Regioselective synthesis of cytotoxic 4-(1-alkynyl)-substituted 2-(5H)-furanones

Article abstract of DOI:10.1016/j.tet.2003.09.061

4-(1-Alkynyl)-3-bromo- and 4-(1-alkynyl)-3-chloro-2(5H)-furanones have been regioselectively synthesized in moderate to good yields by a new version of the Pd/Cu-catalyzed Sonogashira reaction involving treatment of 1-alkynes with 3,4-dibromo- and 3,4-dic

Full text of DOI:10.1016/j.tet.2003.09.061

Tetrahedron 59 (2003) 9091–9100
Regioselective synthesis of cytotoxic 4-(1-alkynyl)-substituted
2-(5H)-furanones
*
Fabio Bellina, Elisabetta Falchi and Renzo Rossi
Dipartimento di Chimica e Chimica Industriale, University of Pisa, Via Risorgimento 35, I-56126 Pisa, Italy
Received 21 July 2003; revised 26 August 2003; accepted 18 September 2003
Abstract—4-(1-Alkynyl)-3-bromo- and 4-(1-alkynyl)-3-chloro-2(5H)-furanones have been regioselectively synthesized in moderate to
good yields by a new version of the Pd/Cu-catalyzed Sonogashira reaction involving treatment of 1-alkynes with 3,4-dibromo- and 3,4-
dichloro-2(5H)-furanone, respectively, in the presence of KF as a base. 4-(1-Alkynyl)-3-bromo-2(5H)-furanones have been found to be able
to undergo Stille-type and Suzuki-type reactions with aryl(tributyl)tins and arylboronic acids, respectively, to give 4-(1-alkynyl)-3-aryl-
2(5H)-furanones in modest to satisfactory yields. Some 4-(1-alkynyl)-substituted 2(5H)-furanones so prepared have been found to exhibit
significant cytotoxic activities, especially against human leukemia cell lines.
q 2003 Published by Elsevier Ltd.
1. Introduction
nones of general formula 5a, 5b, 6 and 7.
2(5H)-Furanone derivatives include 3,4,5-trisubstituted
compounds, such as natural and unnatural (Z)-4-aryl-5-[1-
(aryl)methylidene]-3-halo-2(5H)-furanones 11–4 and natu-
rally-occurring nostoclides I (2a) and II (2b),5 that exhibit
cytotoxicity against human cancer cell lines.
Moreover, 3,4-diaryl-2(5H)-furanones 3 have also been
reported as cytotoxic agents.4,6,7 Thus, compounds 3a–d
have been found to have significant cytotoxic activities
against A549, SK-MEL-2 and MCF-7 cell lines6 and
compounds 3d and 3f, which were very recently tested in
the in vitro human disease-oriented tumor cell line screen-
ing panel developed at the US National Cancer Institute
(NCI), have been found to exhibit potent cytotoxicity,
especially against human leukemia cell lines where they
showed log10 GI50 values lower than 28.7
Recently, as part of our ongoing research program directed
towards the development of efficient procedures for the
preparation of unsymmetrical 3,4-disubstituted 2(5H)-
furanone derivatives, which are cytotoxic against human
tumor cell lines, we decided to investigate the use of readily
available 3,4-dibromo- and 3,4-dichloro-2(5H)-furanone,
(4a) and (4b) respectively,8 for the selective synthesis of
potentially cytotoxic 4-(1-alkynyl)-substituted 2(5H)-fura-
In fact, examples either of 3-bromo- and 3-chloro-2(5H)-
furanones or of alkynyl-substituted heterocycles that exhibit
significant cytotoxicity have been reported in the litera-
ture.1,9–11 In this paper we wish to report an account on the
results of our synthetic efforts to prepare compounds 5a, 5b,
6 and 7 and of some tests performed to evaluate the
cytotoxic activities of some these 2(5H)-furanone deriva-
tives.
Keywords: 2-(5H)-furanones; regioselectivity; palladium catalysis;
cytotoxicity; Sonogashira reaction.
*
Corresponding author. Tel.: þ39-509-182-14; fax: þ39-509-182-60;
e-mail: rossi@dcci.unipi.it
0040–4020/$ - see front matter q 2003 Published by Elsevier Ltd.
doi:10.1016/j.tet.2003.09.061

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F. Bellina et al. / Tetrahedron 59 (2003) 9091–9100
under phase-transfer conditions,16 i.e. in a 1:1 mixture of
toluene and water in the presence of 10 mol% BnEt3NþCl2
(entries 1–4); (ii) the use of a base such as K3PO4 or K2CO3
in these last reaction conditions resulted in the decompo-
sition of 4a (entries 7 and 8); (iii) CsF and KF promoted the
cross-coupling reaction (entries 3 and 6), but the use of
4.0 equiv. of KF (entry 3) allowed us to obtain 5aa in a
higher yield; and (iv) a lower yield of 5aa was obtained
when 1.5 equiv. instead of 4.0 equiv. of KF were used
(compare entries 4 and 5). Moreover, very long reaction
times were required for complete reaction when 1.5 equiv.
of KF were used. Finally, it is worth mentioning that the
reactions shown in entries 1–6 of Table 1 occurred with
regioselectivity higher than 98%.
2. Results and discussion
2.1. Synthesis of 4-(1-alkynyl)-3-bromo- and 4-(1-
alkynyl)-3-chloro-2(5H)-furanones
We then tested the efficiency of the PdCl2(RCN)2 (R¼Ph,
Me)/CuI/P(2-furyl)3/KF systems for the synthesis of
3-bromo-4-[(p-tolyl)ethynyl]-2(5H)-furanone (5ab) and
4-[(alkyl)ethynyl]-3-bromo-2(5H)-furanones such as com-
pounds 5ac, 5ad, 5ae, 5af and 5ag from the corresponding
1-alkynes and 4a. As shown in Scheme 2, compound 5ab
was obtained in 71% yield by reaction of 4a with 1.2 equiv.
of 10b in a 1:1 mixture of toluene and water at 508C for 74 h
in the presence of 4.0 equiv. of KF, 10 mol% BnEt3NþCl2
and the catalyst system C previously employed to synthesize
5aa in 85% yield (entry 3, Table 1).
We began our synthetic studies by investigating the
synthesis of 3-bromo-4-(phenylethynyl)-2(5H)-furanone
(5aa) and in a preliminary experiment we found that
reaction of 4a with 1.05 equiv. of tributyl(phenylethynyl)tin
(8) in a mixture of THF and acetonitrile at 408C for 20 h, in
the presence of 10 mol% PdCl2(PPh3)2 and 10 mol% CuI,
provided the desired cross-coupled product 5aa with
complete regioselectivity but in modest yield (17%)
(Scheme 1). The structure of compound 5aa could be
anticipated given that 4a represents the cyclic analog of
methyl (Z)-2,3-dibromopropenoate and that, similarly to
this compound, it may exhibit regioselectivity in Pd-
catalyzed cross-coupling reactions.12 The structure of 5aa
was confirmed by its conversion to the known 2(5H)-
furanone 9a,13 which was obtained in 62% yield by
treatment of 5aa with 4.0 equiv. of activated zinc dust14 in
refluxing THF for 27 h, followed by acidic hydrolysis
(Scheme 1).
