Mucochloric acid: A useful synthon for the selective synthesis of 4-aryl-3-chloro-2(5H)-furanones, (Z)-4-aryl-5-[1-(aryl)methylidenel-3-chloro-2(5H)-furanones and 3,4-diaryl-2(5H)-furanones

Article abstract of DOI:10.1002/ejoc.200300097

3,4-Dichloro-2(5H)-furanone, which has been prepared efficiently from mucochloric acid, has been transformed selectively into 4-aryl-3-chloro-2(5H)-furanones either by Suzukior Stille-type reactions. These monochloro derivatives have been used as precursors either to (Z)-4-aryl-5-[1-(aryl)methylidene]-3-chloro-2(5H)-furanones, including naturally occurring rubrolide M, or to unsymmetrical 3,4-diaryl-2(5H)-furanones. Some 2(5H)-furanone derivatives so prepared have been found to exhibit significant cytotoxic activity in vitro against the NCI three-cell-line panel, but limited cytotoxicity against the NCI human tumor 60 cell-line panel. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300097

FULL PAPER
Mucochloric Acid: A Useful Synthon for the Selective Synthesis of 4-Aryl-3-
chloro-2(5H)-furanones, (Z)-4-Aryl-5-[1-(aryl)methylidene]-3-chloro-2(5H)-
furanones and 3,4-Diaryl-2(5H)-furanones
Fabio Bellina,*[a] Chiara Anselmi,[a] Francesca Martina,[a] and Renzo Rossi*[a]
Keywords: CϪC coupling / Heterocycles / Natural products / Palladium
3,4-Dichloro-2(5H)-furanone, which has been prepared effi-
ciently from mucochloric acid, has been transformed select-
ively into 4-aryl-3-chloro-2(5H)-furanones either by Suzuki-
or Stille-type reactions. These monochloro derivatives have
been used as precursors either to (Z)-4-aryl-5-[1-(aryl)methy-
anones. Some 2(5H)-furanone derivatives so prepared have
been found to exhibit significant cytotoxic activity in vitro
against the NCI three-cell-line panel, but limited cytotoxicity
against the NCI human tumor 60 cell-line panel.
lidene]-3-chloro-2(5H)-furanones, including naturally occur- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
ring rubrolide M, or to unsymmetrical 3,4-diaryl-2(5H)-fur-
Germany, 2003)
Introduction
The 2(5H)-furanone moiety occurs in many natural prod-
ucts that exhibit biological activities ranging from anti-
biotic,[1,2] cytotoxic,[3Ϫ5] and antitumor properties[6] to inhi-
bition of cholesterol biosynthesis.[7] In addition, 2(5H)-fu-
ranone derivatives find a variety of applications in organic
synthesis.[8Ϫ10] The long-standing interest in these hetero-
cyclic compounds is testified by the wide variety of methods
reported in the literature for their preparation.[11Ϫ13]
A
good many of the recently reported efforts on the synthesis
of 2(5H)-furanone derivatives have focused, however, on
transition metal-catalysed processes.[14Ϫ16] Recently, our
interest in the design and use of simple and efficient pro-
cedures for the synthesis of natural and non-natural oxy-
gen-containing heterocycles[17Ϫ22] has led us to explore the
utility of 3,4-dibromo-2(5H)-furanone (2) (Figure 1) for the
preparation of compounds containing the 2(5H)-furanone
moiety by transition-metal-catalysed reactions.[23Ϫ26] In
particular, we found that 2 could be converted selectively
into 4-aryl-3-bromo-2(5H)-furanones 3 either by Suzuki-
type reaction with arylboronic acids or by Stille-type reac-
tions with trialkyl(aryl)tin reagents[23,24] (Figure 1). Bro-
mides 3 were then converted by Pd-catalysed reaction with
trialkyl(aryl)tin reagents into 3,4-diaryl-2(5H)-furanones
4,[23] including 4a, which is a precursor to Vioxx (Ro-
fecoxib) (4b),[10,23] a cyclooxygenase-2 (COX-2) inhibitor.
Bromides 3 were also converted into 4-aryl-3-methyl-2(5H)-
Figure 1. Chemical structures of compounds 2, 3, 4, 4a, 5, 6, 6a,
7, 7a, 8, 9, 9a, 10, 11a and 11b prepared from mucobromic acid (1)
[a]
`
Dipartimento di Chimica e Chimica Industriale, Universita di
Pisa,
furanones 5,[23] which are substances that exhibit antifungal
properties,[27] 4-aryl-2(5H)-furanones 6,[23] including 6a,
which is a precursor to rubrolides C and E,[28] and (Z)-4-
Via Risorgimento n. 35, 56126 Pisa, Italy
Fax: (internat.) ϩ 39-050/918260
E-mail: bellina@dcci.unipi.it
rossi@dcci.unipi.it
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DOI: 10.1002/ejoc.200300097
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Mucochloric Acid: A Useful Synthon for the Selective Synthesis of Furanones
FULL PAPER
aryl-5-[1-(aryl)methylidene]-3-bromo-2(5H)-furanones 7,[24] ited by several compounds of general formula 13, 14 and 4
including the compound with the structure corresponding against human cancer cell lines.
to that reported in the literature for naturally occurring rub-
rolide N (7a)[3] (Figure 1). We also showed that 2 is a useful
Results and Discussion
precursor to 4-alkyl-3-bromo-2(5H)-furanones 8,[25] unsym-
metrical 3,4-dialkyl-2(5H)-furanones 9,[25] including the ra-
Synthesis of 3,4-Dichloro-2(5H)-furanone and 4-Aryl-3-
chloro-2(5H)-furanones
cemic form of phytopathogenic seiridin (9a),[29] and 3-
benzyl-4-isopropyl-2(5H)-furanone (10),[26] which is a pre-
cursor to nostoclide I (11a) and II (11b),[30] a pair of cyto-
toxic 2(5H)-furanones[31] (Figure 1).
Chemically pure 12, which was used as a starting material
for the synthesis of compounds 13, 14 and 4, was prepared
by reaction of mucochloric acid (16) with NaBH4 in meth-
anol according to a modification of a literature pro-
cedure[36] (Scheme 1). This modification, which involved re-
moval of methanol under reduced pressure before the crude
reaction mixture underwent the usual workup, allowed us
to obtain 12 in 89% yield.
More recently, we decided to investigate the use of 3,4-
dichloro-2(5H)-furanone (12) for the synthesis of 4-aryl-3-
chloro-2(5H)-furanones 13, symmetrical and unsymmetri-
cal 3,4-diaryl-2(5H)-furanones 4, and (Z)-4-aryl-5-[1-(aryl)-
methylidene]-3-chloro-2(5H)-furanones 14, including rub-
rolide M (14a), which is a natural product that proved to
be significantly cytotoxic against four cancer cell lines[3]
(Figure 2). Our attention towards 14a and some of its con-
geners was due to the fact that this rubrolide is the most
active among the four (Z)-4-aryl-5-[1-(aryl)methylidene]-3-
chloro-2(5H)-furanones isolated from Synoicum bloch-
manni.[3] On the other hand, we were interested in de-
veloping a convenient and efficient procedure for the syn-
thesis of 3,4-diaryl-2(5H)-furanones 4, since these com-
pounds can be considered as (Z)-restricted analogues of
combretastatin A-4 (15) (Figure 2), the potent antimitotic
and cytotoxic compound isolated from Combretum caf-
frum,[32,33] and some of them have been demonstrated to be
potent and selective COX-2 inhibitors.[34,35] In particular,
we examined the possibility of accessing compounds 13, 14
and 4 starting from 12 through chemistry similar to that we
have used successfully for the preparation of compounds
3Ϫ10 starting from 2. On the other hand, 12 (98% chemi-
cally pure) was prepared in 92% yield by treatment of muc-
ochloric acid (16), which is a commercially available com-
pound that is much less expensive than mucobromic acid
(1), with NaBH4 in methanol.[36] In this paper we provide
a full account on the results of these studies[37] and describe
the results of tests to evaluate the cytotoxic activity exhib-
Scheme 1. Synthesis of 3,4-dichloro-2(5H)-furanone (12)
It is interesting to note that applying a similar modifi-
cation to the protocol previously employed to prepare 3,4-
dibromo-2(5H)-furanone (2) from 1,[24] allowed us to in-
crease the yield of chemically pure 2 from 75 to 88% yield.
