Regioselective synthesis of natural and unnatural (Z)-3-(1- alkylidene)phthalides and 3-substituted isocoumarins starting from methyl 2- hydroxybenzoates

Article abstract of DOI:10.1016/S0040-4020(00)00125-3

(Z)-3-(1-Alkylidene)phthalides and 3-substituted isocoumarins, which include compounds bearing a substituent on their benzene ring, have been selectively and efficiently synthesized by a new protocol which involves: (i) the conversion of methyl 2-hydroxybenzoates into the corresponding nonaflates; (ii) Pd-catalyzed alkynylation reactions of these derivatives; (iii) the conversion of the so obtained methyl 2-(1-alkynyl)benzoates into the corresponding carboxylic acids followed by a transition metal-catalyzed heteroannulation reaction. This procedure has been used to prepare either natural products such as senkyunolide B, senkyunolide C, 3-propylisocoumarin and artemidin, or the MEM-ether of senkyunolide E. The regioselectivity of the transition metal-catalyzed cyclization reactions of 2-(1-alkynyl)benzoic acids has proven to be affected either by the catalyst used or the type of 1- alkynyl group present in these carboxylic acids. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00125-3

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 2533–2545
Regioselective Synthesis of Natural and Unnatural
(Z)-3-(1-Alkylidene)phthalides and 3-Substituted Isocoumarins
Starting from Methyl 2-Hydroxybenzoates
*
Fabio Bellina, Donatella Ciucci, Piergiorgio Vergamini and Renzo Rossi
Dipartimento di Chimica e Chimica Industriale, University of Pisa, Via Risorgimento 35, I-56126 Pisa, Italy
Received 10 December 1999; revised 24 January 2000; accepted 10 February 2000
Abstract—(Z)-3-(1-Alkylidene)phthalides and 3-substituted isocoumarins, which include compounds bearing a substituent on their benzene
ring, have been selectively and efficiently synthesized by a new protocol which involves: (i) the conversion of methyl 2-hydroxybenzoates
into the corresponding nonaflates; (ii) Pd-catalyzed alkynylation reactions of these derivatives; (iii) the conversion of the so obtained methyl
2-(1-alkynyl)benzoates into the corresponding carboxylic acids followed by a transition metal-catalyzed heteroannulation reaction. This
procedure has been used to prepare either natural products such as senkyunolide B, senkyunolide C, 3-propylisocoumarin and artemidin, or
the MEM-ether of senkyunolide E. The regioselectivity of the transition metal-catalyzed cyclization reactions of 2-(1-alkynyl)benzoic acids
has proven to be affected either by the catalyst used or the type of 1-alkynyl group present in these carboxylic acids. ᭧ 2000 Elsevier Science
Ltd. All rights reserved.
Introduction
displayed by 3-substituted isocoumarins of general formula
2, which correspond to regioisomers of compounds 1.5,6
Thus, a number of methods have been reported for the
synthesis either of compounds 17,8 or 2.9
(Z)-3-(1-Alkylidene)phthalides 1 represent an important
class of naturally occurring lactones,1 which are character-
ized by interesting biological properties. In fact, compounds
1, which have been isolated from the rhizome of Cnidium
species or Ligusticum wallichi, commonly known as
Senkyu in Japan, are used in the treatment of anemia and
women’s disease,2 as cardiokinetics, antistenocardiacs, anti-
arrhytmics, vasodilators and coronary artery dilators.3
Moreover, antispasmodic activity has been observed for a
series of synthetic compounds of general formula 1.4 A wide
range of biological and pharmacological activities are also
Scheme 1.
Keywords: cross-coupling reactions; heteroannulation reactions; regioselectivity; transition metal catalysts.
* Corresponding author. Tel.: ϩ39-050-918275; fax: ϩ39-050-918260; e-mail: bellina@dcci.unipi.it
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00125-3

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F. Bellina et al. / Tetrahedron 56 (2000) 2533–2545
Recently, much attention has been particularly directed to
the selective synthesis of 3-ylidenephthalides and 3-substi-
tuted isocoumarins, which do not contain a substituent on
their benzene ring, by transition metal-catalyzed hetero-
annulation reactions.7d,7f,9d,9e In particular, it has been
found that (Z)-3-(1-alkylidene)-phthalides 5 and 3-substi-
tuted isocoumarins 6 can be obtained as major and minor
products, respectively, either by reaction of 2-iodobenzoic
acid (3) with 1-alkynes (4) in the presence of a base and
catalytic quantities of Pd(PPh3)4 and CuI7f or by cyclization
of 2-(1-alkynyl)benzoic acids 7 in DMF solution in the
presence of catalytic amounts of AgI or Ag7d (Scheme 1).
(Z)-3-ylidenephthalides 1 and their structural analogues.
The protocol which we used to prepare these compounds
involved: (i) the conversion of commercially available and
cheap methyl 2-hydroxybenzoates 8 into the corresponding
nonaflates 9; (ii) Pd-catalyzed alkynylation reactions of
compounds 9; (iii) the conversion of the so obtained methyl
2-(1-alkynyl)benzoates 10 into the corresponding
carboxylic acids 11 followed by selective 5-exo-dig or
6-endo-dig cyclization of these last compounds in the
presence of catalytic amounts of Ag powder or AgNO3,
respectively.
However, these transition metal-catalyzed reactions have
not been used so far to prepare naturally-occurring (Z)-3-
(1-alkylidene)phthalides save (Z)-3-(1-butylidene)phthalide
(1a),7d a substance which has been isolated from Levisticum
officinale1a and Apium graveolens dulce.10
In this paper we wish to describe in detail these synthetic
studies which allowed us to prepare selectively compounds
1a–h and 2a–e. These substances include some natural
products, i.e. senkyunolide B (1g),1c senkyunolide C
(1h),1e senkyunolide E (1e),1c 3-propylisocoumarin (2a)5c
and artemidin (2d).5b Moreover, we will show that the
regioselectivity of the heteroannulation reactions of
carboxylic acids 11a–d and 11f is strongly affected either
by the catalyst used for these reactions, i.e. AgNO3 or Ag
powder, or the type of 1-alkynyl group present in these
compounds.
It has also been reported that isocoumarins of general
formula 6 can be obtained as major products by treatment
of 3 with 1-alkynes 4 in the presence of Pd(PPh3)4, Et3N and
ZnCl2 in DMF,9e by reaction of 2-(1-alkynyl)benzoic acids 7
with Et3N and catalytic amounts of PdCl2(CH3CN)2,9f by
cyclization of compounds 7 in the presence of a mineral
acid11 as well as by CuI-catalyzed cyclization of these
carboxylic acids prepared in situ from 3 and 1-alkynyl-
copper compounds.9b However, to the best of our knowl-
edge, no catalytic method has been used so far to prepare
3-substituted isocoumarins of general formula 2 bearing a
substituent on their benzene ring.
Finally, we will report that, whereas saponification of
compounds 10, which have been prepared by Pd-catalyzed
reaction of nonaflates 9 with 1-alkynylzinc halides or a
1-alkynylstannane, followed by acidification, affords the
desired carboxylic acids 11, an analogous reaction sequence
involving compounds 10, which have been prepared by
treatment of 9 with 1-alkynes 4 in the presence of catalytic
amounts of Pd(PPh3)4 and CuI, provides heteroannulation
products which consist of 3-substituted isocoumarins 2 or
mixtures of 2 and the corresponding compounds 1.
In the context of our studies on the transition metal-
catalyzed synthesis of unsaturated lactones,12 recently we
developed a general procedure for the regioselective
synthesis either of natural and unnatural 3-substituted
isocoumarins 2 or direct precursors to naturally-occurring
Results and Discussion
Commercially available methyl 2-hydroxybenzoates 8a–c,
which we used as starting materials for the synthesis of
carboxylic acids of general formula 11, were converted in

F. Bellina et al. / Tetrahedron 56 (2000) 2533–2545
2535
Scheme 2.
quantitative yield into the corresponding crude nonaflates
9a–c by reaction with 1.5 equiv. of NaH in DMF at 0ЊC
followed by treatment with 1.5 equiv. of perfluoro-1-
butanesulfonyl fluoride at 0ЊC for 1.5 h and at room
temperature for 3 h. So prepared crude compounds 9a–c,
which had chemical purity higher than 96%, were then
converted into methyl 2-(1-alkynyl)benzoates of general
formula 10 using three different procedures. The first of
these (Procedure A), which involved the cross-coupling
reaction between 1-alkynylzinc halides 12a,f and
compounds 9a–c in THF at 65ЊC in the presence of catalytic
amounts of Pd(dba)2 and 1,10-bis(diphenylphosphino)ferro-
cene (dppf), gave compounds 10a, 10b, 10c and 10f in 65,
90, 84 and 52% yield, respectively (Scheme 2).
in the presence of Et3N and catalytic amounts of Pd(PPh3)4
and CuI. Compounds 10a and 10e were so prepared in 75
and 84% yield starting from 1-pentyne (4a) and 1-pentyn-3-ol
(4e), respectively, and 9a (Scheme 3).
It must be noted that, despite their efficiency, above
mentioned Procedures A and B did not appear suitable to
prepare methyl (E)-2-(3-hexen-1-ynyl)benzoate (10d),
which, according to our retrosynthetic analysis, was a
precursor to artemidin (2d). In fact, these procedures
required the use of (E)-3-hexen-1-yne (4d), which is a
previously unreported substance for which an efficient
synthesis seemed difficult owing to its volatility.
1-Pentynylzinc chloride (12a) was prepared by treatment of
1-pentyne (4a) with 1 equiv of ethylmagnesium bromide in
THF at 50ЊC followed by transmetallation of the resulting
1-pentynylmagnesium bromide with 1.3 equiv. of dry ZnCl2
in THF at 0ЊC. 3-(2-Methoxyethoxymethoxy)-1-pentynyl-
zinc bromide (12f) was prepared by treatment of the corre-
sponding 1-alkyne, 4f, with 1 equiv. of butyllithium in THF
at Ϫ78ЊC followed by transmetallation of the resulting
1-alkynyllithium with 1.2 equiv. of dry ZnBr2 in THF. On
the other hand, compound 4f was prepared by reaction of
commercially available 1-pentyn-3-ol (4e) with 1.5 equiv.
of MEM-chloride and 1.5 equiv. of EtN(i-Pr)2 in CH2Cl2 at
room temperature.
Thus, we prepared compound 10d by Pd-catalyzed cross-
coupling reaction between 9a and (E)-1-tributylstannyl-3-
hexen-1-yne (16) (Procedure C), which was stereo-
selectively and efficiently synthesized in two steps starting
from (E)/(Z)-1-bromo-1-butene (13) (Scheme 4).
According to a general procedure for the stereoselective
synthesis of (E)-1-trimethylsilyl-3-en-1-ynes,13 trimethyl-
silylethynylzinc chloride (14) was reacted with a molar
excess of 13 (E/Zˆ62/38) in THF at room temperature to
give chemically and stereoisomerically pure (E)-1-
trimethylsilyl-3-hexen-1-yne (15) in 66% yield. Using a
catalytic method for the direct conversion of 1-alkynyl-
The second procedure for the synthesis of compounds 10
(Procedure B) involved the cross-coupling reaction of
nonaflate 9a with a 1-alkyne 4 in DMF at room temperature
silanes into the corresponding 1-tributylstannanes,1g,12f,14
mixture of 0.46 equiv. of bis(tributyltin)oxide and 1 equiv.
a
Scheme 3.
Scheme 4.

