A mild one-pot synthesis of S-aryl carbamimidothioates using diazonium salts under catalyst-free condition

Article abstract of DOI:10.1007/s00706-015-1465-0

A simple, new method for the synthesis of S-aryl carbamimidothioates is described using aryl diazonium fluoroborates, aryl isothiocyanates, amines, and Et₃N as the base at room temperature.

Full text of DOI:10.1007/s00706-015-1465-0

Monatsh Chem
DOI 10.1007/s00706-015-1465-0
ORIGINAL PAPER
A mild one-pot synthesis of S-aryl carbamimidothioates
using diazonium salts under catalyst-free condition
1
Gholamhossein Khalili
Received: 2 November 2014 / Accepted: 22 March 2015
ꢀ
Springer-Verlag Wien 2015
Abstract A simple, new method for the synthesis of S-
aryl carbamimidothioates is described using aryl diazoni-
combinatorial chemistry because of assembly efficiency,
environmental compatibility, and operational simplicity [2,
3]. In this area, isothiourea compounds have received much
attention due to the presence of this moiety in many molecules
that are widely used in functional materials and pharmaceu-
ticals [4, 5]. Recently, thiourea derivatives emerged as
powerful tools for asymmetric organocatalysis [6]. Therefore,
we would like to disclose our recent efforts toward the syn-
thesis of various carbamimidothioate derivatives via catalyst-
free tandem reactions of amines with aryl isothiocyanates in
the presence of aryl diazonium salts. Usually, the methods
employed for the synthesis of carbamimidothioates include
copper-catalyzed arylation of thiourea compounds in the
presence of diazonium salts [7]. In addition, Kartritzky and
co-workers [8, 9] reported formation ofS-aryl isothiourea bya
metathesis exchange reaction between isothioureas and aryl
isocyanates. An S-aryl carbamimidothioate has been previ-
ously formed in a low yield as an unwanted by-product via a
reaction involving benzyne as the electrophile [10]. To cir-
cumvent these difficulties, the choice of a metal with
moderate affinity for aryl diazonium salts or the development
of metal-free S-arylation would be highly desirable. We
herein present a new three-component coupling under mild,
economic and efficient conditions that are desirable for this
Caryl–S bond formation (Scheme 1).
um fluoroborates, aryl isothiocyanates, amines, and Et N as
3
the base at room temperature.
Graphical Abstract
R
H
N
R1
R1
S
N
Et N, DMF
r.t , 8 h
3
R
N2 BF4
+
N
C
S
N
Keywords Diazonium salt ꢀ Carbamimidothioate ꢀ
Aryl isothiocyanate ꢀ Aryl thiourea
Introduction
In recent decades, the development of practical, efficient, and
rapid synthetic methodologies for the construction of fasci-
nating molecules from readily available reagents in both
organic chemistry and biochemistry has been a key target in
modern organic synthesis [1]. To this end, multistep reactions,
performed in a one-pot process, such as tandem, domino, and
cascade reactions, have attracted much attention in
Results and discussion
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-015-1465-0) contains supplementary
material, which is available to authorized users.
We started our studies by exposing aryldiazonium fluoro-
borates 1 to aryl thiourea, prepared in situ by the reaction
of secondary amines 3 with aryl isothiocyanates 2 in DMF
under air atmosphere. A facile reaction leading to the
&
Gholamhossein Khalili
khalili_gh1352@yahoo.com
0
1
exclusive formation of aryl N,N-dialkyl-N -arylcarbamimi-
Chemistry Department, Islamic Azad University,
Bushehr Branch, Bushehr, Iran
dothioates 4 occurred. But these products are not prepared
123

G. Khalili
Scheme 1
R
R1
H
N
R1
S
N
Et
r.t , 8 h
N, DMF
3
R
N BF
+
N C S
+
2
4
N
1
2
3
4
1
Product
R
R
Amine 3
Yield /%
4
4
a
NO
2
H
Morpholine
Diethylamine
Diethylamine
Diethylamine
Morpholine
Morpholine
Diethylamine
Morpholine
72
70
68
67
76
68
71
65
b
OMe
H
H
H
4
c
4
d
NO
2
H
4
e
OMe
H
4
f
NO
NO
Cl
2
4-F
4-F
2,4-Cl
4
4
g
2
h
2
with good total yield by two-step synthesis compared to the
one-pot reaction.
open chain amine 3 to aryl isothiocyanate 2. Then, the
aryldiazonium fluoroborate 1 is attacked by the aryl
thiourea ion 6 to form products 4, through N elimination
The products were characterized by spectroscopic ana-
1
lysis. The H NMR spectrum of 4a showed signals for the
2
(Scheme 2).
morpholine ring at d = 3.67 ppm, and signals at
In summary, we have uncovered a novel and sim-
0
6
.67–8.03 ppm for phenyl and 4-nitrophenyl moiety. The
ple synthesis of N,N-dialkyl-N -arylcarbamimidothioate
1
3
C resonance signals of the two OCH CH N groups were
2
derivatives by reaction of amines, aryl isothiocyanates with
aryl diazonium salts under catalyst-free conditions. This
reaction will be useful for the conversion of aryl thiourea to
aryl carbamimidothioate.
2
seen at d = 48.5 and 66.4 ppm, whereas the imine signal
was seen at 150.2 ppm. The structure of 4a was established
unambiguously by an X-ray crystallography (Fig. 1).
On the basis of nucleophilic reaction of sulfur atom
with diazonium salts [11], it is reasonable to assume that
aryl thiourea 5 results from the first addition of cyclic and
Experimental
An Electrothermal-9100 apparatus was used for melting
points. The data of IR, NMR, elemental analysis, and mass
spectra were recorded by Shimadzu-IR-460 spectrometer,
Bruker DRX-400, Vario EL III CHNOS, and Finnigan-
MAT-8430EI-MS, respectively.
General procedure for the synthesis of 4
Aryl isothiocyanate 2 (2.2 mmol) and amine 3 (2 mmol) in
3
cm DMF were reacted for 20 min at room temperature.
6
Then, Et N (2 mmol) and aryl diazonium fluoroborate 3
3
(2.2 mmol) were added and the reaction was allowed to stir
for 8 h at this temperature. The mixture was poured into
3
3
8
cm H O, extracted twice with 10 cm AcOEt, dried
2
(MgSO ), and the solvent was evaporated. The reaction
4
Fig. 1 Structure of product 4a
mixture was purified by silica gel column chromatography
1
23

