A Platform of Regioselective Methodologies to Access Polysubstituted 2-Methyl-1,4-naphthoquinone Derivatives: Scope and Limitations

Article abstract of DOI:10.1002/ejoc.201600144

A platform of synthetic methodologies has been established to access a focused library of polysubstituted 3-benzylmenadione derivatives functionalized on the aromatic ring of the naphthoquinone core. Two main routes were explored: 1) The naphthol route, starting from either an α-tetralone or a propiophenone, and 2) the regioselective Diels-Alder reaction, starting from various dienes and two 2-bromo-5(or 6)-methyl-1,4-benzoquinones. 6-Substituted 2-methylnaphthols were synthesized by using a xanthate-mediated free-radical addition/cyclization sequence for the construction of the 6-substituted menadione subunit. Furthermore, an efficient and simple new pathway that allows the formation of 6- or 7-substituted 3-(substituted-benzyl)menadione regioisomers from a common commercial scaffold has also been developed by the naphthol route, advantageous with regard to step economy. Our synthetic methodologies exemplified by 34 compounds have allowed structure-activity relationships to be deduced for use as the basis for the development of new antimalarial redox-active polysubstituted benzylmenadione derivatives.

Full text of DOI:10.1002/ejoc.201600144

DOI: 10.1002/ejoc.201600144
Full Paper
1,4-Naphthoquinone Synthesis
A Platform of Regioselective Methodologies to Access
Polysubstituted 2-Methyl-1,4-naphthoquinone Derivatives:
Scope and Limitations
Elena Cesar Rodo,[a] Liwen Feng,[a] Mouhamad Jida,[a] Katharina Ehrhardt,[a,b][‡]
Max Bielitza,[a] Jérémy Boilevin,[a] Michael Lanzer,[c] David Lee Williams,[d]
Don Antoine Lanfranchi,*[a] and Elisabeth Davioud-Charvet*[a]
Abstract: A platform of synthetic methodologies has been es- menadione subunit. Furthermore, an efficient and simple new
tablished to access a focused library of polysubstituted 3-ben- pathway that allows the formation of 6- or 7-substituted 3-(sub-
zylmenadione derivatives functionalized on the aromatic ring stituted-benzyl)menadione regioisomers from a common com-
of the naphthoquinone core. Two main routes were explored: mercial scaffold has also been developed by the naphthol
1) The naphthol route, starting from either an α-tetralone or a route, advantageous with regard to step economy. Our syn-
propiophenone, and 2) the regioselective Diels–Alder reaction, thetic methodologies exemplified by 34 compounds have al-
starting from various dienes and two 2-bromo-5(or 6)-methyl- lowed structure–activity relationships to be deduced for use as
1,4-benzoquinones. 6-Substituted 2-methylnaphthols were syn- the basis for the development of new antimalarial redox-active
thesized by using a xanthate-mediated free-radical addition/ polysubstituted benzylmenadione derivatives.
cyclization sequence for the construction of the 6-substituted
Introduction
do not contain the 2-methyl substituent, rendering their syn-
thesis easy and straightforward from substituted benzenes.[5a]
1,4-Naphthoquinones are ubiquitously distributed throughout
Also, among the menadione derivatives, the substitution pat-
tern has to be considered (Figure 1). Functionalization of the
eastern part of the molecule affords the vitamin K series upon
isoprenylation of vitamin K3 (menadione).[6] By using solid- and
solution-phase synthesis, a library of synthetic menadione,
juglone, and plumbagin derivatives has been prepared allowing
the introduction of broad structural diversity into the eastern
part of the quinone core.[7] Functionalization of the western
part of menadione is also commonly found in plants, as exem-
plified by chimaphilin derivatives[8] (Figure 1). Larger ring sys-
tems (e.g., biaryls, macrocycles), although less common, appear
in natural products, as exemplified by bivitamin K,[9] gossypol-
all kingdoms of life, including eubacteria, archaebacteria, fungi,
protists, plants, and animals.[1] They have been used for centu-
ries in folk medicine, cosmetics, and industrial dye applica-
tions.[2] Well-known examples[3] of 1,4-naphthoquinones are the
menadione (2-methyl-1,4-naphthoquinone, also called vita-
min K3) and plumbagin (2-methyl-5-hydroxy-1,4-naphthoquin-
one) derivatives, exemplified by the bio-inspired representatives
in Figure 1. Owing to the broad occurrence of the 1,4-naphtho-
quinone motif in compounds of natural origin and their pecu-
liar redox properties,[4] there is a growing interest in the chemis-
try of polysubstituted 1,4-naphthoquinones as final products or
key synthetic intermediates. Numerous 1,4-naphthoquinones[5]
[a] UMR 7509 Centre National de la Recherche Scientifique and Strasbourg
University, Bioorganic and Medicinal Chemistry, European School of
Chemistry, Polymers and Materials (ECPM),
25 Rue Becquerel, 67087 Strasbourg, France
E-mail: lanfranchi@unistra.fr
elisabeth.davioud@unistra.fr
http://www-ecpm.u-strasbg.fr/umr7509/labo_davioudcharvet/
[b] Center of Infectious Diseases, Parasitology, Heidelberg University,
Im Neuenheimer Feld 324, 69120 Heidelberg, Germany
[c] German Centre for Infection Research (DZIF), Partner Site Heidelberg,
Heidelberg, Germany
[d] Department of Immunology/Microbiology, Rush University Medical Center,
1735 West Harrison Street, Chicago, IL 60612, USA
[‡] Present address: Institut de Biologie Moléculaire et Cellulaire,
Strasbourg, France.
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600144.
Figure 1. Natural and synthetic polysubstituted menadione derivatives.
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Scheme 1. Synthesis of synthetic 3-benzylmenadione derivatives and aza analogues.
one,[10] and the antibiotic chaxamycin A,[11] which result from ammonium peroxydisulfate[21] to afford the corresponding alk-
biotransformations of low-weight menadione-, plumbagin-, and ylated product in good yields (Scheme 1).
chimaphilin-based scaffolds upon dimerization, isoprenylation
of mevalonate, and macrocyclization, etc. (Figure 1). Therefore,
the synthetic methodologies have to be highly regioselective
for the preparation of menadione derivatives.
Thus, identification of plasmodione, currently a first antima-
larial lead/early hit, highlights the potential of redox-active 3-
benzylmenadiones (benzylMDs) with the following properties:
A large chemical space for derivatization and a wide range of
In contrast to the previous eastern-substituted series, general redox potentials. The generation of more effective analogues
methods for regioselective transformations to prepare synthetic can only be approached by the total synthesis of 2-methyl-1,4-
menadione derivatives substituted at both the phenyl ring naphthoquinones substituted on the phenyl ring, which neces-
(“western” part) and quinone moiety (“eastern” part) of the 1,4- sitates the total regiocontrol of the synthetic reactions. Owing
naphthoquinone core are rare. Although numerous reports to the lack of versatile and general methodologies to prepare
have described synthetic routes to various menadione deriva- polysubstituted 3-benzyl-2-methyl-1,4-naphthoquinone deriva-
tives, large collections with a diversity of substitutions in the tives, the study described herein focused on the development
western ring are not commercially available in bulk. Although and application of efficient methods to overcome these short-
regioselective annulations of quinones by the Diels–Alder strat- comings (see Scheme 2).
