A rapid and convenient synthesis of gem-bis(dithiocarbamate) derivatives from primary aliphatic amines, carbon disulfide, and aromatic aldehydes using boron trifluoride-diethyl etherate

Article abstract of DOI:10.1016/j.tetlet.2014.04.106

An efficient route for the synthesis of gem-bis(dithiocarbamate) derivatives is developed using dithiocarbamic acid salts generated from primary aliphatic amines and CS₂. The method offers high yields, employs mild reaction conditions, and demonstrates excellent functional group compatibility. The structures of the products were confirmed spectroscopically and by X-ray analysis.

Full text of DOI:10.1016/j.tetlet.2014.04.106

Accepted Manuscript
A rapid and convenient synthesis of gem-bis(dithiocarbamate) derivatives from
primary aliphatic amines, carbon disulfide and aromatic aldehydes using boron
trifluoride-diethyl etherate
Firouzeh Nemati, Ali Ghorbani Gharjeh Ghiyaei, Behrouz Notash, Mojtaba
Hajiloo Shayegan, Vahid Amani
PII:
S0040-4039(14)00743-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.106
TETL 44568
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 February 2014
29 March 2014
30 April 2014
Please cite this article as: Nemati, F., Ghorbani Gharjeh Ghiyaei, A., Notash, B., Shayegan, M.H., Amani, V., A
rapid and convenient synthesis of gem-bis(dithiocarbamate) derivatives from primary aliphatic amines, carbon
disulfide and aromatic aldehydes using boron trifluoride-diethyl etherate, Tetrahedron Letters (2014), doi: http://
dx.doi.org/10.1016/j.tetlet.2014.04.106
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Graphical Abstract
A rapid and convenient synthesis of gem-bis(dithiocarbamate) derivatives from primary
aliphatic amines, carbon disulfide and aromatic aldehydes using boron trifluoride-diethyl
etherate
Firouzeh Nemati*, Ali Ghorbani Gharjeh Ghiyaei, Behrouz Notash, Mojtaba Hajiloo Shayegan,
Vahid Amani

A rapid and convenient synthesis of gem-bis(dithiocarbamate) derivatives from primary
aliphatic amines, carbon disulfide and aromatic aldehydes using boron trifluoride-diethyl
etherate
Firouzeh Nemati*a, Ali Ghorbani Gharjeh Ghiyaeia, Behrouz Notashb, Mojtaba Hajiloo
Shayeganc, Vahid Amanid
aDepartment
Of
Chemistry,
Semnan
University,
Semnan,
Iran,
E-mail:
fnemati_1350@yahoo.com; fnemati@semnan.ac.ir, Tel: +98 09122057819, Fax: +98 (231)
3354057
bChemistry Department, Shahid Beheshti University, G. C., Evin, Tehran 1983963113, Iran.
cDepartment of Chemistry, Sharif University of Technology, P.O. Box 11465-9516.
dDepartment of Chemistry, Shahre-rey Branch, Islamic Azad University, Tehran, Iran.
Abstract
An efficient route for the synthesis of gem-bis(dithiocarbamate) derivatives is developed using
dithiocarbamic acid salts generated from primary aliphatic amines and CS2. The method offers
high yields, employs mild reaction conditions, and demonstrates excellent functional group
compatibility. The structures of the products were confirmed spectroscopically and by X-ray
analysis.
Keywords: Dithocarbamic acid salt; Primary aliphatic amine; Carbon disulfide; Boron triflouride
–diethyl etherate.
1

