# Simple Syntheses of Two New Benzo-Fused Macrocycles Incorporating Chalcone Moiety

Authors: Rina Mondal; Swati Samanta; Saheli Sarkar; Asok K. Mallik
Journal: International Scholarly Research Notices
 (2014)

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## Abstract

Simple syntheses of the benzo-fused 26-membered macrocyclic bischalcone (19E,43E)-2.11.27.36-tetroxaheptacyclo[44.4.0.04,9.012,17.021,26.029,34.037,42]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 the benzo-fused 13-membered macrocyclic chalcone (19E)-2.11-dioxatetracyclo[19.4.0.04,9.012,17]pentacosa-1(25),4(9),5,7,12(17),13,15,19,21,23-decaen-18-one (5) using very common starting materials and reagents are described. The compounds are new and they have been characterized from their analytical and spectral data.


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## Body

## 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)-2.11.27.36-tetroxaheptacyclo [44.4.0.04,9.012,17.021,26.029,34.037,42] 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[19.4.0.04,9.012,17] 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 ando-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 bischalcone3was obtained in moderate yield (Scheme 1). In order to achieve the synthesis of5, 2,2′-dihydroxychalcone (4) was first constructed fromo-hydroxyacetophenone and salicylaldehyde by Claisen-Schmidt reaction. The reaction between4 and 1,2-(bis-bromobenzyl)benzene was then done by following the typical procedure for alkylation of phenols (K2CO3/acetone, reflux, 12 h) (Scheme 2). This reaction gave5 in very good yield and no trace of any macrocyclic bischalcone7 (a possible product through bimolecular cyclization of the intermediate6) (Scheme 3).Scheme 1
Synthesis of the macrocyclic bischalcone3.Scheme 2
Synthesis of the macrocyclic monochalcone5.Scheme 3
A possible way of formation of macrocyclic bischalcone from6.The new compounds3 and5 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 http://dx.doi.org/10.1155/2014/485014.


## 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.1H and 13C NMR spectra were recorded in CDCl3 on a Bruker AV-300 (300 MHz) spectrometer. Analytical samples were routinely driedin vacuo at room temperature. Microanalytical data were recorded on a Perkin-Elmer 2400 Series II C, H, N analyzer. ESIMS(+) mass spectrum of3 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°C. 1H and 13C 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 fromo-xylene by benzylic bromination with NBS [NBS (2.2 equiv.), (PhCOO)2 (trace), refluxed in CCl4, 12 h, yield: 83%), m.p. 94°C (lit. [27] 92–96°C); 1H NMR (CDCl3): δ 4.66 (br. s, 4H, –CH2-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 7 h. Removal of methanol by distillation and addition of water followed by extraction with ethyl acetate gave crude alkylation product1, which was purified by rapid column chromatography followed by crystallization from CHCl3-petroleum ether (yield: 66%). The physical and spectral data of1 were as follows: colourless needles, m.p. 118–120°C; 1H NMR (300 MHz, CDCl3): δ 5.31 (br. s, 4H, 2 × –OCH2–), 7.05 (dt, 4H,J = 7.2 and 1.5 Hz), 7.42–7.45 (m, 2H, ArH), 7.50–7.57 (m, 4H), 7.82 (dd, 2H,J= 7.8 and 1.8 Hz), and 10.45 (br. s, 2H, 2 × –CHO).