Having secured a good route to 12, next we turned our at-
tention to the preparation of 4-aryl-3-chloro-2(5H)-fu-
ranones 13 starting from this dichloride. Determination of
reaction conditions that allow the selective production of
compounds 13, however, required considerable experiment-
ation. In fact, in a preliminary attempt to prepare 3-chloro-
4-phenyl-2(5H)-furanone (13a) by reaction of 12 with 1.1
equiv. of phenylboronic acid (18a) under the conditions
commonly used for monoarylation of 2,[23,24] i.e., by heating
under reflux in THF for 22 h in the presence of
[PdCl2(MeCN)2] (5 mol %), AsPh3 (20 mol %) and Ag2O
(3.0 equiv.), we found that the conversion of the reaction
was very low (ca. 10%) and that the major reaction product
was biphenyl (19a) derived from the Pd-catalysed self-coup-
ling of 18a.[38] We observed also that 19a was the major
product when 12 was treated with of 18a (1.1 equiv.) in
methanol at 40 °C for 23 h in the presence of sodium acet-
ate (1.5 equiv.) and [PdCl2(PPh3)2] (3 mol %) or in toluene
at 80 °C for 6 h in the presence of Ag2O (3.0 equiv.),
[Pd2(dba)3] (2.5 mol %) and tBu3P (5 mol %). We found,
however, that the formation of 18a could be minimized ef-
fectively when the Suzuki-type reaction was performed by
treating 12 with of 18a (1.3 equiv.) in toluene at 80 °C in
the presence of KF and catalytic amounts of [Pd2(dba)3]
and tBu3P (Scheme 2).
Figure 2. Chemical structures of compounds 4, 12, 13, 14, 14a, 15,
16, 17a and 17b
Scheme 2. Synthesis of compounds 13a and 4c
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F. Bellina, C. Anselmi, F. Martina, R. Rossi
FULL PAPER
Table 1. Synthesis of 4-aryl-3-chloro-2(5H)-furanones 13 by Suzuki-type reactions
Entry[a]
Boronic acid
Ar1
Reaction time [h]
Product
13/4 molar ratio[b]
18
13
Isolated yield of 13 (%)
1
2
3
4
5
18a
18b
18c
18d
18e
C6H5
3-Cl,4-MeOC6H3
4-ClC6H4
4-MeOC6H4
4-MeSC6H4
24
21
27
24
24
13a
13b
13c
13d
13e
13
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
63
57
42
61
33
[a] All these reactions were performed under argon using 1.05 equiv. of 18. [b] Determined by GLC analysis of the crude reaction mixtures.
Under these conditions, the conversion of the reaction interesting to note that the yields of the reactions between
was almost quantitative and the amount of 19a in the crude 12 and 18 were increased using the procedure described by
reaction mixture was ca. 4%, but the desired product 13a Zhang and co-workers for the synthesis of a precursor to
was obtained along with a comparable amount of 3,4-di- Vioxx.[40] Thus, reaction of 12 with 2.0 equiv. of 18d in a
phenyl-2(5H)-furanone (4c). This result indicates that, al- 1:1 mixture of toluene and water in the presence of CsF
though it might be expected that the CϪCl bond at the and catalytic amounts of [PdCl2(PPh3)2] and BnEt3NϩClϪ
activated 4-position of 12 is more reactive than that at the (Method B) furnished 13d in 80% yield (Scheme 3). More-
3-position and, therefore, that the Pd-catalysed reaction over, a very similar reaction of 12 with 2.0 equiv. of 18e
might occur selectively at C-4, the selectivity of the cross- gave 13e in 80% yield (Scheme 3).
coupling reaction was negligible, probably because of the
very high activity of the catalyst system used. Therefore, we
examined the use of other electron-rich phosphane ligands,
such as Cy3P (Cy ϭ cyclohexyl) and (o-biphenyl)P(tBu)2,
in place of tBu3P. However, this modification, as well as the
use of a base such as CsF or Cs2CO3 in place of KF, did
not increase either the regioselectivity of the reaction or the
Scheme 3. Pd-catalysed syntheses of compounds 13d and 13e by
yield of 13a. Moreover, the cross-couplings performed using
CsF or Cs2CO3 in THF at room temperature resulted in
side reactions, which produced extensive decomposition of
Suzuki-type reactions under phase-transfer conditions
It should be noted, however, that, unlike our method, this
12. Finally, we found that the reaction of 12 with 1.05 equiv. literature procedure[40] involves the use of a very large mo-
of 18a in the presence of KF and catalytic amounts of lar excess of the requisite arylboronic acid and that, at least
[Pd2(dba)3] and (o-tolyl)3P (Method A) produced a reaction in our hands, it required reaction times significantly longer
mixture containing 13a contaminated by less than 6 and than those of our protocol. Moreover, this literature pro-
12% of 4c and 19a, respectively, and that chromatographic cedure furnished reaction mixtures contaminated by large
purification of this mixture allowed the isolation of pure amounts of the biaryl compounds derived from self-coup-
13a in 63% yield (Table 1, Entry 1). These reaction con- ling of the arylboronic acids.
ditions were then used to prepare compounds 13b, 13c, 13d,
Even though the results obtained for the synthesis of
compounds 13 by Suzuki-type reaction were quite satisfac-
and 13e.[39]
As shown in Table 1, which summarizes the results of the tory, we found it desirable to search for a new and efficient
preparation of these compounds, the selectivity of the reac- route to these monochloro derivatives from 12. Thus, we
tions involving arylboronic acids 18b؊e was found unex- investigated the Pd-catalysed Stille-type reaction of 12 with
pectedly to be much higher than that observed for the reac- aryl(tributyl)tin reagents 20[41] and, after some screening
tion between 18a and 12. On the other hand, similar to the experiments, found that the reaction of 12 with aryltin re-
situation that was observed in the preparation of 13a, the agents 20a, 20b, 20c, 20d, 20e, 20f and 20g in N-methylpyr-
crude reaction mixtures corresponding to the preparation rolidinone (NMP) at 85 °C in the presence of catalytic
of compounds 13b, 13c, 13d and 13e were contaminated by amounts of [Pd2(dba)3] and (o-tolyl)3P furnished com-
less than 12% of the biaryls 19b؊e derived from self-coup- pounds 13a, 13c, 13d, 13e, 13f, 13g and 13h in 53, 61, 78,
ling of arylboronic acids 18b؊e. Remarkably, all reaction 73, 55, 75 and 67% yield, respectively. As shown in Table 2,
mixtures derived from the cross-couplings of 12 with 18a؊e which summarizes the results of these reactions, the selec-
(Entries 1Ϫ5, Table 1) were free of traces of the regioiso- tivity of the reactions of 12 with aryltin reagents 20, except
mers of the desired monoarylated products 13a؊e. It is also for the reaction between 12 and 20g (Entry 7), was lower
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Mucochloric Acid: A Useful Synthon for the Selective Synthesis of Furanones
FULL PAPER
Table 2. Synthesis of 4-aryl-3-chloro-2(5H)-furanones 13 by Stille-type reactions
Entry[a]
Aryltributylstannane
Ar1
Reaction time [h]
Product
20
13
13/4 molar ratio[b]
Isolated yield of 13 (%)
1
2
3
4
20a
20b
20d
20e
20c
20f
20g
C6H5
4-ClC6H4
4-MeOC6H4
4-MeSC6H4
2-thienyl
3,4-(MeO)2C6H3
2-naphthyl
20
21
21
24
21
23
44
13a
13c
13d
13e
13f
13g
13h
36
8
25
53
61
78
73
55
75
67
23
5
n.d.
