Simple and catalyst-free method for the synthesis of diaryl selenides by reactions of arylselenols and arenediazonium salts

Article abstract of DOI:10.1016/j.tetlet.2013.12.086

We describe here a simple and catalyst-free method to synthesize diaryl selenides by reaction of arenediazonium tetrafluoroborate salts with arylselenols, generated in situ by using diaryl diselenides and hypophosphorous acid (H₃PO₂), using THF as solvent. This is a direct nucleophilic aromatic substitution (SNAr) reaction performed with diaryl diselenides and arenediazonium salts bearing electron-withdrawing and electron-donating groups affording the corresponding diaryl selenides in moderated to good yields.

Full text of DOI:10.1016/j.tetlet.2013.12.086

Tetrahedron Letters 55 (2014) 1057–1061
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Simple and catalyst-free method for the synthesis of diaryl selenides
by reactions of arylselenols and arenediazonium salts
Renata A. Balaguez, Vanessa Gentil Ricordi, Camilo S. Freitas, Gelson Perin, Ricardo F. Schumacher,
⇑
Diego Alves
Laboratório de Síntese Orgânica Limpa, LASOL, CCQFA, Universidade Federal de Pelotas, UFPel, P.O. Box 354, 96010-900 Pelotas, RS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe here a simple and catalyst-free method to synthesize diaryl selenides by reaction of arene-
diazonium tetrafluoroborate salts with arylselenols, generated in situ by using diaryl diselenides and
hypophosphorous acid (H3PO2), using THF as solvent. This is a direct nucleophilic aromatic substitution
(SNAr) reaction performed with diaryl diselenides and arenediazonium salts bearing electron-withdraw-
ing and electron-donating groups affording the corresponding diaryl selenides in moderated to good
yields.
Received 22 November 2013
Revised 18 December 2013
Accepted 23 December 2013
Available online 3 January 2014
Keywords:
Organoselenium compounds
Selenol
Crown Copyright Ó 2014 Published by Elsevier Ltd. All rights reserved.
Arenediazonium salts
Hypophosphorous acid
Nucleophilic aromatic substitution
Organoselenium compounds are attractive molecules due their
selective reactions1 and the interest in the synthesis of these com-
pounds has increased in the last years because of their applicability
in materials2 and biological areas.3 Diaryl selenides are certainly
the organoselenium compounds most studied and a large number
of methodologies have been reported to prepare these com-
pounds.1a–d Additionally, diaryl selenides have attracted consider-
able attention because of their biological activities (e.g. anticancer,
antitumor, antiviral, antimicrobial, and antioxidant) and some bio-
logically important molecules containing the diaryl selenide skele-
ton are shown in Figure 1.4
an attention in developing of simple, selective, and catalyst-free
methodologies to produce diaryl selenides in high yields.
In this sense, the reactions of nucleophilic arylselenium species
with arenediazonium salts are an interesting approach for the syn-
thesis of diaryl selenides.6 Arenediazonium salts have been utilized
as reactive aryl halide surrogates in transition metal-catalyzed
cross-coupling reactions for C–C and C-Heteroatom bond forma-
tion.7 In the case of C–Se bond formation by using arenediazonium
salts, recently Ranu and co-workers described a great procedure for
the synthesis of diaryl selenides by the reaction of diazonium tet-
rafluoroborates and diaryl diselenides on alumina surface under
ball-milling without any solvent or metal.6a Reactions of arene-
diazonium salts with diaryl diselenides were also reported earlier
by the same author and in a simple one-pot reaction in the pres-
ence of Zn dust in dimethyl carbonate under microwave irradia-
tion. In this work are described a wide range of functionalized
diaryl chalcogenides obtained in high purity and good yields.6b
In view of the explained above and according to our interest in
the development of protocols correlated to the synthesis of diaryl
selenides,8 we report here our contribution to the application of
arenediazonium salts in the synthesis of diaryl selenides. The pres-
ent methodology describes the simple and catalyst-free aromatic
nucleophilic substitution (SNAr) of arenediazonium salts with aryl-
selenols, generated in situ by reaction of diaryl diselenides with
hypophosphorous acid (H3PO2) (Scheme 1).
