Sonochemistry: An efficient alternative to the synthesis of 3-selanylindoles using CuI as catalyst

Article abstract of DOI:10.1016/j.ultsonch.2015.05.012

Ultrasonic (US) irradiation was successfully used as an alternative energy source to prepare 3-selanylindoles through the direct selanylation of indoles with diorganyl diselenides using CuI (20 mol%) as catalyst and DMSO as the solvent. By using this US-p

Full text of DOI:10.1016/j.ultsonch.2015.05.012

Accepted Manuscript
Sonochemistry: an efficient alternative to the synthesis of 3-selanylindoles using
CuI as catalyst
Beatriz M. Vieira, Samuel Thurow, Juliana S. Brito, Gelson Perin, Diego Alves,
Raquel G. Jacob, Claudio Santi, Eder J. Lenardão
PII:
S1350-4177(15)00141-8
DOI:
http://dx.doi.org/10.1016/j.ultsonch.2015.05.012
ULTSON 2871
Reference:
Ultrasonics Sonochemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
2 March 2015
29 April 2015
13 May 2015
Please cite this article as: B.M. Vieira, S. Thurow, J.S. Brito, G. Perin, D. Alves, R.G. Jacob, C. Santi, E.J.
Lenardão, Sonochemistry: an efficient alternative to the synthesis of 3-selanylindoles using CuI as catalyst,
Ultrasonics Sonochemistry (2015), doi: http://dx.doi.org/10.1016/j.ultsonch.2015.05.012
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Sonochemistry: an efficient alternative to the synthesis of 3-
selanylindoles using CuI as catalyst.
Beatriz M. Vieiraa, Samuel Thurowa, Juliana S. Britoa, Gelson Perina, Diego Alvesa, Raquel
G. Jacoba, Claudio Santib, Eder J. Lenardãoa,*
a Laboratório de Síntese Orgânica Limpa - LASOL - Universidade Federal de Pelotas - UFPel - P.O. Box 354,
96010-900, Pelotas – RS, Brazil.
b Dipartimento di Chimica e Tecnologia del Farmaco, Group of Catalysis and Green Chemistry, Università
degli Studi di Perugia, Perugia, Italy.
* corresponding author. Tel: +55 (53) 3275-7533.
E-mail adresses: biamvieira14@hotmail.com (B.M. Vieira), samuelthurowdoug@gmail.com (S. Thurow),
julianabrit@gmail.com (J.S. Brito), gelson_perin@ufpel.edu.br (G. Perin), diego.alves@ufpel.edu.br (D.
Alves), raquel.jacob@ufpel.edu.br (R.G. Jacob), claudio.santi@unipg.it (C. Santi), lenardao@ufpel.edu.br
(E.J. Lenardão).
Abstract: Ultrasonic (US) irradiation was successfully used as an alternative
energy source to prepare 3-selanylindoles through the direct selanylation of
indoles with diorganoyl diselenides using CuI (20 mol%) as catalyst and DMSO as
the solvent. By using this US-promoted reaction, eleven 3-organylselanylindoles
were prepared selectively and in good yields. A comparative study between the
reactions under conventional heating, microwave and ultrasound irradiations was
performed, and it was observed advantage in using US over the other heating
systems.
Keywords: sonochemistry; 3-arylselanylindoles; organoselenium; copper-
catalysis; green chemistry.