A mild one-pot synthesis of S-aryl carbamimidothioates…
Scheme 2
R1
R1
S
R1
H
N
S
N
Et N
N
3
N C S
+
N
HN
5
2
3
6
R
N
R
N2
R1
-N2
R1
+
R
N BF
S
2
4
S
N
N
1
N
4
7
1
3
using 30 % ethyl acetate in hexane as eluent to give
6.98–7.00 (m, 2H), 7.05 (br, 5H) ppm;
C NMR
product 4.
(100.6 MHz, CDCl ): d = 13.4, 44.1, 121.7, 122.1,
3
1
26.5, 128.1, 128.7, 130.5, 131.0, 133.5, 150.6 ppm; EI-
4
-Nitrophenyl N-phenylmorpholine-4-carbimidothioate
?
MS: m/z = 284 (M , 25), 109 (65), 77 (100).
(
4a, C H N O S)
1
7 17 3 3
0
Colorless powder; yield 72 %; m.p.: 120 ꢁC; IR (KBr):
4-Nitrophenyl-N,N-diethyl-N -phenylcarbamimidothioate
-
1
;
m = 2926, 1610, 1564, 1495, 1321, 1210, 950, 731 cm
(4d, C H N O S)
1
7 19 3 2
1
H NMR (400.1 MHz, CDCl ): d = 3.67 (br, 8H),
Colorless powder; yield 67 %; m.p.: 75 ꢁC; IR (KBr):
m = 2918, 1586, 1531, 1489, 1423, 1350, 1208, 1121,
3
6
.67–6.71 (m, 2H), 6.92–6.98 (m, 1H), 7.10–7.16 (m,
3
3
H), 7.30 (d, J = 9.0 Hz, 2H), 8.03 (d, J = 9.0 Hz, 2H)
-1
1
2
934 cm ; H NMR (400.1 MHz, CDCl ): d = 1.26 (t,
3
1
3
3
3
3
3
3
J = 6.8 Hz, 6H), 3.63 (q, J = 6.8 Hz, 4H), 6.66 (d,
ppm; C NMR (100.6 MHz, CDCl ): d = 48.5, 66.4,
1
3
3
J = 7.6 Hz, 2H), 6.88 (t, J = 7.2 Hz, 1H), 7.07 (t,
22.2, 123.6, 128.2, 129.5, 143.1, 145.8, 147.7, 149.8,
?
50.2 ppm; EI-MS: m/z = 343 (M , 15), 155 (56), 109
3
J = 8.0 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 7.99 (d,
13
J = 8.8 Hz, 2H) ppm; C NMR (100.6 MHz, CDCl3):
1
(
64), 77 (100). Crystallographic data for this compound
have been deposited at the Cambridge Crystallographic
Data Centre as CCDC-1013351.
d = 13.7, 44.6, 122.2, 123.6, 126.4, 128.2, 129.5, 143.1,
145.8, 147.7, 149.8 ppm; EI-MS: m/z = 329 (M , 15), 155
?
(68), 109 (70), 77 (100).
0
4
-Methoxyphenyl-N,N-diethyl-N -phenylcarbamimidoth-
ioate (4b, C H N OS)
1
4-Methoxyphenyl N-phenylmorpholine-4-carbimidothioate
8 22 2
Brown oil; yield 70 %; IR (KBr): m = 2910, 1574, 1468,
(4e, C H N O S)
1
8 20 2 2
-
1
1
1
415, 1249, 1106, 837 cm
3
;
H NMR (400.1 MHz,
Brown oil; yield 76 %; IR (KBr): m = 2901, 1578, 1468,
1412, 1263, 1165, 1021, 823, 741 cm
-1
1
CDCl ): d = 1.08 (t, J = 6.8 Hz, 6H), 3.49 (q,
;
H NMR
3
3
J = 6.8 Hz, 4H), 3.68 (s, 3H), 6.56–6.58 (m, 2H), 6.60
(400.1 MHz, CDCl ): d = 3.54 (br, 4H), 3.59 (br, 4H),
3
3
d, J = 8.8 Hz, 2H), 6.78 (t, J = 7.6 Hz, 1H), 6.92 (d,
3
(
3
3.79 (s, 3H), 6.75–6.78 (m, 4H), 7.00 (br, 1H), 7.14 (d,
13
13
J = 8.8 Hz, 2H), 6.99–7.02 (m, 2H) ppm; C NMR
3
3
J = 7.2 Hz, 2H), 7.21 (d, J = 7.2 Hz, 2H) ppm;
C
(
100.6 MHz, CDCl ): d = 13.5, 44.2, 55.3, 114.3, 121.4,
NMR (100.6 MHz, CDCl ): d = 48.5, 55.3, 66.4, 114.6,
3
3
1
22.0, 123.5, 128.1, 133.3, 150.6, 152.5, 158.9 ppm; EI-
121.8, 122.6, 123.2, 128.4, 133.6, 150.0, 155.1, 159.2 ppm;
?
EI-MS: m/z = 328 (M , 10), 140 (61), 109 (70), 77 (100).
?
MS: m/z = 314 (M , 20), 140 (50), 109 (75), 77 (100).
0
Phenyl-N,N-diethyl-N -phenylcarbamimidothioate
4-Nitrophenyl N-(4-fluorophenyl)morpholine-4-carbimi-
(
4c, C H N S)
2
dothioate (4f, C H FN O S)
3 3
1
7
20
17 16
Brown oil; yield 68 %; IR (KBr): m = 2908, 1588, 1523,
Colorless powder; yield 68 %; m.p.: 111 ꢁC; IR (KBr):
m = 2914, 1613, 1579, 1523, 1441, 1325, 1281, 1213,
1121, 931, 841, 720 cm ; H NMR (400.1 MHz, CDCl ):
-
1
1
1
431, 1265, 1121, 963 cm
3
;
H NMR (400.1 MHz,
-1 1
CDCl ): d = 1.08 (t, J = 7.2 Hz, 6H), 3.49 (q,
3
3
3
J = 7.2 Hz, 4H), 6.58–6.60 (m, 2H), 6.77–6.80 (m, 1H),
d = 3.68 (br, 8H), 6.64–6.67 (m, 2H), 6.81–6.86 (m, 2H),
123

