Indian Journal of Che mistry Vol. 4313 , August 2004, pp. 1729- 1736

A novel synthesis of bromomethoxy disubstituted derivatives of benzocycIobutenone

P V Barve*+ & P Schiess

Inst itute of Organic C hemistry , University o f Basel, St. Johannsring 19, C I-I-4056, Basel, Switzerland.

Received 26 February 2003; lIccepled (revised) II March 2004

Flash vacuum pyrolysis of orlho-methyl aromatic acid c hlorides has been used to prepare a variety of substituted de-rivatives of the benzoeyelobutenone ring system start ing from simple precursors. The signilicance of the present react ion lies in the fact that the bromine atom present in the aromatic nucleus, re mains undisturbed during the high temperature treatment employed in the pyrolysi s and forms, a bromomethoxyketone successfully . Th is is an a ltogether new approach.

IPC: Int.CI7 C 07 C 13/00

Flash vacuum pyrolysis of 2-methylbenzoyl chloride by e liminatio n of hydrogen chloride has been used to prepare benzocyclobutenone ring system. A variety of substituted derivatives of benzocyclobutenone can be prepared starti ng from simple precursors. A typical apparatus for vapour phase pyrolysis is shown in Figure 1. It consists of an evaporator zone from where the reactant is transported by distillation under reduced pressure to the ho t tube or pyrolyser maintained at temperatures between 300-800°C. The products formed are swept from the reaction chamber by a s low strea m of nitrogen gas and are isolated after condensation at low temperatures. Flash vacuum

pyrolysis is characte ri zed by the use of low pressure, in the range of 10-2 to 10-4 mm and short contact times generally in the range of 0.00 1 to I sec. Thi s permits the degradation products of primary reaction to survive the pyrolysis and e merge from the oven. The unique cis course of the reaction allows formation of o nly a single product, which might not be possible under other e liminating conditions. In order to minimize the formation of products due to secondary reactions and rearrange ments, pyrolysis te mperature, rate of reactant addition into pyrolyser and pressure of the system are monitored. The pyrolysis temperature and rate of evaporation are chosen such that about

___ J •

+ Present address: K. J. Somaiya College o f Science and Comillerce, Vidyavihar, Mumbai 400077, Indi a

-; 3

I . Distillation flask 2. Pyrolyzer of quart. 3. Cool linger 4. Thermoclcment

Figure 1

1730 INDIAN J. CHEM., SEC B, AUGUST 2004

50% of the acid chloride is recovered back afte r hydrolysis from the product mix ture and can be reused. Therefore, a correcti on is required in the calcul ation of yie lds with respect to the amount of ac id chloride actually converted to the produc t.

Thc signi ficance of the present reacti on lies in the fact that the bromine ato m present in the aro matic nucleus remains undi sturbed during the hi gh tempera-ture trea tment employed in the pyro lys is and forms a bro mo methoxy di substitued derivative o f benzo-cycl obutenone successfull y. Thi s is an a ltogether new approach.

The 6-alkoxy substituted deri vatives of berlZo-cyclobutenones have been used in the synthes is o f naphthalenc building blocks, which may be further usc-ful in the synthes is of naphthy li soquinoline alkaloids '.

Results and Discussion The preparation o f 3-bromo-6- methoxybenzo-

cyclobuten- I-one 7b and its isomers was reported 2.3

by a different route, invo lving the reactio n between 2,5-dihydroanisole and dibromocarbene to g ive 1:2 adduct which , when boiled with pyridi ne, gave pyridinium salts. These were converted by the Krbhnke reactio n with p-nitrosodimethylaniline into 7b. Its isomer 5-bro mo-6-methoxybenzocyc lobuten-I-one 7a and 7b have been also pre pared by react io n of 6-methoxybenzocyc lobuten-l -one with trimethy l-ammonium tribro mide and zinc chlori de'.

We now report that the isomeric bromomethoxy-di substituted deri vatives of benzocyc]obutenone, 7a and 7b, can be obtained by an entire ly d iffe rent route.