1. Introduction
The structural unit heterocyclic indole is widely distributed as basic frame
both in naturally occurring bioactive molecules and in synthetic ones. Uses of
compounds containing the indole scaffold include drugs, agrochemicals, dyes and
pigments (indigo and analogs), dietary supplements, nutraceuticals, flavor
enhancers and perfumes [1-3]. 3-Arylthioindoles (Figure 1) are an emergent class
of synthetic indoles, which have been shown to possess important
pharmacological properties, including selective inhibition of the COX-2 enzyme
similar to etoricoxib and analogs (compounds I and II) [4], anti HIV-1 [5] and anti-
asmathic [6]. The imidazole-functionalyzed 3-arylthioindole III and the 3-
arylsulfonyl indole IV are potent anti-cancer, acting by inhibiting the polymerization
of tubulin [7]. Compounds III and IV proved to be even more active than
combretastatin-A-4, which is a natural compound with excellent antineoplastic
properties (Fig.1 ).
In vitro and in vivo models studies have been demonstrated the
pharmacological properties of organoselenium compounds [8-10], which include
antinociceptive
[11,12],
hepatoprotective
[13,14],
anti-cancer
[15-18],
antidepressant [18,19], memory enhancer [19] and GPx-like activities [20-22].
The so-called “synthetic multivalent molecules”, which combine two or more
bioactive moieties, have been used as an effective stratagem for designing new
drugs [23]. In this line, 3-arylselanylindoles could be an interesting target to
prospect novel drugs candidates and the first bioassays involving this class of
compounds appeared only this year [24]. 3-Arylselanylindole V and the selenoxide
VI (Fig. 1) were superior to combretastatin-A-4 in inhibiting the tubulin
polymerization and disrupt tubulin microtubule dynamics. The selenide V was
obtained by the reaction of 1,2-bis-(3,4,5-trimethoxyphenyl)diselenide with 5-
methoxy-1,2-dimethyl-1H-indole in the presence of I2/FeCl3, and under microwave
irradiation for 30 min. at 80 oC [24].

Figure 1. Chalcogenoindoles with analog activities to etoricoxib and combretastatin A-4.
The synthesis and pharmacological studies of 3-arylthioindoles are well
documented [1-6]. However, in spite of a large number of pharmacological
activities reported for both, the indole scaffold and organoselenium compounds,
the synthesis and potential bioactivity of 3-arylselenoindoles have not been
extensively explored [25-27]. These compounds can be obtained by two main
routes: (A) the electrophilic cyclization of 2-alkynylanilines [28-30]; and (B) the
direct selanylation of the indole by electrophilic selenium species [31-34]. Because
it involves the use of easily available indole as starting material, approach B is the
more attractive. This protocol, however, suffers of the inconvenience of having to
previously prepare the (in most cases) unstable electrophilic species of selenium.
This drawback was circumvented by Silveira and co-workers [32], which used the
PhSeSePh/TCCA/MgO system to generate PhSeCl in situ. In addition, these
reactions are not atom economic, once only a portion of the atoms involved (the
arylselenium moiety of the electrophile) is incorporated in the final product [35,36].
More recently, the microwave-promoted synthesis of 3-arylthio and 3-
arylselenoindoles starting from ArYYAr (Y= S, Se) in the presence of I2/DMSO
[37], using (NH4)2S2O8 in refluxing MeOH [38] or I2/EtOH (only two examples with
selenium) [39] were described. These approaches enable to incorporate two ArSe
of ArSeSeAr, improving the atomic efficiency of the reaction.
Cu-catalytic coupling processes are an interesting alternative to CAr-Se
bond formation, being a versatile method, which use generally mild reaction
conditions. [40-42] Furthermore, the use of non-noble metals, such as copper in

