Copper complexes and carbon nanotube-copper ferrite-catalyzed benzenoid A-ring selenation of quinones: An efficient method for the synthesis of trypanocidal agents

Article abstract of DOI:10.1039/c9nj02026h

We report a new method for A-ring selenation of naphthoquinones and anthraquinones and discuss the relevant trypanocidal activity of the synthesized compounds. We have demonstrated three efficient strategies for the preparation of the target selenium derivatives, i.e. (a) copper(i) thiophene-2-carboxylate and in situ generated Santi's reagent were used to prepare selenium-substituted benzenoid quinones, (b) copper complexes and (c) carbon nanotube-supported copper ferrite as catalysts in the presence of AgSeR-salts were also used for the synthesis of selenium-containing quinoidal derivatives. These new methods provide efficient and practical strategies for the preparation of selenium-based quinones. In addition, we have discovered nine compounds with potent trypanocidal activity. The derivatives 2a-2e showed potent trypanocidal activity with IC₅₀ values in the range of 13.3 to 37.0 μM.

Full text of DOI:10.1039/c9nj02026h

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Braga and E. N. da Silva Júnior, New J. Chem., 2019, DOI: 10.1039/C9NJ02026H.
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PAPER
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Copper complexes and carbon nanotube-copper ferrite-catalyzed
benzenoid A-ring selenation of quinones: An efficient method for
the synthesis of trypanocidal agents†
Guilherme A. M. Jardim,a,b Icaro A. O. Bozzi,a Willian X. C. Oliveira,a Camila Mesquita-Rodrigues,c
Rubem F. S. Menna-Barreto,c Ramar A. Kumar,d,e Edmond Gravel,d Eric Doris,d* Antonio L. Bragab
and Eufrânio N. da Silva Júniora,f*
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Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
We report a new method for A-ring selenation of naphthoquinones and anthraquinones and discuss the relevant
trypanocidal activity of the synthesized compounds. We have demonstrated three efficient strategies for the preparation of
the target selenium derivatives, i.e. a) copper(I) thiophene-2-carboxylate and in situ generated Santi reagent were used to
prepare selenium-substituted benzenoid quinones, b) copper complexes and c) carbon nanotube-supported copper ferrite
as catalysts in the presence of AgSeR-salts were also used for the synthesis of selenium-containing quinoidal derivatives.
These new methods provide efficient and practical strategies for the preparation of selenium-based quinones. In addition,
we have discovered nine compounds with potent trypanocidal activity. The derivatives 2a-2e showed potent trypanocidal
activity with IC50 values in the range of 13.3 to 37.0 μM.
carcinoma cells (HepG2). These results have led researchers to
postulate that selenoquinones possess anti-HepG2 activity.7
1. Introduction
Selenium-containing compounds have attracted increasing interest
in the scientific community due to their implication in various redox
processes, which has led to the discovery of biologically-active
molecules with, for example, antitumor properties.1 In general, Se-
based compounds exert their cytotoxic effects by acting as pro-
oxidants that alter cellular redox homeostasis. Yet, the precise
intracellular targets and mechanisms of cell death are intrinsically
related to the chemical properties of the respective seleno-
compounds, as recently discussed by Fernandes and co-authors.2
There are several well-known compounds based on chalcogens,3
for instance, hybrid redox substances have been prepared by
combining the quinoidal system and the selenium atom (Scheme
1A).4-8 In this context, different research groups, including Bates,4
Ruan and Fan,5 Batteux, Herling and Jacob,6 Wessjohann,7 as well as
Braga and da Silva Júnior,8 have developed several synthetic methods
to introduce selenium into the quinoidal backbone and evaluated
their biological potential. It has been found that selenoquinones are
involved in the downregulation of the Bcl-2 and Ki-67 expression
levels and also activate the expression of caspase-8 in hepatocellular
(A) Selenium-containing quinones with diverse biological applications (Refs 4-8):
O
O
O
OH
OH
O
O
N
Se
Se
Se
O
O
O
O
Se
N
N
O
O
H
N
Ph
N
Se
N
O
O
Me
O
Se
O
Me
S
Se
O
O
H
O
N
O
(B) A-ring functionalization on quinoidal compounds (Refs 12-15):
Key issue:
da Silva Júnior and
- New methods for
A-ring functionalization
- Important to develop
efficient catalytic reactions
for A-ring substitution
Ackermann groups
OH
O
[O]
Ru
R1
R2
O
da Silva Júnior and
Bower groups
da Silva Júnior
group
R
H
A
O
B
I
O
S
O
AgSR
Cu
NIS
Rh
R1
R2
R1
R1
R2
R2
R3
O
O
O
da Silva Júnior and
Ackermann groups
O
A-ring substituted
naphthoquinones with
trypanocidal activity
R3
R1
R2
Ru
O
a. Institute of Exact Sciences, Department of Chemistry, Federal University of Minas
Gerais, Belo Horizonte, MG, 31270-901, Brazil. E-mail: eufranio@ufmg.br.
b. Department of Chemistry, Federal University of Santa Catarina, 88040-900
Florianópolis, Brazil
(C) This work: C-5 Selenation of naphthoquinoidal compounds
Santi reactant formation:
SeCl
SeZnCl
Se
Zn, THF
Reflux
SOCl2
Se
c. Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, RJ, 21045-900, Brazil
d. Service de Chimie Bioorganique et de Marquage (SCBM) CEA, Université Paris-
Saclay 91191 Gif-sur-Yvette (France), E-mail: eric.doris@cea.fr
e. SRM Research Institute, Department of Chemistry, SRM Institute of Science and
Technology, Kattankulathur, 603203 Chennai, India
Hexane, 45 ºC
Strategy: in situ formation
of Santi reactant
R
- Catalytic options: CuTC, copper
complexes and carbon nanotube-
copper ferrite as catalysts
- PhSeCl and RSeAg as source of
selenium
PhSeCl
Zn
Se
A
O
O
I
O
f. Institut für Organische und Biomolekulare Chemie, Georg-August-Universität
Göttingen, Tammannstraße 2, 37077, Göttingen, Germany
† Electronic Supplementary Information (ESI) available with spectra for all selenated
A
Cu
O
Scheme 1 Overview.
compounds. See DOI: 10.1039/x0xx00000x
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In addition, chalcogen-containing β-lapachone derivatives have observed (Table 1, entry 1). As the formation of the desired product
shown cytotoxic activity against various cancer cell lines (leukemia, was detected in very low quantities, we applied higher temperature
human colon carcinoma, prostate, human metastatic prostate, (100 °C) and increased the amount of zinc to 3.0 equiv. Under these
ovarian, central nervous system and breast), demonstrating, in some conditions, 2a was isolated in 64% yield (entry 2). Subsequently, we
cases, IC50 values below 1 µM.8b,8c These two cases exemplify the used 1.5 equiv. of PhSeCl and 3.0 equiv. of zinc powder to improve
biological potential of selenium-containing quinones as antitumor the reaction conditions (entry 3). These conditions allowed the
View Article Online
DOI: 10.1039/C9NJ02026H
agents.
preparation of 2a with a slight improvement of the yield (68%) in
Methods for the insertion of chalcogens at the C-2 or C-3 comparison with entry 2 (64%). Further refinement aimed at
positions of quinonoid systems with the use of nucleophilic selenium maximizing the yield of 2a was accomplished as shown in entry 4.
sources are well developed.9 Simple modifications to the B-ring of the When 10 mol% of copper, 2.0 equiv. of PhSeCl and 5.0 equiv. of zinc
naphthoquinoidal moiety via Michael addition reactions10 or the were used, the selenated derivative 2a was obtained in 81% yield.
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formation of radicals11 have been exhaustively explored in the
literature on the chemistry of quinones.
