Expedient syntheses of naturally occurring ±-3-benzylphthalides and ±-3-aryl-8-hydroxy-3,4-dihydroisocoumarins: Structure revision of the ±-3-benzylphthalide isolated from Frullania falciloba

Article abstract of DOI:10.1039/b106268a

A simple synthesis of ±-3-benzyl-7-methoxyphthalides (1b,1d and 4a-c) from 7-methoxyphthalides (3a-c) and a novel AlCl₃-catalysed conversion of ±-3-benzyl-7-methoxyphthalides (1d,4a-c) to 4′-O-methylhydrangenol 5a, 4′,6-O,O-dimethylthunberginol

Full text of DOI:10.1039/b106268a

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Expedient syntheses of naturally occurring ( )-3-benzylphthalides
and ( )-3-aryl-8-hydroxy-3,4-dihydroisocoumarins:
Structure revision of the ( )-3-benzylphthalide isolated
from Frullania falciloba
1
Raghao S. Mali,* Kantipudi N. Babu and Prakash G. Jagtap
Garware Research Center, Department of Chemistry, University of Pune, Pune-411 007, India.
E-mail: rsmali@chem.unipune.ernet.in; Fax: ϩ (91) 020-5651728
Received (in Cambridge, UK) 13th July 2001, Accepted 29th August 2001
First published as an Advance Article on the web 23rd October 2001
A simple synthesis of ( )-3-benzyl-7-methoxyphthalides (1b, 1d and 4a–c) from 7-methoxyphthalides (3a–c) and a
novel AlCl3-catalysed conversion of ( )-3-benzyl-7-methoxyphthalides (1d, 4a–c) to 4Ј-O-methylhydrangenol 5a,
4Ј,6-O,O-dimethylthunberginol-C 5b and related compounds (5c and 5d) is described.
Introduction
Results and discussion
Several 3-benzyl-7-hydroxy/methoxyphthalides and 3-aryl-8-
hydroxy-3,4-dihydroisocoumarins have been isolated from
natural sources. Thus, balantiolide 1a, O-methylbalantiolide 1b
and the benzylphthalide 1c have been isolated1 from Frullania
muscicola. The first isolation2 of 1a was reported in 1986 from
the New Zealand liverwort Balantiopsis rosea. The phthalide
1d, isolated3 in 1987 from the Australian liverwort Frullania
In continuation of our work on the synthesis of naturally
occurring phthalides9a and 3-aryl-3,4-dihydroisocoumarins,10h
we report herein a novel method for the synthesis of ( )-
3-benzyl-7-methoxyphthalides (1b, 1d, 4a–c) and their one-
step conversion into 3-aryl-8-hydroxy-3,4-dihydroisocoumarins
(5a–d). In the present approach (Scheme 1) phthalide anions are
generated from phthalides, and are then treated with benzyl
bromides to obtain ( )-3-benzylphthalides in a single step.
Thus, 7-methoxyphthalide 3a on reaction with LDA in THF at
Ϫ78 ЊC followed by treatment with 4-methoxybenzyl bromide
furnished ( )-3-(4-methoxybenzyl)-7-methoxyphthalide 4a, mp
108–109 ЊC, in 56% yield. The phthalide 3b on similar reaction
with LDA and 4-methoxybenzyl bromide provided ( )-3-
(4-methoxybenzyl)-5,7-dimethoxyphthalide 1d, mp 158–159 ЊC,
in 54% yield. The aromatic protons of the phthalide ring of 1d
appeared as doublets (J = 2.0 Hz) at δ 6.17 and 6.39. These
chemical shifts correspond to those (δ 6.11 and 6.29) reported3
for the natural product (mp 78–80 ЊC), for which the structure
1e was erroneously assigned. The aromatic protons of the
phthalide ring in synthetic 1e appear9a as singlets at δ 6.45 and
7.23. These chemical shifts are totally different to those
reported for the natural phthalide. Hence the structure 1d was
assigned to the natural phthalide. Though there is a difference
in the mps of the synthetic and the natural phthalide, the
1H NMR and IR spectral data are identical. The difference in
melting points could be due to polymorphism.
