A Mild and Versatile Friedel–Crafts Methodology for the Diversity-Oriented Synthesis of Redox-Active 3-Benzoylmenadiones with Tunable Redox Potentials

Article abstract of DOI:10.1002/chem.201904220

A series of highly diversified 3-aroylmenadiones was prepared by a new Friedel–Crafts acylation variant/oxidative demethylation strategy. A mild and versatile acylation was performed between 1,4-dimethoxy-2-methylnaphthalene and various activated/deactivated benzoic and heteroaromatic carboxylic acids, in the presence of mixed trifluoroacetic anhydride and triflic acid, at room temperature and in air. The 1,4-dimethoxy-2-methylnaphthalene-derived benzophenones were isolated in high yield, and submitted to oxidative demethylation with cerium ammonium nitrate to produce 3-benzoylmenadiones. All 1,4-naphthoquinone derivatives were investigated as redox-active electrophores by cyclic voltammetry. The electrochemical data recorded for 3-acylated menadiones are characterized by a second redox process, the potentials of which cover a wide range of values (500 mV). These data emphasize the ability of the generated structural diversity at the 3-aroyl chain of these electrophores to fine-tune their corresponding redox potentials. These properties are of significance in the context of antimalarial drug development and understanding of the mechanism of bioactivation/action.

Full text of DOI:10.1002/chem.201904220

A Journal of
Accepted Article
Title: A Mild and Versatile Friedel-Crafts Methodology for the Diversity-
Oriented Synthesis of Redox-Active 3-Benzoylmenadiones with
Tuneable Redox Potentials
Authors: Leandro Cotos, Maxime Donzel, Mourad Elhabiri, and
Elisabeth Davioud-Charvet
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10.1002/chem.201904220
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A Mild and Versatile Friedel-Crafts Methodology for the Diversity-
Oriented Synthesis of Redox-Active 3-Benzoylmenadiones with
Tuneable Redox Potentials
Leandro Cotos,[a] Maxime Donzel,[a] Mourad Elhabiri,*[a] and Elisabeth Davioud-Charvet,*[a]
Abstract: A series of highly diversified 3-aroylmenadiones was All 1,4-naphthoquinone derivatives were investigated as
prepared by a new Friedel-Crafts acylation variant/oxidative redox-active electrophores by cyclic voltammetry. The
demethylation strategy. A Mild and versatile acylation was electrochemical data recorded on 3-acylated menadiones are
performed between 1,4-dimethoxy-2-methylnaphthalene and characterized by a second redox process whose potentials
various activated/deactivated benzoic and heteroaromatic cover a wide range of values (500 mV). These data
carboxylic acids, in the presence of mixed trifluoroacetic emphasize the ability of the reached structural diversity at the
anhydride and triflic acid, at room temperature and air moisture. 3-aroyl chain of these electrophores to fine-tune their
The 1,4-dimethoxy-2-methylnaphthalene-derived benzopheno- corresponding redox potentials. These properties are of
nes were isolated in high yield, and submitted to oxidative significant importance in the context of antimalarial drug
demethylation with cerium ammonium nitrate to produce 3- development and understanding of the mechanism of
benzoylmenadiones.
bioactivation/action.
Benzoyl-1,4-naphthoquinones are also privileged scaffolds in
Introduction
medicinal chemistry.[6],[7] From a synthetic point of view, they are
valuable molecular templates in drug discovery to produce lead
compounds or crucial intermediates in multistep synthesis to build
complex natural products (Figure 1).[9] As such, 2-benzoyl-NQs
have been reported as key intermediates for the synthesis of 7H-
benzo[c]xanthen-7-ones,[10] or advanced precursors to obtain the
complex polycyclic 1,4-dioxygenated xanthone aglycone, IB-
00208.[9] These key moieties have also defined a smart strategy
in the total 4 step-synthesis of the naturally occurring red pigment
radermachol,[11] improving the previous synthetic scheme.[12]
1,4-Naphthoquinones (NQs) are redox-active compounds
widespread in all kingdoms of life, synthesized in microorganisms
and plants used in traditional medicine as secondary bioactive
metabolites.[1] They are well represented in numerous natural
products with biological activities (e.g. antibiotic, anticancer,
antiparasitic) and are generated in many vital metabolic
processes.[2] Structurally, the NQ core, in its oxidized form (NQox),
is responsible for redox properties due its ability to accept one or
two electrons. In the presence of oxygen, the resulting dihydro-
naphthoquinone (NQred) can transfer 1 or 2 electrons in reactions
regenerating the NQox form, and releasing reactive oxygen
species.[3] Numerous NAD(P)H-dependent flavoproteins of the
oxido-reductase family reduce NQs, and these latter were
described as redox-cyclers or “subversive substrates” of these
flavoenzymes[4] (Figure 1). A well-known example is menadione
(2-methyl-1,4-naphthoquinone or vitamin K3). In particular, 3-
benzoylmenadiones (1) were proven to be highly oxidant
compared to the parent menadiones[5] and proposed to be the
active principles of potent antimalarial 3-benzylmenadiones.[6]
Variation of the substitution pattern at the west or east parts of the
electroactive core of NQs[2],[7],[8] modulates the electrochemical
properties and thus both their biological and pharmacokinetic
activities.
[a]
Dr. L. Cotos, M. Donzel, Dr. M. Elhabiri, Dr. E. Davioud-Charvet,
Laboratoire d'Innovation Moléculaire et Applications (LIMA),
UMR7042 CNRS-Unistra-UHA, European School of Chemistry,
Polymers and Materials (ECPM), 25, rue Becquerel, F-67087
Strasbourg, France. E-mail : elhabiri@unistra.fr;
Figure 1. Natural and synthetic menadione derivatives polysubstituted at the
aromatic ring including menadione (2-methyl-1,4-naphthoquinone).
elisabeth.davioud@unistra.fr
Supporting information for this article is given via a link at the end of
the document.
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Scheme 1. Synthesis of 3-benzoylmenadione derivatives 1 (R = Me) starting from 1,4-dimethoxy-2-methyl-naphthalene 3 and benzoic acids 4.
