Multicomponent reaction of amine, carbon disulfide, and fluoronitrobenzene via nucleophilic attack on the fluorinated carbon for the synthesis of nitrophenyl methylcarbamodithioates

Article abstract of DOI:10.1002/jccs.201900111

In this paper, multicomponent reaction of amine, carbon disulfide and fluoronitrobenzene is reported for the synthesis of nitrophenyl methylcarbamodithioate derivatives. The method is based on the nucleophilic attack of the activated methylcarbamodithioate salt to fluoronitrobenzene. Several starting materials are tested and successfully produced the corresponding nitrophenyl methylcarbamodithioate. A possible mechanism for the reaction is suggested.

Full text of DOI:10.1002/jccs.201900111

Received: 23 March 2019
Revised: 14 May 2019
Accepted: 21 May 2019
DOI: 10.1002/jccs.201900111
A R T I C L E
Multicomponent reaction of amine, carbon disulfide, and
fluoronitrobenzene via nucleophilic attack on the fluorinated
carbon for the synthesis of nitrophenyl methylcarbamodithioates
Saeed Bahadorikhalili1 | Sayyad Mohammadi2 | Mehdi Asadi2 | Maliheh Barazandeh2
Mohammad Mahdavi3
|
1Institute of Mechanics, Iranian Space
Research Center, Shiraz, Iran
In this paper, multicomponent reaction of amine, carbon disulfide and
fluoronitrobenzene is reported for the synthesis of nitrophenyl methylcarbamodithioate
derivatives. The method is based on the nucleophilic attack of the activated meth-
ylcarbamodithioate salt to fluoronitrobenzene. Several starting materials are tested and
successfully produced the corresponding nitrophenyl methylcarbamodithioate. A possi-
ble mechanism for the reaction is suggested.
2Department of Medicinal Chemistry,
Faculty of Pharmacy, Tehran University of
Medical Sciences, Tehran, Iran
3Endocrinology and Metabolism Research
Center, Endocrinology and Metabolism
Clinical Sciences Institute, Tehran
University of Medical Sciences, Tehran, Iran
K E Y W O R D S
Correspondence
amine-CS2 reaction, aromatic nucleophilic substitution, multicomponent reaction, nitrophenyl
methylcarbamodithioate
Mohammad Mahdavi, Endocrinology and
Metabolism Research Center, Endocrinology
and Metabolism Clinical Sciences Institute,
Tehran University of Medical Sciences,
Tehran, Iran.
Email: momahdavi@sina.tums.ac.ir
Multicomponent reactions, containing amine and carbon
disulfide, have attracted interests as a powerful tool for organic
1 | INTRODUCTION
synthesis with high efficiency, high atom economy, short reac-
tion time, and simple reaction setup.[13–15] This strategy has
been used for the synthesis of several organic compounds using
catalytic or multicomponent reactions. Gold-catalyzed func-
tionalization reactions,[15] and multicomponent reactions[16]
based on amine and CS2 are of examples of this approach in
the organic synthesis. This method is used for the synthesis of
complex compounds, including dialkylaminocarbothioyl
thioureas,[17] naphthoquinon-1,3-dithioles,[18] 2-thioxo-1,
3-thiazolanes,[19] 4-oxo-2-thioxo-1,3-thiazinanes,[20] 2-thioxo-
2,3-dihydroquinazolin-4(1H)-one,[21] and stable ionic liquids.[22]
Regarding the applicability of nucleophilic substitution reactions
on benzene on the one hand, and multicomponent reactions
based on amine and carbon disulfide on the other hand; in this
article, we develop a novel method based on multicomponent
reactions of amine and carbon disulfide including
Nucleophilic substitution reactions on benzene have been of
high interest among researchers. Several reviews and books
have focused on this class of reactions.[1–3] Due to this interest,
several efforts have been focused on this strategy for the syn-
thesis of a diversity of organic compounds.[4,5] This reaction
has been used for the synthesis of fluorinated aromatic com-
pounds[6,7] or a number of complex natural products such as
martinellic acid[8] and ( )-coerulescine and ( )-horsfiline.[9]
Among different substrates, which are used as a target for the
nucleophilic attack on the aromatic ring, fluoronitrobenzene is
extensively used because of its ability to undergo this
reaction.[10]
Nucleophilic
substitution
reaction
of
fluoronitrobenzene with 4-methoxyaniline in ionic liquids[11]
and aromatic amines[12] has been used for the synthesis of
more complex organic compounds.
© 2019 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J Chin Chem Soc. 2019;1–5.
http://www.jccs.wiley-vch.de
1