1
falciloba, was assigned structure 1e on the basis of H NMR
spectral data. The revised structure 1d has now been assigned to
it.4
A
large number of 3-aryl-8-hydroxy-3,4-dihydroiso-
coumarins, such as hydrangenol 2a, phyllodulcin 2b and
thunberginols C, D, E and G 2c–f, have been reported5 from
Hydrangeae Dalcis folium (Amacha in Japanese), the fermented
and dried leaves of Hydrangea macrophylla. The leaves of this
plant are used as a sweetening agent. Phyllodulcin 2b shows anti-
fungal activity and is found to be 600–800 times sweeter than
sucrose.6 The thunberginols6 2c–f and hydrangenol 4Ј-O-
glucoside7 showed antiallergic activity in an in vitro bioassay
using the Schults–Dale reaction in sensitized guinea pig bron-
chial muscle. These isocoumarins also exhibit antimicrobial5,8
activity against oral bacteria.
In view of their natural occurrence, biological activities,
and utility as synthetic intermediates, several methods have
been developed for the synthesis of 3-benzylphthalides and 3-
aryl-8-hydroxy-3,4-dihydroisocoumarins. Most of the methods
reported9 for the synthesis of 3-benzylphthalides involve
formation of 3-benzylidenephthalides, which on catalytic hydro-
genation provide the corresponding 3-benzylphthalides. The
approaches developed10 for 3-aryl-8-hydroxy-3,4-dihydroiso-
coumarins involve heteroatom-directed lithiation reaction of
benzamides or cyclization of stilbenecarboxylic acids. The
stilbenecarboxylic acids are obtained from 3-benzylphthalides
or from phthalaldehydic acids and 2-halomethyl benzo-
ates using the Wittig reaction. Most of the approaches
for 3-benzylphthalides and 3-aryl-8-hydroxy-3,4-dihydroiso-
coumarins involve multistep sequences of reactions. The
conversion of 3-benzylphthalides into 3-aryl-8-hydroxy-3,4-
dihydroisocoumarins involves three steps.10a Hence, it was felt
necessary to develop convenient methods for the synthesis of
( )-7-methoxy-3-benzylphthalides and ( )-3-aryl-8-hydroxy-
3,4-dihydroisocoumarins.
The phthalides 3b and 3c on similar reaction with benzyl
bromides, in the presence of LDA, gave the 3-benzylphthalides
1
1b, 4b and 4c in 40–56% yield. The H NMR spectral prop-
erties of 1b are identical with those reported for the natural
O-methylbalantiolide.1
The 3-benzylphthalide 4a on reaction with AlCl3 in methyl-
ene dichloride at room temperature gave 4Ј-O-methylhydran-
genol 5a, mp 121–122 ЊC (lit.,10c mp 123 ЊC) in 77% yield. Its
spectral properties are identical with those reported for the
natural product. The novelty of this reaction is that it provides
a ( )-3-aryl-8-hydroxy-3,4-dihydroisocoumarin in a single step
from 7-methoxy-3-benzylphthalide. Selective demethylation of
the 8-methoxy group of the isocoumarin also occurred in this
step. 3-Benzylphthalides 1d and 4b on similar reaction with
AlCl3 gave 4Ј,6-O,O-dimethylthunberginol-C 5b (63%) and the
isocoumarin 5c (73%), respectively. The 3-benzylphthalide 4c
DOI: 10.1039/b106268a
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This journal is © The Royal Society of Chemistry 2001
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tion mixture was stirred at Ϫ78 ЊC for 30 min and a solution of
the corresponding benzyl bromide (1.35 mmol) in THF (5 mL)
was added. Stirring was continued and the reaction mixture was
allowed to come to room temperature during 2 h. Water (10
mL) was added to the reaction mixture. THF from the aqueous
solution was removed in vacuo. The residue was acidified with
dil. HCl and extracted with CHCl3 (3 × 10 mL). The combined
organic layers were washed with water and dried over Na2SO4.
The gummy mass, obtained after evaporation of solvent, was
purified by chromatography on silica gel, using EtOAc–hexane
(3 : 7) as eluent, to give the ( )-3-benzylphthalides (1b, 1d and
4a–c).