One of the strategies to build 2-benzoyl-1,4-naphtoquinone
moieties is based on the generation of the 2-benzoyl-1,4-dihydro-
naphthalene, this hydroquinone is readily oxidized into the target
quinone moiety. Photo-Friedel-Crafts acylation of NQs with a
large stoichiometric excess of aromatic aldehydes provided the 2-
benzoyl-dihydro-naphthalene derivatives (Scheme 1).[13] Previous
work of the group to synthesize 3-benzoylmenadione derivatives
1 was based on the formation of a carbanion after i) bromination
of the reduced and protected form of menadione, i.e. the 1,4-
dimethoxy-2-methylnaphthalene, ii) halogen/metal exchange,
followed by iii) addition of benzoic chloride to give 2-benzoyl-3-
methyl-1,4-dimethoxy-naphthalene derivatives 2, and finally, iv)
oxidative demethylation by cerium ammonium nitrate (CAN)
(Scheme 1).[5b],[14]
Nevertheless, noticeable progress has been made by using
trifluoroacetic anhydride or trifluoroacetic
(TFAA)[29]
acid/trifluoroacetic anhydride (TFA/TFAA),[11],[30] under mild
heating conditions and air moisture, to allow SEAr of activated and
non-strong deactivated benzoic acids, depending on the
nucleophilicity strength of the aromatic compound.
Taking the acylation of 1,4-dimethoxy-2-methylnaphthalene 3
by several activated and (strongly) deactivated benzoic/
heteroaromatic carboxylic acids 4 as a model reaction to
incorporate a new pattern of substitution at C-3 of menadione, we
developed a versatile Friedel-Crafts acylation variant to produce
the benzophenone intermediates in mild conditions, i.e. air
moisture and room temperature, in moderate to excellent yields
(Scheme 1). In
a
second step, the diversified 3-
Friedel-Crafts acylation process is widely used to synthesize
benzophenones moieties (Scheme 1). From the original
version[15] based on the use of AlCl3 in stoichiometric amount with
a benzoyl chloride at high temperature, the corresponding
acylium cation is formed, allowing an electrophilic aromatic
substitution (SEAr) by the corresponding aromatic nucleophile. In
this scenario, HCl(g) and toxic aluminium metal waste are
generated. Several improvements were further described, e.g.
solvent-free conditions made the process greener when Zn[16] or
ZnO[17] were used as Lewis acids. Alternatively, Brønsted acid to
activate the aroyl chloride was reported using a catalytic amount
benzoylmenadiones 1 were almost quantitatively produced after
demethylation/oxidation with CAN. All the final compounds were
evaluated for their electrochemical properties by cyclic
voltammetry. Thus, the incorporation of the broad structural
diversity in the 3-acylated chain of menadione brought new
insights in the understanding of the bioactivation/action
mechanisms and the structure-electroactivity relationships of this
important new electrophore series at the origin of the potent
antimalarial activity of 3-benzylmenadiones.
of the non-toxic perfluorinated acid resin Nafion-H[18]
,
Results and Discussion
trifluoromethanesulfonic acid (or triflic acid, TfOH)[19] and
bis(trifluoromethylsulfonylimino)-trifluoromethanesulfonic acid.[20]
Combination of Lewis and Brønsted acids was also shown to be
an efficient acylation method using benzoyl chlorides.[21] Benzoyl
chlorides are known to be substrates for benzoyltriflate generation
providing excellent acylating agents.[22] To render the process
more efficient, benzoic acids can be used as acylating reactants
to avoid the use of chlorinated reagents. Methanesulfonic acid
appeared in literature to perform acylations in combination with
other reagents, such as Eaton’s reagent (P2O5)[23], Alumina[24] or
Graphite.[25] Also, P2O5[26] and the combination P2O5/SiO2[27] was
applied to activated and deactivated benzoic acids, and
methanesulfonic anhydride[28] was shown to promote acylation of
aryl and alkyl carboxylic acids in metal- and halogen free
conditions. Most of the cited methodologies required dry
conditions, high temperatures, or pre-activation of the reagents.
Preliminary Study
Previous strategies developed in the team to obtain
polysubstituted 3-benz(o)ylmenadiones at both aromatic parts
west (quinonic moiety) and east (benzoic core) were based on the
Kochi-Anderson reaction shown in Scheme 2.[6],[7b] Phenylacetic
acids in the presence of a catalytic amount of silver salt with
stoichiometric excess of an oxidant (peroxodisulfate) undergo
radical decarboxylation upon heating. The resulting benzyl radical
specifically thus undergoes a nucleophilic radical addition to
menadione core at the C-3 position generating the corresponding
3-benzylmenadione. In the next step, 3-benzoylmenadiones 1
were produced by benzylic oxidation using CrO3/H5IO6 reagent
system.[6]
2
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A
first straightforward pathway to synthesize 3-
benzoylmenadiones 1 was investigated by a silver(I)-catalyzed
decarboxylation reaction[31] between menadione and α-
ketoaromatic acids 5 according to the reaction shown in Scheme
2. To do so, starting α-keto acids 5a and 5a’ had to be prepared,
first, by a described method[32] and were obtained with 80 and
98%, respectively. When the Kochi-Anderson reaction conditions
were applied to menadione and α-ketoaromatic acids 5, an acyl
radical
was
generated,
producing
directly
the
3-
benzoylmenadione derivatives 1a and 1a’ in 45% and 41% yield,
respectively (Scheme 2).
Scheme 3. Side-reactions occurring via the 1,4-dihydro- or 1,4-dimethoxy- 2-
methylnaphthalene intermediates.
Preliminary Friedel-Crafts Reaction Study
In this work, our objective was to develop a chemical library
of structurally diversified electroactive 3-(hetero)aroylmenadiones
1 after incorporation of polysubstituted (hetero)aromatics moieties
and to modulate their redox characteristics. Diversity-oriented
synthesis (DOS) implies the generation, under efficient and
versatile procedures, of functionally diverse small-molecules
acting as chemical modulators.[35] In the new strategy reported
herein, diversity at the east aromatic part of 3-benzoylmenadione
was reached using a large array of readily commercially available
benzoic and heteroaromatic carboxylic acids as starting materials.
