Investigation of the reaction of dithiocarbamic acid salts with aromatic aldehydes

Article abstract of DOI:10.1021/ol301598u

A reaction of dithiocarbamic acid salts with carbonyl compounds was investigated for the first time in the presence of BF₃?OEt ₂. The reaction is temperature dependent and gives gem-bis(dithiocarbamates) at 35-45 °C as a molecule with high equivalents of dithiocarbamate groups. At lower temperatures (15-20 °C), the 2-iminium-1,3-dithietane is obtained as the only product. The structure of a 2-iminium-1,3-dithietane was accomplished by X-ray crystallographic analysis.

Full text of DOI:10.1021/ol301598u

ORGANIC
LETTERS
2012
Vol. 14, No. 15
3838–3841
Investigation of the Reaction
of Dithiocarbamic Acid Salts with
Aromatic Aldehydes
Azim Ziyaei Halimehjani,*,† Mojtaba Hajiloo Shayegan,‡
Mohammad Mahmoodi Hashemi,‡ and Behrooz Notash§
Faculty of Chemistry, Tarbiat Moallem University, 49 Mofateh Street, Tehran, Iran,
Department of Chemistry, Sharif University of Technology, P.O. Box 11465-9516
Tehran, Iran, and Chemistry Department, Shahid Beheshti University, G. C., Evin,
Tehran 1983963113, Iran
ziyaei@tmu.ac.ir
Received May 28, 2012
ABSTRACT
A reaction of dithiocarbamic acid salts with carbonyl compounds was investigated for the first time in the presence of BF3 OEt2. The reaction is
3
temperature dependent and gives gem-bis(dithiocarbamates) at 35À45 °C as a molecule with high equivalents of dithiocarbamate groups. At
lower temperatures (15À20 °C), the 2-iminium-1,3-dithietane is obtained as the only product. The structure of a 2-iminium-1,3-dithietane was
accomplished by X-ray crystallographic analysis.
Dithiocarbamic acids are the analogue of carbamic acids
in which both oxygen atoms are replaced by sulfur atoms.
These compounds are good nucleophiles and react with
different electrophiles such as alkyl halides,1 epoxides,2
R,β-unsaturated carbonyl compounds,3 etc.4 Although the
dithiocarbamic acids are not stable, their esters or their
complexes with metals are stable and have found wide
applications as fungicides and pesticides in agriculture,5
sulfur vulcanization in rubber manufacturing,6 rad-
ical chain transfer agents in the reversible additionÀ
fragmentation chain transfer (RAFT) polymerizations,7
organic intermediates,8 and medicinal chemistry.9 To the
best of our knowledge, there is not any report on the
(6) (a) Nieuwenhuizen, P. J.; Ehlers, A. W.; Haasnoot, J. G.; Janse,
S. R.; Reedijk, J.; Baerends, E. J. J. Am. Chem. Soc. 1999, 121, 163–168.
(b) Messer, W. E. US Patent 1893630, 1930.
† Tarbiat Moallem University.
‡ Sharif University of Technology.
§ Shahid Beheshti University.
(7) (a) Lai, J. T.; Shea, R. J. Polym. Sci., Part A: Polym. Chem. 2006,
(1) Azizi, N.; Aryanasab, F.; Saidi, M. R. Org. Lett. 2006, 8, 5275–5277.
(2) (a) Ziyaei Halimehjani, A.; Saidi, M. R. Can. J. Chem. 2006, 84,
1515–1519. (b) Azizi, N.; Pourhasan, B.; Aryanasab, F.; Saidi, M. R.
Synlett 2007, 2797–2800.
ꢀ
44, 4298–4316. (b) Dureaault, A.; Gnanou, Y.; Taton, D.; Destarac, M.;
Leising, F. Angew. Chem., Int. Ed. 2003, 42, 2869–2872. (c) Bathfield,
M.; D’Agosto, F.; Spitz, R.; Charreyre, M. T.; Delair, T. J. Am. Chem.
Soc. 2006, 128, 2546–2547.
(3) Azizi, N.; Aryanasab, F.; Torkiyan, L.; Ziyaei, A.; Saidi, M. R.
J. Org. Chem. 2006, 71, 3634–3635.
(4) Yavari, I.; Hosseini, N.; Moradi, L.; Mirzaei, A. Tetrahedron
Lett. 2008, 49, 4239–4241.
(5) (a) Marinovich, M.; Viviani, B.; Capra, V.; Corsini, E.; Anselmi,
L.; D’Agostino, G.; Nucci, A. D.; Binaglia, M.; Tonini, M.; Galli, C. L.
Chem. Res. Toxicol. 2002, 15, 26–32. (b) Malik, A. K.; Rao, A. L. J.
J. Agric. Food Chem. 2000, 48, 4044–4047. (c) Weissmahr, K. W.;
Houghton, C. L.; Sedlak, D. L. Anal. Chem. 1998, 70, 4800–4804.
(8) (a) Tsuboi, S.; Takeda, S.; Yamasaki, Y.; Sakai, T.; Utka, M.;
Ishida, S.; Yamada, E.; Hirano, J. Chem. Lett. 1992, 1417–1418.
(b) Katritzky, A. R.; Singh, S.; Mahapatra, P. P.; Clemense, N.; Kirichenko,
K. ARKIVOC 2005, 9, 63–68. (c) Blanrue, A.; Wilhelm, R. Synthesis
2009, 583–586. (d) Zhang, D.; Chen, J.; Liang, Y.; Zhou, H. Synth.
Commun. 2005, 35, 521–526. (e) Aryanasab, F.; Ziyaei Halimehjani, A.;
Saidi, M. R. Tetrahedron Lett. 2010, 51, 790–792. (f) Ziyaei Halimehjani,
A.; Pourshojaei, Y.; Saidi, M. R. Tetrahedron Lett. 2009, 50, 32–34.
(g) Rozen, O.; Mishani, E.; Rozen, S. Tetrahedron 2010, 66, 3579–3582.
r
10.1021/ol301598u
Published on Web 07/23/2012
2012 American Chemical Society

