Polyethylene glycol (PEG 300) and water-ethanol as benign solvent systems for the synthesis of a novel series of 2-hydroxynaphthalen-1(4H)-ones

Article abstract of DOI:10.1080/00397911003797916

An improved, clean, simple, and efficient method for the synthesis of new series of 2-hydroxy-4-methylenenaphthalen-1(4H)-one is described. This new process involves a domino Michael addition of various methylene acid compounds with the sodium salt of 1,2-naphthoquinone-4-sulfonate either in basic (tBuOK) polyethylene glycol (PEG300) at room temperature or in a basic (NaOH) water-ethanol medium at 40C by a crushing in a mortar or a traditional heating. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911003797916

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Polyethylene Glycol (PEG 300) and
Water–Ethanol as Benign Solvent Systems
for the Synthesis of a Novel Series of 2-
Hydroxynaphthalen-1(4H)-Ones
D. Villemin a , M. Benabdallah a b , N. Choukchou-Braham b & B.
Mostefa-Kara b
a ENSICAEN, Université de Caen, Caen, France
b Laboratoire de Catalyse et Synthèse en Chimie Organique, Faculté
des Sciences, Université Abou-Bakr Belkaid, Tlemcen, Algéria
Version of record first published: 13 Sep 2010.
To cite this article: D. Villemin, M. Benabdallah, N. Choukchou-Braham & B. Mostefa-Kara (2010):
Polyethylene Glycol (PEG 300) and Water–Ethanol as Benign Solvent Systems for the Synthesis of a
Novel Series of 2-Hydroxynaphthalen-1(4H)-Ones, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 40:20, 3109-3118
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Synthetic Communications1, 40: 3109–3118, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911003797916
POLYETHYLENE GLYCOL (PEG 300) AND
WATER–ETHANOL AS BENIGN SOLVENT SYSTEMS
FOR THE SYNTHESIS OF A NOVEL SERIES OF
2-HYDROXYNAPHTHALEN-1(4H)-ONES
D. Villemin,1 M. Benabdallah,1,2 N. Choukchou-Braham,2 and
B. Mostefa-Kara2
1
´
ENSICAEN, Universite de Caen, Caen, France
2
`
Laboratoire de Catalyse et Synthese en Chimie Organique, Faculte des
Sciences, Universite Abou-Bakr Belkaid, Tlemcen, Algeria
´
´
´
An improved, clean, simple, and efficient method for the synthesis of new series of
2-hydroxy-4-methylenenaphthalen-1(4H)-one is described. This new process involves a
domino Michael addition of various methylene acid compounds with the sodium salt of
1,2-naphthoquinone-4-sulfonate either in basic (tBuOK) polyethylene glycol (PEG300)
at room temperature or in a basic (NaOH) water–ethanol medium at 40 ꢀC by a crushing
in a mortar or a traditional heating.
Keywords: Acid methylene; 2-hydroxynaphthalen-1(4H)-one; lawsone; Michael addition; 1,2-naphthoqui-
nomethane; polyethylene glycol (PEG300); water–ethanol media
INTRODUCTION
Green chemistry has become an important field of research in organic
synthesis, attracting more scientists and researchers in this area.[1] Volatile, toxic,
and hazardous organic solvents are continuously being replaced by either the use
of solvent-free techniques[2] or use of ionic liquids,[2] water,[2,3] supercritical media,[4]
or phase-transfer catalysts. Polyethylene glycol (PEG)[5] and water[6] have recently
attracted considerable attention as potential alternatives to conventional organic
solvents in a variety of syntheses because PEG[7] is inexpensive, readily available,
easily degradable, and not very toxic.[7,1b] Although the PEG300 is also known as
a particularly ecofriendly solvent, it also is highly stabile, is recyclable, helps main-
tain a neutral reaction medium,[2] and acts as a phase-transfer catalyst in various
reactions with inorganic bases, particularly in the condensation–elimination reaction
(Michael addition[8]). Michael addition is one of the many valuable methods
widely used in organic synthesis to make carbon–carbon and carbon–heteroatom
connections.[9]
Received February 17, 2010.
Address correspondence to D. Villemin, ENSICAEN, LCMT-UMR 6507 CNRS, Universite de
Caen, 14050 Caen, France. E-mail: didier.villemin@ensicaen.fr
´
3109

3110
D. VILLEMIN ET AL.
Figure 1. Basic structure of natural naphthoquinones.
Quinones are important structural units present in many natural products,
which can undergo various biological transformations. They have been isolated
from various microorganisms, fungi, higher plants, and animals. The largest
subgroups of natural quinones are the naphthoquinones, of which more than 350
are found in nature.[10] Among the structurally diverse naphthoquinone natural
products, lawsone,[11] lapachol,[12] and several 1,4- and 1,2-naphthoquinones are
associated with diverse biological activities[11,13] and are used as antibacterial, fungi-
cidal, antimalarial, trypanocidal, and antitumoral agents.[14] For this reason, and
because they offer various industrial applications as well as being intermediates in
heterocycle synthesis, naphthoquinones have been the subject of much interest for
a number of years now.[10] They are similar to quinomethanes, which are key inter-
mediates in the synthesis of drugs, as well being regarded as enzymes inhibitors.[15]
The high interest in naphthoquinone derivatives is largely dependent on
substituents being either on the quinonic or on adjacent rings. The presence of a
group alkyl, alkene, and aryl substituted on carbon 3 or 4 (Fig. 1) seem to be a
major contribution to the biological and pharmacological activity. The diversity of
their natural origins and activities has motivated research into their synthesis and
pathways to structural analogs.