egy are commonly used to build the 1,4-naphthoquinone nu-
cleus in the total synthesis of natural products,[12] it remains a
challenge to control the regioselectivity of the reaction when
Results and Discussion
moderately reactive dienes with unsymmetrical 2-methylquin-
Chemistry
ones are used in the cycloaddition reaction.[13] Many factors
increasing the regioselectivity of [4+2] cycloaddition reactions Many methodologies for the preparation of synthetic and natu-
have been reported: 1) The presence of Lewis[14] and Brøn- ral 1,4-naphthoquinone derivatives have been reported in the
sted[15] acid catalysts, 2) the presence of a halogen atom such literature. In general, these synthetic routes utilize a naphthol
as a bromine at the quinone dienophilic double bond, which intermediate, which, upon oxidation, affords the related 1,4-
also facilitates HBr elimination and the recovery of the quinone naphthoquinone. A more direct and regioselective approach is
moiety following the cycloaddition.[16] Various combinations of based on the Diels–Alder reactions of 1,4-benzoquinones and
factors governing the regioselectivity of cycloaddition reactions dienes.[13,14,16] However, in the case of menadione, the 2-methyl
can produce highly selective results, but these approaches de- group presents two major difficulties that need to be overcome:
pend on structural features of the substrates, which results in 1) It leads to dissymmetry of the molecule and 2) its acidic
unpredictable reaction outcomes.
hydrogen atoms are responsible for the instability of the me-
nadione core in basic media. For these reasons, and aside from
a few examples,[22] there are no general methodologies to pre-
pare polysubstituted menadiones with various substituents in-
troduced regioselectively at any locus of the aromatic ring, in
particular, at C-6 or C-7 of the menadione core.
The recent discovery of the antimalarial lead 3-[4-(trifluoro-
methyl)benzyl]menadione (Scheme 1), henceforth called plas-
modione (compound 1c in refs.[17–19]), has led to reassessment
of the synthetic methodologies used to prepare large numbers
of diverse analogues and potential metabolites functionalized
on both the eastern and western parts of the molecule
As a continuation of our studies into antiplasmodial drug
(Scheme 1). As a first step to access the target molecules, we development, we envisaged that polysubstituted 2-methyl-1,4-
reported a methodology for the preparation of polysubstituted naphthoquinones could also be synthesized through two key
6-methylquinoline-5,8-dione scaffolds (5- and 8-azamenadione strategies (Scheme 2): the Diels–Alder and naphthol routes. To-
analogues).[20] The methodology consisted of a two-step se- ward this end, it was decided to prepare these scaffolds starting
quence involving a regioselective (hetero) Diels–Alder reaction from various commercially available 4-substituted propiophen-
followed by radical alkylation of the 1,4-naphthoquinone core ones 5a and 5b, 6- and/or 7-substituted tetralones 1a–d, or
with a carboxylic acid in the presence of AgI nitrate and dienes in the presence of the corresponding 2-bromo-5-methyl-
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Scheme 2. Platform of synthetic methodologies to prepare a large number of diverse polysubstituted menadiones and analogues of the redox-active antimalar-
ial lead 3-[4-(trifluoromethyl)benzyl]menadione, called plasmodione (Scheme 1).
1,4-benzoquinone (12a) or 2-bromo-6-methyl-1,4-benzoquin- onate derivative, the treatment of which with NaBH4 in aqueous
one (12b). In this study, a small library of menadione analogues THF at 0 °C directly afforded the desired 2-methylnaphthols 4
was built as key intermediates for the preparation of benzylMD in good yields.
derivatives that might be useful as templates both in drug dis-
covery and medicinal chemistry. Thus, we report herein new
Synthesis of Methylnaphthols 9 from Propiophenones
regioselective synthetic methods to obtain polysubstituted
menadiones by both the naphthol and Diels–Alder strategies
(Scheme 2).
Since the pioneering work of Quiclet-Sire and Zard, extensive
research efforts have focused on the construction of diverse
polysubstituted naphthols as starting blocks for the synthesis
of complex natural products.[26] Few examples of naphthoquin-
ones have been reported; the synthesis of ( )-10-norparvulen-
one and ( )-O-methylasparvenone were developed starting
from commercially available m-methoxyphenol, hinging on a
xanthate-mediated addition/cyclization sequence for the con-
struction of the α-tetralone subunit, but lacking the methyl
group.[27] Furthermore, the synthesis of 6,7-substituted 2-meth-
yltetralones was also developed by using a xanthate-mediated
free-radical addition/cyclization sequence for the construction
of the α-methyltetralone subunit starting from 4-substituted
propiophenones, first by us,[28a–c] and then by others.[28d] Thus,
bromopropiophenones 5 were easily synthesized from com-
mercial propiophenones by bromination with Br2 in AcOH.[29]
The treatment of propiophenones 5 with potassium ethyl
xanthate in acetone at 0 °C afforded the desired radical precur-
sors 6 in good yields (Scheme 4). Zard's procedure was used
for the preparation of the key bicyclic intermediates 8, starting
with the radical addition of the xanthates 6 to vinyl pivalate
using dilauroyl peroxide (DLP) as initiator in 1,2-dichloroethane
(DCE) to yield the protected xanthates 7, which can be used as
a starting point for another radical sequence. When the
xanthate 7 solutions were heated at reflux in DCE and treated
with 1.2 equiv. of DLP (added portionwise), tetralones 8 were
obtained in yields of 25 and 26 %.
Naphthol Route – Synthesis of Methylnaphthols 4 and 9
Two methods were employed to synthesize the polysubstituted
methylnaphthols using commercially available tetralones or
propiophenones.
Synthesis of Methylnaphthols 4 From Tetralones
The commercially available 1-tetralones 1 were quantitatively
transformed in the presence of ethyl formate and tBuOK into
the corresponding 2-hydroxymethylene derivatives
2
(Scheme 3).[23] These compounds were aromatized with di-
chloro-5,6-dicyano-1,4-benzoquinone (DDQ) in dioxane[24] to
afford the intermediates 3 in good yields. Then the formyl
group was reduced under mild conditions using a known proto-
col.[25] 1-Hydroxy-2-naphthaldehydes
3 were treated with
ClCO2Et in the presence of Et3N to give quantitatively the carb-
The selection of vinyl pivalate as the radical trap was not
arbitrary. It was anticipated that the OPiv group could serve as
a leaving group for the aromatization in acidic media to facili-
tate the last step of the route. Next, tetralones 8 were treated
with p-toluenesulfonic acid (PTSA)[27b] in toluene at reflux to
Scheme 3. Preparation of 2-methylnaphthols 4 starting from tetralones.
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The oxidation reactions of naphthols 4 and 9 with PIDA were
successfully performed, and moderate-to-good yields of 10a–d
and 11a,b were obtained when the reactions were conducted
on a multigram scale. Thus, a large variety of menadione ana-
logues can be prepared by this approach (Scheme 5).
Scheme 5. Oxidation of the corresponding α-naphthols 4 and 9 to menadi-
one analogues 10 and 11.
Scheme 4. Preparation of 2-methylnaphthols via xanthates.
give the corresponding naphthols
(Scheme 4).
9 in excellent yields
Diels–Alder Route – Synthesis of Methylmenadiones
14a–e
Regioselective annulations of quinones by Diels–Alder reactions
can be achieved when haloquinones react with dienes bearing
electron-donating groups in the presence of Lewis acids.[37] In
this work, 5-, 6-, 7-, 8-methyl or 6,7-dimethylmenadione deriva-
tives 13a–e were obtained by ZnBr2-catalyzed Diels–Alder reac-
tions with piperylene, isoprene, or 2,3-dimethylbuta-1,3-diene
as the diene and 2-bromo-5-methylbenzoquinone (12a) or 2-
bromo-6-methylbenzoquinone (12b) as the dienophile. The
oxidation of the Diels–Alder adducts was not anticipated to be
difficult: Treatment of the reaction mixture under basic condi-
tions is a common method for generating oxidized naphtho-
quinones. Disappointingly, in contrast to the examples reported
in the literature, elimination of HBr did not occur in situ and
several conditions had to be tested to find a convenient
method to synthesize the methylmenadione scaffolds. Heating
the cycloadduct intermediate in toluene at reflux for 24 h or
treating it with oxidizing agents such as CAN or DDQ[38] af-
forded the starting material. Furthermore, the addition of bases
such as Et3N or iPr2NEt did not promote the desired elimination,
but degradation of the intermediate. In fact, the cycloaddition
product displayed an unusual sensitivity to basic conditions.
