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Simple syntheses of two new benzo-fused macrocycles incorporating chalcone moiety.

1. Introduction

Chalcones (1,3-diphenyl-2-propen-1-ones) [1] are known to possess a range of important biological activities, such as antibacterial [2], antifungal [3], antileishmanial [4], antimalarial [4], antifilarial [5] anti-inflammatory [6-8], antiprotozoal (antileishmanial and antipanosomal) [9], antimicrobial [10-13], larvicidal [14], anticonvulsant [15], anti-HIV [16], antitumor [17], and anticancer [18] activities, and they could be readily transformed into varieties of other compounds, many of which are biologically active heterocycles [19, 20]. Owing to such biological activities of chalcones, the chemical literature shows the synthesis of a wide range of chalcones and their analogues [4, 8-13, 21-23]. Again, since macrocyclic compounds are well-known for their ability to show the important property of molecular recognition, macrocyclic systems containing the chalcone moiety are expected to generate compounds having interesting biological and material properties [24, 25]. Our research on such compounds has been initiated through the synthesis of a number of macrocyclic bis- and monochalcones reported recently [26]. In continuation of that study we have synthesized a benzo-fused 26-membered macrocyclic bischalcone, namely, (19E,43E)- [44.4.0.[0.sup.4,9].[0.sup.12,17].[0.sup.21,26].[0.sup.29,34].[0.sup.37,42]] pentaconta-1(46),4(9),5, 7,12(17),13,15,19,21,23,25,29,31,33,37,39,41,43,47,49-icosaene 18,45-dione (3), and a benzo-fused 13-membered macrocyclic monochalcone, namely, (19E)-2.11-dioxatetracyclo[19.4.0. [0.sup.4,9].[0.sup.12,17]] pentacosa-1(25),4(9),5,7,12(17),13,15,19,21,23-decaen-18-one (5), by use of readily available starting materials. Herein we report the synthesis of these two hitherto unknown compounds.

2. Results and Discussion

Alkylation products of salicylaldehyde and o-hydroxyacetophenone by the use of 1,2-(bis-bromobenzyl)benzene as alkylating agent were first prepared. The resulting dialdehyde (1) and diketone (2), both new compounds, were then subjected to Claisen-Schmidt reaction under high dilution condition when the macrocyclic bischalcone 3 was obtained in moderate yield (Scheme 1). In order to achieve the synthesis of 5, 2,2,-dihydroxychalcone (4) was first constructed from o-hydroxyacetophenone and salicylaldehyde by Claisen-Schmidt reaction. The reaction between 4 and 1,2(bis-bromobenzyl)benzene was then done by following the typical procedure for alkylation of phenols ([K.sub.2]C[O.sub.3]/acetone, reflux, 12 h) (Scheme 2). This reaction gave 5 in very good yield and no trace of any macrocyclic bischalcone 7 (a possible product through bimolecular cyclization of the intermediate 6) Scheme 3).



The new compounds 3 and 5 were characterized from their analytical and spectral data which are presented in the Experimental Section as well as in the Supplementary File in the Supplementary Material available online at

3. Experimental

Melting points were taken in open capillary tubes and are uncorrected. IR spectra were recorded on a Perkin Elmer FT-IR spectrophotometer (Spectrum BX II) in KBr pellets. [sup.1]H and [sup.13]C NMR spectra were recorded in CD[Cl.sub.3] on a Bruker AV-300 (300 MHz) spectrometer. Analytical samples were routinely dried in vacuo at room temperature. Microanalytical data were recorded on a Perkin-Elmer 2400 Series II C, H, N analyzer. ESIMS(+) mass spectrum of 3 was measured with a Waters Micromass Q-Tof micro instrument. Column chromatography was performed with silica gel (100-200 mesh) and TLC with silica gel G made of SRL Pvt. Ltd. Petroleum ether used had the boiling range of 60-80[degrees]C.1 H and [sup.13]C NMR and mass spectra of different compounds can be found in the Supplementary Material.

3.1. 1,2-Bis(bromomethyl)benzene. This compound was prepared from o-xylene by benzylic bromination with NBS [NBS (2.2 equiv.), [(PhCOO).sub.2] (trace), refluxed in C[Cl.sub.4], 12 h, yield: 83%), m.p. 94[degrees]C (lit. [27] 92-96[degrees]C); [sup.1]H NMR (CD[Cl.sub.3]): [delta] 4.66 (br. s, 4H, -C[[].sub.2]-Br), 7.29-7.31 (m, 2H, Ar-H), 7.33-7.38 (m, 2H, Ar-H).