( )-3-(3,4-Dimethoxybenzyl)-5,7-dimethoxyphthalide
(O-
methylbalantiolide 1b). The anion generated from the phthalide
3b on reaction with 3,4-dimethoxybenzyl bromide gave 1b in
56% yield, mp 158 ЊC (lit.,1 mp not mentioned); νmax/cmϪ1
(Nujol) 1745; δH (300 MHz) 3.07 (dd, 1H, J = 13.5, 6.0,
ArCHH), 3.17 (dd, 1H, J = 13.5, 6.1, Ar-CHH), 3.81 (s, 3H,
OCH3), 3.83 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.92 (s, 3H,
OCH3), 5.55 (t, 1H, J = 6.1, ArCHO), 6.20 (d, 1H, J = 1.0,
ArH), 6.39 (d, 1H, J = 1.0, ArH), 6.72–6.80 (m, 3H, ArH)
(Found: C, 66.45; H, 6.12. C19H20O6 requires C, 66.27; H,
5.85%).
under similar conditions provided the 8-hydroxy-3,4-dihydro-
isocoumarin 5d (63%) along with a minor amount of the
7-hydroxy-3-benzylphthalide 1f (19%).
Conclusion
We have developed a simple and useful method for the synthesis
of ( )-3-benzyl-7-methoxyphthalides from 7-methoxyphthal-
ides and their single-step conversion into ( )-3-aryl-8-hydroxy-
3,4-dihydroisocoumarins. This procedure can be used as an
excellent alternative to previous syntheses of such compounds.
( )-3-(4-Methoxybenzyl)-5,7-dimethoxyphthalide 1d. The
anion generated from the phthalide 3b on reaction with 4-
methoxybenzyl bromide gave 1d, in 54% yield, mp 158–159 ЊC;
νmax/cmϪ1 (Nujol) 1760; δH (200 MHz) 3.05, 3.10 (2 × dd, 2H,
J = 14.0, 6.0, ArCH2), 3.75 (s, 6H, 2 × OCH3), 3.88 (s, 3H,
OCH3), 5.41 (t, 1H, J = 6.0, ArCHO), 6.17 (d, 1H, J = 2.0,
ArH), 6.39 (d, 1H, J = 2.0, ArH), 6.77 (m, 2H, ArH), 7.08 (m,
2H, ArH) (Found: C, 68.50; H, 5.88. C18H18O5 requires C,
68.78; H, 5.77%).
Experimental
All melting points are uncorrected. The IR spectra were
recorded on a Perkin-Elmer FTIR-1615 spectrophotometer,
and NMR spectra in CDCl3 solutions on a JEOL FX 90Q
(90 MHz), AC 200 Bruker (200 MHz) or Varian VXR 300S
(300 MHz) spectrometer. Chemical shifts are expressed in δ
(ppm) downfield from TMS as internal standard, and coupling
constants J are in hertz. n-Butyllithium (prepared) was a
1.25 M solution in n-hexane, whose exact titre was determined
by titration using diphenylacetic acid.11 THF was distilled over
LiAlH4 before use. Phthalides 3a–c were prepared according to
the literature procedure.12 Elemental analyses were obtained
using Hosli’s rapid carbon/hydrogen analyser. All reactions
were performed in oven (125 ЊC)-dried glassware under an inert
atmosphere of dry N2.
( )-3-(4-Methoxybenzyl)-7-methoxyphthalide 4a. The anion
generated from the phthalide 3a on reaction with 4-meth-
oxybenzyl bromide yielded 4a in 56% yield, mp 108–109 ЊC;
νmax/cmϪ1 (Nujol) 1760; δH (90 MHz) 3.11 (d, 2H, J = 6.0,
ArCH2), 3.75 (s, 3H, OCH3), 3.97 (s, 3H, OCH3), 5.52 (t, 1H,
J = 6.0, ArCHO), 6.63–7.25 (m, 6H, ArH), 7.52 (t, 1H, J = 8.0,
ArH) (Found: C, 72.05; H, 5.54. C17H16O4 requires C, 71.82; H,
5.67%).
