethane (DCM) (Table 1, entry 3). The polar solvent
dimethylformamide (DMF) could get target product 1a in moderate yield (Table 1, entry 6).
Unfortunately, the grenary solvent H2O could not give the target product. Later we have
checked with the nonpolar solvents like n-hexane and n-heptane. Unfortunately no
Table 1. Solvent optimization.
Entry
Solvent
Ethanol
Ethyl acetate
DCM
MeOH
DMSO
DMF
H2O
n-Hexane
n-Heptane
–
EtOH/H2O (1:1)
EtOH/H2O (1:2)
EtOH/H2O (2:1)
EtOAc/H2O (1:1)
EtOAc/H2O (1:2)
EtOAc/H2O (2:1)
Conversion (%)a
1
85
95
30
45
70
70
ND
ND
ND
ND
75
45
75
75
50
85
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
aConversion was confirmed by TLC.

SYNTHETIC COMMUNICATIONS®
1761
Table 2. Base optimization for the construction of isothiocyanate.
Entry
Base
Et3N
conversion (%)a
1
2
3
4
5
95
40
30
ND
95
Pyridine
NaOAc
NaOH
NaHCO3
aConversion was confirmed by TLC.
nonpolar solvent could give the target product. Very interestingly, no reaction occurred in
the absence of solvent and the starting material was recovered intact. 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 the target product in 75% yield (Table 1, entries 11 and 13) and another homo-
geneous mixture (ethanol/H2O, 1:2) could give the target product in just 45% yield (Table 1,
entry 12). The heterogeneous solvent mixtures (ethyl acetate/H2O, 1:1) gave the target
product in 75% yield (Table 1, entry 14). Very interestingly, another heterogeneous reac-
tion mixture ratio (EA/H2O, 2:1) could obtain the target product in 85% yield (Table 1,
entry 16). The reaction with other orgnaic base pyridine could give the expected product
in lower yields. Later, the inorganic bases sodium bicarbonate, sodium acetate, and sodium
hydroxide were also checked. Among them, sodium bicarbonate is best for this reaction
and it could give the target product in 95% yield (Table 2, entry 5). Finally, different cobalt
sources were examined, and all showed similar activity. Similarly, lowering of the reaction
temperature (10 °C) or base (1 equiv) led to the formation of a target product. The control
experiment confirmed that in the absence of the cobalt salts no reaction occurred and
starting material was recovered intact (Table 3).
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
Table 3. Catalyst standardization for synthesis of isothiocyanate.
Entry
Catalyst
conversion (%)a
1
2
3
4
5
6
CoCl2·6H2O
CoSO4·H2O
Co(NO3)2·6H2O
CoCl2·6H2O
CoCl2·6H2O
-
95
95
95
95
70
ND
aConversion was confirmed by TLC.

1762
M. SEELAM ET AL.
rings. In this connection, the various substrates bearing electron-donating and electron-
withdrawing groups were examined under the standard reaction conditions (Table 4).
The phenyl ring, having electron-donating groups such as 4-methyl (4) or 4-methoxy
Table 4. Substrate scope for the synthesis of isothiocyanates.
Entry
1
Substrate
Product
Isolated yield (%)a
95
2
3
4
81
97
96
5
82
6
7
65
75
8
9
82
92
10
11
87
85
1
Compounds were confirmed by both IR and H NMR analysis.

SYNTHETIC COMMUNICATIONS®
1763
(3), could give their respective aromatic isothiocyanates (4a and 3a; Table 4, entries 3 and
4) in high yield. The unsubstituted phenyl ring (1) also gave the target product in quanti-
tative yield (1a; Table 4, entry 1). Electron-withdrawing groups such as 4-fluoro (7) and 4-
chloro (2) substituents gave their final products (7a and 2a) in 75–81% yields (Table 4,
entries 2 and 7). The aryl ring, having a strong electron-withdrawing group –NO2 on
the second position (6), gave the final product in moderate yield (6a; Table 4, entry 6). Dis-
ubstituted (8) and ortho-substituted (5) aryl rings could give their respective isothiocya-
nates in good yield (8a and 5a; Table 4, entries 5 and 8). Finally we have also studied
about aliphatic anilines. The aliphatic substrates (9, 10, 11) readily underwent reaction
to produce the target products (9a, 10a, 11a) in high yields (Table 4, entries 9–11).
The substrate scope was also developed using another optimal reaction EtOAc/H2O
(2:1) [Eq. (1)]. Both electron-donating and electron-withdrawing substituents on aryl ring
could give their respective target products in 60–87% yields. Following a similar method-
ology, we have successfully obtained aliphatic isothiocyanates such as n-butyl, cyclohexyl,
and benzyl groups from their respective amines.
The mechanism of formation for phenyl isothiocyante from anilines is shown in
Scheme 1, which we propose based on experimental evidence and literature reports. As
we show in Scheme 1, aniline (1) reacts with carbon disulfide in the presence of a base
(sodium bicarbonate) and solvent to give thiocarbomate salt K. It may coordinate with
cobalt salt and remove the proton to afford the intermediate M. The intermediate M
may give the target product along with by-product cobalt sulfide and polysulfide (the extra
sulfur might have converted into as sulfide)[14] via intermediate N.
Scheme 1. Proposed mechanism.

1764
M. SEELAM ET AL.
Experimental
Representative experimental procedure for the synthesis of phenyl isothiocyanate
To a stirred solution of respective solvent (4–5 ml), aniline (2 mmol, 186 mg) was added
slowly, and then carbon disulfide (20 mmol, 1.21 ml) and sodium bicarbonate (2 mmol,
212 mg) were added at room temperature. The whole reaction mixture was stirred for 1 h
(until a yellow color solid formed) at room temperature. Thiocarbamate formation was
monitored by thin-layer chromatography (TLC). To this, CoCl2·6H2O (25 mol%, 75 mg)
was added slowly, followed by sodium bicarbonate (2 mmol, 212 mg) for 10 min, and the
reaction mixture was stirred for 1 h. During this period, a black color precipitate was
observed and settled at the bottom of the round-bottom flask. The progress of the
reaction was investigated by TLC (5% ethyl acetate in hexane). After finishing the reaction,
the reaction mixture was transferred into centrifuged tubes and the mixture was centrifuged
for 10 min by using a centrifugation machine. The black color solid settled in the bottom of
the centrifuge tubes. The clear solution was concentrated by a using rotary evaporator and
the crude mixture was purified by silica-gel (60–120 mesh) column chromatography using
2% ethyl acetate in hexane as eluent to obtain phenyl isothiocyanate 1a as an oily liquid.
Isothiocyanatobenzene (Table 4, Entry 1)
Analytical TLC on silica gel, 1:49 ethyl acetate/hexane Rf ¼ 0.9; colorless liquid; yield 95%;
1H NMR (400 MHz, CDCl3) δ 7.37–7.33 (m, 2H), 7.29–7.25 (m, 3H); FT-IR (KBr) 3064,
2364, 2063, 1693, 1489, 1070, 927, 909, 769 cmÀ 1.
Conclusion
The reactions were neat, clean, and efficient. During the reaction process we did not
observe any other by-products (no other products were observed except isothiocyanate).
The reactions are rapid and facile and were accomplished at room temperature. All the
substrates could obtain their target products in good to excellent yields.
Acknowledgments
The authors are thankful to the Department of Chemistry, Bapatla Engineering College, Bapatla, for
providing work space and to Icon Pharmaceutical Laboratory for providing instrumental support.
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