The starting substance 3a, for the preparation of 7a, was obtained as a side product, as shown in Scheme I, during the preparation of ethy l 2-hydroxy-6-methyl-benzoate3,4. It must have been formed through the action of bromine used fo r the aro mati zation of the cyclohexenone derivative 1, obtained through the condensation o f acetoaceti c ester with c rotonaldehyde5, not reported in the literature6. 3 appeared to be a new

I)Br?/AcOH - .. 2)Heat

OH OH

& COOC'H' + R'rBrCOOC,H'

~CHJ ¥CH3

3

33 :R 1= H, R2= Br

SOCh

DM F

6

RI 2 3

Scheme I

4

Scheme II

33 : R1= H, R2= Br 3b: R1= Br, R2= H

OCH1

~*' COOH KOH.. 0

CH1 RI

5

7

BARVE et al.: BROMOMETHOXY DISUBSTITUTED DERIVATIVES OF BENZOCYCLOBUTENONE 173 1

compound. Its I H NMR spectrum showed the presence of two orlho aromatic protons, indicated by a doublet, with identical coupling constants. So 3 could be identical with either 3a or 3b. The structure o f 3 was establi shed as 3a after subjecting it to a series o f reactions as shown in Scheme II. Methylation of 3a using dimethyl sulphate and potassium carbonate in acetone afforded 4a, which on hydrolys is with potass ium hydroxide in tri ethylene glycol gave the corresponding acid Sa. Subsequent treatment with thionyl chloride using DMF as a cata lyst resulted in the formation of the corresponding acid chloride 6a. The crude ac id chloride was pyrolysed at 520°ClO.05 mm to give 7a. The pyro lysis experiments were a lso perfomed at aspirator pressure of 13 mm. However, the yields obtained under these conditions were low. This can be attributed to the secondary bimolecular reactions which are poss ible at higher pressure9.

The ketone obtained appeared to be diffe rent frum 7b, which has m.p.7SOC I-3, because it had m.p. 117.5-18.5°C, and the spectral constants were also not identi cal. So, structure 7 must be identical with 7a since its spectra l constants were identical with similar compound reported by Bungard el al. I prepared by a diffe rent route and the starting substance in Scheme II must be 3a. (The y ie ld of 7a is much higher by our method as compared to that reported in lite rature I).

The substitutio n patte rn o f the bromomethoxy disubstituted derivati ves o f benzocyclobute none 7b has a lready been proved as shown in Scheme III, by its fiss ion under a lkaline conditions to g ive 2-bromo-5-methoxyphenylacetic ac id 8b, di stinguished from its isomers by its NMR spectrum3.7-9 . Alkaline fi ss ion of unsubstituted benzocyclobuteno ne has been reported II to g ive approx imate ly equal amounts o f 0 -toluic and phe nylacetic ac id derivatives, formed by the two poss ible cleavage modes (8a,b), whereas

inferred from li terature3.7.12 the regioche mical course of thi s carbon-carbo n c leavage depends strong ly on the presence of substituents in the aromatic ring. The bromomethoxy ke to ne 7b is reported to give onl y the phenylaceti c ac id 9b, probably owing to low electron dens ity at B carbo n ato m in inte rmedi ate structure 8 (Scheme III), where the - I effec t of the o-methoxy g ro up is comparable with its + E effect7. This ex pl ai ns the regioselecti ve nature of the abo ve reaction and prevents fi ssio n by mode a , and formatio n o f 5b. Alkaline fi ss ion o f the new keto ne 7a gave the phenylacetic ac id deri vati ve 9a (m. p. 103. 5- 104.5°C), as expected but diffe rent from 9b (m. p. 11 4-1 5°cl The keto ne 7a gave orange colo ured 2,4-dinitro-phenyl hydrazone derivative (m.p. 309- IO°C, dec).

