Arylation of lawsone through BF3-mediated coupling of its phenyliodonium ylide with activated arenes and aromatic aldehydes

Article abstract of DOI:10.1016/j.tet.2010.04.120

Phenyliodonium ylide of lawsone, activated by BF₃·Et ₂O, reacts with electron-rich arenes to afford the corresponding 2-aryl-3-hydroxy-1,4-naphthoquinones, in a coupling reaction without metal catalysts. The same type of products, in greater variety and higher yields, are obtained from the reaction of the BF₃·Et₂O- activated ylide with aromatic aldehydes in a synthetically and mechanistically interesting deformylation reaction.

Full text of DOI:10.1016/j.tet.2010.04.120

Tetrahedron 66 (2010) 5786e5792
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Arylation of lawsone through BF3-mediated coupling of its phenyliodonium ylide
with activated arenes and aromatic aldehydes
*
*
Elias Glinis, Elizabeth Malamidou-Xenikaki , Haris Skouros, Spyros Spyroudis , Maria Tsanakopoulou
Laboratory of Organic Chemistry, Chemistry Department, Aristotle University of Thessaloniki, Thessaloniki 54124, 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 by BF3$Et2O, reacts with electron-rich arenes to afford the
corresponding 2-aryl-3-hydroxy-1,4-naphthoquinones, in a coupling reaction without metal catalysts.
The same type of products, in greater variety and higher yields, are obtained from the reaction of the
BF3$Et2O-activated ylide with aromatic aldehydes in a synthetically and mechanistically interesting
deformylation reaction.
Received 24 March 2010
Received in revised form 28 April 2010
Accepted 28 April 2010
Available online 23 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Lawsone
Phenyliodonium ylide
Arylation
Hydroxyquinones
Coupling
1. Introduction
H
N
H
C
O
C
CH3
O
O
H3C
O
Aryliodonium ylides of hydroxyquinones offer an interesting
example of compounds in which the chemistry of organic hyper-
valent iodine adds synthetic potentiality to an already important
class: hydroxyquinones.
The term hydroxyquinones refers to quinones bearing at least
one hydroxyl at the quinone moiety. A great number of them are
found in nature,1 in simple or more complicate structures, and their
majority exhibits some kind of biological activity. Their chemistry
has been reviewed some years ago.2
CH2
O
HO
H3C
H3C
H
O
COOH
O
HO
OH
NH
4, Nakijiquinone
O
6, Topaquinone
5, Tridentoquinone
its 3,3-dimethyl allyl derivative, lapachol (2), obtained from the
homonymous tree, exhibits an impressive list of biological activi-
ties: anti-abscess, anti-ulcer, antileishmanial, anticarcinomic,
antiedemic, anti-inflammatory, antimalarial, antiseptic, antitumor,
antiviral, bactericidal, fungicidal, insectifugal, pesticidal, protistici-
dal, respiradepressant, schistosomicidal, termiticidal, and viricidal.4
Bis-indolyl-dihydroxybenzoquinones, asterriquinones (3), exhibit
a range of biological activities against cancer and diabetes,5 while
nakijiquinone (4) displays pronounced cytotoxicity against certain
leukemia and carcinoma cells and acts as inhibitor of receptor
tyrosine kinases, responsible for some types of cancer.6 Tridento-
quinone (5), the main pigment of an edible mushroom, exhibits an
interesting structure and its biosynthesis was extensively studied,7
and finally topaquinone (6), is the active site organic cofactor in
copper-containing amine oxidases, which catalyze the enzymatic
deamination of amines to aldehydes.8
A few representative examples of naturally occurring hydroxy-
quinones in varying degrees of structure complexity are cited
below.
O
O
O
Ind
OH
Ind
OH
OH
HO
O
O
O
3. Asterriquinones
1, Lawsone
2, Lapachol
2-Hydroxy-1,4-naphthoquinone, lawsone (1), the main com-
ponent of a natural hair dye, was also proved a potent detector of
latent finger marks on cloth or paper under infrared light,3 whereas
These few examples out of a great number of naturally occurring
hydroxyquinones emphasize the importance of this class of
* Corresponding authors. E-mail address: sspyr@chem.auth.gr (S. Spyroudis).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.120

E. Glinis et al. / Tetrahedron 66 (2010) 5786e5792
5787
compounds. Their diverse chemistry is enriched with the
O
O
O
R1
R2
OH
Nu
involvement of hypervalent iodine chemistry: unsubstituted at the
position next to hydroxy group hydroxyquinones form readily
the corresponding zwitterionic iodonium compounds 8 (Scheme 1)
upon reaction with diacetoxyiodobenzene (and other diacetoxy-
iodoarenes as well).9
R1
R2
O
NuH
-PhI
IPh
O
8
10
Scheme 3. Nucleophilic displacement of the phenyliodonio group.
