An efficient four-component synthesis of dithiocarbamate derivatives

Article abstract of DOI:10.1016/j.tetlet.2013.07.124

An environmentally benign, one-pot, four-component synthesis of chemically and pharmaceutically interesting dithiocarbamate derivatives is reported. The one-pot reaction of various aromatic aldehydes, ketones, aliphatic amines, and carbon disulfide, in the presence of potassium hydroxide in urea-choline chloride deep eutectic solvent or ethanol, leads to the corresponding dithiocarbamates in good to excellent yields. This method provides a convenient and time-saving strategy, with a simple work-up procedure.

Full text of DOI:10.1016/j.tetlet.2013.07.124

Accepted Manuscript
An efficient four-component synthesis of dithiocarbamate derivatives
Najmedin Azizi, Meysam Khajeh, Morteza Hasani, Sahar Dezfooli
PII:
S0040-4039(13)01292-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.07.124
TETL 43322
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
11 May 2013
8 July 2013
24 July 2013
Please cite this article as: Azizi, N., Khajeh, M., Hasani, M., Dezfooli, S., An efficient four-component synthesis
of dithiocarbamate derivatives, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.07.124
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
An efficient four-component synthesis of
dithiocarbamate derivatives
Leave this area blank for abstract info.
Najmedin Azizi,* Meysam Khajeh, Morteza Hasani, Sahar Dezfooli
O
S
N
NH
S
O
EtOH
O
rt, 4 h
90%
H
S
C
S

1
Tetrahedron Letters
journal homepage: www.elsevier.com
An efficient four-component synthesis of dithiocarbamate derivatives
Najmedin Azizi, Meysam Khajeh, Morteza Hasani, Sahar Dezfooli
Chemistry & Chemical Engineering Research Center of Iran, P.O. Box 14335-186, Tehran, Iran
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An environmentally benign, one-pot, four-component synthesis of chemically and
pharmaceutically interesting dithiocarbamate derivatives is reported. The one-pot reaction of
various aromatic aldehydes, ketones, aliphatic amines, and carbon disulfide, in the presence of
potassium hydroxide in urea-choline chloride deep eutectic solvent or ethanol, leads to the
corresponding dithiocarbamates in good to excellent yields. This method provides a convenient
and time-saving strategy, with a simple work-up procedure. Elsevier Ltd. All rights reserved.
Available online
Keywords:
dithiocarbamate
multicomponent reaction
green chemistry
choline chloride–urea
aldehydes
enzymes, and exert toxic effects. Some of modes of action of
DTC compounds have been exploited in clinical applications in
recent years. Therefore, the syntheses and applications of
dithiocarbamate derivatives have received considerable attention,
and there are many reports on their synthesis and their
applications in chemistry, biology, medicine and nanomaterials. 4
The synthesis of diverse, biologically important molecules
from simple and readily available starting materials under
economic conditions is an enduring challenge for synthetic
organic chemists. Multicomponent reactions (MCRs), are
convergent reactions with high atom efficiency, where three or
more starting materials are combined together in a single reaction
flask to generate product. The MCRs proceed with highly atom
economic and increasing molecular diversity and complexity for
parallel synthesis in combinatorial chemistry.1
As part of our interest in developing green reaction media for
the synthesis of useful compounds, we have succeeded in
developing the one-pot synthesis of dithiocarbamates from
amines, carbon disulfide, and alkyl halides under catalyst-free
reaction conditions.5 Encouraged by these successful efforts and
whilst aiming to demonstrate the efficiency and generality of
dithiocarbamates, we present a mild, reliable, efficient and
scalable four-component synthesis of dithiocarbamate derivatives
under mild conditions.
Dithiocarbamates (DTC) and their derivatives are functional
organosulfur compounds that were first used as fungicides during
2
World War II.
Besides their wide use in agriculture as
fungicides for treatment of crops, vegetables, seeds, and
ornamental plants, they are also used as mediators in living
radical polymerization via the reversible addition fragmentation
chain transfer (RAFT) mechanism. Dithiocarbamates are found
in many biologically important compounds, and have a variety of
applications such as in the rubber industry as vulcanization
accelerators, as animal repellants, and as biocides in many
household products.3 Because they have strong metal binding
capacity, they can act as inhibitors of enzymes and have a
profound effect in biological systems, and are widely used in
medicinal chemistry and cancer treatment. dithiocarbamates were
used as efficient ligands in surface science and nanomaterial
chemistry. Furthermore, they are useful building blocks in the
synthesis of biologically active heterocyclic compounds and solid
support grafting materials. DTC anions are highly reactive, and
can conjugate with other molecules containing SH groups and
form metal chelates. The multisite interactions of DTC allow
Initial experiments established that the reaction of
benzaldehyde (1a), (0.50 mmol), acetophenone (2a) (0.50 mmol),
carbon disulfide (1.0 mmol) and pyrrolidine (3a) (1.0 mmol) as
both a reagent and catalyst proceed smoothly in water at room
temperature to afford dithiocarbamate (4a) in 50% yield after 4
hours. The four-component reaction was optimized by changing
various reaction parameters including the temperature, the
additive, the solvents and the order of addition of the reactants
and the results are summarized in Table 1. Screening of different
additives in water revealed that sodium hydroxide was the most
effective at room temperature in terms of yields and cost. The
reaction yields were not increased by the use of higher quantities
of additive, longer reaction times and elevated temperatures (60
°C). A number of solvents including a deep eutectic solvent
(DES),
polyethylene
glycol
(PEG),
tetrahydrofuran,
dichloromethane and ethanol were used, the ethanol and DES
them to influence the biological activities of different proteins,
———
 Corresponding author. fax: +98-21-445-80762; e-mail: azizi@ccerci.ac.ir