catalytic amount, is important to the development of eco-friendly organic synthesis
[40]. The use of Cu-catalysis to prepare 3-arylchalcogenylindoles was described
by Zhou and co-workers. [43,44] They performed the chalcogenoamination of 2-
alkynylanilines with dichalcogenides in the presence of CuI (10 mol%), DMSO and
CsCO3 at 80 °C for 4 h [43] or the reaction of indole with diaryl dichalcogenides in
o
presence of CuI and DMSO at 110 C for 10-18 h [44]. As the authors were
interested in the synthesis of 3-arylthioindoles, only diphenyl diselenide was used
in these reactions.
On the other hand, ultrasonic irradiation (US) have gained popularity in the
past decades as a versatile tool in a large variety of industrial and academic
applications [45-50] The role of ultrasound waves as a green tool in promoting
organic synthesis (the so-called sonochemistry) is well documented [49,50]. This
non-conventional energy source is able to accelerate reactions or even to change
completely their course and selectivity, through the formation of new reactive
intermediates and compounds that are not usually observed under classical
thermal conditions [49]. In addition, reactions under US are considered
environmentally friendly processes, being less energy consumer and generating
fewer side products [45-50].
Despite the large interest in organoselenium compounds, the number of
papers describing the use of sonochemistry to prepare these species is limited
[51-56] and, to the best of our knowledge, the Cu-catalyzed C-Se bond formation
on the synthesis of 3-arylselanylindoles by direct selanylation of indoles has not
yet been extensively studied [44]. Besides, in view of the important biological
activities recently discovered of 3-arylselanylindoles, the development of general,
selective and greener methods to prepare this class of compounds is desirable.
Due our continued interest in the development of green procedures to
access organoselenium compounds with potential pharmacological activities
[12,31,57-61], we present here the results on the study of the sonochemical
synthesis of 3-arylselanylindoles, through the direct selenylation of indoles using
diorganyl diselenides under Cu-catalysis. Moreover, we have developed a
comparative study of this new reaction under conventional thermal heating,
microwave and ultrasonic irradiation, aiming to show the role of the ultrasound in
this synthesis.
2. Experimental

2.1. General procedure for the synthesis of 3-organylselanylindoles 3:
Indole 1 (0.5 mmol), diorganyl diselenide 2 (0.3 mmol), CuI (0.0114g, 20 mol %),
and DMSO (0.5 mL) were added in a glass tube. The reaction was performed
using three different methods: Method A (Ultrasound): The US probe was placed
in a glass vial containing the reaction mixture. The amplitude of the US waves was
fixed in 60%. The temperature was monitored and after 1 min was around 60-61
oC, which maintains until the end of the reaction. Method B (Microwave): The
glass tube was sealed and placed in a CEM Discover microwave apparatus. A
maximum irradiation power of 100 W and a temperature of 60 °C were applied for
2 hours. Method C (Oil Bath): The glass tube was placed in a pre-heated oil bath
at 60 °C and the mixture was vigorously stirred. The progress of the reaction was
monitored by TLC and the resulting solution was stirred for the time indicated in
Table 2. After that, the reaction mixture was received in water (10.0 mL), extracted
with ethyl acetate (3 x 5.0 mL), dried over MgSO4 and concentrated under
vacuum. The residue was purified by preparative chromatographic plate using
ethyl acetate/hexane as the eluent.
3-(Phenylselanyl)-1H-indole (3a)
White solid; mp 130-131 °C. Lit. [33]: 135.4–137.0 °C. Yield, Method A: 0.1010g
1
(74%); Method B: 0.0273g (20%); Method C: 0.0614g (45%); H NMR (CDCl3,
300 MHz): δ = 8.34 (br s, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.40-7.37 (m, 2H), 7.24-
7.08 (m, 7H). 13C NMR (CDCl3, 75 MHz): δ = 150.43, 137.06, 134.55, 129.69,
128.92, 125.74, 113.60, 113.10, 40.24. MS m/z (rel. int.): 273 (18.4), 193 (100.0),
116 (6.4), 77 (7.0).
5-Bromo-3-(phenylselanyl)-1H-indole (3b)
White solid; mp 102-104 °C. Lit. [33]: 108.1–109.4 °C. Yield: Method A: 0.1684g
(96%); Method B: 0.0122g (7%); Method C: 0.1667g (95%); 1H NMR (CDCl3, 400
MHz): δ = 8.47 (br s, 1H), 7.76 (d, J = 1.4 Hz, 1H), 7.41 (d, J = 2.5 Hz, 1H), 7.31
(dd, J = 8.6, 1.8 Hz, 1H), 7.26-7.07 (m, 6H). 13C NMR (CDCl3, 100 MHz): δ =
135.0, 133.3, 132.4, 131.8, 129.0, 128.6, 125.9, 125.8, 122.8, 114.3, 112.9, 97.7.
MS m/z (rel. int.): 351 (36.5), 271 (100.0), 192 (36.9), 115 (12.1), 77 (12.6).
1-Methyl-3-(phenylselanyl)-1H-indole (3c)