Finally, the reaction was optimized by the addition of 1 equiva-
lent of pyridine as base. Note that the addition of pyridine fol-
lowing the cycloaddition favors HBr elimination and prevents
product degradation. In this way, treatment of the cycloadduct
with pyridine and dehydrogenation with DDQ in dioxane af-
Synthesis of Polysubstituted Menadiones 10 and 11
To find the best reaction conditions for the synthesis of the
prototype menadione derivatives, 6-methoxy-2-methylnaphthol
(4a) was chosen as the model substrate to optimize the reac-
tion conditions. In the literature, many oxidizing agents have
been employed for this purpose, including copper or copper(II)
chloride (CuCl2),[22a] hypervalent iodine derivatives (phenyliodo-
nium diacetate, PIDA),[30] Fremy's salt,[31] manganese dioxide
(MnO2),[32] chromium trioxide (CrO3),[33] and radical oxidation
[cerium(IV) ammonium nitrate, CAN],[34] to cite but a few. We
tested several conditions for the oxidation of 6-methoxy-2-
methylnaphthol to 6-methoxymenadione (Table 1). The reac-
tion did not proceed when performed with MnO2 or Ag2O[35]
for 48 h. Oxidation by CAN, NBS (N-bromosuccinimide),[36] and
CuCl2 gave the desired menadione after 1–2 h in poor yields.
Using Fremy's salt as the oxidizing reagent gave the 6-methoxy-
menadione in quantitative yield when the reaction was per-
formed on a small scale. However, Fremy's salt is unstable and
expensive. For this reason, we selected PIDA, which gave a yield
of 60 %, as the most appropriate oxidizing agent and pragmatic
choice for the large-scale preparation of the 6-methoxymenadi-
one.
Table 1. Optimization of the oxidation of 2-methylnaphthols 4a.
Conditions
Yield [%]
MnO2 (5 equiv.), CH2Cl2, 48 h, r.t.
Ag2O (5 equiv.), CH2Cl2, 48 h, r.t.
CuCl (3 equiv.), air, r.t., 2 h
NBS (4 equiv.), AcOH/H2O, 1 h, 65 °C
CAN (3 equiv.), MeCN/H2O, 1 h, r.t.
Fremy's salt (2.8 equiv.), KH2PO4 (0.8 equiv.), acetone/
H2O, 2 h, 0 °C
(starting material)
(starting material)
40
40
24
99
PIDA, (2.5 equiv.), MeCN/H2O, 2 h, –5 to 10 °C
60
Scheme 6. Synthesis of methylated menadiones by Diels–Alder reactions.
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forded the corresponding methylmenadiones 13a–e in satisfac- son reaction[21]) between commercial phenylacetic acids and
tory yields (Scheme 6).
the synthesized menadione analogues (2-methyl-1,4-naphtho-
quinones), as shown in Scheme 8.
Synthesis and Functionalization of 6- and
7-Hydroxymenadiones
6- and 7-Hydroxymenadiones 14a and 14b were synthesized
by Diels–Alder reactions using Danishefsky's diene[39] and
bromo-1,4-benzoquinones 12a and 12b as substrates, respec-
tively (Scheme 7).
Scheme 8. Synthesis of 3-benzylmenadione derivatives.
This synthetic methodology is the most useful pathway for
the preparation of alkylated menadiones in bulk. The scope of
this versatile reaction is illustrated by the successful use of 4′-Br,
4′-CF3, 2′,5′-diMeO, and 3′,5′-diMeO-functionalized phenylacetic
acids and a wide array of substituted menadiones in the reac-
tion. Only alcohols and amino groups have been reported to
stop the AgII catalysis under Kochi–Anderson reaction condi-
tions.[17] The overall yields of this reaction are presented in
Table 2. It is noteworthy that this procedure offers an efficient
synthesis of 3-(substituted-benzyl)menadione derivatives. Fur-
thermore, Z and Z′ could be electron-donating or -withdrawing
functionalities at different positions of the substrate; they were
well tolerated and gave the desired compounds in good-to-
excellent yields. As expected, the reaction was compatible with
a wide range of substituents, such as halogens, methyl, meth-
Table 2. Synthesis of 3-(substituted-benzyl)menadione derivatives 17–20 by
the Kochi–Anderson reaction.
BenzylMD[a]
Z
Z′
Yield [%]
17a
17b
17c
17d
17e
17f
6-MeO
7-MeO
6,7-diMeO
7-F
6-F
6-Cl
6-MeO
7-MeO
6,7-diMeO
7-F
6-F
8-Me
7-Me
5-Me
6-Me
6,7-diMe
8-Me
7-Me
5-Me
6-Me
6,7-diMe
6-TfO
4′-CF3
4′-CF3
4′-CF3
4′-CF3
4′-CF3
4′-CF3
4′-Br
4′-Br
4′-Br
4′-Br
4′-Br
4′-CF3
4′-CF3
4′-CF3
4′-CF3
4′-CF3
4′-Br
4′-Br
4′-Br
4′-Br
4′-Br
4′-CF3
4′-CF3
3′,5′-diMeO
2′,5′-diMeO
3′,5′-diMeO
2′,5′-diMeO
3′,5′-diMeO
2′,5′-diMeO
4′-CF3
80
70
80
65
55
71
78
63
75
86
85
75
68
76
65
87
67
70
76
50
82
80
70
77
65
55
72
71
65
77
70
Scheme 7. Synthesis and functionalization of hydroxymenadione derivatives
by Diels–Alder reactions.
The cycloadducts of 1,3-dioxybutadienes and bromoquin-
ones underwent aromatization with the loss of 1 equivalent of
MeOH. The reactions were carried out in CH2Cl2 by using pyrid-
ine as a base to promote the elimination of HBr. Indeed, depro-
tonation of the hydroxy group with pyridine and subsequent
reaction with triflic anhydride, carbamoyl chloride, or acetic an-
hydride in CH2Cl2 afforded the desired menadione derivatives
15a–d, respectively, in excellent yields (Scheme 7). However,
the reaction did not proceed when pyridine was used in the
reaction with diethyl chlorophosphate.[40] Finally, after further
optimization using Ag2O in CH2Cl2, 6- and 7-phosphate diethyl
esters 16a and 16b were obtained in yields of 60 and 65 %,
respectively (Scheme 7). Thus, diversely functionalized mena-
diones can be easily synthesized in excellent yields starting
from readily prepared hydroxymenadiones, as exemplified by 6-
hydroxymenadione 14a (Scheme 7).
18a
18b
18c
18d
18e
19a
19b
19c
19d
19e
20a
20b
20c
20d
20e
20f
20g
20h
20i
20j
20k
20l
20m
20n
20o
7-TfO
7-MeO
7-MeO
6,7-diMeO
6,7-diMeO
6-MeO
6-MeO
6-P(O)2(EtO)2
7-P(O)2(EtO)2
Synthesis of 3-(Substituted-benzyl)menadione Derivatives
3-(Substituted-benzyl)MD derivatives were synthesized by Jac-
obsen–Torssell reactions[41] (better known as the Kochi–Ander-
4′-CF3
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oxy, and protected hydroxy groups, providing the correspond-
ing products with good purity. In all cases, the results show
excellent efficiency of the Ag(II)-mediated radical decarboxyl-
ation reaction between menadiones and commercial phenyl-
acetic acids, affording 31 targeted products (17a–f, 18a–e, 19a–
e, and 20a–o) in good-to-excellent yields (50–87 %). In general,
the reactions were clean, rapid, and efficient.