In a previous study on the preparation of thiolated benzenoid A-
ring-modified quinonoid compounds, we demonstrated the
To address the lack of methods for benzenoid A-ring effectiveness of copper(I) thiophene-2-carboxylate (CuTC) for the
functionalization of naphthoquinones, the research groups of Bower insertion of the chalcogenium into iodinated naphthoquinones.15
and da Silva Júnior described the first and robust method for C-5 Thus, CuTC was our first choice for the study reported herein. Despite
selective C–H iodination of deactivated naphthoquinones via the effectiveness of the system (entry 4), we also evaluated CuI as an
catalysis with rhodium complexes.12 Later, the groups of da Silva alternative source of copper but it was much less active for the
Júnior and Ackermann reported ruthenium-catalyzed reactions for C- introduction of selenium at the C-5 position of 1,4-NQs, as the
5
selective C–H oxygenation of naphthoquinones and product 2a was obtained in only 22% yield (entry 5).
anthraquinones.13 This method allowed the A-ring oxygenation of
The use of different solvents, for instance, DMF and DCE did not
quinones, providing access to an important class of bioactive promote any further improvement (entries 6 and 7), nor did different
hydroxylated compounds. Following the same strategy, the same temperatures (entries 8-10). In all cases, 2a was obtained in yields
authors also described C–H alkenylation of unactivated not higher than 81% (entry 4).
naphthoquinones.14a These methods were versatile for the direct
Using PhSeBr instead of PhSeCl led to a decrease in the yield of
preparation of trypanocidal compounds. In general terms, all of the 2a, which was isolated in 33% yield (entry 11). Finally, two control
methods encompass C–H bond reactions through weak O- experiments confirmed the essential role played by copper (entry 12)
coordination by means of rhodium or ruthenium species.14b Recently, and zinc (entry 13) in the obtention of 2a.
our group also developed
a
direct sequential C–H
Table 1 Selected optimization results.
iodination/organoylthiolation method for the benzenoid A-ring
modification of quinonoid deactivated systems.15 In this work, the
insertion of sulfur into the quinone was shown to be an important
factor for increasing the trypanocidal activity of the compounds,
reflecting the importance of preparing hybrid substances containing
redox quinoidal and chalcogen systems (Scheme 1B).
Ph
I
O
Se
O
[Cu]-source
PhSeCl or PhSeBr (Y equiv)
Zn (Z equiv), Solvent (0.1 M)
Temp (ºC), 18 h
O
O
2a
1a
Entry [Cu]-source (mol %)
Y
Z
Solvent Temp (oC) Yield (%)
Given our recent success in the preparation of naphthoquinones
A-ring functionalized via reactions in only one or two steps (Scheme
1B), we report herein an efficient and reliable strategy for the
CuTC (5)
CuTC (5)
CuTC (5)
CuTC (10)
CuI (10)
1
1.0
1.0
1.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
3.0
3.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
-
DMAc
DMAc
DMAc
DMAc
DMAc
DMF
rt
Traces
64
2
100
100
100
100
100
100
60
installation of selenium atoms in
a
broad range of 1,4-
3
68
4
81
naphthoquinones (1,4-NQs) and 9,10-anthraquinones. For the first
time, a strategy for the A-ring selenation of 1,4-NQs was established
by employing different sources of copper as catalysts. In addition, we
evaluated the action of the compounds against Trypanosoma cruzi,
the etiological agent of Chagas disease.
5
22
CuTC (10)
CuTC (10)
CuTC (10)
CuTC (10)
CuTC (10)
CuTC (10)
-
6
40
7
DCE
NR
36
8
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
9
80
78
10
11a
12
13
130
100
100
100
26
2. Results and discussion
33
Traces
NR
Santi and co-workers demonstrated the efficient use of bench-stable
phenyl selenolate as a nucleophilic reagent in various organic
transformations.16 Based on these findings, we planned the
selenation of iodinated 1,4-NQs with the use of PhSeCl or PhSeBr in
the presence of zinc powder to generate the Santi reagent in situ,
and with a copper source as the catalyst (Scheme 1C). Preliminary
studies involved the reaction of 5-iodo-1,4-naphthoquinone 1a with
PhSeCl and zinc (1.0 equiv. of both reactants), 5.0 mol% of copper
and dimethylacetamide (DMAc) as the solvent at room temperature
but, under these conditions, only traces (≤5%) of the product 2a were
CuTC (10)
1a
General reaction conditions:
(
)
(0.1 mmol), PhSeCl (0.2 mmol),
.
CuTc or CuI (5.0 or 10.0 mol %), Zn (1.0, 3.0 or 5.0 mmol); Solvent (1 mL) NR =
For all cases starting material was recovered. Yields of isolated products. aPhSeBr
was used.
Exemplification of the process
To evaluate the scope and limitations of this novel method, we
prepared a set of RSeCl that were used to synthesize selenated
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quinones from 5-iodo-1,4-naphthoquinone 1a. Nakanishi and also outline the preparation of selenium-containing anthraquinones
collaborators have previously described the synthesis of selenated via the protocol described herein. These new naphthoquinone
anthraquinones using diselenide as a reactant.17 In this report, we derivatives and anthraquinones are shown in Scheme 2.
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9
R
SeCl
I
O
O
Se
O
O
(2.0 equiv)
R
10
11
12
13
14
15
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CuTc (10 mol%)
Zn (5.0 equiv), DMAc (0.1 M)
100 ºC, 18 h
Cl
F
MeO
Me
Se
O
Se
O
Se
O
Se
O
Se
O
O
O
O
O
O
2c:
42%
2a:
2d:
60%
81%
2b:
2e:
56%
58%
Cl
F
MeO
Me
Se
O
Se
O
Se
O
Se
O
Se
O
O
O
O
O
O
2h:
74%
2f:
2i:
74%
79%
2g:
2j:
76%
66%
*2.5 equivalents of Zn were used for the reactions with anthraquinone.
Scheme 2 Scope of the selective selenation protocol involving 1,4-naphthoquinones and 9,10-anthraquinones using CuTC as catalyst.
In order to confirm the structure of the selenated products, we loading to 2.5 mol%, 2a was produced in 56% yield when
prepared crystals of the naphthoquinones 2a, 2c, 2d and 2e and Cu(DMPHEN)2Cl was used as the catalyst (entry 6) and 96% yield with
anthraquinones 2h and 2i for subsequent crystallographic analysis. the use of Cu(PPh3)3Br as the copper source (entry 7). Experiments
The structures were solved by X-ray analysis and desired products aimed at reducing the catalyst loading to 1.0 mol% (entry 8) and
were confirmed. ORTEP-3 representations of the asymmetric unit of decreasing the temperature (entry 9) were also carried out, however
the compounds are shown in Figure 1.
with unsatisfactory outcomes. Finally, the reaction in the absence of
Based on the methodology previously described by our group,15 copper was also investigated but resulted in no formation of 2a
we postulated that the use of AgSeR-salts18 could be beneficial for (entry 10).
preparing the chalcogen-containing quinones. This method would
The optimized method described in Table 2 was used for the
allow the synthesis of the desired molecules in the absence of Zn synthesis of selenium-based quinones from iodinated derivatives of
powder. Our initial attempts involved the reaction of 1a with the naphthoquinones and anthraquinones. The scope of this
CuTC catalyst at room temperature (Table 2, entry 1). Here, the C-5 methodology is outlined in Scheme 3. Initially, the quinonoid
selenation was achieved but only traces of the product 2a (≤5%) were compounds described in Scheme 2 were also prepared using this
obtained. The use of 10 mol% of CuTC and a high temperature (100 alternative method. Compounds were synthesized in moderate to
°C) was adequate for the formation of 2a in 85% yield (entry 2). Next, high yields (Scheme 3). In general, the method involving the use of
we accomplished further refinements aimed at minimizing the AgSeR-salts and Cu(PPh3)3Br as the catalyst was the most effective,
amount of CuTC. With the use of 5 mol% of the catalyst, compound as molecules were obtained in better yields when compared to the
2a was achieved in 86% yield (entry 3). Even with this valuable result Santi reagent-based method.
in hand, we decided to continue our efforts toward obtaining
alternative copper-based catalysts. Consequently, Cu(DMPHEN)2Cl
and Cu(PPh3)3Br were also evaluated as copper sources. To our
delight, the use of 5 mol% of these catalysts allowed the isolation of
2a in 96 and 95% yield, respectively. On decreasing the catalyst
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Fig. 1 ORTEP-3 projections of naphthoquinones 2a, 2c, 2d and 2e and anthraquinones 2h and 2i with displacement ellipsoids at the 70% probability level.
