Synthesis of 3-arylisocoumarins, including thunberginols A and B, unsymmetrical 3,4-disubstituted isocoumarins, and 3-ylidenephthalides via iodolactonization of methyl 2-ynylbenzoates or the corresponding carboxylic acids

Article abstract of DOI:10.1016/S0040-4020(03)00212-6

3-Aryl-4-iodoisocoumarins, which were readily and efficiently prepared by regioselective iodolactonization of methyl 2-ynylbenzoates or the corresponding carboxylic acids, were used as precursors either to 3-arylisocoumarins, including naturally-occurring

Full text of DOI:10.1016/S0040-4020(03)00212-6

Tetrahedron 59 (2003) 2067–2081
Synthesis of 3-arylisocoumarins, including thunberginols A and B,
unsymmetrical 3,4-disubstituted isocoumarins,
and 3-ylidenephthalides via iodolactonization of methyl
2-ynylbenzoates or the corresponding carboxylic acids
a
a
a
b
Renzo Rossi,a Adriano Carpita, Fabio Bellina, Paolo Stabile and Luisa Mannina
,
,
*
*
aDipartimento di Chimica e Chimica Industriale, University of Pisa, via Risorgimento 35, I-56126 Pisa, Italy
` `
Facolta di Scienze M.F.N., Universita del Molise, via Mazzini 8, 86170 Isernia, Italy
b
Received 18 November 2002; revised 15 January 2003; accepted 6 February 2003
Abstract—3-Aryl-4-iodoisocoumarins, which were readily and efficiently prepared by regioselective iodolactonization of methyl 2-ynyl-
benzoates or the corresponding carboxylic acids, were used as precursors either to 3-arylisocoumarins, including naturally-occurring
thunberginols A and B, or to unsymmetrical 3,4-disubstituted isocoumarins. On the other hand, (Z)- and (E)-3-iodomethylidenephthalides,
which were regioselectively prepared by iodolactonization of methyl 2-ethynylbenzoate, were employed as starting materials for the
stereospecific synthesis of (Z)- and (E)-3-ylidenephthalides, respectively. Some 3-arylisocoumarins and unsymmetrical 3,4-disubstituted
isocoumarins showed certain cytotoxic activity against human cancer cell lines in vitro. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
During the course of our earlier studies on the synthesis of
biologically active naturally-occurring heterocycles and
their analogues,16 we investigated the synthesis of 3-alkyl-
and 3-(1-alkenyl)isocoumarins 1 and we found that these
substances, including naturally-occurring 3-propyliso-
coumarin (1a) and artemidin (1b), can be selectively
prepared by AgNO3-catalyzed cyclization of 2-(1-ynyl)-
benzoic acids 2.14e
Isocoumarin structures are important components in many
natural products that exhibit a broad range of biological
activitities including antiallergic and antimicrobial,1,2
immunomodulatory,3 cytotoxic,4 antifungal,5 antiinflamma-
tory,6 antiangiogenic,7 anticalmodulin-sensitive cyclic
guanosine 30,50-monophosphate phosphodiesterease8
effects, and differentiation inducing activity against leu-
kemic cells.9 Isocoumarins10 are also useful intermediates
in the synthesis of a variety of important compounds
including some isoquinoline alkaloids.11 Thus, a number of
methods have been reported in the literature for the
synthesis of isocoumarins.12 For example, in the last 10
years 3-substituted isocoumarins with no substituent at the
4-position have been synthesized either by a variety of
traditional approaches13 or by utilizing transition metal-
catalyzed reactions.14 The synthesis of 3,4-disubstituted
isocoumarins has received considerable attention too6,15
and, recently, a number of these compounds have been
prepared in good yields via palladium-catalyzed annulation
of internal alkynes.15d However, this last catalytic method is
somewhat limited in synthetic scope since it is highly
regioselective only for symmetrical disubstituted acetylenes
containing a highly sterically demanding group in the
position adjacent to the carbon–carbon triple bond.
More recently, we decided to investigate new general
procedures for the efficient and selective synthesis of
3-arylisocoumarins 3, including thunberginols A (3a)17
and B (3b)18 and derivatives of these natural products, and
of unsymmetrical 3,4-disubstituted isocoumarins 4, and to
perform a preliminary evaluation of the cytotoxic activity of
these substances against human cancer cell lines.
We were led to prepare compounds 3a and 3b by the
impracticality of their previously developed syntheses17,18
and by the interesting biological activities of these
isocoumarins. In fact, compounds 3a and 3b, which have
been isolated from Hydrangea Dulcis Folium, the fermented
and dried leaves of Hydrangea macrophylla SERINGE var.
Keywords: isocoumarins; phthalides; iodine; palladium catalysis;
cytotoxicity; thunberginols.
*
Corresponding authors. Tel.: þ39-50-918214; fax: þ39-50-918260;
e-mail: rossi@dcci.unipi.it
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00212-6

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R. Rossi et al. / Tetrahedron 59 (2003) 2067–2081
regioselective iodolactonization of this compound followed
by Stille-type reactions, we developed a convenient new
procedure for the preparation of 3-ylidenephthalides (12).
Finally, we will describe the results of tests to evaluate the
cytotoxic activity exhibited by several compounds 3 and 4
against human cancer cell lines.
2. Results and discussion
2.1. Synthesis of starting materials
The 3-aryl-4-iodoisocoumarins used in this study were
compounds 5a–e.
thunbergii MAKINO, possess a variety of biological
properties,2,3 including activity against mouse myeloid
leukemia cells9 and, thus, are of potential interest for
treatment of cancers. As shown in Scheme 1, we planned to
synthesize compounds 3 and 4 from 3-aryl-4-iodoiso-
coumarins 5 by highly chemoselective palladium-catalyzed
hydrodehalogenation of these halides19 and by Stille-type
reactions,20 respectively. In fact, we recently found that a
variety of iodides 5 can be selectively prepared in moderate
to excellent yields by iodolactonization of 2-(arylethynyl)-
benzoic acids 7 or the corresponding methyl esters 6.21
The results obtained in the study of the synthesis of
compounds 3, including thunberginols A (3a) and B (3b)
and their precursors, and of unsymmetrical 3,4-disubstituted
isocoumarins 4 form the subject of this paper.22 Herein, we
will also report that in an attempt to synthesize 4-substituted
isocoumarins 9 with no substituent at the 3-position23
starting from methyl salicylate (10) by a methodology
similar to that used to prepare compounds 4, i.e. by
conversion of 10 into methyl 2-ethynylbenzoate (11) and
Recently, we synthesized four of these iodo derivatives, i.e.
compounds 5a–5c, and 5e, by iodolactonization of the
corresponding methyl 2-(arylethynyl)benzoates 6 or 2-(aryl-
ethynyl)benzoic acids 7.21a In particular, compounds 5a and
5c were selectively prepared in 89 and 98% yield,
respectively, by reaction of methyl 2-(3,4-dimethoxy-
phenyl)ethynyl-6-methoxybenzoate (6a) and methyl
4-methoxy-2-(4-methoxyphenyl)ethynylbenzoate (6c) with
3.0 equiv. of iodine in MeCN at room temperature for
3 h.21a Compound 5b was prepared in 47% yield by
treatment of methyl 6-methoxy-2-phenylethynylbenzoate
(6b) with 1.0 equiv. of ICl in CH2Cl2 at room temperature
for 3.5 h and iodide 5e was selectively obtained in 88%
yield by reaction of 2-(phenylethynyl)benzoic acid (7a)
with 3.0 equiv. of iodine and 3.0 equiv. of NaHCO3 in
MeCN at room temperature for 1.5 h.21a,24 The substrates of
these iodolactonization reactions, i.e. esters 6a–6c and the
carboxylic acid 7a, were prepared in 80–86% overall yield
starting from methyl 2-hydroxybenzoates 8a, 8b and 10 via
palladium-catalyzed reaction between 2-(arylethynyl)zinc
chlorides and nonaflates (perfluorobutane sulfonates) 13
derived from these o-hydroxyesters.21a
Scheme 1. Retrosynthesis of compounds 3 and 4.

R. Rossi et al. / Tetrahedron 59 (2003) 2067–2081
2069
with a molar excess of 3,4-dimethoxyphenylethynylzinc
chloride (16) in THF at 608C in the presence of 1 mol%
Pd2(dba)3 and 2 mol% 1,10-bis(diphenylphosphino)ferro-
cene (dppf) to give compound 6d in 85% yield. Finally,
reaction of this ester with 3.0 equiv. of iodine in MeCN at
room temperature followed by treatment with an aqueous
Na2S2O3 solution and purification of the resulting reaction
mixture by MPLC on silica gel provided regioselectively
iodide 5d in 67% yield. Concentration of the first eluted
fractions of this chromatographic purification also allowed
isolation of methyl 4,6-dimethoxy-2-(3,4-dimethoxyben-
zoyl)methylbenzoate (17) in ca. 9% yield. The structure
of this unexpected compound was established on the basis of
1
its IR, H and 13C NMR spectra and by a combination of
1
NMR techniques which included H–1H COSY, hetero-
nuclear multiple quantum coherence (HMQC) and hetero-
nuclear multiple bond correlation (HMBC).
Possible processes for the formation of compounds 5d and
17 are shown in Scheme 3. The desired reaction to form 5d
should involve the electrophilic attack of iodine on the
carbon–carbon triple bond of 6d to form regioselectively
vinyl cation 18b in which the positive charge is stabilized by
the electron-rich 3,4-dimethoxyphenyl group. Subsequent
intramolecular nucleophilic attack of the methoxycarbonyl
group followed by elimination of methyl iodide from
methyloxonium iodide 19 so obtained should then lead
regioselectively to 5d. On the other hand, nucleophilic
attack of water on 18 during the workup of the reaction
mixture should provide a-iodoketone 20b and hydrogen
iodide. Protodeiodination of 20b in the presence of Na2S2O3
as a scavenger of iodine should then produce ketone 17.
On the other hand, the previously unknown 4-aryl-3-
iodoisocoumarin 5d was selectively prepared in five steps
and in 35% overall yield starting from commercially
available 2,4,6-trihydroxybenzoic acid monohydrate (14)
by the reaction sequence illustrated in Scheme 2, which was
similar to that previously employed in our laboratory to
synthesize 5a and 5c.21a Thus, methyl ester 15, which was
prepared in 82% yield from 14, was converted in 80% yield
into the o-hydroxyester 8c by treatment with 1.1 equiv. of
BCl3 in CH2Cl2. Reaction of 8c with NaH in DMF followed
by treatment with perfluoro-1-butanesulfonyl fluoride
provided 13d in 94% yield. This nonaflate was then reacted
2.2. Synthesis of 3-arylisocoumarins from 3-aryl-4-iodo-
isocoumarins
With 3-aryl-4-iodoisocoumarins 5 in hand we then turned
our attention to the conversion of these iodo derivatives into
3-arylisocoumarins 3 and we found that the palladium-
catalyzed triethylammonium formate reduction19 of iodides
5a–5d provided selectively compounds 3c, 3d, 3f, and 3j
in 93, 90, 93, and 98% yield, respectively (Scheme 4).
Compound 3c was then demethylated by treatment with
5.2 equiv. of BBr3 in CH2Cl2 at room temperature followed
by hydrolysis to give thunberginol A (3a) in 85% yield17
(Scheme 4). The spectral data of this compound were in
agreement with those of the natural product isolated from
the fermented and dried leaves of H. macrophylla.2
On the other hand, reaction of 3d and 3j with 4.5 and
10.0 equiv. of BBr3, respectively, in CH2Cl2 at room
temperature followed by hydrolysis furnished compound
3e and thunberginol B (3b) in 98 and 81% yield,
respectively (Scheme 4). The spectral properties of 3b
proved to be in agreement with those previously reported.2,25
We next attempted to perform the complete O-demethyl-
ation of compound 3f by treatment with 5.2 equiv. of BBr3
in CH2Cl2 at room temperature for 1.42 h followed by
hydrolysis. However, we found that this reaction provided
selectively the monohydroxy derivative 3h in 72% yield.
The structure of this compound was unambiguously
Scheme 2. (a) K2CO3 (6.0 equiv.), Me2SO4 (6.0 equiv.), acetone, 26 h,
42–458C, 82% yield. (b) BCl3 (1.1 equiv.), CH2Cl2, 270 to þ208C,
40 min, 80% yield. (c) NaH (1.5 equiv.), DMF, 0.5 h at 08C, then 1 h at rt.
(d) n-C4F9SO2F (1.15 equiv.), 2 h, rt, 94% yield based on 8c. (e) 3,4-
(MeO)2C6H3CuCZnCl (16) (1.20 equiv.), Pd2(dba)3 (1 mol%), dppf
(2 mol%), THF, 608C, 17 h, 85% yield. (f) I2 (3.0 equiv.), MeCN, rt, 2 h
then aq. Na2S2O3, 67% yield for 5d and 9% yield for 17.
1
established on the basis of its H and 13C NMR spectra at