Study of the IH NMR spectrum of Sa under high fi e ld resolutio n, di stinctly showed a small coupling between the methyl protons at C-6 and the aromatic proton at the ortho carbo n, C-5 (J=0.6 Hz). Thi s is not poss ible in ~he case o f 5b, where the orlho position of the methyl group is occupied by a bromine ato m. In order to suppo rt thi s route fo r the formation of bromomethoxy disubstituted derivati ves of beno-zyclobuteno ne, we dec ided to synthes ize 7b in a similar manner. The correspo nding acid 5b was prepared , as shown in Scheme IV, by bro minatio n, by using bromine in ace ti c ac id 13, o f 6-methoxy-2-methyl benzoic ac id 10 obtained from 2 by methylatio n fo llowed by hydrol ys is. The pyrol ys is o f the ac id chlo ride 6b at 550°C/ 0.02 mm gave the expected ketone 7b (m. p. 73-74°C). The spectral constants were a lso in agreement with the literatu re values l.3. The ke tone 7b gave yellow colo ured 2,4-dinitrophenylhydrazone deri vative (m. p. 288-90°C). A correction in calculation of the theoretical yie ld was required to make in the abo ve pyro lys is experiments. Because about 50% of the ac id chlo ride was

NaOH •

[I r-~OCH3 bO~

Q ;> a Na __ OCl-h

¢-CHrCOOH Br Br Br

7b 8 9b

NaOH •

B r~3

VCI-h-COOH

7a 9a Scheme III

1732 INDIAN J. CHF.M., SEC B, AUGUST 2004

2 4b

10 Sb 6b

~o Br

7b

Scheme IV

recovered and converted back into the corresponding acid. The yields were recalculated with respect to the acid actually consumed.

Experimental Section Melting points were determined with a Kofler-hot

stage apparatus and are uncorrected. The Infrared spectra were determined with a Perkin-Elmer 781 Spectrophotometer. IH NMR at 60 MHz were determined with Varian-em-360 spectrometer. IH NMR spectra at 400 MHz and the \3C NMR spectra at 22.63 MHz and 100 MHz were determined with a Fourier-Transform-NMR from TYP Bruker WH 90 using TMS as an internal standard. The UV spectra were determined on a Varian Cary 219 Spectrophotometer. The mass spectra were deter-mined with a 5970A Hewlett-Packard mass spectro-meter. GC was taken on Varian 1400 with FlO, using nitrogen as a carrier gas and a glass column 2m x 3mm, 3% Carbowax 20M on Chromosorb W A W DMCS 80-100 mesh. The pyrolysis apparatus as described by Strubin4 consisted of a I cm x 30 cm long Quartz tube, heated by an e lectric oven and merged with a collection receiver made of pyrex glass. The substance to be pyrolysed was distilled from a round bottomed flask. The distillate directly entered the hot Quartz tube. The temperature measurement of the hot tube was monitored with a thermocouple and a Teacon U R 410 Controller. The collection receiver, cooled with isopropanol-dry ice

mixture, was directly connected to a cold trap. Liquid nitrogen was used for cooling the cold trap, which was directly connected to a vacuum system (Figure 1).

Ethyl 2-hydroxy-6-methylbenzoate 2. The cyclo-hexenone derivative, ethyl 5-methyl-3-oxocyclo-hexene-4-carboxylate 1 was prepared as described in literature6 , b.p. 85°-95°C/ 0.5 torr (ref. 6 b.p. 80o-95°C/ 0.5 torr). Cyclohexenone derivative 1 (68g, 0.373 mole), and carbon tetrachloride (250 mL) were kept in a 2L flask cooled to O°C in an ice-bath and stirred magnetically. A solution of bromine(60g,0.374 mole) in 250 mL acetic ac id was added dropwise in 45 min. After the bromine addition was complete, the c lear solution was stirred for 30 min and allowed to attain the room temperature in I hr. Then it was heated under reflux in an oil-bath maintained at 98°C overni ght. A conti nuous nitrogen flow was mai .tained to aid the removal of hydrogen bromide. The dark reaction mixture was cooled to room temperature. Dichloromethane (500 mL) and waLr (600 mL) were added after thorough mixing with the he lp of a separatery funnel, the organic layer was separated. The water layer was extracted with dichloromethane (500 mL). The combined organic layers were washed with saturated sod ium bicarbonate so lution (500 mL) followed by brine solution (500mL), dri ed over anhydrous sodium sulphate, filtered and the solvent dichloromethane was removed using rota vapour at 45°C. The dark brown oil was steam-distilled in 3hr.

