Indian Journal of ChemistryVol. 37B, March 1998, pp. 281 - 284

Synthesis of an intermediate, 7,8-~Ll1!~~!"tyl-2-t~!ralQ.D:e,for occidol "isomer-I and occidol isomer-II__ ."__ ••_, •. _ _v·'. _ _,. •• ,.

Note

genation of 8, as IH NMR spectra showed twodifferent signals for aromatic methyl groups. Thenaphthalene derivative 8 on Birch reduction" as wellas on reaction with sodium in ethanol" yielded theintermediate, 7,8-dimethyl-2-tetralone 10. Thetetralone 10 could be converted into occidol isomer-I 11 by Vilsmeier-Haack reactionI0. The occidolisomer-II 12 could be obtained from the tetralone10 via carbethoxylatiorr' followed by Clemmensenreduction and reaction with methylmagnesiumiodide.

( M T Bachute &:R B Mane"~. ",

Department of Chemistry, Shivaji University,Kolhapur 416004, .India

Received 21 October 1997 ; accepted (revised)23 January 1998

(~l!91!': is succinoylated with ~£C~£._~ydride to yield3-(p-methoxybenzoyl) propionic acid .¥.····Tliti .acid onClemmensen reduction gives 4-(p-methoxy. phenyl) butyric Experimental Sectionacid hhich OJ esterification atTords(rn.e~yl 4-<!'-methoxy-) Anisole (BOH), succinic anhydride (freshlyphenyl~utyr~tC:i~ l?e ester ~ on reaction WIth methyl- prepared), anhydrous aluminium chloride (Riedel)magnesium Iodide gives 5-(p-methoxyphenyl)-2-methyl-. th I iodid (B' 'pentan-2-ol .-which is cycIised with PPA to furnish •...7_l, me y . 1 e OH), ZInC wool (E. Merck),methoxy-I, l-dimethyltetralin \~ The tetralin A undergoes magnesium (BDH), orthophosphoric acid (BDH),aromatization with p-cWoranll or DDQ to atTord7-methoxy- phosphorus pentoxide (BDH), p-chloranil (Fluka)1,2~im~th~1 ~phthalen.e '( the reduction of which with and DOQ (Fluka) were used. Organic extracts were~hum In l~qUldammonia as well as with sodium in ethanol dried over anhyd. sodium sulphate. Melting andyields 7,8-dlmethyl-2-tetralone }9: .." ~ . . .boiling points are uncorrected. IR spectra were

recorded on Perkin-Elmer-783 instrument and IHNMR spectra on Perkin-Elmer R-32 (90 MHz)spectrometer.

3-(p-Methoxybenzoyl) propionic acid 3.Anhyd. aluminium chloride (276 g) was added withstirring to an ice-cold solution of succinic anhydride(100 g) in dry nitrobenzene (300 mL). Anisole(105.8 g) was then added at room temperature withstirring during 3 hr and the mixture stirred foradditional 1 hr. The reaction mixture was thendecomposed with cone. HCI and crushed ice.Nitrobenzene was removed completely by steamdistillation. Residual solution was treated withsodium bicarbonate and extracted with ether. Theether layer was rejected. Sodium bicarbonate layerwas decomposed by HCI (1:I) whereby the crudeketo-acid precipitated out. The crude acid wasrecrystallised from boiling water to get pure 3, yield1108-(54.4%), m.p. 146°C(titSm.p. 146°C).

4-(p-Methoxyphenyl)butyric acid 4. Amalga-mated zinc was prepared by stirring a mixture of Zn

The two isomers, occidol isomer-I 11 and occidolisomer-II 12 are the stress metabolites isolated'from the tobacco leaves (Ntcotina rusticaiinnoculated with tobacco mosaic virus (TMV).Krishna Rao et al.2 have reported the synthesis oftwo isomers.

A new approach for the synthesis of occidolisomers, involving rearrangement of methyl groupsduring dehydrogenation followed by Birch reductionwas planned. Friedel-Crafts reaction of succinicanhydride' with anisole gave 3-(p-methoxybenzoyl)propionic acid 3, which on Clemmensen reduction"yielded 4-(p-methoxyphenyl)butyric acid 4. Theacid 4 on esterification followed by reaction withmethylmagnesium iodide resulted into 5-(p-methoxyphenyl)-2-methylpentan-2-o16. The alcohol6 was cyclodehydrated with PPA~ to give 7-methoxy-I,I-dimethyltetralin 7 which wasaromatized with DOQ6 and also with chloranil' toafford 7-methoxy-I,2-dimethylnaphthalene 8. 1,2-Methyl shift was observed during the dehydro-