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BAHADORIKHALILI ET AL.
product, but in lower isolated yields. In addition, lower
products have been collected, when the reaction is per-
formed in the presence of other bases.
Having the optimized reaction conditions, the generality
of the method is studied for the synthesis of nitrophenyl meth-
ylcarbamodithioate. For this purpose, fluoronitrobenzene
derivatives, in which the nitro group is placed in different
positions, were used. In addition, various amine derivatives
were applied for the synthesis of the desired products. As can
be seen in Table 2, all the starting materials have led to the
desired products in high isolated yields.
A possible mechanism was proposed for the synthesis of
nitrophenyl methylcarbamodithioate derivatives based on pre-
viously reported mechanisms. The use of amines and carbon
disulfide is an appropriate way for the synthesis of nitrogen-
containing and sulfur-containing compounds. The mechanism
of this reaction is well reviewed in the literature.[13,23] In addi-
tion, nucleophilic substitution on aromatic rings, bearing
electron-withdrawing substituents, is previously well stud-
ied.[24,25] The suggested mechanism is presented in Scheme 2.
In the first step, amine (1) is activated by the base. The acti-
vated amine reacts with carbon disulfide (2) to form the
corresponding methylcarbamodithioate (5). The prepared
methylcarbamodithioate reacts with fluoronitrobenzene
(3) and forms 6-fluoro-nitro-6-([methylcarbamothioyl]thio)
cyclohexa-2,4-dien-1-ide (6), leading to the corresponding
nitrophenyl carbamodithioate (4).
SCHEME 1 Synthesis of 4-nitrophenyl methylcarbamodithioate
by multicomponent reaction of amines, carbon disulfide, and
fluoronitrobenzene
fluoronitrobenzene for the synthesis of 4-nitrophenyl meth-
ylcarbamodithioate derivatives (Scheme 1).
2 | RESULTS AND DISCUSSION
The desired 4-nitrophenyl carbamodithioate derivatives
were synthesized in a one-pot process by the reaction
of amines, carbon disulfide, and fluoronitrobenzene
under basic conditions. For finding the optimal reac-
tion conditions, the reaction of pipyridine, CS2, and
fluoronitrobenzene in different solvents by using vari-
ous bases was selected as the model reaction. The
results of the optimization reactions are presented in
Table 1. It can be observed that the desired product is
obtained in the highest yield in dimethylformamide
(DMF) as a solvent in the presence of K3PO4 base at
0ꢀC. Performing the reaction in other solvents gave the
3 | EXPERIMENTAL
3.1 | General
All the chemicals were purchased from Sigma and Merck, and
were used as received without any further purifications. Thin
TABLE 1 Optimization of the reaction conditions
Temperature
(ꢀC)
Isolated
yield (%)
No.
1
Solvent
DMFa
DMF
Base
TEAb
0
21
62
36
49
41
85
45
37
27
34
10
41
TABLE 2 Generality and scope of the method
2
0
K2CO3
DABCOc
KOH
3
DMF
0
4
DMF
0
5
DMF
0
NaOH
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Isolated
yield (%)
R0
6
DMF
0
No.
4a
4b
4c
Amine
7
DMF
25
60
0
Pipyridine
3-NO2
4-NO2
4-NO2
4-NO2
4-NO2
2-NO2
2-NO2
2-NO2
80
8
DMF
2-methoxy aniline
72
9
EtOH
Toluene
H2O
3-methoxypropan-1-amine
2-methoxyethan-1-amine
1-(2-methoxyphenyl)piperazine
Phenyl piperazine
85
10
11
12
0
4d
4e
90
0
85
CH2Cl2
0
4f
75
aDimethylformamide.
bTrimethylamine.
c(1,4-diazabicyclo[2.2.2]octane).
4g
4h
4-methylphenyl piperazine
Benzyl piperazine
75
73

