Ultrasound-assisted synthesis of alkali metals diselenides (M2Se2) and their application for the gram-scale preparation of 2,2’-diselenobis(benzoic acid)

Article abstract of DOI:10.24820/ark.5550190.p010.981

A simple and efficient method to convert elemental selenium into alkali metal diselenide was developed. The use of selenium and metal borohydride in a molar ratio of 1 to 0.125 in the presence of base, under “on water” conditions and ultrasound activation permitted the reduction of Se into Se2^2- to be completed within minutes. Thus obtained metal diselenide aqueous solution was then used in the multigram scale synthesis of 2,2’-diselenobis(benzoic acid) (DSBA) a valuable building block for the development of diverse and pivotal selenorganic compounds.

Full text of DOI:10.24820/ark.5550190.p010.981

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Ultrasound-assisted synthesis of alkali metals diselenides (M2Se2) and their
application for the gram-scale preparation of 2,2’-diselenobis(benzoic acid)
Dorota Krasowska,a Francesca Begini,a Claudio Santi,b Francesca Mangiavacchi,b Jozef Drabowicz,a,c and Luca
Sancinetoa*
aDivision of Organic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Science,
Sienkiewicza, 112, 90-163, Lodz, Poland
bDepartment of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06123 Perugia, Italy
cInstitute of Chemistry, Health and Food Sciences, Jan Dlugosz University in Czestochowa, Armii Krajowej 13/15
42-200 Czestochowa, Poland
Email: sancinet@cbmm.lodz.pl; sancineto.luca@gmail.com
This article is dedicated to Professor Lorenzo Testaferri on the occasion of his retirement
Received 09-18-2019
Accepted 06-30-2019
Published on line 07-05-2019
Abstract
A simple and efficient method to convert elemental selenium into alkali metal diselenide was developed. The
use of selenium and metal borohydride in a molar ratio of 1 to 0.125 in the presence of base, under “on
2-
water” conditions and ultrasound activation permitted the reduction of Se into Se2 to be completed within
minutes. Thus obtained metal diselenide aqueous solution was then used in the multigram scale synthesis of
2,2’-diselenobis(benzoic acid) (DSBA) a valuable building block for the development of diverse and pivotal
selenorganic compounds.
Keywords: Alkali metal diselenides, borohydrides, hydrazine, ultrasound
DOI: https://doi.org/10.24820/ark.5550190.p010.981
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Introduction
Among selenium containing compounds, diselenides are surely valuable since they represent the starting point
for the preparation of nucleophilic,1,2 electrophilic,3 radical selenium-centered reagents4,5 and catalysts for
oxidative transformations.6-9 In addition, aromatic diselenides exert interesting biological activities.10,11 As
shown in Figure 1, the methods reported for their synthesis can be clustered into three groups: (A)
decomposition of selenides,12 selenyl azides,13 selenocyanates14 and selenyl halides;15 (B) nucleophilic
displacement of leaving units, as exemplified in electron withdrawing group (EWG)-containing aromatic
halides or diazonium salts, both operated by alkali metal diselenides (M2Se2) and (C) reaction between a
carbon nucleophile, either an organolithium16 or a Grignard reagent,17 and elemental selenium.
B
EWG
C
A
R
Se
X
M
+
R= Me, N3, CN, X
M= Li, MgBr
X = Cl, F, I, N2
M2Se2
Se
reagents
Se
Se
Figure 1. Synthetic approaches to obtain organic diselenides.
Among the three pathways we focused our attention to route B. In this context the synthesis of M2Se2, where
M is an alkali metal i.e. lithium, sodium or potassium, is usually accomplished right before the reaction with
the organic electrophile since none of M2Se2 is commercially available. Among the three salts, the sodium
containing one is surely the most frequently used and synthetically explored, while there are scarce examples
of K and Li diselenide in literature (Figure 2).
this work:
previous works:
KOH
KBH4 or N2H4, KOH, ))
rongalite + NaOH
NaBH4
K2Se2
Na2Se2
Li2Se2
KBH4
NaBH4 or N2H4, NaOH, ))
LiBH4 or N2H4, LiOH ))
K2Se2
Se
K
Se
Na
Na2Se2
Li
Li2Se2
N2H4 + LiOH
N2H4 + NaOH
Figure 2. Strategies to obtain M2Se2 and summary of the present investigation.
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Sodium diselenide can be obtained alternatively by the reduction of grey selenium with sodium
hydroxymethylsulfinate (rongalite) in the presence of sodium hydroxide in water suspension for 2-5 hours.18,19
Other reducing agents utilized for the preparation of Na2Se2 are: sodium metal reacting in dry and refluxing
THF for 6 hours,20 or hydrazine, provided that the reduction is carried out at 80 °C in water for 1 hour21 or in
methanol at room temperature for 24-60 h.22,23 Given the number of examples, NaBH4 is the reagent of choice
for converting elemental selenium into a Na2Se2 solution. Starting from the seminal paper of Klayman who
first developed a two step procedure to convert Se first into NaHSe and then to Na2Se2 by using equimolar
amounts of NaBH4 in protic solvents at reflux,24 other authors implemented this protocol, with few
modifications25,26(equation 1).