Scheme 2. (a) 10b (1.2 equiv.), BnEt3NþCl2 (10 mol%), PdCl2(PhCN)2
(5 mol%), CuI (10 mol%), P(2-furyl)3 (10 mol%), KF (4 equiv.), toluene–
water (1:1), 508C, 74 h.
On the other hand, Table 2 summarizes the results obtained
in the synthesis of compounds 5ac, 5ad, 5ae, 5af and 5ag,
which was performed in toluene or in a 1:1 mixture of
toluene and water under phase-transfer conditions. Two
aspects of these results merit comments: Firstly, all
preparations reported in Table 2, save that of 5af, occurred
with satisfactory to high yields when they were performed
on a ca. 2 mmol scale. However, when 5ac was prepared on
a ca. 20 mmol scale, it was isolated in a yield of 42%,
significantly lower than that obtained when the reaction was
performed on a 2 mmol scale (compare entry 3 with entries
1 and 2). Secondly, the selectivity of the reactions
summarized in Table 2 proved sometimes to be lower
than that obtained in the preparations of 5aa and 5ab. Thus,
the crude products derived from the preparations of 5ac and
5ag, which are reported in entries 2 and 7, proved to be
contaminated by ca. 3–5% of the corresponding symmetrical
3,4-di(1-alkynyl)-2(5H)-furanones 6a and 6b, respectively.
Scheme 1. (a) PdCl2(PPh3)2 (10 mol%), CuI (10 mol%), THF, MeCN,
408C, 16 h; (b) aq. KF, Et2O and then MPLC on silica gel; (c) activated zinc
dust (4 equiv.), THF, 27 h, reflux; (d) 5% HCl, 08C.
The unsatisfactory yield obtained in the Pd-catalyzed
reaction of 4a with 8 prompted us to explore the preparation
of 5aa via Sonogashira reaction of 4a with phenylacetylene
(10a),15 even though we were conscious that, due to the
rapid decomposition of 4a in the presence of amines, we
could not perform this Pd/Cu-catalyzed reaction in the
classical reaction conditions which involve the use of a base
such as Et2NH, Et3N, i-Pr2NH or EtN(i-Pr)2.15 As shown in
Table 1, we tested some catalyst precursors and bases for the
reaction between 4a and 10a and eventually we found that
the PdCl2(PhCN)2/CuI/P(2-furyl)3/KF system proved to be
the best to prepare compound 5aa (entry 3).
Table 1 also shows that: (i) although the cross-coupling
reaction could be successfully performed in toluene (entry
4), the best results were obtained when it was performed
The first of these compounds was prepared in 27% yield by

F. Bellina et al. / Tetrahedron 59 (2003) 9091–9100
Table 1. Synthesis of 5aa by Sonogashira reaction using different experimental conditions
9093
Entrya
Catalyst systemb
Base (equiv.)
Solventc
Reaction conditions (h/8C)
Yield (%)
1
2
3
4
5
6
7
8
A
B
C
D
C
D
D
D
KF (4.0)
KF (4.0)
KF (4.0)
KF (4.0)
KF (1.5)
CsF (4.0)
K2CO3 (4.0)
K3PO4 (4.0)
Toluene–water (1:1)
Toluene–water (1:1)
Toluene–water (1:1)
Toluene
19/20 then 53/40
144/40
72/40
63
50
85
47
28
66
75/60
Toluene
200/60
48/40
9/40
Toluene–water (1:1)
Toluene–water (1:1)
Toluene–water (1:1)
d
–
d
9/40
–
a
All these reactions were performed on a ca. 2 mmol scale using 1.20 equiv. of 10a and a 7.8:8.4 ratio between the number of ml of the reaction solvent and the
number of mmol of 4a.
b
Catalyst system A: Pd(PPh3)4 (5 mol%), CuI (10 mol%). Catalyst system B: PdCl2(PhCN)2 (5 mol%), CuI (10 mol%), AsPh3 (10 mol%). Catalyst system C:
PdCl2(PhCN)2 (5 mol%), CuI (10 mol%), P(2-furyl)3 (10 mol%). Catalyst system D: PdCl2(MeCN)2 (5 mol%), CuI (10 mol%), P(2-furyl)3 (10 mol%).
BnEt3NþCl2 was used as a phase-transfer catalyst for the reactions performed in a 1:1 mixture of toluene and water.
In this reaction the complete decomposition of 4a was observed.
c
d
reaction of 4a with 3.0 equiv. of 10c in toluene at 908C for
160 h in the presence of 4.0 equiv. of KF, 5 mol%
PdCl2(PhCN)2, 10 mol% CuI, 10 mol% AsPh3 and
5 mol% BnEt3NþCl2 or in 31% yield by treatment of 5ac
with 2.0 equiv. of 10c in toluene at 908C for 73 h in the
presence of 4.0 equiv. of KF, 5 mol% PdCl2(MeCN)2,
10 mol% CuI and 10 mol% AsPh3 (Scheme 3).
It should also be noted that the structural assignment to the
4-(1-alkynyl)-3-bromo-2(5H)-furanones reported in Table 2
could be confirmed by conversion of one of these
compounds, i.e. 5ag, into the corresponding 4-(1-alkynyl)-
2(5H)-furanone 9b by a procedure very similar to that
employed to prepare 9a from 5aa (Scheme 4).
Scheme 3. (a) 10c (3.0 equiv.), PdCl2(PhCN)2 (5 mol%), CuI (10 mol%),
AsPh3 (10 mol%), KF (4 equiv.), toluene, 908C, 160 h; (b) 10c (2.0 equiv.),
PdCl2(MeCN)2 (5 mol%), CuI (10 mol%), AsPh3 (10 mol%), KF
(4 equiv.), toluene, 908C, 73 h.