In our laboratory, we were interested in the synthesis of the reactions without
solvents[16] and in water,[17] ionic liquids,[18] and PEG 300. Therefore, we decided to
study the synthesis of naphthoquinomethanes in water–ethanol and PEG 300, as
part of our program for the development of new synthetic methodologies.
In continuation of our efforts in searching for newer synthetic methodologies
for biologically important 1,2-naphthoquinones,[19] we chose 2-hydroxy-4-
methylenenaphthalen-1(4H)-one as targets.
RESULTS AND DISCUSSION
Keeping in mind availability of starting materials and the synthetic efficiency,
rapidity, and simplicity of procedures, we have developed two efficient methods
for the preparation of a new class of 2-hydroxynaphthoquinomethanes or
2-hydroxy-4-methylenenaphthalen-1-one derivatives with diverse structures in one
pot by two-component condensation.
First, we prepared this novel class of derivatives by a cascade Michael addition
of various acidic methylene compounds (2) with the sodium salt of 1,2-
naphthoquinone-4-sulfonate (1) in the presence of a base such as sodium hydroxide

NOVEL SERIES OF 2-HYDROXYNAPHTHALEN-1(4H)-ONES
3111
Scheme 1. Synthesis of 2-hydroxy-4-methylenenaphthalen-1-one derivatives (3a–p).
(25%), followed by protonation and elimination of sulfur dioxide (SO2) according to
Scheme 1 (method A). The reaction was conducted in water–ethanol media and
produced 2-hydroxy-4-methylenenaphthalen-1-one (3a–p) in moderately low to good
yields. All the synthesized compounds have been characterized by spectral [infrared
1
(IR), H NMR, 13C NMR] studies (Table 1).
The variation of the poor yields obtained with some active methylenes such as
the indene (3p), 1,3-indendione (3o), anthracen-10(9H)-one (3n), and fluorene (3f)
can be explained by the oxidation of these compounds with free air oxygen while
in the presence of a strong base such as sodium hydroxide in an aqueous medium.
Otherwise, the other poor yields obtained in other cases are due either to the strong
acidity of the acid methylene or to the tautomerism observed at some carbonyls (3i,
3j, 3k, 3l, and 3m). For such reasons, we have searched to optimize the operating
conditions of this reaction such as the temperature, the mode of heating, and other
media, all in respect to the criteria of green chemistry. Thus, we have discovered a
simple, fast, and effective method for preparing of 2-hydroxy-4-methylenenaphtha-
len-1-one derivatives: grinding the sodium salt of 1,2-naphthoquinone-4-sulfonate
with various acidic methylene compounds in the presence of a base such as
Table 1. Synthesis of 2-hydroxy-4-methylenenaphthalen-1-one derivatives (3a–p) in water–ethanol
Entry
Product 2
Product 3
Yield (%)
Mp (ꢀC)
d3H ðppmÞ
1
2
Diethyl malonate
Ethyl cyanoacetate
Phenylacetonitrile
Oxindole
3a
3b
3c
3d
3e
3f
56
37
57
80
79
63
60
56
50
48
32
32
25
18
05
00
110
130[20]
198–200
234
7.37
7.50
7.57
7.42
7.62
7.64
7.53
7.51
7.64
7.63
7.61
7.21
7.71
7.12
7.34
—
3
4
5
4-Hydroxyquinolinone
Fluorene
>250
146
215
6
7
Benzofuran-2-one
Benzofuran-3-one
4-Hydroxycoumarine
Pyrimidine-2,4,6-trione
Meldrum’s acid
2,3-Dihydrochromen-4-one
Rhodamine
3g
3h
3i
8
230
202
9
10
11
12
13
14
15
16
3j
178
124
3k
3l
216
210
3m
3n
3o
3p
Anthracen-10(9H)-one
1,3-Indendione
Indene
178
214
—

3112
D. VILLEMIN ET AL.
Table 2. Synthesis of 2-hydroxy-4-methylenenaphthalen-1-one derivatives in PEG 300
Entry
Product 2
Product 3
Yield (%)
Mp (ꢀC)
d3H ðppmÞ
1
2
Diethyl malonate
Ethyl cyanoacetate
Phenylacetonitrile
Fluorene
3a
3b
3c
3f
67
54
70
68
69
65
49
52
58
78
110
130[21]
198–200[19]
146
7.37
7.50
7.57
7.64
7.53
7.51
7.71
7.12
7.34
7.44
3
4
5
Benzofuran-2-one
Benzofuran-3-one
Rhodamine
3g
3h
3l
215
230
6
7
210
178
8
Anthracen-10(9H)-one
1,3-Indendione
Indene
3m
3o
3p
9
10
214
110
potassium tertiobutanolate (tBuOK) in the PEG300 at room temperature, as shown
in Scheme 1 (method B). All the synthesized compounds have been characterized by
1
spectral (IR, H NMR, 13C NMR) studies (Table 2).