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Table 2 Selected optimization results for the selenation reaction in the absence of
Zn.
Ph
I
O
Se
O
[Cu]-source
6
PhSeAg (1.0 equiv)
7
8
9
DMAc (0.1 M)
Temp (ºC), 18 h
O
1a
O
2a
Entry [Cu]-source (mol %) Temp (oC) Yield (%)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
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48
49
50
51
52
53
54
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58
59
60
CuTc (10)
CuTc (10)
1
2
rt
Traces
85
100
100
100
100
100
100
100
80
CuTc (5)
3
86
Cu(DMPHEN)2Cl (5)
Cu(PPh3)3Br (5)
Cu(DMPHEN)2Cl (2.5)
Cu(PPh3)3Br (2.5)
Cu(PPh3)3Br (1)
Cu(PPh3)3Br (2.5)
-
4
96
5
95
Fig. 2 ORTEP-3 projection of anthraquinone 2q with displacement ellipsoids at the 70%
probability level.
6
56
7
96
8
71
Use of copper supported on carbon nanotubes as catalyst
9
82
In the past decade, some of us have been involved in the
development of novel multi-walled carbon nanotubes (MWCNTs)-
based heterogeneous catalysts.19 These hybrids are prepared
according to a layer-by-layer strategy, taking advantage of the self-
assembly properties of a nano-ring-forming amphiphile (DANTA) and
using a cationic polymer (PDADMAC) as a stabilizing layer for metal
particles (Figure 3).19 The method allows the dense and robust
anchoring of metal species at the surface of the nanotubes and the
catalyst produced can be used for the promotion of organic
transformations. The approach has been applied to the
immobilization of various noble metals such as gold,20 rhodium,21
ruthenium22 and palladium23 as well as more abundant metals such
as nickel24 or copper.25 In these systems, carbon nanotubes offer
several advantages including large surface area, stability, and
potential stabilization of transient oxidation states of the catalytic
metals.
10
100
NR
1a
General reaction conditions: ( ) (0.1 mmol), PhSeAg
(0.1 mmol), Solvent (1.0 mL) NR = Starting material was
recovered. Yields of isolated products.
.
After the preparation of compounds 2a-2j, we considered the
synthesis of novel molecules using different selenium salts and 1,4-
NQs. We also used anthraquinones with different substitution
patterns. Compounds 2k-2r were prepared in good to excellent
yields, with the exceptions of compounds 2l and 2n which were
obtained in 41 and 65% yield, respectively (Scheme 3). Suitable
crystals of 2q for X-ray crystallographic studies were obtained aiming
at the unequivocal determination of the position that the selenation
reaction has occurred. ORTEP-3 representation of product 2q is
shown in Figure 3, clearly indicating that the reaction occurred on the
iodine ortho to the carbonyl group.
R3
I
O
Se
O
PhSeAg (1.0 equiv)
Cu(PPh3)3Br (2.5 mol%)
R1
R2
R1
R2
DMAc (0.1 M), 100 ºC, 18 h
O
O
O
Ph
Ph
2a: R = H (96%)
2b: R = OMe (74%)
2c: R = Cl (78%)
2d: R = F (93%)
2e: R = Me (72%)
2f: R = H (86%)
2g: R = OMe (70%)
2h: R = Cl (89%)
2i: R = F (90%)
Se
O
Se
2j: R = Me (74%)
O
O
CF3
O
Se
O
Se
O
Se
O
Se
O
O
O
O
O
2k: 98%
2l: 41%
2m: 84%
2n: 65%
Ph
Ph
Ph
Ph
Se
O
O
Se
O
O
Se
O
Se
O
O
I
Fig. 3 Structures of a) DANTA and b) PDADMAC; c) Overview of the CuFe2O4 catalyst.
NH
NH2
2o: 85%
O
Considering the catalytic efficiency of the CNT-based
nanocatalysts, we used CuFe2O4CNT to efficiently promote the
selenation of naphthoquinones and anthraquinones, since its use for
click reactions has been recently described.25 Initially, the reaction of
2q: 87%
2p: 86%
2r: 95%
O
Scheme 3 Scope of the selenation protocol involving 1,4-naphthoquinones and 9,10-
anthraquinones using Cu(PPh3)3Br as the catalyst.
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1a and PhSeAg with 0.3 mol% of CuFe2O4CNT as the catalyst was
conducted at 100 °C in dimethylacetamide (DMAc) but, under these
conditions, we did not observe any transformation after 1 h with
stirring (Table 3, entry 1). Following our attempts to prepare 2a, we
increased the reaction time to 2, 4, 8 and 12 h (entries 2-5), which
led to a concomitant increase in the yield. Finally, after 18 h of
reaction, 2a was prepared in 74% yield (entry 6). The use of 0.4 or 0.5
mol% of the catalyst did not generate significant changes in the
formation of 2a (entry 7 and 8). The application of a higher
temperature (120 °C) also had no effect on the synthesis of 2a (entry
9). It should be noted that while the “classical” selenation reaction
was carried out with 10 mol% of CuTC or 2.5 mol% of Cu(PPh3)3Br
(Tables 1 and 2), here only 0.3 mol% of CuFe2O4CNT is required for
the preparation of 2a in comparable yield.
View Article Online
R3
PhSeAg (1.0 equiv)
CuFe2O4CNT
(0.3 mol%)
DOI: 10.1039/C9NJ02026H
I
O
O
Se
O
R1
R2
R1
R2
DMAc (0.1 M),
100 ºC, 18 h
O
O
R
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Se
O
O
F3C
Se
Se
O
O
O
2a: 74%
2f: R = H (68%)
2s: R = OMe (73%)
2t: 49%
Ph
Ph
Se
O
O
Se
O
Se
O
Table
3 Selected optimization results for the selenation reaction using
O
O
O
CuFe2O4CNT as catalyst.
Ph
NH
O
O
I
O
Se
O
2v: 56%
2x: 63%
PhSeAg (1.0 equiv)
O
2u: 78%
CuFe2O4CNT (0.3 mol%)
Scheme 4 Scope of the selenation protocol involving 1,4-naphthoquinones and 9,10-
DMAc (0.1 M), 100 ºC, T (h)
anthraquinones using CuFe2O4CNT as catalyst.
O
O
1a
2a
Trypanocidal evaluation of the selenoquinones
Entry CuFe2O4CNT (mol %)
Time (h)
Yield (%)b
Chagas disease, described by the Brazilian Carlos Chagas more than
a century ago, is a parasitic disease caused by the hemoflagellate
protozoan Trypanosoma cruzi (T. cruzi). This illness is considered a
neglected tropical disease, leading to more than 10,000 deaths each
year. The World Health Organization estimates that almost 8 million
people are infected worldwide.26 In Latin American countries where
it is endemic, low-income populations are the most severely
affected, and the relation between considerable morbidity/mortality
and poverty can be clearly observed. Recently, globalization has led
to an intensification of the movement of infected individuals to well-
developed areas such as Europe and North America and
consequently the number of Chagas disease cases has increased in
non-endemic countries.27 Clinically, Chagas disease shows an acute
phase evidenced by the high number of the parasites in the
bloodstream, with unspecific symptoms, and an asymptomatic
chronic stage characterized by reduced parasitemia in spite of the
positive serology.28 During the course of the infection, 20-30% of the
patients will develop cardiac and digestive symptoms, or more rarely,
polyneuropathy.29 Treatment is currently based on only two drugs,
benznidazole and nifurtimox, nitroderivatives active on acute cases
that present notable limitations in chronic patients.30 Controversial
efficacy and severe side effects reinforce the need for new
trypanocidal drugs to be developed.31
NR
NR
Traces
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10
0.3
0.3
0.3
0.3
0.3
0.3
0.4
0.5
0.3
-
4
8
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74
73
51
70c
NR
aGeneral reaction conditions:
(0.2 mmol), CuFe2O4CNT
1a
(0.3 mol%, 157 µL of 1.9 mM aqueous suspension). bIsolated
yields. c120 ºC. NR = for all cases starting material
was
1a
recovered.