2
Tetrahedron Letters
improved the yield at room temperature (Table 1, entries 10 and
Encouraged by this success, several primary and secondary
aliphatic amines were used as substrates. The nature of the amine
had a remarkable influence on the reaction. Secondary amines
such as morpholine, dimethylamine, piperidine, and pyrrolidine
gave good to excellent yields, but moderate yields were obtained
from the reactions of the primary amines: benzylamine and
butylamine under the same reaction conditions. Furthermore,
aromatic amines gave no reaction under the optimized reaction
conditions.
16). In addition, it was found that the order of the addition of
reagents had a considerable effect on the yield (Table 1, entry
17). When the reaction was performed with 1a (0.50 mmol) and
2a (0.50 mmol) in the presence of sodium hydroxide (0.50 mmol)
in ethanol (1 mL) at room temperature for two hours and
followed by co-addition of carbon disulfide (1.0 mmol) and
pyrrolidine (3a) (0.50 mmol) in one portion, then stirring for 2
hours, give product 4a in 90% isolated yield.6
Table 1 Optimization of the model reaction
In conclusion, we have demonstrated the utility of simple
starting materials for the one-pot, four component synthesis of a
range of dithiocarbamates at room temperature in good to
excellent yields. The advantages of this synthetic procedure are
high efficiency, good to high yields, and readily available or
cheap starting materials which make this synthetic strategy
attractive.
O
2a
S
Ph
O
Ph
Solvent, rt, 4 h
N
S
Ph
NH
+
PhCHO
Additive (1 mmol)
S
S
1a
3a
4a
Entry
1
Solvent
H2O
Additive
-
Yield (%)a
50
Acknowledgment
Financial support of this work by the Chemistry and Chemical
Engineering Research Center of Iran is gratefully appreciated.
2
H2O
NaOH
K2CO3
Et3N
DBU
TMG
-
55
3
H2O
50
References and notes
4
H2O
50
1. (a) Zhu, J., Bienaymé, H., Eds. Multicomponent Reactions; Wiley-
VCH: Weinheim, German, 2005; (b) Syamala, M. Org. Prep. Proced.
Int. 2009, 4, 1–68; (c ) Charles M. Marson Chem. Soc. Rev. 2012, 41,
7712-7722 (d)
2. (a) El-Shorbagi, A.-N. Arch. Pharm. 2000, 333, 281–286; (b) Hussein,
M.A.; El-Shorbagi, A.-N.; Khallil, A.-R. Arch. Pharm. 2001, 334, 305–
308; (c) Hemantha, H.P.; Sureshbabu, V.V. Tetrahedron Lett. 2009, 50,
7062–7066; (d) Walter,W.; Bode, K.D. Angew. Chem. Int. Ed. 1967, 6,
281–293.
5
H2O
55
6
H2O
60
7
PEG
60
8
PEG
NaOH
-
65
9
DES
40
3. (a) Hogarth, G. Prog. Inorg. Chem. 2005, 53, 71–561; (b) Rafin, C.;
Veignie, E.; Sancholle, M.; Postal, D.; Len, C.; Villa, P.; Ronco, G. J.
Agric. Food Chem. 2000, 48, 5278-8283; (c) Ronconi, L.; Marzano, C.;
Zanello, P.; Corsini, M.; Miolo, G.; Macca, C.; Trevisan, A.; Fregona,
D. J. Med. Chem. 2006, 49, 1648–1657; (d) Elgemeie G.H. Sayed S.H.
Synthesis 2001, 1747-1771; (e) A. A. Alya, A. B. Brown, T. M.I.
Bedaira, E. A. Ishakb, J. Sulfur Chem. 2012, 33, 605-617.
4. (a) Chaturvedi, D.; Ray, S. Tetrahedron Lett. 2007, 48, 149-151; (b)
Ranu, B. C. Saha, A.; Banerjee, S. E. E. J. Org. Chem. 2008, 519–523;
(c) Azizi, N.; Aryanasab, F.; Torkiyan, L.; Ziyaei, A.; Saidi, M. R. J.