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R. Rossi et al. / Tetrahedron 59 (2003) 2067–2081
Scheme 3. Proposed processes for the reaction between 6d and iodine in MeCN followed by treatment with aqueous Na2S2O3.
600 and 150 MHz, respectively, and by a combination of
1
Specifically, compounds 4a, 4c, 4e, and 4g were synthesized
NMR techniques which included H–1H COSY, nuclear
in 86, 78, 72 and 89% yield, respectively, by treatment of
5a–5d with 3.0 equiv. of 22 in 1-methyl-2-pyrrolidinone
(NMP) at 76–828C for 4.5–10 h in the presence of a
catalyst system consisting of 5 mol% PdCl2[P(o-Tolyl)3]2
and 10 mol% CuI.26,27 On the other hand, 4i was prepared in
66% yield by reaction of 5e with 3.0 equiv. of 22 in NMP at
608C in the presence of 5 mol% PdCl2(PhCN)2, 10 mol%
AsPh3 and 10 mol% CuI.27 Compounds 4a, 4c, 4e and 4g
were then O-demethylated by treatment with BBr3 in
CH2Cl2 at 20–328C to yield compounds 4b, 4d, 4f and 4h in
89, 96, 89 and 58% yield, respectively (Scheme 5). It should
be noted that we successfully used the catalyst system
consisting of 5 mol% PdCl2(PhCN)2, 10 mol% AsPh3 and
10 mol% CuI also for the Stille-type reaction of iodide
5e with an aryltributyltin derivative and with tributyl-
(1-ethoxyethenyl)tin (24). In fact, treatment of 5e with
1.2 equiv. of tributyl(4-methoxyphenyl)tin (23) in NMP at
608C for 54 h in the presence of this catalyst system gave
compound 4j in 58% yield. On the other hand, reaction of 5e
with 1.35 equiv. of 24 in NMP at 81–838C for 47 h in the
Overhauser enhancement spectroscopy (NOESY), HMQC,
and HMBC. We then prepared a derivative of 3h, i.e.
compound 3i, in 74% yield by reaction with 3,4,5-tri-
methoxybenzoyl chloride (21) in the presence of pyridine
(Scheme 4). Finally, we succeeded to obtain the dihydroxy
derivative 3g in 87% yield by reaction of 3f with 8.3 equiv.
of BBr3 in CH2Cl2 at 408C for 27.5 h followed by hydrolysis
(Scheme 4).
2.3. Palladium-catalyzed reactions between 3-aryl-4-
iodoisocoumarins and organotin derivatives
We next examined the use of 4-aryl-3-iodoisocoumarins
5a–e as starting materials for the synthesis of unsym-
metrical 3,4-disubstituted isocoumarins of general formula
4 and, first of all, we investigated the preparation of 3-aryl-
4-methylisocoumarins 4a, 4c, 4e, 4g, and 4i by Stille-type
reactions of these iodo derivatives with tetramethyltin (22)
(Scheme 5).
Scheme 4. (a) Pd(OAc)2 (2 mol%), PPh3 (4 mol%), Et3N (3.0 equiv.), HCOOH (2.0 equiv.), DMF, 60–638C, 3.5–4.5 h, 93% yield for 3c, 90% yield for 3d,
93% yield for 3f, 98% yield for 3j. (b) BBr3 (5.2 equiv.), CH2Cl2, rt, 2 h, 85% yield. (c) BBr3 (4.5 equiv.), CH2Cl2, rt, 1.75 h, 98% yield. (d) BBr3 (8.3 equiv.),
CH2Cl2, 408C, 27 h, 87% yield. (e) BBr3 (5.2 equiv.), CH2Cl2, rt, 1.42 h, 72% yield. (f) 3,4,5-(MeO)3C6H2COCl (21) (1.5 equiv.), pyridine, 488C, 48 h, 74%
yield. (g) BBr3 (10.0 equiv.), CH2Cl2, rt, 72 h, 81% yield.

R. Rossi et al. / Tetrahedron 59 (2003) 2067–2081
2071
Scheme 5. (a) Me4Sn (22) (3.0 equiv.), PdCl2[P(o-Tolyl)3]2 (5 mol%), CuI (10 mol%), NMP, 76–828C, 4.5–10 h, 86% yield for 5a, 78% yield for 5b, 72%
yield for 5c, 89% yield for 5d. (b) BBr3 (5.2 equiv.), CH2Cl2, rt, 2 h, 89% yield. (c) BBr3 (4.5 equiv.), CH2Cl2, rt, 2.5 h, 96% yield. (d) BBr3 (8.3 equiv.),
CH2Cl2, 30–328C, 48 h, 89% yield. (e) Me4Sn (22) (3.0 equiv.), PdCl2(PhCN)2 (5 mol%), AsPh3 (10 mol%), CuI (10 mol%), NMP, 608C, 117 h, 66% yield.
(f) 4-MeOC6H4SnBu3 (23), (1.2 equiv.), PdCl2(PhCN)2 (5 mol%), AsPh3 (10 mol%), CuI (10 mol%), NMP, 608C, 54 h, 58% yield. (g) CH2vC(OEt)SnBu3
(24), (1.35 equiv.), PdCl2(PhCN)2 (5 mol%), AsPh3 (10 mol%), CuI (10 mol%), NMP, 81–838C, 47 h, 70% yield. (h) 2N HCl, THF, rt, 2.25 h, 93% yield.
(i) BBr3 (10.0 equiv.), CH2Cl2, rt, 96 h, 58% yield.
presence of this same catalyst system furnished compound
4k in 70% yield. Acidic hydrolysis of this vinyl ether allowed
then compound 4l to be obtained in 93% yield (Scheme 5).
interesting to establish if these compounds might be
prepared starting from methyl salicylate (10) by a reaction
sequence similar to that used for the preparation of
3,4-disubstituted isocoumarins 4. To this end, nonaflate
25, which derived from 10, was reacted with ethynylzinc
chloride (26) in THF at 62–668C in the presence of 1 mol%
Pd2(dba)3 and 2 mol% dppf to give compound 11 in 60%
yield (Scheme 6).
2.4. Synthesis of 3-ylidenephthalides from methyl
salicylate
Only a few methods have been reported in the literature for
the synthesis of 4-substituted isocoumarins with no
substituent at the 3-position.23 Therefore, we deemed it
However, iodolactonization of 11 by a procedure very
Scheme 6. (a) HCuC–ZnCl (26), THF, 62–668C, 13 h, Pd2(dba)3 (1 mol%), dppf (2 mol%), 60% yield. (b) I2 (3 equiv.), MeCN, 3 h, then MPLC on silica gel,
38% yield for (E)-27 and 56% yield for (Z)-27. (c) ICl, CH2Cl2, rt, 6 h (E)- and (Z)-27 in a 70:30 molar ratio). (d) Pd(OAc)2 (2 mol%), PPh3 (4 mol%), Et3N
(3.0 equiv.), HCOOH (2.0 equiv.), DMF, 60–638C, 30 h, 45% yield from (E)-27 and 51% yield from (Z)-27. (e) (for (E)-27): Me4Sn (22) (3.0 equiv.),
PdCl2[P(o-Tolyl)3]2 (5 mol%), CuI (10 mol%), NMP, 808C, 5 h, 80% yield. (f) (for (Z)-27): 4-Cl-C6H4SnBu3 (30), (1.35 equiv.), PdCl2(PhCN)2 (5 mol%),
AsPh3 (10 mol%), CuI (10 mol%), NMP, 808C, 24 h, 59% yield.

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R. Rossi et al. / Tetrahedron 59 (2003) 2067–2081
Table 1. Primary anticancer assay of 3-arylisocoumarins and unsym-
metrical 3,4-disubstituted isocoumarins
Compound
Percentage of growth inhibition
NCI-H460 (lung)
MCF-7 (breast)
SF-268 (CNS)
3a
3b
3c
3d
3e
3f
3g
3h
3i
4
30
35
115
45
112
21
9
4
84
109
71
107
45
51
54
92
118
89
120
76
114
76
106
90
130
81
3j
85
107
0
57
77
78
23
104
107
9
112
115
21
73
79
4a
4b
4c
4d
4e
4f
75
105
100
6
Scheme 7. Proposed mechanism for the regioselective iodolactonization
reaction of 11.
104
31
4g
4h
4i
4k
4l
96
29
248
78
100
9
239
59
106
50
257
84
similar to that employed for the synthesis of 5a–d, i.e. by
treatment with 3.0 equiv. of iodine in MeCN at room
temperature, furnished a mixture of (E)- and (Z)-3-iodo-
methylenephthalide, (E)- and (Z)-27, in a ca. 37:63 ratio,
respectively, as the only reaction product. These iodides
were separated chromatographically to give 97% pure
(E)-27 and stereoisomerically pure (Z)-27 in 38 and 56%
yield, respectively. We then attempted to modify the regio-
and/or stereoselectivity of the iodolactonization reaction of
11 and we found that treatment of this compound with
1.0 equiv. of ICl in CH2Cl2 at room temperature furnished a
mixture of (E)- and (Z)-27, in a 70:30 ratio, respectively.
Moreover, we observed that the reaction between a solution
of ICl in CH2Cl2 and a molar excess of 11 provided a
mixture of (E)- and (Z)-27, in a 97:3 ratio, respectively. The
structural assignment of these iodides was performed taking
into account that the palladium-catalyzed triethylammo-
nium formate reduction of each of these compounds
provided 3-methylenephthalide (28) (Scheme 6). Moreover,
the presence of absorption at 1776–1780 cm21 in the IR
spectra of these iodides indicated a g-lactone ring. On the
other hand, the stereochemistry of (E)-27 was assigned on
the basis of the known stereochemistry of (E)-29,28,29 which
we prepared in 80% yield by reaction of (E)-27 with a molar
excess of tetramethyltin (22) in NMP at 808C in the presence
of catalytic amounts of PdCl2[P(o-Tolyl)3]2 and CuI.
Furthermore, we found that reaction of stereoisomerically
pure (Z)-27 with tributyl(4-chlorophenyl)tin (30) in NMP at
808C in the presence of 5 mol% PdCl2(PhCN)2, 10 mol%
AsPh3 and 10 mol% CuI provided the known compound
(Z)-3130 in 59% yield (Scheme 6).31
88
72
80
electron-withdrawing group in the ortho-position. Subse-
quent endo-5-trig cyclization should then produce iodide
(E)-27, which easily undergoes partial stereomutation in the
presence of iodine or ICl (Scheme 7).
2.5. Biological results
The cytotoxic activity of compounds 3a–j and 4a–i,k,l was
evaluated in vitro against the National Cancer Institute
(NCI) 3-cell lines panel consisting of MCF-7 (breast),
SF-268 (CNS), and NCI-H460 (lung). In this protocol, each
cell line was inoculated and preincubated on a microtiter
plate. Test agents were then added at a single concentration
(1.00£1024 M) and the culture incubated for 48 h. End-
point determinations were made with sulforhodamine B, a
protein-binding dye. Results for each test (Table 1) are
reported as the percent of growth of the treated cells when
compared to the untreated control cells.
Compounds which reduced the growth of any one of the cell
lines to 32% or less (negative numbers indicate cell kill)
were considered to be active and some of them were passed
on for evaluation in the full panel of 60 cell lines over
a 5-log dose range. Results from Table 1 indicate that
compounds 3a, 3b, 3g, 4b, 4f, 4h, and 4i passed the 3-cell
lines primary screening. The structural features of all these
bioactive compounds save 4i include the presence of a
hydroxy group at the 6-position and/or a 3,4-dihydroxy-
phenyl or a 4-hydroxyphenyl group at the 3-position of the
isocoumarin ring. However, 4i, which was shown to be
highly active in this primary screening, does not contain
hydroxy groups. Analysis of the data reported in Table 1
seems also to link the cytotoxicity of the tested compounds
to the presence of a methyl group at the 4-position of their
isocoumarin ring. In fact, compounds 4b, 4f and 4h, which
are characterized by the presence of a methyl group at
their 4-position, exhibited higher cytotoxicity than the
Finally, it is worth mentioning that no further attempts were
performed to synthesize 4-substituted isocoumarins of
general formula 9 via iodolactonization of 11. In fact, the
results obtained for the reaction of 11 with iodine in MeCN
or with ICl in CH2Cl2, indicated that this electrophilic ring
closure does not involve intermediate 32b, which might be
the precursor to 4-iodoisocoumarin (9a) (Scheme 7). We
rationalized these results assuming that the cyclization
process selectively proceeds via the benzyl cationic
intermediate 32c in which the positive charge is better
stabilized by the aromatic ring, although this ring bears an