Subsequently, we applied the optimized method for the preparation
of selenium-containing quinones using the CuFe2O4CNT nanocatalyst
as an activator. Compounds 2a and 2f were prepared in moderate 74
and 65% yield, respectively, respectively. To verify the efficiency of
the nanocatalyst, we also prepared the quinonoid compound 2s-2x.
This robust and potent catalyst allowed the synthesis of the
selenated derivatives in similar yields with very low metal loading. In
addition to the superior activity of the CuFe2O4CNT nanocatalyst, a
second advantage is the combination of catalytically active copper
with magnetically active iron. If recycling of the catalyst is required,
the latter key feature can be exploited for easy magnetic recovery,
as previously shown by some of us.25
To this end, over the past few years, we have evaluated the
trypanocidal potential of various naphthoquinoidal compounds
containing, for example, hydroxyl,13 imidazole,32 1,2,3-triazole,33
alkyl34 and aryl35 groups. Here, compounds 2a-2e presented potent
trypanocidal activity with IC50 values in the range of 13.3 to 37.0 µM.
Of particular remark are compounds 2c and 2d, which were almost
eight times more active than benznidazole, the positive control and
one of the drugs used against the parasite that causes Chagas'
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disease. Naphthoquinones 2k-2n were also active against the of doublets (ddd), doublet of triplet of doublets (dtd), triplets (t),
View Article Online
parasite with emphasis on compound 2k (IC50 = 23.9 µM) which is doublet of triplets (dt), quintets (quint), sextDeOtsI:(1s0e.x1t0)3a9n/Cd9mNJu0lt2i0p2le6tHs
four times more active than the positive control, benznidazole. (m). The 1H and 13C NMR spectra were referenced to the appropriate
Anthraquinones 2f-2j and 2o-2t were inactive against T. cruzi (Table residual solvent peak or TMS peak. Coupling constants (J) were
4). Compounds 2u-2x were obtained in small amount and were not quoted to the nearest 0.5 Hz. Mass spectra were recorded using a
evaluated against the parasite.
Brüker Daltonics micrOTOF-Q II (APPI+ and ESI+ mode). Infrared
spectra were recorded on a Perkin Elmer Spectrum One FTIR
spectrometer as thin films or solids compressed on a diamond plate.
Table 4 Activity of naphthoquinones on trypomastigote forms of T. cruzi.
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IR bands are described by the wavenumber (ν ̅
, cm-1). Melting points
Compounds IC50/24 ha (µM)
Compounds IC50/24 ha (µM)
were determined using the Stuart SMP30 melting point apparatus
and are uncorrected.
2a
2b
2c
2d
2e
2f
2k
2l
14.4 ± 0.6
23.5 ± 1.1
13.3 ± 1.4
13.4 ± 2.3
37.0 ± 3.7
>4000.0
23.9 ± 1.5
39.0 ± 7.6
37.7 ± 4.6
40.0 ± 4.6
>4000.0
Synthesis of catalysts and substrates: Cu(PPh3)3Br and
Cu(DMPHEN)2Cl were synthesized following previously reported
procedures.37 CuFe2O4CNT was prepared according to the method
described by Gravel and Doris.24 Diselenides were synthesized via the
Grignard reaction followed by transmetalation with Se powder (200
mesh).38 1,2-dibutyldiselane was synthesized through the reaction of
N-butyllithium with Se powder (200 mesh).39 Phenyl
hypochloroselenoites were synthesized by reaction of the
corresponding diselenides with SO2Cl2 in hexane under reflux,
followed by the recrystallization in hexane as previously described in
2m
2n
2o
2p
2q
2r
>4000.0
2g
2h
2i
>4000.0
>4000.0
>4000.0
>4000.0
2s
2t
>4000.0
>4000.0
2j
>4000.0
103.6 ± 0.636
>4000.0
103.6 ± 0.636
Bz
Bz
the
literature
with
minor
modifications.40
Iodinated
aMean ± SD of at least three independent experiments.
naphthoquinones and anthraquinones were prepared via the
rhodium C-H iodination protocol previously reported by our research
group12 or by the methodology reported by Shvartsberg and co-
workers.41 Substrate (1p) was synthesised by acetylation of 1-amino-
4-iodoanthracene-9,10-dione (1o) with acetic anhydride and
pyridine under reflux.42 Substrate (1q) was synthesised by Diels-Alder
reaction of 5-iodo-1,4-naphthoquinone (1a) with 2,3-dimethylbuta-
1,3-diene followed by oxidation with 5% ethanolic potassium
hydroxide solutionand oxygen flux for 16 hours.43
3. Conclusions
In conclusion, we developed an efficient and reliable method for
preparing selenated naphthoquinones and anthraquinones. The
copper complexes and carbon nanotube-copper ferrite were found
to efficiently catalyze the reaction and provide the desired products
in high yield. In addition, the compounds showed action against T.
cruzi and potent trypanocidal compounds were identified. These
new derivatives open up new avenues for the design of potent
compounds that could be used against the parasite that causes
Chagas disease. In broader terms, the strategy described herein
represents a promising approach to the synthesis of A-ring selenated
quinones and may guide the synthesis of redox compounds based on
chalcogen chemistry.
General procedure for the selenation reactions (CuTC as catalyst),
Method A
An oven dried re-sealable reaction tube was loaded with the
corresponding iodinated quinone (0.10 mmol), the corresponding
phenyl hypochloroselenoite (0.20 mmol), copper 2-thiophene
carboxylate (1.9 mg, 10 mol %) and anhydrous DMAc (1.0 mL). The
Zn powder (2.5-5.0 eq.) was then added and the tube was sealed. The
mixture was kept at 100 °C for 18 h. After cooling and solvent
removal by reduced pressure the residue was purified by FCC, under
the conditions noted.
4. Experimental Section
Starting materials obtained from commercial suppliers were used as
received unless otherwise stated. For reagents requiring purification,
standard laboratory techniques based on methods published by
Perrin, Armarego, and Perrin (Pergamon Press, 1966) were
employed. Zinc powder was previously washed with HCl solution (1
M), water and acetone, dried under reduced pressure and stored
under argon. Flash column chromatography (FCC) was performed
using silica gel (Aldrich 40-63 µm, 230-400 mesh). Thin layer
chromatography (TLC) was performed using aluminum-backed 60
F254 silica plates. Visualization was achieved by UV fluorescence.
Proton nuclear magnetic resonance (NMR) spectra were recorded
using a Bruker DRX 400 or a Bruker AVANCE 400 spectrometer. 13C
NMR spectra were recorded at 100 MHz as stated. Chemical shifts
(δ) are given in parts per million (ppm). Peaks are described as
singlets (s), doublets (d), doublet of doublets (dd), doublet of doublet
General procedure for the selenation reactions (Cu(PPh3)3Br as
catalyst), Method B
An oven dried re-sealable reaction tube was loaded with the
corresponding iodinated quinone (0.10 mmol), AgSeR-salts (0.10
mmol) and Cu(PPh3)3Br (2.3 mg, 2.5 mol %). Anhydrous DMAc (1.0
mL) was added and the tube was sealed. The mixture was kept at 100
°C for 18 h. After cooling and solvent removal by reduced pressure
the residue was purified by FCC, under the conditions noted.
General procedure for the selenation reactions (CuFe2O4CNT as
catalyst), Method C
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Solvent system for flash chromatography: hexane/THF: 99/1; mp:
View Article Online
-1
1
DOI: 10.1039/C9NJ02026H
An oven dried re-sealable reaction tube was loaded with the 107.6-111.0 °C; IR (solid, cm ) ν: 2922, 1639, 1568, 1240, 819; H
corresponding iodinated quinone (0.10 mmol), AgSeR-salts (0.10 NMR (400 MHz, CDCl3) δ: 7.89 (d, J = 8.3 Hz, 1H), 7.60 (d, J = 8.7 Hz,
mmol) and CuFe2O4CNT (suspension in H2O 1.9 mM, 157 µL, 0.3 mol 2H), 7.38 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 8.9 Hz, 1H), 7.06 (d, J = 10.3
%). DMAc (1.0 mL) was then added and the tube was sealed. The Hz, 1H), 7.02-6.93 (m, 3H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ:
mixture was kept at 100 °C for 18 h. After cooling, the crude product 185.8, 185.1, 161.1, 143.5, 139.5, 139.2, 137.7, 134.2, 134.0, 132.8,
was extracted with ethyl acetate (3 x 10 mL) and the organic phase 128.4, 124.4, 118.9, 115.9, 55.6; HRMS (APPI+): 360.9974 [M+OH]+.
was dried with MgSO4. After solvent removal by reduced pressure, Cald. for [C17H13O4Se]+: 360.9974.