2536
F. Bellina et al. / Tetrahedron 56 (2000) 2533–2545
Scheme 5.
of 15 in dry THF was treated with a catalytic amount of
tetrabutylammonium fluoride (TBAF) and the resulting
mixture was heated to 65ЊC for 2.5 h. The volatiles, i.e.
THF, the molar excess of 15 and bis(trimethylsilyl)oxide,
which was formed in the reaction, were removed in vacuo to
give in 94% yield the required organotin derivative 16
having chemical purity higher than 97%. Finally, treatment
of 9a with 1.2 equiv. of 16 in DMF at 60ЊC in the presence
of 4 equiv. of LiCl and catalytic amounts of Pd(dba)2 and
dppf provided compound 10d in 41% yield.
nification followed by acidification of methyl 2-(1-alkynyl)-
benzoates 10, which had been prepared by reaction of
methyl 2-halobenzoates with 1-alkynes in the presence of
Et3N and catalytic amounts of PdCl2(PPh3)2 and CuI.11
A
reasonable rationalization for these results could be that (i)
traces of Cu(I) salts contaminate either compounds 10
prepared by these alkynylation reactions or the correspond-
ing carboxylic acids 11 and that (ii) these Cu(I) salts
promote the 6-endo-dig and/or the 5-exo-dig cyclization of
compounds 11. On the other hand, it has been reported that
2-(1-alkynyl)benzoic acids, which are prepared in situ from
2-iodobenzoic acid (3) and 1-alkynylcopper compounds
undergo CuI-catalyzed cyclization to give 3-substituted
isocoumarins 6 or mixtures of 6 and the corresponding 3-
ylidenephthalides 5.7f
Methanol solutions of 10a, which was prepared according to
Procedure A, and compounds 10b, 10c, 10d and 10f were
then reacted with 5 equiv. of an aqueous 2.29 M LiOH solu-
tion at 5ЊC and the resulting lithium carboxylates were trea-
ted at 0ЊC with 10% H2SO4 to give the corresponding
carboxylic acids, i.e. 11a, 11b, 11c, 11d and 11f, respec-
tively, in quantitative yield (Scheme 5).
We next examined the synthesis of some natural and un-
natural isocoumarins, i.e. compounds 2a–d, and some direct
precursors to natural (Z)-3-(1-alkylidene)phthalides, i.e.
compounds 1b, 1c and 1f, by transition metal-catalyzed
heteroannulation reactions of the carboxylic acids which
had been prepared according to Procedures A and C, i.e.
compounds 11a–d and 11f. As shown in Table 1, these
heteroannulation reactions were performed in acetone at
room temperature in the presence of 20 mol% AgNO3
(entries 1, 2, 6 and 9), or in DMF at 60ЊC in the presence
of 10 mol% Ag powder (entries 4, 5, 7 and 8). On the other
hand, compound 11b proved also to be able to undergo
heterocyclization in toluene solution at 110ЊC in the
presence of 5 mol% trans-di(m-acetato)bis[(di-o-tolylphos-
phino)benzyl]dipalladium(II).15 The AgNO3-catalyzed
However, it was found that under these experimental
conditions methyl ester 10a, which had been prepared by
Procedure B, was unexpectedly converted into 3-propyl-
isocoumarin (2a) in 97% yield (Scheme 6).
Moreover, saponification of 10e, which was prepared by
Procedure B, followed by acidification produced a mixture
of senkyunolide E (1e) and 3-(1-hydroxypropyl)isocou-
marin (2e) in a ca. 55:45 ratio, respectively (Scheme 7).
It must be noted that these unexpected results parallel those
which regard the formation of compounds 1 and 2 by sapo-
Scheme 6.
Scheme 7.

Table 1. Transition metal-catalyzed heteroannulation of 2-(1-alkynyl)benzoic acids 11
Entry
Reagent
R1
Catalyst (mol%)
Solvent
Reaction conditions (h/ЊC)
Products
11
R2
1ϩ2
1/2 molar ratio
Yield (%)a,b
1
2
3
4
5
6
7
8
9
11a
11b
11b
11b
11b
11c
11c
11f
C3H7
C3H7
C3H7
C3H7
C3H7
C3H7
C3H7
H
AgNO3 (20)
AgNO3 (20)
Palladacycled (5)
Ag (10)
Ag (10)
AgNO3 (20)
Ag (10)
Acetone
24/20
24/20
6/110
48/60
15/50
24/20
48/60
48/60
24/20
1aϩ2a
1bϩ2b
1bϩ2be
1bϩ2b
1bϩ2b
1cϩ2c
1cϩ2c
1fϩ2f
6/94
6/94
88c
83
3-MeO
3-MeO
3-MeO
3-MeO
4-MeO
4-MeO
H
Acetone
Toluene
DMF
DMFϩEt3N (3 equiv.)
Acetone
DMF
8/80e
(Ͼ98)
71/29
34/66
3/97
86/14
Ͼ99/Ͻ1
72/28
63f
(Ͼ98)
81
54g
C2H5CH(OMEM)
(E)-C2H5-CHvCH–
Ag (10)
AgNO3 (20)
DMF
Acetone
94
11d
H
1dϩ2d
51h
a Isolated yields of the major products of the reaction mixtures.
b Values in parenthesis are referred to GLC conversions.
c Compound 1a was isolated in 5% yield.
d This palladacycle was trans-di(m-acetate)-bis[di-o-tolilphosphino)benzyl]dipalladium.
e The reaction mixture contained a third component which presumably corresponded to the (E)-stereoisomer of 1b.
f Compound 2b was isolated in 19% yield.
g Compound 2c was isolated in 11% yield.
h Compound 2d was isolated in 23% yield.

2538
F. Bellina et al. / Tetrahedron 56 (2000) 2533–2545
reactions involving 11a, 11b and 11c (entries 1, 2 and 6,
Table 1) gave reaction mixtures in which the 3-substituted
isocoumarins 2a, 2b and 2c, respectively, were the major
products and the stereoisomerically pure (Z)-3-(1-alkylide-
ne)phthalides 1a, 1b and 1c, respectively, were the minor
products. Purification of these mixtures by MPLC on silica
gel allowed isolation of naturally-occurring 2a, 2b and 2c in
88, 83 and 81% yield, respectively. Interestingly, a reaction
mixture in which 2b was the major component and 1b the
minor component was also obtained by Pd-catalyzed hetero-
annulation of 11b (entry 3, Table 1). However, this reaction
mixture contained a third component which presumably
corresponded to the (E)-stereoisomer of 1b.
Scheme 8.
It was also observed that the regioselectivity of the AgNO3-
catalyzed heteroannulation reactions of compounds 11 was
affected by the type of 1-alkynyl moieties present in these
acids. In fact, in an attempt to synthesize regioselectively
artemidin (2d), which is an isocoumarin isolated from
Anthemis fuscata,5b by AgNO3-catalyzed lactonization of
11d, a reaction mixture was obtained in which the major
component was stereoisomerically pure (Z)-3-{1-[(E)-pent-
2-enylidene]}phthalide (1d) and the minor component was
2d (entry 9, Table 1). Purification of this mixture by MPLC
on silica gel allowed isolation of 1d and 2d in 51 and 23%
yield, respectively.
Scheme 9.
molar excess of a cold saturated aqueous NaHCO3 solution
provided a complex reaction mixture in which 1f was absent
but compound 1e was the minor product. Interestingly, a
GLC/MS analysis of this crude reaction mixture showed
that, similarly to 1e, two other reaction products had a
prominent peak at M-18.
As shown in Table 1, the regioselectivity of the AgNO3-
catalyzed ring closure reactions of 11b, 11c and 11f was
reversed when the cyclization reactions were catalyzed by
Ag powder and were performed in DMF at 60ЊC. In fact,
these last reactions (entries 4, 7 and 8, Table 1) provided
reaction mixtures in which the (Z)-3-(1-alkylidene)-
phthalides were the major products and the corresponding
3-substituted isocoumarins were the minor products. These
results were in agreement with those previously reported for
the heteroannulation of 11a.7d However, it was observed
that the presence of a base could affect the regioselectivity.
In fact, the reaction mixture, which was obtained by
cyclization of 11b in DMF in the presence of 3 equiv. of
Et3N and a catalytic quantity of Ag powder, proved to be
constituted of a mixture of 1b and 2b in which this last
compound was the major component (entry 5, Table 1). It
is also worth mentioning that the Ag-catalyzed hetero-
annulation reaction of 11f proved to be much more regio-
selective than the corresponding reactions involving 11b
and 11c. In fact, the reaction involving 11f gave 1f, which
was the sole product identified in the crude reaction mixture
(entry 8, Table 1).
Moreover, reaction of 1f with 5 equiv. of ZnBr2 in CH2Cl2
for 6 h at room temperature17 followed by hydrolysis with a
saturated aqueous NaHCO3 solution afforded a reaction
mixture which contained a compound different from 1e as
the sole reaction product. This unidentified compound was
fast running on silica gel chromatography and had a GLC
retention time higher than that of 1e.
In conclusion, we devised a convenient protocol for the
synthesis of 2-(1-alkynyl)benzoic acids 11 and we
employed the AgNO3-catalyzed cyclization reaction of
these carboxylic acids to prepare some 3-substituted iso-
coumarins of general formula 2, which include naturally-
occurring 3-propylisocoumarin (2a) and artemidin (2d). On
the other hand, by Ag powder-catalyzed heteroannulation
reaction of compounds 11 we prepared some precursors to
naturally-occurring (Z)-3-(1-alkylidene)phthalides 1. Finally,
two of these precursors, i.e. compounds 1b and 1c, were
converted to naturally-occurring senkyunolide B (1g) and
senkyunolide C (1h), respectively.
Finally, in order to prepare naturally-occurring senkyun-
olide B (1g), senkyunolide C (1h) and senkyunolide E (1e),
we examined the selective deprotection of the protected
hydroxy group present in compounds 1b, 1c and 1f, respec-
tively. Thus, it was found that demethylation of 1b and 1c
with 2.1–2.5 equiv. of boron tribromide in CH2Cl2 at room
temperature according to a general procedure16 provided 1g
and 1h in 86 and 57% yield, respectively (Schemes 8 and 9).
Experimental
All boiling and melting points are uncorrected. Precoated
Merck 60 F254 plastic 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 data station 86.01. Two types of capillary columns
were used: an Alltech AT-1 bonded FSOT column
Unfortunately, attempts to convert 1f into 1e by protocols
reported in the literature for deprotection of MEM-ethers17
were fruitless. In fact, treatment of 1f with 5 equiv. of TiCl4
in CH2Cl2 at 0ЊC for 20 min followed by addition of a large