Pursuing our ongoing interest to increase the diversity of
available 3-benzylMD derivatives, we decided to regenerate the
hydroxy substituent group by deprotection of the triflate group
in the menadione substrates 20f and 20g. TBAF-promoted tri-
flate removal (in THF at room temperature)[42] was used for this
reaction to yield the expected compounds 21a and 21b quanti-
tatively (Scheme 9).
Scheme 10. Express synthesis of 3-(substituted-benzyl)menadione derivatives
starting from tetralones.
Scheme 9. Synthesis of 6- or 7-hydroxy-3-benzylmenadiones.
functional group (Scheme 11). Subsequently, oxidative addition
and ꢀ-elimination forces a shift of the double bond (Scheme 11)
and finally aromatization to the most thermodynamically stable
naphthol 23a (the calculated free energies were estimated by
ChemBioOffice 2012[53]). Indeed, the active RhI intermediate was
found to be sensitive to oxygen in open air and lost efficiency;
however, the use of well-degassed dry solvents and strict anae-
robic conditions, both the yield (increased to 95 %) and repro-
ducibility of this reaction were optimized.
Expeditious and High-Yielding Route to 3-(Substituted-
benzyl)menadione Derivatives
An elegant pathway that allows the formation of two 3-(substi-
tuted-benzyl)menadione regioisomers at C-6 or C-7 from the
same starting material has also been envisioned. In this new
process, the final benzylic chain is proposed to be introduced in
the first step through the coupling of benzaldehydes to various
commercial tetralones.
In this alternative scenario, the naphthol route is advanta-
geous with regard to step economy, because 6- or 7-substituted
3-benzylMD regioisomers can be prepared in high yields by two
pathways from the same tetralones 1a, 1d, or 1e, that is, in five
steps for the 6-regioisomers 17a and 17e (Schemes 3, 5, and
8), or only in four steps in the following expeditious route to
plasmodione and the regioisomers 17b and 17e, respectively
(Scheme 10). The conditions screened for aromatization in-
cluded treatment of the starting α-methylene ketone 22a with
various oxidation catalysts. These conditions were 1) PIDA,
MeCN, 12 h, room temperature, 2) TFA, CH2Cl2, 12 h, room tem-
perature, 3) tBuOK, DMSO, 12 h, room temperature,[43] 4) RuCl3,
EtOH, 24 h, reflux, 5) DDQ, dioxane, 24 h, reflux, 6) trimethyl-
phenol, TFA, 90 °C, 24 h,[44] 7) MnO2 (5 equiv.), CH2Cl2, 48 h,
room temperature, 8) Ag2O (5 equiv.), CH2Cl2, 48 h, room tem-
perature, 9) CrO3, H2O, AcOH, 90 °C, 12 h, 10) Ag2O (16 equiv.),
6
M HNO3, dioxane, room temperature, 11) CuCl2, THF, H2O,
24 h, room temperature, or 12) RhCl3, (10 mol-%) EtOH, reflux,
6 h.[45] Only RhCl3 efficiently catalyzed the aromatization of the
α-methylenetetralone 22a to the desired naphthol 23a to give
a very satisfactory yield (87 %); all the other reactions led to
recovery of the starting material.
However, the reactivity of the Rh catalyst was highly depend-
ent on the stability of the RhI species. According to the mecha-
nistic study described by Paiaro et al.,[45a] RhIIICl3 is first reduced
by ethanol to form HRhICl2 and then coordinates to the olefin
Scheme 11. Proposed mechanism for the rhodium-catalyzed olefin isomeriza-
tion.
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Compounds 23a, 23d, and 23e were then successfully oxi- the formation of side-products was observed and the yield of
dized with PIDA followed by the Kochi–Anderson reaction to the reaction decreased (Figure 2, b). Based on the kinetic profile
give the three benzylMDs, namely plasmodione, 17b, and 17e determined by 19F NMR analysis in a mixture of CD3CN/D2O,
in moderate-to-good yields.
the protocol of this reaction was optimized to give a yield of
50–60 % after two purification steps (chromatography followed
by precipitation). The preparation of plasmodione and the ana-
logues 17b and 17e (Scheme 10) reflects the optimized proc-
ess.
In the final step, methylation with acetic acid was thought
to be feasible; however, the yields of the preliminary reactions
were not satisfactory. By using a phenylacetic acid as partner in
the coupling reactions with menadiones, the yields of the radi-
cal alkylation products ranged from 50 to 87 %. However, when
using acetic acid instead of phenylacetic acid, the methylation
yield was limited to 30 %, because the stability of the methyl
radical is much lower[46] than that of the benzyl radical, and the
more reactive methyl radical may destroy the desired product.
To increase the yield of this reaction, the relative amounts of
acetic acid, silver nitrate, and ammonium persulfate were varied
without impacting the outcome of the reaction.
To follow the reaction kinetics and track the reaction prod-
ucts by NMR spectroscopy, we used 2-[4-(trifluoromethyl)ben-
zyl]naphthalene-1,4-dione (24e) as the starting material for the
reaction model. After stirring for 30 min, the reaction conver-
sion reached over 50 % and we observed the rapid generation
of 2-benzylMD. After 1 hour, the starting material had been
almost completely consumed and the benzylMD was almost
exclusively the final product, as shown by the complete disap-
pearance of the proton (δ = 6.70 ppm) at C-2 present in the
starting material (see the kinetics of the reaction by the change
in the NMR spectra over time, Figure 2, a). However, after 1 h,
Antimalarial Activities of 3-(Substituted-benzyl)menadione
Derivatives
1,4-Naphthoquinones are widely distributed in naturally occur-
ring quinones. Their role in biochemistry has often been high-
lighted because of their electron-transfer properties in numer-
ous important pathways from the respiratory chain of living
cells to maintaining the redox equilibrium in cytosol. In the first
part of our investigation of menadione properties, we evaluated
the oxidant character of newly synthesized 2-methyl-1,4-
naphthoquinones by cyclic voltammetry to evaluate and estab-
lish a predictive structure–redox potential model (QSPR: quanti-
tative structure–property relationship) based on the electro-
and physicochemical properties of various redox-active com-
pounds.[4b] With these new tools in hand, we made available an
on-line evaluation (through the Web interface) of the oxidant
character of redox agents to help chemists targeting such de-
sired redox properties. Also, seminal studies on several syn-
thetic naphthoquinones found that these compounds possess
antiprotozoal activities.[47] These include potent antimalarial
properties, which have been reported for synthetic atovaquone
(as the main active principle of Malarone®),[48] and by us, for
synthetic 2-methyl-1,4-naphthoquinone (or menadione) deriva-
tives like plasmodione.[17–19] In the present study, we explored
the consequences of the incorporation of halogen, methyl,
methoxy, and hydroxy groups into the phenyl ring of the
menadione core on the antimalarial activity of the privileged
benzylMD structure. Therefore, the structure–activity relation-
ships of the polysubstituted benzylMD series were assessed
through a study of the effect of the functionalization of both
the phenyl ring of the menadione core (Z) and benzyl chain
(Z′) on the antimalarial activities in comparison with the lead
plasmodione, which has been reported previously.[17] The 50 %
inhibitory concentration (IC50) was determined for each com-
pound by using the SYBR green assay in the presence of P.
falciparum strain Dd2 parasitized red blood cells in culture
(Table 3). In parallel, the IC50 values of positive controls, chloro-
quine (82.4 nM) and Methylene Blue (3.6 nM), were determined
to be of the same order of magnitude as the values reported
elsewhere.[18] In the data presented in Table 3, the IC50 values of
the lead plasmodione (Z = H, Z′ = 4′-CF3) and its 4-bromobenzyl
derivative (Z = H, Z′ = 4′-Br), called benzylMD 1a in the previous
report,[17] are lower than the value of the antimalarial drug
chloroquine, attesting to a slightly superior antiplasmodial ac-
Figure 2. a) Kinetic 1H NMR spectroscopy study of the Kochi–Anderson reac-
tion between demethylmenadione 24e and acetic acid. b) Kinetic profile for
the Kochi–Anderson reaction of 24e to plasmodione, determined by 19F NMR
analysis experiments. The two NMR studies were performed in a mixture of
CD3CN/D2O using 1-methyl-4-(trifluoromethoxy)benzene as internal standard.
tivity (58 and 82 vs. 99 nM) against the multidrug-resistant P.
falciparum strain Dd2. Interestingly, among the newly synthe-
sized benzylMD derivatives (Z, Z′), the most potent antimalarial
compounds are the 6- and 7-fluoro analogues of plasmodione,
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Table 3. Averaged IC50 values for polysubstituted 3-benzylmenadione derivatives determined from growth inhibition assays with Plasmodium falciparum strain
Dd2.