O
O
R1
R2
OH
R1
R2
O
PhI(OAc)2
Hydroxyquinones bearing an aryl (or heteroaryl) substituent at
the position adjacent to hydroxyl (10, Nu¼Ar) usually exhibit
varying degrees of biological activity.1,2,5 Hence, direct arylation of
the hydroxyquinone ring is desirable. This arylation is effected by
the reaction of the proper hydroxyquinone with aryldiazonium
salts in alkaline solution, according to an older method,15 but yields
are generally low. In some cases nitroaryl groups can be coupled to
hydroxyquinones using their fluoroenitro derivatives in DMSO/
K2CO3.16
CHCl3 or CH2Cl2
I
Ph
7a-g
or MeOH, 0 o
C
O
O
8a-g
1_
55-96%
a:
R
R2 = -CH=CH_CH=CH-
b: R1 = R2 = H
c: R1 = H, R2 = Me
d:
R
R
R
1 = R2 = Me
1 = H, R2 = Br
1 = H, R2 = Ph
1_ R2
=
e:
f:
g:
R
The use of phenyliodonium ylides of hydroxyquinones facilitates
the preparation of aryl-hydroxyquinones. Phenyliodonium ylide of
2-hydroxy-1,4-naphthoquinone 8a reacts with indole derivatives to
afford the corresponding indolyl-hydroxyquinones in the presence
of catalytic amounts of Cu(II).13
A more general methodology for the arylation of lawsone and its
derivatives through their phenyliodonium ylides was suggested by
Stagliano:17 Stille-type coupling of ylide 8a with arylstannanes 11
leads to 12 (Scheme 4).
Scheme 1. Preparation of phenyliodonium ylides of hydroxyquinones.
These compounds are most conveniently isolated by filtration
and can be stored for long periods without decomposition.
Although their nature is rather zwitterionic, as indicated by the
127
X-ray structure determination of 8a10 and an
I Mossbauer
€
spectral study,11 they are named as phenyliodonium ylides of the
parent hydroxyquinone for simplicity reasons.
Regarding their reactivity two different patterns can be
distinguished:
O
O
OH
O
Me3Sn
R1
Pd(PPh3)4
A. Upon refluxing suspensions of 8 in dichloromethane or ace-
tonitrile the corresponding unstable a,a
0-dioxoketenes 9 are pro-
CuI, DMF
rt
R2
IPh
duced through an iodobenzene elimination/Wolff rearrangement
sequence (Scheme 2).
8a
11
O
O
R1
R2
12
R1, R2 = H, OMe
O
O
R1
R2
Scheme 4. Stille-type coupling of ylide 8a to aryl-hydroxyquinones.
R1
R2
O
heat
-PhI
C
O
Finally, we suggested recently the Suzuki-type coupling of 8a
with the more available and less toxic arylboronates.18 The reaction
takes place with a variety of aryl- and heteroarylboronates in DME/
H2O, giving fair to good yields of aryl lawsone derivatives 13
(Scheme 5).
IPh
O
O
8
9
Scheme 2. Thermal decomposition of ylides to ketenes.
The reaction takes place also with phenyliodonium ylides of
other hydroxyquinones, such as that of hydroxy-triptycenoquinone
Initially it was thought that this ring contraction proceeds
through the formation of carbenes but according to a recent DFT
study12 this transformation follows a single-step, transition-state
concerted pathway with no intermediacy of carbenes. Moreover,
ketene formation is kinetically and thermodynamically more
favorable than aryl migration, observed in other cyclic aryliodo-
nium analogs.
The non isolable ketenes 9 can be trapped with a variety of
nucleophiles,9 some of them leading to interesting enolic struc-
tures. In the absence of such agents, indanedione ketene, derived
from the thermal decomposition of phenyliodonium ylide of law-
sone 8a, dimerizes to a labile spiro oxetanone derivative.13 The
latter reacts again with nucleophiles to afford in one or two steps
a variety of indeno derivatives, some of which exhibit biological
activity.14
O
O
O
OH
O
Pd(OAc)2, PR3
LiOH
+
ArB(OH)2
Ar
IPh
DME/H2O, 4:1
13
rt
8a
O
71-92%
R = Ph, t-Bu
N
Ph,
p-tolyl,
Ar =
Ph
N
O
S
Boc
SO Ph
2
O
B. The second reaction pathway is based on the activation of
the position next to hydroxyl in parent hydroxyquinone by the
aryliodonio group. Indeed, this easy-leaving group can be
substituted by a variety of functional groups, mainly nucleophiles9
(Scheme 3).
Pd(OAc)2, P(t-Bu)3
LiOH
O
O
DME/H2O, 4:1
rt
8g
OH
O
IPh
+
In this case the hydroxyquinone frame is retained and the
reaction can afford naturally occurring hydroxyquinones or their
analogs.
14
ArB(OH)2
O
Ar
13-34%
Scheme 5. Suzuki-type coupling of ylides 8a and 8g to aryl-hydroxyquinones.

5788
E. Glinis et al. / Tetrahedron 66 (2010) 5786e5792
8g, but the yields of the arylated products 14 are considerably
O
lower.
OH
OMe
Searching for
a simpler method of transforming phenyl-
iodonium ylides of hydroxyquinones to aryl-hydroxyquinones, we
encountered Koser’s paper describing the substitution reactions of
electron rich aromatic compounds with BF3-activated iodonium
8%
16c
O
OMe
ylides of acyclic b
-dicarbonyl compounds.19 We tried an analogous
OMe
.
methodology for ylide 8a and report our findings here.
BF3 Et2O
CH2Cl2
rt
O
O
2. Results and discussion
OMe
PhOMe
BF3 Et2O
OH
.
