Styryl and functionalized aryl derivatives of lawsone through metal-free cross-coupling of its BF3-activated phenyliodonium ylide with cinnamaldehydes and arylaldehydes

Article abstract of DOI:10.1016/j.tet.2015.06.037

Phenyliodonium ylide of lawsone activated with BF₃?Et₂O reacts with cinnamaldehydes to afford 2-hydroxy-3-styryl-1,4-naphthoquinones in good to excellent yields and relatively high level of stereospecificity through deformylation of the aldehydes. The product yield is diminished with a methoxy substituted cinnamaldehyde and becomes zero with a dimethoxy substituted substrate giving rise to another product, 2-hydroxy-3-aryl-1,4-naphthoquinone. The reaction of the same ylide with salicylic aldehydes forms 2-hydroxy-3-(2-hydroxyaryl)-1,4-naphthoquinones and/or benzo[d]naphtha[2,1-b]furano-5,6-diones, depending on the reaction conditions applied. Plausible reaction mechanisms explaining the formation of these products are proposed. The products showed potent antioxidant activity and inhibited lipoxygenase.

Full text of DOI:10.1016/j.tet.2015.06.037

Tetrahedron 71 (2015) 5650e5661
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Styryl and functionalized aryl derivatives of lawsone through metal-
free cross-coupling of its BF3-activated phenyliodonium ylide with
cinnamaldehydes and arylaldehydes
,
a
b
Elizabeth Malamidou-Xenikaki a , Maria Tsanakopoulou , Maria Chatzistefanou ,
*
Dimitra Hadjipavlou-Litina b
a Laboratory of Organic Chemistry, School of Chemistry, Faculty of Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
b Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki,
Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
Phenyliodonium ylide of lawsone activated with BF3ꢀEt2O reacts with cinnamaldehydes to afford 2-
hydroxy-3-styryl-1,4-naphthoquinones in good to excellent yields and relatively high level of stereo-
specificity through deformylation of the aldehydes. The product yield is diminished with a methoxy
substituted cinnamaldehyde and becomes zero with a dimethoxy substituted substrate giving rise to
another product, 2-hydroxy-3-aryl-1,4-naphthoquinone. The reaction of the same ylide with salicylic
aldehydes forms 2-hydroxy-3-(2-hydroxyaryl)-1,4-naphthoquinones and/or benzo[d]naphtha[2,1-b]fur-
ano-5,6-diones, depending on the reaction conditions applied. Plausible reaction mechanisms explaining
the formation of these products are proposed. The products showed potent antioxidant activity and
inhibited lipoxygenase.
Received 6 March 2015
Received in revised form 25 May 2015
Accepted 9 June 2015
Available online 16 June 2015
Keywords:
Phenyliodonium ylide
Metal-free cross-coupling
Arylation
Ó 2015 Elsevier Ltd. All rights reserved.
Alkenylation
Anti-lipid peroxidation
1. Introduction
antimicrobial, antiprotozoal, antimalarial, trypanocidal, and anti-
HIV.1,2,5,9e11 Hence, their synthesis has attracted a lot of attention.
Naphthoquinones and more generally quinones are important
molecules and structural units in many natural products.1,2 Interest
in naphthoquinones is in part due to their biological properties,
their use on a large scale as dye reagents and in other industrial
applications and their potential as intermediates in the synthesis of
heterocycles.3 A special subgroup of these compounds is consti-
The construction of a CeC bond at the position next to hydroxyl
can be achieved either by direct insertion of the functional group or
through
a coupling reaction of the aryliodonium ylide of
hydroxynaphthoquinone.12
The direct derivatization method, mainly applied for in-
troducing alkyl groups to the lawsone moiety, includes the reaction
of hydroxynaphthoquinone with diacyl peroxides, R3B or RTeTol
and coupling with free alkyl radicals derived from the de-
carboxylation of the corresponding carboxylic acids.13 A number of
catalyst-free or organocatalyzed enantioselective Michael-type re-
tuted
by
2-hydroxynapthoquinones.4,5
Natural
2-
hydroxynaphthoquinones vary in structural complexity from the
simple hydroxynaphthoquinones such as 2-hydroxy-1,4-
naphthoquinone (lawsone, 1), the main component of a natural
hair dye and a potent detector of latent finger marks on cloth or
paper under infrared light,6 to hydroxyphenylnaphthoquinones3 or
complex structures such as the trimeric hydroxynaphthoquinone
actions between lawsone and nitroolefins,
a,b-unsaturated ketones
or -unsaturated -oxo-esters affording C-alkylated lawsone de-
b,
g
a
rivatives have also been reported.14e19 The insertion of allyl groups
has been achieved by Pd(PPh3)4-catalyzed coupling of hydrox-
ynaphthoquinone with allyl alcohols13 or reaction of its lithium salt
with allyl bromides.20 The direct arylation of lawsone was con-
ducted by coupling with aryldiazonium salts in alkaline solution,
though in low yields.21e23
conocurvone (2),
a
potential anti-HIV agent7,8 (Fig. 1). 2-
Hydroxynaphthoquinones bearing an alkyl (or aryl) substituent at
the position adjacent to hydroxyl, like lapachol (3), atovaquone (5)
and parvaquone (4) (Fig. 1), exhibit usually a broad spectrum of
activities, such as antibacterial, antiplasmodial, antioxidant,
A main pattern of the reaction of the aryliodonium ylides of
hydroxyquinones, which are formed upon reaction of hydrox-
yquinones with PhI(OAc)2, is substitution of the easy-leaving
* Corresponding author. Tel.: þ30 2310 997874; fax: þ30 2310 997679; e-mail
address: malamido@chem.auth.gr (E. Malamidou-Xenikaki).
http://dx.doi.org/10.1016/j.tet.2015.06.037
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

E. Malamidou-Xenikaki et al. / Tetrahedron 71 (2015) 5650e5661
5651
Fig. 1. Representative examples of biologically active hydroxynaphthoquinones and benzofuranonaphthoquinones.
iodonium group by a variety of functional groups, mainly nucleo-
philes.12 In one implementation of this process, some furano-
substituent at C-3 of the quinone ring and in continuation of our
interest on the chemistry of aryliodonium ylides of hydrox-
naphthoquinones were prepared in
a
Sonogashira-type cou-
yquinones, we decided to extent this methodology using a,b-un-
pling24 of the phenyliodonium ylide of lawsone (8) with phenyl-
acetylenes through in situ cyclization of the intermediate alkynyl-
lawsone derivatives. The outcome of the analogous photochemi-
cal reactions was similar.25 Through this process of iodonium group
substitution, the formation of aryl-hydroxynaphthoquinones is also
facilitated. Stagliano accomplished the arylation of lawsone and its
derivatives through a Stille-type coupling reaction of their phe-
nyliodonium ylides with arylstannates (Scheme 1).7,8,26 Indolyl
derivatives of lawsone have also been obtained from the copper-
catalyzed reactions of its phenyliodonium ylide (8) with in-
doles.27 Besides, a variety of aryl and heteroaryl derivatives of
lawsone as well as the 3-styryl-lawsone have been attained
through the Suzuki-type coupling of the same iodonium ylide with
the appropriate aryl, heteroaryl and styryl boronates.28
3-Aryl-2-hydroxy-1,4-naphthoquinones have been used as
synthetic precursors of quinonoid compounds, including indolo-
naphthoquinones ea class of compounds with established29 anti-
neoplastic activitye and benzofuronaphthoquinones of which
representative examples as violet quinone (6) and balsaminone A (7)
are given in Fig. 1.30 In a recent publication31 we reported the
synthesis of 3-arylated and 3-heteroarylated derivatives of 2-
hydroxy-1,4-naphthoquinone through a BF3-mediated reaction of
its phenyliodonium ylide with aryl and heteroarylaldehydes, which
is supposed to proceed through a complex like 9 (Scheme 1). In-
terestingly, the coupling takes place at the ipso carbon of the al-
dehyde with loss of the formyl group.