Usually, the methodologies describe that the CAr–Se bond for-
mation requires long reaction times, harsh reaction conditions,
stoichiometric, or great amount of metallic reagents and some-
times the products are only generated in moderate yields.1a–d To
overcome these limitations, much attention has recently been fo-
cused to develop catalytic systems in transition metal-catalyzed
C
Ar–Se bond formation.5 Generally these catalytic systems involve
particularly specific ligands, which may increase the cost and limit
the scope of applications.5 Commonly, to avoid the foul smelling
nature of selenium reagents, diaryl diselenides are used instead
of arylselenols as coupling partners in the synthesis of diaryl sele-
nides.5 However, sometimes these protocols suffer from long reac-
tion times, the necessity for high temperatures and are suitable for
a relatively narrow scope of substrates.5 Furthermore, there is still
Initially, we choose diphenyl diselenide 1a (0.25 mmol) and 4-
methoxyphenyl diazonium tetrafluoroborate 2a (0.5 mmol) as
model substrates to establish the best conditions for this reaction
⇑
Corresponding author. Tel./fax: +55 5332757533.
E-mail address: diego.alves@ufpel.edu.br (D. Alves).
0040-4039/$ - see front matter Crown Copyright Ó 2014 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.086

1058
R. A. Balaguez et al. / Tetrahedron Letters 55 (2014) 1057–1061
H
N
Se
O
OH
NO2
Se
Se
OH
Se
O
O2N
Br
NO2
MeO
Se
MeO
MeO
Se
MeO
OMe
Br
OMe
O2N
OMe
OMe
Figure 1. Diaryl selenides biologically important.
Se
3
R
1) H3PO2 / THF / r.t., N2
N2BF4
Se
R
R1
Se
R
1
R1
2)
2
Scheme 1. General scheme of the reaction.
Table 1
Optimization of reaction conditions
1) H3PO2 / THF/ t. a., N2
PhSeSePh
MeO
SePh
2)
MeO
N2BF4
2a
1a
3a
Entry
H3PO2 (mL)
Solvent
Arenediazonium salt 2a (mmol)
Timea (h)
Yield of 3ab (%)
1
2
3
4
5
6
7
8
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
THF
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
5
24
9
24
24
24
24
24
5
5
5
5
5
54
41
45
36
30
—
DMF
EtOH
Glycerolc
Toluene
MeCN
CH2Cl2
H2O
THF
THF
THF
THF
—
—
9
0.1
0.5d
0.5d
0.75d
1.0d
1.5d
0.75d
65
69
76
76
78
65
10
11
12
13
14
0.05
0.05
0.05
0.05
0.025
THF
THF
5
a
b
c
This time include preliminary 1 h of diphenyl diselenide cleavato in situ formation of benzeneselenol.
Yields are given for isolated product 3a.
The in situ formation of benzeneselenol was performed at 90 °C for 6 h.
Arenediazonium salt 2a was added in 4 portions during an interval of 30–30 min.
d
and some experiments, including solvent tests and stoichiometry,
were preformed to synthesize diaryl selenide 3a (Table 1). Accord-
ing to the literature, diorganyl diselenides are reduced to the cor-
responding organyl selenols by treatment with H3PO2 and this
fact encouraged us to use this reducing agent to obtain in situ
the nucleophilic selenium species of our reaction.8c,9 While the
arylselenol is generated in situ under nitrogen atmosphere, the
bad smell of this selenating agent does not become an
inconvenience.
Thus, a mixture of diphenyl diselenide 1a and 0.1 mL of H3PO2
(50 wt % in H2O) in THF (1.0 mL) was stirred at room temperature
for 1 h under N2 atmosphere to afford in situ the benzeneselenol.