2Se + 2NaBH4 + 6H2O —→ Na2Se2 + 2H3BO3 + 7H2
(1)
The amount of NaBH4 was dramatically reduced by Yang and coworkers who found, by chance, that the
addition of NaOH permits to use a 1 : 0.125 Se:NaBH4 stoichiometry (equation 2) in the presence of catalytic
amounts of hexadecyltrimethylammonium bromide, as a phase transfer catalyst.27
8Se + NaBH4 + 8NaOH —→ 4Na2Se2 + NaBO2 + 6H2O
(2)
This procedure represents the greenest alternative reported to date in terms of atom economy (93% Vs 75%,
comparing Equations 2 and 1), solvent impact (since the reaction is carried out in water) and time (1.5 hours).
For this reason it was adopted by us10,28 and others29 in selenium-related research projects.
Lithium and potassium diselenides are much less explored and a fewer number of articles have been published
regarding their synthesis. According to equation 3, the solvent free, thermally activated (240 - 360 °C) reaction
between potassium hydroxide and elemental selenium affords K2Se2 along with K2SeO3, through a
disproportionation reaction in which selenium is reduced and oxidized at the same time. This procedure
reported for the first time as early as 1919,30 was then slightly modified by other authors.31,32
5Se + 6KOH —→ 2K2Se2 + K2SeO3 + 3H2O
(3)
In 1988, the one-to-one reaction between Se and potassium metal in THF was published,33 then in 2011, the
procedure with an overstoichiometric amount of potassium borohydride was reported by Chen and
coworkers.34
The synthesis of Li2Se2, on the other hand, was accomplished by the reaction of Li metal and Se in the presence
of electron transfer reagents in dry THF,35 or through the Se reduction using hydrazine hydrate and LiOH.36
In this paper, we report a green protocol for the preparation of M2Se2 using alkali metal borohydrides as
reducing agents that benefits from being conducted under ultrasonic activation and “on water” conditions.
The results of the studies on the use of hydrazine hydrate in the ultrasound-assisted synthesis of M2Se2 are
also included. Sonochemistry is a subject of intense research in the chemistry community since it is emerging
as a valid alternative to conventional heating; the interested reader is directed to recently published
reviews37,38 and books.39,40
The prepared alkali metal diselenides were then challenged in the aromatic nucleophilic substitution of the 2-
carboxybenzenediazonium salt, leading to the preparation of 2,2’-diselenobis(benzoic acid) (DSBA, Figure 3).
The yield of such reaction was then used to infer the reactivity of M2Se2 salts and the reduction efficiency of
both MBH4 or of hydrazine.
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DSBA is a valuable building block since it is used as a key substrate to prepare ebselen, the most studied
selenorganic compound known to date,41-43 ethaselen that is under clinical investigation for the treatment of
thioredoxin reductase overexpressing non-small cell lung cancers44 and DiSeBAs, potent anti-HIV agents10 due
to their ability to inhibit NCp7.45,46 Besides, DSBA itself showed promising biological activities being recognised
by some of us as a hormetine.47
R
O
OH
N
H
O
Se
Se
O
H
N
HO
O
R
O
OH
O
DiSeBAs
O
NaNO2
Se
Se
HCl/H2O
OH
M2Se2
OH
O
30 min, 0°C
2h, 90°C
NH2
+
N2
N
Se
HO
O
ebselen
DSBA
O
Se
N
N
Se
O
ethaselen
Figure 3. Procedure for preparing DSBA and its transformations to ebselen, ethaselen and DiSeBAs.
Results and Discussion
We started our investigation from the synthesis of sodium diselenide in alkaline aqueous solution following
the method reported by Yang in 2002 with few modifications, i. e. removing the phase transfer catalyst, using
ultrasound activation, shortening the reaction time from 1.5 hours to 1 hour and maintaining the temperature
below 30 °C instead of 90° C. After 1 hr sonication a dark reddish brown solution was formed and then
transferred by dropping into a freshly prepared aqueous solution of 2-carboxybenzenediazonium salt28 (Figure
3). For the diazonium salt displacement, after a deep literature analysis,29,34,48 we set the reaction time at two
hours and the temperature at 90°C as we intended to employ the already optimized conditions leading to the
highest possible conversion in a reasonable time. DSBA was thus obtained in 91% yield, clearly indicating that
the ultrasound induced formation of metal diselenide in water is a viable alternative to conventional heating
for this sort of reaction (Table 1, entry 1). Then, we attempted to synthesize sodium diselenide by reducing the
reaction time to 30 and 15 min (entry 2 and 3 respectively). The selenium nucleophilic species were
subsequently treated with 2-carboxybenzenediazonium salt to be transformed into the diaryl diselenide under
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the established conditions. The product of the substitution was obtained in lower yields as a result of a shorter
time and less efficient sodium diselenide formation.