saturated or properly substituted arylaldehydes as substrates,
aiming to further transformation of the initial products to other
important and potentially bioactive compounds as e.g., fur-
anonaphthoquinones and to screen their antioxidant profile. The
results of our research are reported herein.
2. Results and discussion
Ideal candidates for the desired transformations could be law-
sone derivatives with an alkenyl and an o-hydroxy or o-haloge-
nated aryl substituent in position 3 of the quinone ring given that
methods converting analogous substrates to furanonaph-
thoquinones are already known32e37 (Fig. 2).
Our efforts began with salicylic aldehydes. Upon treatment of
ylide 8 with an equimolar amount of BF3$Et2O and a small excess
(1:1.2) of salicylic aldehyde under reflux in chloroform (commercial
grade) solution for 8 h, two products were isolated, namely the (2-
hydroxyphenyl)-hydroxynaphthoquinone (10a) and benzofurano-
o-naphthoquinone (11a) in 9% and 47% yield, respectively (Scheme
2). When the reaction mixture was heated for 2 h, the yield of 10a
was increased to 31% with simultaneous decrease to 5% in the yield
of 11a. Under heating for 14 h, the only isolated product was 11a in
49% total yield. Analogous results were obtained from the reaction
of 5-bromosalicylic aldehyde as depicted in Scheme 2. These results
are indicative of a process in which compound 10 is the initial re-
action product that quantitatively dehydrates to 11 under pro-
longed heating. Thus, this easy, one step coupling reaction between
ylide 8 and salicylic aldehydes seems promising for the preparation
Since a plethora of compounds with biological interest belong to
the class of hydroxynaphthoquinones bearing a carbonaceous

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E. Malamidou-Xenikaki et al. / Tetrahedron 71 (2015) 5650e5661
Scheme 1. Coupling reactions of phenyliodonium ylide of lawsone (8).
Fig. 2. Retrosynthetic scheme for aryl substituted lawsones and furanonaphthoquinones.
of furano-o-naphthoquinones in satisfactory yields. The same re-
action pattern was observed when ylide 8 reacted with 2-hydroxy-
1-naphthaldehyde under similar conditions. Hydroxynaphthyl-
hydroxynaphthoquinone 10c and dinaphthofurandione 11c were
isolated in varying yields depending on heating duration. Specifi-
cally, the isolated yields were 36% and 7% upon heating for 2 h but
0% and 22% after prolonged heating for 11 h, respectively.
Regarding the formation of products 10, a mechanistic scheme
similar to that previously suggested31,38 for the analogous BF3
catalyzed couplings of ylide 8 with arylaldehydes, including an
intermediate analogous to 9 (Scheme 1), could be proposed
(Scheme 2). The transformation of 10 to 11 is attributed to the
electrophilic attack of the BF3-activated quinone carbonyl by hy-
droxyl (12), which is followed by dehydration (Scheme 3).
In an effort to broaden the scope of this reaction, we tried to
synthesize lawsones bearing haloaryl substituents on the C-3 atom
of the quinone ring, using halo-arylaldehydes as starting materials.
The reaction with o-bromobenzaldehyde was performed under the
above reported conditions and reflux of the chloroform (commer-
cial grade) solution continued until consumption of the insoluble
ylide 8 (24 h), established by clearness of the reaction mixture.
Unexpectedly, the desired (2-bromophenyl)-3-hydroxynaph

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5653
Scheme 4. Coupling reactions of ylide
arylaldehydes.
8
with hindered and/or inactivated
consumption of ylide, probably due to steric hindrance and in-
activation of the phenyl ring by the bulky, electron withdrawing o-
nitro group.
An attempt to increase the yield and improve the reaction time
with o-nitrobenzaldehyde, by heating at higher temperature (sol-
vent Cl2C]CCl2, bp 121 ꢁC), was unsuccessful, leading exclusively to
thermal degradation products of ylide. Moreover, efforts to opti-
mize the yields of the reactions with the inactivated, o-substituted
arylaldehydes, using microwave irradiation instead of heating,
were also made. However, under these conditions (MW, 110 ꢁC,
80 min), the only isolable products were 2-arylidene-indanediones
15, resulting through an aldol reaction of the aldehyde with inda-
nedione, the thermal degradation product of ylide 8 (Scheme 5).
Products 14 are supposed to result through a mechanistic
pathway analogous to that previously reported for the formation of
compounds 10.31 In regards to the formation of the unexpected
products 13 that contain two more carbon atoms than the partici-
pating starting materials, a possible explanation could be the in situ
transformation of the inactivated arylaldehydes to the corre-
sponding cinnamaldehydes through an aldol reaction with
CH3CHO. Acetaldehyde originates possibly from EtOH, contained in
small quantities as impurity (w1% as estimated by NMR) in com-
mercial CHCl3, and oxidized in the oxidizing environment of the
hypervalent iodine reagent. BF3-complexed iodonium enolates are
moreover supposed as stronger oxidants than the free ylides.38 To
confirm this hypothesis, the reaction with 2-bromobenzaldehyde
was repeated in CH2Cl2 or CH3CN. From the reaction in dichloro-
methane, the starting material was recovered unchanged, probably
due to the low boiling point of the solvent. Instead, the reaction in
acetonitrile resulted in ylide decomposition products. In the case
where chloroform free of ethanol was used as solvent, product 13a
was not formed. The corresponding to 13a propyl-substituted
product was also not detected when the reaction with 2-
bromobenzaldehyde was performed in ethanol-free chloroform in
the presence of 1 equiv of pentanal, possibly because the aldol re-
action of the active methylene group of pentanal is less favorable
than the respective of the methyl group of acetaldehyde. Surpris-
ingly, product 13a was also not detected when excess of the low
boiling point (21 ꢁC) CH3CHO was added to the reaction mixture of
ylide and 2-bromobenzaldehyde in commercial chloroform. On the
failure of forming coupling products in both last cases, a possible
explanation could also be the eventual binding of the more reactive
Scheme 2. Coupling reaction of ylide 8 with salicylic aldehydes and 2-hydroxy-1-
naphthaldehyde.