BenzylMD
Z
Z′
IC50 [n
M
] (n)[a]
BenzylMD
Z
Z′
IC50 [nM
] (n)[a]
17a
17b
17c
17d
17e
17f
18a
18b
18c
18d
18e
19a
19b
19c
19d
19e
20a
6-MeO
7-MeO
6,7-diMeO
7-F
6-F
6-Cl
6-MeO
7-MeO
6,7-diMeO
7-F
6-F
8-Me
7-Me
5-Me
6-Me
6,7-diMe
8-Me
4′-CF3
4′-CF3
4′-CF3
4′-CF3
4′-CF3
4′-CF3
4′-Br
4′-Br
4′-Br
4′-Br
4′-Br
4′-CF3
4′-CF3
4′-CF3
4′-CF3
4′-CF3
4′-Br
186 58 (3)
3187 (1)
3685 (1)
20b
20c
20d
20e
20f
20g
20h
20i
20j
20k
20m
20n
7-Me
5-Me
6-Me
6,7-Me
6-OTf
4′-Br
4′-Br
4′-Br
4′-Br
4′-CF3
4′-CF3
3′,5′-diMeO
2′,5′-diMeO
3′,5′-diMeO
2′,5′-diMeO
2′,5′-diMeO
4′-CF3
4′-CF3
4′-Br
4′-CF3
4′-CF3
992 107 (3)
1820 71 (3)
171 66 (3)
2706 26 (2)
236 37 (4)
3546 902 (3)
778 89 (4)
2187 (1)
83 12 (4)
59 11 (3)
242 60 (4)
171 69 (3)
3230 (1)
881 129 (4)
74 32 (4)
83 23 (3)
3004 941 (2)
439 205 (5)
3638 193 (2)
215 68 (3)
3243 260 (3)
3761 972 (3)
7-OTf
7-MeO
7-MeO
6,7-diMeO
6,7-diMeO
6-MeO
6-P(O)4(Et)2
7-P(O)4(Et)2
H
2704 (1)
1365 521 (4)
104 58 (4)
157 49 (2)
518 231 (3)
82 20 (7)
58 11 (9)
3698 191 (2)
82.4 1.6 (3)
20o
BenzylMD 1a[b]
Plasmodione[c]
2-Demethylplasmodione 24e
CQ[d]
H
H
–
–
[a] Activity against cultured parasites of the P. falciparum Dd2 strain is presented as mean IC50 values standard deviation (SD) determined from n independent
growth inhibition assays in triplicate using the SYBR® green technique. [b] From ref.[17] [c] Plasmodione, named benzylMD 1c, in ref.[17–19], and its 4-bromo
analogue, named benzylMD 1a in ref.[17], were used as internal references. The lower nanomolar IC50 values previously reported for plasmodione and its 4-
bromo analogue against the drug-multiresistant P. falciparum Dd2 strain were evaluated in a distinct assay based on tritiated hypoxanthine incorporation
(ref.[17]). [d] Methylene Blue [MB, IC50 = 3.6 0.4 (4)] and chloroquine (CQ) were used as standard drugs.
17e (6-F, 4′-CF3), 18e (6-F, 4′-Br), 17d (7-F, 4′-CF3), and 18d (7- tive polysubstituted 2-methyl-3-benzyl-1,4-naphthoquinones
F, 4′-Br), respectively (17e: 59 n
M
, 18e: 83 n
M
, 17d: 83 nM, and by efficient and versatile strategies, namely the naphthol route,
18d: 74 n vs. 58 n with plasmodione), which suggests that starting from either a tetralone or a propiophenone, or regio-
M
M
the introduction of fluorine at C-6 or C-7 might be a favorable/ selective Diels–Alder reactions. These original procedures were
tolerant substitution to maintaining antimalarial activity. In con- found to be useful for the synthesis of focused chemical librar-
trast to the substitution by halogens, the antimalarial activities ies of benzylMD analogues with broad structural diversity. The
of the methylated and methoxylated Z analogues of the lead structural complexity, ease of synthesis, and variation in substi-
plasmodione are significantly reduced, regardless of the substi- tution patterns present in these molecules will allow quantita-
tution position on the phenyl ring, but with substitution at C-6 tive structure–activity relationship studies, useful for various
always being the most favorable when Z′ is an electron-with- biological applications. In this work we have found compounds
drawing group (4′-CF3, 4′-Br). For instance, the IC50 values range displaying a wide variation of activity against P. falciparum para-
from 171 n
18a and 20d with a 4′-Br-benzyl chain, respectively) to 186 n
and 215 n (for the 6-MeO- and 6-Me-substituted benzylMDs
M (for the 6-MeO- and 6-Me-substituted benzylMDs sites. These synthetic templates may be employed as an impor-
M
tant class of “privileged scaffolds” in redox medicinal chemistry.
M
17a and 19d with a 4′-CF3-benzyl chain, respectively). Further-
more, methylation at C-5 or C-8 dramatically reduces the activ-
Experimental Section
ity, with the IC50 values increasing to 3638 n
substituted benzylMD 19c (4′-CF3) and to 3004 n
M
for the 5-Me-
and 3761 n
Detailed descriptions of experimental procedures are given in the
Supporting Information.
M
M
for the 8-Me-substituted benzylMDs 19a and 20a (4′-CF3 and
4′-Br). Finally, 2-demethylplasmodione 24e, with a hydrogen
atom instead of a methyl group at C-2, displays a very weak
antimalarial activity, attesting to the essential requirement of
the 2-methyl group in the menadione core.
General Procedure 1 for the α-Formylation of Tetralone: A mix-
ture of tetralone in toluene (1 equiv., 0.45 mmol mL–1) and ethyl
formate (2.0 equiv.) was prepared. The solution was cooled to
–78 °C under argon and mechanically stirred while potassium tert-
butoxide (2.0 equiv.) was added in portions: The solution became
milky and pinky in color. The solution was warmed to –5 °C until
TLC monitoring (petroleum ether/Et2O, 3:1) indicated the comple-
tion of the reaction. The solution was quenched with 10 % HCl (the
pink color disappeared) and the mixture extracted with Et2O. The
organic phases were dried (brine, MgSO4) and concentrated in
Conclusions
This study has provided new insights into the synthetic meth-
odologies that can be used to prepare various biologically ac- vacuo to yield α-formyl tetralone (usually as a solid).
