Versatile and large-scale synthesis of functional dithiocarbamates in water

Article abstract of DOI:10.1080/00397910903531847

Structural diversity is possible in direct access to functional dithiocarbamates based on a highly efficient and simple one-pot reaction of CS₂, amines, and alkyl halides in nearly quantitative yields in water. Copyright

Full text of DOI:10.1080/00397910903531847

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Versatile and Large-Scale Synthesis of
Functional Dithiocarbamates in Water
Najmedin Azizi a , Fezzeh Aryanasab b , Laleh Tourkian b
Mohammad R. Saidi b
&
a Chemistry and Chemical Engineering Research Center of Iran,
Tehran, Iran
b Department of Chemistry, Sharif University of Technology, Tehran,
Iran
Published online: 14 Dec 2010.
To cite this article: Najmedin Azizi , Fezzeh Aryanasab , Laleh Tourkian & Mohammad R. Saidi
(2010) Versatile and Large-Scale Synthesis of Functional Dithiocarbamates in Water, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
41:1, 94-99, DOI: 10.1080/00397910903531847
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Synthetic Communications1, 41: 94–99, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903531847
VERSATILE AND LARGE-SCALE SYNTHESIS OF
FUNCTIONAL DITHIOCARBAMATES IN WATER
Najmedin Azizi,1 Fezzeh Aryanasab,2 Laleh Tourkian,2 and
Mohammad R. Saidi2
1Chemistry and Chemical Engineering Research Center of Iran, Tehran, Iran
2Department of Chemistry, Sharif University of Technology, Tehran, Iran
Structural diversity is possible in direct access to functional dithiocarbamates based on a
highly efficient and simple one-pot reaction of CS2, amines, and alkyl halides in nearly
quantitative yields in water.
Keywords: Alkyl halides; amine; carbon disulfide; functional dithiocarbamates; structural diversity; water
INTRODUCTION
Development of strategically important processes that are environmentally
cleaner and more efficient, that lead to greater structural variation with simple
workup and excellent yields and purity, and that minimize the formation of waste
are currently receiving considerable attention.[1] Water play an important role in
these processes. Water is an elegant solution with the ultimate goal of hazard-free,
waste-free, and energy efficiency for the synthesis of biologically active compounds
with potential application in the pharmaceutical and agrochemical industries.[2]
Dithiocarbamates are ubiquitous in many biologically important com-
pounds.[3] They have a variety of applications in agriculture[4] as pesticides and in
rubber industries as vulcanization accelerators and antioxidants.[5] Because they
have strong metal-binding capacity, they can act as inhibitors of enzymes, have a
profound effect on biological systems, and are widely used in medicinal chemistry
and cancer treatment.[6] The biological activity of the dithiocarbamates is increased
when they are in the form of heavy-metal salts as versatile classes of ligands with the
ability to stabilize transition metals in a wide range of their oxidation states. They
are also efficient ligands in surface science and nanomaterial chemistry.[7] Further-
more, they are useful building blocks for the synthesis of biologically active
heterocyclic compounds and solid support grafting materials.[8]
There are few reports for the synthesis of dithiocarbamate derivatives in the
literature. Among them, reaction of amine with costly and toxic reagents, such as
thiophosgene and isothiocyanate, is reported as a general route.[9] A one-pot reaction
Received September 6, 2009.
Address correspondence to Mohammad R. Saidi, Department of Chemistry, Sharif University of
Technology, Tehran, Iran. E-mail: saidi@sharif.edu
94