Scheme 3. Proposed mechanistic pathway for the transformation of aryl lawsones 10
to furanonaphthoquinones 11.
thoquinone was not detected in the reaction mixture, the main
product (yield 40%) being 2-(2-bromostyryl)-3-hydroxy-1,4-
naphthoquinone 13a. Furthermore, the analogous reactions of p-
bromo and p-chlorobenzaldehyde upon reflux for 24 h gave, except
from the desired aryl lawsones 14b, c (yields 44% and 31%, re-
spectively), the corresponding styryl lawsones 13b, c, in 20% and 5%
yield (Scheme 4). A single product of relevant structure, 13d, was
also obtained from the reaction of o-nitrobenzaldehyde, although
in very low total yield (10%). In this case, the reaction was consid-
erably slower, requiring double heating time (48 h) for the

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E. Malamidou-Xenikaki et al. / Tetrahedron 71 (2015) 5650e5661
Scheme 5. Formation of 2-arylidene-indanediones from the reaction of ylide 8 with arylaldehydes under microwave irradiation.
alkyl aldehyde with BF3 in a complex analogous to 9, thus excluding
the aryl aldehyde from the coupling reaction. Nevertheless, from
a blank experiment performed by stirring a chloroform solution of
PhCHO with 1 equiv of CH3CHO and catalytical amounts of BF3,
cinnamaldehyde was formed and isolated by column chromatog-
raphy, thus confirming that the aldol reaction can really be per-
formed under the applied conditions. Finally, in order to ascertain
the supposed oxidation of EtOH by a hypervalent iodine reagent,
benzaldehyde, in the presence of BF3, reacted in chloroform
(commercial grade) solution with PhI(OAc)2 in place of ylide 8.
Cinnamaldehyde was actually detected among the products of this
reaction.
Styryl lawsones 13 are formed in cases of arylaldehydes with
inactivated aromatic ring (halo or nitro-substituted) and particu-
larly the stereochemically hindered ortho-substituted ones. Under
these conditions, the transition from an intermediate analogous to
9 (Scheme 1) to product 14 through a SET process is rather un-
favorable, as indicated from the long reaction times and low yields.
Thus, the arylated product 14 was not formed at all from o-bromo
or o-nitrobenzaldehydes whereas p-chloro- and p-bromo-
benzaldehydes afforded the corresponding product in moderate
yields (Scheme 4). In all these cases, a competitive alkenylation
reaction of lawsone by the in situ formed cinnamaldehydes takes
place. It is noteworthy that in these cases too, the coupling re-
actions proceed through an unusual deformylation of cinna-
maldehydes (a mechanism is proposed later in Scheme 10).
Beyond mechanistic interest, the results of these reactions in-
dicate that the cinnamaldehydes can be used for insertion of the
styryl group in the lawsone framework affording very interesting
styryl derivatives. Thus, we tried the reaction of ylide 8 with cin-
namaldehyde, in the presence of BF3, under reflux in chloroform for
2 h. Styryl lawsone 16a was obtained in excellent yield, 90%
(Scheme 6). It is worth mentioning that the reaction of cinna-
maldehyde, performed in the absence of BF3, failed to provide
product 16a and only indanedioneketene dimer and indanedione
self-condensation products, both resulting through thermal deg-
radation of ylide, were obtained.
Scheme 6. Coupling of cinnamaldehyde with ylide 8.
the unsubstituted (Z)-3-phenylacrylaldehyde (‘cis-cinnamalde-
hyde’) was obtained enriched to approximately 93%.
When the coupling reactions were performed with mixtures of
(E,Z)-3-aryl-acrylaldehydes, mixtures of stereoisomeric products 16
of almost invariable percentage were formed, indicating the re-
tention of the starting material molecular geometry to a large ex-
tent. When the enriched (Z)-3-phenylacrylaldehyde (purity 93%)
was used, the coupling product was formed in 38% total yield,
substantially lower than that of the trans isomeric aldehyde. The
two stereoisomers 16b and 16a were isolated as an inseparable
mixture in w28e30% and w8e10% yield, respectively, estimated by
the 1H NMR spectrum of the mixture (Scheme 6). It is calculated
that the quantity of product 16a corresponds to the total amount of
the E-form aldehyde contained in the utilized starting aldehyde
mixture. As estimated, only 26e28% of the starting Z-form alde-
hyde was converted to 16b, indicating that it is evidently less active
due to steric effects, especially in the product 16b.
With the objective to study the effect of the aryl substituents on
the product yield, the reaction was applied to a series of substituted
cinnamaldehydes that were prepared39 as E,Z mixtures from the
corresponding arylaldehydes upon treatment with vinyl acetate, in
the presence of Ba(OH)2, under reflux in THF for 6e12 h. Separation
of the isomeric aldehydes proved very hard; after repeated column
chromatographies, fractions of up to 95% purity of all the trans
isomers were achieved, whereas from all cis isomers only that of
Due to difficulty separating the mixtures of cis, trans products
16, the reactions of the rest cinnamaldehydes were performed with
their pure or enriched trans isomer. All of these reactions led to the

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5655
and in particular electron deficiency of the CH]CH bond. Con-
versely, the purple colored furanoquinone 17b was isolated from
the reaction of the more electron efficient 2-methyl-3-phenyl-
acrylaldehyde (Scheme 8) in 20% yield. The formation of compound
17b likely stems from a cyclization process of the initially formed
corresponding styryl lawsone aided by the Lewis acidic environ-
ment. Finally, coupling reactions attempted with other
a,b-un-
saturated aldehydes, such as crotonaldehyde or acrolein, failed,
leading to aldehyde polymerization products.
This study shows both the necessity of the Lewis acidic catalyst
for the successful outcome of the coupling reactions and also the
essential role of the electron releasing or withdrawing effects of the
aryl substituents of cinnamaldehydes to the formation and distri-
bution of the products. Another notable feature is the observed
stereospecificity and the influence of steric factors. Except signifi-
cantly activated methoxy substituted cinnamaldehydes, cinna-
maldehydes bearing electron donating substituents on the aryl
group appear to improve the coupling reactions thus indicating
their role of acting as electron donors to the electrophilic ylide
moiety. Boron trifluoride could evidently activate both starting
materials, coordinating either with the carbonyl and/or the anionic
oxygen(s) of ylide or with the CHO group of cinnamaldehyde. Co-
ordination of BF3 with the aldehyde is supposed to impair its
electron donor activity whereas coordination with the ylide rather
improves ylide’s electrophilicity. Based on this thought and in re-
lation to the mechanisms proposed previously, we suggest the
mechanistic Schemes 9 and 10 for the formation of the aryl law-
sones 14f, g and 13c-g, respectively.
Scheme 7. Reactions of substituted cinnamaldehydes with ylide 8.
Scheme 8. Reactions of ylide 8 with
a
-substituted cinnamaldehydes.
styryl substituted lawsones 13 with almost absolute retention of
the trans form (Scheme 7) estimated by the 1H NMR spectra of the
mixtures. The reactions of p-methyl- and p-chloro-cinnamaldehyde
gave the corresponding styryl lawsones 13e and 13c in good yields
(69% and 65%) whereas the yield from o-nitro-cinnamaldehyde was
much lower (38%), probably due to inactivation of the conjugated
system by the strong electron attracting nitro group. But paradox-
ically, the yields of the styryl lawsones were lower even when ac-
tivated cinnamaldehydes were used as substrates. Specifically,
styryl lawsone 13f was isolated in 25% yield from the reaction with
the substituted p-methoxy-cinnamaldehyde whereas the corre-
sponding product was not formed at all in the case of the more
activated 2,5-dimethoxy substituted substrate (Scheme 7). How-
ever, in these cases the aryl lawsones 14f and 14g were isolated in
23% and 34% yield, respectively.