3.2.1,2-Bis(2-formylphenoxymethyl)benzene (1). A mixture of salicylaldehyde (2 mmol) and 1,2-bis(bromomethyl)benzene (1 mmol) was refluxed in methanolic KOH (5%, 25 mL) for 7h. Removal of methanol by distillation and addition of water followed by extraction with ethyl acetate gave crude alkylation product 1, which was purified by rapid column chromatography followed by crystallization from CH[Cl.sub.3] petroleum ether (yield: 66%). The physical and spectral data of 1 were as follows: colourless needles, m.p. 118-120[degrees]C; 1H NMR (300 MHz, CD[Cl.sub.3]): [delta] 5.31 (br. s, 4H, 2 x -OC[H.sub.2-]), 7.05 (dt, 4H, J = 7.2 and 1.5 Hz), 7.42-7.45 (m, 2H, ArH), 7.50-7.57 (m, 4H), 782 (dd, 2H, J = 7.8 and 1.8 Hz), and 10.45 (br. s, 2H, 2 x -C[]O).

3.3. 1,2-Bis(2-acetylphenoxymethyl)benzene (2). A mixture of o-hydroxyacetophenone (2 mmol), 1,2-bis(bromomethyl) benzene (1mmol) and anhydrous [K.sub.2]C[O.sub.3] (3g.) was refluxed in dry acetone for 12 h. Usual work-up followed by purification of the resulting crude material by column chromatography over silica gel afforded pure 2 (yield: 78%). The physical and spectral data of 2 were as follows: colourless needles (CH[Cl.sub.3]-petroleum ether), m.p. 74[degrees]C; [sup.1]H NMR (300 MHz, CD[Cl.sub.3]): 5 2.53 (s, 6H, 2 x -COC[H.sub.3]), 5.27 (br. s, 4H, -OC[H.sub.2]), 7.03 (dt, 4H, J = 8.4 and 1.8 Hz), 7.40-7.46 (m, 4H), 7.54 (dt, 2H, J = 8.4 and 1.8 Hz), and 7.71 (dd, 2H, J = 7.8 and 1.8 Hz).

3.4. (19E,43E)-2.n.27.36-Tetroxaheptacyclo[44.4.0.[0.sup.4,9].[0.sup.12,17]. [0.sup.21,26].[0.sup.29,34].[0.sup.37,42]]pentaconta-1(46), 4(9), 5,7,.12(17), 13,15,19,21, 23,25,29,31,33,37, 39,41,43,47,49-icosaene-18,45-dione (3). A mixture of the dialdehyde 1 (1 mmol) and the diketone 2 (1mmol) was dissolved in a KOH solution (10%, 75 mL) in MeOH-[H.sub.2]O (3 : 1) and the mixture was stirred at room temperature. A precipitate began to be formed after ca. 5 h of stirring. The stirring was continued for 72 h and then the solid was collected. The solid thus obtained was almost pure and it was further purified by column chromatography over silica gel followed by crystallization from CH[Cl.sub.3]-petroleum ether (yield: 49%). The analytical and spectral data of the macrocyclic product 3 were as follows: light yellow cubes; m.p. 205-207[degrees]C; IR (KBr, [cm.sup.-1]): 1598 (C=O), 1567, 1485, 1446,1384 [cm.sup.-1]; [sup.1]H NMR (300 MHz, CD[Cl.sub.3]): [delta] 4.85 (s, 4H, -O-C[[].sub.2-]), 5.06 (s, 4H, -C[[].sub.2-]O-), 6.77 (d, 4H, J = 72 Hz), 6.80 (t, 2H, J = 7.5 Hz), 6.97 (t, 4H, J = 7.8 Hz), 7.18-7.26 (m, 10H), 7.27 (d, 2H, J = 16.2 Hz, 2 x H-[alpha]), 7.38 (dt, 2H, J = 7.5 and 1.5 Hz), 7.47 (dd, 2H, J = 8.4 and 1.5 Hz), 7.70 (d, 2H, J = 16.2 Hz, 2 x H-[beta]); [sup.13]C NMR (75 MHz, CD[Cl.sub.3]): S 68.23, 68.48, 112.47, 112.75, 121.04, 121.21, 123.98, 127.65, 128.10, 128.11, 128.48, 129.40, 129.60, 130.10, 130.21, 131.47, 132.23, 133.81,134.42,140.17, 156.42,157.10,194.64 (C=O); MS (TOF MS [ES.sup.+]): m/z 707.18 [(M+Na).sup.+], 685.19 [(M+H).sup.+]. Elemental analysis: Calcd. for [C.sub.46][H.sub.36][O.sub.6]:C, 80.68; H, 5.30. Found: C, 80.56; H 5.42%.


