Direct sequential C-H iodination/organoyl-thiolation for the benzenoid A-ring modification of quinonoid deactivated systems: A new protocol for potent trypanocidal quinones

Article abstract of DOI:10.1039/c8ob00196k

We report a sequential C-H iodination/organoyl-thiolation of naphthoquinones and their relevant trypanocidal activity. Under a combination of AgSR with a copper source, sulfur-substituted benzenoid quinones were prepared in high yields (generally >90%). This provides an efficient and general method for preparing A-ring modified naphthoquinoidal systems, recognized as a challenge in quinone chemistry.

Full text of DOI:10.1039/c8ob00196k

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Direct sequential C-H iodination/organoyl-thiolation for
benzenoid A-ring modification of quinonoid deactivated systems:
A new protocol for potent trypanocidal quinones
Received 00th January 20xx,
Accepted 00th January 20xx
Guilherme A. M. Jardim,a Willian X. C. Oliveira,a Rossimiriam P. de Freitas,a Rubem F. S. Menna-
Barreto,b Thaissa L. Silva,c Marilia O. F. Goulartc and Eufrânio N. da Silva Júniora*
DOI: 10.1039/x0xx00000x
www.rsc.org/
We report a sequential C-H iodination/organoyl-thiolation of naphthoquinones and their relevant trypanocidal activity.
Under a combination of AgSR with a copper source, sulfur-substituted benzenoid quinones were prepared in high yields
(generally > 90%). This provides an efficient and general method for preparing A-ring modified naphthoquinoidal systems,
recognized
as
a
challenge
in
quinone
chemistry.
1,4-Naphthoquinones (1,4-NQs) are considered privileged preparing benzenoid A-ring modified 1,4-NQs represents
structures implicated in important biological processes, as, for challenging task.
a
instance, electron carriers in the electron transport chain involved
in cellular respiration and photosynthesis.1 The notable bioactivity
(A) Accessing -SCF3 and -CF3 substituted 1,4-naphthoquinones (Refs 6-8):
O
B
O
O
O
of naphthoquinones is intrinsically related with redox mechanisms,
generation of reactive oxygen species, and more recently also
associated to inhibition of deubiquitinases2 and other enzymatic
targets. Illustrious 1,4-NQs include atovaquone, the lapachones
and the juglomycins, all of them possessing important biological
activities.2,3 Due of their biological importance, scientific endeavor
has been devoted aiming at new synthetic methods for preparing
1,4-NQs with potential applicability against illness such as Chagas
disease.4
AgSCF3
Oxidant
Zhang and Wang
condition
2
S
R
CF3
R
2
CF3
A
A
B
O
A
B
O
Szabó or Yang
conditions
Qing
Condition
R
CF3-source(a) CF3
I
Zn(SO2CF3)2,
TBHP
=
CF3-source (a)
Zhang and
Wang
CuCN
B pin
Szabó
Yang
Condition
CuI
-BuOH-DCM
O
=
=
,
2
2
Condition
t
condition
FeSO4.7H2O
O
(B) C-5 thiolation: (this work)
I
O
B
O
H
O
B
O
[Rh]
O
cat. Rh(III)
NIS
fast
R
R
A
Among the well-known functional groups in chemistry, -SCF3
and -CF3 groups have attracted attention because of their
importance in pharmaceutical and agrochemical industries.5 For
example, incorporation of the trifluoromethylthio (-SCF3) group into
drug candidates often brings beneficial effects on the drug’s
metabolic stability and bioavailability, as discussed by Xue and co-
workers.5a The strong electronegativity and high lipophilicity of this
group may be associated with an improvement in biological activity.
Moved by this information, recently Szabó,6a Zhang and Wang,6b
Qing7 and Yang8 groups have developed synthetic methods by using
C-H functionalization to introduce fluorinated groups in the
quinoidal system (Scheme 1A). All conditions lead to the insertion
of fluorinated groups at the position C-2, exemplifying well-
established methods for B-ring substitution. As previously discussed
by us,9 flexible protocols for direct functionalization of the
benzenoid A-ring are rare and limited to a few recently reported
examples.10 The development of new strategies/methodologies for
A
R
O
O
- versatile functional
group handle
R
- Preparation in few steps from
commercial quinones
- High yields. Generally > 90%
- Including -SCF3 and -SR,
R = alkyl and aryl
S
A
[Cu]-source
AgSR
R
B
O
Key Issue:
A-ring is very hard to
- Relevant activity against T. cruzi
modify!!
