Synthesis of novel 6,6′-methylene-bis-[3-(2-anilinoacetyl)-4- hydroxycoumarin] derivatives

Article abstract of DOI:10.1248/cpb.56.1732

The synthesis of novel 6,6′-methylene-bis-[3-(2-anilinoacetyl)-4- hydroxycoumarin] derivatives 6a-f was achieved in excellent yields from 6,6′-methylene-bis-[3-(2-bromoacetyl)-4-hydroxycoumarin] 5 and various arylamines. 5,5′-Methylene-bis-ethylsalicylate 3 was obtained by the esterfication of 5,5′-methylene-bis-salicylic acid 2 with ethanol, which was in turn obtained from salicylic acid 1 and formaldehyde. Cyclocondensation of 3 with ethyl acetoacetate resulted in 6,6′-methylene-bis-[3-acetyl-4- hydroxycoumarin] 4, which on selective α-bromination with molecular bromine in the presence of montmorillonite K10-AlCl₃ catalyst, in chloroform-ethyl acetate binary solvent mixture at room temperature, afforded the compound 5 in excellent yield. All the newly synthesized compounds were characterized by their spectral data.

Full text of DOI:10.1248/cpb.56.1732

1732
Notes
Chem. Pharm. Bull. 56(12) 1732—1734 (2008)
Vol. 56, No. 12
Synthesis of Novel 6,6ꢀ-Methylene-bis-[3-(2-anilinoacetyl)-4-
hydroxycoumarin] Derivatives
Cherkupally SANJEEVA REDDY* and Mekala RAGHU
Department of Chemistry, Kakatiya University; Warangal–506 009, India.
Received August 7, 2008; accepted September 17, 2008; published online September 19, 2008
The synthesis of novel 6,6ꢀ-methylene-bis-[3-(2-anilinoacetyl)-4-hydroxycoumarin] derivatives 6a—f was
achieved in excellent yields from 6,6ꢀ-methylene-bis-[3-(2-bromoacetyl)-4-hydroxycoumarin] 5 and various aryl-
amines. 5,5ꢀ-Methylene-bis-ethylsalicylate 3 was obtained by the esterfication of 5,5ꢀ-methylene-bis-salicylic acid
2 with ethanol, which was in turn obtained from salicylic acid 1 and formaldehyde. Cyclocondensation of 3 with
ethyl acetoacetate resulted in 6,6ꢀ-methylene-bis-[3-acetyl-4-hydroxycoumarin] 4, which on selective a-bromina-
tion with molecular bromine in the presence of montmorillonite K10–AlCl3 catalyst, in chloroform–ethyl acetate
binary solvent mixture at room temperature, afforded the compound 5 in excellent yield. All the newly synthe-
sized compounds were characterized by their spectral data.
Key words 4-hydroxycoumarin; selective a-bromination; montmorillonite K10–AlCl3
3-Substituted 4-hydroxycoumarins are a class of fused ring
The coumarin 4 on selective a-bromination with molecu-
heterocycles which occur widely among natural products and lar bromine, in the presence of montmorillonite K10–AlCl3
have importance in medicine.1) Several natural products with catalyst in chloroform–ethyl acetate (1 : 2) binary solvent
the coumarinic moiety exhibit interesting biological and mixture at room temperature, afforded 6,6ꢀ-methylene-bis-
pharmacological properties such as antibacterial,2) anti- [3-(2-bromoacetyl)-4-hydroxycoumarin] 5 in 90% yield.