R. Rossi et al. / Tetrahedron 59 (2003) 2067–2081
Table 2. Cytotoxicity of compounds 3a, 3g, 4b and 4i
2073
Compound
log molar drug concentration required for 50% growth inhibition (log GI50)
Leukemia
MOLT-4
Lung
HOP-92
Colon
HCT-15
CNS
SF-268
Melanoma
SK-MEL-5
Ovarian
IGROV1
Renal
UO31
Prostate
PC-3
Breast
T-470
MGMa
3a
3g
4b
4i
25.82
24.73
25.52
24.96
26.52
24.66
24.97
24.66
25.28
24.67
25.40
24.70
24.84
24.58
25.04
24.76
25.17
24.95
24.58
24.73
25.77
24.70
25.24
24.69
24.93
24.88
24.95
24.72
24.84
24.60
24.89
24.61
25.80
24.70
25.81
24.51
24.88
24.58
25.05
24.70
a
Mean graph midpoint for all human cancer cell lines tested.
corresponding substances, i.e. 3a, 3b and 3g, respectively,
which do not contain this methyl group.
US NCI’s human tumor cell line screen. However, among
these substances only 4b exhibited an indisputable
cytotoxicity.
Compounds 3a, 3g, 4b, and 4i were then tested in US NCI’s
human tumor cell line screen.32 This assay involves
determination of the effect of a test agent on growth
parameters against a panel of approximately 60 human
tumor cell lines, mostly derived from solid tumors. For each
compound, dose–response curves for each cell line were
measured with five different drug concentrations. The
log GI50 values (GI50 being the molar drug concentration
required for half growth inhibition) obtained with selected
cell lines, along with the mean graph mid-point (MGM)
values, are summarized in Table 2. The MGM is based on a
calculation of the average log GI50 for all of the cell lines
tested in which GI50 values below and above the test range
(1024 –1028 M) are taken as the minimum (1028 M)
and maximum (1024 M) drug concentration used in the
screening test. The data summarized in Table 2 indicate an
indisputable cytotoxicyty of compound 4b, which showed a
MGM log GI50 below 25. Moreover, the complete set of
data obtained in this screening panel qualitatively shows
that either the leukemia cell lines or the breast cell line were
relatively more sensitive to compound 4b than were other
cell lines.
4. Experimental
4.1. General
Melting points are uncorrected. Merck precoated 60 F254
aluminum silica gel sheets were used for TLC analyses.
GLC analyses were performed on a Dani GC 1000
instrument with a PTV injector, which was equipped with
a Dani DDS 1000 data station. Two types of capillary
columns were used: an Alltech AT-1 bonded FSOT column
(30 m£0.25 mm i.d.) and an Alltech AT-35 bonded FSOT
column (30 m£0.25 mm i.d.). Purifications by MPLC on
silica gel (Merck silica gel 60, particle size 0.015–
0.040 mm) were performed on a Bu¨chi B-680 system
using a Knauer K-2400 differential refractometer as
detector. Electron impact mass spectra were measured at
70 eV by GLC/MS. GLC/MS analyses were performed
using a Q-mass 910 spectrometer interfaced with a Perkin–
Elmer 8500 gas-chromatograph. The MS spectrum of
compounds 3b and 4f was recorded on a Perkin–Elmer
SCIEX API III triple quadrupole mass spectrometer using
the atmospheric pressure photoionization (APPI) technique
in a tandem mass spectrometry manner. NMR spectra were
recorded on a Varian Gemini 200 MHz spectrometer and a
Varian Gemini 300 MHz spectrometer with TMS as the
internal reference or with a Bruker AMX 600 spectrometer
with solvent (CDCl3 or DMSO-d6) as the internal reference,
respectively. The structures of compounds 3h, 4i, 4j and 17
3. Conclusions
In summary, we have explored a useful and versatile
approach to 3-aryliscoumarins 3, including two natural
products, and unsymmetrical 3,4-disubstituted isocoumar-
ins 4 characterized by an aryl group at the 3-position. A key
step of this approach involves the regioselective iodo-
lactonization of methyl 2-(arylethynyl)benzoates 6 or
the corresponding carboxylic acids 7. The examples we
presented demonstrate that the strategy is general and
should be applicable to the regioselective synthesis of a large
variety of isocoumarin derivatives save 4-substituted
isocoumarins 9 with no substituent at the 3-position.
In fact, we have shown that an attempt to prepare
compounds 9 from methyl 2-ethynylbenzoate (11) accord-
ing to the same strategy used for the synthesis of compounds
3 and 4 provided 3-ylidenephthalides 12 with complete
regioselectivity. Finally, it should be noted that seven
isocoumarin derivatives so prepared, including naturally-
occurring thunberginols A (3a) and B (3b), were found to be
among those significantly active in the NCI 3-cell line, one
dose primary anticancer assay. Four compounds which
passed the 3-cell lines primary screening were then tested in
1
were assigned on the basis of their H NMR and 13C NMR
spectra at 600 and 150 MHz, respectively, and by a
1
combination of NMR techniques which included H–1H
COSY, NOESY (mixing time: 400 ms), HMQC and
HMBC. IR spectra were recorded on a Perkin–Elmer
1725-X FT-IR spectrophotometer. All reactions of air and
water sensitive materials were performed in flame dried
glassware under a positive atmosphere of nitrogen or argon
using standard syringe, cannula and septa techniques.
Solvents were dried and distilled before use. The following
compounds were prepared by published procedures: PdCl2
(PPh3)2,33 Pd(PPh3)4,34 tributyl(4-methoxyphenyl)tin
(23),35 tributyl(4-chlorophenyl)tin (30),27e (3,4-dimethoxy-
phenyl)ethynylzinc chloride (16).21a
4.1.1. Methyl 2,4,6-trimethoxybenzoate (15). K2CO3
(92.9 g, 672 mmol) and dimethyl sulfate (84.80 g, 672 mmol)