Upon reaction of ylide 8a with equimolecular amounts of
anthracene and 9-methylanthracene and 2 equiv of BF3$Et2O in
CH2Cl2 at rt, the corresponding coupling products, hydroxyquinone
derivatives 15a and 15b, were isolated in 56 and 65% yield,
respectively (Scheme 6).
8a
CH2Cl2, rt, 0%
OMe
CHCl3, reflux, 3%
.
OMe
BF3 Et2O
CH2Cl2, rt, 7%
CHCl3, reflux, 10%
16e
Me
O
OH
O
O
OMe
OH
OMe
65%
16a
O
MeO
OMe
OMe
.
BF3 Et2O
CH2Cl2
R
16d
Me
O
O
rt
MeO
OMe
Scheme 7. BF3$Et2O-mediated coupling of ylide 8a with less electron-rich arenes.
OH
8a
.
BF3 Et2O
furan, N-methylpyrrole, thiophene, 2-methylthiophene, and
N-methylindole. In most cases, BF3$Et2O reacted with the
heterocycle.
OMe
CH2Cl2, rt
.
R
BF3 Et2O
Regarding the reaction pathway of the coupling, it must be
similar to the one proposed by Koser19 for analogous couplings and
based on the mechanism of PIFA oxidations of p-cresol ethers,
extensively studied by Kita.20 This mechanism is based on the
assumption that the BF3-complexed iodonium enolates (in our
case 18, Scheme 8) are stronger oxidants than the free ylides (in
our case 8a).
CH2Cl2
OMe
rt
15 a R = H, 56%
b R = CH3, 65%
O
O
OH
O
OMe
+
OMe
O
16b
O
17
O
O
28%
OMe
20%
O
I
BF3
O
I
BF3
-BF3
SET
Scheme 6. BF3$Et2O-mediated coupling of ylide 8a with electron-rich arenes.
ArH
+
+
ArH
Ph
Ph
O
18
O
O
An analogous reaction with 1,3,5-trimethoxybenzene afforded
65% yield of hydroxyquinone 16a, accompanied by varying small
amounts of hexamethoxybiphenyl, whereas 1,4-dimethoxy-
benzene gave besides the expected coupling product 16b (28%), the
benzofurano-o-naphthoquinone derivative 17 in 20% yield. By
conducting the same reaction in refluxing dichloromethane for
12 h, the respective yields were 46 and 9%.
O
O
O
O
OH
Ar
O
SET
-PhI
Ar
H
Ar
H
I
Ph
I
Ph
O
O
13
19
Scheme 8. Proposed reaction pathway.
The above results indicate that the yield of the reaction is not
affected much by the temperature and depends on the reactivity of
the arene. Indeed, the reaction of 8a with 1,3-dimethoxybenzene
afforded only 8% of the coupling product 16c, and cresol methyl
ether gave 7% of the corresponding quinone 16d (Scheme 7). The
yield of the latter was raised to 10% only after conducting the
reaction in refluxing CHCl3 for 30 h. Similarly, anisole did not react at
all with 8a in CH2Cl2 at rt, and coupling was possible in only 3% yield,
only in refluxing CHCl3 and after a prolonged reaction time (36 h).
Other arenes such as toluene, p-xylene, mesitylene, and durene
did not afford coupling products with 8a, at least at rt in
dichloromethane, and that was the case with N,N-dimethyl-p-
toluidine.
The so-formed complex 18 reacts with an electron-rich arene
and through two single-electron-transfer (SET) steps affords the
final coupling products 13.
The same reaction pathway can explain the formation of the
benzofurano-o-naphthoquinone derivative 17 from the reaction of
1,4-dimethoxybenzene with ylide 8a: the intermediate 20, analo-
gous to 19, formed by exactly the same sequence of reaction steps,
in a parallel pathway can lead to 21, which transforms to the final
product 18 with loss of methanol (Scheme 9).
The assumption that 17 is formed during the main reaction
pathway is verified by the fact that it was not possible to transform
the coupling product 16b to the fused 17, in an independent re-
action in the presence of BF3$Et2O in refluxing CH2Cl2 (Scheme 10).
No coupling products were observed from the reaction, under
the same conditions, of 8a with activated heterocyclic rings such as

E. Glinis et al. / Tetrahedron 66 (2010) 5786e5792
5789
OCH3
OCH3
O
O
O
-BF3
SET
SET
O
Ph
-PhI
OCH3
8a
I
H
H3CO
20
O
-CH3OH
OCH3
H
17
O
21
H3CO
Scheme 9. Proposed reaction pathway for the formation of benzofurano-o-naph-
thoquinone 17.
.
BF3 Et2O
17
16b
CH2Cl2, reflux
Scheme 10. The coupling product 16b cannot be transformed to the fused 17, in an
independent reaction.
Regarding the level of activation of the arene, the above
results show that at least two methoxy groups are necessary in
order to obtain satisfactory yields of the coupling products. The
presence of only one methoxy group in the aromatic ring, the
case of anisole, is not enough for an effective electrophilic attack
from the iodine of the ylide. Since two methoxy groups are suf-
ficient for the coupling and one not, we tried the reaction of 8a
with 3,4-dimethoxybenzaldehyde (22), aiming to the partial
deactivation of the aromatic ring by the electron-withdrawing
formyl group. To our surprise, the coupling took place at the ipso
carbon of the aldehyde with obvious loss of the formyl group,
signaling a different kind of reactivity (Scheme 11). After some
experimentation with conditions, the coupling product 16f was
isolated in 92% yield, using equimolecular quantities of ylide and
BF3$Et2O and a small excess (1:1.2) of aldehyde, in refluxing
CHCl3 for 1.5 h.