cancer,3) and inhibitory of platelet aggregation,4) steroid 5a-
reductase,5) and human immunodeficiency virus (HIV)-1
protease.6) Additionally, coumarin derivatives have been used
as active components in the formulation of pesticides, and
additives in manufacture of pharmaceuticals, foods, cosmet-
ics,1) laser dyes and fluorescent markers.7,8) Besides function-
alized coumarins, polycyclic coumarines such as
calanolides,9) isolated from Callophyllum genus and others,
have shown potent anti-HIV (NNRTI) activity. These proper-
ties turn coumarins into very interesting targets to organic
chemists, and several strategies for their synthesis were de-
veloped including Pechmann,10) Perkin,11) Knoevenagel,12)
Reformatsky,13) Claisen,14) Wittig15,16) reactions and Flash
vacuum pyrolysis.17) On the other hand, to the best of our
knowledge, there is no report on the synthesis of 6,6ꢀ-meth-
ylene-bis-[3-(2-anilinoacetyl)-4-hydroxycoumarin] and its
derivatives from any of the afore mentioned reactions using
any reagent. Therefore, in connection with our research on
the design and synthesis of biologically active and
pharmacologically important new heterocycles,18—20) it was
thought worthwhile to synthesize the title compounds with a
view to obtain certain new chemical entities with two active
pharmacophores in a single molecular frame work for the in-
tensified biological and pharmacological properties. The syn-
thetic route leading to the title compounds is summarized in
Chart 1.
For the synthesis of the target compounds 6a—f, the 5,5ꢀ-
methylene-bis-salicylic acid 2 was prepared in 87% yield by
the reaction of salicylic acid 1 with formaldehyde in the pres-
ence of sulfuric acid.21) Subsequent esterification of com-
pound 2 with ethanol in the presence of a catalytic amount of
sulfuric acid at reflux, gave 5,5ꢀ-methylene-bis-ethylsalicy-
late 3 in 84% yield.18) The ester 3 on cyclocondensation with
ethyl acetoacetate, in the presence of sodium ethoxide in
ethanol at reflux, afforded 6,6ꢀ-methylene-bis-[3-acetyl-4-hy-
droxycoumarin] 4 in 88% yield.18)
Chart 1
∗ To whom correspondence should be addressed. e-mail: chsrkuc@yahoo.co.in
© 2008 Pharmaceutical Society of Japan

December 2008
1733
Compound 5 on addition reaction with aniline in ethanol at
reflux gave, after purification by column chromatography, the
6,6ꢀ-methylene-bis-[3-(2-anilinoacetyl)-4-hydroxycoumarin]
6a in 88% isolated yield. The generality of this method was
extended with various arylamines (Chart 1) and the yields
of the products 6b—f were excellent (86—90%) regardless
structural variation in arylamine. Chemical structures of all
the newly synthesized compounds were confirmed by their
IR, 1H-NMR, 13C-NMR and mass spectral analysis.
A heterogenous system consisting of montmorillonite K10
and AlCl3 promotes the side chain bromination of compound
4 with molecular bromine, affording the required product 5
in excellent yield. Montmorillonite K10 and KSF behave as
ditopic catalysts containing both acidic and basic sites.22) The
basic sites ascribable to the negative charges dispersed over
entire sheets of oxygen atoms23) and act as proton acceptor in
the AlCl3 catalyzed enolization reactions.
Chart 2
The bifunctional array containing montmorillonite K10
and a Lewis acid i.e. AlCl3 coordinates and activates the ke-
Uchil and Joshi25) reported the side chain bromination of
tone forming the oxonium salt, which due to its electron at- 2ꢀ-hydroxyacetophenone using molecular bromine and het-
tracting power of the positively charged oxygen facilitates the erogenous catalyst system consisting of mont. K10–AlCl3 in
removal of an a-proton by the basic sites of montmorillonite ethyl acetate solvent but with low (76%) yield and poor
(mont.) thereby converting the compound 4 to its aluminium selectivity. 2ꢀ,6ꢀ-Dihydroxyacetophenone and 2ꢀ,3ꢀ,4ꢀ-trihy-
chloride complex of enol form (Chart 2), which reacts rap- droxyacetophenone resulted in nuclear brominated products.
idly with molecular bromine to give the bromo product 5.