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the residue was purified by FCC, under the conditions noted. (Note:
catalyst suspension was submitted to vigorous stirring for 10 minutes 5-((4-chlorophenyl)selanyl)-1,4-naphthoquinone (2c). Red solid,
prior to the beginning of the reaction).
14.6 mg, 42% yield (Method A), 27.1 mg, 78% yield (Method B).
Solvent system for flash chromatography: hexane/THF: 99/1; mp:
General procedure for the synthesis of AgSeR-salts: A 100 mL round- 138.1-141.3 °C; IR (solid, cm-1) ν: 2925, 1664, 1639, 1298, 788; H
bottom flask was loaded with the corresponding diselenide (2.0 NMR (400 MHz, CDCl3) δ: 7.92 (d, J = 7.4 Hz, 1H), 7.64 (d, J = 8.3 Hz,
mmol), 10 mL of an HCl solution (3.0 mol/L) and 10 mL of Et2O. The 2H), 7.47-7.37 (m, 3H), 7.19 (d, J = 8.1 Hz, 1H), 7.07 (d, J = 10.3 Hz,
mixture was submitted to vigorous stirring until the solution became 1H), 6.97 (d, J = 10.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 185.8,
colorless. The organic phase was separated and added dropwise to a 184.9, 142.1, 139.3, 139.1, 137.8, 136.5, 134.1, 133.1, 130.5, 128.5,
100 mL round-bottom flask containing Et3N (2.0 mmol, 279 µL), 126.8, 124.7; HRMS (APPI+): 364.9476 [M+OH]+. Cald. for
AgNO3 (679.4 mg, 4.0 mmol) and acetonitrile (15 mL). A precipitate [C16H10ClO3Se]+: 364.9478.
was formed, and the mixture was kept under vigorous stirring for 30
min. The precipitate was filtered and washed with acetonitrile (3 x 5-((4-fluorophenyl)selanyl)-1,4-naphthoquinone (2d). Red solid,
10 mL) and Et2O (3 x 10 mL). The resulting solid was dried under 19.9 mg, 60% yield (Method A), 30.8 mg, 93% yield (Method B).
1
reduced pressure to afford the corresponding AgSeR-salts in Solvent system for flash chromatography: hexane/THF: 99/1; mp:
quantitative yields.
1
157.9-161.1 °C; IR (solid, cm-1) ν: 2919, 1646, 1575, 1219, 825; H
NMR (400 MHz, CDCl3) δ: 7.91 (dd, J = 7.5, 1.0 Hz, 1H), 7.68 (dd, J =
N-(4-iodo-9,10-dioxo-9,10-dihydroanthracen-1-yl)acetamide (1p). 8.6, 5.5 Hz, 2H), 7.40 (t, J = 8.2Hz, 1H), 7.18-7.12 (m, 3H), 7.07 (d, J =
Orange solid, 99% yield. Solvent for flash chromatography: toluene; 10.3 Hz, 1H), 6.97 (d, J = 10.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ:
mp: 238.1-240.3 °C; IR (solid, cm-1) ν: 2962, 1677, 1485, 1249, 1094, 185.6, 184.7, 165.1, 162.6, 142.3 (d, J = 0.9 Hz), 139.6 (d, J = 8.1 Hz),
1
800; H NMR (400 MHz, CDCl3) δ: 12.50 (s, 1H), 8.78 (d, J = 9.1 Hz, 139.1, 137.6, 133.9, 133.8, 132.8, 128.3, 124.4, 123.3 (d, J = 3.6 Hz),
1H), 8.35 (d, J = 9.1 Hz, 1H), 8.30-8.25 (m, 1H), 8.25-8.20 (m, 1H), 117.3 (d, J = 21.3 Hz); HRMS (APPI+): 348.9776 [M+OH]+. Cald. for
7.84-7.77 (m, 2H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 186.6, [C16H10FO3Se]+: 348.9774.
181.6, 170.0, 150.0, 143.1, 134.7, 134.2, 133.1, 133.0, 133.0, 127.4,
126.9, 126.2, 86.1, 25.9; HRMS (APPI+): 390.9689 [M]+. Cald. for 5-(p-tolylselanyl)-1,4-naphthoquinone (2e). Red solid, 18.3 mg, 56%
[C16H10INO3]+: 390.9700.
yield (Method A), 23.5 mg, 72% yield (Method B). Solvent system for
flash chromatography: hexane/THF: 99/1; mp: 128.9-130.6 °C; IR
1-iodo-6,7-dimethylanthracene-9,10-dione (1q). Yellow solid, 98% (solid, cm-1) ν: 2912, 1646, 1289, 788; H NMR (400 MHz, CDCl3) δ:
yield. Solvent for flash chromatography: toluene; mp: 245.1-246.3 7.88 (d, J = 7.4 Hz, 1H), 7.58 (d, J = 7.9 Hz, 2H), 7.37 (t, J = 7.8 Hz, 1H),
°C; IR (solid, cm-1) ν: 1677, 1314, 1212, 732; 1H NMR (400 MHz, CDCl3) 7.28-7.20 (m, 3H), 7.06 (d, J = 10.3 Hz, 1H), 6.96 (d, J = 10.3 Hz, 1H),
δ: 8.38 (ddd, J = 13.2, 7.8, 1.2 Hz, 2H), 8.06 (s, 1H), 7.98 (s, 1H), 7.35 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 185.5, 184.9, 142.9, 139.9,
(t, J = 7.8 Hz, 1H), 2.43 (s, 6H); 13C NMR (100 MHz, CDCl3) δ: 181.9, 139.2, 137.4, 136.8, 134.1, 133.8, 132.6, 130.8, 126.1, 124.7, 124.2,
181.6, 148.4, 144.6, 144.0, 136.0, 133.6, 132.3, 131.8, 130.6, 128.7, 21.5; HRMS (APPI+): 327.9996 [M]+. Cald. for [C17H12O2Se]+:
128.2, 127.6, 93.0, 20.3, 20.2; HRMS (APPI+): 361.9798 [M]+. Cald. for 327.9997.
1
[C16H11IO2]+: 361.9804.
1-(phenylselanyl)-9,10-anthraquinone (2f). Orange solid, 28.6 mg,
5-(phenylselanyl)-1,4-naphthoquinone (2a). Red solid, 25.4 mg, 81% 79% yield (Method A), 31.2 mg, 86% yield (Method B), 24.6 mg, 68%
yield (Method A), 30.0 mg, 96% yield (Method B), 23.1 mg, 74% yield yield (Method C). Solvent system for flash chromatography:
(Method C). Solvent system for flash chromatography: hexane/THF: hexane/ethyl acetate: 99/1; mp: 167.5-169.1 °C; IR (solid, cm-1) ν:
99/1; mp: 152.3-154.0 °C; IR (solid, cm-1) ν: 2922, 1661, 1633, 1265, 2922, 1670, 1571, 1265, 704; 1H NMR (400 MHz, CDCl3) δ: 8.39 (d, J
738; 1H NMR (400 MHz, CDCl3) δ: 7.90 (d, J = 7.3 Hz, 1H), 7.71 (d, J = = 7.1 Hz, 1H), 8.29 (d, J = 7.8 Hz, 1H), 8.13 (d, J = 7.4 Hz, 1H), 7.88-
6.7 Hz, 2H), 7.53-7.43 (m, 3H), 7.38 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 8.1 7.77 (m, 2H), 7.75 (d, J = 6.7 Hz, 2H), 7.54-7.44 (m, 3H), 7.41 (t, J = 7.8
Hz, 1H), 7.07 (d, J = 10.3 Hz, 1H), 6.97 (d, J = 10.3 Hz, 1H); 13C NMR Hz, 1H), 7.27 (d, J = 8.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 184.0,
(100 MHz, CDCl3) δ: 185.8, 185.1, 142.7, 139.4, 137.7, 137.7, 134.3, 183.2, 143.3, 137.8, 135.7, 134.6, 134.2, 133.9, 133.0, 133.0, 130.2,
134.0, 132.9, 130.2, 129.9, 128.6, 128.5, 124.5; HRMS (APPI+): 129.8, 129.8, 129.3, 127.7, 127.3, 125.1. Data are consistent with
330.9868 [M+OH]+. Cald. for [C16H11O3Se]+: 330.9868.
those reported in the literature.17
5-((4-methoxyphenyl)selanyl)-1,4-naphthoquinone (2b). Red solid, 1-((4-methoxyphenyl)selanyl)-9,10-anthraquinone (2g). Orange
19.9 mg, 58% yield (Method A), 25.4 mg, 74% yield (Method B). solid, 25.9 mg, 66% yield (Method A), 34.2 mg, 87% yield (Method B).