In case of the methoxy-substituted cinnamaldehydes, their
electron enriched CHO carbonyl coordinates with BF3 and possibly
assists the formation of the intermediate 18 through a Michael-type
addition (Scheme 9). Disposing an electron rich aryl group, due to
the interruption of conjugation with CHO, complex 18 gives suc-
cessively, through an intramolecular-type SET, the biradicals 19 and
20. By loss of PhI and BF3, the labile enol ether 21 is formed and
hydrolyzed in the acidic environment of the reaction or perhaps
during work up by column chromatography.
A complex formation between BF3 and the more electron de-
ficient cinnamaldehydes is rather unfavorable. On the other hand,
the intermediacy of a crowded, as shown by 3D molecular models,
complex like 22 (Scheme 10), which, through a process analogous
with the above suggested (Scheme 9), leads subsequently to bir-
adical 23 and by loss of PhI to the formate 24 and finally to 13c-g, is
not considered very likely because it could not rationalize the ob-
served stereospecificity of the isolated products. The relatively high
level of stereospecificity could be better explained by a mechanism
involving mediation of a carbene, whose electrophilicity is en-
hanced by the coordination of BF3 with the adjacent carbonyls (25).
Being activated, carbene intermediate 25 undergoes electrophilic
attack by the relatively inactivated C]C bond of cinnamaldehyde,
leading through cyclopropanation (26) to the formate 24 and by
subsequent hydrolysis to the final products 13c-g (Scheme 10).
Trans-3-(2-furyl)propenal was utilized in an analogous coupling
reaction with BF3-activated ylide 8. Styryl or aryl lawsone de-
rivatives corresponding to 13 or 14 were not isolated either in
refluxing chloroform or by stirring at rt, probably due to acid-
catalysed polymerization of the substrate. Furthermore, the re-
actions of two a-substituted cinnamaldehydes were studied. From
the reaction of the 2-chloro-3-phenyl-acrylaldehyde, the expected
coupling product was not formed, but instead decomposition of the
starting materials occurred. This is attributed to both steric factors

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E. Malamidou-Xenikaki et al. / Tetrahedron 71 (2015) 5650e5661
Scheme 9. Proposed mechanism for the formation of products 14f, g.
Another possible route could also be a concerted [2þ2] cycloaddi-
tion process of the alkene C]C bond to the ylidic carboneiodine
double bond involving the formation of a four-membered iodocycle
27, which upon reductive elimination of PhI results to the same as
previously mentioned cyclopropyl intermediate 26 and thereafter
to 13c-g. Both these routes have previously been suggested40,41 to
involve in metal-free intramolecular cyclopropanations of alkenes
with iodonium ylides.
A reaction pathway to 13c-g, through an activated carbene like 25,
surelysupportstheexperimentalfindings, that is, the necessityof BF3,
the requirement of cinnamaldehydes with electron donor sub-
stituents as well as the stereospecificity of the reaction. The divergent
behaviour of the most electron enriched methoxy cinnamaldehydes
could be attributed to the possibly faster parallel route (Scheme 9)
leading to products 14f, g. On the other hand and although some
concerted reactions are assisted by Lewis acids and affected by steric
factors, in the present case, a [2þ2] cycloaddition pathway could
rather not explain the effect of the electron donor or acceptor effi-
ciency of the aryl substituents. Based on the above considerations, we
could propose with reservation that a course involving carbene me-
diation is the most likely mechanism operating in the present alke-
nylation reactions of phenyliodonium ylide of lawsone.
promising in respect of their chemical or biological properties. Many
benzo and hydroxynaphthoquinones42 have been reported to act
either as inhibitors of free radical production or as radical scavengers
as well as inhibitors of lipoxygenase (LOX) offering important tools
for psoriasis’ treatment.43 Consequently, compounds with antioxi-
dant properties could be expected to offer protection in in-
flammation and to lead to potentially effective drugs.
Taking into account the multifactorial character of oxidative
stress and inflammation, and the role of hydroxynaphthoquinone
moiety, we decided to evaluate in the present investigation the
parent molecule 2-hydroxy-3-phenyl-1,4-naphthoquinone31 (14h,
R1¼R2¼H), 14c, 2-hydroxy-3-(p-tolyl)-1,4-naphthoquinone31 (14e,
R1¼H, R2¼Me) and 14g as well as the styryl derivatives 13a, c-f, 16a
with regard to their antioxidant ability as well as to their ability to
inhibit soybean LOX and in comparison to well-known antioxidant
agents recommended as references e.g., nordihydroguaeretic acid
(NDGA) and trolox.
The results for the reducing activity (RA) of the examined
compounds was measured at 100 mM (20 min) using the stable free
radical DPPH and depicted in Table in the Supplementary data.
With the exception of 13d and 13f all tested compounds presented
(Table) very high antioxidant activity (75e93%) in the DPPH assay.
All products were found to be very efficient inhibitors of lipid
peroxidation (81e91%), much stronger than the reference com-
pound Trolox (63%). The most potent lipoxygenase inhibitor is 14g,
The aryl lawsones 10, 14 as well as the styryl lawsones 13, 16
obtained from this study have fascinating molecular structures in-
cluding the pharmacophore hydroxy-naphthoquinone core and are

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5657
Scheme 10. Possible routes for the formation of products 13c-g.
whereas all the others are almost equipotent inhibitors. Lip-
ophilicity as a physicochemical property of importance for the bi-
ological activity has been calculated theoretically.44 Further
investigation is in progress in order to delineate the possible
mechanism of action of these new compounds.
their conversion to either styryl or aryl lawsone derivatives is
strongly depended on the nature of the aryl group substituents. 2-
Hydroxy-3-hydroxyaryl-1,4-naphthoquinones formed from the
reactions with salicylic aldehydes are spontaneously transformed
to the important benzo[d]naphtha[2,1-b]furano-5,6-diones under
conditions of prolonged heating. The in vitro results point to the
significant role of the hydroxynaphthoquinone moiety in the an-
tioxidant activity.