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Typical Procedure for the Synthesis of 2-(Hydroxymethylene)-
General Procedure 8 for the Oxidation of Methylnaphthols to
6-methoxy-3,4-dihydronaphthalen-1(2H)-one (2a): Commercially
Menadiones: (Diacetoxyiodo)benzene (PIDA) (12.1 mmol,
available 6-methoxytetralone (12.0 g, 68.14 mmol, 1 equiv.) was 2.1 equiv.) was added portionwise to a stirred solution of the meth-
used as the starting material and treated according to the general ylnaphthol (5.8 mmol, 1 equiv.) in acetonitrile (70 mL) and water
procedure 1 to give 2a (13.62 g, 66.8 mmol), yield 98 %; light-brown (30 mL) at –5 °C over 20–30 min. After stirring for 30 min at –5 °C,
solid; m.p. 66–67 °C (ref.[24] 68–69 °C). 1H NMR (200 MHz, CDCl3):
δ = 7.91 (d, J = 8.6 Hz, 1 H), 6.82 (dd, J = 8.6, 2.4 Hz, 1 H), 6.68 (d,
J = 2.4 Hz, 1 H), 3.82 (s, 3 H), 2.82 (t, J = 7.3 Hz, 2 H), 2.51 (t, J =
the reaction mixture was stirred at room temperature for 1 h. A
saturated NaHCO3 solution was added to the orange reaction mix-
ture and the reaction mixture extracted with Et2O (3 × 120 mL). The
7.3 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 208.1 (C=O), 175.1 combined organic extracts were washed with brine and dried with
(CH), 163.5 (Cq), 144.5 (Cq), 128.8 (CH), 126.2 (CH), 113.1 (CH), 112.6
(Cq), 108.21 (CH), 55.5 (OCH3), 29.4 (CH2), 23.3 (CH2) ppm.
anhydrous MgSO4. The crude was purified by flash chromatography
on silica gel (hexane/Et2O, 2:3) to give the desired compound.
Typical Procedure for the Synthesis of 6-Methoxy-2-methyl-
naphthalene-1,4-dione (10a): Compound 4a was used as the
starting material (2.0 g, 10.63 mmol) and treated according to the
general procedure 8 to give 10a (1.40 g, 6.91 mmol), yield 65 %;
General Procedure 2 for the Aromatization of α-Formyltetra-
lone to α-Formylnaphthol: 2,3-Dichloro-5,6-dicyano-1,4-benzo-
quinone (DDQ; 1.0 equiv.) was added to a solution of α-formyltetra-
1
lone in dioxane (1.0 equiv., 0.2
M) at room temperature. A white
yellow powder; m.p. 146–148 °C (Et2O). H NMR (200 MHz, CDCl3):
precipitate appeared rapidly. After completion of the reaction (TLC
monitoring), the white precipitate was removed by filtration. The
filtrate was concentrated under reduced pressure. The crude was
purified by column chromatography (silica gel, cyclohexane/Et2O,
3:1) to give the desired compound.
δ = 8.04 (d, J = 8.6 Hz, 1 H), 7.49 (d, J = 2.8 Hz, 1 H), 7.18 (dd, J =
8.6, J = 2.8 Hz, 1 H), 6.79 (q, J = 1.8 Hz, 1 H), 3.94 (s, 3 H), 2.18 (d,
J = 1.8 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 185.06 (C=O),
184.56 (C=O), 163.96 (Cq), 148.52 (Cq), 135.25 (CH), 134.33 (Cq),
129.02 (CH), 125.77 (Cq), 120.21 (CH), 109.29 (CH), 55.91 (OCH3),
16.52 (CH3) ppm. HRMS (ESI): calcd. for C12H10O3Na 225.0522 [M +
Na]+; found 225.0522.
Typical Procedure for the Synthesis of 1-Hydroxy-6-methoxy-
2-naphthaldehyde (3a): Compound 2a was used as the starting
material (4.08 g, 19.69 mmol) and treated according to the general
procedure 2 to give 3a (2.86 g, 14.2 mmol), yield 75 %; white pow-
General Procedure 9 for the Preparation of Menadiones by the
Diels–Alder Reaction: A solution of 2-bromo-5-methyl-1,4-benzo-
quinone (12a) or 2-bromo-6-methyl-1,4-benzoquinone (12b;
1.0 equiv.) in dry CH2Cl2 (0.15 mmol mL–1) was added to a suspen-
sion of ZnBr2 (1.2 equiv.) in dry CH2Cl2 (1.5 mmol mL–1). The mixture
was stirred for 5 min and the appropriate diene was added
(10 equiv.). After stirring overnight the reaction mixture was
quenched with a solution of saturated NH4Cl. The reaction mixture
was extracted with CH2Cl2 and the combined CH2Cl2 layers were
washed with brine and dried with MgSO4. Pyridine (2 equiv.) was
added and the mixture was stirred at room temperature for 4 h.
CH2Cl2 was evaporated to yield the quinone as a yellow oil. The
1
der; m.p. 128–129 °C (ref.[24] 133 °C). H NMR (200 MHz, CDCl3): δ =
12.70 (s, 1 H), 9.90 (s, 1 H), 8.35 (d, J = 9.2 Hz, 1 H), 7.45 (d, J =
8.8 Hz, 1 H), 7.26 (d, J = 8.8 Hz, 1 H), 7.18 (dd, J = 9.2, 2.6 Hz, 1 H),
7.09 (d, J = 2.6 Hz, 1 H), 3.96 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 195.6 (C=O), 162.0 (Cq), 161.5 (Cq), 139.6 (Cq), 127.5 (CH), 126.1
(Cq), 119.0 (CH), 116.4 (CH), 116.2 (CH), 113.2 (Cq), 106.3 (CH), 55.5
(OCH3) ppm.
General Procedure
3 for the Reduction of 2-Formyl-1-
naphthols: Triethylamine (1.2 equiv.) was added to a solution of 2-
quinone (1.0 equiv.) was dissolved in dioxane (0.3
M) and DDQ
formyl-1-naphthol in tetrahydrofuran (1.0 equiv., 1 mmol mL–1). The
(1.0 equiv.) was added at room temperature. After completion of
the reaction (TLC monitoring), the white precipitate was removed
by filtration. The filtrate was concentrated under reduced pressure.
The crude was purified by column chromatography (silica gel, cyclo-
hexane/EtOAc, 4:1) to give the desired compound.
solution was cooled to
0 °C and then ethyl chloroformate
(1.2 equiv.) was added over a period of 30 min. The solution was
stirred during 30–60 min (white precipitate formed). The precipitate
(triethylamine hydrochloride) was removed by filtration and washed
with tetrahydrofuran (twice less than the amount used for the reac-
Typical Procedure for the Synthesis of 2,8-Dimethylnaphthal-
ene-1,4-dione (13a): 2-Bromo-6-methyl-1,4-benzoquinone (12b;
2.50 g, 13.55 mmol) and piperylene (10 mL, 135.5 mmol) were used
as the starting materials and treated according to the general pro-
cedure 9 to give 13a (1.76 g, 9.48 mmol), yield 70 %; yellow needles;
m.p. 132 °C (hexane/EtOAc). 1H NMR (300 MHz, CDCl3): δ = 7.99
(dd, J = 10.5, J = 2.4 Hz, 1 H), 7.61–7.49 (m, 2 H), 6.81 (q, J = 2.1 Hz,
1 H), 2.75 (s, 3 H), 2.18 (d, J = 2.1 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 187.51 (C=O), 185.34 (C=O), 149.45 (Cq), 141.28 (Cq),
137.65 (CH), 134.27 (CH), 133.76 (Cq), 132.79 (CH), 129.84 (Cq),
124.99 (CH), 22.89 (CH3), 16.86 (CH3) ppm. HRMS (ESI): calcd. for
C12H11O2 187.0754 [M + H]+; found 187.0761.
tion). An aqueous solution of NaBH4 (4.0 equiv., 2.6 M) was added
to the combined filtrates at 5–15 °C. When the addition was com-
plete, the reaction mixture was stirred at room temperature for 1–
2 h and then diluted with water. The solution was cooled to 0 °C
and made acidic by the slow addition of aqueous HCl (10 %). The
aqueous solution was extracted with Et2O. The organic phases were
washed with a dilute solution of NaOH (10 %), dried (brine, MgSO4),
and concentrated in vacuo to yield methylnaphthol (usually as a
solid or oil that crystallized on standing).