Scheme 1
The lack of general methods to promote these modifications is
associated with deactivated quinoidal systems due to low
nucleophilicity of the benzenoid A-ring and weak coordinating
ability of the B-ring carbonyls in the case of metal catalysis. To the
best of our knowledge, there are only two protocols that enable
catalytic carbonyl directed C-H functionalization in 1,4-NQs.9,10 The
first example was reported by Zhang group, where rhodium
catalysis was used to perform mono alkenylations with amino-
naphthoquinones.9 One drawback of the method described by
Zhang is the necessity of an amino group at C-2 to compensate the
electron deficiency of the quinoidal system and increase the
catalyst substrate coordination allowing an efficient catalytic
process. In this context, recently the da Silva Júnior and Bower
groups have demonstrated the effectiveness of [RhCp*Cl2]2 for the
first catalytic directed ortho-functionalizations of simple (non-bias)
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1,4-NQs by using different electrophilic iodine or bromine sources.10 the oxidative addition product. In this context, we have considered
This innovative method has encouraged us to devote efforts in the the use of this Cu-salt to improve the reactional conditions. As
development of new synthetic methodologies aiming at the expected, CuTc was very valuable and 2a was obtained in 100%
modification of A-ring of the naphthoquinoidal scaffold.
yield in all cases (entries 7-10), except at room temperature (entry
Herein our strategy was based on the general and powerful 6). The scope of this new method is outlined in Scheme 2. Iodinated
method to install iodine at C-5 with high yield and regioselectivity naphthoquinones possessing different pattern of substitution
and subsequently to combine AgSCF3 with
a copper source, underwent trifluoromethylthiolation to furnish 2b, 2c and 2e-i in
achieving the thiolated adducts in only two steps via a direct excellent yields. Only compound 2d was prepared in moderate 44%
sequential C-H iodination/organoyl-thiolation protocol (Scheme 1B). yield, probably due to a larger steric hindrance caused by the bulky
Preliminary studies involved the reaction of 5-iodo-1,4- amide group at C-5. Structural assignments were based on detailed
naphthoquinone 1a with AgSCF3 in room temperature and only NMR analysis (DEPT, COSY, HSQC, HMBC) and X-ray structures of
trace quantities (≤5%) of the product 2a was observed (entry 1). 2a, 2b, 2f, 2d and 2i.
The use of high temperature (100 ºC) produced the desired product
Table 1 Selected optimization results.
in 39% yield (entry 2). Based on the methodology previously
described by Szabó6 and Qing,7 we decided to investigate the
effectiveness of a copper source in this reaction. Pleasingly, the
experiments revealed impressive results. AgSCF3/CuI resulted in the
formation of product 2a in 100% yield (entry 3). CuBr as cooper
source was less effective and product 2a was obtained in 81% yield.
Further refinement aiming to minimize the amount of CuI and
reaction time affords 2a in 90% yield when 5 mol % of copper and
0.5 h was used (entry 5). Despite the effectiveness of the system
(entry 5), we have continued our investigation looking for
alternative Cu-salt for a quantitative preparation of 2a. Copper(I)-
thiophene-2-carboxylate (CuTc) is a well-known agent able to
promote diverse reactions, for instance, Ullmann reaction.11 As
discussed by Liebeskind and co-workers,11 CuTc is a powerful salt
for this reaction, probably due to its ability to allow internal
coordination from the sulfur atom to the metal and/or due to an
inherent ability of the carboxylate to work as a ligand to stabilize
S
A
O
F3C
I
O
B
O
[Cu]-source
AgSCF3 (100 mol%)
B
O
A
DMAc (0.1 M)
Temp (°C), time (h)
2a
1a
Entry Cu-source (mol%) Temp/oC Time/h Yield (%)
trace
39
24
24
0.5
0.5
0.5
24
24
1
r.t.
1
none
100
100
100
100
r.t.