F. Bellina et al. / Tetrahedron 56 (2000) 2533–2545
2539
(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 were
performed on a Bu¨chi instrument, using a Bischoff 8100
differential refractometer as detector. GLC/MS analyses
were performed using a Q-mass 910 spectrometer interfaced
was purified by MPLC on silica gel, using a mixture of
toluene and hexane (80:20) as eluant, to give in 70% yield
chemically pure 9b as a colourless liquid. MS, m/z (%): 464
(4), 181 (100), 149 (62), 122 (19), 107 (33), 95 (10),j 69
(43). IR (film): n 1734, 1480, 1426, 1203, 1145, 1064,
1
1
with a Perkin–Elmer 8500 gas-chromatograph. H NMR
763 cmϪ1. H NMR (200 MHz, CDCl3): d 7.50 (1H, d,
spectra were recorded on a Varian Gemini 200 MHz
spectrometer or a Bruker AMX 600 spectrometer using
TMS and CDCl3 as an internal standard, respectively. 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 an
atmosphere of argon or nitrogen. Air and water sensitive
solutions were transferred with hypodermic syringes or
double ended needles. Solvents were dried and distilled
before use. (E)/(Z)-1-Bromo-1-butene (13) (E/Zˆ62/38;
bp 90–92ЊC) was prepared starting from 1,2-dibromobutane
according to a previously reported procedure.18 Pd(dba)2,
1,10-bis(diphenylphosphino)ferrocene (dppf) and bis(tributyl-
tin)oxide were commercially available. Pd(PPh3)4 was
prepared according to the literature.19
Jˆ7.9 Hz, Harom), 7.38 (1H, t, Jˆ8.0 Hz, Harom), 7.20 (1H,
d, Jˆ8.0 Hz, Harom), 3.94 (3H, s, OMe), 3.92 ppm (3H, s,
OMe). Anal. Calcd for C13F9H9O6S: C, 33.63; H, 1.95.
Found: C, 33.94; H, 1.98.
Methyl 4-methoxy-2-(perfluoro-1-butanesulfonyloxy)-
benzoate (9c). This crude product, which was prepared in
quantitative yield starting from methyl 2-hydroxy-4-
methoxybenzoate (8c) according to the above mentioned
procedure, had: mp 55–60ЊC. MS, m/z (%): 464 (20), 433
1
(10), 369 (9), 153 (27), 125 (11), 107 (10), 51 (100). H
NMR (200 MHz, CDCl3): d 8.06 (1H, d, Jˆ8.8 Hz,
Harom), 6.95 (1H, dd, Jˆ8.8 and 2.4 Hz, Harom), 6.80 (1H,
br s, Harom), 3.93 (3H, s, OMe), 3.88 ppm (3H, s, OMe). This
crude product was used in the next step without any further
purification and characterization.
General procedure for the synthesis of methyl 2-(per-
fluoro-1-butanesulfonyloxy)benzoates 9
General procedure for the Pd-catalyzed cross-coupling
reactions between 1-pentynylzinc chloride (12a) and the
aryl nonaflates 9
A dispersion of NaH (60%, 4.50 g, 112.5 mmol) in mineral
oil was washed with pentane and the residue was diluted
with DMF (220 ml). To the resulting suspension, which was
stirred at 0ЊC, was added dropwise a solution of a methyl
2-hydroxybenzoate 8 (75.0 mmol) in DMF (40 ml) and the
mixture was stirred for 0.5 h at 0ЊC and for 1.5 h at room
temperature. To the resulting reaction mixture, which was
maintained under stirring at 0ЊC, was then added dropwise
perfluoro-1-butanesulfonyl fluoride (26.05 g, 86.25 mmol)
and the mixture was stirred at 0ЊC for 1.0 h and then at
room temperature for 2 h. After this period a GLC analysis
of a sample of the reaction mixture, which was hydrolyzed
with a saturated aqueous NH4Cl solution and extracted with
Et2O showed that the reaction was complete. Thus, the
reaction mixture was poured into a large excess of a cold
saturated aqueous NH4Cl solution and extracted repeatedly
with Et2O (4×100 ml). The collected organic extracts were
washed with water, dried and concentrated in vacuo to give
in quantitative yield crude compounds 9 which had chemi-
cal purity higher than 96%. Compounds 9a, 9b and 9c were
prepared according to this procedure.
A slurry of 1-pentynylzinc chloride (12a) in THF was
prepared by addition of a 0.64 M THF solution of the
corresponding Grignard reagent (50.7 ml, 32.45 mmol) to
a solution of dry ZnCl2 (5.74 g, 42.14 mmol) in THF
(120 ml), which was stirred at 0ЊC. After stirring the
reaction mixture for additional 30 min, Pd(dba)2 (0.25 g,
0.43 mmol), dppf (0.24 g, 0.43 mmol) and a solution of a
crude methyl 2-(perfluoro-1-butanesulfonyloxy)benzoate 9
(21.61 mmol) in THF (30 ml) were sequentially added. The
resulting mixture was allowed to warm up to room tempera-
ture and then heated to 65ЊC for 5 h. After usual workup the
crude reaction product was diluted with the solvent which
was subsequently used for its purification by MPLC on
silica gel and filtered over Celite. The filtrate was concen-
trated in vacuo and the residue was purified by MPLC on
silica gel. Compounds 10a, 10b and 10c were prepared
according to this procedure.
Methyl 2-(1-pentynyl)benzoate (10a). The crude reaction
product, which was obtained from the Pd-catalyzed reaction
between 12a and methyl 2-(perfluoro-1-butanesulfonyloxy)-
benzoate (9a) according to the above mentioned procedure,
was purified by MPLC on silica gel, using a mixture of
toluene and petroleum ether (70:30) as eluant, to give in
65% yield chemically pure 10a as a colourless liquid. MS,
m/z (%): 187 (7), 174 (100), 159 (23), 143 (28), 115 (44), 91
(17), 75 (15). IR (film): n 1734, 1718, 1296, 1251, 1130,
Methyl 2-(perfluoro-1-butanesulfonyloxy)benzoate (9a).
The crude product, which was obtained in quantitative yield
starting from methyl 2-hydroxybenzoate (8a) according to
the above mentioned procedure, had: mp 41–45ЊC. MS, m/z
(%): 434 (6), 339 (33), 151 (16), 135 (33), 123 (65), 95 (90),
1
69 (100). H NMR (200 MHz, CDCl3): d 8.10 (1H, dd,
Jˆ7.7 and 1.7 Hz, Harom), 7.64 (1H, dt, Jˆ7.8 and 1.2 Hz,
Harom), 7.48 (1H, pseudo-t, Jˆ7.1 Hz, Harom), 7.30 (1H, t,
Jˆ7.8 Hz, Harom), 3.97 ppm (3H, s, OMe). This crude
compound was used in the next step without any further
purification and characterization.
1
1085, 759 cmϪ1. H NMR (200 MHz, CDCl3): d 7.88 (1H,
d, Jˆ7.6 Hz, Harom), 7.53–7.27 (3H, m, Harom), 3.91 (3H, s,
OMe), 2.46 (2H, t, Jˆ7.3 Hz, H-30), 1.67 (2H, sext,
Jˆ7.3 Hz, H-40), 1.07 ppm (3H, t, Jˆ7.3 Hz, H-50). Anal.
Calcd for C13H14O2: C, 77.20; H, 6.98. Found: C, 77.06; H,
6.69.
Methyl 3-methoxy-2-(perfluoro-1-butanesulfonyloxy)-
benzoate (9b). Crude compound 9b, which was obtained
in quantitative yield from methyl 2-hydroxy-3-methoxy-
benzoate (8b) according to the above mentioned procedure,
Methyl 3-methoxy-2-(1-pentynyl)benzoate (10b). The
crude reaction product, which was obtained from the

