Synthesis of novel 2,2-disubstituted naphthodioxoles via an unprecedented reaction

Article abstract of DOI:10.1016/j.tetlet.2012.01.126

A reaction of 2,3-dihydroxynaphthalene with ethyl-2,3-dibromo-3-phenyl- propionate or 1,3-diaryl-2,3-dibromo ketone under basic conditions led to the formation of novel 2,2-disubstituted naphthodioxoles.

Full text of DOI:10.1016/j.tetlet.2012.01.126

Tetrahedron Letters 53 (2012) 1905–1907
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of novel 2,2-disubstituted naphthodioxoles via an
unprecedented reaction
Satish Kumar a, Pallvi a, Shally Chadha a, Sumita Dham b, Tanya Hundal c, Kamal K. Kapoor a,
⇑
a Department of Chemistry, University of Jammu, Jammu 180 006, India
b Government College for women, Parade, Jammu 180 001, India
c Department of Chemistry, University of Delhi, Delhi 110 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A reaction of 2,3-dihydroxynaphthalene with ethyl-2,3-dibromo-3-phenyl-propionate or 1,3-diaryl-2,3-
dibromo ketone under basic conditions led to the formation of novel 2,2-disubstituted naphthodioxoles.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 29 November 2011
Revised 28 January 2012
Accepted 30 January 2012
Available online 8 February 2012
Keywords:
Naphthodioxoles
Unprecedented reaction
Dihydroxynaphthalene
The 1,4-benzodioxines are potent biologically active molecules,
reported to possess anti-cancer activity1 and most of them are cura-
tive against the remotely sited Lewis Lung carcinoma.2 They are
known to have an affinity for adrenergic receptor sites and the
strongly basic or quartenary side chains seem to be a prerequisite
for adrenergic neurone blockade.3 2,2-disubstituted benzodioxoles
are widely used as pesticides or pesticide intermediates,4 herbi-
cides,5 anti-oxidants,6 and inhibitors of mono-oxygenase7 enzymes.
A series of benzodioxoles is reported as cannabinoid-1 receptor in-
verse agonists for the treatment of obesity and the (+)-[(R)-2-(2,4-
dichloride-phenyl)-6-fluoro-2-(4-fluorophenyl)-benzo[1,3]dioxol-
5-yl]-morpholin-4-yl-methanone) 1 has shown promising results.8
The 2,2-disubstituted-5-hydroxy-1,3-benzodioxoles 2 are shown to
have greater anti-oxidant effects than the parent sesamol
(5-hydroxybenzo[1,3]dioxole) due to the introduction of lipophilic
side chain at position 2 on the dioxole ring.9
O
O
CH3
R1
O
O
N
O
O
HO
F
2
1
F
O
O
COOEt
X
Br
O
OH
OH
5
K2CO3
OEt
Br
acetone, reflux
3
4
EtOOC
O
O
6
Scheme 1. Synthesis of ethyl-2-(2-phenylnaphtho[2,3-d][1,3]dioxol-2-yl)-acetate.
⇑
Corresponding author.
E-mail address: k2kapoor@yahoo.com (K.K. Kapoor).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.126

