A green route for synthesis of new 1,2-naphthoquinomethane acetonitriles in water

Article abstract of DOI:10.1080/00397910903457340

A series of new 2-(3-hydroxy-4-oxo-4H-naphthalen-1-ylidene) acetonitriles was prepared by the cascade Michael addition-elimination reaction of sodium 1,2-naphthoquinone-4-sulfonate with various substituted acetonitriles compounds in ethanol-water in prese

Full text of DOI:10.1080/00397910903457340

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A Green Route for Synthesis of New 1,2-
Naphthoquinomethane Acetonitriles in
Water
Didier Villemin a , Mohammed Benabdallah a b , Nadjib Rahmoun b ,
Cyril Jouannic a , Noureddine Choukchou-Braham b & Bachir Mostefa-
Kara b
a ENSICAEN, UCBN, LCMT-UMR 6507 CNRS, Caen, France
b Département de Chimie, Laboratoire de Catalyse et Synthèse en
Chimie Organique, Université de Tlemcen, Tlemcen, Algéria
Version of record first published: 05 Nov 2010.
To cite this article: Didier Villemin , Mohammed Benabdallah , Nadjib Rahmoun , Cyril Jouannic ,
Noureddine Choukchou-Braham & Bachir Mostefa-Kara (2010): A Green Route for Synthesis of New
1,2-Naphthoquinomethane Acetonitriles in Water, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 40:23, 3514-3521
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Synthetic Communications1, 40: 3514–3521, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903457340
A GREEN ROUTE FOR SYNTHESIS OF NEW
1,2-NAPHTHOQUINOMETHANE ACETONITRILES
IN WATER
Didier Villemin,1 Mohammed Benabdallah,1,2
Nadjib Rahmoun,2 Cyril Jouannic,1 Noureddine
Choukchou-Braham,2 and Bachir Mostefa-Kara2
1ENSICAEN, UCBN, LCMT-UMR 6507 CNRS, Caen, France
2
´
Departement de Chimie, Laboratoire de Catalyse et Synthese en Chimie
Organique, Universite de Tlemcen, Tlemcen, Algeria
`
´
´
A series of new 2-(3-hydroxy-4-oxo-4H-naphthalen-1-ylidene) acetonitriles was prepared
by the cascade Michael addition-elimination reaction of sodium 1,2-naphthoquinone-4-sul-
fonate with various substituted acetonitriles compounds in ethanol-water in presence of
basic catalyst.
Keywords: Antibacterial; cascade reaction; 1,2-naphthoquinomethane; water solvent
INTRODUCTION
Hydroxynaphthoquinones are well known for their chemical and biological
properties.[1] The hydroxynaphthoquinones like lawsone[2] and lapachol[3] (Fig. 1)
have drawn large interest for being natural products with interesting pharmacologi-
cal antitumoral, antiprotozoal, anti-inflammatory, antiviral, and antifungal proper-
ties.[4–6] Parvaquone, buparvaquone and atovaquone (Fig. 1)[7] represent three
synthetic naphthoquinones that were explored for use as antileishmanial and antima-
larial drugs during World War II, but this research was temporarily discontinued.
Other hydroxynaphthoquinones like conocurvone were shown to inhibit the
cytopathogenic efects of HIV-1 in human T-lymphoblastic cells.[8] Some have even
reached clinical use level. We are interested in the antimicrobial and antifungal
properties of new hydroxynaphthoquinone derivatives.
Although naphthoquinones are relatively well described, 2-hydroxyl-1,4-
naphthoquinomethanes remain poorly understood.[9] Naphthoquinomethanes are
the equivalent of quinomethanes as the reactive intermediate in benzenic serie.
[10,11]
Recently, organic reactions under green conditions, in water
or a benign
solvent like ethanol have received considerable attention, because of their environ-
mental, acceptability, abundance and low cost.
Received August 7, 2009.
Address correspondence to Didier Villemin, ENSICAEN, UCBN, LCMT-UMR 6507 CNRS,
´
Universite de Caen, Caen 14050, France. E-mail: didier.villemin@ensicaen.fr
3514