2540
F. Bellina et al. / Tetrahedron 56 (2000) 2533–2545
Pd-catalyzed reaction between 12a and methyl 3-methoxy-
2-(perfluoro-1-butanesulfonyloxy)benzoate (9b) according
to the above mentioned procedure, was purified by MPLC
on silica gel using toluene as eluant, to give in 90% yield
chemically pure 10b as a pale yellow liquid. MS, m/z (%):
232 (20), 217 (26), 204 (67), 189 (51), 143 (31), 115 (100),
75 (81). IR (film): n 1732, 1468, 1434, 1306, 1269, 1061,
warm up to 0ЊC within 1.5 h and then it was cooled to
Ϫ78ЊC. A solution of dry ZnBr2 (9.57 g, 42.50 mmol) in
THF (50 ml), which was cooled to Ϫ20ЊC, was then
added and the mixture was allowed to warm up to 10ЊC
within 2 h. It was then cooled to 0ЊC and Pd(dba)2 (0.31 g,
0.54 mmol), dppf (0.30 g, 0.54 mmol) and a solution of 9a
(11.83 g, 27.24 mmol) in THF (35 ml) were sequentially
added. The resulting mixture was allowed to warm up to
room temperature and then it was maintained under reflux
for 17 h. After this period the reaction mixture was cooled to
room temperature, poured into a large excess of a saturated
aqueous NH4Cl solution and extracted repeatedly with Et2O
(3×100 ml). The collected organic extracts were washed
with water, dried and concentrated in vacuo. The residue
was purified by MPLC on silica gel, using a mixture of
toluene and AcOEt (90:10) as eluant, to give 10f (4.32 g,
52% yield) as a colourless liquid. MS, m/z (%): 276 (1), 217
(28), 201 (15), 187 (15), 89 (13), 59 (100). IR (film): n 1732,
1
758 cmϪ1. H NMR (200 MHz, CDCl3): d 7.41 (1H, d,
Jˆ7.7 Hz, Harom), 7.26 (1H, t, Jˆ8.0 Hz, Harom), 7.00 (1H,
d, Jˆ8.0 Hz, Harom), 3.90 (3H, s, OMe), 3.89 (3H, s, OMe),
2.52 (2H, t, Jˆ7.0 Hz, H-30), 1.68 (2H, sext, Jˆ7.0 Hz,
H-40), 1.09 ppm (3H, t, Jˆ7.0 Hz, H-50). Anal. Calcd for
C14H16O3: C, 72.39; H, 6.94. Found: C, 72.78; H, 7.21.
Methyl 4-methoxy-2-(1-pentynyl)benzoate (10c). The
crude reaction product, which was obtained from the
Pd-catalyzed reaction between 12a and methyl 4-methoxy-
2-(perfluoro-1-butanesulfonyloxy)benzoate (9c) according to
the above mentioned general procedure, was purified by
MPLC on silica gel, using a mixture of hexane and
CH2Cl2 (50:50) as eluant, to give in 84% yield chemically
pure 10c as a pale yellow liquid. MS, m/z (%): 232 (1), 204
(100), 173 (22), 161 (31), 115 (21), 101 (16), 75 (21). IR
1295, 1256, 1129, 1110, 1083, 1033 cmϪ1 1H NMR
.
(200 MHz, CDCl3): d 7.92 (1H, dd, Jˆ7.7 and 1.8 Hz,
Harom), 7.56–7.32 (3H, m, Harom), 5.18 (1H, d, Jˆ7.0 Hz,
H-100), 4.80 (1H, d, Jˆ7.0 Hz, H-100), 4.61 (1H, t, Jˆ6.4 Hz,
H-30), 3.91 (3H, s, COOMe), 3.87–3.56 (4H, m, H-200 and
H-300), 3.40 (3H, s, H-400), 1.94–1.80 (2H, m, H-40),
1.11 ppm (3H, t, Jˆ7.3 Hz, H-50). Anal. Calcd for
C17H22O5: C, 66.65; H, 7.24. Found: C, 66.87; H, 7.51. A
GLC analysis showed that 10f had chemical purity higher
than 98%.
(film): n 1729, 1712, 1601, 1286, 1263, 1210, 1136 cmϪ1
.
1H NMR (200 MHz, CDCl3): d 7.89 (1H, d, Jˆ8.8 Hz,
Harom), 7.00 (1H, d, Jˆ2.5 Hz, Harom), 6.82 (1H, dd, Jˆ8.8
and 2.5 Hz, Harom), 3.88 (3H, s, OMe), 3.83 (3H, s, OMe),
2.47 (2H, t, Jˆ7.0 Hz, H-30), 1.67 (2H, sext, Jˆ7.3 Hz,
H-40), 1.08 ppm (3H, t, Jˆ7.3 Hz, H-50). Anal. Calcd for
C14H16O3: C, 72.39; H, 6.94. Found: C, 72.55; H, 7.05.
3-(2-Methoxyethoxymethoxy)-1-pentyne (4f). A solution
of 2-methoxyethoxymethyl chloride (9.99 g, 80.24 mmol)
in CH2Cl2 (50 ml) was added dropwise to a solution of
1-pentyn-3-ol (4e) (4.50 g, 53.49 mmol) and EtN(i-Pr)2
(10.37 g, 80.24 mmol) in CH2Cl2 (50 ml) which was stirred
under nitrogen at room temperature. The resulting mixture
was stirred for 3 h at room temperature, poured into a large
excess of 5% HCl and extracted repeatedly with Et2O. The
collected organic extracts were washed with a saturated
aqueous NaHCO3 solution and water, dried and concen-
trated under reduced pressure. The residue was fractionally
distilled to give 4f (6.60 g, 72% yield) as a colourless liquid.
bp 93–94ЊC/15 Torr. MS, m/z (%): 113 (2), 105 (4), 89 (28),
Pd(0)/Cu(I)-catalyzed cross-coupling reaction of methyl
2-(perfluoro-1-butanesulfonyloxy)benzoate (9a) with
1-alkynes 4
To a suspension of Pd(PPh3)4 (1.73 g, 1.50 mmol) and
compound 9a (6.51 g, 15.0 mmol) in deareated dry DMF
(60 ml), which was stirred under argon, were sequentially
added a 1-alkyne 4 (22.5 mmol), Et3N (4.18 ml, 30.0 mmol)
and CuI (0.57 g, 3.0 mmol) and the resulting reaction
mixture was stirred at room temperature for 24 h. It was
then poured into a large excess of a saturated aqueous
NH4Cl solution and the resulting mixture, which was stirred
in the air for 0.5 h, was extracted repeatedly with Et2O
(4×50 ml). The collected organic extracts were washed
with water, dried and concentrated in vacuo. The residue
was diluted with the solvent which was subsequently used
for its purification by MPLC on silica gel and filtered over
Celite. The filtrate was concentrated in vacuo and the
residue was purified by MPLC on silica gel. This procedure
was employed to prepare compound 10a and methyl 2-(3-
hydroxy-1-pentynyl)benzoate (10e) in 75 and 84% yield,
respectively. The spectral properties of 10a were in good
agreement with those of the compound which was prepared
by Pd-catalyzed cross-coupling reaction between 9a and
12a.
1
73 (13), 67 (34), 65 (11), 59 (100). H NMR (200 MHz,
CDCl3): d 5.02 (1H, d, Jˆ7.1 Hz, H-10), 4.73 (1H, d,
Jˆ7.1 Hz, H-10), 4.32 (1H, dt, Jˆ6.4 and 2.2 Hz, H-3),
3.76–3.54 (4H, m, H-20 and H-30), 3.40 (3H, s, H-4), 2.41
(1H, d, Jˆ2.2 Hz, H-1), 1.85–1.65 (2H, m, H-4), 1.03 ppm
(3H, t, Jˆ7.3 Hz, H-5). Anal. Calcd for C9H16O3: C, 62.77;
H, 9.36. Found: C, 62.91; H, 9.71.
Methyl
2-[3-(2-methoxyethoxymethoxy)-1-pentynyl]-
benzoate (10f). A 1.91 M hexane solution of butyllithium
(18.6 ml, 35.50 mmol) was added dropwise to a solution of
3-(2-methoxyethoxymethoxy)-1-pentyne (4f) (6.10 g,
35.42 mmol) in THF (100 ml) which was stirred under
argon at Ϫ78ЊC. The resulting mixture was allowed to