1906
S. Kumar et al. / Tetrahedron Letters 53 (2012) 1905–1907
Figure 1. Showing an ORTEP view of the molecule at 50% probability and its labeling scheme.
Naphthodioxoles have been prepared from 2,3-dihydroxynaphtha-
In view of the rich biological activities associated with benzodi-
oxines, we wished to prepare novel naphthodioxines to study their
biological activity.
lene by treatment with diazodiphenylmethane and dichlorodicyanoqui-
none,13 thiophosgene,14 bromochloromethane,15 1-ethynesulfonyl-4-
methylbenzene,16 dimethylacetylene-dicarboxylate (DMADC).17
2,3-Dihydroxynaphthlene was treated10 with ethyl-2,3-dibro-
mo-3-phenylpropionate in the presence of anhydrous potassium
carbonate and to our chagrin, the formation of the desired product
naphtho(2,3-b)[1,4]-dioxine 5 did not occur as revealed by the
NMR (1H and 13C) data. Analysis of spectroscopic data (vide experi-
mental), spoke in favor of the formation of ethyl-2-(2-phenylnaph-
tho[2,3-d][1,3]dioxol-2-yl)-acetate 611 (Scheme 1).
The most diagnostic signal in the 1H NMR spectrum being the
singlet at d 3.35 for 2-protons in the aliphatic region. Further cor-
roboration to the proposed structure 6 came from the X-ray crys-
tallographic data.12 Figure 1 shows the ORTEP diagram of 6. All
the bond lengths and bond angles are normal. A least square plane
may be passed through the naphthodioxole moiety with the ester
and the phenyl groups lying almost perpendicular on each side of
this plane as shown below in Figure 2 forming a T-shaped
structure.
There are weak C–Hꢀ ꢀ ꢀO type H-bonding interactions found in
the crystal structure (Fig. 3). Each molecule is H-bonded to its cen-
trosymmetric counterpart through the aryl carbon C3 and dioxole
oxygen O2 (C3–H3ꢀ ꢀ ꢀO2i) forming a self assembled dimer, down
the a axis. These dimers are further strengthened by C3–H3ꢀ ꢀ ꢀO4i
and C5–H5ꢀ ꢀ ꢀO4i H-bonding interactions Figure 3a. These H-
bonded dimers are further attached to each other through H-bond-
ing interactions of phenylene carbon C18 with carbonyl oxygen O3
(C18–H18ꢀ ꢀ ꢀO3ii) and dioxole oxygen O1 (C18–H18ꢀ ꢀ ꢀO1ii) forming
a linear chain running along the b axis. These chains are also sup-
ported by C–Hꢀ ꢀ ꢀ
p interactions between methyl carbon C15 and
the naphthalene moiety with a C–Hꢀ ꢀ ꢀ
p (centroid) distance of
0
3.024(5) ÅA (shown as H1ꢀ ꢀ ꢀC10 interaction in Fig. 3b). These cen-
trosymmetric chains form a 3D network due to
between symmetry related phenylene and naphthalene rings.
To explore the scope of reaction, a variety of ,b-dibromochal-
pꢀ ꢀ ꢀ
p interactions
a
Figure 2. Showing a T-shaped structure of the molecule with the naphthalene-
dioxide ring in a plane.
cones (Scheme 2) were used and the results are depicted in
(Table 1).