Scheme 1. Synthesis of gem-Bis(dithiocarbamte) and 2-Iminium 1,3-Dithietane with Reaction of Benzaldehyde and Dithiocarbamic
Acid Salt
reaction of dithiocarbamic acids with carbonyl compounds.
In continuation of our interest toward the synthesis of
dithiocarbamates and their applications as intermediates
for the synthesisof biologically activecompounds,10 herein
we report the reaction of dithiocarbamic acid salts with
carbonyl compounds for the first time for the synthesis of
gem-bis(dithiocarbamates) and 2-iminium-1,3-dithietane
salts with the reaction of an aldehyde, CS2, and an amine
this reaction because highly stable metal dithiocarbamate
complexes are produced.
After optimizing the reaction conditions, we next exam-
ined the generality of these conditions to other substrates
using several amines and aldehydes. The results are sum-
marized in Tables 1 and 2. A variety of aromatic aldehydes
with electron-donating and -withdrawing groups on the
benzene ring were used in this reaction with high to ex-
cellent yields. In addition, different aliphatic secondary
amines such as pyrrolidine, piperidine, diethylamine, and
morpholine give high to excellent yields. The reaction does
not give the desired products with primary aliphatic amines,
aromatic amines, ketones, and aliphatic aldehydes. The
dithietane and gem-bis(dithiocarbamate) products are white
to yellowish solids which are stable for several months.
Terephthaldehyde was used in this reaction and the
desired product with four dithiocarbamate groups 4 was
obtained in high yields (Scheme 2).
in the presence of BF3 OEt2 as catalyst.
3
We began our investigations with a one-pot, three-
component reaction of diethylamine, CS2, and benzalde-
hyde in the presence of BF3 OEt2 in CHCl3 at room tem-
3
perature. Noproduct was obtainedunder these conditions.
Therefore, an alternative synthetic strategy was pursued.
The dithiocarbamic acid salt 1 was prepared in a different
vessel and was added to the solution of benzaldehyde and
BF3 OEt2 in CHCl3 at room temperature. We found that
3
the reaction was completed and the mixture of products
2 and 3 were obtained in 70:30 ratios. By changing the
reaction temperature, we found out that the formation of
the products is temperature dependent. At 35À45 °C, the
gem-bis(dithiocarbamate) 2 was obtained as the only
product, while at low temperatures (15À20 °C) the 2-(N,N-
diethyliminium)-4-phenyl-1,3-dithietane tetrafluoro-
borate 3 was obtained as the only product. It seems that the
synthesis of gem-bis(dithiocarbamates) passes through the
dithietane ring formation (Scheme 1). Attempt to obtain
the products using a Bronsted acid such as sulfuric acid,
TFA, or PTSA was not successful. We also observed that
the transition-metal salts as Lewis acids are not suitable for
Scheme 2. Reaction of Dithiocarbamic Acid Salt with
Terephthaldehyde
(9) (a) Aboul-Fadl, T.; El-Shorbagi, A. Eur. J. Med. Chem. 1996, 31,
165–169. (b) Cascio, G.; Lorenzi, L.; Caglio, D.; Manghisi, E.; Arcamone,
F.; Guanti, G.; Satta, G.; Morandotti, G.; Sperning, R. Farmaco 1996, 51,
189–196. (c) Imamura, H.; Ohtake, N.; Jona, H.; Shimizu, A.; Moriya, M.;
Sato, H.; Sugimoto, Y.; Ikeura, C.; Kiyonaga, H.; Nakano, M.; Hagano,
R.; Abe, S.; Yamada, K.; Hashizume, T.; Morishima, H. Bioorg. Med.
Chem. Lett. 2001, 9, 1571–1578. (d) Gerhauser, C.; You, M.; Liu, J.;
Moriarty, R. T.; Hawthorne, M.; Mehta, R. G.; Moon, R. C.; Pezzuto,
J. M. Cancer Res. 1997, 57, 272–278. (e) Scozzafava, A.; Mastorlorenzo, A.;
Supuran, C. T. Bioorg. Med. Chem. Lett. 2000, 10, 1887–1891. (f) Hou,
X. L.; Ge, Z. M.; Wang, T. M.; Guo, W.; Cui, J. R.; Cheng, T. M.; Lai,
C. S.; Li, R. T. Bioorg. Med. Chem. Lett. 2006, 16, 4214–4219.
Deprotection of the gem-bis(dithiocarbamates) was in-
vestigated in the presence of different acids such as HCl,
HClO4, HNO3, and H2SO4 in water. Although it is well
documented that the gem-bis (dithiocarbamates) con-
verted to 2-iminium-1,3-dithietane rings with concentrated
H2SO4 and 70% HClO4,11 but these compounds are stable
in aqueous solution of HCl, HClO4 and H2SO4 for several
(10) (a) Ziyaei Halimehjani, A.; Maleki, H.; Saidi, M. R. Tetrahedron
Lett. 2009, 50, 2747–2749. (b) Ziyaei Halimehjani, A.; Marjani, K.;
Ashouri, A. Green Chem. 2010, 12, 1306–1310.
(11) Ueno, Y.; Okawara, M. Chem. Lett. 1973, 863–866.
Org. Lett., Vol. 14, No. 15, 2012
3839