Benzoic acids and heteroaromatic carboxylic acids are acylating
substrates for the Friedel-Crafts reaction. The west aromatic part
of the 3-benzoylmenadione 1 core was introduced via its 1,4-
dimethoxy-2-methylnaphthalene precursor 2 upon the Friedel-
Crafts acylation. In the next step, the diversified 3-
benzoylmenadiones 1 were generated upon selective oxidative
demethylation using CAN (Scheme 4).
Scheme 2. Kochi-Anderson reactions used to synthesize 3-benz(o)yl-
menadiones, in particular 3-benzoylmenadiones 1a and 1a’.
However, these strategies to build the 3-benzoylmenadione
1 core displayed several drawbacks to provide a widely diversified
chemical library. Phenylacetic and α-ketoaromatic acids are not
broadly commercially available. The synthesis of phenylacetic
acids from benzaldehydes[33] and benzoic acids[34] are not very
convenient to build a chemical library because it involves multiple
steps, long time of reactions, expensive reagents with non
versatile protocols to achieve their production. In the next step,
the benzylic oxidation with CrO3/H5IO6 proceeded with low to
moderate yields along with many side-products and high toxicity
for the environment.[6] In parallel, synthesis of 3-
benzoylmenadiones (e.g. 1a, 1a’, Scheme 2) from α-ketoaromatic
acids 5 resulted in poor yields. The use of the Kochi-Anderson
reaction showed incompatibilities with hydroxyl[6] and amino[7c]
Scheme 4. Synthesis of 3-(hetero)aroylmenadione derivatives 1 based on
Friedel-Crafts acylation/oxidative demethylation.
The key point is the development of a Friedel-Crafts acylation
reaction, which allows electrophilic aromatic substitution from
activated or deactivated benzoic and heteroaromatic carboxylic
acids under mild conditions, thus promoting an easy experimental
protocol, e.g. no air moisture-sensitive reagents, no high
temperatures, activating the acylating agents in situ. TFA/TFAA
reagent system has been reported to be an efficient practical
system to achieve the SEAr under mild heating conditions, in open
air with air moisture compatibility. As it was reported, this
methodology proceeds with non-strongly deactivated and
activated benzoic acids 4 (Scheme 5), depending on the
nucleophicity of the aromatic nucleophile. Due the high electronic
density of 1,4-dimethoxy-2-methylnaphthalene 3, we first started
the screening from activated benzoic acids 4a-c to generate the
groups, and low efficiency to introduce pyridine rings[7a]
.
Firstly, the direct functionalization
of
the
benz(o)ylmenadione skeleton has proven to be difficult due the
presence of the C2-methyl group attached to the quinone moiety,
which is highly base-sensitive. Secondly, the functionalization of
the benz(o)ylmenadione derivatives through the 1,4-dihydro- or
1,4-dimethoxy-3-methyl-2-benz(o)yl-naphthalene intermediates
was found difficult to handle (Scheme 3). On the one hand, the
1,4-dimethoxy groups of the benzyl intermediate were
demethylated using proton assistance as previously described
with the benzylic oxidation using CrO3/H5IO6 (or oxone) as
reagents, i.e. formation of several side products was observed
(Scheme 3). On the other hand, in contact with oxygen traces (i.e.
despite an argon atmosphere), the produced 2-benzoyl-1,4-
dihydro-3-methylnaphthalene intermediate was quickly oxidized
into its quinone form before methylation occurred (Scheme 3).
2-benzoyl-3-methyl-1,4-dimethoxy-naphthalene
intermediates
2a-c derivatives with moderate to good yields (Scheme 5). The
3
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mechanism of the reaction likely proceeds through the in situ
generation of the mixed anhydride, i.e. an acyltrifluoroacetyl
intermediate,[36] formed between the benzoic acid and TFAA. This
intermediate is protically activated by TFA to promote the
formation of the corresponding acylium cation. Subsequently,
SEAr of 1,4-dimethoxy-2-methylnaphthalene 3 produced the
corresponding 2-benzoyl-3-methyl-1,4-dimethoxy-naphthalene
derivatives 2a-c. Then, following oxidative demethylation by CAN,
the 3-benzoylmenadiones 1 were generated in excellent yields.
Noteworthy, CAN oxidation is sensitive to the electronic density of
the aromatic ring.
investigated the acylation of 1,4-dimethoxy-2-methylnaphthalene
by 3-fluoro-4-nitrobenzoic acid and monitored the progression of
the reaction by TLC upon addition of TFAA (4 mL) and TfOH (2
equiv. in 10 mL of dichloromethane) to the reaction mixture at 0°C
in open air, and reaction at room temperature without dry
conditions (Table 1, entry 1).
The formation of the targeted compound was clearly evidenced
after one hour of reaction, and the desired diarylketone
intermediate was isolated in 73 % yield after overnight time of
reaction at room temperature. The effect of TfOH on the acylation
reaction was then investigated by adding different amounts of
TfOH (Table 1, entries 1-4). Catalytic amount of TfOH (0.1 equiv.)
provided the product only in traces (entry 4), and the unreactive
starting materials was mainly observed in the crude by NMR.
Increasing the TfOH amount up to 20% allowed the reaction to
proceed but with less than 50% conversion and in low yield (entry
4). Finally, by adding 0.5 equiv. of TfOH, a full conversion was
achieved and the benzophenone was isolated in 82% yield (entry
2). Reducing the quantity of TFAA up to 2 equiv. (entry 5) with the
optimized TfOH amount (0.5 equiv.) afforded the product with the
same yield and with a much cleaner reaction crude. Furthermore,
we checked that TFAA or TFAT did not react with 1,4-dimethoxy-
2-methylnaphthalene in the absence of the benzoic acid. An
excess of 1.5 equiv. of 1,4-dimethoxy-2-methylnaphthalene was
required toward benzoic acid because it enhanced the rate of the
reaction under these conditions to observe completion of the
reaction overnight. Thus, with an easy defined experimental
procedure, these experimental conditions at room temperature
allowed us to build a wide variety of 2-benzoyl-3-methyl-1,4-
dimethoxy-naphthalene derivatives 2a-u, including those from
strongly deactivated benzoic acids, through an efficient Friedel-
Crafts acylation variant (Scheme 6). In the next step, the
corresponding 3-aroylmenadiones 1a-u diversified at their east
aromatic part were prepared following CAN oxidation with
moderate to good yields (72-97%) in the majority of the cases
(Scheme 6).