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Solvent for flash chromatography: toluene; mp: 226.9-229.0 °C; IR 5-(butylselanyl)-1,4-naphthoquinone (2l). Red solid, V1ie4w.9Armticlge,O5n1lin%e
(solid, cm-1) ν: 2928, 1661, 1565, 1249, 701; 1H NMR (400 MHz, CDCl3) yield (Method B). Solvent system for DflOaIs:h10.c10h3r9o/mC9aNtoJg0r2a0p2h6yH:
δ: 8.39 (d, J = 7.5 Hz, 1H), 8.29 (d, J = 7.0 Hz, 1H), 8.12 (d, J = 7.3 Hz, hexane/ethyl acetate: 10/1; mp: 68.3-70.0 °C; IR (solid, cm-1) ν: 2919,
1
1H), 7.86-7.77 (m, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.42 (t, J = 7.8 Hz, 1H), 1664, 1646, 1255, 772; H NMR (400 MHz, CDCl3) δ: 7.94 (d, J = 7.5
7.28 (d, J = 11.5 Hz, 1H), 6.99 (d, J = 8.4 Hz, 2H), 3.88 (s, 3H); 13C NMR Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.02 (d, J =
(100 MHz, CDCl3) δ: 183.8, 183.1, 160.8, 143.9, 139.0, 135.5, 134.3, 10.2 Hz, 1H), 6.94 (d, J = 10.2 Hz, 1H), 2.94 (t, J = 7.5 Hz, 2H), 1.80
134.2, 134.1, 133.9, 133.7, 132.8, 132.7, 129.6, 127.5, 127.2, 127.0, (quint, J = 7.5 Hz, 2H), 1.56 (sext, J = 7.5 Hz, 2H), 1.00 (t, J = 7.3 Hz,
124.8, 119.4, 115.6, 55.4. Data are consistent with those reported in 3H).; 13C NMR (100 MHz, CDCl3) δ: 185.4, 184.9, 141.1, 139.5, 137.5,
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the literature.17
137.0, 134.2, 132.7, 132.6, 129.1, 126.1, 123.7, 30.5, 24.8, 23.4, 13.7;
HRMS (APPI+): 295.0233 [M+H]+. Cald. for [C14H15O2Se]+: 295.0232.
1-((4-chlorophenyl)selanyl)-9,10-anthraquinone (2h). Orange solid,
29.4 mg, 74% yield (Method A), 35.3 mg, 89% yield (Method B). 5-((3-(trifluoromethyl)phenyl)selanyl)-1,4-naphthoquinone (2m).
Solvent system for flash chromatography: hexane/ ethyl acetate: Orange solid, 32.0 mg, 84% yield (Method B). Solvent system for flash
99/1; mp: 230.1-233.0 °C; IR (solid, cm-1) ν: 2922, 1568, 1469, 1271, chromatography: hexane/ethyl acetate: 10/1; mp: 159.1-160.9 °C; IR
704; 1H NMR (400 MHz, CDCl3) δ: 8.38 (d, J = 6.8 Hz, 1H), 8.30 (d, J = (solid, cm-1) ν: 1649, 1571, 1305, 1122, 769; 1H NMR (400 MHz, CDCl3)
7.9 Hz, 1H), 8.15 (d, J = 7.4 Hz, 1H), 7.82 (quint, J = 7.3 Hz, 2H), 7.67 δ: 7.99 (s, 1H), 7.92 (t, J = 8.7 Hz, 2H), 7.77 (d, J = 7.8 Hz, 1H), 7.60 (t,
(d, J = 8.1 Hz, 2H), 7.44 (d, J = 7.9 Hz, 3H), 7.26 (d, J = 3.8 Hz, 1H); 13
C
J = 7.7 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 7.09 (d,
NMR (100 MHz, CDCl3) δ: 183.8, 182.9, 142.5, 138.9, 136.2, 135.5, J = 10.3 Hz, 1H), 6.99 (d, J = 10.3 Hz, 1H); 13C NMR (100 MHz, CDCl3)
134.4, 134.1, 133.6, 133.0, 132.8, 130.3, 129.7, 127.5, 127.3, 127.1, δ: 185.6, 184.6, 141.2, 140.9, 139.1, 137.7, 134.1 (q, J = 7.7 Hz), 133.9,
125.1. Data are consistent with those reported in the literature.17
133.8, 133.0, 132.4, 132.1, 130.3, 129.5, 128.3, 126.5 (q, J = 3.3 Hz),
124.6; HRMS (APPI+): 381.9713 [M]+. Cald. for [C17H9F3O2Se]+:
1-((4-fluorophenyl)selanyl)-9,10-anthraquinone (2i). Orange solid, 381.9720.
28.2 mg, 74% yield (Method A), 34.3 mg, 90% yield (Method B).
Solvent system for flash chromatography: hexane/ethyl acetate: 5-((2-methoxyphenyl)selanyl)-1,4-naphthoquinone (2n). Orange
99/1; mp: 207.2-210.0 °C; IR (solid, cm-1) ν: 2922, 1664, 1568, 1271, solid, 22.3 mg, 65% yield (Method B). Solvent system for flash
1
800, 707; H NMR (400 MHz, CDCl3) δ: 8.37 (d, J = 6.9 Hz, 1H), 8.29 chromatography: hexane/ethyl acetate: 10/1; mp: 185.9-187.2 °C; IR
(d, J = 8.5 Hz, 1H), 8.13 (d, J = 7.3 Hz, 1H), 7.86-7.77 (m, 2H), 7.71 (dd, (solid, cm-1) ν: 2922, 1642, 1568, 1243, 760; 1H NMR (400 MHz, CDCl3)
J = 8.3, 5.7 Hz, 2H), 7.43 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), δ: 7.89 (d, J = 7.4 Hz, 1H), 7.71 (d, J = 7.3 Hz, 1H), 7.51 (t, J = 7.7 Hz,
7.16 (t, J = 8.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ: 184.05, 183.13, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 7.09-7.01 (m, 3H),
165.23, 162.75, 143.11, 139.8 (d, J = 8.1 Hz), 135.69, 134.59, 134.3 6.95 (d, J = 10.3 Hz, 1H), 3.79 (s, 3H); 13C NMR (100 MHz, CDCl3) δ:
(d, J = 2.5 Hz), 133.80, 133.13, 132.96, 129.86, 127.71, 127.31, 185.6, 184.9, 160.6, 141.8, 139.3, 139.2, 137.4, 134.1, 133.9, 132.4,
125.21, 124.2 (d, J = 3.7 Hz), 117.5 (d, J = 21.2 Hz). Data are consistent 132.1, 128.5, 124.2, 121.9, 117.0, 111.3, 56.0; HRMS (APPI+):
with those reported in the literature.17
343.9949 [M]+. Cald. for [C17H12O3Se]+: 343.9952.