BARYE el al.: BROMOMETHOXY DISUBSTITUTED DERIY ATIYES OF BENZOCYCLOBUTENONE 173 ~

team distillate was ex tracted with 2 x lL ether. )rganic layer was washed with brine soluti o n mL), dried over anhydrou s sodium sulphate, :d and the sol vent ether removed by rotavapo ur 1°C. The resulting 152.9g of brown oil was ed under reduced pressure. Fraction I was ted at 65-88°CIO.02 mm and Fraction II was ted at 88- 11O°C/0.02 mm. Fraction I was ved in 500 mL of methano l-water (4: 1) and :i to O°C with stirring. White crysta ls (I 12.9g, 0), m.p. 39-40.5°C (ref. 6 m.p. 42°C) were led, after drying in vacuum for two days. lyl 3-bromo-2-hydroxy-6-methylbenzoate 3a. on II in the above procedure was dissolved in 80 F ethanol by warming slow ly. On cooling to room :rature white crystals appeared, which on ion and washing with 20mL of ice-cold ethanol , dried in vacuum to g ive white crystals, m.p. 53-

( 15.3g, 15.8%) (ref. 6 not reported). Further ::ation gave crystals, m. p. 56.2-56.8°C. Anal. for C,oH"BrOJ (259.09): C, 46.35; H, 4.28; Br, Found: C, 46.27; H, 4. 17 ; Br, 30.86%; UV

,01): 2 11 , 249, 3 19 nm (around 20000, 9700, ; IR (KBr): 2990,2940, 1665, 1595, 1475 , 141 0, 1370, 1330, 1295 , 1260, 11 95, I 160, 11 05, 1020,

390, 870, 8 15, 795, 750 (br), 650 cm"; MS: mlz ve intensity) 260/258 (M+ 2 1/21 ), 214/212 (M+ OH , 99/100), and other peaks; 'H NMR: (CDC I), ~): 1.42 (3 H, t, 1= 7Hz,-CH3), 2.50 (3H, S,-CH3), 2H, q, 1= 7Hz,-CH2), 6.60 ( I H, d, 1= 8Hz, ArH), I H, d, 1=8Hz,ArH), 11. 88 br(l H, s, replaceable,-'3C NMR: (CDC I3. 22.63 MHz): 14.2 (q), 23.7

2.2 (t), 109.0 (s), 11 3.9 (s), 123.5 (d), 137.2 (d) , (s), 159. 1 (s), 171.3 (s). ~y l 3-bromo-2-methoxy-6-methylbenzoate 4a. I soluti on of dimethyl sulphate (2.75 mL, 5 mole) and acetone (25 mL), potass ium nate (5.8g, 0.0043 mole) and 3a(5.68g, 0.022 were added. The mixture was refluxed under an

;phere of nitrogen for 5hr. GC exam inati on of on mixture showed presence of 30% of the Ig materi al after half an ho ur, 16.5% after 2hr, afte r 4 hr and 8.5 % after 5 hr. Then the reactio n re was cooled to room temperature. etone was removed with a rota vapour. The ,e was di ssolved in 50 mL of ether and stirred 3.5 mL of triethylamine for Ihr. The reaction re was filtered. The so lid res idue washed with 2

mL of ether. The ether ex tracts were then ~d with water, 2N HCI , water, 2N NaOH, water rine and dried over anhydrou s sodi um sulph ate.

Removal of the solvent y ie lded 4.5g of brown o il. Di st ill ation in a Kugelrohr apparatus, with an oven temperature of 90-1 OO°C (0. 1 mm) affo rded 4a as (' co lo urless o il , b. p. 87-88°CIO.07 mm (4.45g, 75%). fo und to be homogeno us by Gc. Anal. Calcd fOl CllH13B r03 (272.9): C, 48.37; H, 4.80. Found : C 48.45; H,5.07% ; IR (film): 2990, 2940, 1735 (br: 1595,1465,1400, 1365, 1270, (br), 1220, 1145, 1095 1060, 1020, 1000,920,880,860,8 10,730,6 10 cm" 'H NMR (CDCl3, 60 MHz): 1.35 (3H, t, 1= 7H z -CH3), 2.23 (3 H, s,-C H3), 3.85 (3 H, s,-OCH3), 4.3/ (2H, q, 1=7 HZ,-CH2), 6.80 ( I H, d , 1= 8Hz, ArH ) 7.40 (I H, d , 1= 8Hz, ArH ); ' 3C MR (C DC I3, 22.6:: MHz): 0 14.3 (q), 18.8 (q) , 6 1. 3 (q), 62.0 (q), 11. 4 1 (s) , 127. 1 (d), 13 1. 0 (s), 134. 1 (s), 136.1 (s), 154.2 (s) 166.9 (s).