S. Kumar et al. / Tetrahedron Letters 53 (2012) 1905–1907
1907
Figure 3. Showing the self assembled dimer (a) and a linear tape (b) running along the b axis. C (green), O (red), H(grey).
R2OC
O
Br
O
R1
R1
OH
OH
K2CO3
R2
Br
O
acetone, reflux
8
3
7
Scheme 2. Synthesis of 2,2-disubstituted napthodioxoles from 1,3-diaryl-2,3-dibromoketone.
3. (a) McLean, R. A.; Geus, R. J.; Mohrbacher, R. J.; Mattis, P. A.; Ullyot, G. E. J.
Pharmacol. Exp. Ther. 1960, 129, 11; (b) Exley, K. A. Brit. J. Pharmacol. 1957, 12,
297.
4. (a) Anderson, M., Brinnard, A. G., Woodall, R. E. Eur. Patent 235642, 1992.; (b)
Tozzi, A. Eur. Patent 11874, 1993.; (c) Anderson, M., Brinnard, A. G., Woodall, R.
E. Eur. Patent, 95537, 1993.
5. Arndt, F.; Franke, H. Ger. Patent 1976, 2624822.
6. Minh, T. H.; Cole, E. R.; Crank, G. Aust. patent 1980, 533866.
7. Cole, E. R.; Crank, G.; Minh, H. T. Aust. J. Chem. 1980, 33, 675.
8. Alig, L.; Alsenz, J.; Andjelkovic, M.; Bendels, S.; Benardeau, A.; Bleicher, K.;
Bourson, A.; Pierson, P. D.; Guba, W.; Idbrand, S. H.; Plancher, J. M. J. Med. Chem.
2008, 51, 2115–2127.
Table 1
Synthesis of 2,2-disubstituted napthodioxoles from 1,3-diaryl-2,3-dibromoketone
S. No.
R1
R2
Yield (%)
mp (°C)a
a
b
c
d
e
f
H
H
H
H
4-Cl
4-Me
4-Br
C6H5
65
70
68
65
75
70
65
172–174
215–216
202–203
227–229
218–219
205–206
235–236
4-ClC6H4
4-MeC6H4
4-BrC6H4
C6H5
C6H5
C6H5
g
9. Cole, E. R.; Crank, G.; Minh, H. J. Agric. Food Chem. 1982, 30, 719–724.
10. Quaglia, W.; Pigini, M.; Tayebati, S. K.; Piergentili, A.; Giannella, M.; Marucci,
G.; Melchiorre, C. J. Med. Chem 1993, 36, 1520–1528.
a
Melting points are uncorrected.
11. Procedure for preparation of ethyl-2-(2-phenylnaphtho[2,3-d][1,3]dioxol-2-yl)-
acetate, 6: A mixture of 2,3-dihydroxynaphthalene (0.8 g, 5 mmol) and ethyl-
2,3-dibromo-3-phenyl propionate (1.7 g, 5 mmol) in 30 ml of dry acetone was
refluxed with stirring in presence of 1 g of anhydrous K2CO3 for 6–7 h. After the
completion of reaction (TLC), the reaction mixture was filtered to separate
K2CO3 and acetone was distilled off. The residue after dilution with
ethylacetate (50 mL) was washed with water (15 mL), dil NaOH (5 mL), brine
(5 mL) and dried (Na2SO4). The solution was concentrated and the residue
obtained was column chromatographed using gradient of pet ether and ethyl
acetate mixture to yield the desired product 6 (1.1 g, 65%). MP: 82 °C, 1H NMR
(CDCl3, 300 MHz): d 7.65–7.14 (m, 11H), 4.02 (q, 2H, J = 7.1 Hz), 3.35 (s, 2H),
1.03 (t, 3H, J = 7.1 Hz); 13C NMR (CDCl3, 75 MHz): d 167.34 (C, O–C@O), 147.28,
139.35, 130.46, 129.84, 129.31, 128.40, 126.96, 125.18, 124.24, 115.08, 103.96,
60.92 (CH2, OCH2CH3), 45.26, 13.84 (CH3, OCH2CH3); MS(ESI) m/z: 334.93
[M+1]+. Anal. calcd for C21H18O4: C, 75.51; H, 5.38%. Found: C, 75.46; H, 5.43.
12. Crystal data: C21 H18 O4, Mol. Wt. 334.35, k = 0.71069 Å, monoclinic, P21/n,
In summary the reaction provides an easy and mild method for
the formation of 2,2-disubstituted naphthodioxoles from easily
and cheaply available starting materials.
Acknowledgments
The authors wish to thank the Department of Chemistry, Uni-
versity of Jammu for providing laboratory facilities, IIIM Jammu
for recording the analytics and DST, GOI (Project No. SR/S1/OC-
38/2010) for funding.
a = 13.410(5) Å,
b = 8.307(4) Å,
c = 15.572(5) Å,
b = 92.890(5) Å,
Supplementary data
V = 1732.5(12) Å3, Z = 4, R1 = 0.0704, wR2 = 0.1312(for observed data),
R1 = 0.1899, wR2 = 0.1780 for all data. CCDC No. 831678. The relevant
crystallographic and refinement parameters, important bond lengths and
angles and H-bonds are given in Supplementary data.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.01.126.
13. Oshima, T.; Nishioka, R.; Nagai, T. Tetrahedron Lett. 1980, 21, 3919–3922.
14. Gleiter, R.; Uschmann, J. J. Org. Chem. 1986, 51, 370–380.
15. Zelle, R. E.; McClellan, N. J. Tetrahedron Lett. 1991, 32, 2461–2464.
16. Llubes, M.; Mazzega, P. Synthesis 1996, 12, 1481–1484.
17. Fan, M. J.; Li, G. Q.; Li, L. H.; Yang, S. D.; Liang, Y. M. Synthesis 2006, 14, 2286–
2292.
References and notes
1. Barron, D. I.; Bavin, P. M. G.; Durant, G. J.; Natoff, I. L.; Spickett, R. G. W.;
Vallence, D. K. J. Med. Chem. 1963, 6, 705.
2. Lee, H. H.; Palmer, B. D.; Boyd, M.; Baguley, B. C.; Denny, W. A. J. Med. Chem.
1992, 35, 258.