92 JOURNAL OF CHEMICAL RESEARCH 2007
OCH3
OCH3
OCH3
CHO
Cl
COOH
COOH
i
ii
iii
H3CO
COOC2H5
14
H3CO
H3CO
COOC2H5
Cl
15
7
Scheme 2 Reagents and conditions: (i) DMF-POCl3, 80°C, (ii) SO2Cl2 (excess), dioxan, reflux; and (iii) 5% aq. NaOH,
heat followed by 1:1 HCl.
acidified by 1:1 HCl. A white solid separated out, which was filtered,
dried and recrystallised from alcohol–water to obtain the desired 2-
chloro-3,5-dimethoxyphenylacetic acid (11) as white crystals.
yield: 82%; m.p. 161°C. IR: 2400–3000, 1710 cm-1; 1H NMR:
(CDCl3, 300 MHz); data d 3.83 (s, 6H), 3.88 (s, 2H), 6.49 (bs, 1H),
6.65 (bs, 1H); Anal. calcd. for C10H11ClO4: C, 52.07; H, 4.81. Found:
C, 52.27; H, 4.84.
ester (12) provided the aldehyde (13) which was eventually
oxidised to 6-chloro-3,5-dimethoxyhomophthalic acid (6),
a key intermediate of the naturally occurring 5-chloro-8-
hydroxy-6-methoxy-3-methyl-3,4-dihydro-isocoumarin (1),
known to exhibit fungicidal activity.
After a lucrative and successful synthesis of (6), we focused
on attaining the other target molecule viz. 4,6-dichloro-3,5-
dimethoxyhomophthalic acid (7). In view of the fact that
sulfuryl chloride is known to convert aromatic aldehydes
to the corresponding acid chlorides we chose to synthesise
(7), starting from ethyl 3,5-dimethoxyphenylacetate (14) as
depicted in Scheme 2.
Vilsmeier–Haack formylation of (14) afforded the aldehyde
(15), which was refluxed with excess sulfuryl chloride and
the ensuing intermediate subjected to alkaline hydrolysis to
furnish (7) in moderate yield.
To conclude, a successful synthesis of 6-chloro-3,5-
dimethoxyhomophthalic acid (6) and 4,6-dichloro-3,5-
dimethoxyhomophthalic acid (7), key intermediates for
the naturally occurring isocoumarins (3) and (4), was
accomplished using easily accessible starting materials,
involving simple reaction conditions and convenient workup.
Ethyl 2-chloro-3,5-dimethoxyphenylacetate (12): 2-Chloro-3,5-
dimethoxyphenylacetic acid (11) (21.69 mmol) was dissolved in dry
ethanol (50 ml). To this solution, conc. H2SO4 (0.5 ml) was added
and refluxed on a water bath for 2 h. Excess ethanol was removed
under reduced pressure and the residue poured over crushed ice.
An oily product separated out, which was extracted with (20 ml ¥ 3)
portions of ether. The ether layer was washed with water, 10%
NaHCO3 and again with water, dried over anhydrous Na2SO4 and
concentrated in vacuo to yield an oily residue that was purified by
column chromatography over silica gel using hexane as eluent to
obtain (12) as white crystals.
yield: 90%; m.p. 61°C. IR 1745 cm-1; 1H NMR: (CDCl3, 300 MHz);
data d 1.26 (t, J = 6 Hz, 3H), 3.74(s, 2H), 3.79 (s, 3H), 3.87 (s, 3H),
4.18 (q, J = 6 Hz, 2H), 6.45 (bs, 2H). Anal. calcd. for C12H15ClO4: C,
55.71; H, 5.84. Found: C, 55.73; H, 5.85.
Ethyl
2-chloro-3,5-dimethoxy-2-formyl-phenylacetate
(13):
DMF (1.8 ml, 23.22 mmol) was cooled in an ice-bath and POCl3
(2.16 ml, 23.22 mmol) was added with stirring while maintaining the
reaction temperature below 5°C. Dimethoxyphenyl acetate (12 or 14)
(19.34 mmols) was added to the Vilsmeier–Haack complex at 0–5°C.
The reaction mixture was allowed to attain room temperature and
then it was heated at 80°C for 3 h. The resulting dark red mixture was
cooled and decomposed over saturated solution of sodium acetate
under stirring. Workup provided the aldehydes (13 or 15) as cream
coloured solids which were purified by column chromatography over
silica gel using hexane–ethylacetate as eluent and recrystallised from
hexane-acetone to obtain (13 or 15) as white crystals.
Experimental
Melting points were determined in capillaries and are uncorrected.
1H NMR measured in CDCl3 on a Varian 300 MHz spectrometer.
The chemical shifts are expressed in parts per million (ppm) using
TMS as an internal standard. Coupling constants are in Hertz.
IR spectra were recorded on Perkin Elmer spectrometer and are
reported in wavenumber (cm-1). Elemental analyses were acquired
using HOSLI semi-automatic CHN analyser.