FUNCTIONAL DITHIOCARBAMATE SYNTHESIS
95
of amines with carbonyl sulfide and alkyl halides in an organic solvent has also been
developed.[10] However, many isothiocyanates are hazardous and tedious to prepare,
display poor long-term stability, and are associated with the formation of side reac-
tions such as urethane in alcoholic medium. Furthermore, their reactions require
toxic reagents and harmful organic solvents such as dimethylformamide (DMF),
and dimethyl sulfoxide (DMSO) with limited substrate and moderate yields.
RESULTS AND DISCUSSION
Our interest in dithiocarbamate chemistry led us to contemplate the possibility
of using water as solvent and catalyst for the synthesis of dithiocarbamates.[11]
Recently, we have investigated simple synthesis of dithiocarbamates under solvent-
free conditions.[11d] However, in the case of large-scale synthesis of functional dithio-
carbamates, the reaction temperature should be exactly maintained at room
temperature.
We herein report a highly efficient and large-scale preparative procedure for
the preparation of S-alkyl dithiocarbamates with a one-pot reaction of amines,
CS2, and alkyl halides. The products were obtained with high purity and in excellent
yield without using any catalyst in pure water (Scheme 1).
In an initial experiment, benzyl chloride 1 (4 mmol) was treated with CS2
(8 mmol) and diethyl amine 2 (8 mmol) in water (5 mL) in the absence of any catalyst
at room temperature. After 8 h, the benzyl chloride was consumed and the corre-
sponding dithiocarbamates 3a were formed as the only detectable product with
97% yield (Scheme 1). To test the feasibility of a large-scale reaction, 1 (100 mmol)
was treated with 2 (200 mmol) and CS2(200 mmol) in water (100 mL) at room tem-
perature. The product was isolated in 92% yield after 8 h. Furthermore, it was poss-
ible to monitor the reaction visually. A white suspension solution was obtained after
addition of the amine to the benzyl chloride and CS2 in water. When the reaction was
completed, a viscose orange liquid or solid was formed. Also, it is important to note
that in the large-scale production, the workup is very simple and does not use any
organic solvent. The pure product was obtained just by decanting.
Dithiocarbamates with functional groups are very useful compounds, and
there is the possibility of manipulating these functional groups for the synthesis of
the heterocyclic compounds containing sulfur and nitrogen building blocks or elab-
orating them to introduce other functional groups. In light of these promising
results, we then focused our attention on the use of methyl bromoacetate as the
source of alkyl halide. When a secondary amine, such as diethylamine (6 mmol),
CS2 (6 mmol), and methyl bromoacetate (3 mmol) were mixed in water, the corre-
sponding dithiocarbamate was derived from the one-pot reaction in excellent yields
(Table 1, entry 1). In a similar manner, several primary and secondary aliphatic
Scheme 1. Preparation of dithiocarbamates in water.

96
N. AZIZI ET AL.
Table 1. Synthesis of highly functional dithiocarbamates in water
Entry
Amine
Bromoester
Yield
IR (cmꢀ1
)
1
2
3
R3 ¼ H,R4 ¼ Me
R3 ¼ H,R4 ¼ Et
R3 ¼ Me,R4 ¼ Me
95[6c]
94[6c]
92
680, 1010, 1726
684, 1015, 1730
670, 1005, 1728
4
5
6
R3 ¼ H,R4 ¼ Me
R3 ¼ H,R4 ¼ Et
R3 ¼ Me,R4 ¼ Me
97[10f]
94[10f]
90[6c]
683, 1154, 1720
680, 1130, 1718
688, 1015, 1740
7
8
9
R3 ¼ H,R4 ¼ Me
R3 ¼ H,R4 ¼ Et
R3 ¼ Me,R4 ¼ Me
97[10f]
97[10f]
92[10f]
688, 1020, 1742
672, 1105, 1725
690, 1035, 1735
10
11
12
R3 ¼ H,R4 ¼ Me
R3 ¼ H,R4 ¼ Et
R3 ¼ Me,R4 ¼ Me
90
88
84
690, 1030, 1520, 1732
665, 1130, 1510, 1720
692, 1080, 1515, 1710
13
14
15
R3 ¼ H,R4 ¼ Me
R3 ¼ H,R4 ¼ Et
R3 ¼ Me,R4 ¼ Me
92a
8a
85a
670, 1090, 1460, 1510, 1732
662, 1088, 1467, 1528, 1735
668, 1092, 1468, 1515, 1715
aMixture of two disastereoisomers.
bConversion yields.
amines such as piperidine, pyrrolidine, and diallylamine reacted with methyl bro-
moacetate, ethyl bromoacetate, and methyl 2-bromopropionate to afford the corre-
sponding products in excellent yields. Reaction of optically pure (R)-(þ)-
1-phenylethylamine gave a mixture of two diastereoisomer in excellent yield. When
the reaction was completed, the products were extracted by ethyl acetate, followed
by concentration under reduced pressure to afford a quantitative recovery of very
1
clean crude product. The H NMR spectrum of the crude product did not show
any trace of the starting material or by-products in most cases.
CONCLUSION
In summary, the unique aspects of this protocol arise from the near-perfect
reliability of the water-catalyzed synthesis of S-alkyl dithiocarbamate in a one-pot
reaction. The reaction is experimentally simple, proceeding well in water without
any promoter or harsh condition, requiring only commercially available starting
materials. Virtually no by-products were formed in most cases. Equally important
is the wide scope, high selectivity, and nearly quantitative yields of this transform-
ation. In this procedure, the components are simply mixed in water with stirring,