White solid; mp 63-65 °C. Lit. [34]: 67 °C. Yield: Method A: 0.1334g (93%);
1
Method B: 0.0287g (20%); Method C: 0.1148g (80%); H NMR (CDCl3, 400
MHz): δ = 7.62 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.28-7.18 (m, 4H),
7.15 (t, J = 7.9 Hz, 1H), 7.11-7.03 (m, 3H), 3.70 (s, 3H). 13C NMR (CDCl3, 100
MHz): δ = 137.4, 135.6, 134.2, 130.6, 128.8, 128.5, 125.4, 122.4, 120.4, 120.3,
109.5, 95.9, 33.0. MS m/z (rel. int.): 287 (21.8), 207 (100.0), 130 (15.5), 77 (6.7).
3-[(4-Methoxyphenyl)selanyl]-1H-indole (3d):
White solid; mp 77-79 °C. Yield: Method A: 0.0348g (23%); Method B: 0.0257g
1
(17%); Method C: 0.0560g (35%); H NMR (CDCl3, 300 MHz): δ = 8.24 (br, s,
1H),), 7.63 (d, J = 7.7 Hz, 1H), 7.31-7.29 (m, 2H), 7.23-7.11 (m, 5H), 6.69-6.64 (m,
2H), 3.65 (s, 3H).13C NMR (CDCl3, 75 MHz): δ = 158.2, 136.2, 131.1, 130.6,
129.7, 123.3, 122.7, 120.6, 120.2, 114.7, 111.3, 99.1, 55.2. MS m/z (rel. int.): 303
(13.5), 223 (100.0), 180 (24.8), 77 (12.2). HRMS calcd. for C15H13NOSe: [M + H]+
304.0241. Found: 304.0229.
3-(o-Tolylselanyl)-1H-indole (3e)
Yellow solid; mp 104-106 °C. Yield: Method A: 0.0846 g (59%); Method B:
1
0.0358g (25%); Method C: 0.0617g; H NMR (CDCl3, 300 MHz): δ = 8.30 (br s,
1H), 7.60 (d, J = 7.9 Hz, 1H), 7.40-7.36 (m, 2H), 7.24 (dt, J = 8.0, 1.1 Hz, 1H),
7.19-7.09 (m, 2H), 7.04-6.96 (m, 1H), 6.86-6.79 (m, 2H), 2.46 (s, 3H). 13C NMR
(CDCl3, 75 MHz): δ = 136.4, 136.0, 134.5, 131.5, 129.8, 127.8, 126.4, 125.3,
122.9, 120.8, 120.3, 111.4, 97.0, 21.2. MS m/z (rel. int.): 287 (43.6), 206 (80.9),
117 (100.0), 77 (8.4). HRMS calcd. for C15H13NSe: [M + H]+ 288.0291. Found:
288.0280.
3-(4-Chlorophenylselanyl)-1H-indole (3f)
White solid; mp 132-133 °C. Lit. [37]: 134−135.0 °C. Yield: Method A: 0.0859 g
1
(56%); Method B:0.0260g (17%); Method C: 0.0322g (21%); H NMR (CDCl3,
300 MHz): δ = 8.40 (br s, 1H) 7.59 (d, J = 7.9 Hz, 1H), 7.43-7.39 (m, 2H), 7.26 (td,
J = 8.0, 1.1 Hz, 1H), 7.22-7.05 (m, 5H). 13C NMR (CDCl3, 75 MHz): δ = 136.3,
132.0, 131.5, 131.2, 129.9, 129.6, 128.9, 123.0, 120.9, 120.1, 111.4, 97.7. MS m/z
(rel. int.): 307 (19.3), 227 (100.0), 116 (5.8), 77 (4.1).
3-[(4-Fluorophenyl)selanyl]-1H-indole (3g)