Organic dithiocarbamates are valuable synthetic intermediates that are found in a variety of
biological compounds (Figure 1).1,2 They have received considerable attention because of their
pivotal role in agriculture and as linkers in solid phase organic synthesis.3-7 They are also used in
the rubber industry as vulcanization accelerators and as inhibitors of enzymes.8,9 One area that
has been intensely studied is their activity against cancer.10-13
Figure 1.
Dithiocarbamates represent a versatile class of ligands with the ability to stabilize transition
metals in a wide range of oxidation states.14 They have also been widely used in the synthesis of
amino-1,3,4-thiadiazoles,15
thioureas,16-19
aminobenzimidazoles,20
isothiocyanates,21-23
alkoxyamines,24 2-imino-1,3-dithiolane,25 and for the total syntheses of natural compounds. 26, 27
These compounds exhibit good nucleophilic reactivity with electrophiles such as alkyl halides,
epoxides, and α,β-unsaturated carbonyl compounds to give products that can be exploited easily
in functional group transformations and have applications in organic synthesis and industry.28-33
Ziyaei-Halimehjani et al. previously reported the reaction of dithiocarbamic acid salts with aryl
aldehydes in the presence of BF3.Et2O. The reaction is temperature-dependent and gives gem-
bis(dithiocarbamates) and 2-iminium-1,3-dithietane as the only products at 35-45 °C and 15-20
°C, respectively. They indicated that the reaction does not give the desired products with primary
aliphatic amines.34 It should be noted that their method was conducted with secondary aliphatic
amines, which are more nucleophilic than their primary equivalents.
Most reports on these compounds have dealt solely with the properties of
dialkyldithiocarbamates, and little mention has been made of the properties of
2

monoalkyldithiocarbamates.35-38 The synthesis of derivatives of monoalkyldithiocarbamates is
therefore of interest. This study examines the reactions of primary aliphatic amines, CS2, and
aromatic aldehydes in the presence of BF3·OEt2 as the catalyst.
Considering the above reports and in order to investigate the possibility of a one-pot
synthesis of the target compounds, the reaction conditions were initially optimized using n-
propylamine, CS2, and 4-chlorobenzaldehyde as model substrates in the presence of BF3·OEt2.
Different solvents and temperatures were examined, but, unfortunately, no product was obtained
under these conditions. As an alternative, the dithiocarbamic acid salt was prepared in a different
vessel and was added to a solution of 4-chlorobenzaldehyde and BF3·OEt2 in chloroform at room
temperature. These conditions led to the formation of the gem-bis(dithiocarbamate) product (3a)
in high yield and in a short reaction time (Scheme 1).
Scheme 1.
In an effort to improve the reaction conditions and to scrutinize the possibility of the
formation of a 2-imino-1,3-dithietane ring (4a), different amounts of BF3·OEt2 and varying the
reaction temperature (-10 to 80 °C) were investigated. Lowering or raising the temperature or
amount of BF3·OEt2 did not lead to production of 2-imino-1,3-dithietane 4a; only gem-
bis(dithiocarbamate) 3a was obtained. Other reaction parameters were subsequently examined,
such as the addition of stronger bases including triethylamine and NaOH and changing the
reagent ratios in the model reaction. These efforts also failed to give 2-imino-1,3-dithietane.
Accordingly, 1.7 mL of BF3.OEt2 was found to be the optimum amount of catalyst for obtaining
the gem-bis(dithiocarbamate) at room temperature in chloroform. Incremental changes in the
amount of BF3.OEt2 or the temperature did not produce useful increases in the product yield. The
most suitable mole ratio of CS2:amine:aldehyde was 5:10:2.
3

Using the optimized reaction conditions, the scope and limitations of this process were
explored with a range of aromatic aldehydes and primary aliphatic amines. As can be seen from
Table 1, aromatic aldehydes containing either electron-donating or electron-withdrawing groups
reacted efficiently, giving high yields of the gem-bis(dithiocarbamate) derivatives. This protocol
proved to be clean and fast. Pure products were isolated in yields of 80-97% after 25-210 min
following a simple work-up (Table 1). Notably, thiophene-2-carbaldehyde successfully produced
the desired products, which are useful for synthetic elaboration (Table 2, entries 5 and 6).
Unfortunately, benzylamine and an aryl aldehyde with an NO2 functional group produced
unstable products that decomposed immediately after work-up (Table 1, entries 13 and 14).
Table 1.
The deprotection of synthetic gem-bis(dithiocarbamate) derivatives in the presence of dilute
nitric acid returned the corresponding aldehydes in excellent yields after 10-15 minutes with the
evolution of NO2 gas. This procedure can be used for the protection of a carbonyl group in
aldehydes, since deprotection of gem-bis(dithiocarbamates) can be carried out in aqueous nitric
acid.39-41
1
The structures of products 3a-l were characterized using FTIR, H NMR, and 13C NMR
spectroscopy and elemental analyses. For example, the FTIR spectrum of compound 3b revealed
characteristic absorptions at 3238 cm-1 for N-H and 1175 cm-1 for C=S stretching vibrations. The
1H NMR spectrum of 3b showed a singlet for the benzylic hydrogen at δ 6.99. The resonance
appearing low field at δ 8.0 (N-H), supported the formation of a thioamide functional group. The
13
1H-decoupled C NMR spectrum of 3b showed nine distinct resonances in agreement with the
4