Scheme 5. Preliminary study on the Friedel-Crafts reaction to build 2-acylated
3-methyl-1,4-dimethoxy-naphthalene derivatives 2a-c.
In the 2-benzoyl-3-methyl-1,4-dimethoxy-naphthalene 2a two
pairs of 1,4-dimethoxy moieties are present. Nevertheless, the
most electronically rich naphthalene moiety (west aromatic part)
promotes faster oxidation than the phenyl fragment (east aromatic
part), and only the desired 3-benzoylmenadione 1a was obtained.
When TFA/TFAA reagent mixture was applied to strongly
deactivated benzoic acids, such as 3-fluoro-4-nitrobenzoic acid,
the targeted compound was not obtained. Even by increasing the
temperature and with longer time of reaction, the
acyltrifluoroacetate intermediate was probably not formed with
strongly deactivated benzoic acids, despite the presence of the
electronically rich aromatic nucleophile, i.e. 1,4-dimethoxy-2-
methylnaphthalene. Therefore, we directed our acylation study by
screening reagents able to activate (strongly) deactivated benzoic
acids, like 4d (Scheme 5), in mild heating conditions and air
moisture, to achieve a versatile methodology.
Table 1. Optimization of the model Friedel-Crafts reaction
conditions with 1,4-dimethoxy-2-methylnaphthalene 3[a] and 3-
fluoro-4-nitrobenzoic acid 4d[b].
Entry
TfOH (equiv.)
2
TFAA (equiv.)
53
Yield % [c]
73
1
2
3
4
5
0.5
0.2
0.1
0.5
53
53
53
2
82
50
Development of an Optimized Friedel-Crafts Variant
In very specific applied cases, the use of TfOH/TFAA in an
equimolecular mixture was used in biological chemistry
applications for ferrocene[37] and (D)-biotin[38] acylations.
Surprisingly, this reagent system was never applied to perform
SEAr with deactivated aromatic carboxylic acids. Once TfOH and
TFAA are combined, the strong trifluoroacetyl agent, i.e.
trifluoroacetyl triflate (TFAT), is proposed to be generated.[39] We
trace
82
[a] 1.5 equiv., [b] 1.0 equiv., [c] yield after purification.
4
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Scheme 6. Scope of the Friedel-Crafts reaction variant between 3-methyl-1,4-dimethoxy-naphthalene 3 and benzoic acids, heteroaromatic carboxylic acids 4 with
base sensitive moieties. The ratio between the formed Friedel-Crafts products acylated at C-2, C-6 or C-7 was deduced from a regioisomeric analysis based on
carbonyl signals of 13C-NMR of the reaction crude. *: 1.5 equiv. of TfOH was used and the reaction duration was 48h. **: upon addition of 4 equiv. of a mixture
TfOH/TFAA (1:1). Abbrev.: The product code of the desired product is 1a-u; 1a-u-reg1 stands for regioisomer 1 (position C-6, vide infra), and 1a-u-reg2 for
regioisomer 2 (position C-7, vide infra).
In parallel, an analysis of the regioisomers was performed by 13
C
from 45 to 82 % yield. The acylation reaction was observed to be
sensitive to steric effects when a bulky group is adjacent to the
carboxylic acid (ortho), like in the example 2i the desired
benzophenone is obtained in low yield (27%), supporting the
formation of another regioisomer isolated in 71 % yield, by
acylation of the 1,4-dimethoxy-2-methylnaphthalene in position
C-6. With halogens (I, Br, F) in para, benzophenones 2j-2k-2l
were produced in moderate to good yields (47-72-58%,
respectively), with a regioselectivity of about 70%. With a Cl atom
in meta position, the corresponding benzophenone 2c was
obtained in 82% yield with minor regioisomers. Examples with
deactivated benzoic acids, incorporating strong electron-
withdrawing groups (NO2 and CF3) in para or meta, combined or
not with other functionalities (iodo or fluoro), provided excellent
yields and regioselectivity. The example 2h, where a strong
deactivated benzoic acid including CF3 (para) and NO2 (meta),
NMR from the crude of the reaction to quantify their nature and
the corresponding ratio formed during the acylation reaction
(Scheme 6, and the Supporting Information for details from page
S13) by integrating the carbonyl signals of the acylated
compounds.[40] After isolation and purification of each
regioisomer from the crude of the reactions to produce 2i, 2p,
and 2q it was possible to attribute the carbonyl signals of each
isolated regioisomers upon their 13C NMR analysis. Their
structures were found to correspond to the acylated products in
position C-6 (regioisomer 1) or C-7 (regioisomer 2) of the 1,4-
dimethoxy-2-methylnaphthalene core. The new experimental
conditions led to improved (or similar) yields of the acylation
products 2a-2c with respect to the previously reported cases
using the non-deactivated benzoic acids depicted in Scheme 5.
In the case of 2c with a Cl atom in meta, the yield was improved
5
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has to be highlighted with the resulting 67% yield of the isolated
benzophenone upon addition of 1.5 equiv. of TfOH, attested by
the observation of only one carbonyl signal in the crude of the
13C NMR spectrum. The use of non activated heteroaromatic
carboxylic acids, like 2-thiophene carboxylic acid or 2-furoic acid
led to acylated products 2p and 2q incorporating thiophene and
furan moieties in the east aromatic part (Scheme 6), from
moderate to low yields of the desired product. However, in both
cases, i.e. 2p and 2q, and also in the case of 2i, the formation of
regioisomers was obtained in higher proportion, probably due to
steric effects. However, benzophenone 2q was obtained with
easier experimental conditions compared to the reported
reaction using polyphosphoric acid at high temperature.[41] Direct
introduction of acid-sensitive moieties like amino group, pyridine
and pyrimidine rings could be achieved after addition of 4 equiv.
of a mixture TfOH/TFAA (1:1). Examples 2r and 2s incorporate
an amino group in para in the aromatic and pyridine moiety. The
excess of generated TFAT allowed the transient protection of the
amino group through a trifluoroacetyl amide group. Consequently,
in both cases, moderate yields were obtained with low
regioselectivity. The trifluoroacetyl amide group was removed in
basic conditions. Pyrimidine fragment incorporating CF3 was
introduced in product 2t formed in 11% yield but no regioisomer
was detected. With the CF3 group in the same position located in
the pyridine fragment, only traces of product 2u were observed.