The results obtained were good in terms of yields. In a pilot experiment, a
mixture of sodium salt of 1,2-naphthoquinone-4-sulfonate 1 (1.920 mmol), acidic
methylene compounds 2 (1.920 mmol), and tBuOK (1.728 mmol) in the presence
of a catalytic amount of PEG 300 (2–5 ml) was ground using a mortar and pestle
of an appropriate size for about 6–10 min. The reaction was performed at ambient
temperature during which almost a 5 ꢀC increase in temperature was observed. This
increase in reaction temperature indicated that 2-hydroxy-4-methylenenaphthalen-
1-one formation was an exothermic process in PEG 300. The minimal quantity of
the PEG 300 protects the reagents very well, and the short time ignores secondary
reactions such as the oxidation of the diketone, the anthracen-10(9H)-one, and the
indene. The reaction proceeds very cleanly under mild conditions and is compatible
with a wide range of functional groups. The advantages of this new method are oper-
ational simplicity, good yields of products in short reaction times, ecofriendly proto-
col (PEG 300 is soluble in water), and easy workup procedures.
CONCLUSIONS
In summary, we have developed an efficient, mild, and convenient one-pot pro-
cedure for the condensation of various acid methylene compounds with the sodium
salt of 1,2-naphthoquinone-4-sulfonate in basic water–ethanol medium or PEG 300
by traditional heating or a crushing in a mortar at room temperature. The present
procedure described here has the advantages of mild reaction conditions, good to
high yields of products, shorter reaction times, and operational simplicity and meets
the criteria of green chemistry.
EXPERIMENTAL
The melting points were measured using a Bank Kofler Heizbank apparatus
(standard WME 50–260 ꢀC) and were uncorrected. IR spectra were obtained as
solids with a Fourier transform Perkin–Elmer Spectrum One instrument with

NOVEL SERIES OF 2-HYDROXYNAPHTHALEN-1(4H)-ONES
3113
attenuated total reflection (ATR) spectroscopy accessory. The wave numbers n are
1
expressed in centimetersꢁ1. Only significant absorptions are listed. The H NMR
spectra were recorded either at 400 MHz or 250 MHz and 13C NMR spectra were
likewise recorded at either 100.6 MHz or 62.9 MHz on a Bruker AC 400 or AC
¨
250 spectrometers, respectively. Samples were registered in CDCl3 or dimethylsulfox-
ide (DMSO) using tetramethylsilane (TMS) as an internal standard. The chemical
shifts are expressed in d units (ppm) and quoted downfield from TMS. The multi-
plicity is reported as s, singlet; d, doublet; t, triplet; q, quartet; and m, multiplet.
General Procedure for the Preparation of 2-Hydroxy-4-
methylenenaphthalen-1-one 3 in Water–Ethanol and in PEG 300
Method A (in water–ethanol)[19]. A solution of acidic methylene com-
pounds 2 (1.92 mmol) in ethanol (8 ml) was added at 40 ꢀC to a stirred solution of
sodium 1,2-naphthoquinone-4-sulfonate 1 (0.50 g, 1.92 mmol) in H2O (22 ml). After
10 min, a 25% aqueous basic solution of sodium hydroxide (0.50 ml) was added while
stirring. The mixture was then stirred at 40 ꢀC for 2 h. The reaction mixture was then
cooled and acidified using a concentrated hydrochloric acid (HCl) solution (37%) to
give a solid that was collected, dried under vacuum, and identified as compound
2-hydroxy-4-methylenenaphthalen-1-one (3).
Method B (in PEG 300). A mortar was charged with the sodium salt of
1,2-naphthoquinone-4-sulfonate 1 (0.50 g, 1.920 mmol), acidic methylene com-
pounds 2 (1.920 mmol), tBuOK (0.20 g, 1.728 mmol), and a catalytic amount of
PEG 300 (2–5 ml). The mixture was ground with a pestle in the mortar at 25 ꢀC
for 6–10 min. After the reaction mixture was neutralized with diluted hydrochloric
acid (HCl) solution, and then the formed solid crystals were isolated by filtration;
the obtained solid was then dissolved in methylene chloride (10–20 ml). The organic
phase was dried on anhydrous sodium sulfate, filtered, and then concentrated in
vacuo to give the pure compound 2-hydroxy-4-methylenenaphthalen-1-one (3).
Selected Data
Diethyl (3-hydroxy-4-oxonaphthalen-1-ylidene)malonate (3a). Obtained
from diethyl malonate (0.31 g, 1.92 mmol); brown solid (0.34 g, 56%, method A;
0.40 g, 67%, method B); mp 110 ꢀC; IR 3100, 1700, 1654, 1629, 1591, 1220 cmꢁ1
;
1H NMR (DMSO) d (ppm) 1.30–1.46 (t, 6H), 4.35–4.54 (m, 4H), 7.21 (s, 1H),
7.37 (s, 1H), 7.61–7.75 (t, 1H), 7.83–90 (t, 1H), 7.95–8.12 (d, 1H), 8.47–8.50 (d,
1H); 13C NMR (DMSO) d (ppm) 14.1, 14.5, 60.2 (2C), 112.2, 119.3, 126.8, 128.6,
129.5, 132.4, 132.9, 135.3, 145.7, 159.1, 167.5, 170.7, 179.7.