hours except inthe presence of nitricacid, the aldehyde was
recovered after fewminutes withevolutionof NO2 gas with
excellent yields (Scheme 3). This procedure is also effective
for acid-sensitive compounds such as 2q without affecting
the methoxy group. The mechanism of deprotection is not
yet known. The gem-bis(dithiocarbamates) are also stable
in aqueous basic medium for several hours.
Table 2. Diversity in the Synthesis of 2-Iminium 1,3-Dithietane
Tetrafluoroborate
Scheme 3. Deprotection of gem-Bis(dithiocarbamates) 2l, 2n,
and 2q
a Isolated yield.
Table 1. Synthesis of gem-Bis(dithiocarbamates) with Various
Amines and Aldehydes
Figure 1. ORTEP representations of the structure of 3m. Ther-
mal ellipsoids have been drawn at the 50% probability level.
˚
Selected bond lengths (A) and angles (deg): C(8)ÀS(1), 1.729(3);
C(8)ÀS(2), 1.727(3); C(8)ÀN(1), 1.290(3); C(7)ÀS(1), 1.847(2);
C(7)ÀS(2), 1.847(3); S(2)ÀC(8)ÀN(1), 128.53(19)°; S(1)ÀC(8)À
N(1), 129.57(19)°; S(2)ÀC(8)ÀS(1), 101.90(13)°; S(2)ÀC(7)À
S(1), 93.23(11)°; S(2)ÀC(7)ÀC(4), 115.28(16)°; S(1)ÀC(7)À
C(4), 114.25(16)°.
peakat 7À8 ppm for the benzylic hydrogen. Also the 13C of
dithiocarbamate moiety was assigned at 185À195 ppm in
13C NMR spectra.The benzylic hydrogen in the dithietane
ring was observed at 5.5À6.5 ppm as singlet in 1H NMR
spectra. In addition, the peak at 175À185 ppm in 13C
NMR was assigned to the carbon of the iminium moiety in
the dithietane products. The peak near À152 ppm in the
a Isolated yield.
1
The structures of products were confirmed by H and
13C NMR spectroscopy and CHN analysis.The 1H NMR
spectra of the gem-bis(dithiocarbamates) show a singlet
3840
Org. Lett., Vol. 14, No. 15, 2012