While the oxidative demethylation by CAN produced the 3-
acylated menadiones 1a-1q in 63-97% yields (Scheme 6), only
two nitrogen-based benzophenones (2r-2t) led to complex
mixtures under these deprotection conditions.
reagent, generated by mixing TfOH and TFAA. TFAT was indeed
described as more reactive than TFAA.[39] In this scenario, the
acyltrifluoroacetyl intermediate might be formed for deactivated
benzoic acids. During the process of trifluoroacetylation, one
molecule of TfOH is produced, which, due to its excellent proton
donor properties, efficiently activates the acyltrifluoroacetate at
low temperature and promotes the formation of the acylium cation,
allowing the SEAr of 1,4-dimethoxy-2-methylnaphthalene. Upon
acylation, the intermediate 2’ (Scheme 7), which is in equilibrium
with the enolic form (more stable by conjugation), is generated.
The OH-enol function likely allowed the regeneration of TfOH and
then, release of the targeted benzophenone derivative. In situ
TFAT formation from TfOH and TFAA was supported by reacting
the costly and highly unstable commercial TFAT with 1,4-
dimethoxy-2-methylnaphthalene and 3-fluoro-4-nitrobenzoic acid,
under the same experimental conditions of the herein described
Friedel-Crafts acylation variant. The reaction afforded the desired
benzophenone in 77% yield (Scheme 8).
Scheme 8. TFAT as the key reagent for Friedel-Crafts acylation of 1,4-
dimethoxy-2-methylnaphthalene by the deactivated 3-fluoro-4-nitrobenzoic acid.
Redox Properties
Mechanistic Insight
We will herein discuss the electrochemical data of our
homogenous series of 3-acylated-menadiones (Scheme 6).
These redox-active compounds only differ by the substitution
pattern of their aroyl subunit on the east part of the molecule thus
allowing evidencing the key role of this moiety (electronic and
steric effects) on the redox modulation of the NQ core.
Based on our present results and a literature report, a possible
acylation reaction pathway is depicted in Scheme 7, with the
reaction between the 1,4-dimethoxy-2-methylnaphthalene and a
substituted benzoic acid representative. The mechanism of the
reaction is proposed to proceed through the formation of an
acyltrifluoroacetyl intermediate from benzoic acid, promoted by
the in situ generation of the reactive trifluoroacetyl triflate (TFAT)
Scheme 7. Putative mechanism of the Friedel-Crafts variant reaction.
6
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Scheme 9. Proposed mechanism for the consecutive 1-electron transfers centred on 3-benzoylmenadiones derivatives.
Table 2. Electrochemical data measured using cyclic voltammetry (CV)[a] and Square Wave Voltammetry (SWV)[b] for all 3-benzoylmenadione derivatives
examined in this work. Solvent: DMSO; I = 0.1 M n-Bu4NPF6, v = 200 mV s-1. (E1/2 (V), ∆E (mV), ∆E1/2 = E11/2-E21/2 (V))
Carbonyl
group
Nitro group
Quinone
E11/2(E)[a]
E21/2(E)
E31/2(E)[a]
E41/2(E)[a]
E51/2(E)[a]
∆E1/2
E11/2 – E2
(V)
E1
E2
E3
E4
E5
[b]
[b]
[b]
[b]
[b]
1/2
1/2
1/2
1/2
1/2
Cpds
1/2
[V(mV)][a]
[V][b]
[V(mV)][a]
[V][b]
[V(mV)][a]
[V]b
[V(mV)][a]
[V(mV)][a]
[V][b]
-
[V][b]
-
3-benzoyl-
menadione 1[5]
1a
-0.47(92)
-1.19(72)
0.72
-0.529(90) / -0.526(78)
-0.505
-0.467(90) / -0.463(73)
-0.447
-0.444(88) / -0.445(73)
-0.427
-0.418(125) / -0.409(91)
-0.469
-0.412(92) / -0.413(77)
-0.390
-0.409(89)/ -0.408(86)
-0.385
-0.419(82) / -0.422(76)
-0.396
-0.387(94) / -0.403(78)
-0.362
-0.434(80) / -0.425(76)
-0.404
-0.455(90) / -0.444(77)
-0.435
-0.450(88) / -0.449(64)
-0.424
-0.457(90) / -0.451(74)
-0.433
-1.131(94) / -1.128(87)
-1.106
-1.172(88) / -1.166(73)
-1.147
-1.152(92) / -1.157(82)
-1.139
-0.773(99) / -0.778(97)
-0.755
-0.812(96) / -0.808(77)
-0.789
-0.942(95)/ -0.945(86)
-0.914
-0.948(60) / -0.938(52)
-0.933
-0.822(87) / -0.826(82)
-0.798
-1.056(76) / -1.055(70)
-1.038
-1.110(96) / -1.094(77)
-1.091
-1.134(92) / -1.131(73)
-1.102
-1.196(92) / -1.192(80)
-1.176
br
-
-
-
-
-
-
0.601
0.700
0.712
0.286
0.399
0.533
0.519
0.436
0.634
0.656
0.678
0.743
1b
1c
1d
1e
1f
-1.610
-1.638(85)
-1.594
-1.002(102) / -0.997(61)
0.977
-1.178(105) / -1.22 (92)
-1.192
-1.148(96) / -1.140(74)
-1.128
-1.28(86) / -1.291(67)
-1.24
-1.285(111) / -1.273(85)
br
-1.249
-
-1.484
br
-
1g
1h
1i
br
nd / -0.985(52)
-0.952
-1.182(84) / -1.24(72)
-1.728
-1.615
-1.573
-1.613
-1.624
-1.158
-
-
-
-
-
-
-
-
1j
1k
1l
-0.431(87) / -0.417(80)
-0.397
-1.021(86) / -1.005(80)
-0.984
1m
-
-
-
-
0.587
na
-1.87
nd
1n[b]
E1red = -0.45
E2red = -1.065
-0.423(90) / -0.420(74)
-0.397
-0.462(96) / -0.460(79)
-0.489
-0.468(100) / -0.464(82)
-0.447
-0.488(88) / -0.485(70)
-0.466
-1.055(94) / -1.053(80)
-1.029
-1.168(100) / -1.168(79)
-1.202
-1.159(92) / -1.211(76)
-1.135
-1.093(102) / -1.117(79)
-1.069
1o
1p
1q
1s
-
-
-
-
0.632
0.713
0.691
0.603
-1.607
-1.750
-1.631
-1.577
-
-
-1.953
[a] CVs and [b] SWVs measured in DMSO with 0.1 M n-Bu4PF6 electrolyte support at 25°C. v = 200 mV s-1; reference electrode = KCl(3 M)/Ag/AgCl; working
electrode = glassy carbon disk of 0.07 cm2 area. E11/2 and E21/2 are related to the quinone-centred redox processes, E31/2 is related to the carbonyl benzoyl unit while
E41/2 and E51/2 characterize the nitro-centred redox processes. br = broad. nd = not determined. na = not applicable. [b] Measured at v = 500 mV s-1. The values in
italics correspond to measurements at 50 mV s-1.