Scheme 12. Coupling reaction of ylide 8a with aromatic aldehydes.
Although no coupling was observed from the reaction with
heteroarenes, as it was mentioned earlier, some interesting results
were obtained from the reaction with heteroaromatic aldehydes:
thiophene-2- and 3-carbaldehydes afforded the corresponding
coupling products 23a and 23b in 43 and 62% yield, respectively. It
must be noted that, although compound 23b was isolated from the
Suzuki-type reaction of 8a with thiophen-3-ylboronic acid, the 23a
isomer was never detected from the corresponding reaction with
thiophen-2-ylboronic acid.18
Indole carbaldehydes afforded very low yields (5%) of the
indolyl-hydroxynaphthoquinones 24a and 24b, perhaps suggesting
that part of BF3$Et2O binds to nitrogen, blocking the course of the
reaction. This assumption may also explain the fact that no cou-
pling took place between 8a and pyrrole-2-carbaldehyde. The same
was true for the reaction with furfural, where an extensive poly-
merization was observed.
O
OHC
BF3.Et2O
OH
8a
OMe
OMe
O
Regarding the mechanism of the reaction it is obviously differ-
ent from the corresponding of the reaction with arenes, suggested
in Scheme 8. Here a coupling/deformylation sequence takes place.
A plausible reaction mechanism explaining this sequence is pre-
sented in Scheme 13.
OMe
22
16f
OMe
Yield of 16f
Reaction Conditions
CH2Cl2, rt, 24 h
CH2Cl2, reflux, 7 h
CHCl3, reflux, 1.5 h
40%
57%
92%
O
O
OBF3
Scheme 11. Reaction conditions for the effective coupling of ylide 8a with 3,4-dime-
thoxybenzaldehyde (22).
OBF3
O
CH
OHC
+
X
I
I
X
18
Similar conditions were applied for the reaction of 8a with other
aromatic aldehydes and the results are presented in Scheme 12. All
the reactions were performed in dispersions of refluxing CHCl3, till
the occurrence of a clear solution. The time for the completion of
each reaction and the yield of the coupling product appear on
Scheme 12.
25
O
Ph
O
Ph
SET
O
O
OBF3
CH
OBF3
CH
O
O
I
I
X
27
O
From the above results it is obvious that the coupling reaction of
8a with aromatic aldehydes gives better yields than the corre-
sponding with arenes. The results of the reaction with substituted
benzaldehydes suggest that the richer in electrons the aromatic
ring the higher the yield of the coupling products 16b,e,fei (and the
shorter the reaction time). The reaction with anthracene-9-car-
baldehyde affords the coupling product 15a in 65% yield (compared
to 56% yield of the same product resulting from the reaction with
anthracene, Scheme 6).
X
O
Ph
26
Ph
-PhI
O
O
O
O
O
OBF3
OH
O
OCH
H2
O
CH
-BF3
-HCO2H
X
X
O
O
X
28
29
30 (13)
Scheme 13. Reaction mechanism of the BF3$Et2O-mediated coupling of phenyl-
iodonium ylide of lawsone with aromatic aldehydes.

5790
E. Glinis et al. / Tetrahedron 66 (2010) 5786e5792
The initially formed ylide-BF3 complex 18 reacts with aldehyde to
the corresponding complex 25, which through an intramolecular-
type SET gives biradical 26. The latter transforms to the coupled
biradical 27, which with loss of PhI and subsequent loss of BF3 af-
fords the ester 29 (1,4-dioxo-3-aryl-1,4-dihydronaphthalenyl-2-
formate). Finally, formate 29 is hydrolyzed, probably during work-
up on the chromatography column, to the desired arylated lawsone
derivatives 30 (or 13 in more general presentation, Scheme 5). This
reaction pathway seems plausible, although in the absence of solid
evidence, an ionic mechanism, involving electrophilic addition of
the aryliodonium group to the arene followed by ligand coupling,
cannot be completely excluded.
This is an unusual hypervalent iodine and BF3-mediated defor-
mylation reaction that treats aldehydes as potential arylating
agents. Decarbonylation of aldehydes is well known in organome-
tallic chemistry and they are used as CO sources in Pauson/Khand-
type reactions catalyzed by transition metals.21
(CDCl3, 75 MHz) d 183.8, 181.5, 154.7, 135.5 135.2 133.4, 131.4, 129.9,
129.8, 129.0, 128.4, 127.6, 126.6, 126.2, 125.4, 125.2; ESI-HRMS m/z
calcd for C24H14O3þH (MHþ) 351.10157, found 351.10146.