Aldehyde(13):yield:83%;m.p.121°C.IR1700,1745cm-1;1HNMR:
(CDCl3, 300 MHz); data d 1.25 (t, J = 6 Hz, 3H), 3.94 (s, 3H), 3.98
(s, 3H), 4.17 (q, J = 6 Hz, 2H), 4.32 (s, 2H), 6.49 (s, 1H), 10.43
(s, 1H). Anal. calcd. for C13H15ClO5: C, 54.46; H, 5.27. Found: C,
54.50; H, 5.30.
2-Chloro-3,5-dimethoxybenzyl chloride (9): 3,5-Dimethoxybenzyl
chloride (8) (5 g, 26.81 mmol) was dissolved in dry ether (50 ml)
and cooled in ice–salt mixture. Then a solution of sulfuryl chloride
(SO2Cl2) (2.15 ml, 26.81 mmol) in dry ether (15 ml) was slowly
added and the mixture was stirred for 30 min under ice-cooling.
The reaction mixture was poured into ice-water (50 ml), stirred
well and the ethereal layer was separated, washed with water, 10%
NaHCO3 solution then again with water and dried over anhydrous
Na2SO4. The residual solid obtained after removal of the solvent was
recrystallised from methanol to give 2-chloro-3, 5-dimethoxybenzyl
chloride (9) as colourless needles.
Aldehyde (15): yield: 80%; m.p. 110°C, (lit10. m.p. 108–110°C).
1
IR 1705, 1735 cm-1; H NMR: (CDCl3, 300 MHz); data d 1.25 (t,
J = 6 Hz, 3H), 3.94 (s, 3H) 3.98 (s, 3H), 4.17 (q, J = 6 Hz, 2H),
4.32 (s, 2H), 6.49 (s, 2H) 10.35 (s, 1H), Anal. calcd. for C13H16O5: C,
61.90; H, 6.35. Found: C, 61.93; H, 6.38
6-Chloro-3,5-dimethoxyhomophthalic acid (6): A mixture of
ethyl 2-chloro-3,5-dimethoxy-2-formyl-phenylacetate (13) (1.5 g,
5.24 mmol), 1,4-dioxan (20 ml) and water (5 ml) was heated to 80°C
and treated with a solution of KMnO4 (1.16 g, 7.33 mmol) dissolved
in water (15 ml). After completion of the addition, stirring was
continued at 80°C for 45 min. The reaction mixture was then basified
with NaOH (5%) and immediately filtered hot. The filtrate was
acidified with conc. H2SO4 to provide a cream coloured solid, which
was purified by recrystallisation from dichloromethane (CH2Cl2)
to furnish the desired 6-chloro-3,5-dimethoxyhomophthalic acid (6)
as colourless crystals.
yield: 95%; m.p. 87°C, (lit7. m.p. 87°C).
2-Chloro-3,5-dimethoxybenzyl cyanide (10): The chloride (9)
(22.62 mmol) was dissolved in DMF (40 ml) and to this solution
anhydrous, powdered potassium cyanide (67.03 mmol) was added.
This heterogeneous reaction mixture was stirred vigorously at room
temperature for 8 h and then it was carefully filtered under suction.
The filtrate was diluted with water (75 ml) and cooled to 5°C.
Acream coloured solid separated out which was filtered, dried, purified
by column chromatography over silica gel using hexane as eluent
and recrystallised from hexane–ethylacetate to obtain 2-chloro-3,
5-dimethoxybenzyl cyanide (10) as white crystals.
yield: 66%; m.p. 222°C, (lit7. m.p. 215–225°C). IR 2500–3000,
1
1700 cm-1; H NMR: (CDCl3, 300 MHz); data d 3.89 (s, 3H), 3.90
yield: 85%; m.p. 115°C, IR: 2250 cm-1; 1H NMR: (CDCl3,
300 MHz); data d 3.79 (s, 6H), 3.87 (s, 2H), 6.46 (bs, 2H); Anal.
calcd. for C10H10ClNO2: C, 56.72; H, 4.76. Found: C, 56.75;
H, 4.80.
2-Chloro-3,5-dimethoxyphenylacetic acid (11): To a solution of
2-chloro-3,5-dimethoxybenzyl cyanide (10) (23.64 mmol) in methyl
alcohol (30 ml) was added, 20 ml of 20% alc. KOH solution and the
resultant mixture was refluxed on a steam bath for 4 h. Excess methyl
alcohol was then removed under reduced pressure and the residue was
(s, 2H), 3.96 (s, 3H), 6.81 (s, 1H) Anal. calcd. for C11H11ClO6: C,
48.10; H, 4.04. Found: C, 48.12; H, 4.08.
4,6-dichloro-3,5-dimethoxyhomophthalic acid (7): Ethyl 3,5-
dimethoxy-2-formyl-phenylacetate (15) (1 g, 3.97 mmol) was
dissolved in 1,4-dioxan (15 ml). To this solution sulfuryl chloride
(SO2Cl2) (1.3 ml, 16.17 mmol) was added and the resultant mixture
was refluxed in an oil bath for 1 h. The reaction mixture was then
cooled to room temperature and poured into ice-cold water. It was
extracted with three 10 ml portions of dichloromethane. The combined
PAPER: 06/4365