used for the regioselective monoalkynylation of 4a were
unsuitable for the synthesis of 4-(1-alkynyl)-3-chloro-
2(5H)-furanones 5b from the corresponding 1-alkynes 10
and 4b. Moreover, very low conversions were also obtained
when 4b was reacted with 1.2 equiv. of 10a (i) in toluene at
1008C for 47 h, in the presence of 2 mol% Na2PdCl4,
We then continued our studies on the regioselective
monoalkynylation reactions of 3,4-dihalo-2(5H)-furanones
by investigating the Sonogashira reaction of 3,4-dichloro-
2(5H)-furanone (4b). We found that, unfortunately, the
reaction conditions and the catalyst systems successfully
Table 2. Sonogashira reaction between 4a by Sonogashira reaction and aliphatic 1-alkynes 10
Entrya
1-Alkyne
R
Catalyst
systemb
Solvent
Reaction conditions
(h/8C)
Product
Yield (%)
10
5
1
2
3c
4
5
6
7
10c
10c
10c
10d
10e
10f
10g
n-Bu
n-Bu
n-Bu
t-Bu
Me2COH
Me3Si
n-Hexyl
C
D
D
C
D
D
C
Toluene–water (1:1)
Toluene
Toluene
Toluene–water (1:1)
Toluene
Toluene
39/40
76/60
112/65
49/40
51/65
5ac
5ac
5ac
5ad
5ae
5af
5ag
72
91
42
84
40
30
75
24/40 then 87/60
91/40
Toluene–water (1:1)
a
Unless otherwise reported these reactions were performed on a ca. 2 mmol scale using 1.2 equiv. of 1-alkyne 10. The reactions in toluene–water (1:1) were
performed in the presence of 10 mol% BnEt3NþCl2.
Catalyst system C: PdCl2(PhCN)2 (5 mol%), CuI (10 mol%), P(2-furyl)3 (10 mol%). Catalyst system D: PdCl2(MeCN)2 (5 mol%), CuI (10 mol%),
P(2-furyl)3 (10 mol%).
This reaction was performed on a ca. 20 mmol scale.
b
c

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F. Bellina et al. / Tetrahedron 59 (2003) 9091–9100
of 5ac with 3.0 equiv. of aryl(tributyl)tin 11a in NMP at
808C for 28 h in the presence of 5 mol% PdCl2[P(o-tolyl)3]2
and 10 mol% CuI provided 7a in 50% yield (entry 1,
Table 3). On the other hand, reaction of 5aa with 1.4 equiv.
of 11b or 1.5 equiv. of 11c under similar experimental
conditions produced compounds 7b and 7c in 36 and 15%
yield, respectively (entries 2 and 3, Table 3).
Scheme 4. (a) Activated zinc dust (4 equiv.), THF, 20 h, reflux; (b) 5%
HCl, 08C.
Better results were obtained in the synthesis of compounds 7
by a Suzuki-type reaction.
1.5 mol% CuI, 1.4 equiv. of KF and 4 mol% t-Bu3P, (ii) in a
1:1 mixture of toluene and water for 71 h at room
temperature in the presence of 4.0 equiv. of KF, 5 mol%
BnEt3NþCl2, 5 mol% Pd(PPh3)4 and 10 mol% CuI or (iii)
in toluene at 808C for 18 h in the presence of 1.0 equiv. of
KF, 2.5 mol% Pd2(dba)3, 10 mol% CuI and 10 mol%
P(o-tolyl)3. Under these reaction conditions significant
amounts of 1,4-diphenylbutadiyne derived from homo-
coupling of 10a were also obtained. Finally, we found that
reaction of 4b with 3.0 equiv. of 10a in a 1:1 mixture of
toluene and water at 658C for 165 h in the presence of
4.0 equiv. of KF, 5 mol% PdCl2(MeCN)2, 10 mol% CuI,
10 mol% PCy3 and 5 mol% BnEt3NþCl2 provided 3-
chloro-4-(phenylethynyl)-2(5H)-furanone (5ba) in 51%
yield and with complete regioselectivity (Scheme 5).
Interestingly, these reaction conditions proved also to be
suitable for the preparation of compound 5bb in 31% yield
by reaction of 4b with 10c (Scheme 5).
In fact, when 5ac was treated with 2.0 equiv. of the
arylboronic acid 11d in a 1:1 mixture of toluene and water at
608C for 23 h in the presence of 3.0 equiv. of CsF, 5 mol%
PdCl2(PPh3)2 and 5 mol% BnEt3NþCl2, compound 7a
could be isolated in a 59% yield. Moreover, reaction of
5aa with 2.0 equiv. of arylboronic acid 11e under very
similar reaction conditions provided compound 7d in 69%
yield. It should be noted that we prepared this last
compound since the presence of the 3,4,5-trimethoxyphenyl
group at C-3 seems to be essential for the cytotoxicity of
2(5H)-furanone derivatives against murine and human
tumor cell lines.19
2.3. Biological results
The cytotoxic activities of compounds 5aa, 5ab, 5ac, 5ad
and 7a were evaluated in vitro against the NCI three-cell
lines panel consisting of MCF7 (breast), SF-268 (CNS), and
NCI-H460 (lung). The protocol used involved inoculation
and preincubation of each cell line on a microtiter plate.
Tests 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 4) are
reported as the percent of growth of the treated cells when
compared to the untreated control cells.
2.2. Synthesis of 3-aryl-4-(1-alkynyl)-2(5H)-furanones
Scheme 5. (a) 10a or 10c (3.0 equiv.), BnEt3NþCl2 (5 mol%),
PdCl2(MeCN)2 (5 mol%), CuI (10 mol%), PCy3 (10 mol%), KF
(4 equiv.), toluene–water (1:1), 658C, 165–167 h.
Compounds which reduced the growth of any one of the cell
lines to 32% or less were considered to be active and some of
them were passed on for evaluation over a 5-log dose range in
the NCI’s in vitro human disease-oriented tumor cell line
screening panel that consisted of 60 human tumor cell lines
arranged in nine subpanels, representing diverse histologies.20
Results from Table 4 indicate that compounds 5aa, 5ac, 5ad,
We next turned our attention to the synthesis of 3-aryl-4-(1-
alkynyl)-2(5H)-furanones by Stille-type17 or Suzuki-type
reactions18 of bromides 5a with aryl(tributyl)tins or
arylboronic acids, respectively. Thus, we found that reaction
Table 3. Synthesis of 4-(1-alkynyl)3-aryl-2(5H)-furanones 7
Entrya
Reagents
11 (equiv.)
Catalyst
systemb
Solvent
Reaction conditions
(h/8C)
Product
Yield (%)
5a
R
Ar
M
7
1
2
3
4
5
5ac
5aa
5aa
5ac
5aa
n-Bu
Ph
Ph
n-Bu
Ph
11a (3.0)
11b (1.4)
11e (1.5)
11d (2.0)
11e (2.0)
4-MeOC6H4
2-MOMOC6H4
2-furyl
4-MeOC6H4
3,4,5-(MeO)3C6H2
SnBu3
SnBu3
SnBu3
B(OH)2
B(OH)2
E
E
E
F
F
NMP
NMP
NMP
toluene–water (1:1)
toluene–water (1:1)
28/80
28/80
28/80
23/60
70/60
7a
7b
7c
7a
7d
50
36
15
59
69
a
The coupling reactions involving arylboronic acids were performed in the presence of 3.0 equiv. CsF and 5 mol% BnEt3NþCl2.