Scheme 4. Proposed Mechanism for Preparation of the Dithietane Ring
19F NMR spectra was assigned to the tetrafluoroborate
anion. In addition, the boron was observed around À20
ppm in 11B NMR. A single crystal of 3m (see Table 2, entry
13) was prepared in CHCl3, and X-ray crystallographic
analysis established the structure of the 1,3-dithietane ring.
ORTEP representations are shown in Figure 1 (CCDC no.
870959; for details of the crystal structure data and refine-
ment of 3m see the Supporting Information. The formation
of the dithietane ring results a highly distorted tetrahe-
dron structure around the central C(7) atom. As shown
in Figure 1, the observed bond distances of C(8)ÀS(1),
using an aldehyde, CS2, and an amine catalyzed by BF3 OEt2
3
in chloroform. The gem-bis(dithiocarbamates) may be used
as new fungicides, especially gem-bis(dithiocarbamate)
prepared with terephthaldehyde with high equivalents of
dithiocarbamate in its structure.12 In addition, we believe
this procedure for the synthesis of gem-bis(dithiocarbamates)
as a new protective methodology can be utilized widely in
modern organic synthesis for the protection of carbonyl
group in aldehydes.13 In addition, deprotection of gem-
bis(dithiocarbamates) is simple and can be carried out in
aqueous nitric acid. We have shown a novel and efficient
procedure for the synthesis of substituted 2-iminium-1,3-
dithietane rings14 in one step. The key advantages of this
protocol are its operational simplicity, high to excellent
yields of products, and its ability to directly access the
substituted 2-iminium-1,3-dithietane salts in one step.
˚
˚
1.729(3) A and C(8)ÀS(2), 1.727(3) A, are virtually equal
and very similar and which are shorter than C(7)ÀS(1),
˚
˚
1.847(2) A and C(7)ÀS(2), 1.847(3) A because of incor-
poration of sulfur atoms in resonance with iminium group.
A proposed mechanism for the preparation of 1,3-
dithietane ring is given in Scheme 4. Reaction of an amine
with carbon disulfide gave the dithiocarbamic acid salt 1
which then added to an activated aldehyde with BF3 to
prepare the intermediate 5. Intramolecular addition of the
sulfur atom gave the dithietane ring with removal of the
oxygen group at low temperature. At higher temperatures,
intermolecular of another dithiocarbamic acid salt with
intermediate 5 gave the gem-bis (dithiocarbamate).
Acknowledgment. We are grateful to the Research
Council of Sharif University of Technology for financial
support. We also thank the Faculty of Chemistry of
Tarbiat Moallem University for supporting this work.
Supporting Information Available. Full experimental
details, characterization data, copies of 1H and 13C NMR
spectra for all compounds, mass spectra for 2a and 3f, and
X-ray data for 3m (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
In conclusion, for the first time, we have shown that the
reaction of dithiocarbamic acid salts with carbonyl com-
pounds can be used for the preparation of gem-bis(dithio-
carbamates) and substituted 2-iminium-1,3-dithietane rings
(14) (a) Bollinger, F. G. U.S. Patent 4,311,572, 1982; Chem. Abstr.
1982, 96, 142833e. (b) Bollinger, F. G. U.S. Patent 4,231,783, 1980;
Chem. Abstr. 1979, 92, 76492g. (c) Teach, E. G. U.S. Patent 4,451,280,
1984; Chem. Abstr. 1983, 98, 6348z. (d) Bollinger, F. G. U.S. Patent
4,411,688, 1983; Chem. Abstr. 1983, 98, 16668h. (e) Gutman, A. D. U.S.
Patent 4,414,019, 1983; Chem. Abstr. 1984, 98, 48681y.
(12) Len, C.; Boulogne-Merlot, A. S.; Postel, D.; Ronco, G.; Villa, P.;
Goubert, C.; Jeufrault, E.; Mathon, B.; Simon, H. J. Agric. Food Chem.
1996, 44, 2856–2858.
(13) Recent references for the protection of carbonyl compounds:
(a) Carmeli, M.; Rozen, O. Tetrahedron Lett. 2006, 47, 763–766. (b) Ren,
Y.-M.; Cai, C. Tetrahedron Lett. 2008, 49, 7110–7112. (c) Srivastava, P.;
Srivastava, R. Catal. Commun. 2008, 9, 645–649.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 15, 2012
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