Dithioates of Meldrum's acid, dimedone, and barbituric acid, novel sulfur transfer reagents for the one-pot copper-catalyzed conversion of aryl iodides into diaryl disulfides

Article abstract of DOI:10.1016/j.tetlet.2015.12.085

We report herein the first application of CH-acid dithioates as sulfur transfer reagents. A new route for the synthesis of diaryldisulfides using the copper-catalyzed conversion of aryl iodides in the presence of Melderum's acid, dimedone or barbituric acid dithioates is discussed.

Full text of DOI:10.1016/j.tetlet.2015.12.085

Accepted Manuscript
Dithioates of Meldrum’s acid, dimedone, and barbituric acid, novel sulfur trans-
fer reagents for the one-pot copper-catalyzed conversion of aryl iodides into
diaryl disulfides
Azizollah Habibi, Mohammad Hadi Baghersad, Mina Bilabary, Yousef
Valizadeh
PII:
S0040-4039(15)30500-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.12.085
TETL 47132
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 October 2015
17 December 2015
22 December 2015
Please cite this article as: Habibi, A., Baghersad, M.H., Bilabary, M., Valizadeh, Y., Dithioates of Meldrum’s acid,
dimedone, and barbituric acid, novel sulfur transfer reagents for the one-pot copper-catalyzed conversion of aryl
iodides into diaryl disulfides, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.12.085
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Dithioates of Meldrum's acid, dimedone, and barbituric acid, novel sulfur transfer reagents for
the one-pot copper-catalyzed conversion of aryl iodides into diaryl disulfides
Azizollah Habibi, Mohammad Hadi Baghersad, Mina Bilabary and Yousef Valizadeh

1
Tetrahedron Letters
Dithioates of Meldrum's acid, dimedone, and barbituric acid, novel sulfur transfer
reagents for the one-pot copper-catalyzed conversion of aryl iodides into diaryl
disulfides
Azizollah Habibia, , Mohammad Hadi Baghersada, Mina Bilabarya and Yousef Valizadeha
a Faculty of Chemistry, Kharazmi University, No. 43. P. Code 15719-14911.; Tehran, Iran
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We report herein the first application of CH-acid dithioates as sulfur transfer reagents. A new
route for the synthesis of diaryldisulfides using the copper-catalyzed conversion of aryl iodides
in the presence of Melderum’s acid, dimedone or barbituric acid dithioates is discussed.
Available online
Keywords:
copper-catalyzed conversion
sulfur transfer reagent
diaryl disulfide
dithioates
25, 26
Disulfide compounds have significant industrial and
disulfide in the presence of acetylenedicarboxylates.
continuation of our work on copper-catalyzed reactions,
In a
we
1-6
27
biological applications
and are utilized in the synthesis of
natural products and medicinal compounds,7,8 as well as in the
preparation of organic reagents such as sulfenyls and sulfinyls.9,10
They also play an important role in protein and peptide synthesis,
as vulcanizing agents, in the preparation of dynamic
combinatorial libraries, catenanes and macrocycles, carceplexes,
dendrimers, rotaxanes and micelles.11 Due to their widespread
usage, the development of new synthetic methods for these
compounds is still of interest. The most common methods for
preparing disulfides such as the oxidation of thiols, reductive
coupling of sulfonyl chlorides, reaction of activated aromatic
compounds, alkynes and alkenes with sulfur monochloride
(S2Cl2), and radical cyclization of substituted aminothiourea
derivatives have been reviewed in detail by Witt.12 Recently,
sulfur transfer reagents such as thiourea, potassium thiocyanate,
thiosemicarbazide, sodium sulfide, 5-methyl-1,3,4-oxadiazole-2-
thiolate, thioacetamide and morpholin-4-ium morpholine-4-
carbodithioate have also been used for the synthesis of sulfides
were interested in the copper-catalyzed conversion of aryl iodides
into the corresponding diaryldisulfides using dithioates of
Melderum's acid, dimedone, and barbituric acid as sulfur transfer
reagents (Scheme 1). 28
Scheme 1. Copper-catalyzed conversion of aryl iodides into
diaryl disulfides using dithioates.