NEW 1,2-NAPHTHOQUINOMETHANE
3515
Figure 1. Natural products.
RESULTS AND DISCUSSION
Based on the Fieser synthesis,[9] we decided to investigate the synthesis of series
of new 2-hydroxynaphthoquinomethanes in aqueous from 1,2-naphthoquinone-4-
sulfonate 1 and substituted acetonitriles 2a–m. Synthesis of this type of compounds
involves a base catalyzed Michael-type addition, followed by a protonation
and elimination of a sulphur dioxide (Scheme 1). Production of 2-hydroxynaphtho-
quinomethanes 3a–m is achieved in moderate acceptable to excellent yields
(Table 1).
The results are reported in Table 1.
Scheme 1. Synthesis of 2-hydroxynaphthoquinomethanes in aqueous solvent.
Table 1. Synthesis of 2-hydroxynaphthoquinomethanes in aqueous solvent
Entry
R
Product
Yield (%)
1
2
CN
3a
3b
3c
3d
3e
3f
91
37
44
30
60
57
60
74
92
67
51
32
46
COOEt
CONH2
SCH3
3
4
5
thiophen-3-yl
phenyl
6
7
2,6-dichlorophenyl
3,4-dimethoxyphenyl
4-methoxyphenyl
4-nitrophenyl
4-chlorophenyl
1,3-phenylene
1,4-phenylene
3g
3h
3i
8
9
10
11
12
13
3j
3k
3l
3m

3516
D. VILLEMIN ET AL.
Scheme 2. Synthesis of bis-hydroxynaphthoquinones.
The one-pot two component condensation-elimination reactions of 1,2-
naphthoquinone-4-sulfonate with various active cyanomethylenes compounds, in
the presence of sodium hydroxide (25%) as a base, proceeded rapidly by heating
(40 ꢀC) the mixture in a water-ethanol mixture for 2 hours.
It is noteworthy that different bases (triethylamine, potassium tert-butoxide,
sodium ethoxide and potassium carbonate) have been tried to catalyze this reaction,
before retaining 25% NaOH in the water-ethanol mixture, for its convenience and in
respect to the criteria of ‘‘Green Chemistry.’’
The meta and paraphenylene diacetonitriles afford new bis-hydroxynaphtho-
quinomethanes (3l, 3m) (Scheme 2). These molecules can be of interest, some bisqui-
nones are natural products that possess a diverse array of biological activities.[8,12]
Because of the tautomeric equilibrium (Scheme 3), 2-hydroxynaphthoquino-
methane can be obtained in three different forms (A-C). Thus, the exact structures
obtained by our method were confirmed as compounds 3a–m in enolic form (B),
by several techniques (1HNMR, 13CNMR, IR, and MS).
The structures of 2-(3-hydroxy-4-oxo-4H-naphthalen-1-ylidene) acetonitriles
were modelled. Equilibrium geometry were optimized first by molecular mechanic
by using the force field MMFF and then by semi-empirical calculation with
PM3.[13] The best geometry obtained were calculated with density functional
B3LYP (6–31Gꢁ). Whereas the Lawsone has a plane structure, the structures of
the hydroxynaphthoquinomethanes are concave. The structures obtained with B
=
(R CN) and Lawsone were presented in Fig. 2.
The in vitro antibacterial activity of compounds 3a–m against four pathogenic
bacteria, namely Pseudomonas aeruginosa and Escherichia coli, which are grams (ꢂ),
Enterococcus faecalis and Staphylococcus aureus which are grams (þ), was investi-
gated and compared to gentamycin. Compounds 3j and 3k showed a very interesting
Scheme 3. Tautomeric equilibrium.

NEW 1,2-NAPHTHOQUINOMETHANE
3517
Figure 2. Structures of hydroxynaphthoquinomethanes.
antibacterial effect against Staphylococcus aureus and Enterococcus faecalis. This
research must be sustained for further optimizations.
EXPERIMENTAL
Melting points are determinated and uncorrected. IR spectra were obtained as
solids with a Fourier transform Perkin Elmer Spectrum One with ATR accessory.
1
Only significant absorptions are listed. The H NMR and 13C NMR spectra were
recorded in CDCl3 and DMSO-d6, with a Bruker AC 250 spectrometer. Mass
spectra were recorded on a QTOF Micro (Waters), ionisation electrospray positive
(ESI), lockspray PEG, infusion introduction (5 mL=min), source temperature
80 ꢀC, desolvatation temperature 120 ꢀC. Optimisation of conformations and theor-
etical calculations were performed with Spartan software.[13]
General Procedure for the Preparation of
2-Hydroxynaphthoquinomethane
A solution of acidic methylene compounds 2a–m (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 minutes, stirring was maintained and a
25% aqueous basic solution of soda (0.50 ml) was added. The mixture is stirred at
40 ꢀC for 2 hours. It cools the mixture and they are acidified by an acid solution
of HCl (37%) to give a solid that was collected, dried under vacuum and identified
as 2-hydroxynaphthoquinomethanes 3a–m.
2-(3-Hydroxy-4-oxo-4H-naphthalen-1-ylidene) malononitrile (3a). Obtained
from malonodinitrile (0.13 g, 1.92 mmol); green solid, 0.38 g (91%), Mp.: 189–190 ꢀC;
IR 3387, 2217, 2203, 1659, 1623, 1590, 1402, 1264 cmꢂ1; 1HNMR (DMSO) d (ppm)
7.56 (s, 1H), 7.72 (s, 1H), 7.77–7.84 (m, 2H), 8.29–8.33 (m, 1H), 8.90 (d, 1H);
13CNMR (DMSO) d (ppm) 40.8; 113.5; 114.6; 126.8; 128.6; 129.1; 130.1; 133.4;