3. Conclusions
In summary, the transformation of lawsone to 2-hydroxy-3-
aryl-1,4-naphthoquinones or 2-hydroxy-3-styryl-1,4-naphtho
quinones was conveniently achieved through a two-step course,
including first the formation of its phenyliodonium ylide and sub-
sequently the metal-free coupling reactions with functionalized
arylaldehydes or cinnamaldehydes mediated by BF3. The reactions
with cinnamaldehydes exhibit remarkable stereospecificity and
4. Experimental
4.1. General
Microwave irradiation was carried out with Biotage (Initiator
2e0) MW oven. Melting points were measured on a Kofler hot-

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E. Malamidou-Xenikaki et al. / Tetrahedron 71 (2015) 5650e5661
stage and are uncorrected. NMR spectra were recorded at room
temperature (rt) on a Bruker AM 300 spectrometer at 300 MHz for
1H and 75 MHz for 13C, using CDCl3 or CDCl3/DMSO-d6 (containing
20e25% DMSO-d6) as solvent. Chemical shifts are expressed in
(MþNaþMeOH)þ; Calcd for C16H7BrO3: C, 58.74; H, 2.16. Found: C,
58.87;
H,
2.06
and
2-(5-bromo-2-hydroxyphenyl)-3-
hydroxynaphthalene-1,4-dione (10b), (70 mg, 40%), red oil; IR
(KBr) cmꢂ1 3442, 1653, 1590, 1292; 1H NMR (CDCl3- DMSO-d6)
d
values (ppm) relative to TMS as internal standard for 1H and
d
8.08 (d, J¼7.5 Hz, 1H), 7.97 (d, J¼7.2 Hz, 1H), 7.68 (dd appearing as
relative to TMS (0.00 ppm) or to CDCl3 (77.05 ppm) for 13C NMR
spectra. Coupling constants J are reported in Hertz. IR spectra were
recorded on a PerkineElmer 1600 series FTIR spectrometer and are
reported in wave numbers (cmꢂ1). Column chromatography was
carried out using Merck silica gel. Petroleum ether refers to the
fraction boiling between 60 and 80 ꢁC. Phenyliodonium ylide of
lawsone 8 was prepared from lawsone and PhI(OCOCH3)2 according
to a literature method.25
t, J¼7.5 Hz, 1H), 7.55 (dd appearing as t, J¼7.2 Hz, 1H), 7.53 (s, 1H),
7.20 (d, J¼8.4 Hz, 1H), 6.80 (d, J¼8.4 Hz, 1H); 13C NMR (CDCl3-
DMSO-d6) d 187.1, 182.9,163.0,154.8,135.0,134.6, 134.2,131.6, 130.7,
130.1, 126.5, 125.7, 124.1, 120.0, 118.3, 110.8; ESI-LCMS m/z negative
343/345 (MꢂH)ꢂ. Anal. Calcd for C16H9BrO4: C, 55.68; H, 2.63.
Found: C, 55.35; H, 2.45.
4.2.3. Reaction with 2-hydroxy-1-naphthaldehyde. Reaction time
2 h.
4.2. General procedure for the thermal BF3$Et2O-mediated
coupling of phenyliodonium ylide of lawsone (8) with ar-
yladehydes or cinnamaldehydes
4.2.3.1. Dinaphtho[1,2-b:10,2’-d]furan-12,13-dione (11c). (10 mg,
7%), red crystals, mp 275e276 ꢁC (lit.45 mp 278e281 ꢁC); IR (KBr)
cmꢂ11670, 1217; 1H NMR (CDCl3, 39 ꢁC)
d
9.49 (d, J¼8.4 Hz,1H), 8.11
A suspension of ylide 8 (188 mg, 0.5 mmol), BF3$Et2O (0.06 mL,
0.5 mmol) and the appropriate arylaldehyde or cinnamaldehyde
(0.6 mmol) in CHCl3 (10 mL) was stirred under reflux (1.5e48 h)
until a clear solution results, indicating the consumption of ylide 8.
The resulting intensively colored suspension, after concentration,
was subjected to column chromatography (silica gel, petroleum
ether: ethyl acetate 3: 1, gradually increasing to 1: 1) to afford the
coupling products. Styryl lawsones were always eluted first fol-
lowed by the aryl lawsones. Whenever the reactions resulted in
mixtures of benzonaphthofurandiones and aryl lawsones, the for-
mer were also eluted first from the column. All solid products were
crystallized from CH2Cl2dpetroleum ether mixtures.
(d, J¼7.5 Hz, 1H), 7.96e7.78 (m, 3H), 7.72e7.60 (m, 3H), 7.54 (dd
appearing as t, J¼8.1 Hz, 1H), 7.48 (dd appearing as t, J¼7.5 Hz, 1H);
13C NMR (CDCl3, 39 ꢁC)
d 179.4,173.7,161.1,152.9,134.6,130.9,130.0,
129.3, 128.9, 128.2, 127.9, 127.7, 127.2, 126.8, 126.5, 125.3, 122.5,
119.4, 118.0, 110.8; ESI-LCMS m/z positive 299 (MþH)þ; Calcd for
C
20H10O3: C, 80.53; H, 3.38. Found: C, 80.74; H, 3.40 and 2,3΄-
dihydroxy-1,2΄-binaphthyl-10,4΄-dione (10c), (57 mg, 36%), red crys-
tals, mp 220e222 ꢁC (lit.46 mp 222 ꢁC); IR (KBr) cmꢂ1 3388, 1673,
1638, 1621, 1269; 1H NMR (CDCl3þDMSO-d6)
d 8.08e7.99 (m, 2H),
7.78e7.59 (m, 4H), 7.51e7.43 (m, 1H), 7.24e7.12 (m, 3H); 13C NMR
(CDCl3þDMSO-d6)
d 187.1, 181.6, 166.6, 152.9, 134.9, 133.9, 133.6,
130.9, 130.7, 128.3, 128.0, 127.2, 126.0, 125.8, 125.2, 124.6, 121.8,
119.4, 116.3, 115.7; ESI-LCMS m/z positive 317 (MþH)þ, negative m/z
315 (MꢂH)ꢂ; Calcd for C20H12O4: C, 75.94, H: 3.82. Found: C, 75.84;
H, 3.69.
4.2.1. Reaction with 2-hydroxybenzaldehyde. Reaction time 8 h.
4.2.1.1. Benzo[d]naphtho[1,2-b]furan-5,6-dione (11a). (58 mg,
47%), orange crystals, mp 199e202 ꢁC (lit.30 mp 197e199 ꢁC); IR
4.2.4. Reaction with 2-bromobenzaldehyde
(KBr) cmꢂ11675, 1213; 1H NMR (CDCl3)
d
8.06 (d, J¼7.5 Hz, 1H), 8.02
4.2.4.1. (E)-2-(2-Bromostyryl)-3-hydroxynaphthalene-1,4-dione
(13a). (71 mg, 40%), yellow crystals, mp 192e195 ꢁC; IR (KBr) cmꢂ1
(d, J¼7.1 Hz, 1H), 7.82 (d, J¼7.5 Hz, 1H), 7,67 (dd appearing as t,
J¼7.5 Hz, 1H), 7.56e7.46 (m, 2H), 7.41e7.30 (m, 2H); 13C NMR
3254, 1657, 1646, 1257; 1H NMR (CDCl3)
d
8.31 (d, J¼16.5 Hz, 1H),
(CDCl3)
d 180.1, 174.6, 162.7, 155.3, 135.3, 131.3, 130.5, 129.8, 128.0,
8.20 (d, J¼7.8 Hz, 1H), 8.11 (dd, J1¼7.5 Hz, J2¼1.2 Hz, 1H), 8.06 (brs,
1H), 7.83e7.68 (m, 3H), 7.60 (d, J¼7.8 Hz, 1H), 7.34 (d, J¼16.5 Hz,
overlapping with a triplet, 2H), 7.16 (dt, J1¼7.5 Hz, J2¼1.5 Hz, 1H);
127.0, 125.7, 123.6, 123.4, 122.4, 116.6, 111.8; ESI-LCMS m/z positive
249 (MþH)þ; Calcd for C16H8O3: C, 77.42; H, 3.25. Found: C, 77.64;
H, 3.42 and 2-hydroxy-3-(2-hydroxyphenyl)naphthalene-1,4-dione
(10a), (12 mg, 9%), red crystals, mp 275e278 ꢁC; IR (KBr) cmꢂ1
13C NMR (CDCl3)
d 184.0, 181.2, 152.2, 137.84, 137.80, 135.2, 133.3,
133.2, 132.9, 129.7, 127.7, 127.3, 127.0, 126.2, 124.9, 120.0, 118.4; ESI-
LCMS m/z negative 353/355 (MꢂH)ꢂ; Calcd for C18H11BrO3: C,
60.87; H, 3.12. Found: C, 60.51; H, 3.10.