Typical Procedure for the Synthesis of 6-Methoxy-2-methyl-
naphthalen-1-ol (4a): Compound 3a was used as the starting ma-
terial (1.32 g, 6.47 mmol) and treated according to the general pro- General Procedure 10 for the Diels–Alder Reaction with
cedure 3 to give 4a (0.85 g, 4.53 mmol), yield 70 %; deliquescent
white powder. H NMR (300 MHz, CD2Cl2): δ = 8.03 (d, J = 9.8 Hz, 1
Danishefsky's Diene: 1-Methoxy-3-(trimethylsiloxy)-1,3-butadiene
(2.0 equiv.) was added dropwise to 2-bromo-5-methyl-1,4-benzo-
quinone (12a) or 2-bromo-6-methyl-1,4-benzoquinone (12b;
1
H), 7.24 (AB system, J = 8.1 Hz, 2 H), 7.11 (m, 2 H), 5.19 (s, 1 OH),
3.90 (s, 3 H), 2.37 (s, 3 H) ppm. 13C NMR (75 MHz, CD2Cl2): δ = 158.1 1.0 equiv.) in CH2Cl2 (0.2
M) at 0 °C. The solution was stirred at room
(Cq), 15.7 (CH3), 55.8 (OCH3), 149.4 (Cq), 135.3 (Cq), 130.3 (CH), 123.2
(CH), 120.1 (Cq), 119.5 (CH), 118.3 (CH), 114.8 (Cq), 106.2 (CH) ppm.
MS (EI): m/z (%) = 188.1 (100) [M]+, 145.0 (83), 115.0 (62), 189.1 (15)
[M + H]+.
temperature for 2 h, then pyridine (1.5 equiv.) was added, and the
suspension stirred under air at room temperature for 6 h. Concen-
tration and flash column chromatography (ethyl acetate/toluene,
1:2) gave hydroxy-2-methylnaphthalene-1,4-dione.
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Typical Procedure for the Synthesis of 6-Hydroxy-2-methyl-
alkene (3.31 mmol, 1 equiv.) and RhCl3 (0.331 mmol, 0.1 equiv.) was
naphthalene-1,4-dione (14a): 2-Bromo-6-methyl-1,4-benzoquin- heated at reflux in ethanol (70 mL) for 6 h. During this process,
one (12b; 2.00 g, 9.90 mmol, 1 equiv.) and Danishefsky's diene
(2.9 mL, 14.85 mmol, 1.5 equiv.) were used as the starting materials
and treated according to the general procedure 10 to give 14a
(1.60 g, 8.50 mmol), yield 86 %; orange solid; m.p. 175 °C (hexane/
EtOAc). 1H NMR (400 MHz, [D6]DMSO): δ = 10.96 (s, 1 H), 7.92 (d,
J = 8.4 Hz, 1 H), 7.29 (d, J = 2.8 Hz, 1 H), 7.19 (dd, J = 8.4, J = 2.8 Hz,
1 H), 6.93 (q, J = 1.6 Hz, 1 H), 2.15 (d, J = 1.6 Hz, 3 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 185.18 (C=O), 184.31 (C=O), 163.07 (Cq),
148.75 (Cq), 135.27 (CH), 134.49 (Cq), 129.56 (CH), 124.44 (Cq), 121.03
(CH), 111.82 (CH), 16.45 (CH3) ppm. HRM (ESI): calcd. for C11H9O3
189.0546 [M + H]+; found 189.0557.
when the reaction was carried out in open air, oxygen was observed
to interfere in the catalytic cycle by oxidizing Rh(I) to Rh(III)* species,
accounting for the arrest of the isomerization reaction. Thus, well-
degassed solvent and strict anaerobic conditions were necessary
for this reaction to occur. After concentration, the residue was parti-
tioned between water and ethyl acetate, and the organic phase was
dried with MgSO4 and concentrated. Chromatography (cyclohex-
ane/EtOAc, 5:1) gave the pure products in excellent yields.
Typical Procedure for the Synthesis of 2-[4 (trifluoro-
methyl)benzyl]naphthalen-1-ol (23e): Yield 96 %; white solid;
m.p. 83.5–84 °C (cyclohexane). 1H NMR (300 MHz, CDCl3): δ = 7.87–
7.84 (m, 1 H), 7.65–7.61 (m, 1 H), 7.37–7.26 (m, 5 H), 7.20–7.14 (m,
2 H), 7.10–7.05 (m, 1 H), 4.99 (s, 1 H, OH), 4.03 (s, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 148.63 (Cq), 144.05 (Cq), 133.82 (Cq), 128.90 (2
CH), 128.81 (q, J = 33.42 Hz, Cq), 128.63 (CH), 128.00 (CH), 126.79
(CH), 125.71 (CH), 125.63 (q, J = 3.83 Hz, 2 CH), 124.59 (Cq), 124.2
(q, J = 264.23 Hz, CF3), 120.98 (CH), 120.72 (CH), 119.57 (Cq), 36.2
(CH2) ppm. 19F NMR (376 MHz, CDCl3): δ = –62.39 ppm. MS (EI): m/z
(%) = 302.1 (100) [M]+. HRMS (ESI): calcd. for C18H14F3O 303.0991
[M + H]+; found 303.0996.
General Procedure 13 for the Synthesis of Benzyl Menadione
Derivatives: The corresponding menadione derivative (1 equiv.,
0.05 mmol mL–1) and phenylacetic acid derivative (2 equiv.) were
added to a stirred solution of MeCN/H2O (3:1) and heated at 85 °C
(70 °C in the flask). AgNO3 (0.35 equiv.) was first added and then
(NH4)2S2O8 (1.3 equiv., 0.36 mmol mL–1) in MeCN/H2O (3:1) was
added dropwise. The reaction mixture was then heated for 2–3 h
at 85 °C. MeCN was evaporated and the mixture extracted with
DCM. The crude mixture was purified by flash chromatography on
silica gel using a mixture of diethyl ether and cyclohexane as eluent.
When necessary, the benzylmenadione was recrystallized from hex-
ane or a mixture of EtOAc/hexane to give the desired analytically
pure benzylMD derivatives in good-to-excellent yields.
General Procedure for the Oxidation of the Benzylnaphthol
Derivatives to 2-Benzyl-1,4-naphthoquinones: (Diacetoxyiodo)-
benzene (PIDA) (5.29 mmol, 2.1 equiv.) was added portionwise to a
stirred solution of naphthol (2.65 mmol, 1 equiv.) in acetonitrile
(35 mL) and water (12 mL) at –5 °C over 20–30 min. After stirring
for 30 min at –5 °C, the reaction mixture was stirred at room tem-
perature for 1 h. A saturated NaHCO3 (15 mL) solution was added
to the orange reaction mixture and the mixture was extracted with
Et2O (3 × 50 mL). The combined organic extracts were washed with
brine and dried with anhydrous MgSO4. The crude product was
purified by flash chromatography on silica gel (cyclohexane/EtOAc,
1:10 to 1:5) to give the corresponding desired benzylMDs in excel-
lent yields.