According to the previously reported work by Yavari and co-
workers regarding the S-arylation of the malononitrile-CS2
adduct, 29 initially we had decided to apply the same reaction for
S-arylation of dithioates of Melderum's acid, dimedone, and
barbituric acid. However, in all examined cases a diaryldisulfide
was obtained as the only product, indicating that dithioates of the
mentioned CH-acids acted as good sulfur transfer reagents.
13
and disulfides from alkyl or aryl halides. More recently, the
dithioate of morpholine has been used as a sulfur transfer reagent
for the synthesis of aryl and alkyl disulfides. 14
Furthermore, active methylene compounds have received
widespread attention in the synthesis of organic compounds. 15 - 21
Meldrum's acid, dimedone, barbituric acid and their derivatives
have been widely used for the preparation of biologically active
The required dithioates were readily prepared by the reaction
of CS2 with the enolate anion of the above CH-acids in the
presence of Et3N. To optimize the reaction conditions,
iodobenzene was chosen as a model substrate and different
parameters such as catalyst, base, solvent and temperature were
investigated. Optimization of the reaction conditions for
compounds, intermediates, heterocycles and in multistep drug
22 - 24
synthesis.
We recently developed a concise and effective
synthesis for a series of novel ketene dithioacetals by the
condensation of active methylene compounds with carbon
———
 Corresponding author. Tel-Fax: +98-21-88848949; e-mail: habibi@khu.ac.ir

2
Tetrahedron Letters
dithioates of dimedone, Meldrum's acid, and barbituric acid are
Table 1. Optimization of reaction conditions for the dithioate
of dimedone a
compiled in Tables 1, 2 and 3, respectively. In all three cases, we
observed that when the reaction was performed in air, the desired
product was not formed and no reaction occurred in the absence
of a copper catalyst (Tables 1-3, entry 4). The greatest activity
was found at 100 °C for Meldrum's acid and barbituric acid
dithioates (Tables 2 and 3, entry 3), and at 60 °C for dimedone
dithioate (Table 1, entry 2). Different Cu sources were tested
using CS2 in DMF (Tables 1-3, entries 5-9) and the best
conversion was observed with CuCl. The reaction was also
examined with different catalyst loadings showing that 10 mol%
of CuCl (relative to the aryl iodide) was optimal. At lower
catalyst loadings the reaction was not complete and increased
catalyst loadings did not have a significant impact on the
efficiency of the reaction (Table 1-3, entries 10 and 11). A
solvent effect was observed and DMF was the best solvent for
the reaction of dimedone and Meldrum's acid dithioates with
iodobenzene while in the case of the barbituric acid dithioate,
DMSO was the best solvent (Tables 1-3, entries 12-15). Next,
we investigated the effect of the base on the reaction. No
improvement was shown using bases other than Et3N in the cases
of Meldrum's acid and dimedone dithioates, however, the
addition of a mineral base increased the yield when using
barbituric acid dithioate (Table 3, entries 16-18).
Entry
Catalyst
Solvent
T (°C)
t (h)
2a (%)
1
2
CuCl
CuCl
CuCl
-
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
25
60
100
60
60
60
60
60
60
60
60
60
60
60
60
24
4
4
4
4
4
4
4
4
4
4
4
4
4
4
10
72
72
-
3
4
5
CuI
62
20
70
47
55
40
74
66
-
6
CuO
CuOb
CuSO4
7
8
9
Cu(OAc)2 DMF
10
11
12
13
14
15
CuClc
CuCld
CuCl
CuCl
CuCl
CuCl
DMF
DMF
DMSO
H2O
Therefore our most general optimal reaction conditions for the
conversion of iodobenzene into the titled product using dithioates
of Meldrum's acid, dimedone and barbituric acid as sulfur
transfer reagents are as follows; for dimedone dithioate: 10 mol%
CuCl as catalyst, DMF as solvent and the reaction carried out at
60 °C under an N2 atmosphere. For Meldrum's acid dithioate: 10
mol% CuCl as catalyst, DMF as solvent and the reaction carried
out at 100 °C under an N2 atmosphere, and for barbituric acid
dithioate: 10 mol% CuCl as catalyst, Cs2CO3 as the second base,
DMSO as the solvent and the reaction was carried out at 100 °C
under an N2 atmosphere.
1,4-Dioxane
Toluene
25
40
aModel reaction conditions: PhI (1.0 mmol), CuCl (0.1 mmol), DMF (2 mL),
dimedone dithioate solution in DMF contains dimedone (1 mmol), CS2 (1
mmol) and Et3N (2 mmol), under a N2 atmosphere.
bCuO nanoparticles. (CuO nanoparticles were synthesized as described in the
literature).31
cCuCl (0.05 mmol).
dCuCl (0.2 mmol).
Table 2. Optimization of reaction conditions for the dithioate
of Meldrum’s acid a
Next, we investigated the scope of the reaction with respect to
aryl iodides (Table 4). Most of the aryl iodides examined under
the optimized reaction conditions gave good yields. Table 4
shows that the dithioate of Meldrum's acid was the best sulfur
donor and barbituric acid dithioate was better than dimedone
dithioate. Sterically hindered aryl iodides gave the corresponding
diaryl disulfides in good yields (Table 4, entries 2, 3, 8 and 9).
Aryl iodides with nitro substituents such as 1-iodo-4-
Entry
Catalyst
Solvent
T (°C)
t (h)
2a (%)
nitrobenzene,
1-iodo-2-nitrobenzene
and
1-iodo-2,4-
1
2
CuCl
CuCl
CuCl
-
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
25
60
100
60
60
60
60
60
60
60
60
60
60
60
60
24
4
4
4
4
4
4
4
4
4
4
4
4
4
4
Trace
55
94
-
dinitronenzene were also examined under optimized reaction
conditions but no desired product was obtained.
3
On the basis of previously reported findings in the literature,
the proposed mechanism for the copper-promoted conversion of
an aryl halide into a diaryldisulfide using a sulfur donor may
involve two main steps.13, 14, 30 In the first step, aryl thiolate is
generated in the coupling reaction between the sulfur donor and
aryl halide via an Ullman-type mechanism. Then, the generated
thiolate is converted into the corresponding disulfide by an
oxidative coupling. It is obvious that the oxidative coupling of
the arylthiolate must use a stoichiometric copper salt or oxygen
as the oxidant. However, in our case, when the reaction was
performed in air, the desired product was not formed. Moreover,
in order to check the presence of the phenyl thiolate as the
intermediate, the synthesis of diphenyl disulfide from thiophenol
was studied under optimal reaction conditions, but no product
was found in this case. Therefore, it is possible that this reaction
proceeds through the activation of the aryl iodide via a Cu(I)/
Cu(II) redox couple SET (Single Electron Transfer) mechanism
4
5
CuI
85
50
94
66
80
64
95
88
-
6
CuO
CuOb
CuSO4
7
8
9
Cu(OAc)2 DMF
10
11
12
13
14
15
CuClc
CuCld
CuCl
CuCl
CuCl
CuCl
DMF
DMF
DMSO
H2O
1,4-Dioxane
Toluene
20
60
Model reaction conditions: PhI (1.0 mmol), CuCl (0.1 mmol), DMF (2 mL),
Meldrum's acid dithioate solution in DMF contains Meldrum's acid (1 mmol),
CS2 (1 mmol) and Et3N (2 mmol), under a N2 atmosphere.
bCuO nanoparticles.
followed by in situ generation of a thiolate radical via an SRN
1
(Unimolecular Radical Nucleophilic Substitution) mechanism
and finally, thiolate radical coupling to form the
diaryldisulfide.13g, 33
cCuCl (0.05 mmol).
dCuCl (0.2 mmol).

3
Table 3. Optimization of reaction conditions for the dithioate
Table 4. Copper-catalyzed conversion of aryliodides to
symmetrical diaryldisulfide by dithioates
of barbituric acid a
Entry Catalyst
Solvent
Base
T (°C) t (h) 2a (%)
Yield (%)a, X =
Entry
ArI
ArSSAr
1
2
CuCl
CuCl
CuCl
-
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
-
25
24
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
Trace
25
64
-
O
CH2
72
NH
85
-
60
3
-
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
1
2a 32a
94
1a
4
-
5
CuI
-
55
30
64
46
50
44
65
68
-
6
CuO
CuOb
CuSO4
-
2
3
4
5
6
2b32b
3c 32c
2d13k
2e 32d
2f 32e
80
83
88
78
83
58
61
66
56
61
71
74
79
69
74
1b
1c
1d
1e
1f
7
-
8
-
9
Cu(OAc)2 DMF
-
10
11
12
13
14
15
16
17
18
CuClc
CuCld
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
DMF
-
DMF
-
DMSO
H2O
-
-
1,4-Dioxane
Toluene
DMSO
DMSO
DMSO
-
-
-
40
74
85
75
K2CO3
Cs2CO3
K3PO4
aModel reaction conditions: PhI (1.0 mmol), CuCl (0.1 mmol), DMSO (2
mL), barbituric acid dithioate solution in DMSO contains barbituric acid (1
mmol), CS2 (1 mmol) and Et3N (2 mmol), under a N2 atmosphere.
bCuO nanoparticles
7
8
2g 32f
80
74
58
52
71
65
1g
1h
cCuCl (0.05 mmol).
dCuCl (0.2 mmol).
In conclusion, we have reported for the first time, a new route for
the synthesis of diaryldisulfides by the copper-catalyzed
conversion of aryl iodides using dithioates of Melderum's acid,
dimedone, and barbituric acid as effective sulfur transfer
reagents. This method offers several advantages including
operational simplicity, good yields, and easy work-up
procedures.
2h32g
9
2i 13l
91
77
69
55
82
68
1i
1j
10
2j 32h
11
12
2k32i
69
74
47
52
60
65
1k
1l
2l32j
13
62
45
55
1m
2m
aIsolated yield

4
Tetrahedron
J.; Sasson, Y. Tetrahedron Lett. 2007, 48, 6048; (h) Kelly, C. B.;
Lee, C.; Leadbeater, N. E. Tetrahedron Lett. 2011, 52, 4587; (f)
Wu, X. M.; Hu, W. Y. Chin. Chem. Lett. 2012, 23, 391; (g)
Soleiman-Beigi, M.; Mohammadi, F. Tetrahedron Lett. 2012, 53,
4028; (h) Soleiman-Beigi, M.; Hemmati, M. Appl. Organometal.
Chem. 2013, 27, 734.
References and notes
1.
(a) Oae, S. Organic Sulfur Chemistry, Structure and Mechanism;
CRC Press: Boca Raton, FL, 1991; (b) Cremlyn, R. J. An
Introduction to Organosulfur Chemistry; John Wiley and Sons:
New York, 1996; (c) Jocelyn, D. C. Biochemistry of the Thiol
Groups; Academic: New York, 1992.
(a) Metzner, P.; Thuillier, A. Sulfur Reagents in Organic
Synthesis; Katritzky, A. R.; Meth Cohn, O.; Rees, C. W., Eds.;
Academic Press: San Diego, 1994; (b) Kondo, T.; Mitsudo, T.
Chem. Rev. 2000, 100, 3205; (c) Alves, D.; Lara, R. G.; Contreira,
M. E.; Radatz, E. S.; Duarte, L. F. B.; Perin, G. Tetrahedron Lett.
2012, 53, 3364.