3-Bromo-2-methoxy-6-methylbenzoic acid Sa The hydrolysis of 4a(4.65g, 0.017 mole) was effectec by heat ing, under re flux using magnetic stirrer, in , so luti on of 2.35g of potassium hyd rox ide in 35 mL 01 triethylene g lycol and 10 mL of water, under ar atmosphere of nitrogen. The temperature of th ~ reaction mi xture was maintained at 110° C by heatin ~ in an o il-bath. The heating was cont inued for 16hr The reaction mixture was cooled to O°C, diluted witt 37.5 mL of water, acidified with 2N HC I(p H I). Th~ precipitated acid was ext rac ted with 3 x 125 mL 01 ether. The ether ex tracts were washed with 2N HC and brine, and treated with saturated solu tion 01 sodium bicarbonate till pH 8. The bicarbonate extrac' was collected. T he ether layers were washed wit~ saturated sol ution of sodium bicarbonate. Ac idification of the comb ined sodium bicarbonal~ ex tracts with cone.HC I till pH I, gave upon cool ing white crystals , which were filtered, washed wit~ water, and dried in vacuo to y ie ld sa( 1. 9g, 46%). II formed white need les from [. mixture of ethy l acetate·

pet.ether (b. p. 40-65°C), m. p. 124-25.5°C. Ana l. Calcd fo r C9H9BrOJ (244.9) : C, 44. 10; H, 3.70; Br 32.60. Found: C, 44.06; H, 3.71 ; Br, 32. 15%. IR (KBr): 2950, 1705 , 1695 , 1590, 1570, 1475 , 1455 1290, 1300 (br) , 1225 , 11 60, 1110, 1000, 920 (br) 820,740,720,665 cm" ; IH NMR (CDCb, 400 MH z) 2.4 (3 H, d , 1= 0.6 Hz,-CH3), 3.97 (3H,s -OCH3), 6.9 1 ( 11-1 , dd , 1= 8Hz and 0.6 Hz, ArH ), 7.53 ( IH , d, 1= 8Hz, ArH ), 10.6 br ( I H, s, replaceab le,-COOH ) '3C NMR (CDC I3, ]00 MH z): 19.5 (q), 62.5 (q), 11 4.: (s), 127.5 (d) , 128.9 (s), 135.0 (d), 136.9 (s), 154.4 (s) 172. 1 (s); MS : mlz (relative intensity) 246/244 (M+ 25/29), 228/226 (M+ -H20, 10011 00), 199/197 (M < -CHO, H20 , 101 I 0) and other peaks.