### 3.3. 1,2-Bis(2-acetylphenoxymethyl)benzene (2)

A mixture ofo-hydroxyacetophenone (2 mmol), 1,2-bis(bromomethyl)benzene (1 mmol) and anhydrous K2CO3 (3 g.) 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 pure2(yield: 78%). The physical and spectral data of2 were as follows: colourless needles (CHCl3-petroleum ether), m.p. 74°C; 1H NMR (300 MHz, CDCl3): δ 2.53 (s, 6H, 2 × –COCH3), 5.27 (br. s, 4H, –OCH2), 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)-2.11.27.36-Tetroxaheptacyclo[44.4.0.04,9.012,17.021,26.029,34.037,42]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 dialdehyde1 (1 mmol) and the diketone2 (1 mmol) was dissolved in a KOH solution (10%, 75 mL) in MeOH-H2O (3 : 1) and the mixture was stirred at room temperature. A precipitate began to be formed afterca. 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 CHCl3-petroleum ether (yield: 49%). The analytical and spectral data of the macrocyclic product3 were as follows: light yellow cubes; m.p. 205–207°C; IR (KBr, cm−1): 1598 (C=O), 1567, 1485, 1446, 1384 cm−1; 1H NMR (300 MHz, CDCl3): δ 4.85 (s, 4H, –O–CH2–), 5.06 (s, 4H, –CH2–O–), 6.77 (d, 4H,J = 7.2 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 × H-α), 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 × H-β); 13C NMR (75 MHz, CDCl3): δ 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+):m/z 707.18 (M+Na)+, 685.19 (M+H)+. Elemental analysis: Calcd. for C46H36O6: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 ofo-hydroxyacetophenone and salicylaldehyde with aqueous alkali, m.p. 162–164°C (lit. [28] 168°C).1H NMR (300 MHz, CDCl3): δ 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 = 7.8 and 1.8 Hz), 7.52 (dt, 1H,J = 7.5 and 1.5 Hz), 7.63 (dd, 1H,J = 7.8 and 1.9 Hz), 7.87 (d, 1H,J = 15.6 Hz, H-α), 7.96 (dd, 1H,J = 8.1 and 1.5 Hz), 8.21 (d, 1H,J = 15.6 Hz, H-β), 12.92 (s, 1H, 2′-OH).


### 3.6. (19E)-2.11-Dioxatetracyclo[19.4.0.04,9.012,17]pentacosa-1(25),4(9),5,7,12(17),13,15,19,21,23-decaen-18-one (5)

To a mixture of4 (1 mmol) and 1,2-bis(bromomethyl)benzene (1 mmol) in dry acetone (25 mL), anhydrous K2CO3 (3 g) 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 pure5 as light yellow crystals (yield: 57%), m.p. 160–162°C, IR (KBr) cm−1: 3028, 2903, 1585, 1562, 1470, 1453, 1436, 1297, 1249, 1152, 1058, 960, 745. 1H NMR (300 MHz, CDCl3): δ 5.28 (s, 4H, 2 × ArCH2O–), 7.01–7.10 (m, 2H), 7.11 (d, 1H,J= 16.5 Hz, H-α), 7.23–7.38 (m, 7H), 7.45–7.51 (m, 2H), 7.58 (dd, 1H,J= 7.5 and 1.8 Hz, protonortho to C=O), 7.66 (d, 1H,J= 16.5 Hz, H-β), 13C NMR (75 MHz, CDCl3): δ 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+):m/z (M+Na)+ 365.00. Elemental analysis: Calcd. for C23H18O3: C, 80.68; H, 5.30. Found: C, 80.45; H, 5.44%.


## 3.1. 1,2-Bis(bromomethyl)benzene

This compound was prepared fromo-xylene by benzylic bromination with NBS [NBS (2.2 equiv.), (PhCOO)2 (trace), refluxed in CCl4, 12 h, yield: 83%), m.p. 94°C (lit. [27] 92–96°C); 1H NMR (CDCl3): δ 4.66 (br. s, 4H, –CH2-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 7 h. Removal of methanol by distillation and addition of water followed by extraction with ethyl acetate gave crude alkylation product1, which was purified by rapid column chromatography followed by crystallization from CHCl3-petroleum ether (yield: 66%). The physical and spectral data of1 were as follows: colourless needles, m.p. 118–120°C; 1H NMR (300 MHz, CDCl3): δ 5.31 (br. s, 4H, 2 × –OCH2–), 7.05 (dt, 4H,J = 7.2 and 1.5 Hz), 7.42–7.45 (m, 2H, ArH), 7.50–7.57 (m, 4H), 7.82 (dd, 2H,J= 7.8 and 1.8 Hz), and 10.45 (br. s, 2H, 2 × –CHO).