White solid; mp 117-118 °C. Yield: Method A: 0.0582g (40%); Method B:
0.0436g; Method C:0.0887g; 1H NMR (CDCl3, 300 MHz): δ = 8.28 (br s, 1H), 7.62
(d, J = 7.7 Hz, 1H), 7.38-7.35 (m, 2H), 7.26-7.14 (m, 4H), 6.80 (t, J = 8.7 Hz, 2H).
13C NMR (CDCl3, 75 MHz): δ = 161.4 (d, 1JC-F = 244.7 Hz), 136.3, 131.0, 130.6 (d,
3JC-F = 7.6 Hz), 129.6, 127.8 (d, 4JC-F = 3.2 Hz), 123.0, 120.9, 120.1, 116.0 (d, 2JC-F
= 21.6 Hz), 111.4, 98.4. MS m/z (rel. int.): 291 (12.9), 211 (100.0), 183 (15.4), 77
(3.8). HRMS calcd. for C14H10FNSe: [M + H]+ 292.0041. Found: 292.0030.
3-{[3-(Trifluoromethyl)phenyl]selanyl}-1H-indole (3h)
Yellow solid; mp 70-71 °C. Lit. [37]: 75.8−77.0 °C. Yield: Method A: 0,1244g
1
(73%); Method B: 0.0170g (10%); Method C: 0.1142g (67%); H NMR (CDCl3,
300 MHz): δ = 8.43 (br s, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.53 (s, 1H), 7.46 (d, J =
2.5 Hz, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.33-7.24 (m, 3H), 7.22-7.14 (m, 2H). 13C
2
NMR (CDCl3, 75 MHz): δ = 136.4, 135.2, 131.7, 131.6, 131.5, 131.0 (q, JC-F
=
32.1 Hz), 129.6, 129.2, 125.0 (q, 3JC-F = 3.9 Hz), 123.8 (q, 1JC-F = 272.8 Hz), 122.3
3
(q, JC-F = 3.8 Hz), 121.1, 120.0, 111.5, 97.1. MS m/z (rel. int.): 341 (17.4), 261
(100.0), 116 (8.4), 77 (4.2).
5-Bromo-3-(4-chlorophenylselanyl)-1H-indole (3i)
White solid; mp 136-138 °C Lit. [32]: 118-121°C. Yield: Method A: 0.1347 g
1
(70%); Method B: 0.0327g; Method C: 0.1636g (85%); H NMR (CDCl3, 300
MHz): δ = 8.4 (br s, 1H), 7.73-7-72 (m, 1H), 7.45 (d, J = 2.5 Hz, 1H), 7.33 (dd, J =
8.6, 1.8 Hz, 2H), 7.27 (d, J = 8.6 Hz, 1H), 7.13-7.06 (m, 4H). 13C NMR (CDCl3, 75
MHz): δ = 135.0, 132.4, 131.7, 131.5, 129.9, 129.8, 129.1, 126.0, 122.7, 114.4,
112.9, 97.5. MS m/z (rel. int.): 385 (4.7), 306 (100.0), 190 (22.1), 114 (15.3), 75
(14.9).
3-(4-Chlorophenylselanyl)-1-methyl-1H-indole (3j)
White solid; mp 116-119 °C. Lit. [32]: 110-114 °C. Yield: Method A: 0.0979 g
1
(61%); Method B: 0.0272g (17%); Method C: 0.1316g (82%); H NMR (CDCl3,
300 MHz) δ = 7.57 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.30-7.25 (m, 2H),
7.20-7.03 (m, 5H), 3.78 (s, 3H). 13C NMR (CDCl3, 75 MHz) δ = 137.4, 135.6,
132.4, 131.4, 130.3, 129.7, 128.9, 122.5, 120.5, 120.2, 109.6, 95.5, 30.0. MS m/z
(rel. int.): 321 (13.1), 240 (100.0), 130.0 (29.0), 77 (13.9).