282 INDIAN J. CHEM., SEC. B, MARCH 1998

o

© c( ~ ~ i}Zn-Hg - M)MeO anhydrous MeO COOH HCl MeO COOH

AlCl3 41 1 3

_D_D_O__ ~ i}N,'UquidNH,

Ch':"nil M'O. N"';;tOH JM'O~

9

7

oDVl, 10

HO~

12

(185 g), HgCh (14 g), cone. HCI (9 mL) and H20(225 mL) for 20 min in a three-necked flask fittedwith a vertical condenser connected to a gasabsorption trap. Then the supernatant solution wasdecanted. Cone. HCl (190 mL), H20 (140 mL),toluene (150 mL) and 3-(p-methoxybenzoyl)propi-ODic acid 3 (75 g) were added to the aboveamalgamated zinc. The mixture was refluxedvigorously for 45 hr. After each 6 hr intervaladditional 190 mL cone. HCl was added. Aftercooling to room temperature two layers wereseparated. The aqueous layer was diluted withwater and extracted with ether. Toluene layer andether layer were combined, washed with water anddried over anhyd. calcium chloride. The solvent wasremoved by distillation under reduced pressure.Crude acid obtained was recrystallised from hotwater to get pure 4, yield 66 g (94%), m.p. 63°C(litll m.p. 60°C).

Methyl 4-(p-methoX)'phenyl)butyrate 5. Amixture of 4 (40 g), methyl alcohol and cone.

PPA

•(COOHh

HO:CV HO~11 13

H2S04 (8 mL) was refluxed on a water-bath for 9hr. The reaction mixture was diluted with waterand methanol was distilled on a water-bath. Theresidual soluticn was extracted with ether. Theether layer was successively washed with water,saturated NaHC03, water, dil. NaOH and water.Dried ether layer was distilled off to get pure 5,yield 31 g (72.4%), b.p. 138°C1l0 mm; IR (Neat) :1735 em" (-COOMe); IH NMR (CC4) : 1.83 (2H,quintet,J=7Hz, -CH2-), 2.2 (2H,t, J=7Hz, -CH2-adjacent to ester), 2.53 (2H,t, J=7 Hz, CJis-CHr),3.55 (3H,s, - COOCH3), 3.67 (3H,s, -OCH3), 6.68(2H,d, J=8.5 Hz, Ar-H ortho to -OCH3) and 6.97(2H,d, J=8.5 Hz, Ar-H meta to -OCH3) (Found:C, 69.40, H, 7.70. CI2HI603requires C, 69.23, H,7.69 %).

5-(p-Methoxyphenyl)-2-methylpentan-2-ol 6.To a well stirred solution of Grignard reagent,prepared from methyl iodide (7.1 mL) andmagnesium (3.08 g) in dry ether, was added 5 (l0.4g) in ether (50 mL) dropwise and stirring was

further continued for 4 hr. The reaction mixturewas decomposed by ice-cold saturated solution ofammonium chloride (80 mL). Organic material wasextracted with ether. Ether layer was washed twicewith water and dried. Removal of ether afforded analcohol 6, yield 9.54 g (91.7%); IR (Neat): 3400em" (alcoholic OH)~ IH NMR (CC4): 1.11 (6H,s,gem-dimethyl), 1.5 (4H,m, -CH2-CH2), 2.2 (lH,s,-OH), 2.5(2H,t, J=7 Hz, CJ{s-CH2-), 3.7 (3H,s,-OCH3), 6.68 (2H,d, J=8.S Hz, Ar-H ortho to-OCH3), and 7.0 (2H,d, J=8.S Hz, Ar-H meta to-OCH3) (Found: C, 75.10, H, 9.43. C\3H2002

requires C, 75.00, H, 9.61 %).

7-Methoxy-l,l-dimethyltetralin 7. The alcohol6 (8g) was added with stirring to PPA [preparedfrom P20S (51.5 g) and orthophosphoric acid (41.6ml.r]. The mixture was stirred for 2 hr and finallyheated on a water-bath for 45 min. It was cooledand decomposed by crushed ice. Organic materialwas extracted with ether and ether layer waswashed successively with water, diI. NaOH andwater. Ether layer was dried over anhyd. calciumchloride. Removal of the ether yielded cyclisedproduct which was chromatographed over silica-gel(pet.ether) to get pure 7, yield 7.6 g (96%); IR(Neat): no alcoholic OH group; IH NMR (CC4):1.27 (6H,s, gem-dimethyl), 1.65 (4H,m,-CH2-CH2-),

2.67 (2H,t, J=7 Hz, CJ{s-CH2), 3.72 (3H,s,-OCH3), 6.56 (lH, dd, ortho and (l. meta) J=8 Hz,Ar-H ortho to -OCli.3), 6.8 (IH,d, J=2 Hz, Ar-Hortho to -OCH3: which is only meta coupled), 6.88(1H,d, J=8 Hz, Ar-H meta to -OCH3) (Found:C,82.20, H,9.60. C\3HI80 requires C,82.10,H,9.47%).