1734 INDIAN J. CH EM .. SEC S, AUGUST 2004

5-BI'omo-6-methoxybenzocyclobutcn-l-one 7 a. To a mi xture of Sa (4.0 g , 0.016 mo le) and 5 drops of OMF as a catalyst, thionyl chloride (1.75 mL, 0.024 mole) was added. The reaction mi xture was refluxed in an o il-bath , whose temperature was g radu ally increased to 120°e. After the evo lutio n of gas bubbles stopped, the heating was continued fo r further ha lf an hour with the oi l-bath temperature at BO°e. The excess of thi ony l c hloride was re moved u ing water vacuum at 80°e. The crude ac id c hloride 6a was pyrolysed, in J hr and 45 min in a Kugelrohr, w ith an o ven te mpe rature of 7S-83°C, at the pyrolysis temperature of 530°ClO.05 mm. Then the reaction zone was flushed with nitrogen gas a nd the system was opened to the atmosphere. The pyrolysate was extracted with 80 mL of ether, stirred wi th a magnetic stirrer, with equal vo lume of saturated so luti on of sod ium bicarbonate, fo r 16hr for hydrol ys is of the unconverted acid chloride 6a. The aqueous layer was extracted w ith e ther. The co mbined e ther extracts were washed w ith saturated so luti on of sodium carbonate, 2N NaOH at O°C, water, dried over anhydrous sodi um su lphate, and the solvent removed. Sublimation of the ne utra l sol id res idue, in a Kugelrohr apparatus, w ith an oven temperature of 75-11 5°C (0.05 mm) affo rded 2. J g of pale ye ll ow sublimate, m. p. 100-1 16°C, which on recrystallisation from pet. ethe r (b. p. 70-96°C) affo rded 7a in the form of white needle shaped crysta ls ( 1.4 g, 38%), 52% \V.r.t. converted acid, m. p. 117.5-1 8.5°C (ref. 3

m.p.75°C if it were 7b). Acid ifi cation of the aq ueous layers w ith conc. HCI

gave white crysta ls of the unreacted ac id ( 1.I g , 27 %), m.p. I 23-24°e. The y ie ld of 7a was 38% with respect to the ac id subjected to py ro lys is and 52.0% W.r.t. acid actu all y consumed. Anal. Calcd for C9H7Br02 (226.9): C, 47.60; H, 3.09; Br, 35.21. Found: C, 47.49; H, 3. 12 : Br, 35. 13% ; MS: mlz (re lative intensity) 228/226 (M +, 100199), 2 13/2 1 J (M+,-CH3. 9/8) , 199/197 (M+,-C2Hs, 7/6), 185/183 (M+, -C)H7 or -CH}CO, 47/46) and o the r peaks; IR ( KBr): 1775,1760,1595 (s), 1470, 1430, 1410, 1275, 11 20, 1085, 1050, 990 and 820 cm· l ; UV (ethano l) : 220,260 and 3 13 nm (29800, 8500, 2100); I H NMR (COCh, 400 MH z): 3.90 (2H, d, J= 0.8 HZ,-CH2), 4.24 (3 H, S,-OC H3), 6.93 ( IH , dxt, J= 8 Hz and 0.8 Hz, A rH ), 7.67 ( I H, d, J= 8 Hz, ArH ); 13C NMR (COC I}, 100 MH z): 50.9 (t), 60.95 (q), J 10.2 (s) , J 16.4(d), 133.0 (s) , 140.7 (d) , 149.7 (s) , 150.1 (s) , 183.2 (s).

2,4-Dinitrophenylhydrazone derivative of 7a. The 2, 4-di nit rophenylhydrazine reagent was prepared

by dissolving 0.4 g o f 2, 4-dinitrophenylhydrazine in 2.0 mL of conc. H2S04 and 3.0 mL of water was added d ropwise w ith stirring unt il so lution was comple te. T o the warm solutio n 10.0 mL of ethano l were added and the solution was fi ltered. 1.5 mL of the freshly prepared 2, 4 -dinitrophenylhydrazi ne reagent was added to the solutio n of 0.04 g of the ketonic compound prepared in 2.0 m L of ethanol. C rysta ls appeared within 5 to 10 m In. On filtration 0.068 g (94. 7%) of the derivative was obta ined. It was dissolved in 3.0 mL of ethano l (95 %) and heated w ith e thyl acetate until so lution was obtained. The ho t sol ution was filtered a nd a llowed to tand for 12 hr. On f i Itration 0.04g (55.76%) of o range crysta ls were obtained. Further purifi cati o n from chloroform and ethy l acetate gave the correspond ing 2, 4-di nilro-phenylhydrazone as orange ye llow crystals (from ethyl acetate and c hl oroform), m. p. 309- 10°C (dec.). Anal. Calcd fo r Ci sHIIBrOsN4 (406.9): C, 44.24; H, 2.70; N, 13.76; Br, 19.64. Found: C, 44.15; H, 2.76 ; N, 13. 74 ; Br, 19.90%.