(a) Block, E. Angew. Chem. Int. Ed. Engl. 1992, 31, 1135; (b)
Huang, X.-Y.; Wang, Q.; Liu, H.-L.; Zhang, Y.; Xin, G.-R.; Shen,
X.; Dong, M.-L.; Guo, Y.-W. Phytochemistry 2009, 70, 2096.
(a) Anfinsen, C. Science 1973, 181, 223; (b) Goulding, C. W.;
Sawaya, M. R.; Parseghian, A.; Lim, V.; Eisenberg, D.; Missiakas,
D. Biochemistry 2002, 41, 6920; (c) Furukawa, Y.; Fu, R.; Deng,
H. X.; Siddique, T.; O’Halloran, T. Proc. Natl. Acad. Sci. U.S.A.
2006, 103, 7148.
(a) Field, L.; Grimaldi Jr, J. A.; Hanley, W. S.; Holladay, M. W.;
Ravichandran, R.; Schaad, L. J.; Tate, C. E. J. Med. Chem. 1977,
20, 996; (b) Vrudhula, V. M.; MacMaster, J. F.; Kerr, Z. D. E.;
Senter, P. D. Bioorg. Med. Chem. Lett. 2002, 12, 3591; (c) Henne,
W. A.; Doorneweerd, D. D.; Hilgenbrink, A. R.; Kularatne, S.A.;
Low, P. S. Bioorg, Med. Chem. Lett. 2006, 16, 5350.
14. Soleiman-Beigi, M.; Arzehgar, Z. J. Sulf. Chem.2015, 395.
15. Di Mola, A.; Massa, A. Curr. Org. Chem. 2012, 16, 2290.
16. Gerencser, J.; Dorman, G.; Darvas, F. QSAR Comb. Sci. 2006, 25,
439.
17. Tietze, L. F.; Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967.
18. Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem.
2004, 4957.
19. Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, 2006.
20. Yavari, I.; Sabbaghan, M.; Hossaini, Z. Mol. Diversity 2007, 11, 1.
21. Rodriguez, H.; Suarez, M.; Perez, R.; Petit, A.; Loupy, A.
Tetrahedron Lett. 2003, 44, 3709.
2.
3.
4.
22. McNab, H. Chem. Soc. Rev. 1978, 7, 345.
23. Chen, B. C. Heterocycles 1991, 32, 529.
24. Ivanov, A. S. Chem. Soc. Rev. 2008, 37, 789.
25. Habibi, A.; Valizadeh, Y.; Alizadeh, A.; Amiri Rudbari, H.;
Nardo, V. M. J. Sulf. Chem. 2014, 35, 362.
26. Habibi, A.; Valizadeh, Y.; Alizadeh, A. Helv. Chim. Acta 2015,
98, 67.
27. Kianmehr, E.; Baghersad, M. H. Adv. Synth. Catal. 2011, 353,
2599.
28. See ESI for details.
29. Yavari, I.; Sodagar, E.; Nematpour, M. Helv. Chim. Acta 2014, 97,
420
30. Lenardo, E. J.; Lara, R. G.; Silva, M. S.; Jacob, R. G.; Perin, G.
Tetrahedron Lett. 2007, 48, 7668.
5.
6.
(a) Ulman, A. Chem. Rev. 1996, 96, 1533; (b) Sudharsanam, R.;
Chandrasekaran, S.; Das, P. K. J. Mat. Chem. 2002, 12, 2904; (c)
Gamez, J. A.; Serrano-Andres, L.; Yanez, M. Chem. Phy. 2010,
12, 1042.
7.
8.
(a) Arisawa, M.; Fujimoto, K.; Morinaka, S.; Yamaguchi, M. J.
Am. Chem. Soc. 2005, 127, 12226; (b) Nishiyama, Y.;
Kawamatsu, H.; Sonoda, N. J. Org. Chem. 2005, 70, 2551.