Catalyst system E: PdCl2[P(o-tolyl)3]2 (5 mol%), CuI (10 mol%). Catalyst system F: PdCl2(PPh3)2 (5 mol%).
b

F. Bellina et al. / Tetrahedron 59 (2003) 9091–9100
9095
Table 4. Primary anticancer assay of 4-(1-alkynyl) substituted 2(5H)-
furanone derivatives
general formula 5a have been found to exhibit significant
cytotoxic activities, especially against human leukemia cell
lines.
Compound
Percentage of growth inhibition
NCI-H460 (lung)
MC F 7 (breast)
SF-268 (CNS)
4. Experimental
5aa
5ab
5ac
5ad
5ba
7a
1
64
1
1
3
1
101
2
1
0
39
98
1
55
43
105
67
Melting points and boiling points are uncorrected. Precoated
Merck 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. NMR spectra were
recorded on a Varian Gemini 200 MHz spectrometer with
TMS as the internal standard. IR spectra were recorded on a
Perkin–Elmer 1725-X FT-IR spectrophotometer. All reac-
tions of air and water sensitive materials were performed in
flame-dried glassware under a positive atmosphere of 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)2,21 Pd(PPh3)4,22 PdCl2(PhCN)2,21 PdCl2(MeCN)2,23
3,4-dibromo-2(5H)-furanone (4a),2,4 3,4-dichloro-2(5H)-
furanone (4b),3,4 tributyl(4-methoxyphenyl)tin (11a).24
(2-Methoxymethoxy)phenyl bromide [bp 98–998C/8 Torr],
which was used for the preparation of tributyl[(2-methoxy-
methoxy)phenyl]tin (11b), was prepared in 90% yield from
commercially available 2-bromophenol according to the
procedure used for the synthesis of 2-bromo-5-methoxy-
methoxy-1,4-naphthoquinone.25
80
6
114
54
7d
5ba and 7d passed the three-cell lines primary screening, but
only 5ac was found to be significantly cytotoxic against the
three cell lines. Compounds 5aa, 5ac and 5ad were further
evaluated for potential anticancer activity in the 60 human
tumor cell line panel.
For each compound, dose-response curves for each cell lines
were measured with five different drug concentrations. The
log10 GI50 values (GI50 being the molar drug concentration
required for half growth inhibition) obtained with leukemia
cell lines, along with the mean graph mid-point (MGM)
values, are summarized in Table 5. The MGM is based on a
calculation of the average log10 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 screen-
ing test.
The data summarized in Table 5 indicate the indisputable
cytotoxicity of compounds 5aa, 5ab and 5ac, which showed
MGM log10 GI50 values below-5, and the potent cytotoxic
activities of 5aa and 5ac against the following human
leukemia cells: CCRF-CEM, HL-60(TB), K-562, RPMI-
8226, and SR. These cell lines were relatively more
sensitive to compounds 5aa and 5ac than were other
tumor cell lines.
Tributyl(phenylethynyl)tin (8), tributyl(2-furyl)tin (11c), 4-
methoxyphenylboronic acid (11d) and 3,4,5-trimethoxy-
phenylboronic acid (11e) are commercially available
reagents.
3. Conclusions
In summary, we have shown that 4-(1-alkynyl)-3-bromo-
2(5H)-furanones 5a and the corresponding 3-chloro
derivatives 5b can be regioselectively and efficiently
prepared by modified versions of the Sonogashira reaction
between 1-alkynes and 3,4-dibromo-2(5H)-furanone (4a)
and 3,4-dichloro-2(5H)-furanone (4b), respectively, which
involve the use of KF as a base. We have also shown that
compounds 5a are useful precursors to 4-(1-alkynyl)-3-aryl-
2(5H)-furanones 7. Interestingly, some compounds of
4.1. General
4.1.1. Synthesis of 3-bromo-4-phenylethynyl-2(5H)-fura-
none (5aa) by Pd-catalyzed reaction between tributyl
(phenylethynyl)tin (8) and 4a. A flame-dried flask flushed
with argon was charged with PdCl2(PPh3)2 (0.133 g,
0.19 mmol), CuI (0.036 g, 0.19 mmol), 4b (1.90 mmol), 8
Table 5. Cytotoxicity of compounds 5aa, 5ac and 5ad
Compound
log10 GI50,a Leukemia
MGMb
CCRF-CEM
HL-60(TB)
K-562
RPMI-8226
SR
5aa
5ac
5ad
26.09
26.62
25.67
27.70
26.48
26.28
25.58
26.43
25.38
26.86
26.80
26.66
26.73
26.44
.24.00
25.32
25.70
25.49
a
Log molar drug concentration required for 50% growth inhibition.
Mean graph midpoint for all human cancer cell lines tested (ca. 60).
b

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F. Bellina et al. / Tetrahedron 59 (2003) 9091–9100
(0.78 g, 1.99 mmol) and a deaerated 10:1 mixture of THF
and CH3CN (10 ml) and the mixture was stirred at 408C for
16 h. It was then allowed to cool to 208C and poured into a
saturated NH4Cl solution (50 ml) and extracted with AcOEt
(4£50 ml). The organic extract was stirred for 4 h with an
aqueous semisaturated KF solution (100 ml) and filtered
through Celite. The filtrate was extracted with AcOEt
(3£20 ml), washed with brine, dried over Na2SO4 and
concentrated under reduced pressure. The residue was
purified by MPLC on silica gel, with a mixture of CH2Cl2
and hexane (50:50þ1% AcOEt) as eluent, to give 5aa
(85 mg, 17% yield) as a pale yellow crystalline solid. Mp
141–1428C. MS, m/z (%): 264 (39, Mþ), 262 (39, Mþ), 235
(29), 233 (30), 153 (100), 126 (85), 125 (28), 102 (13), 75
(28). IR (KBr): n 2201, 1760, 1585, 1437, 1345, 1261, 1096,
(5 mol%), CuI (10 mol%) and AsPh3 (10 mol%); catalyst
system C consisted of PdCl2(PhCN)2 (5 mol%), CuI
(10 mol%) and P(2-furyl)3 (10 mol%) and catalyst system
D consisted of PdCl2(CH3CN)2 (5 mol%), CuI (10 mol%)
and P(2-furyl)3 (10 mol%). The reactions in a 1.1 mixture of
toluene and water were performed in the presence of
BnEt3NþCl2 (10 mol%). After completion of the reaction,
the reaction mixture was allowed to cool to 208C, poured
into a saturated aqueous NH4Cl solution (75 ml) and
extracted with AcOEt (4£30 ml). The organic extract was
washed with brine (30 ml), dried over Na2SO4 and
concentrated under reduced pressure. The residue was
purified by MPLC on silica gel. Tables 1 and 2 summarize
the results obtained in the synthesis of 5aa and 5ac–5ag,
respectively. Entries 6–8 of Table 1 summarize the attempts
we made to perform the cross-coupling reaction between 4a
and 10a using CsF, K2CO3 or K3PO4 respectively, instead
of KF as a base. The procedure involving treatment of 4a
with 10 and 4.0 equiv. of KF in a 1:1 mixture of toluene and
water in the presence of 10 mol% BnEt3NþCl2 and the
catalyst system C was used to prepare 5aa (entry 3, Table 1)
and 5ac, 5ad and 5ag (entries 1, 4 and 7, respectively,
Table 2). On the other hand, the procedure involving
treatment of 4a with 10 in toluene in the presence of
4.0 equiv. of KF and catalyst system D was used to prepare
5ac, 5ae and 5af (entries 2, 5 and 6, respectively, Table 2).