4-Bromo-3-methoxy-phenylacetic acid 9a. The ketone 7a (0.30g, 0.0013 mole), was dissolved by warming in ethano l ( 10.0 mL), aqueous sodium hydrox ide ( 10% w/v; 5 mL) was added dropwise over 5 min and the so luti on was kept at 60°C for 10 min. Water (10 mL) was added and the solution was evaporated to about half its volume. Charcoal was then added and the solution was fi Itered and the fi Itrate was made up to 20 mL with water and acid ified with conc. HCI. The mixture was cooled in ice for 2h r and the solid obtained was filtered off, washed and dried (0.22g, 66%), In. p. 102-04°e. It formed white needles from water, In. p. 103.5-4.5°e. Anal. Calcd for C9 H9 Br03 (244.9): C, 44. 10; H, 3.68; Br, 32.63. Found: C, 43.44; H, 3.65; Br, 32.89% ; IR (KBr): 2985, 2970, 1705. 1695, 1590, 1580, 1485,1460, 1450, 1405, 1335, 1295, 1280, 1255, 1225, 1170 (br), 1130, 1040, 1025, 920,900,845,8 10,755, 71 0,685,645 cm· l ; MS: mlz (re lative intensity) 246/244 (M+, 62/62), 20 1/1 99 (M+ -COOH, 96/1 00) , 171 1169 (M\ -COOH,-CI-hO, 7111) and other peaks; IH NMR (COCl), 400 MHz): b 3.6 1 (2 H, s,-CH2), 3.88 (3 H, s,-OCH3), 6.76 ( I H,dd, J=2 and 8 Hz, 6-H), 6.82 (I H, d , J= 2Hz, 2- H) , 7.48 (I H, d, J=8Hz, 5-H), 11 .2 br ( I H, s, replaceab le,-COOH); 13C NMR (COCl3, 100 MHz): 40.9 (t), 56.2 (q), 110.8 (s), 11 3. 1 (d), 122.7 (d), 133.3 (d ), 133.8 (s), 155.9 (s), 177.6 (s).

2-Methoxy-6-methylbenzoic acid 10. It was prepared as described in literature6 by treat ing 2 with K2C03 and OMS in ace tone fo ll owed by hydrolysis

BARVE er al.: BROMOMETHOXY DISUBSTITUTED DERIVATIVES OF BENZOCYCLOBUTENONE 1735

with dilute ethanolic solution of sodium hydroxide. The ethanol was removed at reduced pressure. The aqueous solution was acidified with conc. HCI. The precipitated acid was filtered and recrystallized from 20% methanol to give crystals, m. p. 138-39°C (ref. 6

m. p. 139-41 °C). 3-Bromo-6-methoxy-2-methylbenzoic acid Sb. In

a 250 mL 4-necked fl ask, fitted with a mechanica l st irrer, a dropping funnel and having an outlet for hydrobromic acid gas, which was absorbed in water, are placed 8.25g (0.050 mol e) of 6-methoxy-2-methyl benzoic acid 10 and 42.5 mL of g l. acetic acid. The mixture was stirred at 45°C till the solution resulted. It was then cooled to 35°C, and to thi s was, added a solution of 2.5 mL (0.050 mol e) of bromine in 40.0 mL of gl. acetic acid with vigorous stin'ing over a period of 2 hr. When all the bromine was added the solution was stirred for further half an hour and then poured over 150g of crushed ice and cooled in an ice-bath for about 2 hr. The fine, white crystals of 3-bromo-6-methoxy-2-methylbenzoic acid thus obtained were filtered and washed with cold water till free from acetic acid. The crude product was dried at 50°C using water vacuum, yield 10.02 g, m. p. 150-60°C. On recrystallisation from a mixture of CH2Cl2. pet. ether (b. p. 40-6SOC), white crystals were obtained, yield 8.6g(70%), m. p. 162-63 dc. Anal. C:lled for C9H9Br03 (244.9): C, 44.10; H, 3.68; Br, 32.63. Found: C, 43.78; H, 3.68; Br, 32.74%; IR (KBr): 2960 (br), 1695 , 1585 , 1475 , 1430, 1380, 1280, 1265, 1085, 885 (br) , 800, 770, 710, 640 cnf' ; 'H NMR (COCl3, 400 MH z): 2.45 (3 H, s,-CH )), 3.86 (3H ,s,-OCH3), 6.71 (lB, d, 1= 9 Hz, ArH), 7.55 (lH, d, 1= 9Hz, ArH), 10.0 br ( I H, s, replaceab le,-COOH ); '3C NMR (COCl), 100 MHz): 20.41 (q), 56.25 (q) , 110.37 (d), 116.47 (s), 124.30 (s), 134.39 (d), 135.99 (s), 155.59 (s), 172.54 (s).