3518
D. VILLEMIN ET AL.
134.6; 153.5; 155.4; 179.2; MS-ESI m=z [MþH]þ calcd. for C13H6N2O2 223.0508
found 223.0528; 205.1; 196.1; 169.1.
Cyano-(3-hydroxy-4-oxo-4H-naphthalen-1-ylidene) acetic acid ethyl
ester (3b). Obtained from ethyl cyanoacetate (0.21 g, 1.92 mmol); yellow solid,
0.19 g (37%), Mp.: 130 ꢀC [Lit.[14] 129.9–130.4 ꢀC]; IR 3342, 2205, 1703, 1654,
1
1629, 1591, 1229 cmꢂ1; HNMR (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 (m, 1H); 8.88 (d, 1H); 13CNMR
(CDCl3) d (ppm) 14.1; 63.1; 102.5; 110.5; 127.7; 128.1; 129.5; 132.1; 132.6; 134.0;
150.9; 151.2; 162.5; 179.5; MS-ESI m=z [MþH]þ calcd. for C15H11NO4 270.0766
found 270.0769; 242.2; 224.1; 214.2; 196.1.
2-Cyano-2-(3-hydoxy-4-oxo-4H-naphthalen-1-ylidene) acetamide (3c).
Obtained from cyanoacetamide (0.16 g, 1.92 mmol); yellow solid 0.2 g (44%), Mp.:
205–208 ꢀC; IR 3457, 3368, 2194, 1698, 1660, 1630, 1600, 1417, 1228 cmꢂ1; 1HNMR
(DMSO) d (ppm) 7.44 (s, 1H); 7.58–7.72 (m, 2H); 7.92 (s, 1H); 8.18 (d, 1H); 8.76 (d,
1H); 10.26 (s, 2H); 13CNMR (DMSO) d (ppm) 111.1; 113.1; 117.1; 124.2; 126.3;
128.3; 130.2; 132.4; 140.1; 147.9; 168,1; 179.7; MS-ESI m=z [MþH]þ calcd. for
C13H8N2O3 241.0614 found 241.0623; 223.1; 225.1; 214.2; 198.2.
2-(3-Hydroxy-4-oxo-4H-naphthalen-1-ylidene)-2-(methylthio) acetoni-
trile (3d). Obtained from methylthioacetonitrile (0.17 g, 1.92 mmol); orange solid
0.14 g (30%), Mp.: 188–190 ꢀC; IR 3281, 2198, 1620, 1593, 1417, 1225 cmꢂ1; 1HNMR
(CDCl3) d (ppm) 2.71 (s, 3H), 7.10 (s, 1H); 7.49 (s, 1H), 7.58–7.64 (m, 1H), 7.70–7.77
(m, 1H), 8.26–8.30 (m, 1H), 8.96 (d, 1H); 13CNMR (CDCl3) d (ppm) 17.5; 110.1;
112.9; 115.6; 125.3; 127,.4; 128.3; 130.1; 133.5; 138.1; 148.9; 179.9; MS-ESI m=z
[MþH]þ calcd. for C13H9NO2S : 244.0433 found 244.0444; 226.1; 217.1; 196.1.
2-(3-Hydroxy-4-oxo-4H-naphthalen-1-ylidene)-2-(thiophen-3-yl) aceto-
nitrile (3e). Obtained from 2-(thiophen-3-yl) acetonitrile (0.24 g, 1.92 mmol);
orange solid 0.32 g (60%), Mp.: 181 ꢀC; IR 3325, 2194, 1634, 1595, 1417, 1239 cmꢂ
1HNMR (CDCl3) d (ppm) 7.15 (s, 1H); 7.20 (s, 1H); 7.28–7.31 (m, 1H);
1
;
7.49–7.51 (m, 2H); 7.67 (t, 1H); 7.82 (t, 1H); 8.31–8.34 (m, 1H); 9.06 (d, 1H);
13CNMR (CDCl3) d (ppm) 108.1; 112.1; 120.1; 125.5; 127.3; 127.6; 128.7; 128.9;
129.2; 130.7; 132.9; 133.6; 135.3; 140.5; 149.3; 179.4; MS-ESI m=z [MþH]þ calcd.
for C16H9NO2S 280.0432 found 280.0442; 262.1; 253.1; 273.2; 234.1.
2-(3-Hydroxy-4-oxo-4H-naphthalen-1-ylidene)-2-phenylacetonitrile (3f).
Obtained from phenylacetonitrile (0.23 g, 1.92 mmol); yellow solid 0.30 g (57%),
1
Mp.: 198–200 ꢀC; IR 3321, 2193, 1632, 1595, 1415, 1224 cmꢂ1; HNMR (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 (d, 1H); 9.12 (d, 1H); 13CNMR (CDCl3) d (ppm) 112.1; 118.5; 126.6; 127.6;
129.2; 129.7; 129.9; 130.3; 130.8; 133.7; 141.1; 149.1; 179.4; MS-ESI m=z [MþH]þ
calcd. for C18H11NO2 274.0868 found 274.0.878; 256.2; 247.2; 228.2.
2-(2,6-Dichlorophenyl)-2-(3-hydroxy-4-oxo-4H-naphthalen-1-ylidene)
acetonitrile (3g). Obtained from 2,6-dichlorophenylacetonitrile (0.36 g,
1.92 mmol); yellow solid 0.39 g (60%), Mp.: 165–166 ꢀC; IR 3342, 2198, 1640,
1
1593, 1557, 1407, 1218 cmꢂ1; HNMR (CDCl3) d (ppm) 6.98 (s, 1H); 7.00 (s, 1H);
7.39–7.56 (m, 1H); 7.7–7.75 (t, 1H); 7.85–7.89 (t, 1H); 8.24–8.28 (m, 2H);