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R. Rossi et al. / Tetrahedron 59 (2003) 2067–2081
were added to a solution of 90% pure 2,4,6-trihydroxy-
benzoic acid monohydrate (14) (21.00 g, 112 mmol) in dry
acetone (420 ml) and the resulting mixture was stirred for
26 h at 42–458C. It was then filtered and the filtrate was
concentrated under reduced pressure. The solid residue was
recrystallized from hexane to give 15 (14.60 g, 58% yield)
as a colorless solid. Concentration of the mother liquors
followed by recrystallization from methanol of the resulting
solid residue provided a further amount of pure 15 (6.22 g,
24% yield). Mp 708C (lit.36 mp 69–708C). MS, m/z (%): 226
(23), 196 (11), 195 (100), 180 (10), 165 (4), 152 (6), 137
ethynyl]benzoate (6d). A slurry of (3,4-dimethoxyphenyl)-
ethynylzinc chloride (16) in THF was prepared by addition
of a THF solution of the corresponding Grignard reagent
(0.505 M, 76.0 ml, 38.4 mmol) to a slurry of dry ZnCl2
(6.80 g, 49.9 mmol) in THF (52 ml), which was stirred at
08C. After stirring for additional 20 min at this temperature,
a solution of 13d (15.81 g, 31.99 mmol), Pd2(dba)3
(0.293 g, 0.320 mmol), and dppf (0.355 g, 0.640 mmol) in
THF (128 ml) was added. The resulting mixture was
allowed to warm up to rt and then heated to 608C for
17 h. After usual workup the crude reaction product was
diluted with a mixture of benzene and AcOEt (9:1) (150 ml)
and filtered. The filtrate was concentrated and the residue,
which was diluted with CH2Cl2 (35 ml), was purified by
MPLC on silica gel with a mixture of benzene and AcOEt
(9:1) as eluent, to give 6d (9.69 g, 85% yield) as a colorless
solid. Mp 58–618C. IR (KBr): n 2205, 1731, 1598, 1578,
1
(10), 109 (3), 77 (3). H NMR (200 MHz, CDCl3): d 3.79
(6H, s, OMe), 3.81 (3H, s, OMe), 3.87 (3H, s, OMe),
6.09 ppm (2H, s, H-3 and H-5).
4.1.2. Methyl 2-hydroxy-4,6-dimethoxybenzoate (8c). A
1 M solution of BCl3 in CH2Cl2 (66.1 ml, 66.1 mmol) was
added during 20 min to a solution of compound 15 (13.59 g,
60.07 mmol) in dry CH2Cl2 (74 ml), which was stirred at
2708C. The reaction mixture was then allowed to warm up
to 208C and stirred at this temperature for 40 min. It was
then poured into 10% aqueous HCl (115 ml) and extracted
with CH2Cl2 (5£100 ml). The organic extract was washed
with water (3£70 ml), dried over Na2SO4 and concentrated
under reduced pressure. The residue was purified by MPLC
on silica gel with CH2Cl2 as eluent to give compound 8c
(10.20 g, 80% yield) as a colorless solid. Mp 107–1098C
(lit.37 mp 1078C). IR (KBr): n 1642, 1614, 1444, 1314,
1276, 1221, 1162, 1112, 821 cm21. MS, m/z (%): 212 (32),
181 (24), 180 (100), 152 (35), 138 (7), 137 (46), 109 (10), 95
1
1514, 1266, 1245, 1157, 1134 cm21. H NMR (200 MHz,
CDCl3): d 3.82 (3H, s, OMe), 3.83 (3H, s, OMe), 3.89 (3H,
s, OMe), 3.90 (3H, s, OMe), 3.94 (3H, s, OMe), 6.46 (1H, d,
J¼2.1 Hz, H-3 or H-5), 6.66 (1H, d, J¼2.1 Hz, H-5 or H-3),
6.83 (1H, d, J¼8.1 Hz, H-50), 6.99 (1H, d, J¼2.0 Hz,
H-20), 7.10 ppm (1H, dd, J¼8.1, 2.0 Hz, H-60). 13C NMR
(50 MHz, CDCl3): d 52.3, 55.6, 55.9 (2C), 56.0, 85.4, 89.5,
92.9, 107.8, 111.0, 114.3, 115.0, 118.8, 123.6, 125.2, 148.7,
148.9, 158.0, 161.4, 167.4 ppm. Anal. calcd for C20H20O6:
C, 67.41; H, 5.66. Found: C, 67.11; H, 5.61.
4.1.5. 4-Iodo-6,8-dimethoxy-3-(3,4-dimethoxyphenyl)iso-
coumarin (5d) and methyl 4,6-dimethoxy-2-(3,4-di-
methoxybenzoyl)methylbenzoate (17). To a solution of
6d (6.67 g, 18.7 mmol) in MeCN (214 ml) was added iodine
(14.28 g, 56.28 mmol) and the mixture was stirred under
nitrogen in the dark at rt for 2 h. It was then poured into a
10% aqueous Na2S2O3 solution (300 ml) and extracted with
CHCl3 (6£250 ml). The organic extract was washed with
water (75 ml), dried over Na2SO4 and concentrated under
reduced pressure. The solid residue was recrystallized from
THF to give chemically pure 5d (4.63 g) as a yellow solid.
Evaporation of the mother liquors furnished a residue,
which was purified by MPLC on silica gel with a mixture of
CH2Cl2 and AcOEt (8:2) as eluent to give a further amount
of chemically pure 5d (1.22 g). The overall yield was 67%.
Mp 237.5–238.58C. IR (KBr): n 1739, 1609, 1514, 1465,
1
(13), 81 (9). H NMR (200 MHz, CDCl3): d 3.80 (3H, s,
OMe), 3.82 (3H, s, OMe), 3.91 (3H, s, OMe), 5.96 (1H, d,
J¼2.6 Hz, H-5 or H-3), 6.10 (1H, d, J¼2.6 Hz, H-3 or H-5),
12.03 ppm (1H, s, OH). 13C NMR (50 MHz, CDCl3): d 52.1,
55.4, 56.0, 91.4, 93.3, 96.4, 162.0, 165.2, 165.8, 171.5 ppm.
The spectral properties of this compound were in agreement
with those previously reported.37
4.1.3. Methyl 4,6-dimethoxy-2-(perfluoro-1-butanesulfo-
nyloxy)benzoate (13d). A 60% dispersion of NaH in
mineral oil (2.26 g, 56.6 mmol), which was maintained
under an atmosphere of nitrogen, was washed with pentane
(4£20 ml). Dry DMF (75 ml) was added to the residue and
the mixture was stirred at 08C. A solution of 8c (8.00 g,
37.7 mmol) in dry DMF (22 ml) was then added dropwise
and the mixture was stirred at 08C for 0.5 h and at rt for 1 h.
Perfluoro-1-butanesulfonyl fluoride (7.79 ml, 43.4 mmol)
was added and the resulting mixture was stirred at rt for 2 h.
It was then poured into a saturated aqueous NH4Cl solution
(300 ml) and extracted with Et2O (5£150 ml). The organic
extract was washed with water (3£50 ml), dried over
Na2SO4 and concentrated under reduced pressure to give
compound 13d (17.53 g, 94% yield) as a pale yellow solid.
Mp 44–47.58C. MS, m/z (%): 494 (58), 463 (94), 183 (100),
181 (15), 180 (88), 179 (20), 152 (17), 137 (36), 69 (36). 1H
NMR (200 MHz, CDCl3): d 3.85 (3H, s, OMe), 3.86 (3H, s,
OMe), 3.90 (3H, s, OMe), 6.43 (1H, d, J¼2.2 Hz, H-5 or
H-3), 6.48 ppm (1H, d, J¼2.2 Hz, H-3 or H-5). GLC
analysis showed that 13d had chemical purity higher than
97%. This product was used in the next step without any
further purification and characterization.
1
1342, 1257, 1231, 1132, 1000 cm21. H NMR (200 MHz,
CDCl3): d 3.95 (6H, s, OMe), 3.97 (3H, s, OMe), 4.01 (3H,
s, OMe), 6.57 (1H, d, J¼2.2 Hz, H-7 or H-5), 6.95 (1H, d,
J¼8.0 Hz, H-50), 6.99 (1H, d, J¼2.2 Hz, H-5 or H-7), 7.21
(1H, d, J¼1.8 Hz, H-20), 7.31 ppm (1H, dd, J¼8.0, 1.8 Hz,
H-60). 13C NMR (50 MHz, CDCl3): d 55.8, 55.9, 56.1, 56.6,
75.8, 98.9, 102.6, 107.6, 110.1, 112.8, 123.4, 127.9, 142.5,
148.1, 150.3, 156.0, 157.9, 163.5, 165.5 ppm. Anal. calcd
for C19H17IO6: C, 48.74; H, 3.66. Found: C, 48.68; H, 3.60.
Concentration of the first eluted fractions of the above
mentioned chromatographic purification allowed isolation
of compound 17 (0.60 g, 9% yield) as a pale yellow solid.
Mp 190–1938C. IR (KBr): n 2984, 1702, 1680, 1586, 1514,
1311, 1256, 1153, 1024 cm21. 1H NMR (600 MHz, CDCl3):
3.76 (3H, s, COOMe), 3.78 (3H, s, H-10), 3.82 (3H, s, H-7),
3.92 (3H, s, H-700), 3.94 (3H, s, H-800), 4.26 (2H, s, H-10),
6.36 (1H, d, J¼2.1 Hz, H-3), 6.40 (1H, d, J¼2.1 Hz, H-5),
6.89 (1H, d, J¼8.3 Hz, H-500), 7.56 (1H, d, J¼00 1.9 Hz, H-200),
7.65 ppm (1H, dd, J¼8.3, 1.9 Hz, H-6 ). 13C NMR
4.1.4. Methyl 4,6-dimethoxy-2-[(3,4-dimethoxyphenyl)-

R. Rossi et al. / Tetrahedron 59 (2003) 2067–2081
2075
(150 MHz, CDCl3): d 43.3, 52.1, 55.4, 56.0, 56.1 (2C), 97.7,
107.2, 110.1, 110.7, 116.1, 123.2, 129.8, 136.3, 149.0,
153.4, 159.1, 161.8, 168.3, 195.5 ppm.
this compound, which had chemical purity higher than 98%,
were in agreement with those previously reported.38
4.2.3. 6-Methoxy-3-(4-methoxyphenyl)isocoumarin (3f).
The crude reaction product, which was obtained by
palladium-catalyzed triethylammonium formate reduction
of 5c, was purified by MPLC on silica gel with a mixture of
benzene and AcOEt (95:5) as eluent, to give 3f as a colorless
solid in 93% yield. Mp 145–1478C. MS, m/z (%): 282 (91),
254 (100), 239 (18), 211 (50), 195 (22), 139 (18), 127 (20),
119 (17), 77 (21). IR (KBr): n 1736, 1606, 1515, 1493, 1266,
1175, 1065, 1023, 831 cm21. 1H NMR (200 MHz, CDCl3):
d 3.86 (3H, s, OMe), 3.92 (3H, s, OMe), 6.76 (1H, s, H-4),
6.83 (1H, d, J¼2.6 Hz, H-5), 6.91–6.99 (2H, m, H-arom),
6.99 (1H, dd, J¼8.8, 2.6 Hz, H-7), 7.75–7.86 (2H, m,
H-arom), 8.20 ppm (1H, d, J¼8.8 Hz, H-8). 13C NMR
(50 MHz, CDCl3): 55.4, 55.6, 100.2, 107.5, 113.3, 114.1
(2C), 116.0, 124.5, 126.7 (2C), 131.7, 140.1, 154.1, 160.9,
162.1, 164.6 ppm. Anal. calcd for C17H14O4: C, 72.33; H,
5.00. Found: C, 72.25; H, 4.67.
4.2. General procedure for the synthesis of 3-aryliso-
coumarins by palladium-catalyzed triethylammonium
formate reduction of 3-aryl-4-iodoisocoumarins
Formic acid (99%, 393 mg, 8.54 mmol) was added to a
degassed mixture of a 3-aryl-4-iodoisocoumarin 5
(4.27 mmol), Et3N (1.79 ml, 12.8 mmol), Pd(OAc)2
(19.2 mg, 0.0854 mmol), and triphenylphosphine
(44.8 mg, 0.171 mmol) in dry DMF (120 ml) and the
mixture was stirred at 60–638C for 3.5–4.5 h under
argon. After this period of time GLC analysis showed that
compound 5 had been completely consumed. The mixture
was then cooled to rt, diluted with water (300 ml), and
extracted with AcOEt (5£120 ml). The organic extract was
dried over Na2SO4, concentrated under reduced pressure
and the residue was purified by MPLC on silica gel. This
procedure was used to prepare compounds 3c, 3d, 3f and 3j
from 5a–5d, respectively. It should be noted that the crude
reaction mixture which was obtained by palladium-
catalyzed triethylammonium formate reduction of 5c was
extracted with CHCl3 (5£120 ml) instead of being extracted
with AcOEt.
4.2.4. 6,8-Dimethoxy-3-(3,4-dimethoxyphenyl)isocou-
marin (3j). The crude reaction product, which was obtained
by palladium-catalyzed triethylammonium formate reduc-
tion of 5d, was purified by MPLC on silica gel with a
mixture of CH2Cl2 and AcOEt (80:20) as eluent, to give 3j
as a colorless solid in 98% yield. Mp 144.5–1468C (lit.13b
mp 155.9–157.28C). IR (KBr): n 1721, 1640, 1598, 1565,
4.2.1. 3-(3,4-Dimethoxyphenyl)-8-methoxyisocoumarin
(3c). The crude reaction product, which was obtained by
palladium-catalyzed triethylammonium formate reduction
of 5a, was purified by MPLC on silica gel with a mixture of
benzene and AcOEt (65:35) as eluent, to give compound 3c
as a pale yellow solid in 93% yield. Mp 148–1508C (lit.13b
152.8–154.48C) MS, m/z (%): 312 (100), 284 (46), 269 (22),
165 (12), 142 (10), 119 (15), 76 (10). IR (KBr): n 1729,
1
1516, 1254, 1209, 1151, 991 cm21. H NMR (300 MHz,
CDCl3): d 3.89 (3H, s, OMe), 3.92 (3H, s, OMe), 3.95 (3H,
s, OMe), 3.97 (3H, s, OMe), 6.39 (1H, d, J¼2.2 Hz, H-7 or
H-5), 6.41 (1H, d, J¼2.2 Hz, H-5 or H-7), 6.64 (1H, s, H-4),
6.88 (1H, d, J¼8.4 Hz, H-50), 7.31 (1H, d, J¼2.1 Hz,
H-20), 7.41 ppm (1H, dd, J¼8.4, 2.1 Hz, H-60). 13C NMR
d 55.5, 55.9, 56.0, 56.2, 98.3,
(75 MHz, CDCl3):
1
1698, 1566, 1515, 1254, 1077, 1021, 991, 805 cm21. H
100.0, 100.6, 102.9, 108.1, 110.9, 118.5, 124.6, 142.4,
149.0, 150.5, 154.1, 158.8, 163.1, 165.2 ppm. Anal.
calcd for C19H18O6: C, 66.66; H, 5.30. Found: C, 66.56;
H, 5.27.
NMR (200 MHz, CDCl3): d 3.93 (3H, s, OMe), 3.98 (3H, s,
OMe), 4.01 (3H, s, OMe), 6.74 (1H, s, H-4), 6.90 (1H, br d,
J¼8.1 Hz, H-7), 6.92 (1H, d, J¼8.4 Hz, H-50), 6.99 (1H, dd,
J¼8.1, 1.0 Hz, H-5), 7.35 (10H, d, J¼2.2 Hz, H-20), 7.46 (1H,
dd, J¼8.4, 2.2 Hz, H-6 ), 7.59 ppm (1H, pseudo-t,
J¼8.1 Hz, H-6). 13C NMR (50 MHz, CDCl3): d 56.0,
56.1, 56.3, 100.5, 108.2, 108.8, 109.4, 111.0, 117.7, 118.5,
124.6, 135.6, 140.6, 149.0, 150.6, 153.8, 159.0, 161.5 ppm.
The spectral properties of this compound were in agreement
with those previously reported.2,21a
4.2.5. 8-Hydroxy-3-(3,4-dihydroxyphenyl)isocoumarin
(thunberginol A) (3a). A mixture of 3c (0.781 g,
2.50 mmol) and
a 1 M CH2Cl2 solution of BBr3
(5.2 equiv., 13.0 ml, 13.0 mmol) was stirred at rt under
nitrogen for 2 h. The solution was then poured into ice water
(100 ml) and the mixture was extracted with AcOEt
(6£150 ml). The organic extract was washed with brine
(2£70 ml), dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified by MPLC on
silica gel with a mixture of CHCl3, MeOH and water
(10:1:1, lower phase) as eluent to give 3a (0.57 g, 85%
yield) as a colorless solid. Mp 249–2528C (lit.2 mp 2408C).
IR (KBr): n 3428, 1666, 1611, 1566, 1527, 1454, 1217,
4.2.2. 8-Methoxy-3-phenylisocoumarin (3d). The crude
reaction product, which was obtained by palladium-
catalyzed triethylammonium formate reduction of 5b, was
purified by MPLC on silica gel with a mixture of benzene
and AcOEt (87.5:12.5) as eluent, to give 3d as a pale yellow
solid in 90% yield. Mp 144–1468C (lit.38 mp 143–1458C).
MS, m/z (%): 252 (100), 223 (57), 205 (27), 165 (27), 152
(32), 119 (23), 105 (88), 91 (28), 77 (80). IR (KBr): n 1725,
1
1171, 820 cm21. H NMR (200 MHz, DMSO-d6): d 6.87
(1H, br d, J¼8.1 Hz, H-50), 6.93 (1H, br d, J¼8.0 Hz, H-7),
7.10 (1H, br d, J¼8.0 Hz, H-5), 7.23 (1H, s, H-4), 7.24 (1H,
br d, J¼8.1 Hz, H-60), 7.29 (1H, br s, H-20), 7.69 (1H, dd,
J¼8.1, 8.0 Hz, H-6), 10.85 ppm (3H, br s, OH). 13C NMR
(50 MHz, DMSO-d6): d 100.5, 105.0, 112.0, 113.9, 115.9,
116.4, 116.8, 122.1, 137.4, 138.4, 145.5 147.6, 152.6, 160.2,
165.0 ppm. These NMR data were in satisfactory agreement
with those of 3a, which was isolated from the fermented and
dried leaves of H. macrophylla.2
1
1568, 1477, 1274, 1219, 1108, 992, 767, 689 cm21. H
NMR (200 MHz, CDCl3): d 4.03 (3H, s, OMe), 6.86 (1H, s,
H-4), 6.94 (1H, d, J¼8.1 Hz, H-7 or H-5), 7.03 (1H, d,
J¼8.1 Hz, H-5 or H-7), 7.39–7.51 (3H, m, H-arom), 7.62
(1H, pseudo-t, J¼8.1 Hz, H-6), 7.83–7.93 ppm (2H, m, H-
arom). 13C NMR (50 MHz, CDCl3): d 56.3, 101.7, 109.2,
109.8, 118.0, 125.2 (2C), 128.6 (2C), 129.8, 131.7, 135.7,
140.4, 153.8, 158.9, 161.5 ppm. The spectral properties of