As shown in entry 3 of Table 2, compound 5ac was also
synthesized on a 20 mmol scale using a procedure very
similar to that employed in entry 2. Finally, it must be
mentioned that compound 5ab was prepared by a procedure
very similar to that used in entry 3 of Table 1 to prepare 5aa
(Scheme 2).
1
1032, 990, 802, 687 cm21. H NMR (200 MHz, CDCl3): d
4.88 (2H, s, H-5), 7.45 (3H, m, Harom), 7.60 ppm (2H, m,
Harom). 13C NMR (50 MHz, CDCl3): d 72.3, 78.9, 108.7,
114.7, 120.6, 128.7 (2C), 130.6, 132.2 (2C), 143.3,
168.6 ppm. Anal. calcd for C12H7BrO2: C, 62.37; H, 3.05.
Found: C, 62.30; H, 2.99.
4.1.2. Conversion of compound 5aa into 4-phenylethy-
nyl-2(5H)-furanone (9a). A suspension of zinc dust
(0.71 g, 10.9 mmol, Aldrich cat. No 20,998-8) in deaerated
THF (15 ml) containing 1,2-dibromoethane (0.037 ml,
0.43 mmol) was heated under argon to 658C for 1 min and
cooled to room temperature. Chlorotrimethylsilane
(0.042 ml, 0.33 mmol) was added. After 15 min at room
temperature, a solution of 5aa (0.71 g, 2.71 mmol) in THF
(5 ml) was added dropwise and the mixture was stirred
under reflux for 27 h, cooled to room temperature and
allowed to settle. The clear solution of the organozinc
derivative so obtained was poured into 5% HCl (70 ml)
cooled at 08C and extracted with AcOEt (4£50 ml). The
organic extract was washed with brine (20 ml), dried over
Na2SO4 and concentrated under reduced pressure. The
residue was purified by MPLC on silica gel, with a mixture
of toluene and AcOEt (96:4) as eluent, to give 9a (0.31 g,
62% yield) as a pale yellow solid. Mp 85–878C. MS, m/z
(%): 184 (95, Mþ), 155 (20), 127 (22), 126 (100), 98 (6), 87
(6), 77 (10), 74 (11), 63 (9). IR (KBr): n 2200, 1776, 1747,
4.2.1. 3-Bromo-4-phenylethynyl-2(5H)-furanone (5aa).
The crude reaction product, which was obtained by Pd/
Cu-catalyzed reaction of 4a with 10a (entry 3, Table 1), was
purified by MPLC on silica gel, with a mixture of CH2Cl2
and hexane (50:50þ1% AcOEt) as eluent, to give 5aa in
85% yield. The physical and spectral properties of this
compound were in agreement with those of 5aa prepared by
Pd-catalyzed reaction between tributyl(phenylethynyl)tin
(8) and 4a.
1
1611, 1445, 1312, 1152, 1152, 1029, 882, 850 cm21. H
NMR (200 MHz, CDCl3): d 4.91 (2H, d, J¼2.2 Hz, H-5),
6.26 (1H, t, J¼2.2 Hz, H-3), 7.43 (3H, m, Harom), 7.54 ppm
(2H, m, Harom). 13C NMR (50 MHz, CDCl3): d 72.9, 79.2,
104.9, 120.7, 122.0, 128.6 (2C), 130.2, 131.9 (2C), 147.0,
173.1 ppm. The physical and spectral properties of this
compound were in agreement with those previously
reported.13
4.2.2. 3-Bromo-4-(p-tolyl)ethynyl-2(5H)-furanone (5ab).
The crude reaction product, obtained by reaction of p-
tolylacetylene (10b) with 4a at 508C for 74 h in a 1:1
mixture of toluene and water, in the presence of 4.0 equiv.
of KF, 10 mol% BnEt3NþCl2 and catalyst system C
(Scheme 2), was purified by MPLC on silica gel, with a
mixture of toluene and AcOEt (99:1), followed by
recrystallization from CH2Cl2 and hexane, to give 5ab as
a light brown solid in 71% yield. Mp 115–1178C. MS, m/z
(%): 278 (81, Mþ), 276 (90, Mþ), 249 (51), 247 (52), 167
(100), 152 (20), 140 (94), 139 (92), 63 (64). IR (KBr): n
2204, 1767, 1594, 1445, 1326, 1205, 1179, 1028, 984, 834,
4.2. General procedures for the synthesis of 4-(1-
alkynyl)-3-bromo-2(5H)-furanones 5a from 1-alkynes 10
and 4a
1
A mixture of compound 4a (0.48 g, 2.0 mmol) and a 1-
alkyne 10 (2.4 mmol) in a deaerated 1:1 mixture of toluene
and water (15.6–16.8 ml) or deaerated toluene (16.0 ml)
was reacted under argon with 4.0 equiv. of KF in the
presence of catalyst system A, B, C, or D for the period of
time and at the temperature indicated in Table 1 or 2.