Then we proceeded in examining potassium borohydride as reducing agent by using 0.125 moles of KBH4 for
each moles of selenium under sonochemical activation. If compared to the procedure reported in literature,
where equimolar amounts were used34 this method is much more atom economical. As reported in Table 1,
entries 4-6 the reactions led to the target product in very good (entry 6, 86%) to excellent yields (entry 4 and
5, 91 and 94% respectively). Head to head comparison between the reactions to produce K2Se2 and Na2Se2
within 15 min reveals that KBH4 gives better results (entry 6) than NaBH4 (entry 3).
Finally, the same investigations were carried out using LiBH4 (entries 7-9) and also in these cases DSBA was
synthesized in excellent yields. To the best of our knowledge, the use of LiBH4 for the preparation of Li2Se2 was
never reported before.
Table 1
Entry
M
Na
Na
Na
K
K
K
Li
Li
Time (min)
Yield of DSBA
91%
1
2
3
4
5
6
7
8
9
60
30
15
60
30
15
60
30
15
81%
50%
91%
94%
86%
91%
90%
90%
Li
All the reactions were carried out in water as a solvent using the following
scale: Se = 2.19 mmoles, MBH4 = 0.275 mmoles, MOH = 3.29 mmoles, H2O
= 2ml. The diazonium salt displacement was carried out using the
following scale diazonium salt =2.19 mmoles, H2O = 4 ml, 90 °C, 2 hours.
The yield refers to isolated product.
We were interested in examining the effect of ultrasound on the formation of metal diselenides produced
by the reduction of selenium using hydrazine hydrate in alkaline aqueous solution. The yields of the reactions
were estimated by the same chemical correlation based on the reaction of the diselenide with diazonium salt.
We choose to set the reaction time to 1 hour since it is reported in literature that this time is sufficient at 80°C
in water.21 As reported in Table 2, entry 1, trace amount of DSBA were obtained by using NaOH as metal
source after 1 hour of sonication. Lithium and potassium gave slightly better results, which however were far
from the expected yields if compared with any alkali metal borohydride mediated reduction.
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Table 2
Entry
M
Na
K
K
K
Time (min)
Yield
5%
7%
13%
17%
10%
1
2
3
4
5
60
15
30
60
60
Li
All the reactions were carried out in water as a solvent using the
following scale: Se = 2.19 mmoles, N2H4 = 17.5 mmoles, MOH =
3.29 mmoles; H2O = 2ml. The diazonium salt displacement was
carried out using the following scale diazonium salt = 2.19
mmoles, H2O = 4 ml, 90 °C, 2 hours. The yield refers to isolated
product.
On the basis of this investigation we selected as best condition to synthesize M2Se2 those displayed in
Table 1, entry 5. In the DSBA synthesis KBH4 indeed granted 94% yield after just 30 minutes of reaction time
where sodium borohydride gave 81%. Lithium was as effective as potassium but it is much more expensive.
According to Sigma-Aldrich supplier sodium and potassium borohydrides have comparable costs
(approximately 30 € for 25 g with ≥ 97.0% purity). With the best conditions in our hands we briefly tested the
“on water” synthesis of other synthetically relevant organic diselenides, i. e. dimethyl diselenide (DMDS) and
dibenzyl diselenide (DBDS) (Scheme 1 and Table 3).
Scheme 1. Synthesis of DMDS and DBDS.
DBDS was synthesized in excellent yield performing the nucleophilic substitution reaction under
conventional heating at the temperature of 90 °C (Table 3, entry 1). The same reaction carried out by adding
benzyl chloride to the sonicating aqueous solution of K2Se2 did not afforded the desired diselenide. On the
contrary, the addition of stoichiometric amounts of methyl iodide led to the formation of the desired DMDS in
40% yield (entry 5). Interestingly the same reaction performed under conventional heating at 50 and 90 °C led
to the DMDS formation in lower yields (entry 3 and 4). In all the cases DMDS was obtained as a mixture of
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selenide and polyselenides. The DSBA synthesis under sonication (entry 7) occurred, even though with a lower
efficiency if compared to the standards conditions (entry 6).
Table 3
Entry
Product
DBDS
DBDS
DMDS
DMDS
DMDS
DSBA
Condition
90°C
)))
Yield
94%
traces
20%
23%
40%
94%
60%
1
2
3
4
5
6
7
90°C
50°C
)))
90°C
)))
DSBA
All the reactions were carried out in water as a solvent using the
following scale: Se = 2.19 mmoles, KBH4 = 0.275 mmoles, KOH = 3.29
mmoles, H2O = 2ml. The reaction time is 2 hours in each case. The
yield refers to isolated product.
Finally, having selected the best the conditions (Table 1 entry 5) we tested the scalability of the DSBA
synthesis by doubling each time the amount of reactants for four consecutive reactions (Figure 4).
Figure 4. Scalability of the DSBA synthesis, in red the amount of DSBA obtained.
As shown in Figure 4, we demonstrated that the reported procedure is scalable for at least 35 mmoles of
selenium (2.8 grams) and anthranilic acid (4.8 grams) allowing us to prepare almost 7 grams of DSBA in one
shot. This point is really important for a future industrial application of such valuable compound.
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Conclusions
Alkali metal diselenides are pivotal reagents to install the diselenide functional group onto organic substrates.