Ͼ 71
Ͼ 99
6
7[c]
[a]
[b]
Unless otherwise reported, all these reactions were performed under argon using 1.10 equiv. of 20. Determined by GLC analysis of
[c]
the crude reaction mixtures. This reaction was performed using 1.05 equiv. of 20g.
than that of the reaction of 12 with arylboronic acids
18b؊e, but the yields of compounds 13 prepared by the
Stille-type reaction were generally higher than those ob-
tained by reaction of 12 with arylboronic acids in toluene
at 85 °C in the presence of KF and catalytic amounts of
[Pd2(dba)3] and (o-tolyl)3P.
Synthesis of (Z)-4-Aryl-5-[1-(aryl)methylidene]-3-chloro-
2(5H)-furanones, Including Rubrolide M
Having found a good route to compounds 13, next we
turned our attention to their use in the preparation of rub-
rolide M (14a) and some of its non-natural congeners
characterized by methoxyaryl moieties. To this end, we
examined the possibility of using a procedure similar to that
recently employed to prepare compounds 17a and 17b start-
ing from 4-(4-methoxyphenyl)-2(5H)-furanone.[28] It should
be noted that we successfully employed this procedure re-
cently for the preparation of several (Z)-4-aryl-5-[1-(aryl)-
methylidene]-3-bromo-2(5H)-furanones 7,[10] including a
compound whose structure corresponds to that reported in
Scheme 4. Synthesis of compounds 14eϪi from 13b,d and aryl alde-
hydes 21aϪc
Table 3. Synthesis of (Z)-4-aryl-5-[1-(aryl)methylidene]-3-chloro-
the literature for rubrolide N (7a).[3] Thus, compound 13 2(5H)-furanones 14eϪi by introduction of a 1-(aryl)methylidene
unit at the C-5 position of compounds 13b and 13d
was treated with tert-butyldimethylsilyl trifluoromethanes-
ulfonate (TBDMSOTf), N,N-diisopropylethylamine and an
Entry[a] Reagents
Compound
Product
14 Isolated yield (%)
aryl aldehyde 21, and the mixture was treated with DBU
and then with 3  HCl to give the required compound 14
stereoselectively (Scheme 4). Compounds 14e and 14h were
prepared by this procedure in 46 and 43% yield, respec-
tively, from reaction of 21a with 13d and 13b, respectively
(Table 3, Entries 1 and 4).
On the other hand, compounds 14f and 14g were simi-
larly prepared in 65 and 51% yield, respectively, by reaction
of 21b with 13b and 13d, respectively (Table 3, Entries 2
and 3). An attempt to prepare 14i from 13b and 21c accord-
ing to this procedure was fruitless, however, with the desired
Aldehyde
Y
13
X
21
Z
1
2
3
4
5
13d
13b
13d
13b
13b
H
Cl
H
Cl
Cl
21a Br
H
H
H
H
14e
14f
14g
14h
46
65
51
43
21b
21b
H
H
21a Br
21c Br Br 14i
n.d.
[a]
These syntheses were performed using the experimental con-
ditions indicated in Scheme 4.
compound being obtained in a negligible GLC yield unsuccessful. In fact, no desired compound 14i was ob-
(Table 3, Entry 5). Moreover, another attempt to synthesize tained and only the loss of 13b was observed.
14i by a protocol very similar to that previously employed
The first total synthesis of rubrolide M (14a) was then
to prepare cardenolide 23 from 22 (Figure 3)[42] was also completed by treatment of 14e with 9.0 equiv. of BBr3 in
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F. Bellina, C. Anselmi, F. Martina, R. Rossi
FULL PAPER
successfully for Suzuki-[49] and Stille-type reactions[50] in-
volving unactivated or deactivated aryl or vinyl chlorides.
Thus, we investigated the synthesis of symmetrical 3,4-di-
aryl-2(5H)-furanones 4c and 4d by reaction of 12 with 3.0
equiv. of 18a and 18d, respectively, in the presence of KF
and catalytic amounts of [Pd2(dba)3] and tBu3P[49a][49l] and
we found that these reactions, when performed in toluene at
85 °C, furnished 4c and 4d in 63 and 67% yield, respectively
(Table 4, Entries 1 and 2).[51]
Figure 3. Chemical structures of compounds 22 and 23
Toluene was found to be the solvent of choice since the
reactions performed in THF or dioxane furnished large
amounts of biaryl 19 derived from self-coupling of aryl-
boronic acids 18. On the other hand, as shown in Entry 3
of Table 4, 4c was prepared in 60% yield by reaction of 12
with 20a in toluene at 95 °C in the presence of KF and
catalytic amounts of [Pd2(dba)3] and tBu3P. [49b]
Next we investigated the synthesis of unsymmetrical 3,4-
diaryl-2(5H)-furanones by Suzuki- and Stille-type reactions
involving compounds 13. As shown in Table 5 Ϫ which
summarizes the reagents, the experimental conditions used
and the results obtained in the synthesis of compounds 4a
and 4e؊j Ϫ four of these compounds, i.e., 4e, 4f, 4g, and
4h, are characterised by a 3,4,5-trimethoxyphenyl group at
C-3 of their 2(5H)-furanone ring. In fact, this group seems
to be essential for the cytotoxicity of 2(5H)-furanone de-
rivatives against murine and human tumor cell lines.[52]
Moreover, the 3,4,5-trimethoxy substituent in a phenyl ring
of combretastatin A-4 (15) has been demonstrated to be
essential for the bioactivity of this substance,[53] of which
compounds 4 can be considered (Z)-restricted analogues.
The other two unsymmetrical 3,4-diaryl-2(5H)-furanones
that we synthesized were 4a and 4i, which are structurally
related to 4f and 4g. As shown in Table 5, the catalyst sys-
tem consisting of [Pd2(dba)3] and tBu3P was suitable for the
reaction of 18f with 13a, 13d, 13g and 13h in toluene in the
presence of KF and furnished 4e, 4f, 4g and 4h in 42, 58, 58
and 39% yield, respectively (Table 5, Entries 1, 2, 4 and 5).
Scheme 5. Demethylation reaction of compounds 14e and 14f
CH2Cl2 followed by hydrolysis (Scheme 5). This demeth-
ylation reaction furnished 14a, in 97% yield, having spectral
properties in good agreement with those reported for the
natural product.[3] Compound 14f gave compound 14j in
98% yield under similar reaction conditions (Scheme 5).