2
none
100
81
3
CuI (10)
CuBr (10)
CuI (5)
4
90
5
24
6
CuTc (10)
CuTc (10)
CuTc (10)
CuTc (10)
CuTc (5)
100
100
100
100
50
7
100
100
100
8
0.5
0.5
9
10
O
O
O
O
[RhCp*Cl2]2 (3.75 mol%)
AgNTf2 (20 mol%)
AgSCF3 (100 mol%)
CuTc (5 mol%)
F3CS
I
R2
R2
R2
Cu(OAc)2 (100 mol%),
DMAc (0.1 M), 100°C
0.5-1h
NIS (100 mol%)
R1
R1
R1
CH2Cl2, 45 oC, 60 W, 2-8 h
O
O
1,4-NQs
2a-i
1a-i
O
F3C
F3C
F3C
S
O
S
O
S
O
NH
O
S
F3C
O
O
O
O
O
O
O
2a
2b
95% yield
2c
2d
44% yield
100% yield
95% yield
F3C
F3C
F3C
F3C
F3C
S
O
S
S
O
S
O
S
O
S
O
Ph
O
O
2e
O
O
2h
94% yield
O
O
2g
O
2i*
92% yield
F3C
2f
92% yield
87% yield
79% yield
Scheme 2 Scope of the selective trifluoromethylthiolation protocol.*Iodinated derivative 1i used to prepare compound 2i was not prepared by C-H activation reaction.
The potential of the trifluoromethylthiolation method herein respective quinones-based trifluoromethyl sulfoxide 3a and 3b in
described for preparing benzenoid substituted quinonoid moderate 74% and 70% yields, respectively. The structure of 3a was
compounds was also investigated with the derivatizations of 5- also solved by crystallographic methods, reconfirming the obtention
trifluoromethylthio-1,4-naphthoquinone 2a and anthraquinone 2i. of the product already determined by NMR and HRMS analysis.
Reactions of 2a and 2i with MCPBA in CH2Cl2 afforded the Ruthenium trichloride-sodium periodate system described by Su12
2 | Org. Biomol. Chem., 2018, 00, 1-3
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was used to perform the oxidation of the -SCF3 group to the has been attempted by using 2a as substrate. In this case, we have
respective sulfone which afforded 3c in excellent 92% yield and the recovered the starting material in 42% yield and the product of
structure was also confirmed by X-ray studies. The same procedure oxidation was not observed (Scheme 3).
CF3
Projections ORTEP-3 of 3a and 3c
F3C
F3C
O
S
O
S
O
O
S
O O
NaIO4 (3 eq.)
MCPBA (1.2 eq.)
RuCl3.H2O (1 mol%)
CH2Cl2, CH3CN, H2O
1h
CH2Cl2, 0°C to r.t.
overnight
O
O
O
Anthraquinone 3c
Naphthoquinone 2a
Anthraquinone 2i
Naphthoquinone 3a
74% yield
92% yield
Anthraquinone 3b
Reaction with 2a, starting
material recovered (42%)
70% yield
Scheme
3
Derivatizations
based
on
the
oxidation
of
2a
and
2i.
The versatility of the sequential C-H iodination/organoyl-
1-Iodo-anthraquinone was used to prepare 4g in 91% yield
thiolation process was also studied by using different AgSR-salts for (Scheme 4B). Subsequently, 4g was oxidized via Su procedure12 and
preparing new sulfur-containing quinones 4a-f. With the iodinated the product 5 was prepared in 89% yield. The structure of 5 was
quinone 1a in hands the respective sulphides 4a-f were prepared in also determined by X-ray analysis in addition to conventional
excellent yields with exception of compound 4b synthesized in 61% methods of analysis.
yield (Scheme 4A). Compounds 4d, 4e and 4g were also solved by X-
Exploratory reactions aiming to propose a mechanism for the
ray crystallography. Benzyl, alkyl and aryl derivatives were easily organoyl-thiolation process were conducted. As suggested by Szabó
prepared showing clearly the potential of this methodology for the group,6 CF3 radicals may be involved in the reaction of C-H
preparation of A-ring substituted quinones with different trifluoromethylation of quinones. TEMPO, which is a well-known
substitution patterns. These important findings open new avenues, radical scavenger, was used to evaluate the presence of radicals in
for example, related to Medicinal Chemistry, where in general it is those reactions. Thus, we have accomplished inhibition
necessary the synthesis of a family of compounds aiming SAR experiments with TEMPO, 4-oxo-TEMPO and 4-hydroxy-TEMPO
investigation.