F. Bellina et al. / Tetrahedron 56 (2000) 2533–2545
2541
Methyl 2-(3-hydroxy-1-pentynyl)benzoate (10e). The
crude reaction mixture, which was obtained from the
Pd(0)/Cu(I)-catalyzed reaction between 9a and 3-hydroxy-
1-pentyne (4e), was purified by MPLC on silica gel, using a
mixture of toluene and Et2O (70:30) as eluant, to give in
84% yield compound 10e as an orange liquid. MS, m/z (%):
203 (4), 190 (35), 157 (100), 129 (58), 101 (79), 77 (28), 57
(21). IR (film): n 1718, 1435, 1298, 1279, 1256, 1084,
Methyl (E)-2-(3-hexen-1-ynyl)benzoate (10d). A flame
dried reaction vessel, which was maintained under an
argon atmosphere, was charged with methyl 2-(perfluoro-
1-butanesulfonyloxy)benzoate (9a) (7.49 g, 17.25 mmol),
Pd(dba)2
(0.396 g,
0.689 mmol),
dppf
(0.760 g,
1.379 mmol), LiCl (2.92 g, 68.99 mmol) and deareated
DMF (100 ml) and the mixture was stirred. A deareated
solution of 16 (7.64 g, 20.70 mmol) in DMF (30 ml) was
then added and the resulting mixture was stirred at 60ЊC for
80 h. It was then cooled to room temperature, poured into a
large excess of a saturated aqueous NH4Cl solution and
extracted repeatedly with Et2O. The collected organic
extracts were washed with water and concentrated in
vacuo. The residue was diluted with Et2O and stirred at
20ЊC with an aqueous 6 M solution of KF (150 ml) for
24 h. The mixture was then diluted with Et2O (150 ml),
filtered over Celite and the filtrate was extracted with
Et2O (3×50 ml). The collected organic extracts were
washed with water, dried and concentrated in vacuo. The
residue was purified by MPLC on silica gel, using a mixture
of toluene and hexane (60:40) as eluant, to give 10d (1.51 g,
41% yield) as an orange liquid. MS, m/z (%): 214 (22), 199
1
759 cmϪ1. H NMR (200 MHz, CDCl3): d 7.92 (1H, d,
Jˆ7.3 Hz, Harom), 7.55–7.35 (3H, br m, Harom), 4.61 (1H,
t, Jˆ6.0 Hz, H-30), 3.91 (3H, s, OMe), 2.75 (1H, br s, OH),
1.85 (2H, quint, Jˆ7.3 Hz, H-40), 1.10 ppm (3H, t,
Jˆ7.3 Hz, H-50). Anal. Calcd for C13H14O3: C, 71.54; H,
6.46. Found: C, 71.14; H, 6.25. A GLC analysis showed that
10e had chemical purity higher than 99%.
(E)-1-Trimethylsilyl-3-hexen-1-yne (15). 1-Trimethylsilyl-
acetylene (17.71 g, 180.3 mmol) was added dropwise to a
0.67 M THF solution of ethylmagnesium bromide (269 ml,
180.3 mmol) which was maintained under stirring at 65ЊC.
After the addition was complete, heating was continued for
1 h. The THF solution, which was cooled to 20ЊC, was then
added to a solution of dry ZnCl2 (26.58 g, 195.0 mmol) in
THF (180 ml) cooled to 0ЊC and the resulting mixture was
stirred for 0.5 h. A degassed solution of Pd(PPh3)4 (5.57 g,
4.82 mmol) and (E)/(Z)-1-bromo-1-butene (13) (E/Zˆ62/
38; 42.0 g, 311.0 mmol) in THF (210 ml), which was
prepared immediately prior to use, was added and the result-
ing mixture was stirred for 58 h at room temperature. It was
then poured into a large excess of a saturated aqueous
NH4Cl solution and the resulting mixture was extracted
with pentane (4×100 ml). The collected organic extracts
were filtered, washed with water, dried and concentrated
at 760 Torr. The residue was fractionally distilled using a
Fischer Spaltrohr System to give chemically and stereo-
isomerically pure 15 (18.12 g, 66% yield) as a colourless
liquid. bp 73–75ЊC/25 Torr. (Lit.20 bp 84–86ЊC/56
Torr). MS, m/z (%): 152 (20), 137 (100), 109 (11), 93 (5),
83 (25), 73 (10), 59 (23). 1H NMR (200 MHz, CDCl3): d 6.24
(1H, dt, Jˆ15.9 and 6.4 Hz, H-4), 5.48 (1H, dt, Jˆ15.9 and
1.6 Hz, H-3), 2.30–1.95 (2H, m, H-5), 0.99 (3H, t, Jˆ
7.4 Hz, H-6), 0.16 ppm (9H, s, SiMe3).
1
(41), 181 (76), 153 (88), 128 (100), 115 (74). H NMR
(200 MHz, CDCl3): d 7.93 (1H, d, Jˆ7.6 Hz, Harom),
7.55–7.29 (3H, m, Harom), 6.36 (1H, dt, Jˆ15.9 and
6.7 Hz, H-40), 5.77 (1H, d, Jˆ15.9 Hz, H-30), 3.93 (3H, s,
OMe), 2.21 (2H, pseudo-quint, Jˆ7.4 Hz, H-50), 1.06 ppm
(3H, t, Jˆ7.4 Hz, H-60). Anal. Calcd for C14H14O2: C, 78.48;
H, 6.58. Found: C, 78.70; H, 6.71.
2-(1-Pentynyl)benzoic acid (11a). Compound 10a (3.0 g,
14.83 mmol), which was prepared by Pd-catalyzed cross-
coupling reaction between 9a and 12a, was dissolved in
methanol (7 ml) and the resulting solution was added to a
mixture of an aqueous 2.29 M LiOH solution (32.4 ml,
74.15 mmol) and methanol (90 ml), which was stirred at
5ЊC. The resulting mixture was stirred at 5ЊC for 22 h and
then concentrated at room temperature under reduced
pressure. The residue was diluted with water and extracted
with Et2O (3×75 ml). The aqueous phase was cooled to 0ЊC,
acidified with cold 10% H2SO4 and extracted with Et2O
(3×75 ml). The collected organic extracts were washed
with water, dried and concentrated in vacuo to give 11a
1
(E)-1-Tributylstannyl-3-hexen-1-yne (16). A flame dried
reaction vessel, which was maintained under an argon
atmosphere, was charged with a degassed solution of
compound 15 (3.81 g, 25.00 mmol) in THF (60 ml) and
bis(tributyltin)oxide (6.86 g, 11.50 mmol). A 1 M THF
solution of TBAF (0.50 ml, 0.50 mmol) was added and
the mixture was magnetically stirred at 60ЊC for 2.5 h, at
which time the volatiles were removed in vacuo. The
residue was filtered over Celite to give compound 16
(8.49 g, 94% yield) as a yellow liquid. MS, m/z (%): 313
(41), 311 (34), 257 (40), 255 (33), 199 (100), 197 (78), 121
(2.79 g, quantitative yield) as a solid. mp 35–37ЊC. H
NMR (200 MHz, CDCl3): d 8.07 (1H, d, Jˆ7.7 Hz, Harom),
7.54–7.36 (3H, m, Harom), 2.48 (2H, t, Jˆ7.0 Hz, H-30), 1.68
(2H, sext, Jˆ7.1 Hz, H-40), 1.09 ppm (3H, t, Jˆ7.1 Hz,
H-50). This crude compound was used in the next step
without any further purification and characterization.
3-Methoxy-2-(1-pentynyl)benzoic acid (11b). Compound
10b, which was prepared by Pd-catalyzed cross-coupling
reaction between 9b and 12a, was converted in 99% yield
into the title compound by a procedure similar to that
employed to prepare 11a. Compound 11b, which was a
1
(60). H NMR (200 MHz, CDCl3): d 6.20 (1H, dt, Jˆ15.9
1
and 6.8 Hz, H-4), 5.52 (1H, d, Jˆ15.9 Hz, H-3), 2.11 (2H,
quint, Jˆ6.8 Hz, H-5), 1.71–1.45 (6H, br m, H-10),
1.42–0.81 ppm (24 H, br m, H-20, H-30, H-40 and H-6).
GLC and TLC analyses showed that compound 16 had
chemical purity higher than 97%. This crude compound
was used in the next step without any further purification
and characterization.
colourless solid, had: mp 82–86ЊC. H NMR (200 MHz,
CDCl3): d 10.50 (1H, br s, COOH), 7.65 (1H, d,
Jˆ7.9 Hz, Harom), 7.32 (1H, t, Jˆ8.1 Hz, Harom), 7.07 (1H,
d, Jˆ8.1 Hz, Harom), 3.91 (3H, s, OMe), 2.54 (2H, t,
Jˆ7.0 Hz, H-30), 1.69 (2H, sext, Jˆ7.3 Hz, H-40),
1.09 ppm (3H, t, Jˆ7.3 Hz, H-50). This crude compound
was used in the next step without any further purification
and characterization.