Synthesis of 3,4-Diaryl-2(5H)-furanones
Although several methods have been reported in the lit-
erature for the preparation of 3,4-diaryl-2(5H)-
furanones,[10,23,27,43Ϫ48] we decided to study the synthesis
of these biologically interesting compounds by Pd-catalysed
reactions between 12 or compounds 13 and arylboronic ac-
ids 18 or aryl(tributyl)tins 20. Since the procedures to be
used involved CϪC bond-forming reactions at the unacti-
vated 3-position of the 2(5H)-furanone derivatives, which
were intermediates of these coupling reactions or were used
We also made an attempt to prepare 4h in a higher yield
as starting materials, we examined the use of some catalyst by using the air-stable palladacycle, [chloro{bis(2-
systems and experimental conditions previously employed norbornyl)phosphanyl}(2Ј-dimethylamino-1,1Ј-biphenyl-2-
Table 4. Synthesis of symmetrical 3,4-diaryl-2(5H)-furanones 4
Entry[a]
Organometallic compounds
Catalyst system[b]
Reaction conditions [h; °C]
Product
Yield (%)
18 or 20
Ar
M
4
1
2
3
18a
18d
20a
C6H5
4-MeOC6H4
C6H5
B(OH)2
B(OH)2
SnBu3
A
A
B
42; 85
46; 85
114; 95
4c
4d
4c
63
67
60
[a]
All these reactions were carried out in toluene using 3.0 equiv. of 18 or 20. The reactions involving 18 were performed in the presence
[b]
of 3.0 equiv. of KF, and the reactions involving 20 were performed in the presence of 2.0 equiv. of KF. Catalyst system A: Pd2(dba)3
(2.5 mol %), tBu3P (5 mol %). Catalyst system B: Pd(OAc)2 (5 mol %), Cy3P (10 mol %).
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Mucochloric Acid: A Useful Synthon for the Selective Synthesis of Furanones
FULL PAPER
Table 5. Synthesis of unsymmetrical 3,4-diaryl-2(5H)-furanones 4
Entry[a]
Organic electrophile
Organometallic compounds
18 or 20
Catalyst
system[b]
Reaction
conditions [h; °C]
Product
4
Yield
(%)
13
Ar
Ar1
M
1
2
3
4
5
6
7
13a
13d
13d
13g
13h
13d
13e
13e
C6H5
18f
18f
18f
18f
18f
20f
20a
18a
3,4,5-(MeO)3C6H2
3,4,5-(MeO)3C6H2
3,4,5-(MeO)3C6H2
3,4,5-(MeO)3C6H2
3,4,5-(MeO)3C6H2
3,4-(MeO)2C6H3
C6H5
B(OH)2
B(OH)2
B(OH)2
B(OH)2
B(OH)2
SnBu3
A
A
C
A
A
B
B
C
22; 85
45; 85
28; 85
47; 85
45; 85
50; 95
55; 95
23; 95
4e
4f
42
58
14
58
39
46
26
25
4-MeOC6H4
4-MeOC6H4
3,4-(MeO)2C6H3
2-naphthyl
4-MeOC6H4
4-MeSC6H4
4-MeSC6H4
4f
4g
4h
4i
4a
4a
SnBu3
B(OH)2
C6H5
[a]
All these reactions were carried out in toluene using 1.5 equiv. of 18 or 20. The reactions involving 18 were performed in the presence
[b]
of 3.0 equiv. of KF and those involving 20 were performed in the presence of 2.0 equiv. of KF.
Catalyst system A: [Pd2(dba)3] (2.5
mol %), tBu3P (5 mol %). Catalyst system B: [Pd(OAc)2] (5 mol %), Cy3P (10 mol %). Catalyst system C: [chloro{bis(2-
norbornyl)phosphanyl}(2Ј-dimethylamino-1,1Ј-biphenyl-2-yl)palladium()] (1 mol %).
Biological Results
yl)palladium()], as the catalyst precursor. In fact, this com-
plex has been reported to catalyse efficiently the reaction of
4-chloroanisole with 18a.[49e] The reaction between 13d and
18f in toluene at 85 °C in the presence of KF and 1 mol %
of this palladacycle, however, gave 4f in only 14% yield
(Table 5, Entry 3). On the other hand, the use of the catalyst
system consisting of [Pd(OAc)2] and Cy3P allowed the prep-
aration of compounds 4i and 4a in 46 and 26% yield,
respectively, by treatment of 13d and 13e with 20f and 20a,
respectively (Table 5, Entries 6 and 7). Compound 4a was
also synthesized in 25% yield by reaction of 13e with 18f in
the presence of KF and 1 mol % of [chloro{bis(2-
norbornyl)phosphanyl}(2Ј-dimethylamino-1,1Ј-biphenyl-2-
yl)palladium()] (Table 5, Entry 8).
Finally, compounds 4f and 4g were treated with a large
molar excess of BBr3 in CH2Cl2, followed by hydrolysis
(Scheme 6), to evaluate the cytotoxic activities of unsym-
metrical 3,4-diaryl-2(5H)-furanones characterised by
hydroxy groups in their aromatic rings. These reactions pro-
vided compounds 4j and 4k in almost quantitative yield and
having chemical purity greater than 96%.
The cytotoxic activities of compounds 13a, 14a, 14e, 14f,
14g, 14h, 14j, 4e, 4g, 4j, and 4k were evaluated in vitro
against the National Cancer Institute (NCI) three-cell-line
panel consisting of MCF-7 (breast), SF-268 (CNS) and
NCI-H460 (lung). The protocol used involved inoculation
and pre-incubation of each cell line on a microtiter plate.
Test agents were then added at a single concentration (1.00
ϫ 10Ϫ4 ) and the culture incubated for 48 h. End-point
determinations were made with sulforhodamine B, a pro-
tein-binding dye. Results for each test (Table 6) are reported
as the percentage of growth of the treated cells when com-
pared to the untreated control cells. Compounds that re-
duced the growth of any one of the cell lines to 32% or less
were considered to be active and some of them were passed
Table 6. Primary anticancer assay of some compounds of general
formula 13, 14 and 4
Entry Compound Percentage of growth inhibition
Activity
NCI-H460
(lung)
MCF-7
(breast)
SF-268
(CNS)
1
2
3
4
5
6
7
8
13a
14a
14e
14f
14g
14h
14j
4e
91
0
88
20
89
62
0
8
4
0
0
88
1
67
10
15
65
0
29
8
0
31
1
97
20
32
3
active
active
inactive
active
active
active
active
active
active
active
active
1
32
14
32
62
9
10
11
4g
4j
4k
1
Scheme 6. Demethylation reaction of compounds 4f and 4g
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F. Bellina, C. Anselmi, F. Martina, R. Rossi
FULL PAPER
on for evaluation in the full panel of 60 cell lines over a Experimental Section
5-log dose range.[54]
Results from Table 6 indicate that all tested compounds,
except 14e, passed the three-cell-line primary screening, but
that only 14a, 14f, 14j, 4e, 4g and 4j were significantly cyto-
toxic against all three cell lines (Entries 2, 4, 7Ϫ10). On the
other hand, 4k showed strong cytotoxic activity against
NCI-H-460 and MCF-7, but not against the SF-268 cell
line (Entry 11), and compounds 13a, 14g and 14h exhibited
limited cytotoxicity. In fact, 13a and 14h reduced the
growth of the SF-268 cell line only to less than 32% (Entries
1 and 6 and 14g reduced, to a limited extent, either the
MCF-7 or the SF-268 cell line (Entry 5). With regard to
the cytotoxicity of the (Z)-4-aryl-5-[1-(aryl)methylidene]-3-
chloro-2(5H)-furanones 14, the data of Table 6 seem also
to suggest that, as previously observed for (Z)-4-aryl-5-[1-
(aryl)methylidene]-3-bromo-2(5H)-furanones 7,[24] the pres-
ence of phenol subunits is necessary for compounds 14 to
exhibit high cytotoxic activities. Moreover, these data also
show that: (i) compounds 14 containing methoxyaryl sub-
units are less potent than the corresponding substances
characterised by phenol subunits (compare Entries 3 and 2
or Entries 4 and 7); (ii) the highly cytotoxic compounds
reported in Table 6 include some unsymmetrical 3,4-diaryl-
2(5H)-furanones 4; i.e., some substances that belong to a
class of compounds well known previously as selective
COX-2 inhibitors.