(Scheme 5A). In all cases, quinone 2a was obtained in 100% yield
indicating that the reaction does not proceed via radical
a
(A) Synthesis of sulphide quinones 4a-f from naphthoquinone 1a
mechanism. Subsequently, we have considered three experiments:
(a) Presence and absence of Cu-source, (b) Absence of Ag-source
and (c) Absence of AgSR (Schemes 5B for 2a and SI for 4a). These
experiments have indicated that CuTc and AgSR are essential for
forming 2a and 4a since the absence of Cu-source affords 2a and 4a
in only 39% and 21% yields, respectively. Without Ag-salt, no
reaction was observed in relation to 2a and in the case of 4a, a
complex mixture of products was observed. Finally, the use of
different Ag- and S-salts led to a complex mixture of products in
both cases. Based on our observations and data already reported in
SR
O
I
O
AgSR (100 mol%)
CuTc (5 mol%)
DMAc (0.1 M), 100°C
overnight
O
1a
O
4a-f
R
4c, R = H
97% yield
S
O
S
O
4d, R = OMe
S
O
95% yield
4e, R = Br
100% yield
O
O
the literature,
a proposed mechanism was formulated and
4a
4b
61% yield
4f, R = Me
99% yield
O
93% yield
described in Scheme 5C. The mechanism starts with complexation
between the readily available organosulfur anion and the copper
complex to generate active species TcCuISR plus a free Ag+ cation,
similarly to a Liebeskind–Srogl coupling.13a Another -SR source
(Me4NSCF3 and PhCH2SNa) led to a complex mixture of products,
even with the prior addition of another silver salt (AgOAc), which
leads us to believe that ion exchange between the thio-silver salts
and the CuITc catalytic species is fundamental. In fact, air-stable
bonded copper-thiolate complexes like (bpy)CuISCF3 were broadly
described.13b Finally, an oxidative addition event (A), generates the
metalated species (B) and silver iodide. Reductive elimination (C) of
the CuIII complex affords the desired functionalized
naphthoquinone and regenerates the active CuI species for the next
catalytic cycle.
(B) Synthesis of 4g and its oxidized product 5
I
O
S
O
AgSR (100 mol%)
CuTc (5 mol%)
DMAc (0.1 M), 100°C
overnight
(1 mmol scale)
O
O
4g
91% yield
1-iodo-
anthraquinone
O
NaIO4 (3 eq.)
RuCl3.H2O
(5 mol%)
S
O O
CH2Cl2, CH3CN,
H2O
O
5
89% yield
Scheme 4 (A) Synthesis of sulphide quinones 4a-f. (B) Synthesis of the sulphide quinone
4g and the respective oxidized product 5.
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Table 2. Activity of napththoquinones on trypomastigote forms of T. cruzi.
Compounds
IC50/24 ha (µM)
2a
41.2 (± 3.5)
>1000.0
2b
2c
34.5 (± 6.3)
32.7 (± 4.1)
67.3 (± 5.5)
240.1 (± 14.8)
41.9 (± 5.8)
54.4 (± 5.5)
>1000.0
2d
2e
2f
2g
2h
2i
3a
67.3 (± 6.1)
>1000.0
3b
3c
>1000.0
4a
14.3 (± 0.9)
31.3 (± 2.4)
12.4 (± 2.2)
7.6 (± 0.3)
6.6 (± 0.8)
2.5 (± 0.3)
64.9 (± 5.9)
36.3 (± 2.2)
103.6 ± 0.64a
4b
4c
4d
4e
4f
4g
5
Benznidazole
Scheme 5 Mechanistic investigation for the synthesis of sulphide quinones.
aMean ± SD of at least three independent experiments.
The potential of the sulfur-substituted benzenoid 1,4-NQs 2a-2i,
Table 3. Most active naphthoquinones selected to trypanocidal (in different conditions)
3a-3c, 4a-4g and
5 as trypanocidal compounds have been
and cytotoxicity assays.
investigated by screening them against trypomastigote forms of
Trypanosoma cruzi (Tables 2). Benznidazole (Bz) and nifurtimox (Nif)
are the current drugs used to treat Chagas disease. The efficiency of
these drugs is related to the phase of the disease and their
effectiveness is reduced in advanced stages of the infection. In this
sense, the limited curative capacity in chronic phases, and high toxic
effects make necessary the development of new trypanocidal
drugs.14 To our delight, only compounds 2b, 2i and 3b-c were not
active against the parasite with IC50/24h >1000.0 µM.