2542
F. Bellina et al. / Tetrahedron 56 (2000) 2533–2545
4-Methoxy-2-(1-pentynyl)benzoic acid (11c). Compound
10c, which was prepared by Pd-catalyzed cross-coupling
reaction between 9c and 12a, was converted in quantitative
yield into the title compound by a procedure similar to that
employed to prepare 11a. Compound 11c, which was a
(16). IR (KBr): n 1731, 1656, 1160, 1141, 1019, 762,
1
690 cmϪ1. H NMR (200 MHz, CDCl3): d 8.25 (1H, d,
Jˆ8.0 Hz, Harom), 7.77–7.58 (1H, m, Harom), 7.60–7.30
(2H, m, Harom), 6.26 (1H, s, H-4), 2.51 (2H, t, Jˆ7.5 Hz,
H-10), 1.80–1.65 (2H, m, H-20), 0.99 ppm (3H, t, Jˆ
7.4 Hz, H-30). These spectral data were in good agreement
either with those reported for the natural product5c or with
those reported for 2a prepared starting from 2-iodobenzoic
acid (3).9b
1
colourless solid, had: mp 89–93ЊC. H NMR (200 MHz,
CDCl3): d 10.60 (1H br s, COOH), 8.04 (1H, d, Jˆ
8.8 Hz, H-6), 7.02 (1H, d, Jˆ2.6 Hz, H-3), 6.86 (1H, dd,
Jˆ8.8 and 2.6 Hz, H-5), 3.84 (3H s, OMe), 2.47 (2H, t,
Jˆ7.0 Hz, H-30), 1.68 (2H, sext, Jˆ7.3 Hz, H-40),
1.09 ppm (3H, t, Jˆ7.3 Hz, H-50). This crude compound
was used in the next step without any further purification
and characterization.
Saponification followed by acidification of 10e: synthesis
of (Z)-3-(2-hydroxy-1-butylidene)phthalide (senkyunolide
E) (1e) and 3-(1-hydroxypropyl)isocoumarin (2e)
(E)-2-(3-Hexen-1-ynyl)benzoic acid (11d). Compound
10d, which was prepared by Pd-catalyzed cross-coupling
reaction between 16 and 9a, was converted in 99% yield
into the title compound by a procedure similar to that
employed to prepare 11a. Compound 11d, which was a
Compound 10e (1.0 g, 4.58 mmol), which was prepared by
Pd(0)/Cu(I)-catalyzed reaction of 9a with 4e, was dissolved
in methanol (5 ml) and the resulting solution was stirred at
5ЊC for 18 h with a 2.29 M aqueous LiOH solution (10 ml,
22.90 mmol) and methanol (25 ml). The reaction mixture
was concentrated in vacuo at room temperature and the
residue, which was dissolved in water (15 ml), was
extracted with Et2O (3×50 ml). The aqueous phase was
cooled to 0ЊC, acidified with cold 10% H2SO4 and extracted
with Et2O (3×50 ml). The organic extract was washed with
water, dried and concentrated in vacuo. A GLC analysis of
an Et2O solution of a sample of the residue showed the
presence of two compounds in a ca. 55:45 ratio, which
were subsequently identified as 1e and 2e, respectively.
This oily residue was purified by MPLC on silica gel,
using a mixture of hexane and AcOEt (70:30) as eluant.
Concentration of the first eluted chromatographic fractions
allowed to isolate compound 2e (0.20 g, 21% yield) as an
orange oil. MS, m/z (%): 204 (23), 175 (100), 147 (43), 89
(37), 63 (18), 57 (12), 51 (39). IR (film): n 1718, 1658,
1
colourless solid, had: mp 93–97ЊC. H NMR (200 MHz,
CDCl3): d 10.30 (1H, br s, COOH), 8.06 (1H, dd, Jˆ8.4
and 1.6 Hz, Harom), 7.70–7.30 (3H, m, Harom), 6.37 (1H, dt,
Jˆ15.8 and 6.6 Hz, H-40), 5.77 (1H, dt, Jˆ15.8 and 1.5 Hz,
H-30), 2.20 (2H, dquint, Jˆ7.4 and 1.5 Hz, H-50), 1.04 ppm
(3H, t, Jˆ7.4 Hz, H-60). This crude compound was used
in the next step without any further purification and
characterization.
2-[3-(2-Methoxyethoxymethoxy)-1-pentynyl]benzoic acid
(11f). Compound 10f, which was prepared by Pd-catalyzed
cross-coupling reaction between 9a and 12f, was converted
in quantitative yield into the title compound by a procedure
similar to that used prepare 11a. Crude 11f, which was a
colourless liquid, had: 1H NMR (200 MHz, CDCl3): d 9.87
(1H, br s, COOH), 8.05 (1H, dd, Jˆ7.7 and 1.5 Hz, Harom),
7.60–7.35 (3H, m, Harom), 5.17 (1H, d, Jˆ7.0 Hz, H-100),
4.82 (1H, d, Jˆ7.0 Hz, H-100), 4.61 (1H, t, Jˆ6.4 Hz,
H-30), 3.85–3.50 (2H, m, H-200 or H-300), 3.60 (2H, t,
Jˆ4.4 Hz, H-300 or H-200), 3.41 (3H, s, H-400), 1.89 (2H,
quint, Jˆ7.4 Hz, H-40), 1.11 ppm (3H, t, Jˆ7.4 Hz, H-50).
This crude compound was used in the next step without any
further purification and characterization.
1
1605, 1485, 1328, 1024, 759 cmϪ1. H NMR (200 MHz,
CDCl3): d 8.27–8.23 (1H, m, Harom), 7.71–7.39 (3H, m,
Harom), 6.56 (1H, s, H-4), 4.42 (1H, dd, Jˆ7.3 and 5.4 Hz,
H-10), 2.50 (1H, br s, OH), 2.05–1.81 (2H, m, H-20),
1.00 ppm (3H, t, Jˆ7.4 Hz, H-30). Anal. Calc for
C12H12O3: C, 70.57; H, 5.92. Found: C, 70.85; H, 6.04.
Concentration of the last eluted chromatographic fractions
allowed isolation of compound 1e (0.23 g, 25% yield) as a
pale crystalline solid. mp 86–89ЊC. MS, m/z (%): 204 (4),
175 (100), 147 (75), 129 (11), 104 (5), 57 (16), 51 (67). IR
(KBr): n 1770, 1691, 1279, 1256, 1061, 1007, 970, 767,
Saponification followed by acidification of compound
10a which was prepared by Pd(0)/Cu(I)-catalyzed
reaction between 9a and 4a: synthesis of 3-propyl-
isocoumarin (2a)
1
692 cmϪ1. H NMR (200 MHz, CDCl3): d 7.91 (1H, dt,
Jˆ6.6 and 1.1 Hz, Harom), 7.75–7.50 (3H, m, Harom), 5.66
(1H, d, Jˆ8.5 Hz, H-10), 4.86 (1H, dt, Jˆ8.5 and 6.6 Hz,
H-20), 2.04 (1H, br s, OH), 1.85–1.60 (2H, m, H-30),
1.00 ppm (3H, t, Jˆ7.3 Hz, H-40). These NMR data were
in agreement with those of senkyunolide E (1e) prepared
starting from phthalic anhydride.21 However, this phthalide
was described as a pale yellow oil. Finally, concentration of
the intermediate chromatographic fractions allowed to
obtain a ca. 1:1 mixture of 1e and 2e (0.10 g, 10% yield).
Compound 10a (3.0 g, 14.83 mmol), which was prepared by
Pd(0)/Cu(I)-catalyzed reaction between 9a and 4a, was
dissolved in methanol (7 ml) and the resulting solution
was stirred at 5ЊC for 18 h with a 2.29 M aqueous LiOH
solution (32.4 ml, 74.15 mmol) and methanol (90 ml). The
reaction mixture was concentrated in vacuo at room
temperature and the residue was diluted with water and
extracted with Et2O (3×50 ml). The aqueous phase was
cooled to 0ЊC, acidified with cold 10% H2SO4 and extracted
with Et2O (3×50 ml). The organic extract was washed with
water, dried and concentrated in vacuo. The residue was
purified by MPLC on silica gel, using a mixture of toluene
and petroleum ether (90:10) as eluant, to give 2a (2.62, 94%
yield) as a light yellow solid. mp 28–30ЊC. MS, m/z (%):
188 (36), 159 (14), 131 (38), 118 (100), 103 (15), 89 (60), 77
Preparation of 3-substituted isocoumarins 2 and (Z)-3-
(1-alkylidene)phthalides 1 by treatment of 2-(1-alkynyl)-
benzoic acids 11 with catalytic amounts of AgNO3 or Ag
powder
The AgNO3-catalyzed reactions were performed according
to the following procedure. In a typical experiment AgNO3

F. Bellina et al. / Tetrahedron 56 (2000) 2533–2545
2543
(0.24 g, 1.41 mmol) was added to a degassed solution of a
2-(1-alkynyl)benzoic acid 11 (7.05 mmol) in dry acetone
(70 ml) and the resulting mixture was stirred in the dark
under an argon atmosphere for 24 h at room temperature.
It was then concentrated in vacuo and the residue, which
was diluted with CH2Cl2 (40 ml), was filtered over Celite.
The filtrate, which was analyzed by TLC and GLC/MS, was
concentrated in vacuo and the residue was purified by
MPLC on silica gel. Compounds 11a, 11b, 11c and 11d
underwent the Ag(I)-catalyzed cyclization reactions to
give mixtures of the corresponding 3-substituted iso-
coumarins, i.e. 2a, 2b, 2c and 2d, respectively, and (Z)-3-
(1-alkylidene)phthalides, i.e 1a, 1b, 1c and 1d, respectively
(entries 1, 2, 6 and 9, Table 1). Nevertheless, the 3-substi-
tuted isocoumarins were easily separated from the corre-
sponding (Z)-3-(1-alkylidene)phthalides by MPLC on
silica gel. The 3-substituted isocoumarins 2a, 2b and 2c
were the major products in the case of the Ag(I)-catalyzed
cyclization reactions of 11a, 11b and 11c, respectively
(entries 1, 2 and 6, Table 1). On the contrary, the Ag(I)-
catalyzed cyclization reaction of 11d afforded a reaction
mixture in which the major product was compound 1d
(entry 9; Table 1). On the other hand, the Ag powder-
catalyzed heteroannulation reactions were performed
according to the following procedure. In a typical experi-
ment, Ag powder (5–8 micron, 0.052 g, 0.48 mmol) was
added to a degassed solution of a 2-(1-alkynyl)benzoic
acid 11 (4.81 mmol) in dry DMF (32 ml) and the resulting
mixture was stirred in the dark at 60ЊC for 48 h under an
argon atmosphere. It was then cooled to room temperature,
diluted with water (200 ml) and extracted with CH2Cl2
(5×50 ml). The organic extract was washed with brine
(2×50 ml), dried and concentrated in vacuo. The residue
was purified by MPLC on silica gel. Compounds 11b and
11c underwent this Ag-catalyzed reaction to give mixtures
containing the corresponding 3-substituted isocoumarins,
i.e. 2b and 2c, respectively, and the corresponding (Z)-3-
(1-alkylidene)phthalides, i.e. 1b and 1c, respectively, in
which these last compounds were the major products
(entries 4 and 7, Table 1). On the contrary, the Ag-catalyzed
lactonization of 11f afforded selectively compound 1f (entry
8, Table 1).
last eluted chromatographic fractions allowed to isolate in
88% yield stereoisomerically pure 2a. The physical and
spectral properties of this compound were in good agree-
ment with those of 2a which was prepared by saponification
followed by acidification of 10a which was synthesized by
Pd(0)/Cu(I)-catalyzed reaction between 9a and 4a.
Synthesis of 5-methoxy-3-propylisocoumarin (2b) and
(Z)-4-methoxy-3-(1-butylidene)phthalide (1b)
A GLC analysis of the crude reaction mixture, which was
obtained by AgNO3-catalyzed heteroannulation reaction of
11b (entry 2, Table 1), showed the presence of two
compounds in a ca. 94:6 ratio, which were subsequently
identified as 2b and 1b, respectively. This mixture was
purified by crystallization from hexane to give in 83%
yield chemically pure 2b as a pale yellow crystalline
solid. mp 76–79ЊC. MS, m/z (%): 218 (70), 189 (72), 161
(100), 148 (41), 119 (50), 89 (52), 76 (50). IR (KBr): n
1
1719, 1651, 1482, 1265, 1139, 1034, 763 cmϪ1. H NMR
(200 MHz, CDCl3): d 7.83 (1H, d, Jˆ7.8 Hz, Harom), 7.37
(1H, t, Jˆ8.0 Hz, Harom), 7.12 (1H, d, Jˆ8.0 Hz, Harom), 6.63
(1H, s, H-4), 3.92 (3H, s, OMe), 2.52 (2H, t, Jˆ7.4 Hz,
H-10), 1.74 (2H, sext, Jˆ7.4 Hz, H-20), 0.99 ppm (3H, t,
Jˆ7.4 Hz, H-30). Anal. Calcd for C13H14O3: C, 71.54; H,
6.46. Found: C, 71.61; H, 6.51. On the other hand, a GLC
analysis of the crude reaction mixture, which was obtained
by cyclization of 11b in DMF in the presence of a catalytic
quantity of Ag powder (entry 4, Table 1), showed the
presence of two compounds in a ca. 71:29 ratio, which
were subsequently identified as 1b and 2b, respectively.
This mixture was purified by MPLC on silica gel, using a
mixture of CH2Cl2 and hexane (60:40) as eluant. Concen-
tration of the first eluted chromatographic fractions allowed
to isolate in 63% yield compound 1b as a pale yellow solid.
mp 80–81ЊC. (Lit.22 mp 79–81ЊC). MS, m/z (%): 218 (18),
189 (100), 161 (18), 131 (18), 105 (33), 91 (15), 76 (35). IR
(KBr): n 1770, 1682, 1496, 1278, 1043, 978, 748 cmϪ1. 1H
NMR (200 MHz, CDCl3): d 7.49(1H, dd, Jˆ7.4 and 1.5 Hz,
Harom), 7.43 (1H, dd, Jˆ7.4 and 1.5 Hz, Harom), 7.13 (1H, dd,
Jˆ7.4 and 1.5 Hz, Harom), 5.97 (1H, t, Jˆ7.9 Hz, H-10), 3.99
(3H, s, OMe), 2.45 (2H, pseudo-q, Jˆ7.4 Hz, H-20), 1.56
(2H, m, H-30), 0.99 ppm (3H, t, Jˆ7.3 Hz, H-40). The spec-
tral properties of this compound were in good agreement
with those previously reported. On the other hand, concen-
tration of the last eluted chromatographic fractions allowed
us to isolate compound 2b in 19% yield. The spectral
properties of this compound were in agreement with those
of 2b prepared by AgNO3-catalyzed cyclization reaction of
11b.
Synthesis of 3-propylisocoumarin (2a) and (Z)-3-(1-
butylidene)phthalide (1a) by AgNO3-catalyzed
lactonization of 11a
GLC analysis of the crude reaction mixture, which was
obtained by Ag(I)-catalyzed lactonization of 11a (entry 1,
Table 1), showed the presence of two compounds in a ca.
94:6 molar ratio, which were subsequently identified as 2a
and 1a, respectively. This mixture was purified by MPLC on
silica gel, using a mixture of toluene and petroleum ether
(95:5) as eluant. Concentration of the first eluted chromato-
graphic fractions allowed us to isolate in 5% yield 1a as a
colourless oil. MS, m/z (%): 188 (16), 159 (100), 146 (44),
Synthesis of 6-methoxy-3-propylisocoumarin (2c) and
(Z)-5-methoxy-3-(1-butylidene)phthalide (1c)
A GLC analysis of the crude reaction mixture, which was
obtained by AgNO3-catalyzed cyclization reaction of 11c
(entry 6, Table 1), showed the presence of two compounds
in a ca. 97:3 ratio, which were subsequently identified as 2c
and 1c, respectively. Crystallization of this mixture from
hexane allowed to obtain in 81% yield compound 2c as a
pale yellow crystalline solid. mp 69–73ЊC. MS, m/z (%):
218 (41), 175 (29), 161 (51), 148 (100), 119 (96), 76 (41), 65
(17). IR (KBr): n 1718, 1663, 1605, 1574, 1255, 1221,
1
131 (35), 103 (44), 77 (38), 55 (12). H NMR (200 MHz,
CDCl3): d 7.88 (1H, d, Jˆ7.7 Hz, Harom), 7.75–7.60 (2H, m,
Harom), 7.50 (1H, ddd, Jˆ7.7, 1.0 and 1.0 Hz, Harom), 5.65
(1H, t, Jˆ7.7 Hz, H-10), 2.46 (2H, dt, Jˆ7.7 and 7.3 Hz,
H-20), 1.56 (2H, tq, Jˆ7.3 and 7.3 Hz, H-30), 0.99 ppm
(3H, t, Jˆ7.3 Hz, H-40). These NMR data were in agree-
ment with those previously reported.7d Concentration of the