General Remarks: Melting and boiling points are uncorrected. Pre-
coated Merck 60 F254 aluminium silica gel sheets were used for
TLC analyses. GLC analyses were performed with 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:
Alltech AT-35 bonded FSOT column (30 m ϫ 0.25 mm i.d.) and
Alltech AT-1 bonded FSOT column (30 m ϫ 0.25 mm i.d). Purifi-
cations by MPLC on silica gel (Merck 60 silica gel, particle size
0.015Ϫ0.040 mm) were performed with a Büchi B-680 system and
a Knauer K-2400 differential refractometer as detector. GLC/EI-
MS analyses were performed with a Q-mass 910 spectrometer in-
terfaced with a PerkinϪElmer 8500 gas chromatograph. The
HPLC-MS measurements involving 4g were performed using a
PerkinϪElmer 200 liquid chromatograph interfaced with
a
PerkinϪElmer Sciex API III plus triple-quadrupole mass spec-
trometer. In these measurements, the HPLC analyses were per-
formed using a Supelco Discovery C 18 column (15 cm ϫ 4.6 mm
ϫ 4 µm) and two solvents, A and B, respectively, as mobile phase.
Solvent A was a 5 m aqueous solution of ammonium acetate and
solvent B was acetonitrile saturated with ammonium acetate. The
operative conditions were: 100% A for 5 min; a linear gradient for
30 min until 100% B; 100% B for 5 min. The APCI-mass spectrum
was recorded using the following operative parameters: discharge
current: 3 µA; temperature of the nebulizer: 500 °C; orifice voltage:
60 V; scan range: 100Ϫ400 amu; step 0.2 amu; dwell time: 1 ms;
scan time: 1.58 s; interscan delay: 0.052 ms; resolution Ͼ 1 amu.
IR spectra were recorded with a PerkinϪElmer 1725 FT-IR spec-
trophotometer. NMR spectra were recorded with a Varian Gemini
200 MHz spectrometer with TMS as the internal standard. All re-
actions of air- and water-sensitive materials were performed in
flame-dried glassware under argon by standard syringe, cannula
and septa techniques. The following compounds were prepared by
published procedures: 3-chloro-4-methoxyphenylboronic acid
(18b),[55] tributyl(4-methoxyphenyl)tin (20d),[56] tributyl(4-methyl-
thiophenyl)tin (20e),[57] tributyl(3,4-dimethoxyphenyl)tin (20f),[58]
Compounds 13a, 14a, 14f, 14g, 14h and 14j were then
tested in the USNCI’s human tumor cell-line screen.[54] The
recorded data showed, however, that all the tested com-
pounds exhibited limited cytotoxic activitites, displaying
MGM values of log GI50 between Ϫ4.05 (for 14g) and
Ϫ4.60 (for 13a).
tributyl(4-chlorophenyl)tin
(20b),[59]
tributyl(2-naphthyl)tin
(20g).[60]
Conclusion
3,4-Dichloro-2(5H)-furanone (12): Sodium borohydride (6.24 g,
165.0 mmol) was added in a portionwise manner to a stirred solu-
tion of mucochloric acid (16) (18.47 g, 110.0 mmol) in methanol
(165 mL), which was cooled to 0 °C, and the mixture was stirred
for an additional 30 min. A solution of concentrated sulfuric acid
(10.78 g, 110.0 mmol) in methanol (55 mL), which was cooled to 0
°C, was added and the resulting mixture, which was kept cold for
an additional 10 min, was then concentrated at room temperature
under reduced pressure. The residue was treated with brine
(800 mL) and extracted with diethyl ether (5 ϫ 300 mL). The or-
ganic extract was dried and concentrated under reduced pressure
and the solid residue was recrystallised from a mixture of pentane
and diethyl ether (1:1) to give chemically pure 12 (14.97 g, 89%) as
We have shown for the first time that 3,4-dichloro-2(5H)-
furanone, which can be prepared efficiently from inexpen-
sive, commercially available mucochloric acid, can undergo
regioselective Suzuki- or Stille-type reactions to provide 4-
aryl-3-chloro-2(5H)-furanones in satisfactory yields. We
have also demonstrated that these highly functionalised
compounds are useful precursors either to a variety of (Z)-
4-aryl-5-[1-(aryl)methylidene]-3-chloro-2(5H)-furanones,
including naturally occurring rubrolide M, or to unsym-
metrical 3,4-diaryl-2(5H)-furanones. Moreover, we have
shown that some typical symmetrical 3,4-diaryl-2(5H)-fu-
ranones can be prepared in satisfactory yields by Pd-cata-
lysed reactions of 3,4-dichloro-2(5H)-furanone with a large
molar excess of arylboronic acids and aryl(tributyl)tin re-
agents. Interestingly, some 2(5H)-furanone derivatives, in-
cluding unsymmetrical 3,4-diaryl-2(5H)-furanones and (Z)-
4-aryl-5-[1-(aryl)methylidene]-3-chloro-2(5H)-furanones,
are active in the NCI three-cell-line, one-dose, primary an-
ticancer assay. (Z)-4-Aryl-5-[1-(aryl)methylidene]-3-chloro-
2(5H)-furanones were found, however, to exhibit limited
cytotoxicity against the NCI 60-cell-line panel.
1
a colourless solid; m.p. 49Ϫ50 °C (m.p.[36] 49.5Ϫ50 °C). H NMR
(200 MHz, CDCl3): δ ϭ 4.88 (s, 2 H) ppm. 13C NMR (50 MHz,
CDCl3): δ ϭ 70.9, 121.0, 148.9, 165.7 ppm. The spectral properties
of this compound are in satisfactory agreement with those re-
ported.[36]
Synthesis of 4-Aryl-3-chloro-2(5H)-furanones 13 by Pd-Catalysed
Cross-Coupling Reactions between 12 and Arylboronic Acids 18.