suggested structure. We were also able to obtain suitable crystals of 3c for X-ray crystallography
to confirm the structure of the product.43 The ORTEP view of the single crystal X-ray analysis of
3c with atomic numbering is shown in Figure 2.
Figure 2.
A plausible mechanism for this conversion is illustrated in Scheme 2. The reaction commences
with the coordination of the aldehyde to BF3. The activated carbonyl group is then attacked by
the dithiocarbamic acid salt to form intermediate A. In turn, intermediate A reacts with a second
equivalent of the dithiocarbamic acid salt to yield the gem-bis(dithiocarbamates) after
dehydration. The interaction of non-bonding electrons of nitrogen with BF3 and the lower
basicity of primary aliphatic amines is thought to prevent the synthesis of a 2-imino-1,3-
dithietane.
Scheme 2
To summarize, we have reported an efficient, safe and experimentally simple method for the
synthesis of gem-bis(dithiocarbamate) derivatives. These reactions were carried out using
primary aliphatic amines, CS2 and aromatic aldehydes in the presence of BF3.OEt2 as an acid
catalyst. The significant features of this reaction include short reaction times, no column
chromatographic purification, high yields of products and readily available starting materials.
Acknowledgements
We thank the Department of Chemistry and office of gifted students at Semnan University for
financial support.
References and Notes
5

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42. Typical procedure for the synthesis of gem-bis(dithiocarbamate) 3c:
To a stirred solution of 4-chlorobenzaldehyde (0.28 g, 2 mmol) and BF3·OEt2 (1.7-2 mL) in
CHCl3 (10 mL) was gradually added freshly prepared dithiocarbamic acid salt. [The
dithiocarbamic acid salt was prepared in a separate vessel by the reaction of sec-butylamine
(1.02 g, 14 mmol) and CS2 (0.5 g, 7 mmol) in CHCl3 (10 mL) for 20 min]. The mixture was
stirred at room temperature for 45 min (Table 1). After completion of the reaction as monitored
by TLC, CHCl3 (20 mL) was added to the mixture, which was then washed with H2O (3×60
mL). The organic layer was dried over anhydrous Na2SO4. Evaporation of the solvent and
washing the residue with n-hexane (20 mL) gave the pure product 3c (0.38 g, 92%) as a white
solid.
Compound 3b: IR (KBr, cm-1): ν 3238, 1175; 1H NMR (300 MHz, CDCl3): δ 0.95 (6H, t, J= 7.5
Hz), 1.63-1.76 (4H, m), 3.65-3.71 (4H, m), 6.99 (1H, s), 7.27 (2H, d, J=8.7 Hz), 7.46 (2H, d,
8