BAHADORIKHALILI ET AL.
3
123.4, 130.2, 130.3, 145.4, 146.5, and 192.4 ppm; MS
(70 eV): m/z = 282 (M+).
3.3.2 | 4-Nitrophenyl (2-methoxyphenyl)
carbamodithioate (4b)
White solid; yield: 72%, mp =226–230ꢀC. IR (KBr): 3,060
(C–Haromatic), 1,629 (C=S) cm−1 1H NMR (DMSO-d6,
;
500 MHz): δ = 6.86 (t, J = 7.5 Hz, 1H, H50), 6.96 (d,
J = 8.0 Hz, 1H, H30), 7.11 (d, J = 7.5 Hz, 1H, H60), 7.21 (t,
J = 8.0 Hz, 1H, H40), 7.62 (d, J = 8.0 Hz, 2H, H2,6), 8.17
(d, J = 8.0 Hz, 2H, H3,5), and 10.15 (s, 1H, NH) ppm; 13C
NMR (DMSO-d6, 125 MHz): δ = 55.2, 110.6, 110.8, 120.1,
120.4, 123.4, 123.5, 126.4, 127.8, 129.9, 130.0, 146.2,
146.4, 157.2, and 194.7 ppm; MS (70 eV): m/z = 320 (M+).
SCHEME 2 Suggested mechanism for the synthesis of
nitrophenyl methylcarbamodithioate derivatives
3.3.3 | 4-Nitrophenyl (3-methoxypropyl)
carbamodithioate (4c)
layer chromatography (TLC) was carried out on silica gel
254 analytical sheets obtained from Fluka. Nuclear Magnetic
Resonance (NMR) spectra were recorded on a Bruker FT- 500
spectrometers using tetramethyl silane (TMS) as internal stan-
dard in pure deuterated solvents. Chemical shiftsare given in
the δ scale in parts per million (ppm) and singlet (s), doublet
(d), triplet (t), multiplet (m) and doublets of doublet (dd) are
recorded. The copies of 1HNMR and 13CNMR spectra are
presented in appendix S1. The Infrared (IR) spectra were
obtained on a Nicolet Magna FT-IR 550 spectrophotometer
(potassium bromide disks). Purification of all products was
conducted by recrystallization from ethanol.
White solid; yield: 85%, mp =203–206ꢀC. IR (KBr): 3,426
(N-H), 3,055 (C–Haromatic), 1,607 (C=S) cm−1 1H NMR
;
(DMSO-d6, 500 MHz): δ = 1.80 (t, J = 6.5, 2H, CH2), 3.22
(m, 2H, S-CH2), 3.61(t, J = 6.5 Hz, 2H, O-CH2), 3.99 (s,
3H, O-CH3), 7.63 (d, J = 8.0 Hz, 2H, H2,6), 8.17 (d,
J = 8.0 Hz, 2H, H3,5), and 10.07 (s, 1H, NHThioamide) ppm;
13C NMR (DMSO-d6, 125 MHz): δ = 27.5, 44.5, 57.8,
69.3, 123.4, 123.5, 130.0, 130.1, 146.2, 146.5, and
194.7 ppm; MS (70 eV): m/z = 286 (M+).
3.3.4 | 4-Nitrophenyl (2-methoxyethyl)
carbamodithioate (4d)
3.2 | General procedure for the synthesis of
4-nitrophenyl carbamodithioate derivatives
White solid; yield: 85%, mp =198–200ꢀC. IR (KBr): 3,026
(C–Haromatic), 1,610 (C=S) cm−1; 1H NMR (DMSO-d6,
500 MHz): δ = 3.52 (t, J = 5.5, 2H, S-CH2), 3.74 (t,
J = 5.5 Hz, 2H, O-CH2), 3.99 (s, 3H, O-CH3), 7.63 (d,
J = 8.0 Hz, 2H, H2,6), 8.17 (d, J = 8.0 Hz, 2H, H3,5), and 9.71
(s, 1H, NHThioamide) ppm; 13C NMR (DMSO-d6, 125 MHz):
δ = 46.8, 57.8, 57.9, 68.8, 123.4, 123.5, 130.0, 130.1, 146.2,
146.5, and 195.3 ppm; MS (70 eV): m/z = 272 (M+).
Amine derivative (2 mmol) and K3PO4 (2 mmol) were dis-
solved in DMF (5 mL) and then carbon disulfide (3 mmol)
was added. The reaction mixture was placed in an ice bath and
stirred for 2 hr. Then, fluoronitrobenzene (2 mmol) was added
to the reaction mixture and stirred for 12 hr. After the reaction
completion, monitored by TLC, the precipitate was filtered and
was recrystallized from ethanol and dried at reduced pressure.
3.3.5 | 4-Nitrophenyl 4-(2-methoxyphenyl)
piperazine-1-carbodithioate (4e)
3.3 | Spectral data
3.3.1 | 4-Nitrophenyl piperidine-
1-carbodithioate (4a)
White solid; yield: 85%, mp = 210–215ꢀC. IR (KBr): 3,053
(C–Haromatic), 1,610 (C=S) cm−1 1H NMR (DMSO-d6,
;
White solid; yield: 80%, mp = 205–207ꢀC. IR (KBr): 3,060
500 MHz): δ = 3.87 (s, 3H, O-CH3), 4.10 (m, 4H, N–
CH2-piperazine), 4.51 (m, 4H, N–CH2-piperazine), 6.93 (d,
(C–Haromatic), 1,639 (C=S) cm−1 1H NMR (DMSO-d6,
;
0
0
J = 7.0 Hz, 1H, H3 ), 7.03 (d, J = 7.5 Hz, 1H, H6 ), 7.43 (t,
500 MHz): δ = 1.58–1.61 (m, 2H, CH2), 2.79 (m, 4H,
0
0
0
0
J = 7.5 Hz, 1H, H5 ), 7.57 (t, J = 7.0 Hz, 2H, H4 ), 7.86 (d,
J = 7.5 Hz, 2H, H2,6), and 8.01 (d, J = 7.5 Hz, 2H, H3,5
ppm; 13C NMR (DMSO-d6, 125 MHz): δ = 50.2, 51.9,
2CH2), 4.22 (m,4H, 2CH2), 7.66 (d, J = 8.0 Hz, 2H, H2 ,6 ),
and 8.17 (d, J = 8.0 Hz, 2H, H3 ,5 ) ppm; 13C NMR (DMSO-
d6, 125 MHz): δ = 23.4, 25.1, 25.8, 51.0, 52.8, 123.3,
0
0
)