4.2.2. Reaction with 9-methylanthracene.
4.2.2.1. 2-Hydroxy-3-(10-methylanthracen-9-yl)naphthalene-1,4-
dione (15b). Compound 15b as red crystals in 65% yield: mp >280 ꢁC;
IR (KBr) cmꢀ13329,1664,1647,1590; 1H NMR (CDCl3, 300 MHz)
d 8.38
(d, J¼8.8 Hz, 2H), 8.30 (d, J¼7.3 Hz, 1H), 8.22 (d, J¼7.3 Hz, 1H),
7.91e7.77 (m, 4H), 7.57e7.39 (m, 5H), 3.18 (s, 3H); 13C NMR
(CDCl3þDMSO-d6, 75 MHz)
d 183.6, 180.7, 156.2, 134.0 132.4 132.0,
129.9, 129.1, 128.8 128.4, 126.0, 125.8, 125.6 124.6, 124.3, 13.5; ESI-
HRMS m/zcalcdforC25H16O3þNa (MNaþ) 387.09917, found 387.09916.
4.2.3. Reaction with 1,3,5-trimethoxybenzene.
4.2.3.1. 2-Hydroxy-3-(2,4,6-trimethoxyphenyl)naphthalene-1,4-di-
one (16a). Compound 16a as yellow crystals in 65% yield: mp
257e260 ꢁC; IR (KBr) cmꢀ1 3315, 1677, 1640, 1610; 1H NMR (CDCl3,
3. Conclusions
300 MHz)
d
8.09 (2d, appearing as t, J¼8.5 Hz, 2H), 7.76 (t, J¼6.7 Hz,
1H), 7.69 (t, J¼6.7 Hz, 1H), 7.32 (br s, 1H), 6.23 (s, 2H), 3.86 (s, 3H),
As a conclusion we have described an easy, without the
involvement of metal catalysts, coupling reaction between phenyl-
iodonium ylide of lawsone (acting as a model compound) and both
electron-rich arenes and aromatic aldehydes. Especially the latter
reaction, being site selective and affording satisfactory to highyields
of coupling products with a variety of aromatic aldehydes, might be
the method of choice, for the preparation of aryl-hydroxyquinones.
Since some biologically interesting compounds belong to this class
of quinones, moretargeted molecules can be accessed byapplication
of this methodology, a task, that is, now in progress.
3.74 (s, 6H); 13C NMR (CDCl3þDMSO-d6, 75 MHz)
d 182.6, 180.9,
161.0, 157.9, 154.6 133.4, 132.2, 131.8, 129.5, 125.6, 125.1, 117.4, 101.1,
90.1, 55.0, 54.5; ESI-HRMS m/z calcd for C19H16O6þH (MHþ)
341.10196, found 341.10194.
4.2.4. Reaction with 1,4-dimethoxybenzene.
4.2.4.1. 2-(2,5-Dimethoxyphenyl)-3-hydroxynaphthalene-1,4-dione
(16b). Compound 16b as orange crystals in 28% yield: mp
173e176 ꢁC; IR (KBr) cmꢀ1 3281, 1674, 1649, 1593; 1H NMR (CDCl3,
300 MHz)
J¼7.3 Hz, 1H), 7.68 (t, J¼7.3 Hz, 1H), 6.92 (s, 2H), 6,82 (s, 1H), 3.76 (s,
3H), 3.62 (s, 3H); 13C NMR (CDCl3, 75 MHz)
183.1, 181.5, 153.2,
d
8.15 (d, J¼7.3 Hz, 1H), 8.10 (d, J¼7.3 Hz, 1H), 7.75 (t,
4. Experimental
4.1. General
d
153.0, 151.4, 135.0, 132.9, 129.4, 127.0, 126.1, 120.6, 120.2, 116.8, 115.1,
112.5, 56.4, 55.6; ESI-HRMS m/z calcd for C18H14O5þH (MHþ)
311.09140, found 311.09128 and 8-methoxybenzo[d]naphtho-[1,2-b]
furan-5,6-dione (17) as red crystals in 20% yield: mp 209e211 ꢁC; IR
Melting points were measured on a Kofler hot-stage and are un-
corrected. NMR spectra were recorded at room temperature (rt) on
a Bruker AM 300 spectrometer at 300 MHz for 1H and 75 MHz for 13C,
(KBr) cmꢀ11702,1662, 1633,1592; 1H NMR (CDCl3, 300 MHz)
d 8.07
(d, J¼7.3 Hz, 1H), 7.91 (t, J¼7.3 Hz, 1H), 7.80 (t, J¼7.3 Hz, 1H), 7.68 (t,
using CDCl3 as solvent. Chemical shifts are expressed in
d values
J¼7.3 Hz, 1H), 7.50 (t, J¼7.3 Hz, 1H), 7.05 (s, 1H), 6,96 (d, J¼7.3 Hz,
(ppm) relative to TMS as internal standard for 1H and relative to TMS
(0.00 ppm) or to CDCl3 (77.05 ppm) for 13C NMR spectra. Coupling
constants nJ are reported in Hertz. IR spectra were recorded on
a PerkineElmer 1600 series FTIR spectrometer and are reported in
wave numbers (cmꢀ1). The high resolution mass spectra were
obtained at the facilities of the chemistry department of the Univer-
sity of Leipzig. 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 8a was prepared from
lawsone and PhI(OCOCH3)2 according to the literature method.22
1H), 3.88 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d 180.3, 174.7, 162.2,
159.8, 156.7, 135.4, 130.8, 130.6, 129.5, 128.5, 123.1, 122.7, 116.8,
114.3, 96.6, 55.9; ESI-HRMS m/z calcd for C17H10O4þNa (MNaþ)
301.04713, found 301.04731.