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R. Rossi et al. / Tetrahedron 59 (2003) 2067–2081
4.2.6. 8-Hydroxy-3-phenylisocoumarin (3e). A mixture of
3d (0.500 g, 1.98 mmol) and a 1 M CH2Cl2 solution of BBr3
(4.54 equiv., 8.98 ml, 8.98 mmol) was stirred at rt under
nitrogen for 1.75 h. The crude reaction product, which was
obtained after usual workup, was purified by MPLC on
silica gel with toluene as eluent to give 3e (0.47 g, 98%
yield) as a colorless solid. Mp 128–1308C (lit.39 mp 1428C).
MS, m/z (%): 239 (16), 238 (100), 210 (64), 181 (36), 153
(10), 152 (15), 105 (63), 92 (10), 77 (52). IR (KBr): n 3445,
1.95 mmol) in dry pyridine (3 ml) and the mixture was
stirred at 488C for 48 h. It was then cooled to rt, poured into
ice water (60 ml), acidified with cold 2 M HCl and extracted
with AcOEt (5£50 ml). The organic extract was washed
with water (2£30 ml), dried over Na2SO4 and concentrated
under reduced pressure. The solid residue was recrystallized
from a mixture of benzene and AcOEt (6:1) to give 3i
(0.44 g, 74% yield) as a pale yellow solid. Mp 135–1378C.
IR (KBr): n 1726, 1606, 1463, 1417, 1336, 1203, 1167,
1120, 1058 cm21. 1H NMR (200 MHz, CDCl3): d 3.92 (3H,
s, OMe), 3.94 (6H, s, OMe), 3.95 (3H, s, OMe), 6.87 (1H, d,
J¼2.4 Hz, H-5), 6.87 (1H, s, H-4),0 7.03 (1H, dd, J¼8.8,
2.4 Hz, H-7), 7.26–7.36 (2H, m, H-3 and H-50), 7.46 (2H,0s,
H-200 and H-600), 7.89–7.99 (2H, m, H-20 and H-6 ),
8.22 ppm (1H, d, J¼8.8 Hz, H-8). 13C NMR (50 MHz,
CDCl3): d 55.6, 56.3 (2C), 60.9, 101.9, 107.4 (2C), 107.9,
113.6, 116.5, 122.2 (2C), 123.9, 126.5 (2C), 129.7, 131.8,
139.6, 142.9, 152.1, 153.0 (2C), 153.3, 161.8, 164.5,
164.7 ppm. Anal. calcd for C26H22O7: C, 69.95; h, 4.97.
Found: C, 70.00; H, 4.68.
1677, 1628, 1452, 1223, 1168, 1094, 759, 683 cm21
.
1H NMR (300 MHz, DMSO-d6): d 7.01 (1H, d, J¼8.1 Hz,
H-7 or H-5), 7.16 (1H, d, J¼8.1 Hz, H-5 or H-7), 7.48–7.60
(3H, m, H-arom), 7.74 (1H, pseudo-t, J¼8.1 Hz, H-6), 7.55
(1H, s, H-4), 7.84–7.94 (2H, m, H-arom), 10.85 ppm (1H, s,
OH). 13C NMR (75 MHz, DMSO-d6): d 103.1, 105.7, 114.9,
117.0, 124.8 (2C), 129.0 (2C), 130.1, 131.1, 137.7, 137.9,
151.9, 160.4, 164.8 ppm. Anal. calcd for C15H10O3: C,
75.62; H, 4.23. Found: C, 75.45; H, 4.36.
4.2.7. 6-Hydroxy-3-(4-hydroxyphenyl)isocoumarin (3g).
A mixture of 3f (1.00 g, 3.54 mmol) and a 1 M CH2Cl2
solution of BBr3 (8.33 equiv., 29.5 ml, 29.5 mmol) was
stirred at 408C under nitrogen for 27 h. The mixture was
then cooled to rt, poured into ice water (80 ml) and
concentrated at rt at 20 Torr. The resulting aqueous
suspension was cooled to 08C and filtered. The solid was
washed with cold water (5£5 ml), dissolved in THF (10 ml)
and purified by MPLC on silica gel with a mixture of
CHCl3, MeOH and water (10:2:1, lower phase) as eluent to
give 3g (0.79 g, 87% yield) as a pale yellow solid. Mp
281–2848C. IR (KBr): n 3260, 1679, 1636, 1595, 1463,
1360, 1256, 1174, 844 cm21. 1H NMR (200 MHz, DMSO-
d6): d 6.85–6.96 (2H, m, H-30 and H-50), 6.94 (1H, d,
J¼2.2 Hz, H-5), 6.97 (1H, dd, J¼8.4, 2.2 Hz, H-7), 7.16
(1H, s, H-4), 7.49–7.61 (2H, m, H-20 and H-60), 8.02 (1H, d,
J¼8.4 Hz, H-8), 10.10 (1H, br s, OH), 10.70 ppm (1H, br s,
OH). 13C NMR (50 MHz, DMSO-d6): d 99.5, 109.9, 110.9,
115.6 (2C), 116.6, 122.4, 128.5 (2C), 131.3, 140.0, 153.1,
159.0, 161.0, 163.3 ppm. Anal. calcd for C15H10O4: C,
70.86; H, 3.96. Found: C, 70.78; H, 3.99.
4.2.10. 6,8-Dihydroxy-3-(3,4-dihydroxyphenyl)iso-
coumarin (thunberginol B) (3b). A mixture of 3j
(0.750 g, 2.19 mmol) and a 1 M CH2Cl2 solution of BBr3
(10.0 equiv., 21.9 ml, 21.9 mmol) was stirred at rt under
nitrogen for 72 h. The mixture was then poured into ice
water (60 ml) and concentrated at rt at 20 Torr. The
resulting aqueous suspension was cooled to 08C and filtered.
The solid was washed with cold water (5£4 ml) and purified
by MPLC on silica gel with a mixture of CHCl3, MeOH and
water (10:3:1, lower phase) as eluent to give compound 3b
(0.51 g, 81% yield) as a pale yellow solid. Mp 281–2858C
(lit.2 mp 2448C). Tandem mass spectrometry on the 287
(MþH) ion, m/z (%): 287 (52), 269 (100), 259 (4), 241 (13),
213 (11), 177 (23), 149 (3), 137 (4), 121 (7). IR (KBr): n
3176, 1676, 1530, 1620, 1384, 1246, 1191, 1168,
1
1094 cm21. H NMR (200 MHz, DMSO-d6): d 6.33 (1H,
d, J¼2.1 Hz, H-5 or H-7), 6.50 (1H, d, J¼2.1 Hz, H-7 or
H-5), 6.87 (1H, d, J¼8.4 Hz, H-50), 7.12 (1H, s, H-4), 7.23
(1H, dd, J¼8.4, 2.2 Hz, H-60), 7.28 (1H, d, J¼2.2 Hz, H-20),
9.30 (1H, s, OH), 9.57 (1H, s, OH), 10.96 ppm (2H, s, OH).
13C NMR (50 MHz, DMSO-d6): d 97.8, 100.4, 101.3, 103.0,
112.1, 115.2, 116.8, 122.3, 139.9, 145.4, 147.5, 152.6,
162.4, 164.8, 165.4 ppm. Anal. calcd for C15H10O6: C,
62.94; H, 3.52. Found: C, 62.90; H, 3.49. These NMR data
were in satisfactory agreement with those of 3j, which was
isolated from the fermented and dried leaves of H.
macrophylla.2
4.2.8. 3-(4-Hydroxyphenyl)-6-methoxyisocoumarin (3h).
A mixture of 3f (1.09 g, 3.86 mmol) and a 1 M CH2Cl2
solution of BBr3 (5.20 equiv., 20.1 ml, 20.1 mmol) was
stirred at rt under nitrogen for 1.42 h. The crude reaction
product, which was obtained after usual workup, was
purified by MPLC on silica gel with a mixture of benzene
and AcOEt (80:20) as eluent to give 3h (0.75 g, 72% yield)
as a pale yellow solid. Mp 251–2548C. IR (KBr): n 3446,
1
1691, 1636, 1610, 1272, 1259, 1245, 1077, 831 cm21. H
4.2.11. 3-(3,4-Dimethoxyphenyl)-8-methoxy-4-methyl-
isocoumarin (4a). A deaerated solution of tetramethyltin
(22) (1.84 g, 10.3 mmol) in dry NMP (12 ml) was added to a
degassed mixture of 5a (1.50 g, 3.42 mmol), PdCl2[P(o-
Tolyl)3]2 (134 mg, 0.171 mmol), and CuI (65.2 mg,
0.342 mmol) in dry NMP (38 ml) and the mixture was
stirred under nitrogen at 76–798C for 4.5 h. It was then
cooled to rt, poured into a saturated aqueous NH4Cl solution
(150 ml) and extracted with CHCl3 (6£100 ml). The organic
extract was washed with brine (2£50 ml), dried over
Na2SO4 and concentrated under reduced pressure. The
resulting solid was dissolved in CHCl3 (15 ml) and purified
by MPLC on silica gel with a mixture of benzene and
AcOEt (75:25) as eluent to give 4a (0.96 g, 86% yield) as a
NMR (600 MHz, DMSO-d6): d 3.91 (3H, s, OMe), 6.90
(2H, m, H-30 and H-50), 7.10 (1H, dd, J¼8.7, 2.6 Hz, H-7),
7.13 (1H, d, J¼2.6 Hz, H.5), 7.21 (1H, s, H-4), 7.72 (2H, m,
H-20 and H-60), 8.05 (1H, d, J¼8.7 Hz, H-8), 10.02 ppm
(1H, s, OH). 13C NMR (150 MHz, DMSO-d6): d 56.5,
100.5, 108.9, 113.2, 116.6 (2C), 117.2, 123.3, 127.5 (2C),
131.8, 141.0, 154.4, 160.0, 161.8, 165.3 ppm. Anal. calcd
for C16H12O4: C, 71.64; H, 4.51. Found: C, 71.48; H, 4.48.
4.2.9. 6-Methoxy-3-[4-(3,4,5-trimethoxybenzoyloxy)-
phenyl]isocoumarin (3i). A solution of 3h (0.349 g,
1.30 mmol) in dry pyridine (18 ml) was added to a solution
of 3,4,5-trimethoxybenzoyl chloride (17) (0.450 g,