However, in the present study, when coumarin 4 was bromi-
Side chain bromination reaction was also carried out using nated using the same catalyst system in chloroform–ethyl ac-
various combinations of the catalyst system such as (i) mont. etate binary solvent mixture, only side chain brominated
K10–AlCl3, (ii) mont. KSF–AlCl3, (iii) mont. K10, (iv) product 5 was obtained with high (94%) yield and there was
mont. KSF and (v) AlCl3. The yields (90, 84, 66, 60 and 62% no indication of nuclear bromination.
respectively) of the pure bromo product 5 obtained in all
The mixture of ethyl acetate and chloroform (2 : 1) was
these cases indicate that, mont. K10 is the most efficient pro- used for a-bromination of coumarin 4 since preliminary
moter of the reaction, due to its lower acidity value compared work indicated that this mixed solvent system gave cleaner
to that of mont. KSF.22) Using mont. KSF as the catalyst, a product than either solvent alone. We thus conclude that the
6% fall of yield was observed as compared to that of mont. present method using molecular bromine and heterogenous
K10. The yields of the bromo product 5 also indicate that the catalyst system such as mont. K10–AlCl3 in chloroform–
mixed system of mont. and AlCl3 is an efficient catalyst sys- ethyl acetate binary solvent mixture is the cleanest and the
tem than either component alone. In fact mont. promotes the most convenient method for the preparation of 6,6ꢀ-methyl-
AlCl3 catalyzed enolization of compound 4, wherein it acts ene-bis-[3-(2-bromoacetyl)-4-hydroxycoumarin] 5, which is
as a proton acceptor and increases the enol content of the reported for the first time.
compound 4 and hence an increase in the bromo product 5
yield.
Experimental
General All the reagents and solvents were used as purchased without
Montmorillonite catalyst being water insoluble and stable further purification. Melting points were determined on a Fisher–Johns melt-
ing point apparatus and are uncorrected. IR spectra were obtained on a
was simply recovered by filteration after pouring the reaction
mixture in water. It was washed with ethyl acetate, then with
methanol, air-dried and reused for four times without signifi-
cant loss of activity, giving the compound 5 in 90, 89, 87 and
85% yield respectively.
Perkin-Elmer BX serried FTIR 5000 spectrometer using KBr pellet. NMR
1
spectra were recorded on a Varian 300 MHz spectrometer for H-NMR and
100 MHz for 13C-NMR. The chemical shifts were reported as ppm down
field using TMS as an internal standard. Mass spectra were recorded on a
VG-Micromass 7070H spectrometer operating at 70 eV.
Typical Procedure 6,6ꢀ-Methylene-bis-[3-(2-bromoacetyl)-4-hydroxy-
coumarin] (5) A mixture of compound 4 (0.01 mol) in ethyl acetate
(10 ml) and anhydrous AlCl3 (5 mg) was stirred at room temperature for
15 min. To this, montmorillonite K10 (100 mg) was added and continued
stirring for further 15 min, then bromine (0.02 mol) in chloroform (5 ml) was
added dropwise at a slow rate while stirring. After complete addition of
bromine, stirring was continued for 30 min and the reaction mixture was
poured into 100 ml of cold water. The solid montmorillonite catalyst in the
resulting reaction mixture was recovered by filteration and washed with
fresh ethyl acetate (10 ml) followed by methanol (20 ml), dried and reused.
The methanol and the ethyl acetate washings were combined with the fil-
trate, transferred to a separating funnel and the organic layer was separated
from the aqueous layer. The organic layer was made neutral to pH by vigor-
ous shaking with water and brine solution, separated from the aqueous layer,
dried over anhydrous sodium sulphate, and distilled off under reduced pres-
sure. The crude product 5 obtained was purified by recrystallization from
ethanol.