Trifluoromethylated NQs 2a, 2c-e, 2g and 2h have shown significant
activity against T. cruzi with IC50 in the range of 67.3 to 32.7 µM,
IC50/24 h (µM)
LC50/24 h (µM)
0% blood, 37 °C
10.5 (± 0.2)
3.6 (± 0.7)
Compd
4a
5% blood, 4 °C
0% blood, 37 °C
1.1 (± 0.2)
SI
14.3 (± 0.9)
12.4 (± 2.2)
7.6 (± 0.3)
6.6 (± 0.8)
2.5 (± 0.3)
9.5
4c
0.3 (± 0.04)
1.3 (± 0.03)
1.9 (± 0.03)
0.3 (± 0.06)
12.0
2.5
4d
3.3 (± 0.3)
4e
6.0 (± 1.0)
3.2
4f
3.7 (± 1.4)
12.3
As the trypanocidal activity of naphthoquinones is intrinsically
with special attention to compounds 2c (IC50 = 34.5 µM) and 2d related to their ability to generate reactive oxygen species in a
(IC50 = 32.7 µM). In comparison to the standard drug, Bz (IC50 redox mechanism, we associated the biological activity of selected
=
103.6 µM), 2c and 2d are 3.0 and 3.1-fold, respectively, more compounds with electrochemical studies. Cyclic voltammograms
active. Finally, 4a-g and 5 were also evaluated against the parasite. (CV) of the sulphide naphthoquinones display the common quinone
Compound 4f with IC50 = 2.5 µM was almost 42 times more active behaviour, represented by two redox systems (EpIc/EpIa and
than Bz. This is a promising result, demonstrating the potential of A- EpIIc/EpIIa), as exemplified in Figure 1 for compounds 2a and 2d, in
ring substituted quinones as trypanocidal drugs. Most active several scan rates. The main electrochemical parameters and CVs
quinones evaluated against bloodstream forms of T. cruzi (IC50/24 for 2a, 2b, 2d, 2f and 2h are listed in Table S2 and shown in Figure
h) were also assayed against mammalian cells (LC50/24 h), allowing S1. Considering the ease of the reduction related to EpIc, the
the determination of the selectivity index (SI) derived from the ratio compounds can be ranked as shown in the Figure 1. Redox
of LC50/IC50 (Table 3). Relevant biological aspects are being currently potentials in the range of -0.336 V and -0.440 V correspond to the
investigated in our laboratories and will be reported in due course.
most active quinones.
In conclusion, we have reported efficient and reliable
methodologies for preparing sulfur-substituted benzenoid quinones
in high yields. The chemistry opens up new avenues for the
synthesis of potent trypanocidal drugs. This manuscript represents
successful example of methodologies developed for the preparation
of A-ring substituted quinones. A complex task that requires the use
of powerful but simple strategies based on C-H metalation arsenal.
4 | Org. Biomol. Chem., 2018, 00, 1-3
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This research was funded by grants from CNPq 404466/2016-8,
PVE 401193/2014-4 and PQ 305385/2014-3), FAPEMIG (PPM-
00638-16 and Rede de Pesquisa e Inovação para Bioengenharia de
Nanossistemas - RED-00282-16), FAPERJ, FAPEAL, CAPES and INCT-
Catálise. ENSJ would also like to thank SeSRedCat. There are no
conflicts of interest to declare.
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F3C
F3C
F3C
F3C
F3
C
O
S
O
S
O
S
S
O
S
O
>
>
>
>
F3C
Ph
S
O
NH
O
O
2f
O
2h
54.4 µM*
O
O
2b
O
2a
41.2 µM*
2d
32.7 µM*
O
240.1 µM*
>1000.0 µM*
Fig. 1 Cyclic voltammetry for 2a and 2d (1.0 mM) at GC electrode (3 mm in diameter) in
DMF containing 0.1 M TBAPF6 at different scan rates of 35, 50, 75, 100, 200, 300, 400
and 500 mV s-1. Structures of the trifluoromethylated 1,4-NQs ranked according to data
obtained through electrochemical studies. *IC50/24 h values for the lytic activity on
bloodstream trypomastigotes.
Notes and References
1. T. J. Monks, R. P. Hanzlik, G. M. Cohen, D. Ross and D. G.
Graham, Toxicol. Appl. Pharmacol., 1992, 112, 2.
2. S. Ohayon, M. Refua, A. Hendler, A. Aharoni and A. Brik,
Angew. Chem. Int. Ed., 2015, 54, 599.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 00, 1-3 | 5
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