G. Khalili
13
7.15–7.23 (m, 4H), 7.26–7.28 (m, 1H) ppm; C NMR
3
.30 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H) ppm;
3
7
1
3
C NMR (100.6 MHz, CDCl ): d = 48.3, 66.4, 115.1 (d,
(100.6 MHz, CDCl ): d = 48.5, 66.4, 124.0, 126.9, 127.2,
3
3
2
3
JCF = 19.9 Hz), 122.9 (d, J = 7.1 Hz), 123.9, 129.9,
128.0, 128.9, 129.2, 130.0, 132.7, 133.9, 145.5, 155.0 ppm;
?
EI-MS: m/z = 401 (M , 20), 109 (65), 92 (50), 86 (45), 77
CF
1
42.1, 145.4, 146.2, 150.7, 158.5 (d, J = 216.1 Hz)
1
CF
?
ppm; EI-MS: m/z = 361 (M , 25), 317 (40), 155 (63), 110
53), 109 (70), 77 (100).
(100).
(
Acknowledgments We acknowledge the financial support of
Islamic Azad University, Bushehr Branch.
0
4
-Nitrophenyl-N,N-diethyl-N -(4-fluorophenyl)carbamimi-
dothioate (4g, C H FN O S)
3 2
1
7
18
Colorless powder; yield 71 %; m.p.: 102 ꢁC; IR (KBr):
m = 2908, 1618, 1586, 1545, 1414, 1343, 1241, 1161, 895,
References
-
1
1
7
58 cm ; H NMR (400.1 MHz, CDCl ): d = 1.25 (t,
3
3
3
J = 6.8 Hz, 6H), 3.62 (q, J = 6.8 Hz, 4H), 6.63–6.67
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3
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13
8
2
4
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(
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1
1
52.8, 158.5 (d,
JCF = 216.3 Hz) ppm; EI-MS:
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(
?
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-carbimidothioate (4h, C H Cl N OS)
1
7
15
3 2
Brown oil; yield 65 %; IR (KBr): m = 2914, 1578, 1523,
1
1
-
1
1
1
461, 1243, 1130, 1043, 976, 695 cm
;
H NMR
1. Chatterjee T, Bhadra S, Ranu BC (2011) Green Chem 13:1837
(
(
400.1 MHz, CDCl ): d = 3.61–3.63 (m, 4H), 3.67–3.69
3
3
m, 4H), 6.70 (d, J = 8.4 Hz, 1H), 7.05–7.08 (m, 1H),
1
23