R. Rossi et al. / Tetrahedron 59 (2003) 2067–2081
2077
pale yellow solid. Mp 195.5–198.58C. MS, m/z (%): 327
(15), 326 (70), 299 (21), 298 (100), 283 (38), 252 (15), 165
(13), 149 (11), 77 (8). IR (KBr): n 1728, 1516, 1480, 1254,
(0.28 g, 96% yield) as a pale yellow solid. Mp 161–
162.58C. IR (KBr): n 3434, 1678, 1634, 1457, 1240, 1186,
1
813, 749, 702 cm21. H NMR (200 MHz, DMSO-d6): d
1
1215, 1173, 1048, 1024, 806 cm21. H NMR (200 MHz,
2.22 (3H, s, C–Me), 7.07 (1H, d, J¼8.1 Hz, H-5 or H-7),
7.22 (1H, 0d, J¼8.1 Hz, H-7 or H-5), 7.46–7.68 (5H, m,
H-20, H-3 , H-40, H-50, and H-60), 7.82 (1H, pseudo-t,
J¼8.2 Hz, H-6), 11.20 ppm (1H, s, OH). 13C NMR
(50 MHz, DMSO-d6): d 13.4, 105.4, 110.2, 114.3, 114.9,
128.3 (2C), 129.1 (2C), 129.5, 132.2, 137.6, 138.6, 149.7,
160.6, 165.1 ppm. Anal. calcd for C16H12O3: C, 76.18; H,
4.79. Found: C, 76.11; H, 4.70.
CDCl3): d 2.27 (3H, s, C–Me), 3.94 (6H, s, OMe), 4.03 (3H,
s, OMe), 6.92 (1H, d, J¼8.9 Hz, H-50 or H-60), 7.00 (1H, d,
J¼8.1 Hz, H-5 or H-7), 7.08–7.20 (3H, m, H-arom),
7.70 ppm (1H, pseudo-t, J¼8.1 Hz, H-6). 13C NMR
(50 MHz, CDCl3): d 14.3, 55.9, 56.0, 56.3, 107.9, 109.4,
109.6, 110.3, 112.3, 115.1, 122.7, 125.8, 135.4, 141.8,
148.5, 149.7, 151.6, 159.2, 161.7 ppm. Anal. calcd for
C19H18O5: C, 69.93; H, 5.56. Found: C, 69.85; H, 5.43.
4.2.15. 6-Methoxy-3-(4-methoxyphenyl)-4-methyliso-
coumarin (4e). Reaction of 5c (600 mg, 1.47 mmol) with
tetramethyltin (22) (789 mg, 4.41 mmol) in NMP (16 ml) at
808C for 10 h in the presence of 5 mol% PdCl2[P(o-
Tolyl)3]2 and 10 mol% CuI according to the same procedure
used for the synthesis of 4a provided 98% chemically pure
4e (0.31 g, 72% yield) as a colorless solid. Mp 69–718C.
MS, m/z (%): 296 (40), 269 (18), 268 (100), 253 (66), 225
(15), 182 (9), 135 (17), 92 (18), 77 (22). IR (KBr): n 1703,
4.2.12. 8-Hydroxy-3-(3,4-dihydroxyphenyl)-4-methyliso-
coumarin (4b). A solution of 4a (1.13 g, 3.46 mmol) in a
1 M CH2Cl2 solution of BBr3 (5.20 equiv., 18.0 ml,
18.0 mmol) was stirred for 2 h at rt under nitrogen. The
mixture was then poured into water (150 ml) and extracted
with AcOEt (6£200 ml). The organic extract was washed
with water (1£50 ml) and concentrated under reduced
pressure. The resulting solid residue was dissolved in THF
(10 ml) and purified by MPLC on silica gel with a mixture
of CHCl3, MeOH and water (10:1:1, lower phase) as eluent
to give 4b (0.88 g, 89% yield) as a pale yellow solid. Mp
242–2448C. IR (KBr): n 3297, 1662, 1606, 1513, 1292,
1240, 1215, 1127, 691 cm21. 1H NMR (2000MHz, DMSO-
d6): d 2.21 (3H, s, C–Me), 6.91 (2H, s, H-5 or H-60), 6.99
(1H, d, J¼8.4 Hz, H-7 or H-5), 7.04 (1H, s, H-20), 7.11 (1H,
d, J¼8.2 Hz, H-5 or H-7), 7.75 (1H, pseudo-t, J¼8.2 Hz,
H-6), 9.35 (1H, s, OH), 9.52 (1H, s, OH), 11.22 ppm (1H, s,
OH). 13C NMR (50 MHz, DMSO-d6): d 13.6, 105.1, 108.8,
114.0, 114.3, 115.2, 116.3, 121.0, 123.1, 137.3, 139.0,
144.9, 146.8, 150.3, 160.6, 165.4 ppm. Anal. calcd for
C16H12O5: C, 67.60; H, 4.26. Found: C, 67.91; H, 4.41.
1
1601, 1493, 1441, 1254, 1231, 1182, 1023, 850 cm21. H
NMR (300 MHz, CDCl3): d 2.27 (3H, s, C–Me), 3.87 (3H,
s, OMe), 3.95 (3H, s, OMe), 6.97 (1H, d,0 J¼2.2 Hz, H-5),
6.93–7.02 (2H, m, H-30 and H-50 or H-2 and H-60), 07.06
(1H, dd, J¼8.7, 2.2 Hz, H-7), 7.49–7.56 (2H, m, H-2 and
H-60 or H-30 and H-50), 8.29 ppm (1H, d, J¼8.7 Hz, H-8).
13C NMR (75 MHz, CDCl3): d 13.7, 55.4, 55.6, 106.5,
108.2, 113.7 (2C), 114.0, 115.1, 125.9, 130.9 (2C), 132.7,
141.4, 151.8, 160.3, 162.4, 164.8 ppm. Anal. calcd for
C18H16O4: C, 72.96; H, 5.44. Found: C, 72.85; H, 5.47.
4.2.16. 6-Hydroxy-3-(4-hydroxyphenyl)-4-methyliso-
coumarin (4f). A mixture of 4e (237 mg, 0.800 mmol)
and a 1 M CH2Cl2 solution of BBr3 (8.33 equiv., 6.67 ml,
6.67 mmol) was stirred at 30–328C for 48 h. After workup
according to the procedure used in the synthesis of 3g, the
crude reaction product was dissolved in THF (35 ml) and
purified by MPLC on silica gel with a mixture of toluene
and AcOEt (50:50) as eluent to give chemically pure 4f
(191 mg, 89% yield) as a colorless solid. Mp 309–3138C
(decomposition). Tandem mass spectrometry on the 287
(MþH) ion, m/z (%): 269 (100), 251 (33), 235 (26), 226
(95), 223 (40), 195 (22), 175 (17), 147 (39), 121 (19). IR
(KBr): n 3382, 1687, 1625, 1595, 1495, 1462, 1275, 1109,
4.2.13. 8-Methoxy-4-methyl-3-phenylisocoumarin (4c).
Reaction of 5b (0.700 g, 1.85 mmol) with tetramethyltin
(22) (0.993 g, 5.55 mmol) in NMP (20 ml) at 828C for 4.5 h
in the presence of 5 mol% PdCl2[P(o-Tolyl)3]2 and
10 mol% CuI according to the same procedure used for
the synthesis of 4a provided 98% chemically pure 4c
(0.38 g, 78% yield) as a pale yellow solid. Mp 161–1628C.
MS, m/z (%): 266 (100), 238 (39), 237 (28), 223 (26), 219
(17), 195 (19), 165 (17), 105 (60), 77 (65). IR (KBr): n 1725,
1
1594, 1566, 1479, 1267, 1230, 1095, 1049, 812 cm21. H
1
NMR (300 MHz, CDCl3): d 2.25 (3H, s, C–Me), 4.02 (3H,
s, OMe), 7.01 (1H, d, J¼8.3 Hz, H-5 or H-7), 7.17 (1H, d,
J¼8.3 Hz, H-7 or H-5), 7.39–7.48 (3H, m, H-arom), 7.54–
7.61 (2H, m, H-arom), 7.70 ppm (1H, pseudo-t, J¼8.3 Hz,
H-6). 13C NMR (75 MHz, CDCl3): d 14.1, 56.4, 108.4,
109.7, 109.9, 115.3, 128.1 (2C), 129.2, 129.5 (2C), 133.3,
135.5, 141.7, 151.8, 159.1, 161.8 ppm. Anal. calcd for
C17H14O3: C, 76.68; H, 5.30. Found: C, 76.50; H, 5.28.
830 cm21. H NMR (200 MHz, DMSO-d6): d 2.17 (3H, s,
C–Me), 6.83–6.95 (2H, m, H-30 and H-50 or H-20 and H-60),
6.97 (1H, d, J¼2.2 Hz, H-5), 07.02 (1H, dd, J¼8.8, 2.2 Hz,
H-7), 7.36–7.47 (2H, m, H-2 and H-60 or H-30 and H-50),
8.06 (1H, d, J¼8.8 Hz, H-8), 9.94 (1H, br s, OH), 10.80 ppm
(1H, br s, OH). 13C NMR (50 MHz, DMSO-d6): d 13.3,
107.4, 108.2, 111.5, 115.0 (2C), 116.6, 123.7, 130.7 (2C),
131.5, 140.9, 151.0, 158.3, 161.1, 163.4 ppm. Anal. calcd
for C16H12O4: C, 71.64; H, 4.51. Found: C, 71.53; H, 4.48.
4.2.14. 8-Hydroxy-4-methyl-3-phenylisocoumarin (4d).
A mixture of 4c (0.312 g, 1.17 mmol) and a 1 M CH2Cl2
solution of BBr3 (4.54 equiv., 5.31 ml, 5.31 mmol) was
stirred for 2.5 h at rt under nitrogen. The mixture was then
poured into ice-water (140 ml) and the whole was extracted
with AcOEt (5£70 ml). The organic extract was washed
with water (2£30 ml) and concentrated under reduced
pressure. The solid residue was purified by MPLC on silica
gel with toluene as eluent to give chemically pure 4d
4.2.17. 4-Methyl-3-phenylisocoumarin (4i). A degassed
solution of tetramethyltin (22) (3.54 g, 19.8 mmol) in dry
NMP (3 ml) was added to a deaerated mixture of 5e (2.30 g,
6.61 mmol), PdCl2(PhCN)2 (0.13 g, 0.33 mmol), AsPh3
(0.20 g, 0.66 mmol), and CuI (0.13 g, 0.66 mmol) in dry
NMP (10 ml) and the mixture was stirred under nitrogen for
117 h at 608C. The crude reaction product, which was
obtained after usual workup, was purified by MPLC on

