Synthesis of 2-arylthio arylcyanamides from 2-iodoaryl isothiocyanates: Via a one-pot three-component reaction

Article abstract of DOI:10.1039/c7nj01702b

A one-pot three-component reaction has been described for the synthesis of substituted 2-arylthio arylcyanamides. A cheap and readily available iron source was used as a catalyst for this reaction. Consecutive addition and domino C-S cross-coupling reacti

Full text of DOI:10.1039/c7nj01702b

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Synthesis of 2-arylthio arylcyanamides from
2-iodoaryl isothiocyanates via a one-pot
three-component reaction†
Cite this: New J. Chem., 2017,
41, 8711
Received 16th May 2017,
Accepted 11th July 2017
Srinivasarao Pinapati,a Usharani Mandapati,a Ramana Tamminanab and
a
Rameshraju Rudraraju
*
DOI: 10.1039/c7nj01702b
rsc.li/njc
A one-pot three-component reaction has been described for the
Initially, the optimization of the reaction conditions was
synthesis of substituted 2-arylthio arylcyanamides. A cheap and performed using 4-Me-2-iodophenyl isothiocyanate as a model
readily available iron source was used as a catalyst for this reaction. substrate with different solvents at room temperature (step 1).
Consecutive addition and domino C–S cross-coupling reactions We could observe that the substrate reacted with aq. NH3 in the
have been involved in this reaction.
presence of EtOH, EtOAc, DMF, and DMSO at room temperature to
afford the corresponding thiourea A via complete conversion. Then,
Due to its unique reactivity, a cyano group is recognized as an it took part in an domino intra- and intermolecular C–S cross-
important building block and found in various bioactive molecules coupling reaction with iodobenzene with 10 mol% Fe2(SO4)3ÁH2O,
and functionalized materials.1 Cyanamides are useful precursors 20 mol% ligand (1,10-phenanthroline), and 2 equiv. Cs2CO3 at
and important synthetic intermediates for the synthesis of 100 1C to form the target product 1A via complete conversion. In
biologically, medicinally, and pharmaceutically important hetero- case of solvent optimization, no reactions occurred in non-polar
cycles.2 Since the cyano group can be easily removed from solvents such as n-hexane and n-heptane. Green solvent H2O could
cyanamide and N-alkyl or N-aryl imides,3 it often represents a afford thiourea (1st step) in 70% conversion, but the domino C–S
useful protecting group in the synthesis of secondary and tertiary cross-coupling reaction (2nd step) could not proceed. Various bases
amines containing heterocycles.4 Aromatic cyanamides have also were examined and among them, Cs2CO3 could yield target product
been prepared by both classical and ancient methods.5 In recent via complete conversion (Table 1, entry 10). Other bases gave less
years, the formation of carbon-heteroatom bonds6 towards the effective in the formation of target product. Among the set of three
synthesis of heterocyclic compounds has been developed through ligands L1–L3 screened, L3 was found to be more effective as
cross-coupling reactions using transition-metal-catalysis. Among compared to L1 and L2 (Table 1, entries 11 and 12). Both iron(II)
these, carbon–sulfur bond formation has received significant and iron(III) sources (Fe2(SO4)3ÁH2O, Fe(NO3)3Á9H2O, and FeCl2)
attention due to the presence of this moiety in many molecules exhibited a similar catalytic activity (entries 10 and 13 and 14).
that are of biological, pharmaceutical, and material interest.7 The reaction, either lowering the amount of base (1.5 equiv.) or the
Recently, the compounds, such as 2-(arylthio)arylcyanamides, iron source (5 mol%) gave target product in lower conversion. The
containing the abovementioned moieties have been developed reaction was also checked in the absence of ligand; unfortunately,
from 2-halophenyl thiourea via domino C–S cross-coupling reac- the reaction could not yield target product and formed iodo-
tion using copper as a catalyst.8 To the best of our knowledge, no cyanamide in 25% conversion (Table 1, entry 17). The control
study has been reported on the synthesis of 2-(arylthio)arylcyan- experiment confirmed that the reaction did not proceed (step 2)
amides in the presence of iron as a catalyst. Therefore, herein, we in the absence of the catalyst. The ligand and thiourea were
report the one-pot synthesis of 2-(arylthio)arylcyanamides from recovered intact (Table 1, entry 18).
