Indian Journal of Chemistry Vol. 40B, May 2001 , pp. 372-376

Synthesis of some new 3-(bromophenyl)isocoumarins and their conversion to (dl)-3,4-dihydroisocoumarins

Muhammad T Hussain l, Nasim H Ramal· & Abdul Malik2

lDepartment of Chemistry, Quaid-i-Azam University Islamabad-45320, Pakistan 2H.EJ. Research Institute of Chemistry, University of Karachi-75270, Pakistan

Received 24 September 1998; accepted (revised) 23 October 2000

3-(Bromophenyl)isocoumarins 8a-c have been synthesized by the condensation of homophthalic acid 6 with bromobenzoyl chlorides 7a-c which on alkaline hydrolysis give keto-acids 9a-c. (dl)-3-(Bromophenyl)-3,4-dihydroisocoumarins 12a-c are obtained by reduction of keto-acids 9a-c to racemic hydroxy-acids l la-c followed by cyclodehydration using acetic anhydride. All the compounds have been examined in vitro for their antimicrobial activity.

Examples of naturally occurring brominated isocoumarins and 3,4-dihydroisocoumarins are very rare in literature. Recently, Stadler et at. I have isolated 4-bromo-6-hydroxymellein 1 from the cultures of Lachnum papyraceum. However, non­naturally occurring brominated isocoumarins are abundant. 7-Amino-4-chloro-3-(2-bromoethoxy)iso­coumarin 2 has been synthesized2 and evaluated as a potent inhibitor of human leukocyte elastase and several blood coagulation enzymes3• 7-Amino-3-(2/3-bromopropoxy)-4-chloroisocoumarin has been used4 as calpain inhibitor in the inhibition and treatment of neurodegeneration. Gore et at.5 have prepared 3-bromomethylisocoumarin 3 by bromolactonization of · 3-carboxymethylisocoumarin. Nagarajan et at.6 have reported the synthesis of 3-(4-bromophenyl)iso­coumarin via an organomercurial route which involves reaction of methyl 2-alkynylbenzoates with mercuric acetate to give isocoumarin mercurial which serves as intermediate to afford isocoumarin. Bhakta et at.7 have reported an isocoumarin 4 which has a bromoacetyl group at 4-position. 3-Bromomethyl-6-methoxy-8-hydroxyisocoumarin 5a has been used8 as an intermediate for the synthesis of an ' anticancer antibiotic isocoumarin 5b.

In continuation of our previous studies9 and biological activities ascribed for this class of compounds, prompted us to synthesize 3-(bromo­phenyl)isocoumarins and their corresponding 3,4-di­hydro derivatives. Condensation of bromobenzoyl chlorides 7a-c with homophthalic acid 6 at 20(tC afforded 3-(bromophenyl)isocoumarins 8a-c which showed characteristic singlets at 8 6.87, 6.96 and 6.95 for C4-H in IH NMR spectra and the lactonic

absorptions at 1 735 and 1720, 1747 and 17 15 and 1730 and 1 705 cm-I respectively in IR spectra. The mass spectra showed molecular ion peaks at rnIz 300 and 302 (base peak). Alkaline hydrolysis of isocoumarins 8a-c yielded keto-acids 9a-c which showed singlets at 8 4.70, 4.70 and 4.75, respectively for benzylic -CH2 in I H NMR spectra w�ile absorptions for ketonic and carboxylic carbonyl groups were observed in the range 1680- 1720 cm-I in the IR spectrum. The mass spectra of 9a-c showed characteristic peaks at rnIz 300 and 302 [M+-H20]. Isocoumarins 8a-c were regenerated on refluxing the keto-acids 9a-c with acetic anhydride. Methylation of 9a-c with excess of methyl iodide yielded methyl keto-esters lOa-c. Their structures were confirmed by singlets for CH3 protons at 8 3.72, 3.69 and 3.74, respectively in IH NMR spectra, while absorptions for ketonic and ester carbonyl in the IR spectra were observed at 1730-1720 cm- I . Sodium borohydride reduction of keto-acids 9a-c furnished corresponding racemic hydroxy-acids l la-c which, without purification, were refluxed with acetic anhydride to afford (dt)-3-(bromophenyl)-3,4-dihydroisocoumarins l2a-c (Scheme I). These 3,4-dihydroisocoumarins l2a-c showed typical AB pattern for C3-H and typical ABX pattern for C4-H protons in IH NMR spectra. Each of C4-H showed doublet of doublet at 8 3 . 10-3.28, 3 . 12-3.29 and 3.09-3.28, respectively. The doublet of doublet for C3-H was observed at 8 5.86-5 .87. The carbonyl absorptions were observed at 1 739, 1 741 and 1735 cm-I , respectively, in the IR spectra. High resolution electron ionization mass spectra (HREIMS) of all the synthesized compounds were in good agreement with the calculated values providing further confirmation for their structures.

HUSSAIN et al. : SYNTHESIS OF SOME NEW 3-(BROMOPHENYL)ISOCOUMARINS 373

�CH' _�

o - CI �OCllzCH,Br H,N�6 ©7�. ( 1 ) OH o

(3) (2)

M�X

ifCOOH + � �COOH F1'C .... O

6 7 Br

4h reflux

a) R = --@ Br

b) R = -@ C) R = -@-Br

OH 0 (Sa, X=Br) (Sb, X=OH)

�� �6 � R1

o 8

a) R = Br. R1 =R:!=H b) R1 =Br. R = R:!=H c) R:!=Br. R = R1 =H

As°r1 5..a .. �

oc«: . ��CO, �

10 9

12 1 1 Scheme I

Antibacterial activity Antibacterial activity of the compounds (8-10a-c

and 12a-c) was determined in vitro by standard agar methodlO against various gram negative and gram positive bacteria at a concentration of 200 )..lg/IOO )..lL in DMSO solution (Table I). The results are reported in mm of zone diameter l imits. In general, the isocoumarins 8a-c and keto-esters lOa-c have shown low activity and some of them are practically inactive. The keto-acids 9a-c and dihydroisocoumarins 12a-c were found to be active. None of the compounds has shown activity against Corynebacterium diphtharia.

Antifungal activity The synthesized compounds (8-10a-c and 12a-c)

were tested by agar tube dilution method I I for their antifungal activities determined at 400 )..lg/mL

concentration. The results are reported as linear growth inhibition (LGI) against some human pathogens, animal pathogens and plant pathogens (Table II). It is evident from these results that the compounds have shown considerable growth inhibition against all the tested fungi except Candida albicans. Compound 9b i s the most active against Trichophyton schoenleinii (62.S%) and 12c is the best against Microsporum canis and Aspergillus niger.

Experimental Section Melting points of the compounds were determined

in open capillaries using Gallenkemp melting point apparatus and are uncorrected. IR spectra were recorded on a Hitachi model 270-S0 spectrophoto­meter as KBr discs or as neat liquids; IHNMR (SOOMHz) spectra in CDCh on a Bruker AM-SOO using TMS as internal standard and ElMS on a MAT-1 12-S machine at 70eV.

3-(Bromophenyl)isocoumarins 8a-c. A mixture of homophthalic acid 6 ( 1 1 .2 mmoles) and bromobenzoyl chlorides 7a-c (47 mmoles) was heated under reflux at 200°C for 3 hr on an oil-bath. The residue after concentration was chromatographed on silica gel column using pet. ether (60-80° fraction) to give isocoumarins 8a-c as colourless solid. These were further purified by recrystallization from methanol.

3-(2' -Bromophenyl)isocoumarin 8a: yield 90%, mp 120°C; IR (KBr, cm·I ) : 1 73S, 1720; IH NMR (CDCh): 0 6.87 ( l H, s, H-4), 7 .30 ( 1 H, dd, 1=7.9, 1 .8 Hz, H-S), 7 .40 ( l H, ddd, 1=7.6, 1 .2 Hz, H-S'), 7.S2 (2H, m, H-7,4'), 7.63 ( l H, dd, 1=7.7, 1 .8 Hz, H-3'), 7 .69 ( I H, dd, 1=8.0, 1 .2 Hz, H-6'), 7 .74 ( l H, ddd, 1=7.5, 1 .4 Hz, H-6), 8.33 ( l H, dd, 1=8.0, 1 .3 Hz, H-8); MS: rnIz (%) 302 (95.6), 300 ( 100) [M+], 274 (53.8), 272 (S2.6) [M+-CO], 193 (66) [M+-(CO+Br)] ; HREIMS: Found (Ca1cd) C 15H9028 1Br; 301 .976S (30 1 .9769), CI5H90/9Br; 299.9787 (299.9786).

3-(3'-Bromophenyl)isocoumarin 8b: yield 8S%, mp 149°C; IR (KBr, em-I ) : 1 747, 17 1S ; IH NMR (CDCh): 0 6.96, ( l H, s, H-4), 7.33 ( l H, dd, 1=7.9 Hz, H-S), 7 .S4 (3H, m, H-7,2',S'), 7 .74 ( l H, ddd, 1=7.6, 1 .3 Hz, H-6'), 7 .80 ( l H, ddd, 1=7.9, 1 .8 Hz, H-6), 8.04 ( l H, 1=3.6, 1 .8 Hz, H-2'), 8.3 1 ( I H, ddd, 1=7.9, 1 .3 Hz, H-8); MS: rnIz (%) 302 (96.4), 300 ( l00) [M+], 274 (33.9), 272 (38.3) (4 1 ) [M+-CO], 1 93 (32) [M+-(CO+Br)]; HREIMS: Found (Calcd) C 15H9028 1Br; 301 .9766 (301 .9769), C15H90279Br; 299.9749 (299.9786).

3-(4'-Bromophenyl)isocoumarin 8c: yield 80%, mp 1 32°C; JR (KBr, em- I ) : 1 730, 1 705; IH NMR

374 INDIAN J CHEM, SEC B, MAY 2001

Table I -Antibacterial activity (mm of zone diameter limits) of compounds 8a-e, 9a-e, lOa-e and 12a-e Compd Gram-negative bacteria Gram-Eositive bacteria

11 111 iv V VI vii viii IX X 8a 1 0 1 0 1 1 .5 1 1 1 1 1 0 7 8b 8e 8 8 9a 1 1 10 1 2 1 2 8 9 1 1 9b 9 10 1 1 8 7 8 1 0 8 ge 10 1 0 10 1 2 1 0 1 0 lOa lOb 10e 8 12a 1 I 1 1 8 1 1 1 0 1 0 12b 1 0 1 1 1 0 7 I I 1 1 1 0 1 0 1 0 12e I I 10 1 0 10 8 1 0 Ampicillin 1 8 1 5 1 2 10 1 8 1 3 14 Amoxicillin 26 22 1 8 26 20 25 Piperacillin 16 1 7 2 1 2 1 1 7 Gentamicin 15 18 22 20 22 20 1 6

- = No activity (i) Escheridia coli. (ii) Pseudomonas aerugniosa. (iii) Proteus mirobillis. (iv) Klebsiella pnel/monia. (v) Shigella boydii. (vi) Salmonella typhi. (vii) Bacillus cereus.

(viii) Staphylococcs aurel/s. (ix) Streptococcl/s pyogenes, (x) Corynebacterium diphtharia

Table II - Antifungal activity (Growth inhibition, %) of compounds 8a-e. 9a-e, lOa-e and 12a-e Fungi 8a 8b 8e 9a 9b ge lOa lOb 10e 12a 12b 12c Std.

drugs

Trichophyton schoenleinii 25 37.5 40 1 8.7 62.5 60.7 30 28.4 25.0 1 8.7 20 24 M, K Pseudallescheria boydii 1 2.5 7. 1 8.7 57 7 1 .4 75.3 33 3 1 .7 23.0 1 2.5 15 17 M, K Candida albicans 0 0 0 0 0 0 0 0 0 0 0 0 M. K Aspergillus niger 50.3 47.2 56.4 50 50 55 57 56 50 54 55 59 A, F Microsporum canis 48.8 32 36 33 54 53 3 1 27 25 56 60 67 M, K Trichophyton simii 23 23 35 49 46. 1 50.5 29 38 23 38 40 43 M, K Fusarium oxysporum var. /ycopersici (tomato) 26.6 20 25.4 1 3.3 42.8 35.8 32.3 27. 1 26.6 20 24 34 B. N Macrophomina phaseolin a 1 2.5 12.5 1 6.5 43.7 43.7 46 36.2 40.2 3 1 .2 47 50 62 B, N

M: Miconazole, K: Ketoconazole, A: Amphotericin-B, F: Flucytosine, B: Benlate, N: Nebam

(CDCb): 8 6.95, ( lH, s, H-4), 7 .49 (2H, dd, 1=7.7 Hz, H-3',5'), 7.59 (2H, d, 1=8.8 Hz, H-5,7), 7.75 (3H, d, 1=8.7 Hz, H-6,6',2'), 8.30 ( l H, d, 1=7.5 Hz, H-8); MS: m/z (%) 302 (99. 1 ), 300 ( l 00) [M+], 274 (70.4), 272 (68.9) [M+-CO], 1 93 (6 1 .9) [M+-(CO+Br)]; HREIMS: Found (Caled) C 15H90281Br; 30 1 .9767 (30 1 .9769), CI5H90/9Br; 299.9784 (299.9786).

2-(Bromobenzoylmethyl)benzoic acids 9a-c. A solution of 3-bromophenylisocoumarins 8a-c (5.3 mmoles) in ethanol (50 mL) and potassium hydroxide (5%, 1 00 mL) was refluxed for 4hr. Ethanol was removed from the reaction mixture by distillation. Cold water (20 mL) was added and the reaction mixture was acidified with hydrochloric acid. The reaction mixture was then extracted with dichloromethane (3 x 20mL), dried (Na2S04) and

solvent rotary evaporated to yield keto-acids 9a-c, which were recrystallized from ethyl acetate.

2-(2' -Bromobenzoylmethyl)benzoic acid 9a: yield 83%, mp 1 14°C; IR (KBr, cm' I ) : 1 70 1 , 1 685; IH NMR (CDCh): 8 4.70, (2H, s, CH2), 7 .56-7.62 (3H, m, H-3,5, 5 ') , 7.69-7.72 (2H, m, H-4',6'), 7.97-7 .99 (2H, m, H-4,3'), 8. 1 8 ( l H, d, 1=7.8 Hz, H-6), 1 0.2 ( lH, bs, COOH, 020 exchangeable) ; MS : m/z (%) 320, 3 1 8 (0.7) [M+] , 302, 300 (7. 1 ) [M+-H20] ; HREIMS : Found (Caled) CISHI I038 IBr; 3 19.9870 (3 1 9.9873), C1 5H I I0/9Br; 3 17 .9890 (3 1 7 .989 1 ) .

2-(3'-Bromobenzoylmethyl)benzoic acid 9b: yield 78%, mp 1 42°C; IR (KBr, cm' I) : 1 699, 1 684; IH NMR (CDCI3) : 8 4.70, (2H, s, CH2), 7.34-7.42 (3H, m, H-3,5,5'), 7.73-7.75 (2H, m, H-4',6'), 8 .03-8 .05 (2H, m, H-4,2'), 8.3 1 ( lH, dd, 1=1 .8 Hz, H-6),

HUSSAIN et al. : SYNTHESIS OF SOME NEW 3-(BROMOPHENYL)ISOCOUMARINS 375

10.3 ( lH, bs, COOH, D20 exchangeable); MS: mJz (%) 320, 3 1 8 (0.9) [M+], 302, 300 (8. 1 ) [M+-H20]; HREIMS: Found (Caled) CI5H I I038

IBr; 3 19.9875 (3 1 9.9873), C 15H I I0379Br; 3 17 .9889 (3 17 .989 1 ).

2-(4'-Bromobenzoylmethyl)benzoic acid ge: yield 80%, mp 1 62°C; IR (KBr, em- I) : 1 694, 1 680; IH NMR (CDCh): 8 4.75, (2H, s, CH2), 7.25-7 .47 (2H, m, H-3,5,), 7 .61 -7.68 (4H, m, H-2',3',5',6'), 7 .95 ( lH, d, J=7.5 Hz, H-4), 8 . 1 2 ( 1 H, d, J=7.8 Hz, H-6), 10.5 ( 1H, bs, COOH, D20 exchangeable); MS: mJz (%) 320, 3 1 8 ( 1 .3) [M+] , 302, 300 (9. 1 ) [M+-H20]; HREIMS: Found (Caled) CI5H I I038

IBr; 3 19 .987 1 (3 19.9873), C I5H I IO/9Br; 3 17.9893 (3 17 .989 1 ).

The keto-acids 9a-e were converted back into isocoumarins 8a-e on refluxing with acetic anhydride for 1 hr. These isocoumarins also had the same Rr values as of those synthesized earlier.

Methyl 2-(bromobenzoylmethyl)benzoates lOa-c. The keto-acids 9a-e (0.73 mmoles), methyl iodide in excess and anhydrous potassium carbonate ( 1 .5 g) in dry acetone ( 1 5 mL) were heated under reflux for 2hr. The reaction mixture was filtered while hot. The cake was washed with warm dry acetone ( 10 mL) and solvent evaporated to leave a liquid which was purified by column chromatography using silica gel and pet. ether.

Methyl 2-(2' -bromobenzoylmethyl)benzoate lOa: yield 65%, light yellow oil; IR (KBr, cm· I ) : 1 74 1 , 1720; IH NMR (CDCh): 8 3 .72, (3H, s, OCH3), 4.54 (2H, s, CH2), 7 .28 ( l H, dd, J=7.9 Hz, H-3), 7.5 1 ( lH, dd, J=5.7, 3 .3 Hz, H-5), 7 .66-7.70 (3H, m, H-4,3',5'), 7 .94-7.97 (2H, m, H-4',6'). 8 . 1 7 ( 1 H, dd, J=1 .8 Hz, H-6'); MS: mJz (%) 334, 332 (6. 1 ) [M+], 302, 300 ( 10. 1 ) [M+-CH30H] ; HREIMS: Found (Caled) C 16H 13038 1Br; 334.0030 (334.0029), C16H 130379Br; 332.005 1 (332.0048).

Methyl 2-(3'-bromobenzoylmethyObenzoate lOb: yield 69%, light yellow oil; IR (KBr, cm· I ) : 1 750, 17 15 ; IH NMR (CDCh): 8 3 .69, (3H, s, OCH3), 4.50 (2H, s, CH2), 7.30 ( l H, dd, J=7.5 Hz, H-3), 7 .4 1 ( lH, dd, J=7.6, 1 .3 Hz, H-5), 7 .55 (2H, d, J=8.3 Hz, H-2',5'), 7 .60 ( lH, dd, J=7.5, 1 .5 Hz, H-4). 8 .05-7.98 (3H, m, H-6,4',6'); MS: mJz (%) 334, 332 ( l 6) [M+], 302, 300 (23) [M+-CH30H]; HREIMS: Found (Caled) C16H 13038 1Br; 334.0027 (334.0029), C I6H 130/9Br; 332.0052 (332.0048) .

Methyl 2-(4' -bromobenzoylmethyl)benzoate 10e: yield 70%, light yellow oil; IR (KBr, em-I ) : 1 730, 1720; IH NMR (CDCI3) : 8 3.74, (3H, s, OCH3) , 4.3 1 (2H, s, CH2), 7 . 14 ( l H, d, J=7.5 Hz, H-3), 7.3 1 ( lH, dd, J=7.6, 1 .3 Hz, H-5), 7.55 (2H, d, J=8.3 Hz,

H-3 ',5 '), 7 .59 ( 1 H, dd, J=7.5, 1 .5 Hz, H-4). 8 .01 -7.96 (3H, m, H-6,2',6'); MS: mJz (%) 334, 332 (5 . 1 ) [M+], 302, 300 (30.2) [M+-CH30H] ; HREIMS: Found (Caled) C 16H 1 30381Br; 334.0035 (334.0029), C16H1 30379Br; 332.0045 (332.0048).

(dl)-3-(Bromophenyl)-3,4-dihydroisoeoumarins 12a-e: The keto-acids 9a-e (0.5g, 2.07mmoles), prepared as described above, were dissolved in potassium hydroxide solution ( l %, 25mL) and sodium boronhydride (0.25g) was added. The reaction mixture was stirred for I hr at room temperature. After acidifying with HCI, the whole mixture was extracted twice with ethyl acetate (2x50 mL). Usual work-up gave crude hydroxy-acids lla-c, which were dissolved in acetic anhydride ( lmL) and heated under reflux for 2hr. The reaction mixture was cooled, water (25mL) was added and stirred continuously overnight. The crystals that deposited were collected by filtration and the filtrate was extracted twice with CH2Ch (2x20 mL). The solvent was removed by vacuum distillation. The crude compounds were purified by colu�n chromatography on silica gel with pet. ether, which were recrystall ized from methanol.

(dl)-3-(2' -Bromophenyl)-3,4-dihydroisocoumarin 12a. yield 9 1%, mp 1 10°C; IR (KBr, em-I ) : 1 739; IH NMR (CDCh): 8 3 . 1 0 ( l H, dd, J=1 6.0, 1 2.0 Hz, H-4a), 3.28 ( l H, dd, J=1 6.0, 3.0 Hz, H-4b) 5 .87 ( lH, dd, J=12.0, 3 .0 Hz, H-3), 7.2 1 ( l H, ddd, J=7.5, 1 .5 Hz, H-5), 7 .29 ( 1H, d, J=7.5 Hz, H-7), 7 .36-7.45 (2H, m, H-4',6'), 7 .55-7.60 (2H, m, H-3',5'), 7.72 ( IH, dd, J=7.5, 1 .5 Hz, H-6), 8 . 1 5 ( l H, d, J=7.5 Hz, H-8); MS: mJz (%) 304 (47.9), 302 (48.5) [M+], 1 94 (23), 1 85 ( 100); HREIMS: Found (Caled) CI5H I I028IBr; 303.9930 (303.9923), C 15H I I0279Br; 30 1 .995 1 (30 1 .9942).

(dl)-3-(3' -Bromophenyl)-3,4-dihydroisoeoumarin 12b: yield 75%, mp 1 40°C; IR (KBr, cm· I) : 1 74 1 ; IHNMR (CDCh): 8 3. 1 2 ( 1 H, dd, J=1 6.2, 1 2.5 Hz, H-4a), 3 .29 ( l H, dd, J= 16.2, 3.0 Hz, H-4b) 5 .86 OH, dd. J=1 2.5, 3.0 Hz, H-3), 7 .22 ( l H, ddd, J=7.5, 1 .5 Hz, H-5), 7.30 ( IH, d, J=7.5 Hz, H-7), 7 .36-7.45 (2H, m, H-2',6'), 7.5 1 -7 .62 (2H, m, H-4',5'), 7 .80 ( lH, dd, J=7.5, 1 .5 Hz, H-6), 8 .21 ( l H, d, J=7.5 Hz, H-8); MS: mJz (%) 304 (29.3), 302 (32.7) [M+] , 202(28), 1 85 ( l00); HREIMS: Found (Caled) ,c15HI I028 IBr; 303.9920 (303.9923), C 15HI I0279Br; 301 .9941 (30 1 .9942).

(dl)-3-( 4' -Bromophenyl)-3,4-dihydroisocoumarin 12c: yield 70%, mp 1 90°C; IR (KBr, cm·I ) : 1735; IH NMR (CDCh): 8 3 .09 ( l H, dd, J=1 6.0, 1 2.0 Hz, H-4a), 3 .28 ( l H, dd, J=1 6.0, 4.0 Hz, H-4b), 5.87 OH,

376 INDIAN J CHEM, SEC B, MAY 2001

dd, 1=1 2.0, 4.0 Hz, H-3), 7. 1 9 ( l H, ddd, 1=7.S, I .S Hz, H-S), 7.29 ( l H, d, 1=7.S Hz, H-7), 7.34-7.47 (2H, m, H-2',6'), 7.S3-7.6 1 (2H, m, H-3',S'), 7 .69 ( lH, dd, 1=7.S, I .S Hz, H-6), 8 .0S ( l H, d, 1=7.S Hz, H-8); MS: rnJz (%) 304 (50.3), 302 (52.7) [M+], 202(28), 1 85 ( 100); HREIMS: Found (Caled) C ISHl I028IBr; 303.9925 (303.9923), C lsHI IO/9Br; 301 .9945 (30 1 .9942).

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