NEW 1,2-NAPHTHOQUINOMETHANE
3519
8.32–8.36 (m, 1H); 9.20 (d, 1H); 13CNMR (CDCl3) d (ppm) 111.4; 117.1; 120.2;
126.6; 129.3; 129.4; 130.6; 130.7; 131.6; 132.8; 133.7; 136.3; 141.5; 149.4; 179.4;
MS-ESI m=z [MþH]þ calcd. for C18H9Cl2NO2 342.0088, found 342.0098; 324;
315; 307; 271.
2-(3-Hydroxy-4-oxo-4H-naphthalen-1-ylidene)-2-(3,4-dimethoxyphenyl)
acetonitrile (3h). Obtained from (3,4-dimethoxyphenyl) acetonitrile (0.34 g,
1.92 mmol); red solid 0.47 g (74%), Mp.: 208–210 ꢀC; IR 3343, 2193, 1629, 1592,
;
1520, 1415, 1228 cmꢂ1 1HNMR (DMSO) d (ppm) 3.97 (s, 6H); 6.86 (s, 1H);
7.13–7.23 (m, 3H); 7.35 (s, 1H); 7.84 (t, 1H); 7.92 (t, 1H); 8.26 (m, 1H); 8.99 (d,
1H); 13CNMR (DMSO) d (ppm) 55.7; 55.7; 109.9; 111.7; 112.9; 113.3; 123.2;
125.5; 126.9; 127.1; 130.3; 130.4; 130.8; 131.9; 132.8; 148.8; 149.2; 149.9; 150.9;
178.9; MS-ESI m=z [MþH]þ calcd. for C20H15NO4: 334.1074 found 334.1079;
316.3; 307.3; 288.3.
2-(3-Hydroxy-4-oxo-4h-naphthalen-1-ylidene)-2-(4-methoxyphenyl) aceto-
nitrile (3i). Obtained from 4-methoxyphenylacetonitrile (0.28 g, 1.92 mmol); red
solid 0.54 g (92%), Mp.: 155–156 ꢀC; IR 3321, 2192, 1634, 1622, 1593, 1411,
1
1225 cmꢂ1; HNMR (CDCl3) d (ppm) 3.89 (s, 3H); 6.80–6.84 (d, 1H); 6.97 (s, 1H);
7.15–7.19 (d, 2H); 7.36–7.40 (d, 2H); 7.56–7.62 (t, 1H), 7.68–7.75 (t, 1H),
8.24–8.27 (d, 1H), 9.01 (d, 1H); 13CNMR (CDCl3) d (ppm) 55.5; 109.9; 112.4;
114.6;126.5; 127.5; 130.6; 132.1; 133.5; 141.1; 149.1; 160.0; 177.6; MS-ESI m=z
[MþH]þ calcd. for C19H13NO3 304.0974 found 304.0975; 286.2; 277.1; 258.1.
2-(3-Hydroxy-4-oxo-4H-naphthalen-1-ylidene)-2-(4-nitrophenyl) aceto-
nitrile (3j). Obtained from 4-nitrophenylacetonitrile (0.31 g, 1.92 mmol); brown
solid 0.41 g (67%), Mp.: 216–217 ꢀC; IR 3294, 2197, 1635, 1592, 1515, 1413,
1
1212 cmꢂ1; HNMR (CDCl3) d (ppm) 5.30 (s, 1H); 6.71 (s, 1H); 7.81 (t, 2H); 8.24
(d, 1H); 8.30 (d, 2H); 8.38 (d, 2H); 9.08 (d, 1H); 13CNMR (CDCl3) d (ppm) 109.9;
113.3; 124.4; 126.7; 127.9; 129.4; 131.1; 131.2; 131.4; 132.1; 134.1; 141.3; 149.9;
150.4; 179.3; MS-ESI m=z [MþH]þ calcd. for C18H10N2O4 319.0719 found
319.0721; 301.1; 292.1; 273.1.
2-(4’-Chlorophenyl)-2-(3-hydroxy-4-oxo-4H-naphthalen-1-ylidene) aceto-
nitrile (3k). Obtained from 4-chlorophenylacetonitrile (0.29 g, 1.92 mmol); brown
solid 0.30 g (51%), Mp.: 180–181 ꢀC; IR 3326, 2186, 1632, 1591, 1413, 1227 cmꢂ1
;
1HNMR (CDCl3) d (ppm) 6.84 (s, 1H); 7.06 (s, 1H); 7.41 (d, 2H); 7.49 (d, 2H);
7.71 (t, 1H); 7.82 (t, 1H); 8.33 (d, 1H); 9.06 (d, 1H); 13CNMR (CDCl3) d (ppm)
111.4; 117.1; 120.2; 126.6; 127.7; 129.4; 129.5; 131.6; 132.8; 133.8; 136.3; 141.5;
149.4; 179.4; MS-ESI m=z [MþH]þ calcd. for C18H10ClNO2 308.0474 found
308.0478; 290.2; 281.2; 273.2; 262.2.
Bis(2-(3-hydroxy-4-oxo-4h-naphthalen-1-ylidene)) meta-phenylene di-
acetonitrile (3l). Obtained from meta-Phenylene diacetonitrile (0.30 g, 1.92 mmol);
brown solid 0.29 g (32%), Mp.: 210 ꢀC; IR 3289, 2191, 1650, 1638, 1596, 1409,
1
1222 cmꢂ1 ; HNMR (DMSO) d (ppm) 6.67 (s, 2H); 6.74 (s, 2H); 7.31 (d, 1H);
7.68 (d, 2H); 7.78 (t, 4H); 7.91 (d, 1H); 8.24 (d, 2H); 8.99 (d, 2H); 13CNMR (DMSO)
d (ppm) 112.1; 118.9; 120.5; 122.1; 125.7; 127.1; 128.6; 128.9; 129.5; 130.7; 131.7;
133.1; 135.9; 142.3; 152.6; 179.3.