Catalyst system A consisted of Pd(PPh3)4 (5 mol%) and CuI
(5 mol%); catalyst system B consisted of PdCl2(PhCN)2
743 cm21. H NMR (200 MHz, CDCl3): d 2.40 (3H, s,
CH3), 4.87 (2H, s, H-5), 7.22 (2H, m, Harom), 7.47 ppm
(2H, Harom). 13C NMR (50 MHz, CDCl3): d 21.7, 72.3,
78.6, 109.2, 114.0, 117.5, 129.4 (2C), 132.1 (2C), 141.3,
143.4, 168.7 ppm. Anal. calcd for C13H9BrO2: C, 56.34; H,
3.27. Found: C, 56.22; H, 3.09.
4.2.3. 3-Bromo-4-(1-hexynyl)-2(5H)-furanone (5ac). The

F. Bellina et al. / Tetrahedron 59 (2003) 9091–9100
9097
crude reaction product, which was obtained by reaction of
4a with 1-hexyne (10c) in toluene in the presence of catalyst
system D (entry 2, Table 2), was purified by MPLC on silica
gel, with a mixture of hexane and Et2O (80:20) as eluent, to
give 5ac as a pale orange liquid in 91% yield. MS, m/z (%):
244 (49, Mþ), 242 (62, Mþ), 227 (38), 187 (24), 143 (61),
135 (59), 119 (86), 117 (47), 91 (100), 79 (44), 63 (32). IR
(film): n 2227, 1785, 1765, 1614, 1341, 1288, 1171, 1039,
4.2.7. 3-Bromo-4-(1-octynyl)-2(5H)-furanone (5af). The
crude reaction product, which was obtained by reaction of
4a with 1-octyne (10f) in a 1. 1 mixture of toluene and water
in the presence of catalyst system C (entry 7, Table 2), was
purified by MPLC on silica gel, with a mixture of hexane
and Et2O (80:20) as eluent, to give 5af as an orange liquid in
75% yield. MS, m/z (%): 243 (33), 241 (31), 229 (39), 227
(38), 202 (32), 165 (62), 143 (46), 141 (36), 105 (57), 95
(43), 91 (100). IR (film): n 2228, 1786, 1766, 1613, 1448,
1340, 1171, 1038, 984, 749, 719 cm21. 1H NMR (200 MHz,
CDCl3): d 0.91 (3H, t, J¼6.7 Hz, H-80), 1.46 (8H, m, H-40,
H-50, H-60 and H-70), 2.51 (2H, t, J¼6.9 Hz, H-30), 4.75 ppm
(2H, s, H-5). 13C NMR (50 MHz, CDCl3): d 14.0, 20.2,
22.5, 27.8, 28.4, 31.2, 71.1, 72.6, 112.3, 113.6, 144.3,
168.9 ppm. Anal. calcd for C12H15BrO2: C, 53.16; H, 5.57.
Found: C, 53.07; H, 5.48.
1
984, 749, 719 cm21. H NMR (200 MHz, CDCl3): d 0.95
(3H, t, J¼7.1 Hz, H-60),01.54 (4H, m, H-40 and H-50), 2.52
(2H, m, t, J¼6.7 Hz, H-3 ), 4.77 ppm (2H, s, H-5). 13C NMR
(50 MHz, CDCl3): d 13.5, 19.9, 21.9, 29.9, 71.0, 72.6,
112.3, 113.5, 144.4, 168.9 ppm. Anal. calcd for
C10H11BrO2: C, 49.41; H, 4.56. Found: C, 49.32; H, 4.49.
4.2.4. 3-Bromo-4-(3,3-dimethyl-1-butynyl)-2(5H)-fura-
none (5ac). The crude reaction product, which was obtained
by reaction of 4a with 3,3-dimethyl-1-butyne (10d) in a
1:1 mixture of toluene and water in the presence of
catalyst system C (entry 4, Table 2), was purified by
MPLC on silica gel, with a mixture of hexane and Et2O
(80:20) as eluent, to give 5ad as a colorless solid in 84%
yield. Mp 79–808C. MS, m/z (%): 244 (20, Mþ), 242 (21,
Mþ), 229 (42), 227 (43), 171 (42), 169 (43), 133 (11),
119 (100), 105 (35), 91 (54), 77 (33). IR (KBr): n 2212,
1774, 1758, 1608, 1437, 1342, 1305, 1158, 1028, 988,
4.2.8. Synthesis of 3,4-di(1-hexynyl)-2(5H)-furanone
(6a). Two procedures were used for the synthesis of this
compound. The first of these involved treatment of 4a
(0.49 g, 2.05 mmol) with 1-hexyne (10c) (0.51 g,
6.15 mmol) in deaerated toluene (16 ml) at 908C for 160 h
under argon, in the presence of KF (0.48 g, 8.2 mmol),
PdCl2(PhCN)2 (26.6 mg, 0.10 mmol), CuI (39.0 mg,
0.20 mmol), and AsPh3 (62.8 mg, 0.20 mmol). The mixture
was then allowed to cool to room temperature and worked
up using a procedure very similar to that used for the
preparation of compounds 5a. Purification of the crude
reaction mixture by MPLC on silica gel, with toluene as
eluent, gave 6a (0.14 g, 27% yield) as a light brown liquid.
MS, m/z (%): 244 (100, Mþ), 202 (44), 187 (33), 173 (32),
157 (50), 143 (52), 129 (67), 128 (67), 115 (87), 91 (84), 77
(49). IR (film): n 2216, 1789, 1611, 1456, 1375, 1337, 1125,
1041, 1031, 765 cm21. 1H NMR (200 MHz, CDCl3): d 0.97
(6H, m, H-60 and H-600),0 1.49 (8H, m, H-40, H-400, H-50 and
H-500), 2.49 (4H, m, H-3 and H-300), 4.75 ppm (2H, s, H-5).
13C NMR (50 MHz, CDCl3): d 13.6 (2C), 19.6, 19.9, 21.9
(2C); 30.0, 30.3, 70.2 (2C), 71.6, 102.3 (2C), 111.2, 118.5,
145.2, 171.2 ppm. Anal. calcd for C16H20O2: C, 78.65; H,
8.25. Found: C, 78.49; H, 8.13. The second procedure for
the preparation of 6a involved treatment of 5ac (0.50 g,
2.05 equiv.) with 10ac (0.34 g, 4.10 mmol) in deaerated
toluene (16 ml) at 908C for 73 h under argon, in the presence
of KF (0.48 g, 8.2 mmol), PdCl2(MeCN)2 (26.6 mg,
0.10 mmol), CuI (39.0 mg, 0.20 mmol) and AsPh3
(62.8 mg, 0.20 mmol). This procedure furnished 6a in
31% yield.
1
748 cm21. H NMR (200 MHz, CDCl3): d 1.34 (9H, s, t-
Bu), 4.75 ppm (2H, s, H-5). 13C NMR (50 MHz, CDCl3):
d 28.9, 30.2 (2C), 69.7, 72.5, 113.8, 119.7, 144.2,
168.9 ppm. Anal. calcd for C10H11BrO2: C, 49.41; H,
4.56. Found: C, 49.31; H, 4.44.
4.2.5. 3-Bromo-4-(3-hydroxy-3-methyl-1-butynyl)-
2(5H)-furanone (5ae). The crude reaction product, which
was obtained by reaction of 4a with 3-hydroxy-3-methyl-1-
butyne (10e) in toluene in the presence of catalyst system D
(entry 5, Table 2), was purified by MPLC on silica gel, with
a mixture of CH2Cl2 and AcOEt (90:10) as eluent, to give
5ae as a yellow solid in 40% yield. Mp 73–758C. MS, m/z
(%): 246 (3, Mþ), 244 (2, Mþ), 231 (90), 229 (100), 173
(41), 171 (42), 165 (71), 121 (19), 91 (19), 77 (78), 63 (35).