3449, 1641, 1589, 1533, 1293; 1H NMR (CDCl3þDMSO-d6)
d 8.08 (d,
J¼7.5 Hz, 1H), 8.01 (d, J¼7.5 Hz, 1H), 7.75 (dd appearing as t,
J¼7.5 Hz, 1H), 7.64 (dd appearing as t, J¼7.5 Hz, 1H), 7.38 (dd,
J1¼7.5 Hz, J2¼1.5 Hz, 1H), 7.13 (ddd appearing as dt, J1¼7.5 Hz,
J2¼1.5 Hz,1H), 6.86 (d, J¼7.5 Hz,1H), 6.83 (d, J¼7.5 Hz,1H); 13C NMR
4.2.5. Reaction with 4-bromobenzaldehyde
4.2.5.1. (E)-2-(4-Bromostyryl)-3-hydroxynaphthalene-1,4-dione
(CDCl3þDMSO-d6)
d 188.2, 183.1, 163.7, 155.7, 134.44, 134.37, 132.9,
(13b). (35 mg, 20%), red crystals, mp 181e182 ꢁC; IR (KBr) cmꢂ1
131.2, 130.1, 127.9, 126.3, 125.4, 122.3, 119.4, 118.6, 118.4; ESI-LCMS
m/z positive 267 (MþH)þ, 289 (MþNa)þ, negative m/z 265
(MꢂH)ꢂ; Anal. Calcd for C16H10O4: C, 72.18; H, 3.79. Found: C, 72.02;
H, 4.09.
3358, 1659, 1280; 1H NMR (CDCl3)
d
8.16 (dd, J1¼7.5 Hz, J2¼1.2 Hz,
1H), 8.09 (dd, J1¼7.5 Hz, J2¼1.2 Hz, 1H), 7.88 (d, J¼16.8 Hz, 1H), 7.77
(ddd appearing as dt, J1¼7.5 Hz, J2¼1.5 Hz, 1H), 7.69 (ddd appearing
as dt, J1¼7.5 Hz, J2¼1.5 Hz, 1H), 7.49 (d, J¼8.4 Hz, 2H), 7.44 (d,
J¼8.4 Hz, 2H), 7.36 (d, J¼16.8 Hz, 1H); 13C NMR (CDCl3)
d 184.0,
4.2.2. Reaction with 2-hydroxy-5-bromobenzaldehyde. Reaction
time 4 h.
181.0, 151.9, 137.9, 136.9, 135.1, 133.3, 132.8, 131.9, 129.6, 128.6, 127.2,
126.2, 122.7, 118.5, 118.2; ESI-LCMS m/z negative 353/355 (MꢂH)ꢂ;
Calcd for C18H11BrO3: C, 60.87; H, 3.12. Found: C, 60.83; H, 3.21 and
2-(4-bromophenyl)-3-hydroxynaphthalene-1,4-dione (14b), (73 mg,
44%), red crystals, mp 195e196 ꢁC (lit.47 mp 194e195 ꢁC); IR (KBr)
4.2.2.1. 8-Bromobenzo[d]naphtho[1,2-b]furan-5,6-dione
(11b). (20 mg, 12%), orange crystals, mp 265e266 ꢁC; IR (KBr) cmꢂ1
1675, 1640, 1216; 1H NMR (CDCl3)
d
8.25 (d, J¼1.8 Hz, 1H), 8.15 (dd,
cmꢂ1 3359, 1658, 1627, 1280; 1H NMR (CDCl3)
d
8.17 (dd, J1¼7.5 Hz,
J1¼7.8 Hz, J2¼1.2 Hz, 1H), 7.91 (d, J¼7.5 Hz, 1H), 7.73 (ddd appearing
as dt, J1¼7.5 Hz, J2¼1.2 Hz, 1H), 7.58 (ddd appearing as dt, J1¼7.5 Hz,
J2¼1.2 Hz, 1H), 7.53 (dd, J1¼8.7 Hz, J2¼1.8 Hz, 1H), 7.45 (d, J¼8.7 Hz,
J2¼1.2 Hz, 1H), 8.13 (dd, J1¼7.5 Hz, J2¼1.2 Hz, 1H), 7.86e7.68 (m, 2H),
7.57 (d, J¼8.7 Hz, 2H), 7.39 (d, J¼8.7 Hz, 2H); 13C NMR (CDCl3)
d
183.4, 181.6, 152.3, 135.5, 135.4, 133.2, 132.8, 132.4, 131.1, 129.3,
1H); 13C NMR (CDCl3)
d 179.9, 174.5, 163.6, 154.3, 135.4, 131.8, 130.8,
128.9, 127.3, 126.2, 121.0; ESI-LCMS m/z negative 327/329 (MꢂH)ꢂ;
130.2, 130.1, 127.8, 125.7, 125.3, 123.7, 119.3, 116.1, 113.3; ESI-LCMS
Anal. Calcd for C16H9BrO3: C, 58.38; H, 2.76. Found: C, 58.38; H, 3.06.
m/z positive 349/351 (MþNa)þ, 365/367 (MþK)þ, 381/383

E. Malamidou-Xenikaki et al. / Tetrahedron 71 (2015) 5650e5661
5659
4.2.6. Reaction with 4-chlorobenzaldehyde
4.2.12. Reaction with (E)-3-(2-nitrophenyl)acrylaldehyde
4.2.6.1. Obtained in order of elution: (E)-2-(4-Chlorostyryl)-3-
hydroxynaphthalene-1,4-dione (13c). (8 mg, 5%), red crystals, mp
192e195 ꢁC; IR (KBr) cmꢂ1 3246, 1664, 1645, 1228; 1H NMR (CDCl3)
4.2.12.1. (E)-2-Hydroxy-3-(2-nitrostyryl)naphthalene-1,4-dione
(13d). (61 mg, 38%).