Ethyl 2-cyano(3-hydroxy-4-oxonaphthalen-1-ylidene)acetate (3b). Obtain-
ed from ethyl cyanoacetate (0.21 g, 1.92 mmol); yellow solid (0.19 g, 37%, method
A; 0.28 g, 54%, method B), mp 130 ꢀC [lit.[20] 129.9–130.4 ꢀC]; IR 3342, 2205, 1703,
;
1654, 1629, 1591, 1229 cmꢁ1 1H NMR (CDCl3) d (ppm) 1.43 (t, 3H), 4.41 (q,
2H), 7.50 (s, 1H), 7.70–7.81 (m, 2H), 8.09 (s, 1H), 8.26–8.30 (dd, 1H), 8.88 (d,
1H); 13C NMR (CDCl3) d (ppm) 14.1, 14.6, 63.1, 102.5, 110.5, 127.7, 128.1, 129.5,

3114
D. VILLEMIN ET AL.
132.1, 132.6, 134.1, 150.9, 151.2, 162.5, 179.5; MS-ESI m=z [M þH]þcalcd. for
C15H11NO4 270.0766; found 270.0769; 242, 224, 214, 196.
2-(3-Hydroxy-4-oxonaphthalen-1-ylidene)-2-phenylacetonitrile (3c).
Obtained from phenylacetonitrile (0.23 g, 1.92 mmol); yellow solid (0.30 g, 57%,
method A; 0.37 g, 70%, method B); mp 198–200 ꢀC; IR 3321, 2193, 1632, 1595,
1
1415, 1224 cmꢁ1; H NMR (CDCl3) d (ppm) 6.91 (s, 1H), 6.99 (s, 1H), 7.57 (s,
5H), 7.66–7.72 (t, 1H), 7.78–7.84 (t, 1H), 8.34–8.36 (d, 1H), 9.12–9.14 (d, 1H); 13C
NMR (CDCl3) d (ppm) 112.0, 118.5, 126.6, 127.1 (2C), 127.6, 129.2 (2C), 129.7,
129.9, 130.3, 130.8, 131.3, 133.7, 140.3, 141.1, 149.1, 179.4; MS-ESI m=z [M þH]þ
calcd. for C18H11NO2 274.0868; found 274.0.878; 256, 247, 228.
3-(3-Hydroxy-4-oxonaphthalen-1-ylidene)-1,3-dihydro-indol-2-one (3d).
Obtained from oxindole (0.25 g, 1.92 mmol); pourpre 0.44 g (80%, method A),
1
mp 234 ꢀC; IR 2988, 1673, 1634, 1587, 1558, 1464, 1339, 1258 cmꢁ1; H NMR
(DMSO) d (ppm) 6.72 (s, 1H), 6.98–7.12 (m, 2H), 7.17–7.21 (t, 1H), 7.42 (s,
1H), 7.51–7.47 (t, 1H), 7.71–7.75 (t, 1H), 7.77–7.81 (t, 1H), 8.01 (d, 1H), 8.67
(dd, 1H), 8.85–8.82 (dd, 1H); 13C NMR (DMSO) d (ppm) 108.4 (2C), 112.1,
118.5, 120.7, 125.1, 127.6, 130.3 (2C), 130.4, 131.3, 132.7, 142.0, 144.2, 144.6,
144.9, 170.2, 182.7; MS-ESI m=z [M þ H]þ calcd. for C18H11NO3 290.0817;
found 290.0827; 272, 262, 244.
3-(3-Hydroxy-4-oxonaphthalen-1-ylidene)quinoline-2,4-dione (3e). Obtain-
ed from 4-hydroxyquinolinone (0.31 g, 1.92 mmol); yellow solid 0.48 g (79%, method
A); mp > 250 ꢀC; IR 3256, 1700, 1610, 1602, 1378 cmꢁ1; 1H NMR (DMSO) d (ppm)
6.95–6.98 (d, 1H), 7.40–7.44 (d, 2H), 7.56–7.59 (m, 2H), 7.62 (s, 1H), 7.74 (s, 1H),
8.00–8.04 (d, 1H), 8.27–8.31 (t, 1H), 8.79–8.83 (t, 1H), 9.26–9.30 (d, 1H); 13C
NMR (DMSO) d (ppm) 104.1, 113.6, 116.1, 119.1, 120.5, 123.9, 125.3, 126.4,
127.4, 128.8, 135.3, 136.4, 140.2, 142.8, 145.6, 158.5, 161.6, 182.7, 183.2.
4-(Fluoren-9-ylidene)-2-hydroxynaphthalen-1-one (3f). Obtained from
fluorene (0.32 g, 1.92 mmol); red solid (0.39 g, 63%, method A; 0.42 g, 68%, method
1
B); mp 146 ꢀC; IR 1712, 1609, 1580, 1570, 1446, 1299 cmꢁ1; H NMR (DMSO) d
(ppm) 6.75 (s, 1H), 7.051–7.09 (t, 2H), 7.54–7.64 (m, 2H), 7.64 (s, 1H), 7.67–7.72
(m, 4H), 7.91–7.95 (t, 2H), 8.28–8.31 (dd, 1H), 8.54–8.57 (dd, 1H); 13C NMR
(CDCl3) d (ppm) 111.7, 117.2 (2C), 121.3, 124.7, 125.5, 126.2, 127.3, 127.9, 128.3
(2C), 129.5, 130.2, 131.1, 131.3, 136.7, 141.4, 141.7, 143.7, 144.3, 144.7, 152.2, 179.5.