Method A: A flame-dried reaction vessel, flushed with argon, was
charged with 12 (0.40 g, 2.61 mmol), an arylboronic acid 18
(2.74 mmol), [Pd2(dba)3] (59 mg, 0.065 mmol), (o-tolyl)3P (79 mg,
2296
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Mucochloric Acid: A Useful Synthon for the Selective Synthesis of Furanones
FULL PAPER
0.26 mmol) and KF (0.45 g, 7.83 mmol) in de-aerated dry toluene and petroleum ether to give 13d (0.36 g, 61%) as a colourless solid;
(10 mL), and then the mixture, which was periodically monitored
by GLC and TLC, was stirred at 85 °C for the period of time
indicated in Table 1. After completion of the reaction (21Ϫ27 h),
the mixture was cooled to room temperature, diluted with EtOAc
m.p. 174Ϫ175 °C. EI-MS: m/z (%) ϭ 226 (34) [Mϩ], 224 (100)
[Mϩ], 195 (74), 167 (32), 151 (15), 132 (30), 102 (10). IR (KBr
disk): ν˜ ϭ 1758, 1605, 1512, 1334, 1186, 1033, 829 cmϪ1. 1H NMR
(200 MHz, CDCl3): δ ϭ 3.88 (s, 3 H), 5.19 (s, 2 H), 7.01 (m, 2 H),
(150 mL) and filtered through Celite. The filtrate was concentrated 7.01 (m, 2 H), 7.47 (m, 2 H) ppm. 13C NMR (50 MHz, CDCl3):
under reduced pressure and the residue was purified by MPLC on
silica gel or by recrystallisation. Compounds 13a؊e were prepared
by this procedure (Table 1, Entries 1Ϫ5). Method B: A de-aerated
mixture of compound 12 (0.46 g, 3.00 mmol), an arylboronic acid
18 (6.00 mmol), CsF (1.23 g, 8.10 mmol), [PdCl2(PPh3)2] (0.105 g,
0.15 mmol) and BnEt3NϩClϪ (34 mg, 0.15 mmol), toluene (13 mL)
and water (13 mL) was stirred at room temperature until com-
pound 12 was completely consumed (7Ϫ8 d). The mixture was then
partitioned between 2  HCl (12 mL) and toluene (100 mL) and
the toluene extract was concentrated under reduced pressure. The
solid residue was purified by recrystallisation or by MPLC on silica
gel. Compounds 13d and 13e were prepared by this procedure
(Scheme 3).
δ ϭ 55.5, 70.0, 114.6 (2 C), 121.1, 129.0 (2 C), 130.5, 151.2, 162.1,
169.3 ppm. C11H9ClO3 (224.64): calcd. C 58.81, H 4.04; found C
59.02, H 4.03. This compound was also prepared in 80% yield using
Method B.
3-Chloro-4-(4-methylthiophenyl)-2(5H)-furanone (13e): The crude
product obtained from the Pd-catalysed reaction between 12 and
4-methylthiophenylboronic acid (18e) according to Method A
(Table 1, Entry 5) was purified by MPLC on silica gel with a mix-
ture of CHCl3 and petroleum ether (90:10, ϩ 1% EtOAc) as eluent
to give 13e (0.21 g, 33%) as a pale-yellow solid: m.p. 161Ϫ163 °C.
EI-MS: m/z (%) ϭ 242 (41) [Mϩ], 240 (100) [Mϩ], 213 (13), 211
(36), 167 (12), 148 (22), 74 (9). IR (KBr disk): ν˜ ϭ 1759, 1622 1493,
1069, 1031, 1011, 817 cmϪ1 1H NMR (200 MHz, CDCl3): δ ϭ
.
2.54 (s, 3 H), 5.20 (s, 2 H), 7.32 (m, 2 H), 7.73 (m, 2 H) ppm. 13C
NMR (50 MHz, CDCl3): δ ϭ 14.8, 69.9, 116.0, 124.6, 125.6 (2 C),
127.3 (2 C), 144.5, 151.0, 169.1 ppm. C11H9ClO2S (240.71): calcd.
C 54.89, H 3.77; found C 54.74; H 3.65. This compound was also
prepared in 83% yield using Method B.
3-Chloro-4-phenyl-2(5H)-furanone (13a): The crude product ob-
tained from the Pd-catalysed reaction between 12 and phenylbo-
ronic acid (18a) according to Method A (Table 1, Entry 1) was
purified by MPLC on silica gel with toluene as eluent to give 13a
(0.32 g, 63%) as a pale-yellow solid; m.p. 108Ϫ109 °C. EI-MS: m/
z (%) ϭ 196 (22) [Mϩ], 194 (70) [Mϩ], 165 (100), 137 (61), 105 (27),
101 (30), 75 (21). IR (KBr disk): ν˜ ϭ 1736, 1625, 1495, 1327, 1194,
Synthesis of 4-Aryl-3-chloro-2(5H)-furanones 13 by Pd-Catalysed
Cross-Coupling Reaction between 12 and Aryl(tributyl)tin Reagents
20: A flame-dried reaction vessel, flushed with argon, was charged
with 12 (2.40 g, 2.61 mmol), [Pd2(dba)3] (60 mg, 0.065 mmol), (o-
tolyl)3P (73 mg, 0.261 mmol) and de-aerated NMP (10 mL). A de-
aerated solution of an aryl(tributyl)tin reagent 20 (2.74 mmol) in
NMP (5 mL) was added and the resulting mixture, which was
periodically monitored by GLC, was stirred under argon at 85 °C
for the period of time indicated in Table 2. After completion of the
reaction, the mixture was cooled to room temperature, diluted with
EtOAc (150 mL), stirred at room temperature for 4.5 h in the pres-
ence of KF (1.52 g, 26.1 mmol) and filtered through Celite. The
filtrate was washed with water (50 mL), dried and concentrated un-
der reduced pressure. The residue, which was analysed by GLC and
GLC/MS, was purified by MPLC on silica gel or by recrystallis-
ation. This general procedure was used to prepare compounds 13a,
13c, 13d, 13e, 13f and 13g. Table 2 summarizes the reaction times,
the molar ratios between compounds 13 and the symmetrical 3,4-
diaryl-2(5H)-furanones 4 obtained as by-products of the cross-
coupling reactions, as well as the isolated yields of compounds 13.
It should be noted that the physical and spectral properties of com-
pounds 13a, 13c, 13d and 13e (Table 2, Entries 1, 2, 3 and 4, respec-
tively) are in agreement with those of the same compounds ob-
tained by Pd-catalysed reaction of 12 with arylboronic acids 18a,
18c, 18d and 18e, respectively. As shown in Table 2, the Pd-cata-
lysed reactions of 12 with 20a, 20b, 20d and 20e furnished com-
pounds 13a, 13c, 13d and 13e, respectively, in 53, 61, 78 and 73%
yield, respectively.
1
1036, 767 cmϪ1. H NMR (200 MHz, CDCl3): δ ϭ 5.22 (s, 2 H),
7.52 (m, 3 H), 7.80 (m, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ
70.1, 117.1, 127.1 (2 C), 128.6, 129.1 (2 C), 131.7, 151.7, 169.0 ppm.
C10H7ClO2 (194.62): calcd. C 61.71, H 3.62; found C 61.92, H 3.67.
3-Chloro-4-(3-chloro-4-methoxyphenyl)-2(5H)-furanone (13b): The
crude product obtained from the Pd-catalysed reaction between 12
and 3-chloro-4-methoxyphenylboronic acid (18b) according to
Method A (Entry 2, Table 1) was purified by MPLC on silica gel
with a mixture of CHCl3 and hexane (70:30, ϩ 1% EtOAc) as elu-
ent to give 13b (0.38 g, 57%) as a colourless solid; m.p. 153Ϫ154
°C. EI-MS: m/z (%) ϭ 260 (65) [Mϩ], 258 (100) [Mϩ], 231 (38), 229
(59), 185 (23), 166 (25), 157 (18). IR (KBr disk): ν˜ ϭ 1765, 1615,
1510, 1330, 1265, 1039, 832 cmϪ1 1H NMR (200 MHz, CDCl3):
.