Org. Chem. 2006, 71, 3634–3635; (d) Qian, Y.; Ma, G.-Y.; Ma, Yang,
Y.; Cheng, K.; Zheng, Q-Z.; Mao, W-J. Shi, L.; Zhao, J.; Zhu, H-
L.Bioorg. Med. Chem. 2010, 18, 4310–4316; (e) Alizadeh, A.;
Rostamnia, S.; Zohreh, N.; Hosseinpour, R. Tetrahedron Lett. 2009, 50,
1533-1535; (f) Chaturvedi, D.; Ray, S. Tetrahedron Lett. 2006, 47,
1307–1309; (g) Chaturvedi, D.; Ray, S. Monatsh. Chem. 2006, 137,
311–317; (h) Chaturvedi, D.; Mishra, N.; Mishra, V. Synthesis 2008,
355–357; (i) Chaturvedi, D.; Mishra, N.; Mishra, V. J. Sulfur. Chem.
2007, 28, 39-44; (j) Jana, M.; Kumar Misra, A. Synlett 2012, 23, 2789-
2794; (k) Rostamnia, S. Synthesis 2011, 3080-3082; (l) Gan,S.-F.; Wan,
J.-P.; Pan, Y.-J. Sun, C.-R. Synlett 2010, 973-975; (m) Chatterjee, T.;
Bhadra, S.; Ranu, B.C. Green Chem. 2011, 13, 1837-1842; (n) Bhadra,
S.; Saha, A.; Ranu, B.C. Green Chem. 2008, 10, 1224-1228.
10
11
12
13
14
15
16
17
DES
NaOH
-
65
THF
THF
CH2Cl2
CH2Cl2
EtOH
EtOH
EtOH
DES
25
NaOH
-
45
20
-
45
-
52
NaOH
NaOH
NaOH
74
90
18
92
a
Isolated yield. DES = choline chloride-urea (1:2); PEG =
polyethylene glycol; TMG = 1,1,3,3-tetramethylguanidine
The high yields and mild reaction conditions of this green
process prompted us to explore the four-component coupling
reactions of various aliphatic amines, aromatic aldehydes,
ketones and carbon disulfide, under the optimized reaction
conditions (Table 2). Aromatic aldehydes bearing chloro, bromo,
methyl, or methoxy groups were all able to participate in the
dithiocarbamate synthesis. The electronic effects on the
aldehydes had little influence on the yield and reaction times.
Methyl-, bromo-, methoxy- and chloro-substituted acetophenones
were also well tolerated in the reaction to give the corresponding
dithiocarbamate derivatives in satisfactory yields and short
reaction times. However, a chalcone derived from symmetrical
ketones such as acetone and cyclohexanone did not react under
the reaction conditions and only chalcone derivatives were
obtained.
5. (a) Azizi, N.; Saidi, M. R. Org. Lett. 2005, 7, 3649-3652; (b) Azizi, N.;
Aryanasab, F.; Torkiyan, L.; Ziyaei, A.; Saidi, M. R. J. Org. Chem.
2006, 71, 3634-3636; (c) Azizi, N.; Torkiyan, L.; Saidi, M. R. Org. Lett.
2006, 8, 2079-2082; (d) Azizi, N.; Batebi, E.; Bagherpour, S.; Ghafuri,
H. RSC Adv. 2012, 2, 2289-2292.
6. General Procedure: A dried test tube, equipped with a magnetic stir
bar, was charged with acetophenone (0.50 mmol), an aldehyde (0.50
mmol), and EtOH (1 mL). NaOH (0.50 mmol) was added and the
mixture was stirred under a nitrogen atmosphere at RT until the reaction
was complete (monitored by TLC, usually 2 h). Next, CS2 (1.0 mmol),
and the amine (0.50 mmol) were added and the reaction was stirred at
RT for 1-4 h. After this time, EtOH was removed under reduced
pressure and the resulting solid or viscous liquid was rinsed with water
and purified by column chromatography or recrystallization from EtOH
or Et2O to give pure products. Selected data: Table 2, entry 1: 1H NMR
(500 MHz, CDCl3):  = 1.90–2.00 (4 H, m), 3.55–4.00 (6 H, m), 5.82 (1
H, dd, J =4.2, 9.1 Hz), 7.25–7.58 (8 H, m), 8.00 (2 H, d, J =7.3 Hz). 13
C