3-(3-Hydroxy-4-oxonaphthalen-1-ylidene)benzofuran-2-one (3g). Obtained
from benzofuran-2-one (0.26 g, 1.92 mmol); brown solid (0.33 g, 60%, method A;
0.38 g, 69%, method B); mp 215 ꢀC; IR 3340, 1675, 1650, 1633, 1592, 1445,
;
1296 cmꢁ1 1H NMR (CDCl3) d ppm 6.97–7.01 (t, 1H), 7.11–7.13 (d, 2H),
7.32–7.35 (t, 1H), 7.53 (s, 1H), 7.59–7.67 (m, 2H), 7.70 (s, 1H), 8.24–8.26 (dd,
1H), 8.35–8.55 (dd, 1H); 13C NMR (CDCl3) d (ppm) 110.1, 110.6, 120.1, 121.5,
124.8, 125.8, 128.8, 129.9 (2C), 131.2 (2C), 132.9, 139.9, 147.9, 156.8, 161.4, 167.9,
182.9.
2-(3-Hydroxy-4-oxonaphthalen-1-ylidene)benzofuran-3-one (3h). Obtained
from benzofuran-3-one (0.26 g, 1.92 mmol); brown solid (0.31 g, 56%, method A;
0.36 g, 65%, method B); mp 230 ꢀC; IR 3340, 1675, 1650, 1633, 1592, 1445,

NOVEL SERIES OF 2-HYDROXYNAPHTHALEN-1(4H)-ONES
3115
1296 cmꢁ1; 1H NMR (CDCl3) d ppm 6.97–7.01 (t, 1H), 7.08–7.18 (d, 2H), 7.30–7.36
(t, 1H), 7.51 (s, 1H), 7.55–7.65 (m, 2H), 7.81 (s, 1H), 8.13–8.21 (dd, 1H), 8.23–8.35
(dd, 1H); 13C NMR (CDCl3) d (ppm) 110.9, 116.0, 122.7, 123.6, 124.8, 128.2, 131.0
(2C), 132.8, 134.0, 136.2, 137.0, 138.6, 141.6, 148.4, 166.8, 182.9, 185.0.
3-(3-Hydroxy-4-oxonaphthalen-1-ylidene)chromene-2,4-dione (3i). Obtain-
ed from 4-hydroxycoumarine (0.31 g, 1.92 mmol); ochre solid, 0.31 g (50%, method
1
A); mp 202 ꢀC; IR 3254, 1706, 1613, 1598, 1374 cmꢁ1; H NMR (DMSO) d (ppm)
7.20 (s, 1H), 7.20–7.35 (t, 2H), 7.43–7.59 (t, 1H), 7.64 (s, 1H), 7.70–7.91 (t, 1H),
7.92 (d, 1H), 8.25 (d, 1H), 8.31 (dd, 1H), 8.56 (dd, 1H); 13CNMR (DMSO) d
(ppm) 105.3, 116.3, 118.0, 122.8, 123.9, 127.2 (2C), 130.3, 131.0, 132.3, 132.6,
137.3, 138.1, 150.4, 154.7, 157.6, 173.5, 181.1, 182.7.
5-(3-Hydroxy-4-oxonaphthalen-1-ylidene)pyrimidine-2,4,6-trione (3j).
Obtained from pyrimidine-2,4,6-trione (0.25 g, 1.92 mmol); beige solid, 0.26 g
(48%, method A); mp 178 ꢀC; IR 3226, 1720, 1658, 1616, 1589, 1356,
1247 cmꢁ1 1H NMR (DMSO) d (ppm) 7.22 (s, 1H), 7.63 (s, 1H), 7.72–7.98
;
(m, 2H), 8.06–8.25 (d, 1H), 8.85–8.95 (d, 1H), 11.12 (s, 1H); 13C NMR (DMSO)
d (ppm) 105.5, 115.1, 127.5, 130.6, 131.0, 131.4, 133.3, 141.5, 144.2, 150.2,
151.7, 163.8 (2C), 182.7.
5-(3-Hydroxy-4-oxonaphthalen-1-ylidene)-2,2-dimethyl-1,3-dioxane-4,6-
dione (3k). Obtained from Meldrum’s acid (0.28 g, 1.92 mmol); purple solid, 0.1ꢁ91g
(32%, method A); mp 124 ꢀC; IR 2991, 1704, 1679, 1640, 1578,1592, 1435, 1283cm
;
1H NMR (DMSO) d (ppm) 1.69 (s, 6H), 7.21 (s, 1H), 7.53 (t, 1H), 7.61 (s, 1H),
7.82 (dd, 1H), 7.93 (t, 1H), 7.99 (dd, 1H); 13C NMR (DMSO) d (ppm) 26.4, 28.9,
104.0, 108.3, 113.7, 129.0, 130.6, 131.2, 131.9, 133.0, 139.0, 147.0, 163.8 (2C), 172.0,
182.8.