4
BAHADORIKHALILI ET AL.
55.4, 111.4, 118.5, 121.1, 123.8, 124.9, 125.0, 128.5, 133.0,
133.4, 140.0, 152.2, and 195.9 ppm; MS (70 eV): m/z = 389
(M+).
reaction between the activated methylcarbamodithioate salt and
fluoronitrobenzene. The activated methylcarbamodithioate salt
is prepared by the reaction of amine with carbon disulfide in
the presence of K3PO4 as a base. Several starting materials
were tested and the corresponding nitrophenyl meth-
ylcarbamodithioate was successfully produced, which proved
the generality of the method.
3.3.6 | 2-Nitrophenyl 4-phenylpiperazine-
1-carbodithioate (4f)
White solid; yield: 75%, mp =203–205ꢀC. IR (KBr): 3,062
(C–Haromatic), 1,610 (C=S) cm−1 1H NMR (DMSO-d6,
;
ORCID
500 MHz): δ = 4.09 (m, 4H, N–CH2-piperazine), 4.46 (m, 4H,
N–CH2-piperazine), 6.84–6.99 (m, 5H, Ph), 7.43 (t,
J = 7.5 Hz, 1H, H5), 7.57 (t, J = 7.0 Hz, 2H, H4), 7.85 (d,
J = 7.5 Hz, 2H, H6), and 8.01 (d, J = 7.5 Hz, 2H, H3) ppm;
13C NMR (DMSO-d6, 125 MHz): δ = 49.9, 52.9, 115.7,
115.9, 118.4, 120.5, 128.9, 133.0, 133.4, 141.1, 141.5,
147.7, and 195.2 ppm; MS (70 eV): m/z = 359 (M+).
Mohammad Mahdavi https://orcid.org/0000-0002-8007-
2543
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3.3.7 | 2-Nitrophenyl 4-(p-tolyl)piperazine-
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3.3.8 | 2-Nitrophenyl 4-benzylpiperazine-
1-carbodithioate (4h)
Purple solid; yield: 65%, mp =225–232ꢀC. IR (KBr): 3,035
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500 MHz): δ = 4.09 (m, 4H, N–CH2-piperazine), 4.45–4.52
(m, 4H, N–CH2-piperazine), 4.92 (s, 2H, CH2), 7.23–7.30 (m,
5H, Ph), 7.43 (t, J = 7.5 Hz, 1H, H5), 7.56 (t, J = 7.0 Hz,
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133.0, 133.1, 133.4, 150.2, and 196.1 ppm; MS (70 eV):
m/z = 373 (M+).
4 | CONCLUSIONS
In this article, a novel method is reported for the synthesis of
nitrophenyl methylcarbamodithioate derivatives, based on the
multicomponent reaction of amine, carbon disulfide, and
fluoronitrobenzene. Nitrophenyl methylcarbamodithioate deriv-
atives were synthesized by the nucleophilic substitution
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How to cite this article: Bahadorikhalili S,
Mohammadi S, Asadi M, Barazandeh M, Mahdavi M.
Multicomponent reaction of amine, carbon disulfide,
and fluoronitrobenzene via nucleophilic attack on the
fluorinated carbon for the synthesis of nitrophenyl
methylcarbamodithioates. J Chin Chem Soc. 2019;
1–5. https://doi.org/10.1002/jccs.201900111
SUPPORTING INFORMATION
Additional supporting information may be found online in
the Supporting Information section at the end of this article.