7
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The redox potentials of the substituted 3-aroyl-menadiones 1
(Table 2 and Figures S1-19 in the Supporting Information) were
measured by cyclic voltammetry (CV) and square wave
voltammetry (SWV, Table 2) at 23 ± 1 °C using a glassy carbon
(GC) working electrode in DMSO solvent and tetra-n-
butylammonium hexafluorophosphate (n-NBu4PF6) as the
supporting/inert electrolyte. The electrochemical properties
measured by SWV were found to be in good agreement with
those measured by CV (Table 2). Furthermore, the data recorded
for 1f, 1g, 1h and 1a were found to be in excellent agreement with
those measured in a previous communication.[5]
Irrespective of the substitution pattern of the aroyl subunit, no
alteration of the global electrochemical profile of the NQ core was
observed. Two consecutive one-electron quasi-reversible waves
(E1pc – E1pa ~80-125 mV and E2pc – E2pa ~ 72-100 mV) have been
systematically observed under our experimental conditions. NQ
reduction indeed occurs via two successive one-electron
transfers. The monoradical-anion NQ- is formed in the Epc1
reduction step, and is then reduced to its related dihydro-
naphthoquinone dianion NQ2- in a second Epc2 step. The 3-
benzoylmenadiones 1a-s examined in this work were not
subjected to any inter- or intramolecular proton transfers and
therefore the electrochemical properties were considered to be
strictly associated to the successive formation of the two anionic
reduced species.
product (Figure 1).[10c] Increasing the voltage sweep rate up to 5
V (Figure S14) indeed allowed us to evidence in the first cycle the
characteristic reduction peaks of the benzoquinone unit which
then faded completely in the following cycles as a result of the
reaction.
Combining previously published data[5] with the present ones,
a clear relationship between the half-wave potentials of the first
(E11/2) and second (E21/2) electrochemical processes can be
proposed (Figure ). Exceptions have been, however, observed for
the 2’-substituted benzoyl-menadiones (i.e. steric effect) or
proton-donor substituent such as 4’-OH.[5] This feature suggests
that the substituents borne by the benzoyl core induce sizeable
electronic effects both on the NQ unit or on its 1-electron reduced
semi-quinone, NQ•-. With respect to the first redox process (E1
)
1/2
of 4’-substituted benzoyl-menadiones, the gap in potential was,
however, measured to be only  80 mV between the menadione
substituted with a methoxy group[5] in the 4' position and that
substituted with a nitro group at the same position (1e). This likely
suggests weak to no influence of the benzoyl substitution pattern
on the first electron transfer of the naphthoquinone redox active
core. It is noteworthy, that under its oxidized state, the NQ is
poorly conjugated with its benzoyl counterpart.
In addition to these consecutive one-electron transfers, a third
(i.e. in some cases as for 1h and 1d, a fourth redox wave is also
observed) redox wave at potential value E31/2 of about -1 to -1.2 V
was also observed for the nitro-benzoyl-menadiones 1d, 1e, 1f,
1g and 1h (Figures S4-S8, S19 in the Supporting Information and
Table 2). These additional redox signals most likely result from
the reduction of the nitro function.[42] Finally, a last weak, broad
and ill-defined wave was often observed at much more negative
values (E31/2 >> -1.5 V) and was attributed to oxidation/reduction
processes centred on the benzoyl carbonyl unit (e.g. Figure 3).
Figure 4. Variation of E21/2 (V, second redox step) as a function of E11/2 (V, first
redox step). v = 200 mV s-1; reference electrode = KCl(3 M)/Ag/AgCl; working
electrode = glassy carbon disk of 0.07 cm2 area; auxiliary electrode = Pt wire.
The dashed line is only provided as a guide for the eyes.  Data taken from ref
[5].  Data from this present work.  Compound with particular behaviour (e.g.
2’-substituted or 4’-OH benzoylmenadiones, see text).
By contrast, a marked impact of the 4’-benzoyl substitution can
be observed on the second electron transfer leading to the
dihydro-naphthoquinone dianion NQ2-. Interestingly, the gap in
potential amounts to up 500 mV between the menadione
substituted with a carboxylic group in the 4' position[5] and that
substituted with a nitro group at the same position (1e) (Figure 5).
To rationalize this behaviour, we therefore hypothesized that
upon the first one electron reduction of the benzoyl-menadiones,
the radical is stabilized by the benzoyl carbonyl unit thus allowing
electronic communication between the redox-active NQ core and
the benzoyl subunit (Scheme 9). Consequently, the second one-
electron transfer leading to the dihydro-naphthoquinone dianion
NQ2- is thus highly sensitive to the nature of the benzoyl
substitution (Figure 5 and Figure S1-S19). Within this series of
molecules, the presence of the benzoyl carbonyl function thus
allows significantly modulating over a large potential ( 500 mV)
Figure 3. CV (blue) and SWV (black) profiles of 1e (1.40 mM) measured in
DMSO with 0.1 M n-Bu4PF6 electrolyte support at 25°C. v = 50 mV s-1; reference
electrode = KCl(3 M)/Ag/AgCl; working electrode = glassy carbon disk of 0.07
cm2 area.