δ ϭ 3.98 (s, 3 H), 5.18 (s, 2 H), 7.05 (d, J ϭ 8.8 Hz, 1 H), 7.75 (dd,
J ϭ 8.8, 2.2 Hz, 1 H), 7.84 (d, J ϭ 2.2 Hz, 1 H) ppm. 13C NMR
(50 MHz, CDCl3): δ ϭ 56.4, 69.8, 116.1, 121.9, 123.5, 127.3, 129.0,
149.9, 157.4, 168.9 ppm. C11H8Cl2O3 (259.09): calcd. C 50.99, H
3.11; found C 50.81, H 3.04.
3-Chloro-4-(4-chlorophenyl)-2(5H)-furanone (13c): The crude prod-
uct obtained from the Pd-catalysed reaction between 12 and 4-chlo-
rophenylboronic acid (18c) according to Method A (Table 1, Entry
3) was purified by MPLC on silica gel with a mixture of CHCl3
and hexane (80:20, ϩ 1% EtOAc) as eluent to give 13c (0.25 g,
42%) as a pale-yellow solid; m.p. 168Ϫ170 °C. EI-MS: m/z (%) ϭ
230 (49) [Mϩ], 228 (76) [Mϩ], 199 (100), 139 (24), 136 (51), 99 (22),
74 (19). IR (KBr disk): ν˜ ϭ 1746, 1619, 1493, 1320, 1198, 1041,
3-Chloro-4-(2-thienyl)-2(5H)-furanone (13f): The crude product ob-
tained from the Pd-catalysed reaction between 12 and tributyl(2-
thienyl)tin (20c) (Entry 5, Table 2) was purified by MPLC on silica
gel with a mixture of toluene and EtOAc (97:3) as eluent to give
13f (0.29 g, 55%) as a colourless solid; m.p. 126Ϫ127 °C. EI-MS:
m/z (%) ϭ 202 (38) [Mϩ], 200 (100) [Mϩ], 173 (35), 171 (93), 143
(46), 108 (28), 63 (10). IR (KBr disk): ν˜ ϭ 1777, 1760, 1621, 1346,
825 cmϪ1 1H NMR (200 MHz, CDCl3): δ ϭ 5.21 (s, 2 H), 7.50
.
(m, 2 H), 7.56 (m, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ
69.9, 117.7, 127.0, 128.4 (2 C), 129.5 (2 C), 137.9, 150.4, 168.7 ppm.
C10H6Cl2O2 (229.06): calcd. C 52.43, H 2.64; found C 52.28, H
2.49.
3-Chloro-4-(4-methoxyphenyl)-2(5H)-furanone (13d): The crude
product obtained from the Pd-catalysed reaction between 12 and 4-
methoxyphenylboronic acid (18d) according to Method A (Table 1,
Entry 4) was purified by recrystallisation from a mixture of CH2Cl2
1
1184, 1035, 747 cmϪ1. H NMR (200 MHz, CDCl3): δ ϭ 5.22 (s,
2 H), 7.23 (dd, J ϭ 5.1, 3.7 Hz, 1 H), 7.53 (dd, J ϭ 3.7, 1.1 Hz, 1
H), 7.73 (dd, J ϭ 5.1, 1.1 Hz, 1 H) ppm. 13C NMR (50 MHz,
Eur. J. Org. Chem. 2003, 2290Ϫ2302
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F. Bellina, C. Anselmi, F. Martina, R. Rossi
FULL PAPER
CDCl3): δ ϭ 69.5, 114.25, 127.8, 129.3, 130.7, 131.8, 146.9,
111.8, 112.0, 112.8, 114.4 (2 C), 117.2, 120.0, 126.7, 130.6 (2 C),
168.5 ppm. C8H5ClO2S (200.64): calcd. C 47.89, H 2.51; found C 131.3, 135.4, 145.6, 149.4, 156.5, 161.2, 164.5 ppm. C19H14BrClO4
48.02, H 2.58.
(421.75): calcd. C 54.11, H 3.35; found C 53.95, H 3.06.
3-Chloro-4-(3,4-dimethoxyphenyl)-2(5H)-furanone (13g): The crude
product obtained from the Pd-catalysed reaction between 12 and
tributyl(3,4-dimethoxyphenyl)tin (20f) (Table 2, Entry 6) was puri-
fied by recrystallisation from a mixture of CH2Cl2 and hexane to
give 13g (0.50 g, 75%) as a light-brown solid; m.p. 179Ϫ180 °C. EI-
(Z)-3-Chloro-4-(3-chloro-4-methoxyphenyl)-5-[1-(4-methoxyphenyl)-
methylidene]-2(5H)-furanone (14f): The crude product obtained
from the reaction between 13b and 4-methoxybenzaldehyde (21b)
(Table 3, Entry 2) was recrystallised from a mixture of CH2Cl2 and
petroleum ether to give 14f (0.41 g, 65%) as a pale-yellow solid;
MS: m/z (%) ϭ 256 (32) [Mϩ], 254 (100) [Mϩ], 239 (12), 220 (15), m.p. 148Ϫ150 °C. EI-MS: m/z (%) ϭ 380 (12) [Mϩ], 379 (14) [Mϩ],
147 (20), 131 (11), 89 (12). IR (KBr disk): ν˜ ϭ 1771, 1615, 1519,
378 (67) [Mϩ], 377 (22) [Mϩ], 376 (100) [Mϩ], 148 (28), 91 (16). IR
1291, 1162, 1036, 747 cmϪ1
.
1H NMR (200 MHz, CDCl3): δ ϭ (KBr disk): ν˜ ϭ 1764, 1605, 1498, 1265, 1178, 1019, 824 cmϪ1. H
1
3.95 (s, 3 H), 3.96 (s, 3 H), 5.22 (s, 2 H), 6.97 (d, J ϭ 8.4 Hz, 1 H),
7.31 (dd, J ϭ 8.4, 2.2 Hz, 1 H), 7.51 (d, J ϭ 2.2 Hz, 1 H) ppm.
13C NMR (50 MHz, CDCl3): δ ϭ 56.1 (2 C), 70.1, 110.0, 111.1,
NMR (200 MHz, CDCl3): δ ϭ 3.85 (s, 3 H), 4.00 (s, 3 H), 6.08 (s,
1 H), 6.91 (m, 2 H), 7.10 (d, J ϭ 8.4 Hz, 1 H), 7.43 (dd, J ϭ 8.4,
2.2 Hz, 1 H), 7.56 (d, J ϭ 2.2 Hz, 1 H), 7.73 (m, 2 H) ppm. 13C
114.9, 121.0, 121.4, 149.3, 151.5, 152.1, 169.5 ppm. C12H11ClO4 NMR (50 MHz, CDCl3): δ ϭ 55.4, 56.3, 112.1, 114.4 (2 C), 114.6,
(254.67): calcd. C 56.60, H 4.35; found C 56.54, H 4.27.
117.3, 121.0, 123.2, 125.2, 128.9, 130.1, 132.6 (2 C), 144.5, 148.3,
156.5, 160.7, 164.4 ppm. C19H14Cl2O2 (377.22): calcd. C 60.50, H
3.74; found C 60.59, H 3.95.