In this paper we demonstrated that ultrasonic activation is a valid alternative to normal heating in the
borohydride-mediated reduction of elemental selenium. The procedure allows for the convenient syntheses of
alkali metal diselenides using potassium and lithium borohydrides in a molar ratio of 1:8 to selenium, which
requires only 15- 30 minutes of sonication. For the high yielding reduction of selenium by sodium borohydride
the longer reaction time, 60 minutes of sonication, is required. On the contrary, sonochemistry is not
appropriate when hydrazine hydrate is the reductant. In addition we proved also that, beside NaBH4 and KBH4
also LiBH4 is suitable to convert selenium into diselenide. Finally, the multigram scale synthesis of DSBA was
demonstrated by using potassium diselenide as selenium source, which is also suitable for the preparation of
DBDS.
Experimental Section
General. Reactions were conducted in Schlenk tubes or round bottom flasks and were stirred with Teflon-
coated magnetic stirring bars. The reactions under ultrasound irradiation were performed in a Polsonic® sonic
bath (model Sonic-3) with 80 W and 40 KHz of effective sonication power and frequency, respectively.
Commercially available organic and inorganic reagents were used without further purification. NMR
1
experiments were conducted at 25 °C with a Bruker Avance 200 spectrometer operating at 200.16 MHz for H,
1
13
or with a Bruker Avance III 500 spectrometer operating at 500.13 MHz for H, 125.76 MHz for C and 95.43
MHz Se experiments. H, 13C and 77Se chemical shifts (δ) are reported in parts per million (ppm), and are
cited with respect to TMS (δ = 0.0 ppm), as internal standard (1H) and the residual solvent peak of DMSO-d6 (δ
77
1
= 2.50 and 39.53 ppm in H and C NMR, respectively) or Ph2Se2 (77Se δ = 463 ppm) as the external standard.
Data are reported as: chemical shift (multiplicity, coupling constants where applicable, number of hydrogen
atoms, and assignment where possible). Abbreviations are: s (singlet), d (doublet), t (triplet), q (quartet), dd
(doublet of doublet), dt (doublet of triplet), tt (triplet of triplet), m (multiplet), bs (broad singlet). Coupling
constant (J) quoted in Hertz (Hz) to the nearest 0.1 Hz. High-resolution mass spectrometry (HRMS)
measurements were performed using Synapt G2-Si mass spectrometer (Waters) equipped with an APCI source
and quadrupole-Time-of-Flight mass analyzer. The mass spectrometer was operated in the positive and
negative ion detection modes with discharge current set at 4.0 μA. The heated capillary temperature was 350
°C. The results of the measurements were processed using the MassLynx 4.1 software (Waters) incorporated
with the instrument. Melting points (m.p.) were determined on Mel-Temp® apparatus and are uncorrected.
1
13
General procedure A, preparation of alkali metal diselenide solution with MBH4. A Schlenk tube was charged
with elemental selenium (175 mg, 2.19 mmoles) and filled with argon. A solution of alkali metal hydroxide
(3.29 mmoles) and borohydride (0.275 mmoles) in 2 ml of distilled water was prepared in a test tube, cooled
to room temperature and added at once to the Schlenk tube which was allowed to sonicate for the amount of
time indicated in Table 1. Then a dark solution is formed and used without further purifications.
General procedure B, preparation of alkali metal diselenide solution with hydrazine hydrate. A Schlenk tube
was charged with elemental selenium (175 mg, 2.19 mmol) and then filled with argon. A solution of alkali
metal hydroxide (3.29 mmol) in 2 ml of distilled water along with hydrazine monohydrate (0.85 ml, 17.5
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mmol) was added dropwise. The Schlenk tube was allowed to sonicate for the amount of time indicated in
Table 2. Then a dark suspension is formed and used without further purifications.
2-Carboxybenzenediazonium chloride. 2-Carboxybenzenediazonium chloride aqueous solution (2.19 mmol)
was prepared just before use through the reaction of anthranilic acid (200 mg, 2.29 mmol), sodium nitrite (185
mg, 2.63 mmol) and 0.1 ml of HCl 37 % in 4 ml of distilled water.28 The colourless solution so obtained was
used without further purifications.
Preparation of 2,2’-diselenobis(benzoic acid) (DSBA). The freshly prepared solution of alkali metal diselenide
(1.095 mmol) in water (2 mL) was added dropwise to the solution of 2-carboxybenzenediazonium chloride
(2.19 mmol) at 0°C. The reaction mixture was allowed to reach room temperature with a continuous stirring
and then heated at 90 °C for 2 hours. After this period the solution was passed through a filter with a thin pad
of Celite, and water was used to rinse the Celite. The filtrate was acidified (ca. 7 ml of 1M HCl aq solution) until
a beige precipitation appeared. The formed solid was separated by filtration, solubilized with hot methanol
and evaporated in vacuo to yield the target product as beige solid. Analytically pure samples can be obtained
by recrystallization from dioxane. Mp 290-292 °C (289-292 °C ref28); 1H NMR (DMSO-d6) δ = 13.73 (bs, 1H, OH),
8.02 (d, J 7.8 Hz, 1H, ArCH), 7.66 (d, J 8.17 Hz, 1H, ArCH), 7.48 (t, J 7.87 Hz, 1H, ArCH), 7.35 ppm (t, J 7.56 Hz,
1H, ArCH); 13C NMR (DMSO-d6) = 169.04, 134,08, 133.90, 132.06, 129.93, 129.19, 127.04 ppm. 77Se NMR
(DMSO-d6) = 439.60 ppm. HRMS calculated for C14H10O4NaSe2 = 424.8807, found = 424.8818.