7-Methoxy-l,2-dimethylnaphthalene 8. (a)Using DDQ: A mixture of tetralin 7 (5 g), DDQ(8 g) and dry benzene (25 ml) was refluxed on awater-bath for 1 hr. More DDQ (8 g) was addedand refluxed further for 3 hr. After cooling thereaction mixture, the precipitated hydroquinone wasfiltered off and the solvent was removed undervacuum. The residue was extracted with ether andether layer washed successively with water, dil.NaOH and water and then dried. Removal of etherfurnished crude product which was chromato-graphed over silica-gel (pet. ether) to yield pure 8,yield 4.1 g (83.8%), m.p. 48°C; IH NMR (CC4):2.37 (3H,s, Ar-CH3), 2.42 (3H,s, Ar-CH3), 3.8(3H,3, -OCH3), 7.0 (lH, dd, J=8 & 2.5 Hz, Ar-H

NOTES 283

ortho to -OCH3), 7.05 (lH, d, J=8 Hz, Ar-H onring containing methyl groups), 7.15 (1H,d, J=2.5Hz, Ar-H ortho to -OCH3), 7.42 (lH,d, J=8 Hz,Ar-H meta to -OCH3), 7.58 (lH, d, J=8 hz, Ar-Hon ring containing methyl group) (Found: C,83.90,H,7.69. C\3HI40 requires C, 83.87, H, 7.53%).

(b) Using chloranil : A mixture of tetralin 7(2g), chloranil (11 g) and toluene (l0 mL) wasrefluxed for 20 hr. After completion of reaction(monitored by TLC), toluene was distilled off andmixture was diluted with pet.ether and filtered.Residue was washed repeatedly with 'pet. ether.Removal of pet. ether gave a crude product whichwas purified by column chromatography (silica gel,pet. ether) to yield pure 8, yield 1.4 g (71.7%), m.p.48°C.

7,8-Dimethyl-2-tetralone 10. (a) using sodiumin liquid ammonia: In about 150 mL of ,freshlycondensed ammonia, 7-methoxy-I ,2-dimethylnaphthalene 8 (2.3 g) and absolute ethanol(3 ml.), was added sodium metal (2.7 g) in smallpieces. On addition of sodium metal the reactionmixture became blue. After completion of addition,the blue colour disappeared on stirring forsometime. The ammonia condenser was removedand solid ~CI (2 g) and water (20 mL) wereadded. After evaporation of NH3, the mixture wasextracted with ether. Ether layer was washed withwater and removal of the ether yielded the crudeproduct, enol ether 9 (2.20 g). To this crude enolether 9 (2.2 g) in acetone (15 mL) and methanol (8ml.), oxalic acid (0.5 g in 12 mL H20) was added.The reaction mixture was stirred vigorously for 1.5hr and poured into water. It was extracted with pet.ether and pet. ether extract was dried. The solventwas removed under reduced pressure to furnish thecrude ketone, which was purified by columnchromatography (silica-gel, benzene) to give 10,yield 1.3 g (52%).

(b) Using sodium in ethyl alcohol: Sodium (2.7g) was added during 10 min to a solution of 8 (2.5g) in absolute ethanol (27 mL) and heated underreflux on a water-bath at 115°C. Heating wascontinued until all the metal disappeared. Thecooled solution was then diluted with water (27 mL)and cone. HCI (27 mL) was added as rapidly aspossible. The mixture was heated on a water-bathfor IS min with occasional shaking and then cooled.The cooled solution was extracted with ether. Ether

284 INDIAN J. CHEM., SEC. B, MARCH 1998

layer was washed with water and dried. Removal ofether furnished the ketoee, wIMdl was purified bycolumn chromatography (siliCa gel. benzene) to givepure 10. yield 1.3 g (55%).

The ketooe 10 obtained by both the methods wasidentical in all respects (TLC. IR & IH NMR). IR(Neat): 1710 an-I (C=O); IH NMR (CCL.) : 2.08(3H, s, Ar-CH3). 2.22 (3H,s. Ar-CH3). 2.35 (2H, t,J=7 Hz, -CHr• adjacent to ketone). 2.92 ,(2H, t,J=7 Hz, CJIs - CH2-). 3.34 (2H,s. -CHr• benzylicadjacent to ketone) and 6.82 (2H,s. Ar-H) (Found :C,S2.S0, H,S.20. CI2HI40 requires C,S2.76,H,S.04%).

AcknowledaementMTB thanks the Principal, SSGM College,

Kopargaon for encouragement.

ReferencesI Uegaki R, Fujwnori T, Kubo S & Kato K,

Phytochemi3try, 22, 1983, 1193.

2 Murali D & Krishna Rao G S,lndion J Chem, 26B, 1987,843.

3 Sawhncy S N & Kachra C N. J Indian Chem Soc, 36,1959,486.

4 Vogel A I, Tut book of Practical Organic Chemi3try,(Longman Group Ltd. London) 1956, 738.

5 (a) Bardhan J C & Mukharjee D N, J Chem Soc, 1956,4629.(b) Bachute M T, Sattar Abdus & Mane R B, Indian JChem, JOB. 1991, 1145.

6 Braude F A. Jackman L M & Linstead R P, J Chem Soc,1960,3133.

7 Jackman L M, Review, Advances in Org Chem, Methodsand Results, 2, 1960,329.

8 Brown J K, Bumaham D R & Rogers NAJ, TetrahedronLett, 23, 1966, 2661.

9 Soffer M D, Bellis M P, Gellerson H E & Steward R A,Org Synth, Coli Vol IV, 1963,903.

10 -Reddy P A & Krishna Rao G S, Indian J Chem, 19B,1980,753.

11 Alexander J & Krishna Rao G S, Tetrahedron, 27, 1971,645.