3520
D. VILLEMIN ET AL.
Bis(2-(3-hydroxy-4-oxo-4h-naphthalen-1-ylidene)) para-phenylene dia-
cetonitrile (3m). Obtained from para-Phenylene diacetonitrile (0.30 g, 1.92 mmol);
Orange solid 0.41 g (46%) Mp.: >250 ꢀC; IR 3319, 2192, 1645, 1630, 1584, 1419,
1
1212 cmꢂ1; HNMR (CDCl3) d (ppm) 6.78 (s, 2H); 7.04 (s, 2H); 7.21 (d, 2H); 7.68
(d, 2H); 7.79 (t, 4H); 8.44 (d, 2H); 8.89 (d, 2H); 13CNMR (CDCl3) d (ppm) 112.1;
118.6; 120.4; 126.7; 127.3; 128.8; 129.4; 130.2; 131.7; 133.2; 134.9; 142.6; 151.1; 179.2.
CONCLUSIONS
In conclusion, we have synthesized and screened the in vitro antibacterial
activity of new series of functionalized 1,2-naphthoquinomethane acetonitriles. A
mild base in water-ethanol medium, respecting ecological criteria, was used. Our
results are very promising since two of the compounds are similar to that of the
gentamycin antibiotic.
ACKNOWLEDGMENTS
The authors gratefully acknowledge the CNRS (Centre National de la
´
Recherche Scientifique), the (Region Basse-Normandie), the University ‘‘Abou-Bekr
Belkaid’’ of Tlemcen, and the European Union (FEDER funding) for their financial
support.
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