## 3.3. 1,2-Bis(2-acetylphenoxymethyl)benzene (2)

A mixture ofo-hydroxyacetophenone (2 mmol), 1,2-bis(bromomethyl)benzene (1 mmol) and anhydrous K2CO3 (3 g.) 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 pure2(yield: 78%). The physical and spectral data of2 were as follows: colourless needles (CHCl3-petroleum ether), m.p. 74°C; 1H NMR (300 MHz, CDCl3): δ 2.53 (s, 6H, 2 × –COCH3), 5.27 (br. s, 4H, –OCH2), 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)-2.11.27.36-Tetroxaheptacyclo[44.4.0.04,9.012,17.021,26.029,34.037,42]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 dialdehyde1 (1 mmol) and the diketone2 (1 mmol) was dissolved in a KOH solution (10%, 75 mL) in MeOH-H2O (3 : 1) and the mixture was stirred at room temperature. A precipitate began to be formed afterca. 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 CHCl3-petroleum ether (yield: 49%). The analytical and spectral data of the macrocyclic product3 were as follows: light yellow cubes; m.p. 205–207°C; IR (KBr, cm−1): 1598 (C=O), 1567, 1485, 1446, 1384 cm−1; 1H NMR (300 MHz, CDCl3): δ 4.85 (s, 4H, –O–CH2–), 5.06 (s, 4H, –CH2–O–), 6.77 (d, 4H,J = 7.2 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 × H-α), 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 × H-β); 13C NMR (75 MHz, CDCl3): δ 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+):m/z 707.18 (M+Na)+, 685.19 (M+H)+. Elemental analysis: Calcd. for C46H36O6: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 ofo-hydroxyacetophenone and salicylaldehyde with aqueous alkali, m.p. 162–164°C (lit. [28] 168°C).1H NMR (300 MHz, CDCl3): δ 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 = 7.8 and 1.8 Hz), 7.52 (dt, 1H,J = 7.5 and 1.5 Hz), 7.63 (dd, 1H,J = 7.8 and 1.9 Hz), 7.87 (d, 1H,J = 15.6 Hz, H-α), 7.96 (dd, 1H,J = 8.1 and 1.5 Hz), 8.21 (d, 1H,J = 15.6 Hz, H-β), 12.92 (s, 1H, 2′-OH).


## 3.6. (19E)-2.11-Dioxatetracyclo[19.4.0.04,9.012,17]pentacosa-1(25),4(9),5,7,12(17),13,15,19,21,23-decaen-18-one (5)

To a mixture of4 (1 mmol) and 1,2-bis(bromomethyl)benzene (1 mmol) in dry acetone (25 mL), anhydrous K2CO3 (3 g) 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 pure5 as light yellow crystals (yield: 57%), m.p. 160–162°C, IR (KBr) cm−1: 3028, 2903, 1585, 1562, 1470, 1453, 1436, 1297, 1249, 1152, 1058, 960, 745. 1H NMR (300 MHz, CDCl3): δ 5.28 (s, 4H, 2 × ArCH2O–), 7.01–7.10 (m, 2H), 7.11 (d, 1H,J= 16.5 Hz, H-α), 7.23–7.38 (m, 7H), 7.45–7.51 (m, 2H), 7.58 (dd, 1H,J= 7.5 and 1.8 Hz, protonortho to C=O), 7.66 (d, 1H,J= 16.5 Hz, H-β), 13C NMR (75 MHz, CDCl3): δ 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+):m/z (M+Na)+ 365.00. Elemental analysis: Calcd. for C23H18O3: C, 80.68; H, 5.30. Found: C, 80.45; H, 5.44%.


## 4. Conclusion

Thus, we report very simple syntheses of two new benzo-fused macrocycles incorporating chalcone moiety by the use of very common starting materials. The compounds may find important applications.



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*Source: 485014-2014-10-29.xml*