J=8.7 Hz), 8.00 (2H, s); 13C NMR (75 MHz, CDCl3): δ 11.4, 21.8, 48.9, 59.2, 122.9, 129.5,
132.1, 136, 193.1; Anal. Calcd for C15H21N2S4Br: C, 41.18; H, 4.80; N, 6.40; Found: C, 41.30;
H, 4.99; N, 6.19.
Compound 3c: IR (KBr, cm-1): ν 3238, 1165; 1H NMR (400 MHz, CDCl3): δ 0.91-0.97 (6H, m),
1.22-1.28 (6H, m), 1.57-1.66 (4H, m), 4.59 (2H, m), 7.21 (s, 1H), 7.31-7.42 (4H, m), 8.01 (s,
2H); 13C NMR (75 MHz, CDCl3): δ 11.3, 20.6, 29.9, 55.8, 57.2, 128.9, 129.1, 132.6, 140.1,
195.3; Anal. Calcd for C17H25N2S4Cl: C, 48.51; H, 5.94; N, 6.65; Found: C, 48.71; H, 6.17; N,
6.51.
43. X-ray data for 3c: C34H50Cl2N4S8 (2 molecules in the unit cell), M = 842.16, triclinic system,
space group Pī, a = 12.114(2), b = 13.267(3), c = 14.974(3) Å; α = 95.75(3), β = 110.80(3), γ =
102.12(3)º; V = 2159.0(10) Å3, Z = 2, Dcalcd = 1.295 g cm-3, μ(Mo-Kα)= 0.566 mm-1, crystal
dimensions of 0.40×0.32×0.22 mm. The X-ray diffraction measurement was made on a STOE
IPDS 2T diffractometer with graphite monochromated Mo-Kα radiation. The structure was
solved using SHELXS. The data reduction and structure refinement was carried out with
SHELXL using the X-STEP32 crystallographic software package.44 The non-hydrogen atoms
were refined anisotropically by full matrix least-squares on F2 values to final R1 = 0.0873, wR2 =
0.2053 and S = 1.032 with 463 parameters using 11596 independent reflections (θ range = 2.33-
29.20º). Hydrogen atoms attached to nitrogen atoms were located in the difference Fourier map
and refined isotropically. All other hydrogen atoms were added in idealized positions. The
crystallographic information file has been deposited with the Cambridge Crystallographic Data
Centre, CCDC 985711.
44. X-STEP32 Version 1.07b, Crystallographic Package; Stoe & Cie GmbH: Darmstadt,
Germany, 2000.
9

Table 1. Synthesis of gem-bis(dithiocarbamate) derivatives.42
Entry ArCHO
RNH2
Product
Time (min) Yield (%)a
M.p (C)
81-83
88-89
96-97
104-105
99-100
84-85
94-95
109-110
98-99
68-70
107-108
90-91
92-94
-
1
4-ClC6H4CHO
n-PrNH2
n-PrNH2
s-BuNH2
s-BuNH2
40
90
80
92
87
90
92
95
97
87
91
88
95
85
85
3a
3b
3c
3d
3e
3f
2
4-BrC6H4CHO
4-ClC6H4CHO
2-ClC6H4CHO
60
3
45
4
210
30
5
thiophene-2-carbaldehyde s-BuNH2
thiophene-2-carbaldehyde n-PrNH2
6
30
7
2-naphthaldehyde
2-naphthaldehyde
4-MeOC6H4CHO
4-FC6H4CHO
n-PrNH2
s-BuNH2
s-BuNH2
n-PrNH2
s-BuNH2
n-PrNH2
s-BuNH2
70
3g
3h
3i
8
70
9
45
10
11
12
13
14
25
3j
4-FC6H4CHO
210
30
3k
3l
4-MeC6H4CHO
4-NO2C6H4CHO
4-ClC6H4CHO
3mb
210
70
PhCH2NH2 3nb
aYield of isolated product.
bThese compounds decomposed within one day.
10

Figure 1. Examples of bioactive dithiocarbamate derivatives.
11

Figure 2. The ORTEP diagram of 3c. Thermal ellipsoids are at 30% probability level.
12

Scheme 1. Preliminary studies
13

Scheme 2. A plausible mechanism.
14

Figures and Schemes Captions
Figure 1. Examples of bioactive dithiocarbamate derivatives.
Figure 2. The ORTEP diagram of 3c. Thermal ellipsoids are at 30% probability level.
Scheme 1. Preliminary studies.
Scheme 2. A plausible mechanism.
15