1-(p-tolylselanyl)-9,10-anthraquinone (2j). Orange solid, 28.7 mg, 1-amino-4-(phenylselanyl)-9,10-anthraquinone (2o). Purple solid,
76% yield (Method A), 34.8 mg, 91% yield (Method B). Solvent for 32.1 mg, 85% yield (Method B). Solvent system for flash
flash chromatography: toluene; mp: 195.6-197.0 °C; IR (solid, cm-1) ν: chromatography: hexane/ethyl acetate: 5/1; mp: 203.9-205.0 °C; IR
1
2926, 1636, 1133, 744; H NMR (400 MHz, CDCl3) δ: 8.39 (d, J = 7.0 (solid, cm-1) ν: 3414, 1587, 1633, 1268, 726; 1H NMR (400 MHz,
Hz, 1H), 8.29 (d, J = 7.0 Hz, 1H), 8.12 (d, J = 7.4 Hz, 1H), 7.87-7.75 (m, DMSO) δ: 8.24 (t, J = 7.0 Hz, 2H), 7.96-7.86 (m, 2H), 7.70 (d, J = 7.0
2H), 7.62 (d, J = 7.8 Hz, 2H), 7.41 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 8.1 Hz, Hz, 2H), 7.58-7.46 (m, 3H), 7.04 (d, J = 9.2 Hz, 1H), 6.91 (d, J = 9.2 Hz,
3H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 183.8, 183.1, 143.5, 1H); 13C NMR (100 MHz, DMSO) δ: 183.7, 183.2, 151.8, 137.7, 135.2,
139.8, 137.5, 135.4, 134.3, 133.9, 133.7, 132.8, 132.7, 130.8, 129.6, 134.8, 134.3, 134.0, 132.9, 130.6, 130.2, 130.1, 129.9, 129.1, 127.1,
127.5, 127.0, 125.4, 124.8, 21.4. Data are consistent with those 126.9, 125.2, 112.8; HRMS (APPI+): 380.0179 [M+H]+. Cald. for
reported in the literature.17
[C20H14NO2Se]+: 380.0184.
5-(naphthalen-1-ylselanyl)-1,4-naphthoquinone (2k). Deep red N-(9,10-dioxo-4-(phenylselanyl)-9,10-dihydroanthracen-1-
solid, 35.5 mg, 98% yield (Method B). Solvent system for flash yl)acetamide (2p). Deep red solid, 36.1 mg, 86% yield (Method B).
chromatography: hexane/ethyl acetate: 19/1; mp: 114.9-116.2 °C; IR Solvent system for flash chromatography: hexane/ethyl acetate: 5/1;
1
(solid, cm-1) ν: 1642, 1574, 1286, 769; H NMR (400 MHz, CDCl3) δ: mp: 233.2-234.0 °C; IR (solid, cm-1) ν: 3052, 1577, 1481, 1258, 719;
8.25 (d, J = 8.4 Hz, 1H), 8.09-8.00 (m, 2H), 7.92 (d, J = 8.1 Hz, 1H), 7.85 1H NMR (400 MHz, CDCl3) δ: 12.51 (s, 1H), 8.83 (d, J = 9.4 Hz, 1H),
(d, J = 7.5 Hz, 1H), 7.58-7.44 (m, 3H), 7.19 (t, J = 7.8 Hz, 1H), 7.12 (d, 8.42 (d, J = 8.5 Hz, 1H), 8.32 (d, J = 8.6 Hz, 1H), 7.87 (quint, J = 7.6 Hz,
J = 10.3 Hz, 1H), 6.99 (d, J = 10.3 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H); 13
C
2H), 7.77 (d, J = 6.8 Hz, 2H), 7.60-7.45 (m, 3H), 7.32 (d, J = 8.0 Hz, 1H),
NMR (100 MHz, CDCl3) δ: 185.75, 184.82, 141.81, 139.22, 137.56, 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 187.1, 183.1, 169.9, 140.7,
135.36, 134.49, 134.20, 133.91, 132.70, 131.22, 128.87, 128.50, 138.1, 137.4, 136.5, 134.5, 134.0, 133.3, 132.8, 129.9, 129.6, 129.1,
128.20, 127.65, 127.60, 126.72, 126.35, 124.25; HRMS (APPI+): 127.3, 127.1, 125.4, 118.6, 77.4, 77.0, 76.7, 25.8; HRMS (APPI+):
363.9999 [M]+. Cald. for [C20H12O2Se]+: 364.0003.
421.0216 [M]+. Cald. for [C22H15NO3Se]+: 421.212.
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2-iodo-1-(phenylselanyl)-9,10-anthraquinone (2q). Red solid, 42.5 125.4, 118.7, 25.7; HRMS (APPI+): 472.0448 [M+H]+. Cald. for
View Article Online
DOI: 10.1039/C9NJ02026H
mg, 87% yield (Method B). Solvent for flash chromatography: [C26H17NO3Se]+: 472.0446.
toluene; mp: 117.9-120.0 °C; IR (solid, cm-1) ν: 3058, 1667, 1302, 710;
1H NMR (400 MHz, CDCl3) δ: 8.29-8.24 (m, 2H), 8.19-8.10 (m, 1H), 6,7-dimethoxy-5-(phenylselanyl)naphthalene-1,4-dione (2v). Deep
7.96 (d, J = 8.2 Hz, 1H), 7.82-7.77 (m, 2H), 7.29-7.20 (m, 5H); 13C NMR red solid, 20.9 mg, 56% yield (Method C). Solvent system for flash
(100 MHz, CDCl3) δ: 183.0, 182.5, 145.6, 140.9, 137.7, 134.7, 134.5, chromatography: hexane/ethyl acetate: 99/1; mp: 103.2-105.1 °C; IR
1
134.4, 134.3, 133.8, 132.3, 131.7, 129.4, 127.7, 127.4, 127.1, 126.8, (solid, cm-1) ν: 2937, 1565, 1308, 732; H NMR (400 MHz, CDCl3) δ:
117.1; HRMS (APPI+): 489.8972 [M]+. Cald. for [C20H11IO2Se]+: 7.57 (s, 1H), 7.57-7.52 (m, 2H), 7.28-7.23 (m, 3H), 6.97 (d, J = 10.2 Hz,
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489.8964.
1H), 6.87 (d, J = 10.2 Hz, 1H), 3.96 (s, 3H), 3.35 (s, 3H). 13C NMR (100
MHz, CDCl3) δ: 184.4, 156.5, 153.6, 139.9, 136.3, 133.3, 133.1, 132.0,
6,7-dimethyl-1-(phenylselanyl)-9,10-anthraquinone (2r). Deep 130.3, 128.8, 127.5, 126.7, 109.1, 59.6, 56.3; HRMS (APPI+): 391.0111
yellow solid, 37.1 mg, 95% yield (Method B). Solvent system for flash [M+OH]+. Cald. for [C18H15O5Se]+: 391.0079.
chromatography: hexane/ethyl acetate: 5/1; mp: 198.6-199.8 °C; IR
1
(solid, cm-1) ν: 3067, 1673, 1336, 741; H NMR (400 MHz, CDCl3) δ: 6-methoxy-5-(phenylselanyl)naphthalene-1,4-dione (2x). Deep red
8.14 (d, J = 8.0 Hz, 2H), 8.05 (s, 1H), 7.79 (d, J = 6.7 Hz, 2H), 7.58-7.46 solid, 21.6 mg, 63% yield (Method C). Solvent system for flash
(m, 3H), 7.42 (t, J = 7.8 Hz, 1H), 7.29 (t, J = 6.5 Hz, 1H), 2.49 (s, 3H), chromatography: hexane/ethyl acetate: 99/1; mp: 98.6-99.8°C; IR
2.47 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 184.0, 183.1, 144.3, 143.9, (solid, cm-1) ν: 2919, 1655, 1280, 1026, 831; 1H NMR (400 MHz, CDCl3)
142.6, 137.5, 135.6, 134.1, 132.6, 131.7, 130.8, 129.9, 129.8, 129.5, δ: 8.06 (d, J = 8.5 Hz, 1H), 7.55-7.39 (m, 2H), 7.27-7.19 (m, 3H), 7.03
129.3, 128.4, 128.0, 124.7, 20.3, 20.2; HRMS (APPI+): 392.0322 [M]+. (d, J = 10.3 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.91 (d, J = 10.2 Hz, 1H),
Cald. for [C22H16O2Se]+: 392.0310.