Compound 1n bearing a 2’-fluoro substituent stands in an
interesting contrast with the other systems. Reduction at 1 (or 2)
electrons afforded an anionic species which can rapidly trigger (at
the time scale of the electrochemical experiment) a nucleophilic
substitution, at the 2’-position, leading to a benzoxanthone
8
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span the oxidant character of the semi-quinone NQ•- while slightly
affecting that of the NQ analogue ( 80 mV). These properties are
of significant importance in the context of antimalarial drug
development and understanding of the mechanism of action of
the early lead plasmodione.[6]
parent compound, NQ, at near diffusion-limited rates.[5] Oxygen
and methemoglobin(Fe3+), the major hemoglobin catabolite and
nutriment generated in Plasmodium parasites, play the role of
one-electron acceptors from the semi-quinone NQH•. Upon 1-e−
and 2-e−-reduction, NQH• and NQH2 react rapidly with O2 to
regenerate the non-toxic parent prodrug, NQ, superoxide radicals
and hydrogen peroxide as by-products. Therefore, our
expectation is that under aerobic conditions, NQH• per se does
not contribute significantly to killing the cells, as it has been
observed for plasmodione by the absence of toxicity against
various human cell lines.[6] This bioactivation process was also
reported for the anticancer quinonic mitomycin C.[43] It is well
documented that, while the concentration of O2 in arterial blood is
approximately 13%, O2 concentrations below 7.5% are found in
most organs to which Plasmodium-parasitized red blood cells
sequester, including the bone marrow, brain, and liver.[44]
Therefore, in the hypoxic conditions where malaria parasites can
survive, the half-life of NQH• might be extended, allowing it to
participate in several metabolic transformations, such as the
benzylic oxidation (Scheme 10). Thus, after transport to the
parasitic compartment, NQH• can undergo further reduction by
other key-protein targets to produce the toxic NQH2 (Scheme 10).
Observed parasite killing might be therefore attributable to the
combined flux from both one- and two-electron reducing
pathways generating the protonated NQH• and NQH2 species,
which undergo a series of spontaneous rearrangements (in
particular, phenolic oxidative coupling to form the
benzoxanthones, see structures of 7H-benzo[c]xanthen-7-ones
from Figure 1).[10c] By diversifying the molecular diversity at the
benzoyl chain of 3-benzoylmenadiones 1a-u our data showed
that this aroyl substitution can markedly alter the redox properties
of the NQ electrophore and thus modulate the second one-
electron transfer leading to the dihydro-naphthoquinone NQH2
species. This toxic species resulting from 3-benzoylmenadiones
1 is likely generated in situ in parasites from the antimalarial 3-
benzylmenadione prodrugs and significantly contributes to the
antimalarial activity.
Figure 5. SWV profiles of compound cited as 3k in ref.[5] (1.06 mM, 4’-CN),
compound cited as 3l in ref.[5] (1.03 mM, 4’-OCH3), 1l (1.38 mM, 4’-F), 1j (1.20
mM, 4’-I), compound cited as 3h in ref.[5] (1.19 mM, 4’-H), compound cited as
3f in ref.[5] (0.94 mM, 4’-COOH), 1e (1.40 mM, 4’-NO2), 1m 1.16 mM, 4’-CF3)
measured in DMSO with 0.1 M n-Bu4PF6 electrolyte support at 25°C. v = 200
mV s-1; reference electrode = KCl(3 M)/Ag/AgCl; working electrode = glassy
carbon disk of 0.07 cm2 area.
Bioactivation through redox-cycling of NQ mediated by one-
or two-electron transferring oxido-reductase enzymes is an
oxygen-dependent process (Scheme 10).[4-6] Under aerobic
conditions, we previously showed that both major cytosolic
NADPH-dependent glutathione reductases (and possibly other
reductases) from P. falciparum-parasitized red blood cells
participate in a futile redox cycle in which the production of the
protonated NQH• species from NQ is rapidly back-oxidized to its
Scheme 10. Proposed mechanism of action of antimalarial 3-benzylmenadione prodrugs generating toxic 3-benzoylmenadione 1 metabolites in P. falciparum-
parasitized red blood cells. The first one-electron transfer leading to the semi-quinone NQH• is proposed to be involved in the drug bioactivation (step 1.) while the
second one-electron transfer leading to the dihydro-naphthoquinone NQH2 might be responsible for parasite killing (step 2). For the sake of clarity, only the 1-e−-
reduced NQ species were drawn. Abbrev.: hGR: human glutathione reductase; PfGR: P. falciparum glutathione reductase.
9
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Friedel & Crafts Method
Conclusions
General procedure for the Friedel-Crafts acylation using the reagent
mixture TFA-TFAA: 1,4-dimethoxy-2-methylnaphthalene (1.0 mmol) and
3-chlorobenzoic acid (0.66 mmol) were mixed to a solution of TFAA (2 mL).
Then, 1 mL of TFA was added and the mixture was heated under reflux
for overnight. When the time described for the reaction finished, the system
was cold down and 10 mL of water was added smoothly. At that point,
ethyl acetate (3 x 50 mL) was added, and the organic layers were
combined, dried over magnesium sulfate. The solid was discarded by
filtration, and the excess of the solvent removed under reduced pressure.
The crude was absorbed on silica gel and purified by flash chromatography
with toluene-cyclohexane eluent system.