2544
F. Bellina et al. / Tetrahedron 56 (2000) 2533–2545
1
1144 cmϪ1. H NMR (200 MHz, CDCl3): d 8.17 (1H, d,
Jˆ8.8 Hz, Harom), 6.98 (1H, dd, Jˆ8.8 and 2.3 Hz, Harom),
6.73 (1H, d, Jˆ2.3 Hz, Harom), 6.19 (1H, s, H-4), 3.90 (3H, s,
OMe), 2.49 (2H, t, Jˆ7.5 Hz, H-10), 1.83–1.64 (2H, m,
H-20), 0.99 ppm (3H, t, Jˆ7.3 Hz, H-30). Anal. Calcd for
C13H14O3: C, 71.54; H, 6.46. Found: C, 71.83; H, 6.80.
(%): 200 (100), 185 (12), 172 (28), 157 (47), 129 (33), 115
(18), 89 (57). IR (KBr): n 1729, 1655, 1621, 1059, 972, 961,
1
759 cmϪ1. H NMR (200 MHz, CDCl3): d 8.23 (1H, br d,
Jˆ8.0 Hz, H-8), 7.64 (1H, ddd, Jˆ7.4, 7.4 and 1.4 Hz, H-6),
7.39 (1H, ddd, Jˆ7.4, 7.4 and 1.4 Hz, H-7), 6.67 (1H, dt,
Jˆ15.4 and 6.6 Hz, H-20), 6.25 (1H, s, H-4), 6.02 (1H, dt,
Jˆ15.4 and 1.6 Hz, H-10), 2.38–2.15 (2H, m, H-30),
1.09 ppm (3H, t, Jˆ7.5 Hz, H-40). These spectral properties
were in agreement with those previously reported.9b
On the other hand, a GLC analysis of the crude reaction
mixture, which was obtained by cyclization of 11c in the
presence of a catalytic quantity of Ag powder, showed the
presence of two compounds in a ca. 86:14 molar ratio,
which were subsequently identified as 1c and 2c, respec-
tively (entry 7, Table 1). This mixture was purified by
MPLC on silica gel, using a mixture of CH2Cl2 and hexane
(60:40) as eluant. Concentration of the first eluted chroma-
tographic fractions allowed to isolate in 54% yield chemi-
cally and stereoisomerically pure 1c as a pale yellow solid.
mp 55–56ЊC. (Lit.7c mp 56–57ЊC). MS, m/z (%): 218 (16),
189 (97), 176 (100), 161 (90), 133 (55), 77 (37), 63 (84). IR
(KBr): n 1785, 1617, 1490, 1296, 1063, 859, 775 cmϪ1. 1H
NMR (200 MHz, CDCl3): d 7.77 (1H, br d, Jˆ9.0 Hz,
Harom), 7.10–6.95 (2H, m, Harom), 5.60 (1H, t, Jˆ7.8 Hz,
H-10), 3.92 (3H, s, OMe), 2.44 (2H, pseudo-q, Jˆ7.3 Hz,
H-20), 1.70–1.45 (2H, sext, Jˆ7.3 Hz, H-30), 0.99 ppm (3H,
t, Jˆ7.3 Hz, H-40). The spectral properties of this compound
were in agreement with those previously reported.7c On the
other hand, concentration of the last eluted chromatographic
fractions allowed isolation of pure 2c in 11% yield. The
physical and spectral properties of this compound were in
agreement with those of 2c prepared by AgNO3-catalyzed
cyclization reaction of 11c.
(Z)-3-[2-(Methoxyethoxymethoxy)-1-butylidene]phthalide
(1f). A GLC analysis of the crude reaction mixture, which
was obtained by cyclization of 11f in DMF in the presence
of catalytic quantity of Ag powder (entry 8, Table 1),
showed the presence of a single compound which was
subsequently identified as 1f. This crude mixture was puri-
fied by MPLC on silica gel, using a mixture of toluene and
AcOEt (80:20) as eluant, to give in 94% yield pure 1f as a
colourless liquid. MS, m/z (%): 263 (4), 203 (20), 187 (57),
159 (16), 115 (11), 89 (100), 59 (45). IR (film): n 1789,
1110, 1094, 1037, 998, 977, 765 cmϪ1. 1H NMR (200 MHz,
CDCl3): d 7.95–7.50 (4H, m, Harom), 5.57 (1H, d, Jˆ8.8 Hz,
H-10), 4.86–4.72 (3H, m, H-20 and H-100), 3.82–3.52 (4H,
m, H-200 and H-300), 3.38 (3H, s, H-400), 1.85–1.65 (2H, m,
H-30), 0.99 ppm (3H, t, Jˆ7.5 Hz, H-40). Anal. Calcd for
C16H20O5: C, 65.74; H, 6.89. Found: C, 65.81; H, 6.97.
Synthesis of (Z)-3-{1-[(E)-2-penten-1-ylidene]}phthalide
(1d) and artemidin (2d)
A GLC analysis of the crude reaction mixture, which was
obtained by Ag-catalyzed cyclization reaction of 11d (entry
9, Table 1), showed the presence of two compounds in a ca.
28:72 molar ratio, which were subsequently identified as 2d
and 1d, respectively. This crude mixture was purified by
MPLC on silica gel, using a mixture of toluene and hexane
(90:10) as eluant. Concentration of the first eluted chroma-
tographic fractions allowed to obtain in 51% yield chemi-
cally and stereoisomerically pure 1d as a pale yellow solid.
mp 41–43ЊC. MS, m/z (%): 200 (100), 185 (26), 157 (56),
144 (20), 129 (36), 115 (20), 76 (20). IR (KBr): n 1772,
1659, 1279, 1072, 982, 966, 773 cmϪ1. 1H NMR (600 MHz,
CDCl3): d 7.89 (1H, d, Jˆ7.8 Hz, H-7), 7.67 (1H, m, H-5),
7.65 (1H, m, H-4), 7.49 (1H, ddd, Jˆ7.8, 7.8 and 1.1 Hz,
H-6), 6.67 (1H, ddt, Jˆ15.2, 11.0 and 6.5 Hz, H-20), 6.17
(1H, d, Jˆ11.0 Hz, H-10), 6.07 (1H, dt, Jˆ15.2 and 6.5 Hz,
H-30), 2.24 (2H, qd, Jˆ7.4 and 6.5 Hz, H-40), 1.09 ppm (3H,
t, Jˆ7.4 Hz, H-50). A NOESY experiment showed the
presence of a cross-peak between the resonances of the
H-10 and H-4 protons. 13C NMR (150 MHz, CDCl3): d
166.68 (C-1), 143.34 (C-3), 141.24 (C-30), 139.63 (C-9),
134.20 (C-5), 129.35 (C-6), 125.51 (C-7), 124.19 (C-8),
122.17 (C-20), 119.63 (C-4), 108.34 (C-10), 26.27 (C-40),
13.18 ppm (C-50). Anal. Calcd for C13H12O2: C, 77.98; H,
6.04. Found: C, 78.05; H, 6.24. On the other hand, concen-
tration of the last eluted chromatographic fraction allowed
to isolate in 23% yield chemically pure artemidin (2d) as a
colourless solid. mp 46–48ЊC. (Lit.5b mp 48ЊC). MS, m/z
(Z)-3-(1-Butylidene)-4-hydroxyphthalide (senkyunolide
B) (1g). A 1.0 M CH2Cl2 solution of BBr3 (10.5 ml,
10.50 mmol) was added to a solution of compound 1b
(1.09 g, 5.0 mmol) in dry CH2Cl2 (15 ml), which was stirred
at 0ЊC under an argon atmosphere. The resulting mixture
was allowed to warm up to room temperature and stirred for
7.5 h. It was then poured into ice water and extracted with
Et2O (4×75 ml). The organic extract was washed with brine
(100 ml), dried and concentrated in vacuo. The solid residue
was recrystallized from a mixture of benzene and hexane
(3:1) to give compound 1g (0.88 g, 86% yield) as a colour-
less crystalline solid. mp 162–164ЊC (Lit. mp 165–168ЊC22;
mp 150–153ЊC1c). MS, m/z (%): 204 (14), 175 (100), 147
(28), 119 (22), 91 (41), 65 (17), 55 (14). IR (KBr): n 3233,
1734, 1684, 1467, 1305, 1004, 747 cmϪ1 1H NMR
.
(600 MHz, DMSO-d6): d 11.03 (1H, s, OH), 7.42 (1H, dd,
Jˆ7.9 and 7.9 Hz, H-6), 7.33 (1H, d, Jˆ7.9 Hz, H-7), 7.22
(1H, d, Jˆ7.9 Hz, H-5), 5.90 (1H, t, Jˆ7.6 Hz, H-10), 2.36
(2H, q, Jˆ7.6 Hz, H-20), 1.51 (2H, sext, Jˆ7.6 Hz, H-30),
0.94 ppm (3H, t, Jˆ7.6 Hz, H-40). A NOESY experiment
showed the presence of cross-peaks between the resonances
of the following protons: H-10 and OH; OH and H-6. 13C
NMR (150 MHz, DMSO-d6): d 167.34 (C-1), 153.82 (C-4),
145.08 (C-3), 131.86 (C-6), 126.20 (C-8), 125.72 (C-9),
116.22 (C-7), 112.72 (C-10), 28.52 (C-20), 23.01 (C-30),
14.58 ppm (C-40). The spectral properties of this compound
were in agreement with those previously reported.7e