2078
R. Rossi et al. / Tetrahedron 59 (2003) 2067–2081
silica gel with a mixture of hexane, CH2Cl2 and AcOEt
(80:15:5) as eluent to give 98% chemically pure 4i (1.03 g,
66% yield) as an orange solid. Mp 109–1138C. MS, m/z
(%): 236 (92), 208 (91), 178 (19), 131 (10), 105 (84), 102
(16), 77 (100). IR (KBr): n 1718, 1637, 1486, 1244, 1098,
CvCH), 4.43 (1H, d, J¼2.6 Hz, CvCH), 7.33–7.42 (3H,
m, H-arom), 7.51 (1H, pseudo-dt, J¼7.6, 1.6 Hz, H-6 or
H-7), 7.62 (1H, dd, J¼8.0, 1.6 Hz, H-5), 7.68–7.81 (3H, m,
H-arom), 8.33 ppm (1H, dd, J¼7.4, 1.6 Hz, H-8). 13C NMR
(50 MHz, CDCl3): d 14.4, 63.4, 90.1, 113.9, 120.1, 124.7,
127.9, (2C), 128.0, 128.3 (2C), 129.2, 129.5, 132.8, 134.7,
137.6, 152.9, 155.0, 161.8 ppm. Anal. calcd for C19H16O3:
C, 78.06; H, 5.52. Found: C, 78.21; H, 5.40.
1
1057, 767, 705, 694 cm21. H NMR (600 MHz, CDCl3): d
2.32 (3H, s, C–Me), 7.44 (1H, m, H-40), 7.46 (2H, m, H-30
and H-50), 7.55 (1H, ddd, J¼7.8, 7.2, 1.2 Hz, H-7), 7.59 (2H,
dd, J¼8.0, 1.2 Hz, H-20 and H-60), 7.65 (1H, d, J¼8.0 Hz,
H-5), 7.81 (1H, ddd, J¼8.0, 7.2, 1.2 Hz, H-6), 8.38 ppm
(1H, dd, J¼7.8, 1.2 Hz, H-8). 13C NMR (150 MHz, CDCl3):
d 13.6, 109.1, 120.9, 123.4, 127.9, 128.3 (2C), 129.4, 129.5
(2C), 129.8, 133.3, 134.8, 138.8, 151.2, 162.5 ppm. Anal.
calcd for C16H12O2: C, 81.34; H, 5.12. Found: C, 80.97; H,
4.93.
4.2.20. 4-Acetyl-3-phenylisocoumarin (4l). A solution of
4k (0.400 g, 1.37 mmol) in THF (20 ml) was treated at 08C
with 2 M HCl (10.0 ml, 20.0 mmol) and the resulting
mixture was stirred at rt for 2.25 h. It was then poured into
brine (8 ml) and extracted with benzene (4£50 ml). The
organic extract was washed with a saturated aqueous
NaHCO3 solution (3£30 ml) and water (30 ml), dried over
Na2SO4 and concentrated under reduced pressure. The
residue was dissolved in benzene (4 ml) and purified by
MPLC on silica gel with a mixture of petroleum ether and
AcOEt (85:15) as eluent to give 4l (0.34 g, 93% yield) as a
colorless solid. Mp 126.5–129.58C (lit.40 mp 72–738C).
MS, m/z(%): 265, (15), 264 (94), 263 (100), 249 (50), 205
(12), 187 (14), 165 (20), 105 (71), 77 (55). IR (KBr): n 1746,
4.2.18. 3-Phenyl-4-(4-methoxyphenyl)isocoumarin (4j).
The crude reaction mixture, which was obtained by reaction
of 5c (1.57 g, 4.51 mmol) with 4-methoxyphenyltributyltin
(23) (2.14 g, 5.39 mmol) in NMP at 608C for 54 h in the
presence of PdCl2(PhCN)2 (90 mg, 0.23 mmol), AsPh3
(0138 mg, 0.45 mmol) and CuI (85.6 mg, 0.45 mmol), was
poured into a saturated aqueous NH4Cl solution (150 ml)
and extracted with AcOEt (5£50 ml). The organic extract
was then stirred for 4.5 h at rt with a 8 M aqueous KF
solution (200 ml), filtered over Celitew, and the filtrate was
extracted with AcOEt (3£50 ml). The organic extract was
washed with water (50 ml), dried over Na2SO4 and
concentrated under reduced pressure. The residue was
purified by MPLC on silica gel with toluene as eluent to give
chemically pure 4j (0.86 g, 58% yield) as a colorless solid.
Mp 173–1748C. MS, m/z(%): 328 (100), 251 (49), 223 (31),
207 (18), 152 (31), 105 (83), 77 (62). IR (KBr): n 1732,
1
1694, 1619, 1358, 1240, 1096, 1076, 765, 696 cm21. H
NMR (200 MHz, CDCl3): d 2.14 (3H, s, Me), 7.45–7.59
(4H, m, H-arom), 7.59–7.70 (3H, m, H-arom), 7.78 (1H, dt,
J¼7.7, 1.4 Hz, H-6 or H-7), 8.38 ppm (1H, dd, J¼8.0,
1.8 Hz, H-5 or H-8). 13C NMR (50 MHz, CDCl3): d 32.4,
118.2, 120.0, 123.8, 128.6 (3C), 128.9 (2C), 129.9, 131.0,
131.9, 134.2, 135.2, 153.2, 161.0, 201.9 ppm. Anal.
calcd for C17H12O3: C, 77.26; H, 4.58. Found: C, 77.17;
H, 4.53.
1
1604, 1511, 1480, 1290, 1252, 1171, 766, 695 cm21. H
4.2.21. 6,8-Dimethoxy-3-(3,4-dimethoxyphenyl)-4-
methylisocoumarin (4g). Compound 5d (1.00 g,
2.14 mmol) was reacted with tetramethyltin (22) (1.15 g,
6.41 mmol) at 81–828C for 5.7 h according to the same
procedure used to prepare 4a. The crude reaction product
was dissolved in CH2Cl2 (35 ml) and purified by MPLC on
silica gel with a mixture of CH2Cl2 and AcOEt (80:20) as
eluent to give 4g (0.67 g, 89% yield) as a pale yellow solid.
Mp 188–1918C. IR (KBr): n 1720, 1602, 1518, 1249, 1208,
1173, 1139, 1078, 1017 cm21. 1H NMR (300 MHz, CDCl3):
d 2.24 (3H, s, C–Me), 3.94 (6H, br s, OMe), 3.95 (3H, s,
OMe), 4.00 (3H, s, OMe), 6.50–6.60 (2H, m, H-5 and H-7),
6.92 (1H, d, J¼8.5 Hz, H-50), 7.08–7.18 ppm (2H, m, H-20
and H-60). 13C NMR (75 MHz, CDCl3): d 14.4, 55.6, 56.0,
56.1, 56.4, 97.9, 98.6, 103.6, 107.9, 110.4, 112.5, 122.8,
126.1, 143.7, 148.6, 149.9, 152.2, 159.1, 163.7, 165.3 ppm.
Anal. calcd for C20H20O6: C, 67.41; H, 5.66. Found: C,
67.38; H, 5.60.
NMR (600 MHz, CDCl3): d 3.86 (3H, s, C–Me), 6.95 (2H,
d, J¼8.8 Hz, H-300 and H-500), 7.16 (2H, 0d, J¼8.8 Hz, H-200
and H-600), 7.22 (2H, m, H-30 and H-5 ), 7.23 (1H, ddd,
J¼8.0, 1.2, 0.60Hz, H-5), 7.24 (1H, m, H-40), 7.36 (2H, d,
J¼6.7 Hz, H-2 and H-60), 7.52 (1H, ddd, J¼7.9, 7.2,
1.2 Hz, H-7), 7.64 (1H, ddd, J¼8.0, 7.2, 1.4 Hz, H-6),
8.40 ppm (1H, ddd, J¼7.9, 1.4, 0.6 Hz, H-8). 13C NMR
(150 MHz, CDCl3): d 55.3, 114.5 (2C), 116.5, 120.5, 125.4,
127.9 (2C), 128.0, 128.3, 128.8, 129.2 (2C), 129.5, 132.3
(2C), 133.1, 134.6, 139.2, 151.0, 159.4, 162.3 ppm. Anal.
calcd for C22H16O3: C, 80.47; H, 4.91. Found: C, 80:68; H,
4.95.
4.2.19. 4-(1-Ethoxyethenyl)-3-phenylisocoumarin (4k).
Iodide 5e (1.50 g, 4.31 mmol) was reacted with tributyl
(1-ethoxyethenyl)tin (24) (2.10 g, 5.81 mmol) in dry NMP
(16 ml) for 47 h at 81–838C in the presence of PdCl2
(PhCN)2 (82.7 mg, 0.216 mmol), AsPh3 (13.2 mg,
0.431 mmol) and CuI (82.1 mg, 0.431 mmol). The reaction
mixture was then cooled to rt and worked up according to
the same procedure employed in the preparation of 4j. The
crude reaction product was purified by MPLC on silica gel
with benzene as eluent to give 97% chemically pure 4k
(0.88 g, 70% yield) as a yellow solid. Mp 100–1018C. MS,
m/z(%): 292 (69), 291 (60), 263 (100), 247 (30), 207 (26),
178 (36), 173 (27), 105 (69), 77 (89). IR (KBr): n 1733,
4.2.22. 6,8-Dihydroxy-3-(3,4-dihydroxyphenyl)-4-methyl-
isocoumarin (4h). A mixture of 4g (0.450 g, 1.26 mmol)
and a 1 M CH2Cl2 solution of BBr3 (10.0 equiv., 12.6 ml,
12.6 mmol) was stirred at rt for 96 h. The reaction mixture
was worked up according to the procedure used for the
synthesis of 3g. The resulting crude reaction product was
dissolved in THF (4 ml) and purified by MPLC on silica
gel with a mixture of benzene and THF (60:40) as eluent to
give 4h (0.22 g, 58% yield) as a pale yellow solid. This
compound was recrystallized from a mixture of AcOEt and
hexane. Mp 274–2768C (decomposition). IR (KBr): n 3211,
1
1621, 1316, 1223, 1084, 1060, 1018, 759, 698 cm21. H
NMR (200 MHz, CDCl3): d 1.38 (3H, t, J¼7.2 Hz, Me),
3.94 (2H, q, J¼7.2 Hz, OCH2), 4.19 (1H, d, J¼2.6 Hz,