Typical Procedure for the Synthesis of 2,6-Dimethyl-3-[4-(tri-
fluoromethyl)benzyl]naphthalene-1,4-dione (19d): Yield 65 %;
yellow needles; m.p. 93–94 °C (hexane/EtOAc). 1H NMR (300 MHz,
CDCl3): δ = 7.98 (d, J = 7.4 Hz, 1 H), 7.87 (s, 1 H), 7.53–7.48 (m, 3
H), 7.17 (d, J = 7.4 Hz, 2 H), 4.07 (s, 2 H), 2.48 (s, 3 H) 2.23 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 184.98 (C=O), 184.81 (C=O),
144.82 (Cq), 144.74 (Cq), 144.17 (Cq), 142.31 (Cq), 134.38 (CH), 131.81
(Cq), 129.87 (Cq), 128.87 (2 × CH), 128.58 (q, J = 28.9 Hz, Cq), 126.88
(CH), 126.62 (CH), 125.6 (q, J = 3.8 Hz, 2 CH), 124.18 (q, J = 269.7 Hz,
CF3), 32.34 (CH2), 21.85 (CH3) 13.33 (CH3) ppm. HRM (ESI): calcd. for
C20H15F3O2Na 367.0916 [M + Na]+; found 367.0911.
Typical Procedure for the Synthesis of 2-[4-(Trifluoro-
methyl)benzyl]naphthalene-1,4-dione (24e): Yield 89 %; yellow
needles; m.p. 98–100 °C (hexane/EtOAc). 1H NMR (300 MHz, CDCl3):
δ = 8.13–8.02 (m, 2 H), 7.76–7.71 (m, 2 H), 7.49 [(AB)2 system, J =
8.1 Hz, Δν = 61.8 Hz, 4 H] 6.63 (t, J = 1.5 Hz, 1 H), 3.96 (s, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 184.87 (C=O), 184.72 (C=O), 149.78
(CH), 141.00 (Cq), 135.90 (CH), 133.96 (CH), 133.87 (Cq), 132.05 (Cq),
129.74 (2 CH), 129.41 (q, J = 32.48 Hz, Cq), 126.75 (CH), 126.22 (CH),
125.78 (q, J = 3.83 Hz, 2 CH), 125.77 (Cq), 124.12 (q, J = 269.18 Hz,
CF3), 35.67 (CH2) ppm. 19F NMR (376 MHz, CDCl3): δ = –62.54 ppm.
HRMS (ESI): calcd. for C18H12F3O2 317.0784 [M + H]+; found
317.0791.
General Procedure for the Condensation of 4-Trifluorobenz-
aldehyde and Commercial Tetralones:
A solution of KOH
(41.04 mmol, 1.2 equiv.) in EtOH (105.5 mL) was added to a mixture
of α-tetralone (4.562 mL, 34.2 mmol, 1 equiv.) and 4-CF3-benzalde-
hyde (37.62 mmol, 1.1 equiv.). The solution was stirred at room
temperature for 4 h. The reaction mixture was poured into water
and a white solid precipitated. The solid was filtered, washed with
water (2 × 50 mL), and dried under vacuum to give the desired
alkenes in excellent yields.
Typical Procedure for the Synthesis of (E)-2-[4-(trifluoro-
methyl)benzylidene]-3,4-dihydronaphthalen-1(2H)-one (22e):
Yield 85 %; white solid; m.p. 170–172 °C (from EtOH). 1H NMR
(300 MHz, CDCl3): δ = 8.05 (dd, J = 7.8, J = 1.5 Hz, 1 H), 7.75 (s, 1
H), 7.52 [(AB)2 system, J = 8.1 Hz, 4 H], 7.40, (dd, J = 7.8, 1.5 Hz, 1
H), 7.31–7.28 (m, 1 H), 7.26–7.16 (m, 1 H), 3.01–2.97 (m, 2 H), 2.91–
2.85 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 187.49 (C=O),
143.19 (Cq), 139.47 (Cq), 137.41 (Cq), 134.66 (CH), 133.56 (CH), 133.23
(Cq), 130.02 (q, J = 31.57 Hz, Cq), 129.91 (2 CH), 129.42 (CH), 128.31
(CH), 127.18 (CH), 125.60 (q, J = 3.3 Hz, 2 CH), 124.07 (q, J = 270.3 Hz,
CF3), 28.81 (CH2), 27.20 (CH2) ppm. 19F NMR (376 MHz, CDCl3): δ =
–62.69 ppm. HRMS (ESI): calcd. for C18H14F3O 303.0991 [M + H]+;
found 303.0971.
General Procedure for the Kochi–Anderson Reaction of 2-
Benzyl-1,4-naphthoquinone Derivatives to the Corresponding
3-Benzylmenadiones:
The
2-benzyl-1,4-naphthoquinone
(0.316 mmol, 1 equiv.) and acetic acid (1.58 mmol, 5 equiv.) were
added to a stirred solution of MeCN/H2O (3:1, 9.19 mL) and heated
at 85 °C. AgNO3 (0.11 mmol, 0.35 equiv.) was first added, and then
(NH4)2S2O8 (0.411 mmol, 1.3 equiv.) in MeCN/H2O (3:1, 3.94 mL) was
added dropwise in 5 min. The reaction mixture was then heated for
60 min at 85 °C. MeCN was evaporated and the mixture was ex-
tracted with DCM. The crude mixture was purified by flash chroma-
tography on silica gel using toluene as eluent. When necessary, the
compound was recrystallized from hexane or a mixture of EtOAc/
hexane to give the analytically pure benzylMD derivatives.
General Procedure for the Isomerization to the Corresponding
Benzylnaphthol Derivatives: A solution of the corresponding
Eur. J. Org. Chem. 2016, 1982–1993
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1991
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Full Paper
Biological Assays
Keywords: Synthetic methods · Cycloaddition ·
Regioselectivity · Redox chemistry · Biological activity ·
Quinones
Inhibitors: The chloroquine diphosphate salt and Methylene Blue
trihydrate were purchased from Sigma–Aldrich. The lead plasmodi-
one was prepared as described previously (as benzylMD 1c in
ref.[17]). Stock solutions of Methylene Blue and chloroquine were
prepared in pure water. Stock solutions of the benzylMD derivatives
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(6 mM) were prepared in DMSO and stored in aliquots at –20 °C.
Growth Inhibition Assays: P. falciparum wild-type strain Dd2 was
cultured at 37 °C according to standard protocols[49] in RPMI me-
dium containing 9 % human serum and type A erythrocytes at a
hematocrit level of 3.3 % under a low-oxygen atmosphere (3 % CO2,
5 % O2, 92 % N2, and 95 % humidity). The cultures were synchro-
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ing to standard protocols. The in vitro antimalarial activity is ex-
pressed as 50 % inhibitory concentration (IC50). The activities of the
lead plasmodione, Methylene Blue, and chloroquine against the
P. falciparum Dd2 strain (as presented in Table 3) were determined
by using the SYBR® green I assay as described before.[51,52] Briefly,
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presence of decreasing drug concentrations in microtiter plates
(0.5 % parasitemia, 1.5 % hematocrit final). Each inhibitor was ana-
lyzed in three-fold serial dilution in duplicates and with at least
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E. D.-C. thanks Don Antoine Lanfranchi, in recognition of his
fundamental contribution to the development of the platform
of organic chemistry of the described 2-methyl-1,4-naphtho-
quinones. The authors wish to thank the National Institutes of
Health (NIH), USA (project entitled “Redox balance and drug
development in Schistosoma mansoni”, grant 1R01AI065622-
01A2 to D. L. W.) for creating an effective framework to allow
the set-up of the platform of synthetic methodologies (salary
to D. A. L.). This work was also made possible by grants of
the Agence Nationale de la Recherche (ANR) (ANRemergence2010
program, grant SCHISMAL to E.D.-C.), and of the Laboratoire
d'Excellence ParaFrap (grant LabEx ParaFrap ANR-11-LABX-0024
to E. D.-C.). The French Centre National de la Recherche Scientif-
ique (CNRS) (grant UMR 7509 to E. D.-C.), the University of Stras-
bourg, France, and the International Center for Frontier Re-
search in Chemistry, Strasbourg, France (project entitled
“Redox-active 1,4-naphthoquinones to kill malarial parasites”,
grant ic-FRC-Trinational to E.D.-C.) partly supported this work.
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1993
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim