Indian Journal of Chemi stry Vol. 40B, April 200 1, pp. 274-277

Preparation of ethyl 6-methoxy-7 -methyl-l-aryl/cyclohexyl-4-oxo-2-naphthoates as an intermediates for synthesis of ~-apopicropodophyllin analogues I

N Nanjundaswamy, K M Lokanatha Rai*, C Anjanamurthy & S Shashikanth

Department o f Studies in Chemi stry, Uni versity o f Mysore, Manasagangothri , Mysore 570 006, Ind i'

Received 23 Decelllber 1999: accepted (revised) 29 May 2000

Preparation of te tralone ester 4a-c, an intermediate for the synthesis of ~-apopicropodophy llin analogues via Stobbe condensation of benzopheno ne deri vati ves followed by Friedel Cra ft 's cyc li zation is descri bed.

Podophyllotox in 1 and several of its analogues are used as cy totox ic spindle poisons and antitumor agents some at clinical level2

• Recentl y Lee et 0 1.3

di scovered that some modi fi ed deri vati ves of podophyllotox in possess anti-AIDS property. Earlier, Rai et 0 1. 4 have reported the sy nthesis of analogues of 1 and ~-apopi cropodophy llin 2, with a view to study their structure-antimitotic acti vity relationship. They found some of these deri vati ves possess higher ac ti vity and some have lower acti vity when compared to that of parent molecules5

. We have envisaged that modi fy ing ring A and pendent ring C in 1 and 2 might enhance their biological acti vity and hence decided to sy nthesize the podophyllotoxin analogues 3a-c.

Several synthetic routesO other than Gensler's 7 have been reporled for the sy nthesis of 1 via the tetralone ester 4. ]n the present paper, we deliberately adopted the Gensler's route for the synthesis of 4 because it requires easily ava il able reagents.

Friedel-Craft's acy lation of a-methyl ani sole with acid chlorides 5 usi ng aluminium chloride as catalyst afforded the benzophenones 6 in excellent yield (Scheme I). The Stobbe condensation of the benzophenones 6 using diethyl succinate and potass ium t-butoxide in t-butanol gave the itaconic ac id half es ters 7 (as a mi xture of cis and trails isomers) which on saponi fication with sodium hydroxide gave the itaconi c acids 8 in qualitati ve yield. Reduction of 8 as a mixture of t rails isomers with sodium amalgam as per the method of Shirvaikar and Kulkarni 8 yielded benzhydrylsuccinic acid 9.

The anhydrides 10 obtained by dehydrati on of 9 by acetyl chl oride, was converted to tetralone carboxy lic ac id 11 vi a intramolecular Friedel-Craft's acylation reacti on using anhydrous stanni c chloride. It was then

subjected to es terificati on with abso:ute al cohol and sulphuric acid to yield the required ester 4. All the new synthesized compounds were iden ti fied by IR , 'H NMR and mass spectral analysis. For instance, the 'H NMR spectrum of 4a exhibited a doublet at 8 4.55 ppm (1=10 Hz) due to dibenzy lic pl'Oton C,-H . The large J va lue of 10-12 Hz indicated that C ,-H and C2-

H in 4a were di ax ial. Hence, C,-phenyl and C2-

carboxyl groups should be trails to each other, a confi gurati on being thermodynami cally more stable.

Experimental Section

Melting points were taken on opc: n capillary and are uncorrected. IR spectra were recorded on a Perkin Elmer 399 spectrometer; 'H NMR spectra on a Jeo l 60 MHz NMR spectrometer using CDCI3 as solvent and TMS as internal reference (chem ical shifts in 8, ppm) and mass spectra on Hitachi RMU-61 spectrophotometer and important fragments are given with the relative intensities in the bracket. Thin layer chromatography were obtained on Merck silica gel G coated on glass plates.

General procedure for the preparation of the benzophenones 6a-c

3-Methyl-4-methoxybenzophenone 6a. To a stirred mixture of a-methyl ani sole (1 .22g, 0.0 II mole) and anhydrous aluminium ch loride (1.42g, 0.0 I mole) in dry methylene chloride ( J 5 mL), benzoy l chloride (Sa , 1.406g, 0.0 I mole) in methylene chloride ( 15 mL) was added dropwise over 30 min at room temperature. After 24 hr of stirring about 5mL conc. HCI was added and stirred further for 6 hr. Aqueous 10% NaCI solution (lOmL) was added to break the emulsion and the lower organic layer was

NANJUNDASWAMY el 01.: SYNTHESIS OF ~ -APOPICROPODOPHYLLIN ANALOGUES 275

2

H3C0X) AICI) I + RCOCI -

H3C "'" Sa-c

b

i. KOH ~

H3CO~ H3C~

R 3a-c

a) R = Phenyl; c) R = Cyclohexyl

b) R = 3',4',5'-trimethoxyphenyl

J

OOH

CH,COOEJ I -CH2COOEI

~

I-BuOK/I-B lIOH

AcC! --H3CO%~5 6 OOH ~ I

H3C 2 J OOR' ii . Nn-H g/NnOI-l H3C a

7a-c: R' = Et 8a-c: R' = H

IOa-c

separated and washed with 10% KOH solution (3x I OmL) and then with water (3x I OmL) and finally

with brine solution (3x I OmL). Excess solvent was distilled off on a water-bath and the crude product on crys tallization with methanol gave 6 as white crys talline solid in 90% yield (2.05 g); mp 68-70°C; IR (Nujol) : 1650 (C=O), 1600 cm-I (aromatic C=C) ; ' H NMR (CDCl) : 8 2.3 (s , 3H, CH) , 3.80 (s , 3H, OCH3) , 6.8 (s, I H, Cr H), 7.1-7.5 (m, 5H, Ar-H), 7 .8-7.9 (dd, 2H, 1=8 Hz, Cs-H and C6-H).

3-Methyl-4-methoxy-3', 4', S'-trimethoxybenzo­phenone 6b: Obtained from a -methyl ani sole (1.22 g, 0.0 I mole) and 3,4,S-trimethoxybenzoy l chloride (Sb, 2.39 g, 0.0 I mole) as white crys talline so lid in 80% yield (2.52 g); mp 79-80°C; IR (Nuj ol): 1650 (C=O), 1584 cm-I (aromati c C=C): 'H NMR (CDCI) : 8 2.25 (s , 3H, CH3) , 3.85 (s, 9H, OCH3), 3.9 (s, 3H, OCH3) ,

6.75-7.1 (m, 3 1-1 , Ar-H), 7.5-7. 8 (m, 2H, Ar-H). Cyclohexyl-3-methyI-4-methoxyphenyl ketone

6c: Obtained from a -methy l ani sole ( 1.22 g, 0.01 mole) and cyclohexane carbonyl chloride (Sc, 1.46 g, 0.0 I mole) as pale yellow needl e like crystal s in 70%

lla-c

Sche me I

R 9a-c

OOEt

4a-c

yield (0.86 g); mp 62-64°C ; IR (KBr): 1672 (C=O), 1605 cm-I (aromatic C=C); 'H NMR (CDCI) : 8 1.3-2.0 (m, 10H, cyclohexyl), 2 .2 (s, 3H, CH3) , 3.20 (bs , I H, cyclohexyl), 3 .8 (s, 3H , OCH3), 6.70-6.90 (bd, I H, Cr H), 7.70 (s, IH , Cs-H), 7.80 (s , I H, C6-H).

General procedure for the preparation of itaconic acid 8a-c

3-Methyl-4-methoxydiphenylitaconic acid 8a . Compound 6a (1.13 g, 0.005 mole) was added quickly to freshly prepared potass ium f-butox ide [prepared by the reaction of dry I-butyl alcohol ( 10 mL) with potass ium (0.208 g, 0.0053 g atom) under nitrogen atmosphere at reflux temperature] and di ssolved by boiling the mi xture fo r 0.5 hr under nitrogen. Fresh ly di stilled diethyl succinate ( 1.74 g, 0.0 1 mole) was added rapidly and the reaction mixture re flu xed for 10hr. The cooled mi xture was treated wi th SN hydrochloric ac id (5 mL) and concentrated to 10 mL by di stillati on under reduced pressure. The pasty itaconic acid half ester 7a was then ex tracted into ether (3 x 25 mL) and then into saturated aqueous

276 INDIAN J. CHEM .. SEC B. APRI L 200 1

sodium bi carbonate (3 x 25 mL). The bicarbonate extract was acid ified and the precipitate obtained was extrac ted with ether and dried (Na2S04)' Evaporation of the solvent gave itaconi c half es ter 7a as brown semi -solid in 85% yield ( 1.5 g). The itaconic ac id half ester was then saponified as such by reflu xing in methanol (5 mL)-water (5 mL) mi xture containing sodium hydrox ide (0.6 g) for 8 hr. The pale brown mixture was concentrated to 10 mL and poured into crushed ice (15 g) containing concentrated HCI (5 mL) to give 8a as a brown semi-solid in 80% yield (1.3 g); IR (KBr): 3450-3300 (OH ), 1700 (CH2C=O), 1680 (a,~-unsaturated C=O), 1600 cm' l (aromati c C=C); IH NMR (C DCI3): 83.50 (s, 2H, CH2), 6.80 (s , IH , C2-H), 7,00-7.30 (m, 5H, phenyl), 7.50 (bd, 2H, C~-H and Cs-H ), 8.90-9.00 (bs, 2H, COOH).

3-Methyl-4-methoxy-3' i ,5' -trimethoxydi phenyl­itaconic acid 8b: Obtained from the condensation o f 6b ( 1.58 g, 0.005 mole) with diethyl succin ate ( 1.74 g, 0.0 1 mole) as brown gummy product in 70 % yield (l.45 g); IR (KBr): 3450-3300 (OH ), 1700 (C H2C=O), 1680 (a, ~-unsatura ted C=O), 1590 cm' l (aromatic C=C); I H NMR (CDCb): 8 3.6 (s, 2H, CH2), 3,75 (s , 9H, OCH), 3.8 (s, 3H, C4-OCH3), 6.3-7.3 (m, 5H, ArH), 8,90-9, 10 (bs, 2H, COOH ).

Cyclohexyl - 3-methyl-4-methoxyphenylitaconic acid 8c: Obtained from 6c ( 1.16 g, 0 .005 mole) and diethyl succinate ( 1.61 g, 0 .0092 mole) as brown gummy product in 80 % yield ( 1.33 g); IR (KBr): 3450-3300 (OH ), 1700 (C=O), 1685 (cyclohexy l C=O), 1590 cm'l (C=C); IH NMR (C DC I]): 8(1.l- 1.6 (m, 10H, cyclohexy l), 2.10 (m, I H, CH), 2 .20 (s, 3H, CH3) , 3.80 (s, 3H, OCH3), 6.85 (s, IH , C2-H), 7.40 (d, 2H, C4-H and Cs-H), 8.90-9.10 (bs, 2H, COOH).

General procedure for the preparation of benzhydrylsuccinic acids 9a-c

3-Methyl-4-methoxybenzhydrylsuccinic acid 9a. Powdered 5% sodium amal gam (2 g) was added to a solution of 8a (0.958 g, 2.94 mmoles) in 5% sodium hydroxide (20 mL) solution at - 5°C. The reaction mi xture was kept overni ght at room temperature and filtered. The filtrate was acidified with 5N HCI to give 9a as white solid which on recrystallisati on from ethanol gave white crystalline solid in 80% yie ld (0.768g), mp 152-54°C ; IR (Nujol): 3450-3300 (OH), 1740 (C=O), 164 1 (CO), 1611 cm'l (aromatic C=C); IH NMR (CDCb): 8 2. 10 (s, 3H, CH3), 2.40-2.60 (m, 4H, Cr H, Cr H, C4-H), 3.80(s, 3H, OCH3), 6.60 (s, IH , C.-H), 7.00-7.30 (m, 5H, ArH ), 7.40-7.50 (bs, 2H, Cb-H and Cc -H).

3-Methyl-4-methoxy-3', 4', S'-trirnethoxyphenyl­benzhydrylsuccinic acid 9b: Obtai ned from 8b (0. 12 g, 2.89 mmoles) and sodium amalgam (2 g) as white crystall ine solid in 84% yield (0 .1 02g). mp I 64-66°C; IR (Nujo l): 3400-3300 (OH ), 1740 (C=O ), 1595 cm'l (aromatic C=C): I H NMR (CDCI): 8 2. 15 (s, 3H, CH3), 2.30-2.50 (bm, 4H, C2-H, C)-H, C4-H), 3.70 (s, 9H, OCH), 3.80(s, 3H, OCH3), 6.30 (s, 2H, C2,-H and C6' -H), 6.50 (s, I H, Ca-H), 7.40 (bd, 2H, Cb-H and Cc-

H). 3 - Carboxy - 4 - (3'-methyl-4'-methoxyphenyl)-

4-cyclohexylbutanoic acid 9c: Obtained from 8c (0. 11 6 g, 3.50 mmoles) and 5% sodi um amalgam (2 g) as white crystalline solid in 90% y ield (0.087 g), mp I 42-44"C; IR (Nuj ol ): 3450-3300 (OH), 1740 (C=O), 16 14 cm,l (aromatic C=C); II-[ NMR (CDCI) :

8 1.10-1.60 (m, IIH, C6HII) 2.20 (s , 3H, C H3) , 2.35-2.56 (m, 4H, C2-H , Cr H, C4-H), 6.50 (s, I H, C.-H ), 7.40-7 .50 (d, 2H, Cb- H and Cc-H).

General procedure for the preparation of tetralone acids lla-c

l-Phenyl-4-oxo-6-methoxy-7-methyl-l, 2, 3, 4-tetrahydro-2-naphthoic acid 11a. A solution of 9a (0 .8 15 g, 2.63 mmoles) in acetyl chloride (3 mL) was refluxed for 3 hr. The excess acely l chloride was distilled off and the res idue after di ssolving in benzene (10 mL) was repeatedly ~ashed wi th cold 5% sodium bicarbonate solution (2 >: 5 mL) and then with cold water. The organic layer :.tfter drying over Na2S04 was concentrated to give a pa le brown semi ­solid anhydride lOa in 92% yield (0.74 g); IR: 1785 and 1870 cm,l (for cyclic anhydride) which was cyclized to 11a as fo llows: A solution of anhydride (lOa, 0.77 g, 2.50 mmoles) in dich loromethane (10 mL) was added over a period of 20 min to a magnetically stirred solution of anhydrous stannic chloride in dichloromethane (1 0 mL) at O°c. The reaction mixture was further sti rred at O°C for 6 hr. After completion of the reaction (monitored by T LC), the mi xture was treated with cold 5N hydrochloric ac id. The organi c layer separated was extracted in to chlorofo rm (10 mL) and washed thoroughly with cold 5N hydrochloric acid (2 x 10 mL) then with water (2 x 10 mL). The acidic compound was extracted into the saturated sodium bicarbonate solution (3xlO mL) and then neutrali sed with 6N HCI (5 mL) to give 11a as white solid in 60% yield (0 .45 g) . It was recrystallised from ethanol, mp 145-47°C; IR (Nujol ): 3450-3300 (OH), 1740 (carboxylic CO), 1704 (tetralone CO), 16 10 cm' l (C=C); IH NMR (CDCI) : 8

NANJUNDASWAMY et al.: SYNTHES IS OF I3-APOPICROPODOPHYLLIN ANALOGUES 277

2.20 (s, 3H, CH)), 2.85(d, 2H, J=5 Hz, C3-H), 3. 10-3.20 (m, 1 H, C2-H), 3.90 (s, 3H, OCH3), 4.55 (d, 1 H, J=6 Hz, CI-H), 6.80 (s, 1 H, Cs-H), 7.00-7 .20 (m, 5H, ArH), 7.45 (s, I H, C5-H) Mass (mlz, ReI. Int.): 3 10 (M+, 16),28 1 (2),265 (4),2 11 ( 100), 181 (15), 91 (12); Anal. Caled . for C I<) HIS0 4: C, 73 .53 ; H, 5.85%. Found: C, 73.48; H, 5.90%.

1-(3', 4', S' -Trimethoxyphenyl)-4-oxo-6-methoxy-7-methyl-l,2,3,4-tetrahydro-2-naphthoic acid lIb: Obtained from the reaction of 9b (0.96 g, 2.40 mmoles) with acetyl chloride (3 mL) followed by cyclization using stannic chloride (I.4g, 5.37 mmoles) in dichloromethane as white crystalline solid in 30% yield (0.28 g), mp 156-58°C; IR (KBr): 3450-3300 (OH), 1740 (carboxylic CO), 1700 (tetralone CO), 1600 cm-I (C=C); IH NMR (CDCI)): 8 2.15 (s , 3H, CH)), 2.80 (d, 2H, J=5 Hz, C3-H), 3.10-3 .20 (m, I H, C2-H), 3.75 (s, 9H, OCH3), 3.85 (s, 3H, OCH3), 4.50 (d, J=6Hz, I H, CI-H), 6.35 (s, 2H, i,6'-H) , 6.50 (s, I H, Cs-H), 7.25 (s, I H, ArH) ; Mass (mlz , ReI. Int. ): 400 (M+, 5), 371 (3),265 (4),21 1 ( 100), 181 (14),9 1 (11). Anal. Caled for C22H240 7: C, 65.99; H, 6.04%. Found: C, 65 .92; H, 6.09%.

l-Cyclohexyl-4-oxo-6-methoxy-7 -methyl-l,2,3,4-tetrahydro-2-naphthoic acid lIc: Obtained from the reaction of 9c (0.63 g, 2.00 mmoles) with acetyl chloride (3 mL) followed by cyclization using stannic chloride (1.2g, 4.60 mmoles) in dichloromethane as white crystalline solid in 33% yield (0.1 8 g) , mp 131-35°C. IR (KBr): 3450-3300 (OH), 1740 (carboxylic CO), 1714 (tetralone CO), 1604 cm-I (C=C); IH NMR (CDCI3): 8 1.30-1.90 (m, II H, C6H II), 2.20 (s, 3H, CH3) , 2.85 (d, 2H, J=6 Hz, C3-H), 3.15-3.25 (m, I H, Cr H), 3.90 (s, 3H, OCH3), 4.50 (d, IH, CI-H), 7.30 (s, IH, Cs-H), 7.55 (s, IH, C5-H) Mass (mlz, ReI. Int.): 316 (M+, 18),287 (4), 271 (6),217 (100), 213 (17), 91 (13). Anal. Calcd for: C1 9H240 4: C, 72.13; H, 7.65%. Found: C, 72.10; H, 7.70%.

General procedure for the preparation of tetralone esters 4a-c

Ethyl 6-methoxy-7 -methyl-l-phenyl-4-oxo-2-naphthoate 4a. A solution of keto ac id lIa (0.41 g, 1.23 mmoles) in an absolute ethanol (10 mL) containing concentrated sulphUlic acid (0.1 mL) was refluxed for 5 hr. After completion of the reaction, excess solvent was removed by di stillation and the cooled mixture was diluted with cold water (I5 mL) to give 4a as white solid in 90% yield (0.37 g), mp 107-09°C; IR (KBr): 1725 (ester CO), 1670 (tetralone CO), 1605 cm-I (C=C); IH NMR (CDCI)): 8 0.90-1.20 (t,

3H, CH)), 2.10 (s, 3H, Cr CH3) , 2.85 (d, 2H, J=IO Hz, C3-H), 3.10-3 .25 (m, 1 H, C2-H), 3.70-3 .90 (q, 2H, OCH2), 4.00 (s, 3H, OCH3), 4.55 (d, 1 H, J=IO Hz, CI-H), 7.10-7.80 (m, 7H, ArH). Anal. Caled for C21H220 4: C, 74.54; H, 6.55%. Found: C, 74.50; H, 6.61 %.

Ethyl 6-methoxy-7 -methyl-l-(3',4',S' -trimethoxy­phenyl)-4-oxo-2-naphthoate 4b: Obtained from keto acid lIb (0.44 g, 1.13 mmoles) and ethanol (7 mL) as white solid in 80% yield (0.37 g), mp 127-30°C; IR (KBr): 1755 (ester CO), 1678 (tetral one CO), 1605 cm-I (C=C); IH NMR (CDCI)): 8 1.00-1.30 (t, 3H, CH3), 2.20 (s, 3H, Cr CH3), 2.85 (d, 2H, J=10 Hz, C3-

H), 3.10-3.25 (m, 1 H, C2-H), 3.60-3.80 (q, 2H , OCH2), 3.85 (s, 9H, OCH)), 3.95 (s, 3H, OCH3), 4.55 (d, 1 H, J=IO Hz, CI-H), 6.40-7.20 (bm, 4H, ArH). Anal. Caled for C24 H2S07: C, 67 .28; H, 6.59%. Found: C, 67 .23; H, 6.31 %.

Ethyl 6-methoxy-7 -methyl-l-cyclohexyl-4-oxo-2-naphthoate 4c: Obtained from keto acid lIc (0.31 g, 1.06 mmoles) and ethanol (7 .5 mL) as white solid in 85% yie ld (0.29 g); IR (KBr): 1750 (ester CO), 1670 (tetralone CO), 1604 cm- I (C=C); IH NMR (CDCt3): 8 0.9-1.2 (t, 3H, CH3) , 1.30-1.90 (m, IIH, C6HII ), 2.20 (s, 3H, CH3) , 2.85 (d, 2H, J= 12 Hz, C3-H), 3.15-3.25 (m, I H, CrH), 3.65-3.80 (q, 2H , OCH2), 3.90 (s, 3H , OCH3) , 4.50 (d, IH , J=12 Hz, CI-H), 6.80-7 .20 (bm, 2H, ArH) . Anal. Caled for C21H2S0 4: C, 73.23; H, 8.19%. Found: C, 73.20; H, 9.22%.

Acknowledgement One of the authors (NN) wishes to thank the

University of Mysore, Mysore for providing faciliti es to carry out research work at the Department of studies in chemistry.

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