The choice of solvent was also critical and had a marked
influence on the course of the reaction. Compound 4 did not
react with bromine in the presence of montmorillonite
K10–AlCl3 at an observable rate in carbon tetrachloride but
reacts readily in ethyl acetate and/or chloroform to give the
compound 5, however, better yields were obtained in chloro-
form–ethyl acetate solvent mixture. In SN2 bimolecular sub-
stitution reaction, the reaction will be faster in dipolar aprotic
solvents like ethyl acetate and chloroform than in a neutral
solvent such as carbon tetrachloride, resulting in better yield
and reduced reaction time. Protic solvents have highly devel-
oped structures held together by hydrogen bonds; aprotic sol-
vents have much looser structures and it is easier for a large
anion to be fitted in.24)

1734
Vol. 56, No. 12
6,6ꢀ-Methylene-bis-[3-(2-anilinoacetyl)-4-hydroxycoumarin] (6) To a
stirred solution of 5 (0.01 mol) in ethanol (20 ml) was added arylamine
3.99 (4H, d), 4.03 (2H, s), 6.17 (4H, d, Jꢂ7.8 Hz), 6.98 (4H, d, Jꢂ8.2 Hz),
7.18 (2H, d, Jꢂ8.3 Hz), 7.23 (2H, d, Jꢂ7.8 Hz), 7.56 (2H, s), 8.99 (2H, t),
(0.02 mol) and the mixture was refluxed for 2 h. After completion of the re- 11.41 (2H, s). 13C-NMR d: 19.5, 43.4, 47.4, 100.1, 115.2, 115.8, 117.2,
action (monitored by TLC), the reaction mixture was poured into ice-cold 118.2, 127.6, 130.6, 131.4, 136.3, 148.0, 148.1, 156.8, 179.0, 182.3. MS
water. The crude product formed as solid was filtered, dried and subjected to m/z: 630 (Mꢃ).
coloumn chromatography over silica gel using 30% EtOAc in hexane as elu-
6,6ꢀ-Methylene-bis-[3-(4-methoxy-2-anilinoacetyl)-4-hydroxy-
ent to obtain pure product 6. A similar procedure was used to prepare the coumarin] (6f) Yellow solid, yield 87%, mp 132—134 °C. IR (KBr) cmꢁ1
:
1
other compounds 6b—f.
3450—3360, 2870, 1720, 1565, 1465, 1223, 1175. H-NMR (DMSO-d6) d:
5,5ꢀ-Methylene-bis-salicylic acid (2) White solid, yield 87%, mp 3.99 (4H, d), 3.82 (6H, s), 4.03 (2H, s), 6.21 (4H, d, Jꢂ7.8 Hz), 6.95 (4H, d,
1
238—240 °C (dec.). IR (KBr) cmꢁ1: 3410, 3062, 1702. H-NMR (DMSO- Jꢂ8.2 Hz), 7.16 (2H, d, Jꢂ8.2 Hz), 7.25 (2H, d, Jꢂ7.7 Hz), 7.57 (2H, s),
d6) d: 3.99 (2H, s), 6.92 (2H, d, Jꢂ9.1 Hz), 7.38 (2H, d, Jꢂ9.1 Hz), 7.42
8.97 (2H, t), 11.40 (2H, s). 13C-NMR d: 19.6, 43.4, 47.4, 100.1, 115.2,
(2H, s), 9.87 (2H, s), 10.90 (2H, s). 13C-NMR d: 44.7, 111.2, 123.8, 132.6, 115.9, 117.4, 118.2, 127.7, 130.6, 131.4, 136.3, 148.1, 148.2, 156.7, 179.1,
133.9, 137.9, 161.3, 176.7. MS m/z: 288 (Mꢃ).
182.4. MS m/z: 662 (Mꢃ).
5,5ꢀ-Methylene-bis-ethylsalicylate (3) Pink solid, yield 84%, mp
220—222 °C (dec.). IR (KBr) cmꢁ1: 3367, 3062, 1718, 1220. 1H-NMR
(DMSO-d6) d: 1.41 (6H, t, Jꢂ7.2 Hz), 3.94 (2H, s), 4.30 (4H, q, Jꢂ7.2 Hz),
7.10—7.76 (6H, m), 11.20 (2H, s). 13C-NMR d: 16.0, 43.8, 60.3, 113.4,
119.7, 128.3, 130.1, 131.9, 154.1, 170.2. MS m/z: 344 (Mꢃ).
Acknowledgement The authors thank the Director, Indian Institute of
Chemical Technology, Hyderabad, India for providing the spectral data.
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1
3354, 1719, 1590, 1518, 1470, 1171. H-NMR (DMSO-d6) d: 3.95 (4H, d)
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1
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1
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1