Scale up experiments: Scale up experiments were carried out using K2Se2 prepared within 30 min according
the general procedure A using 30 minutes of sonication time. The amounts adopted are listed in Table 4.
Table 4
Se
KBH4 KOH H2O Antranilic Acid NaNO2 HCl 37% H2O
mmol
ml
2
4
mmol
2.19
4.38
8.74
17.50
35.00
ml
2.19 0.275 3.29
4.38 0.55 6.60
8.74 1.10 13.11
17.50 2.20 26.25 16
35.00 4.40 52.50 32
2.63
5.27
10.50
21.00
42.00
0.1
4
8
16
32
64
0.25
0.55
1.20
2.60
8
Preparation of dibenzyldiselenide (DBDS). To a solution of K2Se2 freshly prepared according to the general
method A using 30 minutes of sonication time, benzyl chloride (2.19 mmoles, 0.25 ml) was added at once. The
reaction was allowed to react for 2h under conventional heating at 90°C or under ultrasonic irradiation. The
reaction was then diluted with water (30 ml) and extracted three times with dichloromethane (3 X 30 ml). The
combined organic extracts were dried over magnesium sulphate, filtered and concentrated in vacuo. The
resulting orange oil was purified by silica gel column chromatography using petroleum ether: ethyl acetate
95:5 as eluent. The compound was isolated as a yellow solid in the yields indicated in Table 3. Mp = 84-86 °C
1
(87-88 °C ref49); H NMR (CDCl3) δ = 7.25 – 7.13 (m, 5H, ArCH), 3.76 (s, 2H, CH2); 13C NMR (CDCl3) δ = 139.08,
77
129.10, 128.52, 127.18, 32.66 ppm; Se NMR = 402.37 ppm.
Preparation of dimethyldiselenide (DMDS). To a solution of K2Se2 freshly prepared through the general
method A using 30 minutes of sonication time, methyl iodide (2.19 mmoles, 0.14 ml) was added at once. The
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reaction was allowed to react for 2 hours under conventional eating at 90°C or under ultrasonic irradiation.
The reaction was allowed to react for 2 hours under conventional eating at 90°C or under ultrasonic
irradiation. The reaction mixture was then diluted with water (30 ml) and extracted three times with diethyl
ether (3 X 30 ml). The combined organic layers were dried over magnesium sulphate, filtered and the solvent
1
was evaporated in vacuo. A dark orange oil was obtained. H NMR analysis carried out in CDCl3 revealed a
mixture of DMDS, dimethyl triselenide and tetraselenide, which was not separated.
Acknowledgements
This project has received funding from the European Union’s Horizon 2020 research and innovation
programme under the Marie Skłodowska-Curie grant agreement No 665778 - POLONEZ funding programme,
National Science Centre, Poland - project registration number 2016/21/P/ST5/03512. This work was carried
out under the umbrella of the International network Selenium, Sulfur, Redox and Catalysis.
Supplementary Material
Supplementary data associated with this article can be found in the online version.
References
1. Monti, B.; Santi, C.; Bagnoli, L.; Marini, F.; Sancineto, L. Zinc Chalcogenolates As Green Reagents. Curr.
Green Chem. 2016, 3, 68–75.
https://doi.org/10.2174/2213346103666160127003716
2. Tidei, C.; Sancineto, L.; Bagnoli, L.; Battistelli, B.; Marini, F.; Santi, C. A Recyclable Biphasic System for
Stereoselective and Easily Handled Hydrochalcogenations. European J. Org. Chem. 2014, 2014, 5968–5975.
https://doi.org/10.1002/ejoc.201402668
3. Sancineto, L.; Palomba, M.; Bagnoli, L.; Marini, F.; Santi, C. Advances in Electrophilic Organochalcogen
Reagents. Curr. Org. Chem. 2015, 20, 122–135.
https://doi.org/10.2174/1385272819666150724233204
4. Renaud, P. Radical Reactions Using Selenium Precursors. In Organoselenium Chemistry. Topics in Current
Chemistry, vol 208.; Wirth, T., Ed.; 2000; pp. 81–112.
https://doi.org/10.1007/3-540-48171-0_4
5. Chu, J. Y. C.; Marsh, D. G.; Guenther, W. H. H. Photochemistry of organochalcogen compounds. I.
Photolysis of benzyl diselenide. J. Am. Chem. Soc. 1975, 97, 4905–4908.
https://doi.org/10.1021/ja00850a020
6. Sancineto, L.; Tidei, C.; Bagnoli, L.; Marini, F.; Lenardão, E.; Santi, C. Selenium Catalyzed Oxidation of
Aldehydes: Green Synthesis of Carboxylic Acids and Esters. Molecules 2015, 20, 10496–10510.
https://doi.org/10.3390/molecules200610496
7. Yu, L.; Ye, J.; Zhang, X.; Ding, Y.; Xu, Q. Recyclable (PhSe)2 -catalyzed selective oxidation of isatin by H2O2: a
practical and waste-free access to isatoic anhydride under mild and neutral conditions. Catal. Sci. Technol.