3-(3-Hydroxy-4-oxonaphthalen-1-ylidene)-2,3-dihydrochromen-4-one
(3l). Obtained from 2,3-dihydrochromen-4-one (0.28 g, 1.92 mmol); brown solꢁid1,
0.19 g (32%, method A); mp 210–216 ꢀC; IR 2988, 1634, 1604, 1465, 1294 cm
;
1H NMR (DMSO) d (ppm) 5.14 (s, 2H), 5.79 (s, 1H), 7.20 (s, 1H), 7.31–7.40 (d,
1H), 7.45–7.62 (m, 2H), 7.96–8.04 (m, 3H), 8.16 (d, 1H), 8.47 (d, 1H); 13C NMR
(DMSO) d (ppm) 62.6, 109.1, 116.9, 121.0, 123.4, 125.9, 126.5, 129.6, 130.1, 132.0
(2C), 132.7, 135.8, 140.1, 147.5, 156.7, 159.1, 182.7, 189.4.
5-(3-Hydroxy-4-oxonaphthalen-1-ylidene)-2-thioxothiazolidin-4-one
(3m). Obtained from rhodamine (0.25 g, 1.92 mmol); black solid, (0.14 g, 25%,
method A; 0.29 g, 49%, method B); mp 210 ꢀC; IR 3410, 3351, 1670, 1633, 1613,
1
1588, 1455, 1407, 1299 cmꢁ1; H NMR (DMSO) d (ppm) 7.67–7.68 (d, 1H), 7.71
(s, 1H), 7.83–7.89 (t, 1H), 7.97–8.00 (d, 1H), 8.16–8.19 (d, 1H), 8.63 (s, 1H), 10.34
(s, 1H); 13C NMR (DMSO) d (ppm) 108.7, 118.5, 126.9, 127.6, 130.0, 132.3,
132.9, 135.8, 143.3, 145.7, 168.4, 182.7, 186.2.
9-(3-Hydroxy-4-oxonaphthalen-1-ylidene)anthracen-10-one (3n). Obtained
from anthracen-10(9H)-one (0.37 g, 1.92 mmol); yellow solid, (0.12 g, 18%, method
A; 0.35 g, 52%, method B); mp 178 ꢀC; IR 3110, 1670, 1650 cmꢁ1; 1H NMR (DMSO)
d (ppm) 5.72 (s, 1H), 6.66 (s, 1H), 7.40 (2H), 7.60 (1H), 7.63 (2H), 7.70 (1H),
7.84–7.91 (m, 4H), 8.47 (d, 1H), 9.39 (d, 1H); 13C NMR (DMSO) d (ppm) 112.8,

3116
D. VILLEMIN ET AL.
121,4, 124.1 (2C), 127.1, 128.6 (2C), 129.0, 130.1 (2C), 131.4, 132.2, 133.0 (2C), 133.5
(2C), 135.4, 139.2 (2C), 141.7, 144.0, 157.1, 182.7, 183.0.
2-(3-Hydroxy-4-oxonaphthalen-1-ylidene)indene-1,3-dione (3o). Obtained
from 1,3-indendione (0.28 g, 1.92 mmol); brown solid, (0.29 g, 05%, method A),
1
(0.34 g, 58%, method B); mp 214 ꢀC; IR 1708, 1685, 1568, 1352 cmꢁ1; H NMR
(DMSO) d (ppm) 7.20 (s, 1H), 7.50 (s, 1H), 7.74–7.78 (t, 2H), 7.91–7.95 (t, 2H),
8.10–8.32 (dd, 2H), 8.72–8.74 (d, 1H), 8.82–8.84 (d, 1H); 13C NMR (DMSO) d
(ppm) 111.5, 120.3 (2C), 125.5, 126.2, 130.2, 130.5, 132.4, 133.3, 134.1 (2C), 137.5,
140.0 (2C), 154.1, 165.6, 182.2, 192.5 (2C).
2-Hydroxy-4-(inden-1-ylidene)naphthalen-1-one (3p). Obtained from
indene (0.22 g, 1.92 mmol); brown solid, 0.41 g (78%, method B); mp 110 ꢀC; IR
1
3281, 1702, 1600, 1586, 1468, 1450, 1403, 1213 cmꢁ1; H NMR (CDCl3) d (ppm)
7.20 (s, 1H), 7.30–7.31 (d, 1H), 7.37–7.41 (t, 1H), 7.44 (s, 1H), 7.48–7.49 (d, 2H),
7.52–7.56 (t, 1H), 7.58–7.60 (d, 2H), 7.70–7.74 (t, 1H), 8.05–8.07 (d, 1H),
8.24–8.26 (d, 1H); 13C NMR (DMSO) d (ppm) 111.2, 118.9, 122.3, 124.3, 125.3,
127.3, 130.3 (2C), 131.4, 132.8, 136.3, 137.6, 139.4, 141.3, 141.6, 143.6, 152.7, 182.7.
ACKNOWLEDGMENTS
We gratefully acknowledge the CNRS (Centre National de la Recherche Scien-
tifique), the (Region Basse-Normandie), the University of Tlemcen, and the Eur-
opean Union (FEDER funding) for their financial support.