In conclusion, we have developed a mild and convenient
Friedel-Crafts variant for acylation of 1,4-dimethoxy-2-
methylnaphthalene by diversely substituted activated or
deactivated benzoic and (hetero)aroyl acids, using the
TfOH/TFAA reagent system through versatile conditions (room
temperature, overnight, air moisture). The Friedel-Crafts reaction
is a very useful reaction to prepare benzophenones derivatives,
and the application of a versatile and mild protocol, suitable for
any starting substituted benzoic acid, to produce diversely
functionalized benzophenone derivatives in satisfactory yields,
renders this reaction attractive for organic synthesis and
medicinal chemistry. Thus, this new variant allowed us to reach a
broad library diversity, both in terms of molecular structure of 3-
acylated menadiones and function – expressed here by tuneable
General procedure for the Friedel-Crafts acylation using the reagent
mixture TfOH-TFAA: 1,4-dimethoxy-2-methylnaphthalene (1.5 mmol) and
benzoic acid (1 mmol) were dissolved in dichloromethane (0.2 M). At 0°C,
TFAA (2 mmol) was added. After stirring for 10 minutes, TfOH (0.5 mmol)
was added cautiously and the reaction mixture was allowed to warm up
slowly at room temperature and stirred for 16h. Then, the reaction was
quenched by an aqueous saturated NaHCO3 solution and the aqueous
phase was extracted three times by dichloromethane. The combined
organic phases were dried over MgSO4 and the solvent was removed
under reduced pressure. The reaction crude was purified by silica gel
chromatography using a mixture of cyclohexane and toluene as eluent to
afford analytically pure Friedel & Crafts products.
E2
values spanning over a broad 500 mV-range of redox
1/2
potentials. Because the antimalarial 3-benzylmenadiones are
thought to be activated through a cascade of redox reactions via
the 3-benzoylmenadiones 1, the library diversity will allow us to
subtly modulate the physico(electro)chemical properties of our
lead antimalarial agents, which is a crucial step in any drug
discovery program.
Oxidative demethylation
Experimental Section
General
procedure:
2-Aroyl-3-methyl-1,4-dimethoxy-naphthalene
Detailed descriptions of experimental procedures, data on product
characterization including spectral data and 1H and 13C NMR spectra of all
new compounds are given in the Supporting Information.
derivative 2 (1 mmol) was dissolved in stirring MeCN (3 mL). Then, at room
temperature, CAN (2.1 mmol) dissolved in water (2 mL) was added drop
by drop. The mixture was stirred at room temperature during 1h. Then,
most of the organic solvent was removed under reduced pressure and the
aqueous phase was extracted three times with dichloromethane.
Combined organic layers were dried over MgSO4 and the solvent was
removed under reduced pressure. Purification by silica gel
chromatography was performed using cyclohexane/EtOAc as eluent.
Typical Procedure for preparing 2-(2,5-dimethoxyphenyl)-2-
oxoacetic acid (5a) or 2-(3,5-dimethoxyphenyl)-2-oxoacetic acid (5a’):
A round bottom flask which had been flushed with argon was charged with
5 mL (31.6 mmol) of 2,5-dimethoxyacetophenone, 7.01 g (63.2 mmol) of
SeO2, and 16 mL of pyridine. The solution was heated at 120 °C. The
temperature gradually dropped to 90°C over 1 h and was heated for an
additional 4h. The solution was concentrated by rotary evaporator until a
small amount of liquid was present. The black selenium residue was rinsed
several times with ethyl acetate. The combined organic layers were
transferred to a separatory funnel containing 100 mL of 0.1 M HCl. The
aqueous layer was extracted three times with ethyl acetate. The aqueous
layer was discarded, and the organic layers were combined and extracted
several times with saturated aqueous NaHCO3. The aqueous layers were
combined, adjusted to pH 1 with conc. HCl, and extracted three times with
ethyl acetate. The final organic layers were dried over Na2SO4 and
concentrated, producing the 2-(dimethoxyphenyl)-2-oxoacetic acid 5a or
5a’.
Acknowledgements
The authors wish to thank the ANR-PRC program (grant
PlasmoPrim project, E.D.C.), the Laboratoire d’Excellence
(LabEx) ParaFrap (grant LabEx ParaFrap ANR-11-LABX-0024,
E.D.C.), for funding and creating a proper framework for this
scientific research. The Centre National de la Recherche
Scientifique (CNRS), the University of Strasbourg (UMR 7042
CNRS-Unistra-UHA), and the International Center for Frontier
Research in Chemistry (ic-FRC) in Strasbourg (ic-FRC-LabEx
Chimie des systèmes complexes, project entitled “Understanding
the mechanisms of antimalarial redox-active substrates in
Kochi-Anderson reaction
General procedure of the for the Silver(II)-Catalyzed Kochi-Anderson
reaction between menadione and α-keto carboxylic acids: A mixture
of menadione (131 mg,0.50 mmol), 2-oxopropionic acid (133 mg, 1.51
mmol), silver(I) nitrate (34 mg, 0.20 mmol), and potassium persulfate (484
mg, 1.79 mmol) in acetonitrile (2 mL) and H2O (6 mL) was heated at 70 °C
for 3 h. The reaction mixture was diluted with ethyl acetate (100 mL),
washed with water (3 x 50 mL), dried (Na2SO4), and concentrated in
vacuum. The crude product was purified by column chromatography over
silica gel (20 g; ethyl acetate/hexane, 1:15) followed by recrystallization
(ethyl acetate/hexane) to give 1a or 1a’.
Plasmodium-infected
red
blood
cells:
a
combined
physicochemical and computational approach to unveiling
biological complexity”) partly supported this work. M.D. thank the
ANR-PRC program (grant PlasmoPrim project) for his salary.
Keywords: acylation • acyltrifluoroacetate • benzoyl •
electrochemistry • Friedel-Crafts
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This article is protected by copyright. All rights reserved.

10.1002/chem.201904220
Chemistry - A European Journal
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Leandro Cotos, Maxime Donzel, Mourad
Elhabiri* and Elisabeth Davioud-
Charvet*
Page No. – Page No.
A Mild and Versatile Friedel-Crafts
Methodology for the Diversity-
Oriented Synthesis of Redox-Active
3-Benzoylmenadiones with tuneable
Redox Potentials
A new Friedel-Crafts acylation variant/oxidative demethylation pathway allowed the
introduction of a broad structural diversity at the aroyl chain of 3-benzoylmenadiones 1.
The electrochemical study highlighted an electronic communication between the redox-
active NQ core and the 3-aroyl subunit, upon the second one-electron transfer, under the
control of the R groups.
This article is protected by copyright. All rights reserved.
12