FUNCTIONAL DITHIOCARBAMATE SYNTHESIS
97
and pure products can be isolated by filtration or simple extraction. Thus, a diverse
set of synthetically useful dithiocarbamate products can potentially be prepared in
onestep by this method. Furthermore, the reactions can be performed on a multi-
gram scale under operationally simple and safe conditions. These results provide
further evidence that assembly of complex products from simple starting materials
can be carried out in water. Further studies aiming to explore novel carbon disulfide
assembly reactions in water are under way in our laboratory.
EXPERIMENTAL
General
NMR spectra were recorded on a Bruker ACF 500 using CDCl3=CCl4 or
CDCl3=DMSO-d6 as solvent. Column chromatography was performed on silica
gel, Merck grade 60. Ethyl acetate, petroleum ether, and water were distilled before
use. Alkyl halides, amines, and other chemicals were purchased and used without
further purification.
General Procedure for the One-Pot Reaction of Amines, CS2, and
Alkyl Halides in Water
An amine (8 mmol) was added slowly to a mixture of carbon disulfide (8 mmol)
and an alkylhalide (4 mmol) in water (5 mL) in an ice bath. The mixture was stirred
at 0 ꢁC for 20 min, warmed to room temperature, and stirred for 6–15 h. After com-
pletion, the reaction mixture was extracted with ethyl acetate and washed with water.
The organic layer was dried over anhydrous sodium sulfate and concentrated, and
the residue was purified by column chromatography (EtOAc and petroleum ether)
to obtain pure products. All compounds were characterized on the basis of NMR
spectroscopic data.
Selected Spectroscopic Data
Table 1, Entry 3. 1H NMR (500 MHz, CDCl3): d ¼ 1.63 (d, J ¼ 7.4 Hz, 3 H),
1.73–1.75 (m, 6 H), 3.79 (s, 3 H), 3.89–3.93 (m, 2 H), 4.20– 4.35 (m, 2 H), 4.84 (q,
J ¼ 7.4, 1 H). 13C NMR (125 MHz, CDCl3): 17.7, 24.6, 25.2, 25.7, 49.4, 50.1, 53.1,
53.8, 173.4, 193.6.
Table 1, Entry 6. 1H NMR (500 MHz, CDCl3): 1.26 (t, J ¼ 7 Hz, 3 H), 1.30 (t,
J ¼ 7.0 3, H), 1.58 (d, J ¼ 7.9 Hz, 3 H), 3.69–3.77 (m, 5 H), 4.00 (q, J ¼ 7.0 Hz, 2 H),
4.78 (q, J ¼ 7.9 Hz, 1 H). 13C NMR (125 MHz, CDCl3): 11.9, 12.9, 17.7, 47.3, 49.3,
50.0, 53.1, 173.3, 193.6.
Table 1, Entry 9. 1H NMR (500 MHz, CDCl3): d ¼ 1.57 (d, J ¼ 7.2 Hz, 3 H),
1.93–1.96 (m, 2 H), 2.04–2.10 (m, 2 H), 3.58–3.63 (m, 2 H), 3.72 (s, 3 H), 3.86–3.88
(m, 2 H), 4.8 (q, J ¼ 7.1 Hz, 1 H), 13C NMR (125 MHz, CDCl3): d ¼ 17.9, 24.6, 26.5,
48.6, 51.0, 53.1, 55.5, 173.1, 190.7.

98
N. AZIZI ET AL.
Table 1, Entry 10. 1H NMR (500 MHz, CDCl3): 3.65 (s, 3 H), 4.04 (s, 2 H),
4.27 (br, 2 H), 4.54 (br, 2 H), 5.11–5.22 (m, 4 H), 5.76–5.79 (m, 2 H), 13C NMR
(125 MHz, CDCl3): 20.7, 53.4, 56.8, 118.9, 131.5, 199.4.
Table 1, Entry 15. 1H NMR (500 MHz, CDCl3): d ¼ 1.57 (d, J ¼ 7.1 Hz, 3 H),
1.64 (d, J ¼ 7.2 Hz, 3 H), 3.86 (s, 3 H), 4.43 (q, J ¼ 7.2 Hz, 1 H), 5.76 (q, J ¼ 7.1 Hz, 1
H), 7.35–7.42 (m, 5 H), 8.17 (br, NH). 13C NMR (125 MHz, CDCl3): d ¼ 17.1, 21.2,
46.8, 53.4, 56.5, 127.0, 128.2, 129.2, 141.7, 173.7, 193.9.
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