(a) Ferris, K. F.; Franz, J. A. J. Org. Chem. 1992, 57, 777; (b)
Antebi, S.; Alper, H. Tetrahedron Lett. 1985, 26, 2609; (c)
Ogawa, A.; Nishiyama, Y.; Kambe, N.; Murai, S.; Sonoda, N.
Tetrahedron Lett. 1987, 28, 3271; (d) Rice, W. G.; Turpin, J. A.;
Schaeffer, C. A.; Graham, L.; Clanton, D.; Buckheit Jr., R. W.;
Zaharevitz, D.; Summers, M. F.; Wallqvist, A.; Covell, D. G. J.
Med. Chem. 1996, 39, 3606.
31. Zhu, J.; Bi, H.; Wang, Y.; Wang, X.; Yang, X.; Lu, L. Mater. Lett.
2007, 61, 523.
32. (a) D. Xiancai, W. Jianming, W. Jianqiang, Y. Jun, L. Jing-Hua,
J. Chem. Res. 2015, 39, 282–285; (b) X. Huilong, C. Jiuxi, L.
Miaochang, W. Huayue, D. Jinchang, Phosphorus, Sulfur and
Silicon and the Related Elements, 2009, 184, 2553-2559; (c) W.
Hang, H. Guojun, S. Yang, L. Yunyun, J. Chem. Research 2014,
38, 96-97; (d) T.-T. Wang, F.-L. Yang, S.-K. Tian, Adv. Synth.
Catal. 2015, 357, 928–932; (e) J.-T. Yu, H. Guo, Y. Yi, H. Fei, Y.
Jiang, Adv. Synth. Catal. 2014, 356, 749–752; (f) A. M. Sipyagin,
V. S. Enshov, S. A. Kashtanov, V. A. Potemkin, J. S. Thrasher, A.
Waterfeld, Russ. Chem. Bull. Int. Ed. 2004, 53, 420-434; (g) W.
Jondorf, Biochem. J. 1955, 61, 0264-6021; (h) Saima, A. G.
Lavekar, R. Kumar, A. K. Sinha, J. Mol. Catal. B-Enzym. 2015,
116, 113–123; (i) Z. Jingwei, S. Tao, J. Huiling, X. Liangzhong,
Z. Shizheng, Chin. J. Chem. 2010, 28, 1623-1629; (j) M.A.
Zolfigol, N. Niknam, M. Bagherzadeh, A. Ghorbani, N. Koukabi,
M. Hajjamia, E. Kolvaria, J. Chin. Chem. Soc. 2007, 54, 1115-
1118.
9.
Kuhle, E. The Chemistry of the Sulfenic Acids; Georg Thieme:
Stuttgart, 1973.
10. (a) Douglass, I. B.; Norton, R. V. J. Org. Chem. 1968, 33, 2104;
(b) Douglass, I. B. J. Org. Chem. 1974, 39, 563.
11. (a) Sevier, C. S.; Kaiser, C. A. Nat. Rev. Mol. Cell. Bio. 2002, 11,
836.
12. Witt, D. Synthesis 2008, 2491.
13. (a) Firouzabadi, H.; Iranpoor, N.; Abbasi, M. Tetrahedron Lett.
2010, 51, 508; (b) Emerson, D. W.; Bennett, B. L.; Steinberg, S.
M. Synth. Commun. 2005, 35, 631; (c) Firouzabadi, H.; Iranpoor,
N.; Gholinejad, M. Adv. Synth. Catal. 2010, 352, 119; (d)
Bandgar, B. P.; Uppalla, L. S.; Sadavarte, V. S. Tetrahedron Lett.
2001, 42, 6741; (e) Sonavane, S. U.; Chidambaram, M.; Almog,
33. (a) Kochi, J. K. Organomethalic Mechanisms and Catalysis;
Academic: New York, 1978; (b) Sperotto, E.; von Klink, G. P. M.;
von Koten, G.; de Vries, J. G. Dalton Trans. 2010, 39, 10338.