4.2.5. Reaction with 1,3-dimethoxybenzene.
4.2.5.1. 2-(2,4-Dimethoxyphenyl)-3-hydroxynaphthalene-1,4-dione
(16c). Compound 16c as yellow crystals in 8% yield: mp
230e232 ꢁC; IR (KBr) cmꢀ1 3309, 1666, 1651, 1609; 1H NMR (CDCl3,
300 MHz)
d
10.10 (br s, 1H), 8.11 (d, J¼7.3 Hz, 1H), 8.08 (d, J¼6.7 Hz,
1H), 7.82e7.70 (m, 2H), 7.11 (d, J¼8.5 Hz, 1H), 6.57 (d, J¼8.5 Hz, 1H),
4.2. General procedure for the BF3$Et2O-mediated coupling of
phenyliodonium ylide of lawsone with arenes
6.54 (s, 1H), 3.84 (s, 3H), 3.74 (s, 3H); 13C NMR (CDCl3þDMSO-d6,
75 MHz) d 182.3, 181.0, 160.3, 157.5, 154.2, 133.5, 131.9, 131.2, 129.4,
125.6, 125.0, 120.2, 112.2, 103.7, 97.8, 54.8, 54.5; ESI-HRMS m/z calcd
A suspension of ylide 8a (376 mg, 1.0 mmol), BF3$Et2O (0.26 mL,
2.0 mmol) and the proper arene (1.0 mmol) in CH2Cl2 (10 mL) was
stirred overnight at rt. 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.
for C18H14O5þNa (MNaþ) 333.07334, found 333.07344.
4.2.6. Reaction with 1-methoxy-4-methylbenzene.
4.2.6.1. 2-Hydroxy-3-(2-methoxy-5-methylphenyl)naphthalene-
1,4-dione (16d). Compound 16d as yellow crystals in 7% yield: mp
146e148 ꢁC; IR (KBr) cmꢀ1 3334, 1673, 1644, 1594; 1H NMR (CDCl3,
300 MHz)
d 8.16 (two overlapping doublets, appearing as t,
4.2.1. Reaction with anthracene.
J¼7.9 Hz, 2H), 7.89 (t, J¼7.3 Hz, 1H), 7.72 (t, J¼7.3 Hz, 1H), 7.46 (br s,
4.2.1.1. 2-(Anthracen-9-yl)-3-hydroxynaphthalene-1,4-dione
(15a). Compound 15a as red crystals in 56% yield: mp 260e262 ꢁC;
IR (KBr) cmꢀ1 3363, 1652, 1632, 1589; 1H NMR (CDCl3, 300 MHz)
1H), 7.20 (d, J¼8.5 Hz,1H), 7.05 (s,1H), 6.91 (d, J¼8.5 Hz,1H), 3.76 (s,
3H), 2.33 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d 183.4, 181.8, 155.2,
152.8, 135.1, 133.1, 132.9, 131.7, 130.8, 129.7, 129.5, 127.2, 126.2, 119.1,
111.4, 55.9, 20.5; ESI-HRMS m/z calcd for C18H14O4þH (MHþ)
295.09648, found 295.09641.
d
8.54 (s, 1H), 8.26 (d, J¼6.7 Hz, 1H), 8.21 (d, J¼7.3 Hz, 1H), 8.05 (d,
J¼8.0 Hz, 2H), 7.86e7.73 (m, 4H), 7.49e7.34 (m, 5H); 13C NMR

E. Glinis et al. / Tetrahedron 66 (2010) 5786e5792
5791
4.2.7. Reaction with methoxybenzene. The coupling product 16e
was not obtained after stirring overnight at rt, but it was isolated in
only 3% yield when the reaction was performed in refluxing CHCl3
for 36 h.
1H), 7.82 (dt, J1¼7.5 Hz, J2¼1.5 Hz, 1H), 7.74 (dt, J1¼7.5 Hz, J2¼1.2 Hz,
1H), 7.67 (br s, 1H), 7.48 (d, J¼8.7 Hz, 2H), 7.42 (d, J¼8.7 Hz, 2H); 13C
NMR (CDCl3, 75 MHz) d 183.5, 181.7, 152.3, 135.4, 134.7, 133.3, 132.8,
132.2, 129.8, 128.5, 128.2, 127.4, 126.3, 121.0.
4.3.7. Reaction with anthracene-9-carbaldehyde.
4.2.7.1. 2-Hydroxy-3-(4-methoxyphenyl)naphthalene-1,4-dione
(16e). Compound 16e as red crystals, mp 170e172 ꢁC (lit.17a mp
4.3.7.1. 2-(Anthracen-9-yl)-3-hydroxynaphthalene-1,4-dione
(15a). Compound 15a in 65% yield, in all respects identical with the
one prepared from the reaction of 8a with anthracene.