3-(Butylselanyl)-1H-indole (3k)
Brown oil. Yield: Method A: 0.1113g (88%); Method B: no reaction; Method C:
0.0670g; 1H NMR (CDCl3, 300 MHz): δ = 8.13 (br s, 1H), 7.75-7.72 (m, 1H), 7.31-
7.27 (m, 1H), 7.24-7.15 (m, 3H), 2.65 (t, J = 7.3 Hz, 2H), 1.61-1.51 (m, 2H), 1.47-
1.29 (m, 2H), 0.83 (t, J = 7.3 Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ = 136.1, 130.2,
130.0, 122.4, 120.2, 120.0, 111.2, 98.6, 32.6, 28.5, 22.6, 13.5. MS m/z (rel. int.):
253 (14.3), 196 (15.5), 117 (100.0), 77 (5.4). HRMS calcd. for C12H15NSe: [M + H]+
254.0448. Found: 254.0436.
3. Results and Discussion
Based on our previous works on the C-H bond cleavage to form new CAr-Se
bond using Cu-catalysis [31,57,58,60,61], here is reported the synthesis of 3-
organylselanylindoles 3, containing a number of substituents both in the indole and
in the organoselenium moieties, according the procedure depicted on Scheme 1.
Scheme 1. Synthesis of 3-arylselanylindoles using ultrasonic irradiation (US).
We start from indole (1a, 0.5 mmol) and diphenyl diselenide (2a, 0.3 mmol)
to establish the best conditions for the direct arylselanylation reaction under
ultrasonic irradiation using different copper species. When a mixture of 1a and 2a
was sonicated in the presence of CuONPs (10 mol%) and DMSO (0.5 mL) as the
solvent during 1h (60% of frequency) no product was observed by TLC or GC-MS
(Table 1, entry 1). Whereas, the use of CuBr and CuCl afforded the desired 3-
(phenylselanyl)-1H-indole 3a in low yields (18% and 34% respectively, entries 2
and 3). When CuI was used as catalyst (10 mol%), the conversion to product 3a
increased to 82% (Table 1, entry 4) and increasing the catalyst amount to 20%
produced slightly better yields (97%, entry 6). The use of stoichiometric amounts
of indole 1a and diphenyl diselenide 2a decreased the conversion to 81% (Table
1, entry 7), indicating that a little excess of diselenide is necessary. We also tested
other solvents, such as water, glycerol, DMF, toluene and THF; but in all the cases
the yields resulted to be not satisfactory, and no reaction was observed using
toluene and THF (Table 1, entries 8-12). The use of FeCl3 and NiCl2 as catalyst

(20 mol5) was also tested; however, low yields of 3-(phenylselanyl)-1H-indole 3a
were obtained after sonication for 1 or 2 h (Table 1, entries 13-14).
Insert Table 1 here
With the optimized conditions in hands, a detailed study was performed with
substituted indoles 1a-e and diorganyl diselenides 2a-g, to verify the scope of the
methodology, as well as the electronic effect of substituents (Table 2, Method A). It
was observed that the presence of the bromo group in the position 5 of the indole
ring in 1b (1.0 h of reaction, 96% yield of 3b) facilitates the reaction compared to
unsubstituted indol 1a, which afforded 3a in 74% yield after 1.5 h (Table 2, entry 2
versus entry 1). Similar behavior was observed when N-methyl-1H-indole 1c was
used, with the N-methyl- substituted selanylindole 3c being obtained in 93% yield
after ultrasonic irradiation for 2 h (Table 2, entry 3, Method A).
The study proceeded fixing the indole 1a to evaluate the effect of electron-
donor and electron-withdrawing groups in the aromatic ring on the organoselenium
reagent 2. When the reaction was carried out using diaryl diselenide 2b,
containing a methoxyl group at the para position of the aromatic ring, the
corresponding 3-arylselanylindole 3c was obtained in 23% yield, even after 20 h of
ultrasonic irradiation. Better results were achieved using the ortho-methyl
substituted diaryl diselenide 2c, which afforded the desired product 3e in 59%
yield after 4 h of reaction (Table 2, entry 5). Diaryl diselenides substituted with
electron-withdrawing groups, such as p-chloro (2d), p-fluoro (2e) and m-
trifluoromethyl (2f), gave good yields of the respective desired products 3f-h in 56,
40 and 73% yield, respectively; even if larger reaction times (4-5 h) are required in
comparison to that with diphenyl diselenide 2a (Table 2, entries 6-8, Method A).
The accelerating effect produced by 5-bromo and N-methyl substituents in
the indole was verified in the reaction with the p-chloro substituted diaryl
diselenide 2d (Table 2, entry 2). Thus, 5-bromo-indole 1b reacted with diselenide
2d to afford the respective arylselanylindole 3i in 70% yield in 1.5 h under
sonication, while 3j was obtained in 61% yield after 6 h from N-methyl-1H-indole
1c and 2d under the same conditions (Table 2, entries 9-10).
To our delight, our new Cu-catalyzed ultrasonic-promoted protocol worked
well also with the reaction of dibutyl diselenide 2g, affording the 3-
butylselanylindole 3k in 88% yield after 5 h (Table 2, entry 11, Method A). This is