d
8.15 (d, J¼7.5 Hz, 1H), 8.06 (d, J¼7.5 Hz, 1H), 7.90 (d, J¼16.8 Hz, 1H),
4.2.13. Reaction with (E)-3-(4-methoxyphenyl)acrylaldehyde
7.74 (ddd appearing as dt, J1¼7.5 Hz, J2¼1.2 Hz, 1H), 7.66 (ddd
appearing as dt, J1¼7.5 Hz, J2¼1.2 Hz, 1H), 7.49 (d, J¼8.4 Hz, 2H), 7.36
4.2.13.1. (E)-2-Hydroxy-3-(4-methoxystyryl)naphthalene-1,4-
dione (13f). (38 mg, 25%), red crystals, mp 143e146 ꢁC; IR (KBr)
(d, J¼16.8 Hz, 1H), 7.31 (d, J¼8.4 Hz, 2H); 13C NMR (CDCl3)
d 183.9,
cmꢂ1 3280, 1652, 1270, 1238; 1H NMR (CDCl3)
d
8.15 (dd, J1¼7.5 Hz,
181.2, 152.3, 137.8, 136.7, 135.0, 134.5, 133.2, 133.1, 129.9, 129.0, 128.4,
127.2, 126.1, 118.7, 118.3; ESI-LCMS m/z negative 309/311 (MꢂH)ꢂ;
Calcd for C18H11ClO3: C, 69.58; H, 3.57. Found: C, 69.34; H, 3.66 and 2-
(4-chlorophenyl)-3-hydroxynaphthalene-1,4-dione (14c), (44 mg, 31%),
yellow crystals. Mp 187e188 ꢁC (lit.31 mp 187e188 ꢁC).
J2¼1.5 Hz, 1H), 8.07 (dd, J1¼7.5 Hz, J2¼1.5 Hz, 1H), 7.93 (d, J¼16.5 Hz,
1H), 7.74 (ddd appearing as dt, J1¼7.5 Hz, J2¼1.5 Hz, 1H), 7.67 (ddd
appearing as dt, J1¼7.5 Hz, J2¼1.5 Hz,1H), 7.54 (d, J¼8.7 Hz, 2H), 7.25
(d, J¼16.5 Hz, 1H), 6.90 (d, J¼8.7 Hz, 2H), 3.83 (s, 3H); 13C NMR
(CDCl3)
d 184.3, 181.0, 160.4, 151.3, 139.2, 135.3, 134.8, 133.1, 130.9,
129.8, 128.7, 127.1, 126.0, 125.1, 115.4, 114.3, 55.4; ESI-LCMS m/z
negative 305 (MꢂH)ꢂ; Calcd for C19H14O4: C, 74.50; H, 4.61. Found:
C, 74.29; H, 4.90 and 2-hydroxy-3-(4-methoxyphenyl)naphthalene-
1,4-dione (14f), (32 mg, 23%), red crystals, mp 171e173 ꢁC (lit.31 mp
170e172 ꢁC);
4.2.7. Reaction with 2-nitrobenzaldehyde
4.2.7.1. (E)-2-Hydroxy-3-(2-nitrostyryl)naphthalene-1,4-dione
(13d). (16 mg, 10%), red crystals, mp 234e236 ꢁC; IR (KBr) cmꢂ1
3281, 1654, 1262;1H NMR (CDCl3þDMSO-d6)
d
8.43 (d, J¼16.2 Hz,
1H), 8.10 (d, J¼6.9 Hz, 1H), 8.00 (t, J¼6.9 Hz, 1H), 7.84 (d, J¼8.1 Hz,
1H), 7.79 (dd, J1¼8.1 Hz, J2¼1.2 Hz, 1H), 7.73 (ddd appearing as dt,
J1¼7.5 Hz, J2¼1.2 Hz, 1H), 7.64e7.53 (m, 3H), 7.33 (ddd appearing as
4.2.14. Reaction with (E)-3-(2,5-dimethoxyphenyl)acrylaldehyde
4.2.14.1. 2-(2,5-Dimethoxyphenyl)-3-hydroxynaphthalene-1,4-
dione (14g). (53 mg, 34%), orange crystals, mp 172e175 ꢁC (lit.31 mp
173e176 ꢁC);
dt, J1¼8.1 Hz, J2¼1.2 Hz, 1H); 13C NMR (CDCl3 þ DMSO-d6)
d 182.4,
147.4,134.2,134.1,133.7,132.1,131.3,130.3,126.9,126.3,126.0,125.8,
125.3, 123.8 (broad), 123.5, 115.8; ESI-LCMS m/z positive 344
(MþNa)þ, negative 320 (MꢂH)ꢂ; Calcd for C18H11NO5: C, 67.29; H,
3.45; N, 4.36. Found: C, 67.07; H, 3.64; N, 4.08.
4.2.15. Reaction with (E)-2-methyl-3-phenylacrylaldehyde
4.2.15.1. 3-Methyl-2-phenylnaphtho[1,2-b]furan-4,5-dione
(17b). (29 mg, 20%), purple crystals, mp 208e215 ꢁC; IR (KBr) cmꢂ1
4.2.8. Reaction with cinnamaldehyde
1664, 1631, 1218; 1H NMR (CDCl3, 300 MHz)
d
8.04 (d, J¼7.7 Hz, 1H),
7.75e7.63 (m, 4H), 7.52e7.38 (m, 4H), 2.53 (s, 3H); 13C NMR (CDCl3,
75 MHz) 180.7, 175.7, 158.8, 151.8, 135.4, 130.4, 129.9, 129.7, 129.0,
4.2.8.1. (E)-2-Hydroxy-3-styrylnaphthalene-1,4-dione
(16a). (124 mg, 90%), red crystals, mp 164e166 ꢁC (lit.28 mp
d
166.5e167.5 ꢁC); 1H NMR (CDCl3)
d
8.10 (dd, J1¼7.5 Hz, J2¼1.2 Hz,
128.9, 128.6, 128.5, 126.2, 123.0, 122.2, 117.1, 10.1; ESI-LCMS m/z
positive 311 (MþNa)þ, 327 (MþK)þ, 343 (MþNaþMeOH)þ; Calcd
for C19H12O3: C, 79.16; H, 4.20. Found: C, 79.05; H, 4.45.
1H), 8.01 (dd, J1¼7.5 Hz, J2¼1.2 Hz, 1H), 7.91 (d, J¼16.5 Hz, 1H), 7.69
(dd, J1¼7.5 Hz, J2¼1.2 Hz,1H), 7.62 (dd, J1¼7.5 Hz, J2¼1.2 Hz,1H), 7.53
(d, J¼6.9 Hz, 2H), 7.44e7.22 (m, 4H); 13C NMR (CDCl3)
d 184.0, 180.9,
151.8, 139.2, 137.8, 134.8, 133.1, 132.7, 129.6, 128.7, 128.6, 127.2, 127.1,
126.0, 118.8, 117.4;
4.3. General procedure for the BF3$Et2O-mediated reaction of
phenyliodonium ylide of lawsone (8) with aryladehydes under
microwave irradiation
4. 2. 9. Reaction with the mixture (9. 3: 0. 7) of (Z)-3-
phenylacrylaldehyde and (E)-3-phenylacrylaldehyde
A suspension of ylide 8 (188 mg, 0.5 mmol), BF3$Et2O (0.06 mL,
0.5 mmol) and the proper arylaldehyde (0.6 mmol) in CHCl3
(10 mL) was added in the reaction vial. The vial was caped and the
mixture was irradiated in the MW oven (110 ꢁC, 80 min) until
a clear solution results. The yellow colored solution was concen-
trated and subjected to column chromatography on silica gel. The
column was eluted with petroleum ether containing increasing
amounts (25%e50%) of ethyl acetate to afford 2-arylidene-indane-
diones 15.