2015, 5, 4830–4838.
Page 10
©ARKAT USA, Inc

Arkivoc 2019, ii, 0-0
Krasowska, D et al.
https://doi.org/10.1039/C5CY01030F
8. Gao, G.; Han, J.; Yu, L.; Xu, Q. Organoselenium-Catalyzed Polymerization of Aniline with Hydrogen Peroxide
as Oxidant. Synlett 2019, 30, A-E.
https://doi.org/10.1055/s-0037-1612088
9. Sancineto, L.; Mangiavacchi, F.; Tidei, C.; Bagnoli, L.; Marini, F.; Gioiello, A.; Scianowski, J.; Santi, C.
Selenium-Catalyzed Oxacyclization of Alkenoic Acids and Alkenols. Asian J. Org. Chem. 2017, 6, 988–992.
https://doi.org/10.1002/ajoc.201700193
10. Sancineto, L.; Mariotti, A.; Bagnoli, L.; Marini, F.; Desantis, J.; Iraci, N.; Santi, C.; Pannecouque, C.; Tabarrini,
O. Design and Synthesis of DiselenoBisBenzamides (DISeBAs) as Nucleocapsid Protein 7 (NCp7) Inhibitors
with anti-HIV Activity. J. Med. Chem. 2015, 58, 9601–9614.
https://doi.org/10.1021/acs.jmedchem.5b01183
11. Lenardão, E. J.; Santi, C.; Sancineto, L. Bioactive Organoselenium Compounds and Therapeutic
Perspectives. In New Frontiers in Organoselenium Compounds; Springer International Publishing: Cham,
2018; pp. 99–143.
https://doi.org/10.1007/978-3-319-92405-2_2
12. Evers, M.; Christiaens, L. New synthetic methodsꢀ: sodium alkanechalcogenates as demethylating agents.
Scope, limitation and new one-pot synthesis of diaryldiselenides. Tetrahedron Lett. 1983, 24, 377–380.
https://doi.org/10.1016/S0040-4039(00)81412-4
13. Back, T. G.; Kerr, R. G. Metathesis of N-silyl compounds with selenenyl chlorides. First preparation of a
selenenyl azide and a triselenenamide. J. Chem. Soc. Chem. Commun. 1987, 134–135.
https://doi.org/10.1039/c39870000134
14. Pinto, B. M.; Sandoval-Ramírez, J.; Sharma, R. D. A Convenient Synthesis of 4,4′-Dimethylaminodiphenyl
Diselenide and 4,4′-Dinitrodiphenyl Diselenide. Synth. Commun. 1986, 16, 553–557.
https://doi.org/10.1080/00397918608078772
15. Młochowski, J.; Kloc, K.; Syper, L.; Inglot, A. D. Recent developments in the chemistry and biology of
diselenides, benzisoselenazolones and seleninic acids. Phosphorus. Sulfur. Silicon Relat. Elem. 1991, 59,
267–270.
https://doi.org/10.1080/10426509108045739
16. Iwaoka, M.; Komatsu, H.; Katsuda, T.; Tomoda, S. Nature of Nonbonded Se···O Interactions Characterized
by 17 O NMR Spectroscopy and NBO and AIM Analyses. J. Am. Chem. Soc. 2004, 126, 5309–5317.
https://doi.org/10.1021/ja049690n
17. Kahr, J.; Moser, C.; Spirk, S.; Belaj, F.; Pietschnig, R. A Structural Comparison of Organoterminated
Selenide, Diselenide, and Triselenide. Phosphorus. Sulfur. Silicon Relat. Elem. 2014, 189, 1467–1474.
https://doi.org/10.1080/10426507.2014.919290
18. Kamigata, N.; Iizuka, H.; Izuoka, A.; Kobayashi, M. Photochemical Reaction of 2-Aryl-1,2-benzisoselenazol-
3(2 H )-ones. Bull. Chem. Soc. Jpn. 1986, 59, 2179–2183.
https://doi.org/10.1246/bcsj.59.2179
19. Erben, F.; Kleeblatt, D.; Sonneck, M.; Hein, M.; Feist, H.; Fahrenwaldt, T.; Fischer, C.; Matin, A.; Iqbal, J.;
Plötz, M.; Eberle, J.; Langer, P. Synthesis and antiproliferative activity of selenoindirubins and
selenoindirubin-N-glycosides. Org. Biomol. Chem. 2013, 11, 3963–3978.
https://doi.org/10.1039/c3ob40603b
20. Selvakumar, K.; Shah, P.; Singh, H. B.; Butcher, R. J. Synthesis, Structure, and Glutathione Peroxidase-Like
Activity of Amino Acid Containing Ebselen Analogues and Diaryl Diselenides. Chem. - A Eur. J. 2011, 17,
12741–12755.
Page 11
©ARKAT USA, Inc

Arkivoc 2019, ii, 0-0
Krasowska, D et al.
https://doi.org/10.1002/chem.201100930
21. Lu, Z.; Yan, X. Synthesis and biological activity of new derivatives of ebselen. Tianjin Huagong 2007, 21, 33–
35.
22. Giurg, M.; Gołąb, A.; Suchodolski, J.; Kaleta, R.; Krasowska, A.; Piasecki, E.; Piętka-Ottlik, M. Reaction of
bis[(2-chlorocarbonyl)phenyl] Diselenide with Phenols, Aminophenols, and Other Amines towards
Diphenyl Diselenides with Antimicrobial and Antiviral Properties. Molecules 2017, 22, 974.
https://doi.org/10.3390/molecules22060974
23. Küppers, J.; Schulz-Fincke, A.; Palus, J.; Giurg, M.; Skarżewski, J.; Gütschow, M. Convergent Synthesis of
Two Fluorescent Ebselen-Coumarin Heterodimers. Pharmaceuticals 2016, 9, 43.
https://doi.org/10.3390/ph9030043
24. Klayman, D. L.; Griffin, T. S. Reaction of selenium with sodium borohydride in protic solvents. A Facile
Method for the introduction of selenium into organic molecules. J. Am. Chem. Soc. 1973, 95, 197–199.
https://doi.org/10.1021/ja00782a034
25. Pacuła, A. J.; Obieziurska, M.; Ścianowski, J.; Kaczor, K. B.; Antosiewicz, J. Water-dependent synthesis of
biologically active diaryl diselenides. Arkivoc 2018, 2018, 153–164.
https://doi.org/10.24820/ark.5550190.p010.311
26. Lou, Z.; Li, P.; Sun, X.; Yang, S.; Wang, B.; Han, K. A fluorescent probe for rapid detection of thiols and
imaging of thiols reducing repair and H2O2 oxidative stress cycles in living cells. Chem. Commun. 2013, 49,
391–393.
https://doi.org/10.1039/C2CC36839K
27. Yang, X.; Wang, Q.; Tao, Y.; Xu, H. A modified method to prepare diselenides by the reaction of selenium
with sodium borohydride. J. Chem. Res. 2002, 160–161.
https://doi.org/10.3184/030823402103171726
28. Nascimento, V.; Ferreira, N. L.; Canto, R. F. S.; Schott, K. L.; Waczuk, E. P.; Sancineto, L.; Santi, C.; Rocha, J.
B. T.; Braga, A. L. Synthesis and biological evaluation of new nitrogen-containing diselenides. Eur. J. Med.
Chem. 2014, 87, 131–139.
https://doi.org/10.1016/j.ejmech.2014.09.022
29. Tang, Y.; Zhang, S.; Chang, Y.; Fan, D.; Agostini, A. De; Zhang, L.; Jiang, T. Aglycone Ebselen and β-d-Xyloside
Primed Glycosaminoglycans Co-contribute to Ebselen β-d-Xyloside-Induced Cytotoxicity. J. Med. Chem.
2018, 61, 2937–2948.
https://doi.org/10.1021/acs.jmedchem.7b01835
30. Schoeller, A. Über eine einfache und bequeme Methode zur Darstellung aromatischer Selenverbindungen.
Berichte der Dtsch. Chem. Gesellschaft (A B Ser. 1919, 52, 1517–1518.
https://doi.org/10.1002/cber.19190520815
31. Press, D. J.; Mercier, E. A.; Kuzma, D.; Back, T. G. Substituent Effects upon the Catalytic Activity of Aromatic
Cyclic Seleninate Esters and Spirodioxyselenuranes That Act as Glutathione Peroxidase Mimetics. J. Org.
Chem. 2008, 73, 4252–4255.
https://doi.org/10.1021/jo800381s
32. Rafique, J.; Saba, S.; Canto, R.; Frizon, T.; Hassan, W.; Waczuk, E.; Jan, M.; Back, D.; Da Rocha, J.; Braga, A.
Synthesis and Biological Evaluation of 2-Picolylamide-Based Diselenides with Non-Bonded Interactions.
Molecules 2015, 20, 10095–10109.
https://doi.org/10.3390/molecules200610095
33. Thompson, D. P.; Boudjouk, P. A convenient synthesis of alkali metal selenides and diselenides in
tetrahydrofuran and the reactivity differences exhibited by these salts toward organic bromides. Effect of
Page 12
©ARKAT USA, Inc

Arkivoc 2019, ii, 0-0
Krasowska, D et al.
ultrasound. J. Org. Chem. 1988, 53, 2109–2112.
https://doi.org/10.1021/jo00244a051
34. Shi, Y.-P.; Chen, B.-Q.; Ma, J.; Liu, Y.-M.; Li, C.-W. Synthesis and Antitumor Activity of 2-(2-Substituted
1,3,4-thiadiazol-5-yl)benzisoselenazol-3(2H)-one Derivatives. Acta Chim. Sin. 2011, 69, 2561–2566.