IR (KBr): n 3470, 2215, 1777, 1615, 1368, 1346, 1288,
1142, 1042, 986, 750 cm21. 1H NMR (200 MHz, CDCl3): d
1.64 (6H, s, CH3), 4.79 ppm (2H, s, H-5). 13C NMR
(50 MHz, CDCl3): d 30.8 (2C), 65.8, 71.9, 72.3, 113.5,
115.2, 143.0, 168.6 ppm. Anal. calcd for C9H9BrO3: C,
44.11; H, 3.70. Found: C, 44.03; H, 3.63.
4.2.6. 3-Bromo-4-(trimethylsilylethynyl)-2(5H)-fura-
none (5af). The crude reaction product, which was obtained
by reaction of 4a with trimethylsilylacetylene (10f) in
toluene in the presence of catalyst system D (entry 6, Table
2), was purified by MPLC on silica gel, with a mixture of
hexane and Et2O (85:15) as eluent, to give 5af as a light
brown solid in 30% yield. Mp 41–448C. MS, m/z (%): 260
(5, Mþ), 258 (5, Mþ), 245 (99), 243 (100), 187 (11), 185
(12), 179 (13), 107 (9), 91 (10), 77 (8). IR (KBr): n 2016,
1780, 1769, 1600, 1434, 1343, 1262, 1253, 1032, 988,
4.2.9. Conversion of compound 5ag into 4-(1-octynyl)-
2(5H)-furanone (9b). Compound 5ag (0.70 g, 2.60 mmol)
was reacted with activated zinc dust (0.68 g, 10.4 mmol,
Aldrich cat. No. 20,998-8) in refluxing THF for 20 h,
followed by acidic hydrolysis according to a procedure very
similar to that used to prepare 9a from 5aa. Purification of
the crude reaction mixture by MPLC on silica gel, with a
mixture of hexane and Et2O (75:25) as eluent, furnished 9b
(0.22 g, 44% yield) as a pale yellow liquid. MS, m/z (%):
163 (30), 149 (20), 119 (25), 107 (18), 105 (56), 92 (36), 91
(100), 79 (46), 77 (36), 69 (31), 63 (43). IR (film): n 2224,
1780, 1751, 1610, 1449, 1292, 1145, 1042, 881, 852,
847 cm21 1H NMR (200 MHz, CDCl3): d 0.29 (9H,
.
SiMe3), 4.78 ppm (2H, s, H-5). 13C NMR (50 MHz,
CDCl3): d 20.6 (3C), 72.4, 92.9, 115.7, 117.2, 143.0,
168.6 ppm. Anal. calcd for C9H11BrO2Si: C, 41.71; H, 4.28.
Found: C, 41.64; H, 4.15.
698 cm21 1H NMR (200 MHz, CDCl3): d 0.90 (3H, t,
.
J¼6.6 Hz, H-80). 1.40 (8H,0 m, H-40, H-50, H-60 and H-70),
2.45 (2H, t, J¼6.9 Hz, H-3 ), 4.77 (2H, t, J¼2.2 Hz, H-5),

9098
F. Bellina et al. / Tetrahedron 59 (2003) 9091–9100
6.09 ppm (1H, t, J¼0, 2.2 Hz, H-3). 13C NMR (50 MHz,
CDCl3): d 14.0, 19.9, 22.5, 27.9, 28.6, 31.2, 71.4, 73.2,
108.3, 121.2, 148.2, 173.6 ppm. Anal. calcd for C12H16O2:
C, 74.97; H, 8.39. Found: C, 74.88; H, 8.26.
756 cm21 1H NMR (200 MHz, CDCl3): d 0.88 (9H, t,
.
J¼7.4 Hz, Sn–C–C–C–CH3), 1.29 (18H, Sn(CH2–CH2–
CH2–C)3, 3.46 (3H, s, OCH3), 5.15 (2H, s, OCH2O), 7.04
(2H, m, Harom), 7.31 ppm (2H, m, Harom). 13C NMR
(50 MHz, CDCl3): d 9.8 (3C), 13.7 (3C), 27.4 (3C), 29.2
(3C), 55.8, 94.0, 112.0, 121.8, 129.6, 130.4, 136.9,
161.6 ppm. Anal. calcd for C20H36O2Sn: C, 56.23; H,
8.49. Found: C, 56.12; H, 8.36.
4.3. General procedure for the synthesis of
4-(1-alkynyl)-3-chloro-2(5H)-furanones 5b
A mixture of compound 4b (0.61 g, 4.0 mmol) and a 1-
alkyne 10 (3.0 mmol) in a deaerated 1:1 mixture of toluene
and water (32 ml) was reacted under argon at 658C for
165–167 h with 4.0 equiv. of KF in the presence of
PdCl2(MeCN)2 (5 mol%), CuI (10 mol%), PCy3
(10 mol%) and BnEt3NþCl2 (5 mol%). The reaction
mixture was then allowed to cool to 208C, poured into a
saturated aqueous NH4Cl solution (75 ml) and extracted with
AcOEt (4£30 ml). The organic extract was washed with brine
(30 ml), dried over Na2SO4 and concentrated under reduced
pressure. The residue waspurifiedbyMPLConsilica gel. This
procedure was used to prepare compounds 5ba and 5bb.
4.4. General procedures for the synthesis of
4-(1-alkynyl)-3-aryl-2(5H)-furanones 7
Two general procedures were used to prepare compounds 7
from the corresponding 4-(1-alkynyl)-3-bromo-2(5H)-fur-
anones 5a. The first procedure involved the Pd-catalyzed
reaction of compounds 7 with aryl(tributyl)tins. According
to this procedure, a flame-dried flask flushed with argon was
charged with PdCl2[P(o-tolyl)3]2 (78.6 mg, 0.10 mmol), CuI
(38.1 mg, 0.20 mmol), a compound 5a (2.0 mmol) and dry
NMP (2.0 ml). A deaerated solution of an organotin
compound 11 (1.4–3.0 equiv.) in NMP (2.5 ml) was
added and the mixture was stirred under argon at 808C for
28 h. The reaction between 5ac and tributyl(4-methoxy-
phenyl)tin (11a) was carried out using a 1:3 molar ratio
between these compounds, but the reactions of 5aa with
tributyl[(2-methoxymethoxy)phenyl]tin (11b) and tribu-
tyl(2-furyl)tin (11c) were performed using a 1:1.4 and
1:1.5 molar ratio, respectively, between the furanone
derivative and the organotin compound. The reaction
mixture was then allowed to cool to room temperature,
diluted with AcOEt (50 ml) and stirred for 3–4 h with a 8 M
aqueous KF solution (50 ml). The mixture was filtered
through Celite and the filtrate was extracted with AcOEt
(4£25 ml). The extract was washed with brine (15 ml), dried
over Na2SO4 and concentrated under reduced pressure. The
residue was purified by MPLC on silica gel. This procedure
was used to prepare compounds 7a, 7b and 7c (entries 1–3,
Table 3).