4.2.9.1. (Z)-2-Hydroxy-3-styrylnaphthalene-1,4-dione (16b) as
inseparable mixture with 16a (w1: 0.35 estimated by 1H NMR). Total
yield 38%; IR (KBr) cmꢂ1 3332, 1645, 1592, 1277; 1H NMR (CDCl3,
45 ꢁC)
d
8.13 (d, J¼7.4 Hz), 8.05 (d, J¼7.2 Hz), 7,95 (d, J¼16.8 Hz),
7.82e7.52 (m), 7.46e7.17 (m), 7.04e6.72 (m), 6.68e6.53 (m, 2H);
13C NMR (CDCl3)
184.1, 180.8, 151.4, 140.4, 136.0, 134.9, 133.2,
d
130.9, 128.8, 128.2, 127.25, 127.18, 126.9, 126.0, 121.7, 119.2; ESI-
LCMS m/z negative 275 (MꢂH)ꢂ; Calcd for C18H12O3: C, 78.25; H,
4.38. Found: C, 78.01; H, 4.61.
4.3.1. Reaction with 2-chlorobenzaldehyde
4.2.10. Reaction with (E)-3-p-tolylacrylaldehyde
4.3.1.1. 2-(2-Chlorobenzylidene)-1H-indene-1,3(2H)-dione
(15a). (87 mg, 65%), yellow crystals, mp 129e132 ꢁC (lit.48 mp
132e133 ꢁC); IR (KBr) cmꢂ1 1734, 1692, 1627; 1H NMR (CDCl3,
4.2.10.1. (E)-2-Hydroxy-3-(4-methylstyryl)naphthalene-1,4-dione
(13e). (100 mg, 69%), red crystals, mp 124e127 ꢁC; IR (KBr) cmꢂ1
3334, 1644, 1276; 1H NMR (CDCl3, 300 MHz)
d
8.11 (d, J¼7.5 Hz, 1H),
300 MHz)
8.08e7.93 (m,2H), 7.87e7.30 (m, 2H), 7.53e7.34 (m, 3H); 13C NMR
(CDCl3, 75 MHz) 189.5,188.6,142.6,142.1,140.4,137.5,135.6,135.5,
d
8.65 (dd, J1¼7.5 Hz, J2¼1.5 Hz, 1H), 8.35 (s, 1H),
8.02 (d, J¼7.5 Hz, 1H), 7.90 (d, J¼16.7 Hz, 1H), 7.69 (dd appearing as
t, J¼7.5 Hz, 1H), 7.61 (dd appearing as t, J¼7.5 Hz, 1H), 7.44 (d,
J¼7.8 Hz, 2H), 7.29 (d, J¼16.7 Hz, 1H), 7.13 (d, J¼7.8 Hz, 2H), 2.33 (s,
d
133.7, 133.4, 130.9, 130.7, 129.9, 126.6, 123.6, 123.5; ESI positive 323/
325 (MþMeOHþNa)þ; Calcd for C16H9ClO2: C, 71.52; H, 3.38.
Found: C, 71.14; H, 3.64.
3H); 13C NMR (CDCl3, 75 MHz)
d 184.1, 180.9, 151.6, 139.4, 138.7,
135.2, 134.7, 133.0, 132.8, 129.7, 129.4, 127.2, 127.1, 125.9,119.0, 116.5.
14.1; ESI-LCMS m/z negative 289 (MꢂH)ꢂ; Calcd for C19H14O3: C,
78.61; H, 4.86. Found: C, 78.35; H, 5.08.
4.3.2. Reaction with 2-bromobenzaldehyde
4.3.2.1. 2-(2-Bromobenzylidene)-1H-indene-1,3(2H)-dione
(15b). (133 mg, 85%), yellow crystals, mp 133e134 ꢁC (lit.49 mp
125.5e126.0 ꢁC); IR (KBr) cmꢂ1 1723, 1685, 1606; 1H NMR (CDCl3)
4.2.11. Reaction with (E)-3-(4-chlorophenyl)acrylaldehyde
4.2.11.1. (E)-2-(4-Chlorostyryl)-3-hydroxynaphthalene-1,4-dione
(13c). (101 mg, 65%).
d
8.54 (dd, J1¼7.8 Hz, J2¼1.5 Hz, 1H), 8.24 (s, 1H), 8.07e7.95 (m, 2H),

5660
E. Malamidou-Xenikaki et al. / Tetrahedron 71 (2015) 5650e5661
7.88e7.78 (m, 2H), 7.67 (dd, J1¼7.8 Hz, J2¼1.2 Hz, 1H), 7.43 (dd
appearing as t, J¼7.2 Hz, 1H), 7.33 (ddd appearing as dt, J1¼7.8 Hz,
Dr. Hadjipavlou-Litina acknowledges Dr. Leo and Biobyte for free
access to C-QSAR program.
J2¼1.8 Hz, 1H); 13C NMR (CDCl3)
d 189.3, 188.3, 144.4, 142.4, 140.3,
135.54, 135.48, 133.6, 133.3, 133.1, 132.4, 130.5, 127.6, 127.1, 123.47,
Supplementary data
123.45; ESI-LCMS m/z negative 343/345 (M-HþMeOH)ꢂ; Calcd for
C
16H9BrO2: C, 61.37; H, 2.90. Found: C, 61.27; H, 2.84.
Supplementary data (1H and 13C NMR spectra for all new com-
pounds and the results of biological tests) associated with this ar-
ticle can be found in the online version, at http://dx.doi.org/
10.1016/j.tet.2015.06.037.
4.3.3. Reaction with 2-nitrobenzaldehyde
4.3.3.1. 2-(2-Nitrobenzylidene)-1H-indene-1,3(2H)-dione
(15c). (80 mg, 57%), yellow crystals, mp 183e185 ꢁC (lit.50 mp
185e187 ꢁC); IR (KBr) cmꢂ1 1732, 1692, 1637, 1519, 1341; 1H NMR
References and notes
(CDCl3)
d
8.27 (s, one H), 8.25 (dd, J1¼8.1 Hz, J2¼1.2 Hz,1H), 8.07 (dd,
J1¼5.9 Hz, J2¼1.8 Hz, 1H), 7.96 (dd, J1¼6.0 Hz, J2¼2.1 Hz, 1H),
7.90e7.80 (m, 3H), 7.73 (ddd appearing as dt, J1¼7.5 Hz, J2¼1.2 Hz,
1H), 7.65 (ddd appearing as dt, J1¼8.1 Hz, J2¼1.5 Hz, 1H); 13C NMR
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