F. Bellina et al. / Tetrahedron 56 (2000) 2533–2545
2545
Wang, G. Y.; Chang, C. W. Tai-wan Yao Hsueh Tsa Chih 1983, 35,
155–162; Chem. Abstr. 1984, 101, 48511y.
5. (a) Barry, R. D. Chem. Rev. 1964, 64, 229–259. (b) Bohlmann,
F.; Zdero, C. Chem. Ber. 1970, 103, 2856–2859. (c) Bohlmann, F.;
Zdero, C. Phytochemistry 1976, 15, 1318–1319.
(Z)-3-(1-Butylidene)-5-hydroxyphthalide (senkyunolide
C) (1h). A 1.0 M CH2Cl2 solution of BBr3 (12.5 ml,
12.50 mmol) was added to a solution of 1c (1.09 g,
5.0 mmol) in dry CH2Cl2 (15 ml), which was stirred at
0ЊC under an argon atmosphere. The resulting mixture
was stirred at room temperature for 6 h and worked up
according to the same procedure employed in the synthesis
of 1g. The crude reaction product was purified by MPLC on
silica gel, using a mixture of petroleum ether and acetone
(80:20) as eluant, to give 1h (0.58 g, 57% yield) as a colour-
less crystalline solid. mp 117–120ЊC (Lit.7c mp 117–
119ЊC). MS, m/z (%): 204 (23), 145 (100), 131 (16), 115
(23), 103 (46), 91 (15), 77 (21). IR (KBr): n 3236, 1753,
6. (a) Turner, W. B. Fungal Metabolites; Academic Press:
London, 1971; Chapter 5. (b) Hill, R. A. Progress in the Chemistry
of Organic Natural Products; Wien-Springer-Verlag: New York,
1986; Vol. 49. (c) Ohta, S.; Kamata, Y.; Inagaki, T.; Masuda, Y.;
Yamamoto, S.; Yamashita, M.; Kawasaki, I. Chem. Pharm. Bull.
1993, 41, 1188–1190.
7. (a) Castro, C. E.; Gaughan, E. J.; Owsley, D. C. J. Org. Chem.
1966, 31, 4071–4078. (b) Mali, R. S.; Jagtap, P. G. J. Chem. Res.
(S) 1993, 184–185. (c) Ogawa, Y.; Maruno, M.; Wakamatsu, T.
Heterocycles 1994, 39, 47–50. (d) Ogawa, Y.; Maruno, M.;
Wakamatsu, T. Heterocycles 1995, 41, 2587–2599. (e) Li, S.;
Wang, Z.; Fang, X.; Yang, Y.; Li, Y. Synth. Commun. 1997, 27,
1783–1791. (f) Kundu, N. G.; Pal, M.; Nandi, B. J. Chem. Soc.
Perkin Trans. 1 1998, 561–568.
1
1739, 1683, 1620 1591, 1316 cmϪ1. H NMR (600 MHz,
CDCl3): d 7.76 (1H, d, Jˆ8.2 Hz, H-7), 7.03 (1H, d,
Jˆ2.0 Hz, H-4), 6.98 (1H, dd, Jˆ8.2 and 2.0 Hz, H-6),
5.57 (1H, t, Jˆ7.6 Hz, H-10), 2.43 (2H, q, Jˆ7.6 Hz,
H-20), 1.54 (2H, sext, Jˆ7.6 Hz, H-30), 0.98 ppm (3H, t,
Jˆ7.6 Hz, H-40). A NOESY experiment showed the
presence of a cross-peak between the resonances of the
H-10 and H-4 protons. 13C NMR (150 MHz, CDCl3): d
167.38 (C-1), 161.62 (C-5), 145.47 (C-3), 142.37 (C-4),
127.26 (C-7), 118.15 (C-6), 117.13 (C-8), 109.80 (C-10),
105.37 (C-4), 27.78 (C-20), 22.49 (C-30), 13.80 ppm
(C-40). The spectral properties of 1h were in satisfactory
agreement with those reported either for the product isolated
from Cnidium officinale1c or compound 1h synthesized from
4-hydroxyphthalic anhydride.7e
8. For a short review on the synthesis of 3-ylidenephthalides, see:
Ref. 7f.
9. (a) Korte, D. E.; Hegedeus, L. S.; Wirth, R. K. J. Org. Chem.
1977, 42, 1329–1336. (b) Batu, G.; Stevenson, R. J. Org. Chem.
1980, 45, 1532–1534. (c) Larock, R. C.; Varaprath, S.; Lau, H. H.;
Fellows, C. A. J. Am. Chem. Soc. 1984, 106, 5274–5284. (d)
Izumi, T.; Nishimoto, Y.; Kohei, K.; Kasahara, A. J. Heterocycl.
Chem. 1990, 27, 1419–1424. (e) Liao, H-Y.; Cheng, C-H. J. Org.
Chem. 1995, 60, 3711–3716. (f) Sashida, H.; Kawamukai, A.
Synthesis 1999, 1145–1148.
10. Van Wassenhove, F.; Dirink, P.; Vulsteke, G.; Schamp, N.
Hort. Sci. 1990, 25, 556–559.
Acknowledgements
11. Villemin, D.; Goussu, D. Heterocycles 1989, 29, 1255–1261.
12. (a) Rossi, R.; Bellina, F.; Bechini, C.; Mannina, L.; Vergamini,
P. Tetrahedron 1998, 54, 135–156. (b) Rossi, R.; Bellina, F.;
Mannina, L. Tetrahedron Lett. 1998, 39, 3017–3020. (c) Rossi,
R.; Bellina, F.; Biagetti, M.; Mannina, L. Tetrahedron Lett.
1998, 39, 7599–7602. (d) Rossi, R.; Bellina, F.; Biagetti, M.;
Mannina, L. Tetrahedron Lett. 1998, 39, 7799–7802. (e) Rossi,
R.; Bellina, F.; Biagetti, M.; Mannina, L. Tetrahedron: Asymmetry
1999, 10, 1163–1172. (f) Rossi, R.; Bellina, F.; Biagetti, M. Synth.
Commun. 1999, 29, 3415–3420. (g) Rossi, R.; Bellina, F.; Catanese,
A.; Mannina, L.; Valensin, D. Tetrahedron, 2000, 56, 479–488.
13. Andreini, B. P.; Carpita, A.; Rossi, R. Tetrahedron Lett. 1986,
27, 5533–5536.
We gratefully acknowledge the financial support from the
`
Ministero dell’Universita e della Ricerca Scientifica e
Tecnologica (MURST) and the University of Pisa.
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