4.3.1. 3-Chloro-4-(phenylethynyl)-2(5H)-furanone (5ba).
The crude reaction product, which was obtained by reaction
of 4b with 10a, was purified by MPLC on silica gel, with a
mixture of toluene and AcOEt (99:1) as eluent, to give 5ba
as a yellow solid in 51% yield. Mp 145–1488C. MS, m/z
(%): 220 (44, Mþ), 218 (100, Mþ), 191 (32), 189 (93), 161
(39), 160 (59), 153 (17), 126 (27), 99 (11), 80 (11). IR
(KBr): n 2207, 1764, 1618, 1438, 1220, 1127, 1036, 1015,
1
975, 763, 749 cm21. H NMR (200 MHz, CDCl3): d 4.91
(2H, s, H-5), 7.44 (3H, m, Harom), 7.58 ppm (2H, s,
Harom). 13C NMR (50 MHz, CDCl3): d 69.9, 70.7, 108.7,
120.5, 127.8, 128.6 (2C), 130.5, 132.1 (2C), 138.8,
167.8 ppm. Anal. calcd for C12H7ClO2: C, 65.92; H, 3.23.
Found: C, 65.75; H, 3.15.
4.3.2. 3-Chloro-4-(1-hexynyl)-2(5H)-furanone (5bb). The
crude reaction product, which was obtained by reaction of
4b with 10c, was purified by MPLC on silica gel, with a
mixture of hexane and Et2O (80:20) as eluent, to give 5bb as
an orange liquid in 31% yield. MS, m/z (%): 200 (14, Mþ),
198 (47, Mþ), 183 (54), 163 (32), 143 (30), 135 (50), 119
(80), 91 (92), 77 (100). IR (film): n 2229, 1776, 1736, 1623,
A second procedure involved the Pd-catalyzed reaction of
compounds 5a with arylboronic acids 11. According to this
procedure, a flame dried flask was charged with PdCl2
(PPh3)2 (64.9 mg, 0.093 mmol), BnEt3NþCl2 (21.2 mg,
0.093 mmol), CsF (0.84 g, 5.55 mmol), a compound 5a
(1.85 mmol), an arylboronic acid 11 (3.70 mmol) and a
deaerated 1:1 mixture of toluene and water (26 ml), and the
mixture was stirred under argon at 608C for the period of
time indicated in Table 3. It was then cooled to room
temperature, extracted with AcOEt (4£50 ml) and filtered
through Celite. The filtrate was washed with brine (30 ml),
dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by MPLC on silica gel.
This procedure was used to prepare compounds 7a and 7d
(entries 4 and 5, Table 3).
1
1446, 1373, 1242, 1178, 1044, 1011, 752 cm21. H NMR
(200 MHz, CDCl3): d 0.95 (3H, t, J¼7.1 Hz, H-60), 1.52
(4H, m, H-40 and H-50), 2.53 (2H, t, J¼7.0 Hz, H-30),
4.79 ppm (2H, s, H-5). 13C NMR (50 MHz, CDCl3): d 13.5,
19.8, 21.9, 29.9, 69.9, 71.0, 112.3, 124.4, 139.9, 168.2 ppm.
60.46; H, 5.58. Found: C, 60.32; H, 5.44.
4.3.3. Tributyl[(2-methoxymethoxy)phenyl]tin (11b). A
0.45 M THF solution of the Grignard reagent derived from
(2-methoxymethoxy)phenyl bromide (110 ml, 49.5 mmol)
was reacted with tributyltin chloride (14.51 g, 44.6 mmol)
for 20 h at 658C. It was then cooled to room temperature,
poured into water (300 ml) and extracted with Et2O
(4£40 ml). The organic extract was dried over Na2SO4
and concentrated under reduced pressure. The residue was
fractionally distilled to give 11b (13.53 g, 71% yield) as a
colorless liquid. Bp 160–1628C/0.8 mbar. MS, m/z (%): 371
(100), 369 (77), 367 (49), 213 (88), 211 (79), 197 (59), 195
(59), 179 (78), 177 (82), 175 (83), 91 (73). IR (film): n 2955,
2926, 1576, 1464, 1435, 1224, 1189, 1154, 1081, 924,
4.4.1. 4-(1-Hexynyl)-3-(4-methoxyphenyl)-2(5H)-fura-
none (7a). The crude reaction product, which was obtained
by Pd-catalyzed reaction of 5ac with 11a (entry 1, Table 3),
was purified by MPLC on silica gel, with a mixture of
CH2Cl2 and hexane (60:40þ1% AcOEt), to give 7a as a pale
yellow solid in 50% yield. Mp 76–788C. MS, m/z (%): 270
(100, Mþ), 227 (13), 213 (24), 185 (11), 183 (17), 171 (33),
169 (12), 1390 (11), 128 (8), 121 (11), 77 (7). IR (KBr): n

F. Bellina et al. / Tetrahedron 59 (2003) 9091–9100
9099
2217, 1752, 1606, 1459, 1370, 1296, 1254, 1181, 1047,
954 cm21 1H NMR (200 MHz, CDCl3): d 0.96 (3H, t,
Acknowledgements
.
J¼7.1 Hz, H-60), 1.53 (4H, m, H-40 and H-50), 2.52 (2H, t,
J¼6.8 Hz, H-30), 3.84 (3H, s, OCH3), 4.77 (2H, s, H-5), 6.95
(2H, m, Harom), 8.11 ppm (2H, m, Harom). 13C NMR
(50 MHz, CDCl3): d 13.5, 19.8, 22.0, 30.1, 55.2, 71.0, 73.3,
108.9, 113.6 (2C), 122.2, 129.1, 129.2 (2C), 136.4, 160.1,
172.8 ppm. Anal. calcd for C17H18O3: C, 75.53; H, 6.71.
Found: C, 75.43; H, 6.66. This same compound was
synthesized in 59% yield by Pd-catalyzed reaction of 5ac
with 11d (entry 4, Table 3).
This work was supported by the Ministero dell’Istruzione,
`
dell’Universita e della Ricerca (MIUR) and the University
of Pisa. We are also grateful to Mr Piergiorgio Vergamini
for recording IR spectra.
References
`
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(entry 2, Table 3), was purified by MPLC on silica gel, with
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1229, 1153, 1080, 1038, 994 cm21. H NMR (200 MHz,
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and hexane (55:45þ1% AcOEt), to give 7c as a pale yellow
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˚
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1640, 1340, 1261, 1099, 1049, 1037, 1017, 970, 802 cm21
.
1H NMR (200 MHz, CDCl3): d 4.93 (2H, s, H-5), 6.55 (1H,
dd, J¼3.4, 1.7 Hz, Harom), 7.30 (1H, d, J¼3.4 Hz, Harom),
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(2C), 172.11 ppm. Anal. calcd for C21H18O5: C, 71.99; H,
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