172e173 ꢁC); 1H NMR (CDCl3, 300 MHz)
d
8.18 (dd, J1¼7.8 Hz,
J2¼1.2 Hz, 1H), 8.12 (dd, J1¼7.5 Hz, J2¼1.2 Hz, 1H), 7.78 (dt, J1¼7.8 Hz,
J2¼1.2 Hz, 1H), 7.70 (dt, J1¼7.5 Hz, J2¼1.2 Hz, 1H), 7.62 (br s, 1H), 7.50
(d, J¼9.0 Hz, 2H), 6.99 (d, J¼9.0 Hz, 2H), 3.85 (s, 3H); 13C NMR
4.3.8. Reaction with thiophene-2-carbaldehyde.
4.3.8.1. 2-Hydroxy-3-(thiophen-2-yl)naphthalene-1,4-dione
(23a). Compound 23a as purple crystals in 43% yield: mp
134e137 ꢁC; IR (KBr) cmꢀ1 3344, 1636, 1602, 1588; 1H NMR (CDCl3,
(CDCl3, 75 MHz) d 184.0, 181.8, 159.9, 151.9. 135.1, 133.1, 132.9, 132.2,
129.4, 127.2, 126.0, 122.2, 121.9, 113.5, 55.3.
300 MHz)
d
8.25 (br s, 1H), 8.21 (dd, J1¼3.9 Hz, J2¼0.9 Hz, 1H), 8.19
4.3. General procedure for the BF3$Et2O-mediated coupling of
phenyliodonium ylide of lawsone with aromatic aldehydes
(dd, J1¼7.8 Hz, J2¼1.2 Hz, 1H), 8.09 (dd, J1¼7.5 Hz, J2¼1.2 Hz, 1H),
7.77 (dt, J1¼7.5 Hz, J2¼1.5 Hz, 1H), 7.69 (dt, J1¼7.5 Hz, J2¼1.5 Hz, 1H),
7.60 (dd, J1¼5.1 Hz, J2¼0.9 Hz, 1H), 7.18 (dd, J1¼3.9 Hz, J2¼5.1 Hz,
A suspension of ylide 8a (188 mg, 0.5 mmol), BF3$Et2O (0.06 mL,
0.5 mmol) and the proper aromatic aldehyde (0.6 mmol) in CHCl3
(10 mL) was refluxed till a clear solution results (0.5e20 h). The
resulting intensively colored solution, 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.
1H); 13C NMR (CDCl3, 75 MHz)
d 183.7, 180.9, 171.2, 150.1, 135.2,
133.4, 132.7, 132.5, 131.1, 129.1, 127.5, 126.8, 126.1, 116.0; ESI-HRMS
m/z calcd for C14H8O3SþNa (MNaþ) 279.00917, found 279.00871.
4.3.9. Reaction with thiophene-3-carbaldehyde.
4.3.9.1. 2-Hydroxy-3-(thiophen-3-yl)naphthalene-1,4-dione
(23b). Compound 23b as purple crystals in 62% yield: mp
125e127 ꢁC (lit.18 mp 126e127 ꢁC).
4.3.1. Reaction with 2,5-dimethoxybenzaldehyde.
4.3.1.1. 2-(2,5-Dimethoxyphenyl)-3-hydroxynaphthalene-1,4-dione
(16b). Compound 16b in 99% yield, in all respects identical with the
one prepared from the reaction of 8a with 1,4-dimethoxybenzene.
4.3.10. Reaction with 1H-indole-3-carbaldehyde.
4.3.10.1. 2-Hydroxy-3-(1H-indol-3-yl)naphthalene-1,4-dione
(24a). Compound 24a as purple crystals in 5% yield: mp
223e226 ꢁC; IR (KBr) cmꢀ1 3385, 3342, 1655, 1626, 1587; 1H NMR
4.3.2. Reaction with 4-methoxybenzaldehyde.
(CDCl3, 300 MHz)
d
9.76 (d, J1¼3.3 Hz, 1H), 9.20 (br s, 1H), 8.34 (s,
4.3.2.1. 2-Hydroxy-3-(4-methoxyphenyl)naphthalene-1,4-dione
(16e). Compound 16e in 78% yield, in all respects identical with the
one prepared from the reaction of 8a with methoxybenzene.
1H), 8.06e8.01 (m, 1H), 7.99e7.93 (m, 2H), 7.79e7.71 (m, 2H),
7.52e7.47 (m, 1H), 7.41e7.31 (m, 2H); 13C NMR (CDCl3, 75 MHz)
d
184.2, 181.4, 151.0, 136.0, 134.8, 134.4, 133.3, 133.1, 129.8, 128.5,
127.3, 126.4, 126.0, 122.6, 122.2, 120.5, 111.3, 106.0, 30.9; ESI-HRMS
4.3.3. Reaction with 3,4-dimethoxybenzaldehyde.
m/z calcd for C18H11NO3þNa (MNaþ) 312.06311, found 312.06316.
4.3.3.1. 2-(3,4-Dimethoxyphenyl)-3-hydroxynaphthalene-1,4-dione
(16f). Compound 16f as red crystals in 92% yield: mp 178e179 ꢁC
4.3.11. Reaction with 1-methyl-1H-indole-3-carbaldehyde.
4.3.11.1. 2-Hydroxy-3-(1-methyl-1H-indol-3-yl)naphthalene-1,4-
dione (24b). Compound 24b as purple crystals in 5% yield: mp
238e241 ꢁC (lit.13 mp 236e240 ꢁC).