the first well succeeded preparation of this compound ever described.
Unfortunately, no reaction was observed with protected indoles N-tosyl (1d) and
N-Boc (1e), even after 24 h of ultrasonic irradiation (Table 2, entries 12-13).
With the aim to compare the effect of different energy sources in the Cu-
o
catalyzed reaction, the direct selenylation of indoles at 60 C in DMSO was also
performed under microwave irradiation (Method B) and thermal heating (Method
C) with an oil bath. The obtained results are depicted in Table 2 and Figures 1 and
2.
In a general way, the microwave irradiation gave low yields of product, while
thermal heating afforded the desired products at similar yields but in larger
reaction times compared to the ultrasonic-promoted reactions. Thus, the reaction
of indole 1a with diphenyl diselenide 2a afforded 3a in 20% and 45% yields after 2
h and 5 h using the Methods B and C respectively (Table 2, entry 1), while only
7% of 3b was obtained after 2 h under MW irradiation (Method B, entry 2). In this
case, thermal heating allowed preparing 3b in 95% yield after 2.5 h (entry 2,
Method C). Noteworthy, no reaction was observed between dibutyl diselenide 2g
and indole 1a using the Method B (MW irradiation), while only 53% of desired
butylselanylindole 3k was isolated after 20 h of reaction (Table 2, entry 11, Method
B versus Method C).
Insert Table 2 here
From the analysis of the results reported in Table 2 and graphically
summarized in Figure 2, it can be seen that the use of microwave is not
appropriated in our reaction, affording the products in modest yields or even failing
completely in some cases. The positive effect of ultrasonic irradiation in the
reaction is highlighted on Figure 3. Despite similar yields were obtained in most of
tested examples, the reaction time is drastically reduced when ultrasound was
used compared to conventional heating. The acceleration of the reaction under
ultrasound is due the cavitation, which leads to turbulent flow of the liquid phase
and enhanced mass transfer in the system [62].

Figure 2
Figure 3.
Based on the recent literature [42,43,60], a plausible mechanism is depicted
in Scheme 2 for the reaction between indole 1a and diphenyl diselenide 2a. At
first, we believe that CuI reacts with diphenyl diselenide forming the intermediate
A, which suffers the attack by the indole to afford B and C; Then, intermediate B
releases a proton to C, to form the product 3a and phenylselenol and regenerating
CuI. PhSeH, in the presence of DMSO and air, is oxidized to PhSeSePh and a
new cycle is initiated. To speculate if the reaction could be catalyzed by iodine
from the copper(I)iodide, similarly to the I2/DMSO- catalyzed, MW- promoted
reaction described by Silveira and Braga [37], the same reaction was tested using
KI instead CuI and no product was detected after 2 h under sonication. Thus, the
presence of copper is crucial for the reaction, reinforcing the proposed
mechanism.