The diphenyl diselenide cleavage was accompanied by the change
in the reaction solution color, from yellow to colorless. After this
arenediazonium salt 2a (0.5 mmol) was added in the reaction ves-
sel and the reaction remained at room temperature for additional
4 h. Under these reaction conditions, the product 3a was obtained
only in moderate yield (Table 1, entry 1). Regarding the influence
of the solvent on the reaction, a range of polar and apolar solvents
were tested on the same protocol described above and the desired
product 3a was obtained in lower yields comparing reaction per-
formed in THF (Table 1, entries 1 vs 2–5). When the reactions were
performed using MeCN, CH2Cl2, and H2O as solvents, the benzene-
selenol formation was not observed (Table 1, entries 6–8). Interest-
ingly, when we carried out the reaction in THF and after the
formation of benzeneselenol we added the arenediazonium salt
2a in four portions during an interval of 30–30 min followed for
additional 2 h, the yield of product 3a was increased to 65%
(Table 1, entry 9). This good result prompted us to perform this
reaction decreasing the quantity of H3PO2 and keeping the addition
of the arenediazonium salt 2a in four portions. To our satisfaction,
the use of 0.05 mL of H3PO2 furnished the desired product 3a in

R. A. Balaguez et al. / Tetrahedron Letters 55 (2014) 1057–1061
1059
Table 2
Generality of the reaction of arenediazonium tetrafluoroborates with in situ generated arylselenolsa
Se
3
R
1) H3PO2 / THF/ 1 h, r. t., N2
N2BF4
Se
R
R1
Se
R
1
R1
2)
, 4 h, r. t., N2
2
ArN2BF4
O
Entry
1
ArSeSeAr
Product
Yield (%)b
Se
N2BF4
Se
Se
76
65
O
O
2a
3a
Se
1a
N2BF4
2
1a
O
3b
2b
Se
N2BF4
3
4
1a
1a
80
80
2c
3c
Se
N2BF4
2d
3d
Se
Cl
N2BF4
5
6
1a
1a
72
70
Cl
Cl
2e
3e
Se
N2BF4
Cl
3f
2f
N2BF4
Cl
Se
7
8
1a
66
69
Cl
2g
3g
Se
F
N2BF4
1a
F
2h
3h
F3C
Se
F3C
Se
Se
CF3
O
9
2a
2a
71
72
3i
Se
1b
F
Se
F
O
Se
10
3j
F
1c
Cl
Se
3k
Se
Cl
O
Se
11
12
2a
2a
70
Cl
1d
Se
Se
Se
O
73
3l
1e
(continued on next page)

1060
R. A. Balaguez et al. / Tetrahedron Letters 55 (2014) 1057–1061
Table 2 (continued)
Entry
ArSeSeAr
ArN2BF4
Product
Yield (%)b
O
Se
Se
Se
O
O
13
2a
80
3m
O
1f
Se
Se
Se
14
2a
63
O
3n
1g
a
The reactions were performed using diselenide 1a–g (0.25 mmol), H3PO2 (50 wt % in H2O; 0.05 mL), THF (1.0 mL), and arenediazonium tetrafluoroborate salt 2a–h
(0.75 mmol), at room temperature under N2 atmosphere.
b
Yields are given for isolated products.
approximately the same yield after 5 h (Table 1, entry 10). Grate-
fully, when the reaction was performed using 0.05 mL of H3PO2
and using an excess of arenediazonium salt 2a, the corresponding
product 3a was obtained in good yields (Table 1, entries 11–13).
When we used 0.025 mL of H3PO2 a slight decrease in the yield
of product 3a was observed (Table 1, entry 14).
(H3PO2), was performed using THF as solvent at room temperature
and establishing a new route to obtain diaryl selenides containing
electron-withdrawing and electron-donating groups in moderate
to good yields.
Acknowledgments
Analysis of the results showed in Table 1 indicated that the
optimum condition were the previous reaction of diphenyl disele-
nide 1a (0.25 mmol) with H3PO2 (0.05 mL) in THF (1.0 mL) at room
temperature for 1 h under N2 atmosphere to in situ formation of
benzeneselenol. Following, arenediazonium salt 2a (0.75 mmol)
was added in 4 portions during an interval of 30–30 min and the
stirring continued at room temperature for additional 2 h.10
In order to demonstrate the efficiency of this reaction, we ex-
plored the generality of our method extending the conditions to
other diaryldiselenides 1a–g differently substituted and different
aromatic diazonium salts 2a–h, and the results are summarized
in Table 2.
The results disclosed in Table 2 reveal that the reaction worked
well with a range of substituted aromatic diazonium salts 2, afford-
ing moderated to good yields of the desired diarylselenides 3. Our
results reveal that the reactions are not sensitive to the electronic
effect of the aromatic ring in the arenediazonium salt. Therefore, a
comparison between the entries 1–3 versus 5–8, which used
arenediazonium salts substituted with electron-donating groups
(EDG) and electron-withdrawing group (EWG), displays similar
yields for the obtained products.
In addition, the possibility of performing the reaction with other
diaryl diselenides 1b–g was also investigated. 4-Methoxyphenyl
diazonium tetrafluorborate 2a was efficiently reacted with a range
of diaryl diselenides containing EDG and EWG groups at the aro-
matic ring, affording the respective diarylselenides 3i–n in accept-
able yields (Table 2, entries 9–14). We also observed that the
reactions are not sensitive to the electronic effect of the aromatic
ring in the arenediazonium salt (Table 2, entries 9–11 vs 12–13).
We found little influence of steric effects on the course of the reac-
tion, once that by using the diselenide 1g containing a mesityl
group, a lower yield of the desired product 3n was achieved
(Table 2, entry 14). These results demonstrated that several sub-
stituents/functional groups such as Me, OMe, Cl, F, and CF3 are
compatible with these reaction conditions.
We are grateful to FINEP, CAPES, CNPq (Grant 473165/2012-0)
and FAPERGS for the financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.201
3.12.086.
References and notes
1. (a) Alberto, E. E.; Braga, A. L. In Selenium and Tellurium Chemistry — From Small
Molecules to Biomolecules and Materials; Derek, W. J.; Risto, L., Eds.; Springer-
Verlag: Berlin Heidelberg, 2011.; (b) Wirth, T. In Organoselenium Chemistry:
Synthesis and Reactions; Wiley-VCH: Weinheim, 2011.; (c) Menezes, P. H.; Zeni,
G. Vinyl Selenides. In Patai’s Chemistry of Functional Groups; John Wiley & Sons:
Oxford, 2011.; (d) Devillanova, F. A. In Handbook Of Chalcogen Chemistry: New
Perspectives in S, Se and Te; Royal Society of Chemistry: Cambridge, 2006.; (e)
Perin, G.; Lenardão, E. J.; Jacob, R. G.; Panatieri, R. B. Chem. Rev. 2009, 109, 1277;
(f) Freudendahl, D. M.; Santoro, S.; Shahzad, S. A.; Santi, C.; Wirth, T. Angew.
Chem., Int. Ed. 2009, 48, 8409; (g) Santi, C.; Santoro, S.; Battistelli, B. Curr. Org.
Chem. 2010, 14, 2442; (h) Freudendahl, D. M.; Shahzad, S. A.; Wirth, T. Eur. J.
Org. Chem. 2009, 1649; (i) Braga, A. L.; Lüdtke, D. S.; Vargas, F. Curr. Org. Chem.
2006, 10, 1921; (j) Godoi, M.; Paixão, M. W.; Braga, A. L. Dalton Trans. 2011, 40,
11347.
2. (a) Rampon, D. S.; Rodembusch, F. S.; Schneider, J. M. F. M.; Bechtold, I. H.;
Gonçalves, P. F. B.; Merlo, A.; Schneider, P. H. J. Mater. Chem. 2010, 20, 715; (b)
Samb, I.; Bell, J.; Toullec, P. Y.; Michelet, V.; Leray, I. Org. Lett. 2011, 13, 1182; (c)
Goswami, S.; Hazra, A.; Chakrabarty, R.; Fun, H.-K. Org. Lett. 2009, 11, 4350; (d)
Tang, B.; Xing, Y.; Li, P.; Zhang, N.; Yu, F.; Yang, G. J. Am. Chem. Soc. 2007, 129,
11666.
3. (a) Parnham, M. J.; Graf, E. Prog. Drug Res. 1991, 36, 9; (b) Mugesh, G.; du Mont,
W. W.; Sies, H. Chem. Rev. 2001, 101, 2125; (c) Nogueira, C. W.; Zeni, G.; Rocha,
J. B. T. Chem. Rev. 2004, 104, 6255; (d) Alberto, E. E.; Nascimento, V.; Braga, A. L.
J. Braz. Chem. Soc. 2010, 21, 2032; (e) Nogueira, C. W.; Rocha, J. B. T. J. Braz.
Chem. Soc. 2010, 21, 2055; (f) Nogueira, C. W.; Rocha, J. B. T. Arch. Toxicol. 2011,
85, 1313.
4. (a) Santos, E. A.; Hamel, E.; Bai, R.; Burnett, J. C.; Tozatti, C. S. S.; Bogo, D.;
Perdomo, R. T.; Antunes, A. M. M.; Marques, M. M.; Matos, M. F. C.; Lima, D. P.
Bioorg. Med. Chem. Lett. 2013, 23, 4669; (b) Millois, C.; Diaz, P. Org. Lett. 2000, 2,
1705; (c) Back, T. G.; Moussa, Z. J. Am. Chem. Soc. 2003, 125, 13455; (d)
Anderson, C.-M.; Hallberg, A.; Haegberg, T. Adv. Drug. Res. 1996, 28, 65; (e)
Clark, L. C.; Combs, G. F.; Turnbull, B. W.; Slate, E. H.; Chalker, D. K.; Chow, J.;
Davis, L. S.; Glover, R. A.; Graham, G. F.; Gross, E. G.; Krongrad, A.; Lesher, J. L.;
Park, K.; Sanders, B. B.; Smith, C. L.; Taylor, R. J. Am. Med. Assoc. 1996, 276, 1957;
(f) Engman, L.; Cotgreave, I.; Angulo, M.; Taylor, C. W.; Paine-Murrieta, G. D.;
Powis, G. Anticancer Res. 1997, 17, 4599; (g) Goudgaon, N. M.; Naguib, F. N.; el
Kouni, M. H.; Schinazi, R. F. J. Med. Chem. 1993, 36, 4250.