(lit.15c mp 180 ꢁC); 1H NMR (CDCl3, 300 MHz)
d
8.19 (d, J¼8.6 Hz,
1H), 8.13 (d, J¼8.6 Hz, 1H), 7.84e7.69 (m, 2H), 7.68 (br s, 1H), 7.18
(dd, J1¼7.7 Hz, J2¼1.7, 1H), 7.10 (d, J¼1.7 Hz, 1H), 6.97 (d, J¼7.7 Hz,
1H), 3.93 (s, 3H), 3.91 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d 184.0,
181.7, 151.9, 149.3, 148.3, 135.2, 133.1, 132.8, 129.3, 127.2, 126.1, 123.9,
122.3, 121.9, 113.9, 110.5, 55.9, 55.8.
References and notes
1. Thomson, R. H. Naturally Occurring Quinones IV; Blackie Academic & Pro-
fessional: London, 1997; and preceding editions.
2. Spyroudis, S. Molecules 2000, 5, 1291.
3. Jelly, R.; Lewis, S. W.; Lennard, C.; Lim, K. F.; Almog, J. Chem. Commun. 2008, 3513.
4. Hussain, H.; Krohn, K.; Ahmad, V. U.; Miana, G. A.; Green, I. R. ARKIVOC 2007, ii,145.
5. Pirrung, M. C.; Fujita, K.; Park, K. J. Org. Chem. 2005, 70, 2537 and references
cited therein.
4.3.4. Reaction with 4-methylbenzaldehyde.
4.3.4.1. 2-Hydroxy-3-p-tolylnaphthalene-1,4-dione
pound 16g as yellow crystals in 76% yield: mp 166e167 ꢁC (lit.23 mp
168 ꢁC); 1H NMR (CDCl3, 300 MHz)
(16g). Com-
d
8.19 (dd, J1¼7.7 Hz, J2¼1.2 Hz,
1H), 8.14 (dd, J1¼7.4 Hz, J2¼1.2 Hz,1H), 7.79 (dt, J1¼7.4 Hz, J2¼1.5 Hz,
1H), 7.71 (dt, J1¼7.5 Hz, J2¼1.5 Hz, 1H), 7.55 (br s, 1H), 7.42 (d,
J¼8.4 Hz, 2H), 7.26 (d, J¼8.1 Hz, 2H), 2.40 (s, 3H); 13C NMR (CDCl3,
6. Stahl, P.; Kissau, L.; Mazitschek, R.; Huwe, A.; Furet, P.; Giannis, A.; Waldmann,
H. J. Am. Chem. Soc. 2001, 123, 11586.
€
7. Lang, M.; Mühlbauer, A.; Graf, C.; Beyer, J.; Lang-Fugmann, S.; Polborn, K.;
Steglich, W. Eur. J. Org. Chem. 2008, 816.
75 MHz)
d 183.8, 181.9, 152.1, 138.7, 135.2, 133.1, 133.0, 130.6, 129.4,
8. Mure, M.; Klinman, J. P. J. Am. Chem. Soc. 1995, 117, 8698.
9. Malamidou-Xenikaki, E.; Spyroudis, S. Synlett 2008, 2725 and references cited
therein.
128.7, 127.3, 127.0, 126.1, 122.3, 21.4.
10. Alcock, N. W.; Bozopoulos, A. P.; Hatzigrigoriou, E.; Varvoglis, A. Acta Crystallogr.,
4.3.5. Reaction with benzaldehyde.
Sect. C 1990, 46, 1300.
11. Nishimura, T.; Iwasaki, H.; Takahashi, M.; Takeda, M. J. Radioanal. Nucl. Chem.
2003, 25, 499.
4.3.5.1. 2-Hydroxy-3-phenylnaphthalene-1,4-dione
(16h). Com-
pound 16h in 56% yield: mp 147e148 ꢁC (lit.22 mp 146 ꢁC), and
spectra identical with the ones reported in the literature.24
12. Bakalbassis, E.; Spyroudis, S.; Tsipis, C. Eur. J. Org. Chem. 2008, 1783.
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V.; Malamidou-Xenikaki, E.; Spyroudis, S.; Giannis, A. ChemMedChem 2008, 3,
429; (c) Malamidou-Xenikaki, E.; Spyroudis, S.; Tsanakopoulou, M.; Krautsc-
heid, H. J. Org. Chem. 2008, 73, 8392; (d) Malamidou-Xenikaki, E.; Spyroudis, S.;
Tsanakopoulou, M.; Hadjipavlou-Litina, D. J. Org. Chem. 2009, 74, 7315.
4.3.6. Reaction with 4-chlorobenzaldehyde.
4.3.6.1. 2-(4-Chlorophenyl)-3-hydroxynaphthalene-1,4-dione
(16i). Compound 16i as yellow crystals in 31% yield: mp
186e188 ꢁC (lit.15a mp 187e188 ꢁC). 1H NMR (CDCl3, 300 MHz)
d
8.19 (dd, J1¼7.7 Hz, J2¼1.2 Hz, 1H), 8.15 (dd, J1¼7.5 Hz, J2¼1.2 Hz,

5792
E. Glinis et al. / Tetrahedron 66 (2010) 5786e5792
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A. G.; Wilson, E.; Wu, M.; Leffler, M. T.; Hamlin, K. E.; Matson, E. J.; Moore, E. E.;
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20. Dohi, T.; Ito, M.; Yamaoka, N.; Moritomo, K.; Fujioka, H.; Kita, Y. Tetrahedron
2009, 65, 10797 and references cited therein.
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