3
MS (ESI) 357 (M+); Anal. Calcd for C20H23NOS2: C, 67.2; H, 6.5; N,
3.9; Found: C, 66.9; H, 6.1; N, 3.85.
NMR (125 MHz, CDCl3): = 24.1, 26.2, 48.1, 51.3, 54.9, 55.1, 127.9,
129.1, 129.4, 129.6, 129.8, 132.1, 137.1, 141.0, 191.1, 197.2; FTIR
(KBr): 2950, 1676 cm-1; MS (ESI) 355(M+); Anal. Calcd for
C20H21NOS2: C, 67.7; H, 5.9; N, 3.9; Found: C, 67.5; H, 6.0; N, 3.8;
Table 2, entry 2: 1H NMR (500 MHz, CDCl3):  =1.26–1.30 (6 H, m),
3.62–4.12 (6 H, m), 5.72 (1 H, dd, J =4.0, 9.2 Hz), 7.22–7.62 (8 H, m),
8.20–8.41 (2 H, m). 13C NMR (125 MHz, CDCl3):  = 12.1, 13.0, 45.7,
47.0, 49.6, 51.8, 122.3, 128.0, 128.6, 128.8, 128.9, 129.0, 130.9, 133.1,
133.4, 137.0, 139.6, 145.1, 194.3, 197.1. FTIR (KBr): 2850, 1670 cm-1;
Supplementary Material
Copies of 1H NMR spectra of the dithiocarbamates are
available.
Table 2 Four-component synthesis of dithiocarbamates
Entry
1
Aldehyde (1)
Ketone (2)
Amine (3)
Product (4)
Yield (%)
90
O
O
S
S
S
N
N
N
H
CH3
3a
S
S
S
O
O
O
O
H
O
O
O
O
CH3
CH3
CH3
CH3
2
3b
75
76
O
H
3
3a
O
S
O
N
H
S
S
O
4
92
3c
3a
O
N
H
5
S
O
85
MeO
H3CO

4
Tetrahedron Letters
O
O
O
S
N
H
O
CH3
S
O
6
3a
71
92
OMe
OCH3
S
N
H
CH3
7
8
S
O
O
3b
3a
O
O
S
N
H
CH3
S
S
83
O2N
NO2
O
O
O
S
N
H
H
CH3
9
O
78
91
3a
3d
O
S
N
CH3
10
11
S
O
O
O
S
O
O
N
S
O
H
H
CH3
CH3
85
60
3e
3f
H
S
S
12
BuHN
S
O
O
O
N
CH3
H
S
O
13
14
85
3a
Cl
O
Cl
O
S
N
H
CH3
S
O
72
3a
Cl
Cl

An efficient four-component synthesis of dithiocarbamate derivatives
Najmadin Azizi, * Meysam Khajeh, Mortaza Hasani , Sahar Dezfooli
O
S
N
NH
S
O
EtOH
rt, 4 h
O
90%
H
S
C
S