REFERENCES
1. (a) Christenson, P. A.; Willis, B. J.; Wehrli, F. W.; Wehrli, S. Chemistry of ambergris, 1: A
short synthesis of (þ)-delta-ambrinol. J. Org. Chem. 1982, 47, 4789; (b) Baj, S.; Siewniak,
A. Synthesis of dialkyl peroxides in the presence of polyethylene glycol or its derivatives as
phase-transfer catalyst in liquid–liquid–liquid system. Appl. Catal. A: Gen. 2007, 321, 175;
(c) Heldebrant, D. J.; Jessop, P. G. Liquid poly(ethylene glycol) and supercritical carbon
dioxide: A benign biphasic solvent system for use and recycling of homogeneous catalysts.
J. Am. Chem. Soc. 2003, 125, 5600; (d) Chen, J.; Spear, S. K.; Huddleston, J. G.; Rogers,
R. D. Polyethylene glycol and solutions of polyethylene glycol as green reaction media.
Green Chem. 2005, 7, 64.
2. Mukhopadhyay, C.; Tapaswi, P. K. PEG-mediated catalyst-free expeditious synthesis
of 2-substituted benzimidazoles and bis-benzimidazoles under solvent-less conditions.
Tetrahedron Lett. 2008, 49, 6237–6240, and references cited therein.
3. Grieco, P. A. Organic Synthesis in Water; Blackie Academic and Professional: London,
1998.
4. Oakes, R. S.; Califford, A. A.; Rayner, C. M. The use of supercritical fluids in synthetic
organic chemistry. J. Chem. Soc., Perkin Trans. 1 2001, 917.
5. (a) Kleber, C.; Andrade, Z.; Alves, L. M. Environmentally benign solvents in organic
synthesis: Current topics. Curr. Org. Chem. 2005, 9, 1995; (b) Liu, Y.; Liang, J.; Hong
Liu, X.; Cai Fan, J.; Cai Shang, Z. Polyethylene glycol (PEG) as a benign solvent for
Knoevenagel condensation. Chin. Chem. Lett. 2008, 19, 1043–1046.
6. (a) Chankeshwara, S. V.; Chakraborti, A. K. Catalyst-free chemoselective N-tert-butyl-
oxycarbonylation of amines in water. Org. Lett. 2006, 8, 3259; (b) Sharma, G.; Kumar,

NOVEL SERIES OF 2-HYDROXYNAPHTHALEN-1(4H)-ONES
3117
R.; Chakraborti, A. K. ‘‘On water’’ synthesis of 2,4-diaryl-2,3-dihydro-1,5-
benzothiazepines catalysed by sodium dodecyl sulfate (SDS). Tetrahedron Lett. 2008,
49, 4269; (c) Chakraborti, A. K.; Rudrawar, S.; Jadhav, K. B.; Kaur, G.; Chankeshwara,
S. V. ‘‘On water’’ organic synthesis: A highly efficient and clean synthesis of 2-aryl=
heteroaryl=styryl benzothiazoles and 2-alkyl=aryl alkyl benzothiazolines. Green Chem.
2007, 9, 1335.
7. Zhang, Z. H.; Yin, L.; Wang, Y. M.; Liu, J. Y.; Li, Y. Indium tribromide in poly(ethylene
glycol) (PEG): A novel and efficient recycle system for chemoselective deprotection of
1,1-diacetates. Green Chem. 2004, 6, 563.
8. (a) Zare, A.; Hasaninejad, A.; Khalafi-Nezhad, A.; Moosavi Zare, A. R.; Parhami, A.;
Nejabat, G. R. A green solventless protocol for Michael addition of phthalimide and sac-
charin to acrylic acid esters in the presence of zinc oxide as a heterogeneous and reusable
catalyst. Arkivoc 2007, 1, 58–69, and references cited therein; (b) Kumar, R.; Chaudhary,
P.; Nimesh, S.; Chandra, R. Polyethylene glycol as a non-ionic liquid solvent for Michael
addition reaction of amines to conjugated alkenes. Green Chem. 2006, 8, 356.
9. (a) Sibi, M. P.; Manyem, S. Enantioselective conjugate additions. Tetrahedron 2000, 56,
8033; (b) Zhou, W.; Li, L.; Xia, C.-G. Highly efficient aza-Michael reactions of aromatic
amines and N-heterocycles catalyzed by a basic ionic liquid under solvent-free conditions.
Tetrahedron Lett. 2006, 47, 7723; (c) Garg, S. K.; Kumar, R.; Chakraborti, A. K. Cop-
per(II) tetrafuoroborate as a novel and highly efficient catalyst for Michael addition of
mercaptans to a,b-unsaturated carbonyl compounds. Tetrahedron Lett. 2005, 46, 1721;
(d) Sharma, G.; Kumar, R.; Chakraborti, A. K. Fluoroboric acid adsorbed on silica gel
(HBF4–SiO2) as a new, highly efficient, and reusable heterogeneous catalyst for
thia-Michael addition to a,b-unsaturated carbonyl compounds. Tetrahedron Lett. 2008,
49, 4272; (e) Sharma, G.; Kumar, R.; Chakraborti, A. K. A novel environmentally
friendly process for carbon–sulphur bond formation catalyzed by montmorillonite clays.