R. Rossi et al. / Tetrahedron 59 (2003) 2067–2081
2079
1655, 1612, 1509, 1451, 1376, 1296, 1256, 1169 cm21. 1H
NMR (200 MHz, CDCl3): d 2.14 (3H, s, C–Me), 6.40 (1H,
s, H-arom), 6.49 (1H, s, H-arom), 6.87 (2H, s, H-arom), 6.98
(1H, s, H-arom), 9.38 (2H, br s, OH), 10.85 (1H, br s, OH),
11.33 ppm (1H, br s, OH). 13C NMRv (50 MHz, CDCl3): d
13.5, 97.9, 101.2 (2C), 108.4, 115.1, 116.2, 120.9, 123.2,
140.7, 144.8, 146.7, 150.4, 162.8, 165.0, 165.5 ppm. Anal.
calcd for C16H12O6: C, 64.00; H, 4.03. Found: C, 63.95; H,
4.17.
(Z)-27 (0.47 g, 56% yield) as a pale yellow solid. Mp 120–
121.58C. MS, m/z (%): 273 (10), 272 (100), 231 (10), 127
(16), 117 (13), 104 (15), 89 (74), 76 (24), 63 (15). IR (KBr):
n 1780, 1643, 1474, 1273, 1066, 983, 741, 713, 685 cm21
.
1H NMR (200 MHz, CDCl3): d 6.42 (1H, s, vCH), 7.60
(1H, pseudo-t, J¼7.5 Hz, H-6 or H-5), 7.66 (1H, d, J¼
7.5 Hz, H-4 or H-7), 7.74 (1H, pseudo-t, J¼7.5 Hz, H-5 or
H-6), 7.88 ppm (1H, d, J¼7.5 Hz, H-7 or H-4). 13C NMR
(50 MHz, CDCl3): d 55.2, 120.3, 125.1, 125.7, 130.5, 134.7,
137.5, 152.9, 165.2 ppm. Anal. calcd for C9H5IO2: C, 39.74;
H, 1.85. Found: C, 39.69; H, 1.80. On the other hand, a
crude mixture of (E)- and (Z)-27 in a 70:30 molar ratio,
respectively, was obtained by reaction of 11 with 1.0 equiv.
of ICl in CH2Cl2 solution in the dark at rt for 6 h.
Purification of this mixture by MPLC on silica gel allowed
isolation of compounds (E)- and (Z)-27 in 44 and 38% yield,
respectively. It should also be noted that a crude mixture of
(E)- and (Z)-27 in a ca. 97:3 molar ratio, respectively, was
obtained by reaction of a CH2Cl2 solution of ICl with a
molar excess of 11 at rt.
4.2.23. Methyl 2-ethynylbenzoate (11). A slurry of
ethynylzinc chloride (26) was prepared by addition of a
THF solution of ethynylmagnesium bromide (0.50 M,
91.9 ml, 45.9 mmol) to a slurry of dry ZnCl2 (8.14 g,
59.7 mmol) in THF (62 ml), which was stirred at 08C. After
stirring for additional 20 min at this temperature, a solution
of methyl 2-(perfluoro-1-butanesulfonyloxy)benzoate (25)
(16.62 g, 38.27 mmol), Pd2(dba)3 (351 mg, 0.383 mmol)
and dppf (424 mg, 0.766 mmol) in THF (153 ml) was added
and the resulting mixture was stirred at 62–668C for 13 h.
The crude reaction product, which was obtained after usual
workup, was purified by MPLC on silica gel with a mixture
of petroleum ether and Et2O (90:10) as eluent to give 11
(3.68 g, 60% yield) as a pale yellow liquid. MS, m/z(%): 160
(70), 159 (44), 131 (13), 130 (16), 129 (87), 102 (77), 101
(100), 75 (45), 74 (27). IR (film): n 2952, 1729, 1434, 1298,
4.2.25. 3-Methylidenephthalide (28). The crude reaction
product of the palladium-catalyzed triethylammonium
formate reduction of (E)-27 (225 mg, 0.827 mmol), which
was performed according to a procedure very similar to that
used to prepare compounds 3c, 3d, 3f, and 3j, was purified
by MPLC on silica gel with a mixture of petroleum ether
and AcOEt (90:10) as eluent to give 28 (54.7 mg, 45%
yield) as a colorless solid. Mp 54–568C (lit.41 mp 54–
558C). MS, m/z (%): 146 (100), 118 (18), 105 (13), 104 (70),
90 (40), 89 (16), 76 (55), 74 (12), 63 (8). IR (KBr): n 1767,
1
1275, 1258, 1132, 1080, 758 cm21. H NMR (200 MHz,
CDCl3): d 3.42 (1H, s, CspH), 3.92 (3H, s, OMe), 7.38 (1H,
pseudo-dt, J¼7.7, 1.7 Hz, H-4 or H-5), 7.46 (1H, pseudo-dt,
J¼7.7, 1.7 Hz, H-4 or H-5), 7.62 (1H, dd, J¼7.7, 1.7 Hz,
H-3 or H-6), 7.93 ppm (1H, dd, J¼7.7, 1.7 Hz, H-6 or H-3).
13C NMR (50 MHz, CDCl3): d 52.0, 81.8, 82.2, 122.4,
128.2, 130.1, 131.5, 132.2, 134.7, 166.1 ppm. Anal.
calcd for C10H8O2: C, 74.99; H, 5.03. Found: C, 74.89; H,
4.98.
1
1661, 1473, 1273, 1013, 950, 763, 686 cm21. H NMR
(200 MHz, CDCl3): d 5.23 (1H, d, J¼3.0 Hz, vCH), 5.25
(1H, d, J¼3.0 Hz, vCH), 7.65–7.70 (1H, m, H-arom),
7.69–7.76 (2H, m, H-arom), 7.92 ppm (1H, d, J¼7.2 Hz,
H-arom). 13C NMR (50 MHz, CDCl3): d 91.2, 120.5, 125.0,
125.3, 130.4, 134.4, 138.9, 151.8, 166.8 ppm. These NMR
data were in agreement with those previously reported.42 It
should be noted that compound 28 was also synthesized
in 51% yield by palladium-catalyzed triethylammonium
formate reduction of (Z)-27.
4.2.24. (E)- and (Z)-3-(Iodomethylidene)phthalide [(E)-
and (Z)-27]. To a deaerated solution of 11 (0.500 g,
3.12 mmol) in MeCN (17 ml) was added iodine (2.38 g,
9.36 mmol) and the mixture was stirred in the dark under
nitrogen for 3 h. After this period of time a GLC analysis
showed the presence of two compounds in a ca. 37:63 molar
ratio, which were subsequently identified as (E)- and (Z)-27,
respectively. The reaction mixture was then poured into a
10% aqueous Na2S2O3 solution (30 ml) and extracted with
AcOEt (4£30 ml). The organic extract was washed with
water (10 ml), dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified by MPLC on
silica gel using a mixture of petroleum ether and AcOEt
(90:10) as eluent. Concentration of the first eluted
chromatographic fractions furnished 97% pure (E)-27
(0.33 g, 38% yield) as a light brown solid. Mp 77.5–808C.
MS, m/z(%): 272 (100), 231 (12), 127 (14), 117 (10), 104
(17), 89 (84), 76 (25), 74 (15), 63 (16). IR (KBr): n 1776,
4.2.26. (E)-3-Ethylidenephthalide [(E)-29]. Compound
(E)-27 (0.800 g, 2.94 mmol) was reacted with tetramethyl-
tin (22) (1.22 ml, 8.82 mmol) in NMP (11 ml) at 808C for
5 h in the presence of PdCl2[P(o-Tolyl)3]2 (116 mg,
0.147 mmol) and CuI (56.0 mg, 0.294 mmol). The crude
reaction product, which was obtained after usual workup,
was purified by MPLC on silica gel with a mixture of
petroleum ether and AcOEt (90:10) as eluent to give 97%
pure (E)-29 (0.38 g, 80% yield) as a colorless solid. Mp 57–
598C (lit.43 mp 59–608C). MS, m/z(%): 160 (82), 132 (13),
131 (24), 105 (25), 104 (100), 103 (20), 77 (20), 76 (41), 74
(12). IR (KBr): n 2923, 1773, 1713, 1673, 1403, 1261, 1071,
908, 714 cm21. 1H NMR (200 MHz, CDCl3): d 2.15 (3H, d,
J¼7.8 Hz, Me), 5.91 (1H, q, J¼7.8 Hz, vCH), 7.56 (1H,
pseudo-dt, J¼7.5, 1.2 Hz, H-5 or H-6), 7.73 (1H, pseudo-dt,
J¼7.5, 1.2 Hz, H-5 or H-6), 7.86 (1H, d, J¼7.5 Hz, H-4 or
H-7), 7.93 ppm (1H, d, J¼7.5 Hz, H-7 or H-4). 13C NMR
(50 MHz, CDCl3): d 11.5, 108.0, 123.0, 125.4, 125.6, 129.4,
1
1627, 1467, 1227, 1096, 1018, 785, 766, 686 cm21. H
NMR (300 MHz, CDCl3): d 6.54 (1H, s, vCH), 7.66 (1H,
pseudo-t, J¼7.5 Hz, H-6 or H-5), 7.79 (1H, pseudo-t,
J¼7.5 Hz, H-5 or H-6), 7.93 (1H, d, J¼7.5 Hz, H-4 or H-7),
8.68 ppm (1H, d, J¼7.5 Hz, H-7 or H-4). 13C NMR
(75 MHz, CDCl3): d 57.7, 124.1, 125.7, 126.4, 131.2,
131.4, 137.7, 148.9, 165.4 ppm. Anal. calcd for C9H5IO2: C,
39.74; H, 1.85. Found: C, 39.61; H, 1.72. Concentration of
the last eluted chromatographic fractions furnished pure
1
134.2, 138.2, 146.2, 166.9 ppm. The H NMR data of this
compound were in agreement with those previously
reported.44

2080
R. Rossi et al. / Tetrahedron 59 (2003) 2067–2081
R. F.; Troyanovich, J. J.; Puar, M. S.; Gullo, V. P. J. Ind.
Microbiol. 1989, 4, 209–213.
4.2.27. (Z)-3-(4-Chlorophenyl)methylidenephthalide
[(Z)-31]. The crude reaction mixture, which was obtained
by reaction of (Z)-27 (424 mg, 1.56 mmol) with tributyl-4-
chlorophenyltin (30) (847 mg, 2.11 mmol) in NMP (11 ml)
at 808C for 24 h in the presence of PdCl2(PhCN)2 830 mg,
0.0780 mmol), AsPh3 (47.8 mg, 0.156 mmol) and CuI
(29.7 mg, 0.156 mmol), was poured into a saturated aqueous
NH4Cl solution (60 ml) and extracted with Et2O (7£50 ml).
The organic extract was partially concentrated and the
residue (50 ml) was stirred for 18 h with a 8 M aqueous KF
solution (50 ml) and filtered over Celitew. The solid residue
was washed with AcOEt (5£40 ml). The collected filtrates
were extracted with AcOEt (4£40 ml) and the organic
extract was dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified by MPLC on
silica gel with a mixture of hexane and benzene (50:50) as
eluent to give compound (Z)-31 (234 mg, 59% yield) as a
pale yellow solid. Mp 148–1508C (lit.30 mp 1508C). MS,
m/z(%): 258 (31), 257 (16), 256 (100), 221 (12), 193 (27),
165 (41), 163 (11), 89 (16), 76 (16). IR (KBr): n 1795, 1355,
1268, 1077, 971, 850, 758, 686, 516 cm21 1H NMR
(200 MHz, CDCl3): d 6.34 (1H, s, vCH), 7.31–7.38 (2H,
br d, J¼8.4 Hz, H-arom), 7.50–7.58 (1H, m, H-4), 7.69–
7.80 (4H, m, H-arom), 7.91 ppm (1H, br d, J¼7.6 Hz, H-7).
13C NMR (50 MHz, CDCl3): d 105.6, 119.3, 123.2, 125.5,
128.8 (2C), 129.9, 131.1 (2C), 131.5, 134.0, 134.5, 140.2,
144.8, 166.6 ppm. The 1H NMR data of this compound were
in agreement with those previously reported.30
9. Umehara, K.; Matsumoto, M.; Nakamura, M.; Miyase, T.;
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Acknowledgements
This work was supported by the Ministero dell’Istruzione,
`
dell’Universita e della Ricerca (MIUR) and the University
1
´
of Pisa. We thank Dr Stephane Viel for obtaining the H
NMR spectra at 600 MHz and the 13C NMR spectra at
150 MHz and Professor Annalaura Segre for the use of
NMR facilities of the Servizio NMR dell’Area della Ricerca
di Roma (CNR). We are also grateful to Mr Piergiorgio
Vergamini for recording IR spectra.
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´
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