Scheme 2: A plausible mechanism for the reaction.
3. Conclusion
In this study, we provide a new, copper-catalyzed ultrasonic-promoted method to
make 3-selanylindoles through the direct selenylation of indole derivatives. The
method is atom-economic and selective, allowing the transfer of the two RSe
groups from the diorganyl diselenide to the indole. A comparative study between
ultrasonic, microwave and conventional thermal heating, showed that ultrasonic
irradiation is advantageous, affording the products selectively in higher yields and
shorter reaction times.
Acknowledgements
The authors are grateful to FAPERGS and CNPq (PRONEM 11/2026-4),
CAPES (Processo 6391/2014-1) for the financial support.
This research was undertaken as part of the scientific activity of the
international multidisciplinary “SeS Redox and Catalysis” network.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.ultsonch.xxxxx.
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Figure captions
Figure 1. Reaction yields according the energy source.
Figure 2. Reaction times using US (green, Method A) and conventional heating (red, Method C).
Tables
Table 1. Optimization studies for preparation of 3-(phenylselanyl)-1H-indole 3aa

Catalyst
(mol%)
3a
Conv. (%)b
Entry
Solvent
1
2
CuONPs (10)
CuBr (10)
CuCl (10)
CuI (10)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
H2O
-
18
34
82
75
97 (69)c
81d
1.5
1
3
4
5
CuI (15)
6
CuI (20)
7
CuI (20)
8
CuI (20)
9
CuI (20)
glycerol
DMF
10
11
12
13
14
CuI (20)
30
nr
CuI (20)
toluene
THF
CuI (20)
nr
FeCl3 (20)
NiCl2.6H2O
DMSO
DMSO
20
6
a
The reaction was performed using indole (1a, 0.5 mmol) and diphenyl
diselenide (2a, 0.3 mmol) in 0.5 mL of solvent under ultrasound irradiation
in 60% of frequency. The final temperature measured in the reaction flask
using DMSO was 60 oC. b Conversion calculated by gas chromatography
c
coupled to a mass spectrometer after 1 h of reaction; Isolated yield. d An
equimolar amount of reagents was used.

Table 2. Synthesis of 3-organylselanylindoles.a
Entry Indole 1a-c
R2 2a-g
Product 3a-m
Methodb Time (h) Yield (%)c
Se
A
B
C
1.5
2
74
20
45
C6H5 2a
1
N
H
3a
5
A
B
1
2
96
7
2
3
2a
C
2.5
95
A
B
C
2
2
5
93
20
80
2a
A
20
23
4
5
1a
1a
4-CH3OC6H4 2b
B
C
2
17
37
24
A
B
C
4
2
59
25
43
2-CH3C6H4 2c
24
A
B
C
7
2
7
56
17
21
6
1a
4-ClC6H4 2d
A
B
C
5
2
40
30
61
7
8
1a
1a
4-FC6H4 2e
24
A
B
C
4
2
73
10
67
3-CF3C6H4 2f
24

Table 2, Continuationa
Entry Indole 1a-c
R2 2a-g
Product 3a–i
Methodb Time (h) Yield (%)c
A
B
1.5
2
70
17
9
1b
1c
2d
C
3
85
A
B
C
6
2
61
17
82
10
2d
24
A
B
C
5
2
88
nr
11
1a
C4H9 2g
20
53
Se
A
B
C
24
2
nr
nr
nr
12
13
2a
2a
N
Ts
3l
24
A
B
C
24
2
nr
nr
nr
24
a The reaction was performed using indole (1, 0.5 mmol), diorganyl diselenide (2, 0.3 mmol), CuI (20 mol%) in
o
DMSO (0.5 mL) at 60 C. b Method A: an ultrasound probe was used; Method B: a scientific microwave
apparatus was used; Method C: conventional heating with an oil bath was used. c Yields of purified products
using preparative chromatographic plates.

Highlights:
Ultrasonic irradiation accelerates the direct selenylation of indoles.
US is more effective than MW irradiation to prepare 3-organylselanylindoles.
CuI in DMSO is effective to prepare 3-organylselanylindoles from RSeSeR and indole.