3.5. 2,2 -Dihydroxychalcone (4). This chalcone was prepared by condensation of o-hydroxyacetophenone and salicylaldehyde with aqueous alkali, m.p. 162-164[degrees]C (lit. [28] 168[degrees]C). [sup.1]H NMR (300 MHz, CD[Cl.sub.3]): [delta] 5.74 (br. s, 1H, 2-OH), 6.88 (br. d, 1H, J = 8.1 Hz), 6.94-7.07 (m, 3H), 7.32 (dt, 1H, J = 78 and 1.8 Hz), 752 (dt, 1H, J = 7.5 and 1.5 Hz), 7.63 (dd, 1H, J = 78 and 1.9 Hz), 7.87 (d, 1H, J = 15.6 Hz, H-[alpha]), 7.96 (dd, 1H, J = 8.1 and 1.5 Hz), 8.21 (d, 1H, J = 15.6 Hz, H-[beta]), 12.92 (s, 1H, 2'-OH). 3.6. (19E)-2.U-Dioxatetracyclo[19.4.0.()4'9.012'17]pentacosa-1(25),4(9),5,7,12(17),13,15,19,21,23-decaen-18-one (5). To a mixture of 4 (1mmol) and 1,2-bis(bromomethyl)benzene (1mmol) in dry acetone (25 mL), anhydrous [K.sub.2]C[O.sub.3] (3g) was added and the mixture was refluxed with stirring for 12 h. Usual work-up of the reaction mixture followed by chromatography of the crude product over silica gel using petroleum ether-ethyl acetate (90: 10, v/v) gave pure 5 as light yellow crystals (yield: 57%), m.p. 160-162[degrees]C, IR (KBr) [cm.sup.-1]: 3028,2903,1585,1562,1470,1453,1436,1297,1249,1152, 1058, 960, 745. [sup.1]H NMR (300 MHz, CD[Cl.sub.3]): S 5.28 (s, 4H, 2 x ArC[H.sub.2][O.sub.-]), 7.01-7.10 (m, 2H), 7.11 (d, 1H, J = 16.5 Hz, H-[alpha]), 7.23-7.38 (m, 7H), 7.45-7.51 (m, 2H), 7.58 (dd, 1H, J = 75 and 1.8 Hz, proton ortho to C=O), 7.66 (d, 1H, J = 16.5 Hz, H-[beta]), [sup.13]C NMR (75 MHz, CD[Cl.sub.3]): S 68.65, 71.70, 113.51, 119.01, 121.67, 123.46, 128.43, 128.81, 129.19, 129.77, 129.79, 129.87, 130.68, 130.88, 131.89, 132.62, 135.18, 135.29, 141.56, 156.71, 156.97, 195.23. MS (TOF MS [ES.sup.+]): m/z [(M+Na).sup.+] 365.00. Elemental analysis: Calcd. for [C.sub.23][H.sub.18][O.sub.3]: C, 80.68; H, 5.30. Found: C, 80.45; H, 5.44%.

4. Conclusion

Thus, we report very simple syntheses of two new benzofused macrocycles incorporating chalcone moiety by the use of very common starting materials. The compounds may find important applications. 10.1155/2014/485014

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.


Financial assistance from the DST-PURSE program, Department of Chemistry, and the UGC-UPE-II program to Jadavpur University is gratefully acknowledged. The authors also acknowledge the DST-FIST program to the Department of Chemistry, Jadavpur University, for providing the NMR spectral data. Rina Mondal and Saheli Sarkar are thankful to the UGC and Swati Samanta is thankful to the CSIR, New Delhi, for their research fellowships.


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Rina Mondal, Swati Samanta, Saheli Sarkar, and Asok K. Mallik

Department of Chemistry, Jadavpur University, Kolkata 700 032, India

Correspondence should be addressed to Asok K. Mallik;

Received 28 June 2014; Revised 27 September 2014; Accepted 3 October 2014; Published 29 October 2014

Academic Editor: Virinder S. Parmar
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Title Annotation:Research Article
Author:Mondal, Rina; Samanta, Swati; Sarkar, Saheli; Mallik, Asok K.
Publication:International Scholarly Research Notices
Article Type:Report
Date:Jan 1, 2014
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