J. Mol. Catal. A Chem. 2007, 263, 143, and references cited therein.
10. (a) Thomson, R. H. Naturally Occurring Quinones, 2nd ed. Academic Press: London,
1971; (b) Thomson, R. H. Naturally Occurring Quinones II: Recent Advances, 3rd ed.
Chapman and Hall: London, 1987; (c) Thomson, R. H. Naturally Occurring Quinones
IV: Recent Advances, 4th ed. Blackie Academic & Professional: London, 1997; (d)
Thomson, R. H. The total synthesis of naturally occurring quinones in the total synthesis
of natural products. In Naturally Occurring Quinones IV: Recent Advances, 4th ed., vol. 8;
Blackie Academic & Professional: London, 1997.
11. Sauriasari, R.; Wang, D.-H.; Takemura, Y.; Tsutsui, K.; Masuoka, N.; Sano, K.; Horita,
M.; Wang, B.-L.; Ogino, K. Cytotoxicity of lawsone and cytoprotective activity of anti-
oxidants in catalase mutant Escherichia coli. Toxicology 2007, 235, 103–111.
12. (a) Gardner, P. R. Superoxide production by the mycobacterial and pseudomonad qui-
noid pigments phthiocol and pyocyanine in human lung cells. Arch. Biochem. BioPhys.
1996, 333, 267–274; (b) Costaa, P. R. R., et al. Synthesis and preliminary pharmacological
evaluation of new (ꢂ) 1,4-naphthoquinones structurally related to lapachol. Bioorg. Med.
Chem. 2002, 10, 2731–2738; (c) Maeda, M.; Murakami, M.; Takegami, T.; Ota, T.
Promotion or suppression of experimental metastasis of B16 melanoma cells after oral
administration of lapachol. Toxicol. Appl. Pharmacol. 2008, 229, 232–238; (d) Ravelo,
A. G.; Estevez-Braun, A.; Perez-Sacau, E. The chemistry and biology of lapachol
´ ´
and related natural products a- and b-lapachones. Stud. Nat. Prod. Chem. 2003, 29,
719–760.
13. Ping, W.; Xiaohong, Z.; Shujiang, T.; Shu, Y.; Hanjie, Y.; Pingkai, O. New potential inhi-
bitors of DNA topoisomerase, part II: Design and synthesis of a-lapachone derivatives
under microwave irradiation. Bioorg. Med. Chem. Lett. 2009, 19, 828–830, and references
cited therein.

3118
D. VILLEMIN ET AL.
14. (a) Solorio-Alvarado, C. R.; Pen˜a-Cabrera, E.; Toledano, C. A. A short synthesis of two
analogues of parvaquone. Arkivoc 2004, 1, 64–70; (b) Kidwai, M.; Bhushan, K. R.; Sapra,
P.; Saxena, R. K.; Gupta, R. Alumina-supported synthesis of antibacterial quinolines
using microwaves. Bioorg. Med. Chem. 2000, 8, 69–72; (c) Munday, R.; Smith, B. L.;
Munday, C. M. Structure–activity relationships in the haemolytic activity and nephrotoxi-
city of derivatives of 1,2- and 1,4-naphthoquinone. J. Appl. Toxicol. 2007, 27, 262–269.
15. (a) Wolkenberg, S. E.; Boger, B. L. Mechanisms of in situ activation for DNA-targeting
antitumor agents. Chem. Rev. 2002, 102, 2417–2496; (b) Yao, D., et al. Synthesis and reac-
tivity of potential toxic metabolites of tamoxifen analogues: Droloxifene and toremifene
o-quinones. Chem. Res. Toxicol. 2001, 14, 1643–1653.
16. Villemin, D.; Cheikh, N.; Mostefa-Kara, B.; Bar, N.; Choukchou-Braham, N.; Didi, M.
A. Solvent-free reaction on KF-alumina under microwave: Serendipitous one-pot domino
synthesis of new isobenzofuran-1(3H)-ones from alpha-hydroxyketones. Tetrahedron Lett.
2006, 47, 5519–5521.
17. Villemin, D.; Nechab, B. A rapid and efficient one-pot synthesis of substituted 2-(5
H)-furanones under focused microwave irradiation. J. Chem. Res., Synop. 2000, 429–431.
18. Villemin, D.; Mostefa-Kara, B.; Bar, N.; Choukchou-Braham, N.; Cheikh, N.;
Benmeddah, A.; Hazimeh, H.; Ziani-Cherif, C. Base-promoted reactions in ionic liquid
solvent: Synthesis of butenolides. Lett. Org. Chem. 2006, 3, 558–559.
19. Villemin, D.; Benabdallah, Med.; Rahmoun, N.; Jouannic, C.; Choukchou-Braham, N.;
Mostefa-Kara, B. A green route for synthesis of 1,2-naphthoquinomethane acetonitriles
in water. Synth. Commun. (in press).
20. Gates, M.; Newhall, W. F. The synthesis of ring systems related to morphine, I:
9,10-Dioxo-13-cyanomethyl-5,8,9,10,13,14-hexahydrophenanthrene. J. Am. Chem. Soc.
1948, 70, 2261–2263.