3-Bromo-6-methoxybenzocyclobuten-l-one 7b. To the mixture of Sb (4g, 0.016 mole) and 5 drops of OMF as a catalyst, thionyl chloride(1.75 mL, 0.024 mole) was added. The reaction mixture was refluxcd in an oil-bath, whose temperature was gradually increased to 120°C. After the evolution of gas bubbles stopped, the heating was continued for further half an hour at 130°C. The excess thionyl chloride was r~moved using water vacuum at 80°C. The crude acid chloride 6b was pyrolysed in 1 hr and 50 min, in a kugelrohr, with an oven temperature of 80-90°C, at the pyrol ys is te mperature of 550°CIO.02 mm' Then the reaction zone was flushed with nitrogen gas and the system was opened to the atmosphere.

The pyrolysate was extracted with 80 mL of ether, stirred with a magnetic stirrer, with equal volume of saturated sodium bicarbonate for 16hr for hydrolysis of the unconverted acid chloride 6b. The aqueous layer was extracted with ether. The combined ether ex tracts were washed with saturated solution of sodi um carbonate, 2N NaOH at O°C and water and dried over anhydrous sodium sulphate. The solvent was removed. Acidi fication of the bicarbonate ex tracts with cone. HCl gave white crystals of the unreac ted acid (1.5g, 38%), m. p. 162-63°C. Subli-mation of the neutral solid res idue in a Kugelrohr apparatus, with an oven temperature of 70-1 00°ClO.05 mm afforded 1. 1 g of white sublimate which on recrystalli sation from pet.ether (70-96°C) gave 7b in the form of white needle shaped crystals (0.5g, 21.6% w.r.t. the acid actually converted), m. p. 73-74°C. While a second sublimation fraction was collected, at the oven temperature of 100-150°CIO.05 mm, weighing 0.30g, m. p. 136-43°C which was unidentified. Anal. Calcd for C9H7Br02 (226.9): C , 47.60; H, 3.09; Br, 35.21. Found: C, 47.39; H, 3.0 I ; Br, 35.17%; IR (KBr) 1785, 1760, 1595 , 1565, 1475, 1435, 1405 , 1350, 1280, 1140, 1095, 1050,990,950, 830,780,685,630 cm" ; UY (ethanol): 228,252, 259 and 319 nm (24800, 8100, 8400, 3400); 'H NMR (COCl), 400 MHz): 3.89 (2H, d, 1= 0.7 HZ,-CH 2), 4.09 (3H , s,-OCH 3), 6.71 (IH ,dd, 1= 9 and 0.7 Hz, ArH), 7.46 (l H, d, 1= 9 Hz,-ArH); I3C NMR (COCl3, 100 MHz): 51.7 (t) , 60.2 (q), 106.3 (s), 118.7 (d), 132.9 (s) , 140.0 (d), 150.2 (s), 153.0 (s), 182.2(s). The 2,4-dinitrophenylhydrazone derivative of 7b was prepared using the procedure as described earlier for the preparation of the 2,4-dinitrophenylhydrazone derivative of 7a. Yellow crystals (from chloroform-ethyl acetate), m. p. 288-89°C, were obtained. Anal. Calcd for C, sHIIBrN40 S (406.9): C, 44.24; H, 2.70; N, 13.76; Br, 19.64. Found: C , 44.11; H, 2.64; 13.55 ; Br, 19.82%.

Acknowledgement

One of the authors (PYB) is thankful to University of Basel , Switzerland for their support.

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