In summary, we developed a simple and catalyst-free method
to synthesize diaryl selenides by reactions using arenediazonium
tetrafluoroborate salts. The aromatic nucleophilic substitution
(SNAr) of arenediazonium salts with arylselenols, generated in situ
by reaction of diaryl diselenides with hypophosphorous acid

R. A. Balaguez et al. / Tetrahedron Letters 55 (2014) 1057–1061
1061
5. For recent reviews see: (a) Beletskaya, I. P.; Ananikov, V. P. Chem. Rev. 2011,
111, 1596; (b) Ananikov, V. P.; Zalesskiy, S. S.; Beletskaya, I. P. Curr. Org.
Synthesis 2011, 8, 2.
9. (a) Günther, W. H. H. J. Org. Chem. 1966, 31, 1202; (b) Salmond, W. G.; Barta, M.
A.; Cain, A. M.; Sobala, M. C. Tetrahedron Lett. 1977, 20, 1683; (c) Comasseto, J.
V.; Petragnani, N. J. Organomet. Chem. 1978, 152, 295.
6. (a) Mukherjee, N.; Chatterjee, T.; Ranu, B. C. J. Org. Chem. 2013, 78, 11110; (b)
Kundu, D.; Ahammed, S.; Ranu, B. C. Green. Chem. 2012, 14, 2024; (c)
Beletskaya, I. P.; Sigeev, A. S.; Peregudov, A. S.; Petrovskii, P. V. J. Organomet.
Chem. 2000, 605, 96; (d) Evers, M. J.; Christiaens, L. E.; Renson, M. J. J. Org. Chem.
1986, 51, 5196.
7. For recent examples see: (a) Mo, F.; Dong, G.; Zhanga, Y.; Wang, J. Org. Biomol.
Chem. 2013, 11, 1582; (b) Bonin, H.; Fouquet, E.; Felpin, F.-X. Adv. Synth. Cat.
2011, 353, 3063; (c) Taylor, J. G.; Moro, A. V.; Correia, C. R. D. Eur. J. Org. Chem.
2011, 1403.
8. (a) Ricordi, V. G.; Freitas, C. S.; Perin, G.; Lenardão, E. J.; Jacob, R. G.; Savegnago,
L.; Alves, D. Green Chem. 2012, 14, 1030; (b) Freitas, C. S.; Barcellos, A. M.;
Ricordi, V. G.; Pena, J. M.; Perin, G.; Jacob, R. G.; Lenardão, E. J.; Alves, D. Green
Chem. 2011, 13, 2931; (c) Thurow, S.; Webber, R.; Perin, G.; Lenardão, E. J.;
Alves, D. Tetrahedron Lett. 2013, 54, 3215; (d) Alves, D.; Santos, C. G.; Paixão, M.
W.; Soares, L. C.; Souza, D.; Rodrigues, O. E. D.; Braga, A. L. Tetrahedron Lett.
2009, 50, 6635.
10. General procedure for the reaction: To a 5 mL round-bottomed flask containing a
solution of appropriate diorganyl diselenide 1a–g (0.25 mmol) in THF (1.0 mL)
under N2 atmosphere, was added H3PO2 50 wt % in H2O (0.05 mL). The
resulting solution was stirred for 1 h at room temperature, when its color
changes from yellow to colorless. After this arenediazonium tetrafluoroborate
salt 2a–h (0.75 mmol) was added in 4 portions during an interval of 30–
30 min, and the reaction remained at room temperature for additional 2 h.
After that, the reaction mixture was received in water (20 mL), extracted with
ethyl acetate (3 Â 5 mL), dried over MgSO4, and concentrated under vacuum.
The residue was purified by column chromatography on silica gel using ethyl
acetate/hexane as the eluent. Selected spectral and analytical data for 4-
Methoxyphenyl-phenyl-selenide 3a:8a 1H NMR (CDCl3, 400 MHz):
d 7.50 (d,
J = 8.8 Hz, 2H); 7.33–7.31 (m, 2H); 7.21–7.16 (m, 3H); 6.84 (d, J = 8.4 Hz, 2H);
3.79 (s, 3H). 13C NMR (CDCl3 100 MHz); d (ppm): 159.7, 136.5, 133.2, 130.9,
129.1, 126.4, 119.9, 115.1, 55.2. MS (relative intensity) m/z: 264 (65), 262 (34),
184 (100), 153 (32), 65 (14).