2-iodoaryl isothiocyanates and aryl iodides using a cheap, readily
Having the optimization reaction conditions in our hand, we
available, and air stable iron source as the catalyst under mild further pursued the scope of the process with respect to the
reaction conditions.
other substrates. Aryl iodides having the electron-donating
groups 4-Me and 4-OMe proceeded reactions to afford their
domino cross-coupled products 1B and 1C in 95% and 97%
yield, respectively. Aryl iodides bearing weak electron with-
drawing substituents 4-Cl and 4-F could give their respective
target products 1D and 1E in 91% and 88% yield. Aryl iodides
possessing strong electron-withdrawing groups 2-NO2 and 4-CN
a Department of Chemistry, Acharya Nagarjuna University, Nagar, Guntur,
AP-522510, India. E-mail: rudrarajurameshraju716@gmail.com
b Department of Chemistry, QIS College of Engineering & Technology Ongole,
Prakasam, AP-523272, India
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c7nj01702b
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Table 1 Standardization for the reaction conditionsa
conversion (eqn (6)) at 100 1C. Moreover, 2-amino benzothiozole
readily underwent the reaction with iodobenzene under the opti-
mized reaction conditions to provide final product 1A in a quantita-
tive yield (eqn (7)). The obtained results clearly suggest that thiourea
first gives 2-amino benzothiozole as an intramolecular C–S cyclized
product that may react with iodobenzene to afford the final product
1A via intermolecular C–S cross-coupling reaction (Scheme 1).
According to the literature reports and experimental evidences,
the mechanism has been proposed (Scheme 2, see the ESI†).
2-Iodophenyl isothiocyanate reacts with aq. NH3 to provide
N-2-iodophenyl thiourea A, which can undergo oxidative addition
with Fe(I) species (thiourea may reduce Fe(III) to Fe(I) active species)9
to yield the Fe(III) intermediate P. It may give 2-aminobenzothiozole
X by intramolecular C–S cyclization using a base via the intermediate
Q. On the other hand, iodobenzene can undergo oxidative
addition with Fe(I) species to give intermediate R, which can
undergo intermolecular C–S cross-coupling reaction with
2-aminobenzothiozole X to afford the intermediate S. This
intermediate can complete catalytic cycle via reductive elimination
to obtain the 2-arylthio aryl cyanamide 1A.
Conversionb
Entry Solvent
Catalyst
Base
Ligand
A
1A
1
2
3
4
5
6
7
8
EtOH
EtOAc
Fe2(SO4)3ÁH2O K3PO4Á3H2O L3
Fe2(SO4)3ÁH2O K3PO4Á3H2O L3
100
100
n.d.
n.d.
n-Hexane Fe2(SO4)3ÁH2O K3PO4Á3H2O L3
n-Heptane Fe2(SO4)3ÁH2O K3PO4Á3H2O L3
n.d. n.d.
n.d. n.d.
H2O
DMF
Fe2(SO4)3ÁH2O K3PO4Á3H2O L3
Fe2(SO4)3ÁH2O K3PO4Á3H2O L3
Fe2(SO4)3ÁH2O K3PO4Á3H2O L3
70
45
45
25
40
n.d.