( )-3-(4-Methoxybenzyl)-5,6,7-trimethoxyphthalide 4b. The
anion generated from the phthalide 3c on reaction with 4-
methoxybenzyl bromide furnished 4b in 55% yield, mp 158 ЊC;
νmax/cmϪ1 (Nujol) 1738; δH (90 MHz) 3.07, 3.41 (2 × dd, 2H,
J = 15.2, 6.3, ArCH2), 3.78 (s, 3H, OCH3), 3.83 (s, 3H, OCH3),
3.85 (s, 3H, OCH3), 4.09 (s, 3H, OCH3), 5.44 (t, 1H, J = 6.3,
ArCHO), 6.29 (s, 1H, ArH), 6.82 (m, 2H, ArH), 7.54 (m, 2H,
ArH) (Found: C, 66.10; H, 6.02. C19H20O6 requires C, 66.27;
H, 5.85%).
General procedure for the synthesis of ( )-3-benzylphthalides
(1b, 1d, 4a–c)
A solution of the appropriate phthalide 3 (1.30 mmol) in THF
(10 mL) was added to a stirred solution of LDA (1.35 mmol) in
THF (5 mL) at Ϫ78 ЊC under nitrogen atmosphere. The reac-
Scheme 1 Reagents and conditions: (i) LDA, THF, Ϫ78 ЊC; (ii) ArCH 2X; (iii) Hϩ; (iv) AlCl3, CH2Cl2.
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( )-3-(3,4-Dimethoxybenzyl)-5,6,7-trimethoxyphthalide 4c.
The anion generated from the phthalide 3c on reaction with
3,4-dimethoxybenzyl bromide gave 4c in 40% yield, as a thick
liquid; νmax/cmϪ1 (Nujol) 1740; δH (90 MHz) 3.08, 3.50 (2 × dd,
2H, J = 14.0, 6.3, ArCH2), 3.80 (s, 12H, 4 × OCH3), 4.06 (s, 3H,
OCH3), 5.45 (t, 1H, J = 6.3, ArCHO), 6.27 (s, 1H, ArH), 6.72
(s, 3H, ArH) (Found: C, 64.01; H, 5.80. C20H22O7 requires C,
64.16; H, 5.92%).
1661; δH (90 MHz) 3.07 (dd, 1H, J = 15.2, 3.8, C4-H), 3.35 (dd,
1H, J = 15.2, 11.4, C4-H), 3.87 (s, 12H, 4 × OCH3), 5.47 (dd,
1H, J = 11.4, 3.8, C3-H), 6.32 (s, 1H, ArH), 6.95 (s, 3H, ArH),
11.08 (s, 1H, exchangeable with D2O, OH) (Found: C, 63.11;
H, 5.79. C19H20O7 requires C, 63.33; H, 5.59%).
Compound 1f was a viscous liquid; νmax/cmϪ1 (nujol) 3340,
1740; δH (90 MHz) 3.07–3.18 (m, 2H, ArCH2), 3.80 (s, 12H,
4 × OCH3), 5.50 (t, 1H, J = 6.3, ArCHO), 6.29 (s, 1H, ArH),
6.34 (s, 1H, exchangeable with D2O, OH), 6.72 (s, 3H, ArH)
(Found: C, 63.22; H, 5.65. C19H20O7 requires C, 63.33; H,
5.59%).
( )-3-Aryl-8-hydroxy-3,4-dihydroisocoumarins 5a–d and the ( )-
3-benzyl-7-hydroxyphthalide 1f: General procedure
A suspension of anhydrous AlCl3 (196 mg, 1.47 mmol) in dry
methylene dichloride (10 mL) was stirred at room temperature
for 20 min. A solution of the appropriate ( )-3-benzylphthalide
1 or 4 (0.49 mmol) in methylene dichloride (10 mL) was added
during in 5 min. The reaction mixture was stirred for 6 h
(monitored by TLC) and poured slowly into ice-cold HCl (1 : 1
conc. HCl–water; 15 mL). The methylene dichloride layer was
separated and the aqueous layer was extracted with methylene
dichloride (2 × 15 mL). The combined organic extract was
washed with water, dried (Na2SO4), and evaporated to give a
solid. It was purified by chromatography over silica gel using
EtOAc–hexane (1 : 9) as eluent to afford a solid, which on
recrystallization from methylene dichloride–hexane provided
Acknowledgements
K. N. B. and P. G. J. are thankful to CSIR, New Delhi, for the
award of SRF. Financial support from CSIR New Delhi is also
gratefully acknowledged.