3.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 185.4, 184.0, 163.1, 139.5,
137.3, 133.8, 132.6, 128.6, 128.2, 127.1, 126.9, 126.8, 114.5, 55.6;
1-((2-methoxyphenyl)selanyl)anthracene-9,10-dione (2s). Orange HRMS (APPI+): 360.9982 [M+OH]+. Cald. for [C17H13O4Se]+: 360.9974.
solid, 28.7 mg, 73% yield (Method C). Solvent for flash
chromatography: toluene; mp: 188.1-190.8 °C; IR (solid, cm-1) ν: Trypanocidal assays: Stock solutions of the compounds were
2925, 1664, 1568, 1271, 757; 1H NMR (400 MHz, CDCl3) δ: 8.44 (d, J prepared in dimethylsulfoxide (DMSO), with the final concentration
= 8.9 Hz, 1H), 8.33 (dd, J = 7.5, 1.4 Hz, 1H), 8.17 (d, J = 6.8 Hz, 1H), of the latter in the experiments never exceeding 0.1%. Preliminary
7.84 (dtd, J = 22.5, 7.5, 1.4 Hz, 3H), 7.56 (t, J = 7.8 Hz, 1H), 7.45 (t, J = experiments showed that at concentrations up to 0.5% DMSO has no
7.8 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.13-7.04 (m, 2H), 3.84 (s, 3H); deleterious effect on the parasites. Bloodstream trypomastigotes of
13C NMR (100 MHz, CDCl3) δ: 183.8, 183.1, 160.6, 142.4, 139.3, 135.5, the Y strain were obtained at the peak of parasitemia from infected
134.3, 134.3, 133.9, 133.7, 132.8, 132.6, 132.0, 129.9, 127.5, 127.0, albino mice, isolated by differential centrifugation and resuspended
124.8, 121.9, 117.7, 111.3, 56.0; HRMS (APPI+): 394.0102 [M]+. Cald. in Dulbecco’s modified Eagle medium (DME) to give a parasite
for [C21H14O3Se]+: 394.0103.
concentration of 107 cells mL-1 in the presence of 10% of mouse
blood. This suspension (100 mL) was added in the same volume of
each compound previously prepared at twice the desired final
6,7-dimethyl-1-((3-(trifluoromethyl)phenyl)selanyl)anthracene-
9,10-dione (2t). Deep yellow solid, 22.5 mg, 49% yield (Method C). concentrations. Cell counts were performed in a Neubauer chamber
Solvent for flash chromatography: toluene; mp: 232.2-234.1 °C; IR and the trypanocidal activity was expressed as IC50, corresponding to
1
(solid, cm-1) ν: 1670, 1323, 1116, 797; H NMR (400 MHz, CDCl3) δ: the concentration that leads to lysis of 50% of the parasites.36
8.18-8.10 (m, 2H), 8.04 (s, 2H), 7.95 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 7.9
Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 9.1 Crystal structure and refinement: X-ray diffraction data for single
Hz, 1H), 2.47 (s, 3H), 2.46 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 184.1, crystals of 2a, 2b, 2d and 2e were collected with an Oxford-
182.9, 144.4, 144.2, 141.4, 140.9, 135.7, 134.1 (q, J = 3.8 Hz), 133.7, Diffraction GEMINI-Ultra diffractometer using Mo-Kα radiation
132.9, 132.4, 132.1, 131.5, 130.8, 130.5, 130.2, 129.9, 128.5, 128.1, (0.71073 Å). Measurements were performed at 250 K. Data
126.3 (q, J = 3.8 Hz), 125.1, 122.3, 20.3, 20.2; HRMS (APPI+): 477.0213 integration and scaling of the reflections for all compounds were
[M+OH]+. Cald. for [C23H16F3O3Se]+: 477.0211.
performed with the CRYSALIS suite.44 Final unit cell parameters were
based on the fitting of all reflection positions. Analytical absorption
corrections and the space group identification were also performed
N-(4-(naphthalen-1-ylselanyl)-9,10-dioxo-9,10-dihydroanthracen-
1-yl)acetamide (2u). Deep red solid, 36.7 mg, 78% yield (Method C). using the CRYSALIS suite.44 The structures of the compounds were
Solvent system for flash chromatography: toluene; mp: 285.2-286.0 solved by direct methods using the SUPERFLIP program.45 The
°C; IR (solid, cm-1) ν: 3061, 1581, 1478, 1258, 766; 1H NMR (400 MHz, positions of all atoms could be unambiguously assigned on
CDCl3) δ: 12.47 (s, 1H), 8.63 (d, J = 9.4 Hz, 1H), 8.45 (d, J = 8.7 Hz, 1H), consecutive difference Fourier maps. Refinements were performed
8.31 (d, J = 7.0 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H) 8.09 (d, J = 6.9 Hz, 1H), using SHELXL46 based on F2 through the full-matrix least squares
8.04 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.86 (dt, J = 13.0, 6.6 routine. All non-hydrogen atoms were refined with anisotropic
Hz, 2H), 7.54 (t, J = 7.5 Hz 2H), 7.47 (t, J = 7.9 Hz, 1H), 7.00 (d, J = 9.3 atomic displacement parameters. All hydrogen atoms were located
Hz, 1H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 188.0, 183.3, 169.9, on difference maps and included as fixed contributions according to
140.7, 137.6, 137.4, 136.8, 135.4, 134.5, 134.2, 134.1, 133.3, 132.8, the riding model.47 Values were C―H = 0.97 Å and Uiso(H) = 1.2 Ueq(C)
131.2, 129.3, 128.9, 128.8, 128.2, 127.6, 127.3, 127.1, 126.7, 126.3, for the aromatic carbon atoms. Molecular graphs were obtained with
ORTEP-348 in association with the POV-Ray software.49 ORTEP-3
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diagrams of the molecules are shown in Scheme 1. CCDC 1906753
(2a), 1906752 (2c), 1906751 (2d) and 1906750 (2e), 1921236 (2h),
1921235 (2i) and 1921237 (2q) contain the supplementary
crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre.
biologically relevant small molecules containing selenium.
Part B. Anti-infective and anticancer Compounds, The
View Article Online
DOI: 10.1039/C9NJ02026H
Chemistry of Organic Selenium and Tellurium Compounds,
ed. Z. Rappoport, John Wiley & Sons, Ltd, Chichester, UK,
2013, vol. 4; (g) A. L. Braga and J. Rafique, Synthesis of
biologically relevant small molecules containing selenium.
Part C. Miscellaneous biological activities, The Chemistry of
Organic Selenium and Tellurium Compounds, ed. Z.
Rappoport, John Wiley & Sons, Ltd, Chichester, UK, 2013,
vol. 4; (h) C. Jacob, G. I. Giles, N. M. Giles and H. Sies,
Angew. Chem., Int. Ed., 2003, 42, 4742-4758.
Acknowledgements
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This research was funded by grants from CNPq (404466/2016-8 and
PQ 305741/2017-9), FAPEMIG (PPM-00638-16, PPM-00635-18 and
Rede de Pesquisa e Inovação para Bioengenharia de Nanossistemas-
RED-00282-16), FAPERJ, CAPES and INCT-Catálise. ENSJ would also
like to thank the SeSRedCat and Capes-Humboldt research fellowship
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88881.145517/2017-01). G.A.M. Jardim acknowledges CNPq for
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Laboratory of Excellence in Research on Medication and Innovative
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Conflicts of interest
There are no conflicts to declare.
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Table of Contents
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Copper complexes and carbon nanotube-copper ferrite-catalyzed benzenoid A-
ring selenation of quinones: An efficient method for the synthesis of trypanocidal
agents
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R3
Selenium
source
Se
O
I
O
R2
R1
R1
R2
Cu
O
O
Application of three different synthetic strategies for the
preparation of selenium derivatives:
- CuTC + Santi reagent
- Copper complex + AgSeR-Salts
- Carbon nanotube-copper ferrite + AgSeR-Salts
23 new selenium-containing quinoidal derivatives
Compounds evaluated against Trypanosoma cruzi
9 compounds with potent trypanocidal activity
A-ring selenation of naphthoquinones and anthraquinones are reported. The reaction
was accomplished in the presence of copper complexes and carbon nanotube-supported
copper ferrite as catalysts and provides an efficient and general method for preparing
selenium-based quinones with trypanocidal activity.