35. Syper, L.; Mlochowski, J. Lithium diselenide in aprotic medium - a convenient reagent for synthesis of
organic diselenides. Tetrahedron 1988, 44, 6119–6130.
https://doi.org/10.1016/S0040-4020(01)89801-X
36. Pacuła, A. J.; Ścianowski, J.; Aleksandrzak, K. B. Highly efficient synthesis and antioxidant capacity of N-
substituted benzisoselenazol-3(2H)-ones. RSC Adv. 2014, 4, 48959–48962.
https://doi.org/10.1039/C4RA08631G
37. Penteado, F.; Monti, B.; Sancineto, L.; Perin, G.; Jacob, R. G.; Santi, C.; Lenardão, E. J. Ultrasound‐Assisted
Multicomponent Reactions, Organometallic and Organochalcogen Chemistry. Asian J. Org. Chem. 2018, 7,
2368–2385.
https://doi.org/10.1002/ajoc.201800477
38. Sancheti, S. V.; Gogate, P. R. A review of engineering aspects of intensification of chemical synthesis using
ultrasound. Ultrason. Sonochem. 2017, 36, 527–543.
https://doi.org/10.1016/j.ultsonch.2016.08.009
39. Chen, D.; Sharma, S. K.; Mudhoo, A. Handbook on Applications of Ultrasound: Sonochemistry for
Sustainability; Chen, D.; Sharma, S. K.; Mudhoo, A., Eds.; CRC Press: Boca Raton, 2011.
40. Mason, T. J.; Lorimer, J. P. Applied Sonochemistry: Uses of Power Ultrasound in Chemistry and Processing;
Mason, T. J.; Lorimer, J. P., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2002.
41. Lesser, R.; Weiss, R. Über selenhaltige aromatische Verbindungen (VI). Berichte der Dtsch. Chem.
Gesellschaft (A B Ser. 1924, 57, 1077–1082.
https://doi.org/10.1002/cber.19240570703
42. Müller, A.; Gabriel, H.; Sies, H. A novel biologically active selenoorganic compound--IV. Protective
glutathione-dependent effect of PZ 51 (ebselen) against ADP-Fe induced lipid peroxidation in isolated
hepatocytes. Biochem. Pharmacol. 1985, 34, 1185–9.
https://doi.org/10.1016/0006-2952(85)90493-9
43. Parnham, M. J.; Sies, H. The early research and development of ebselen. Biochem. Pharmacol. 2013, 86,
1248–1253. doi: 10.1016/j.bcp.2013.08.028
44. Wang, L.; Yang, Z.; Fu, J.; Yin, H.; Xiong, K.; Tan, Q.; Jin, H.; Li, J.; Wang, T.; Tang, W.; Yin, J.; Cai, G.; Liu, M.;
Kehr, S.; Becker, K.; Zeng, H. Ethaselen: A potent mammalian thioredoxin reductase 1 inhibitor and novel
organoselenium anticancer agent. Free Radic. Biol. Med. 2012, 52, 898–908.
https://doi.org/10.1016/j.freeradbiomed.2011.11.034
45. Sancineto, L.; Iraci, N.; Tabarrini, O.; Santi, C. NCp7: targeting a multitasking protein for next-generation
anti-HIV drug development part 1: covalent inhibitors. Drug Discov. Today 2018, 23, 260–271.
https://doi.org/10.1016/j.drudis.2017.10.017
46. Iraci, N.; Tabarrini, O.; Santi, C.; Sancineto, L. NCp7: targeting a multitask protein for next-generation anti-
HIV drug development part 2. Noncovalent inhibitors and nucleic acid binders. Drug Discov. Today 2018,
23, 687–695.
https://doi.org/10.1016/j.drudis.2018.01.022
47. Bartolini, D.; Commodi, J.; Piroddi, M.; Incipini, L.; Sancineto, L.; Santi, C.; Galli, F. Glutathione S-transferase
pi expression regulates the Nrf2-dependent response to hormetic diselenides. Free Radic. Biol. Med. 2015,
88, 466–480.
Page 13
©ARKAT USA, Inc

Arkivoc 2019, ii, 0-0
Krasowska, D et al.
https://doi.org/10.1016/j.freeradbiomed.2015.06.039
48. Gordhan, H. M.; Patrick, S. L.; Swasy, M. I.; Hackler, A. L.; Anayee, M.; Golden, J. E.; Morris, J. C.;
Whitehead, D. C. Evaluation of substituted ebselen derivatives as potential trypanocidal agents. Bioorg.
Med. Chem. Lett. 2017, 27, 537–541.
https://doi.org/10.1016/j.bmcl.2016.12.021
49. Chen, Y.; Tian, F.; Song, M.; Lu, S. Improved Method for the Synthesis of Organic Diselenides from Organic
Halides under Atmospheric Pressure. Synth. Commun. 2007, 37, 2687–2692.
https://doi.org/10.1080/00397910701465404
Page 14
©ARKAT USA, Inc