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coumarins 5a–c. In the case of 4c, along with the isocoumarin
5d the phthalide 1f was also formed.
( )-3-(4-Methoxyphenyl)-8-hydroxy-3,4-dihydroisocoumarin
(4Ј-O-methylhydrangenol, 5a). The benzylphthalide 4a on reac-
tion with AlCl3 provided the isocoumarin 5a in 77% yield, mp
121–122 ЊC (lit.,10c 123 ЊC); νmax/cmϪ1 (Nujol) 1675; δH (90
MHz) 3.08 (dd, 1H, J = 16.0, 5.0, C4-H), 3.33 (dd, 1H, J = 16.0,
12.5, C4-H), 3.80 (s, 3H, OCH3), 5.55 (dd, 1H, J = 12.5, 5.0,
C3-H), 6.61–7.02 (m, 6H, ArH), 7.36 (t, 1H, J = 7.5, ArH),
11.05 (s, 1H, exchangeable with D2O, OH) (Found: C, 71.28;
H, 5.29. C16H14O4 requires C, 71.10; H, 5.22%).
( )-3-(4-Methoxyphenyl)-8-hydroxy-6-methoxy-3,4-dihydro-
isocoumarin (4Ј,6-O,O-dimethylthunberginol-C, 5b). The benzyl-
phthalide 1d on reaction with AlCl3 provided 5b in 63% yield,
mp 118–119 ЊC; νmax/cmϪ1 (Nujol) 1655; δH (90 MHz) 3.05 (dd,
1H, J = 16.0, 5.0, C4-H), 3.33 (dd, 1H, J = 16.0, 12.5, C4-H),
3.80 (s, 6H, 2 × OCH3), 5.47 (dd, 1H, J = 12.5, 5.0, C3-H), 6.36
(s, 1H, ArH), 6.41 (s, 1H, ArH), 6.91 (d, 1H, J = 7.5, ArH), 8.22
(d, 1H, J = 7.5, ArH), 11.22 (s, 1H, exchangeable with D2O,
OH) (Found: C, 68.13; H, 5.59. C17H16O5 requires C, 67.99; H,
5.37%).
( )-3-(4-Methoxyphenyl)-8-hydroxy-6,7-dimethoxy-3,4-di-
hydroisocoumarin 5c. The benzylphthalide 4b on reaction with
AlCl3 furnished 5c in 73% yield, mp 175 ЊC; νmax/cmϪ1 (Nujol)
3350, 1660; δH (90 MHz) 3.04 (dd, 1H, J = 15.2, 3.8, C4-H), 3.32
(dd, 1H, J = 15.2, 11.4, C4-H), 3.80 (s, 3H, OCH3), 3.87 (s, 3H,
OCH3), 3.90 (s, 3H, OCH3), 5.47 (dd, 1H, J = 11.4, 3.8, C3-H),
6.29 (s, 1H, ArH), 6.91 (m, 2H, ArH), 7.36 (m, 2H, ArH), 11.07
(s, 1H, exchangeable with D2O, OH) (Found: C, 65.54; H, 5.60.
C18H18O6 requires C, 65.44; H, 5.49%).
( )-3-(3,4-Dimethoxyphenyl)-8-hydroxy-6,7-dimethoxy-3,4-
dihydroisocoumarin 5d and ( )-3-(3,4-dimethoxybenzyl)-7-
hydroxy-5,6-dimethoxyphthalide 1f. The benzylphthalide 4c on
reaction with AlCl3 gave 5d and 1f in 63 and 19% yield, respect-
ively. Compound 5d had mp 148 ЊC; νmax/cmϪ1 (Nujol) 3409,
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