55
55
75
60
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Fe2(SO4)3ÁH2O KOH
Fe2(SO4)3ÁH2O K2CO3
Fe2(SO4)3ÁH2O Cs2CO3
Fe2(SO4)3ÁH2O Cs2CO3
Fe2(SO4)3ÁH2O Cs2CO3
Fe(NO3)3Á9H2O Cs2CO3
L3
L3
L3
L1
L2
L3
L3
L3
L3
—
—
9
10
11
12
13
14
15c
16d
17e
18
n.d. 100
75
55
25
45
n.d. 100
n.d. 100
FeCl2
Cs2CO3
As suggested by the reviewer, we have checked copper conta-
mination in the iron sources using the AAS experiment. The results
are shown in Table 2. The obtained results clearly proved that our
catalyst (iron source) didn’t contain any copper species. Therefore,
we concluded that the reported reaction was catalyzed by iron source
only. In addition, many researchers have developed cross-coupling
reactions using Iron source as the catalyst.10
Fe2(SO4)3ÁH2O Cs2CO3
Fe2(SO4)3ÁH2O Cs2CO3
Fe2(SO4)3ÁH2O Cs2CO3
55
35
50
65
75
100
n.d.
n.d.
—
Cs2CO3
a
Reaction conditions: 2-iodophenyl isothiocyanate (1 mmol), solvent (2 mL),
aq. NH3 (2 mL), 6 h, room temperature, then, iodobenzene (1 mmol), catalyst
(10 mol%), ligand (20 mol%), base (2 mmol), 6 h, 100 1C. b Isolated yield.
c Catalyst (5 mol%) was used. d Cs2CO3 (1.5 equiv.) was used. e The reaction
gave 2-iodophenyl cyanamide in 25% conversion. n.d. = not detected.
gave their final products in lower yield. It might be occurred due to
the strong electron-withdrawing group at reactive site. Aryl iodide
containing disubstituted groups such as 2,4-di-Me gave desired
product 1I in 90% yield. Aryl iodide holding bulkier group 2-tBu
and 3-Me reacted under the optimized reaction conditions to give
their respective final products 1H and 1J in 82% and 92% yield,
respectively. Similarly, phenyl isothiocyanates bearing 4-Me, 4-OMe,
4-Cl, 4-F, 4-CN, 2-NO2, 2,4-di-Me, 3,4-di-Me, and 2-tBu substituents
readily underwent the reaction with iodobenzene to give their final
products 1K–R in 70–95% yield. The abovementioned results clearly
confirm that the substrates having electron-donating and electron-
withdrawing groups are compatible with this process to afford the
substituted 2-(arylthio)arylcyanamides in good to high yield.
To reveal the mechanism, we carried out some control
experiments (see the ESI†). In the absence of ligand, the reaction
could give 2-iodophenyl cyanamide instead of target product at
optimized temperature (eqn (1)) and room temperature (eqn (2)).
The reaction could not proceed in the absence of both catalyst and
ligand at 100 1C and room temperature (eqn (3)). Next, the reaction
was performed in the presence of both catalyst and ligand at 50 1C,
and the reaction could give intramolecular C–S cyclization product in
20% conversion (eqn (4)). The abovementioned results suggested
that the catalyst (Fe2(SO4)3ÁH2O) could act as a desulphurization
reagent and the ligand was necessary for cyclization. The reaction
gave a mixture of intramolecular C–S cyclization and domino C–S
cyclization products when conducted at 80 1C (eqn (5)), whereas it
could give exclusively domino C–S cyclized product in 100%
Scheme 1 Substrate scope for the synthesis of 2-arylthio arylcyanamides.
Reaction conditions: substituted 2-iodophenyl isothiocyanate (1 mmol),
DMSO (2 mL), aq. NH3 (2 mL), 6 h, room temperature, then, substituted
iodobenzene (1 mmol), Fe2(SO4)3ÁH2O (10 mol%), 1,10-phen (20 mol%),
Cs2CO3 (2 mmol), 6 h, 100 1C.
8712 | New J. Chem., 2017, 41, 8711--8713
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2
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6
Blank solution
0.0000
0.0000
0.0000
0.0000
0.0000
0.0000
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Sample solution-5 (0.01 ppm)
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