-
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
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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
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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
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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.
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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.
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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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