3-Chloro-4-(2-naphthyl)-2(5H)-furanone (13h): The crude product
obtained from the Pd-catalysed reaction between 12 and tributyl(2-
naphthyl)tin (20g) (Table 2, Entry 7) was purified by recrystallis-
(Z)-3-Chloro-4-(4-methoxyphenyl)-5-[1-(4-methoxyphenyl)methyl-
ation from a mixture of CH2Cl2 and hexane to give 13h (0.43 g, idene]-2(5H)-furanone (14g): The crude product obtained from the
67%) as a pale-brown solid; m.p. 193Ϫ194 °C. EI-MS: m/z (%) ϭ reaction between 13d and 4-methoxybenzaldehyde (21b) (Table 3,
246 (33) [Mϩ], 244 (100) [Mϩ], 217 (23), 215 (69), 187 (12), 152 Entry 3) was purified by MPLC on silica gel with a mixture of
(66), 75 (17). IR (KBr disk): ν˜ ϭ 1758, 1611, 1504, 1248, 1039, 820, CHCl3 and hexane (50:50, ϩ 1% EtOAc) as eluent. The chromato-
750 cmϪ1 1H NMR (200 MHz, CDCl3): δ ϭ 5.31 (s, 2 H), 7.60 graphic fractions containing 14g were collected and concentrated
(m, 2 H), 7.92 (m, 4 H), 8.25 (s, 1 H) ppm. 13C NMR (50 MHz, and the solid residue was recrystallised from a mixture of CH2Cl2
CDCl3): δ ϭ 70.2, 123.1, 126.0, 127.2, 127.7, 127.9, 128.3, 128.8, and hexane to give pure 14g (0.29 g, 51%) as a pale-yellow solid;
128.9, 132.6, 133.8, 134.3, 151.6, 169.1 ppm. C14H9ClO2 (248.68): m.p. 169Ϫ170 °C. EI-MS: m/z (%) ϭ 345 (22) [Mϩ], 343 (100)
.
calcd. C 67.62, H 3.65; found C 67.49, H 3.59.
[Mϩ], 299 (3), 252 (8), 167 (2), 51 (4), 39 (12). IR (KBr disk): ν˜ ϭ
1772, 1605, 1504, 1259, 1181, 1018, 826 cmϪ1. 1H NMR (200 MHz,
CDCl3): δ ϭ 3.84 (s, 3 H), 3.90 (s, 3 H), 6.12 (s, 1 H), 6.90 (m, 2
H), 7.07 (m, 2 H), 7.49 (m, 2 H), 7.73 (m, 2 H) ppm. 13C NMR
(50 MHz, CDCl3): δ ϭ 55.3, 55.4, 114.3 (4 C), 114.5, 116.5, 120.3,
125.4, 130.6 (2 C), 132.5 (2 C), 144.8, 149.6 160.5, 161.1,
164.8 ppm. C19H15ClO4 (342.78): calcd. C 66.58, H 4.41; found C
66.49, H 4.35.
General Procedure for the Synthesis of (Z)-4-Aryl-5-[1-(aryl)methyl-
idene]-3-chloro-2(5H)-furanones 14 Starting from Compounds 13 and
Aryl Aldehydes 21: A solution of a compound 13 (1.66 mmol) in
CH2Cl2 (5 mL) was sequentially treated with tert-butyldimethylsilyl
trifluoromethanesulfonate (0.53 g, 1.99 mmol), N,N-diisopropyle-
thylamine (0.87 mL, 4.98 mmol) and an arylaldehyde 21
(1.99 mmol), and the resulting mixture was stirred under argon at
room temperature for 2 h. 1,8-Diazabicyclo[5.4.0]undec-7-ene
(DBU) (0.50 mL, 3.32 mmol) was then added, and the mixture,
which was periodically monitored by TLC analysis, was stirred at
room temperature for 5 h. The mixture was then diluted with
(Z)-5-[1-(3-Bromo-4-methoxyphenyl)methylidene]-3-chloro-4-(3-
chloro-4-methoxyphenyl)-2(5H)-furanone (14h): The crude product
obtained from the reaction between 13b and 21a (Table 3, Entry 4)
was purified by MPLC on silica gel with a mixture of CHCl3 and
CH2Cl2 (60 mL) and washed with 3  HCl (2 ϫ 15 mL). The aque- hexane (50:50, ϩ 1% EtOAc) as eluent. The chromatographic frac-
ous phase was extracted with CH2Cl2 (3 ϫ 20 mL) and the organic
extract was washed with brine (3 ϫ 20 mL) until neutrality, dried
and concentrated under reduced pressure. The solid residue was
purified by recrystallisation and/or by MPLC on silica gel. This
procedure was employed to prepare compounds 14e, 14f, 14g and
14h (Entries 1Ϫ4, Table 3).
tions containing 14h were collected and concentrated under re-
duced pressure and the residue was recrystallised from a mixture
of CH2Cl2 and hexane (ca. 1.5:1) to give pure 14h (0.33 g, 43%) as
a pale-yellow solid; m.p. 215Ϫ217 °C. EI-MS: m/z (%) ϭ 458 (42)
[Mϩ], 457 (100) [Mϩ], 456 (47) [Mϩ], 455 (42) [Mϩ], 210 (19). IR
1
(KBr disk): ν˜ ϭ 1784, 1606, 1499, 1288, 1271, 1009, 818 cmϪ1. H
NMR (200 MHz, CDCl3): δ ϭ 3.94 (s, 3 H), 4.00 (s, 3 H), 6.01 (s,
1 H), 6.91 (d, J ϭ 8.7 Hz, 1 H), 7.10 (d, J ϭ 8.7 Hz, 1 H), 7.42
(dd, J ϭ 8.7, 2.2 Hz, 1 H), 7.56 (d, J ϭ 2.2 Hz, 1 H), 7.77 (dd, J ϭ
8.7, 1.8 Hz, 1 H), 7.92 (d, J ϭ 1.8 Hz, 1 H) ppm. 13C NMR
(50 MHz, CDCl3): δ ϭ 56.3 (2 C), 111.8, 112.1 (2 C), 112.8, 118.1,
120.7, 123.3, 126.5, 128.9, 130.7, 131.4, 135.5, 145.2, 148.1, 156.6,
156.7, 164.1 ppm. C19H13BrCl2O4 (456.12): calcd. C 50.03, H 2.87;
found C 49.95, H 2.79.
(Z)-5-[1-(3-Bromo-4-methoxyphenyl)methylidene]-3-chloro-4-(4-
methoxyphenyl)-2(5H)-furanone (14e): The crude product obtained
from the reaction between 13d and 3-bromo-4-methoxybenzal-
dehyde (21a) (Table 3, Entry 1) was purified by MPLC on silica gel
with a mixture of CHCl3 and hexane (70:30, ϩ 1% EtOAc) as elu-
ent. The chromatographic fractions containing 14e were collected
and concentrated under reduced pressure and the solid residue was
recrystallised from a mixture of CHCl3 and hexane to give 14e
(0.32 g, 46%) as a pale-yellow solid; m.p. 195Ϫ196 °C. EI-MS:
Demethylation of 14e. Synthesis of (Z)-5-[1-(3-Bromo-4-hydroxy-
m/z (%) ϭ 424 (27) [Mϩ], 423 (21) [Mϩ], 422 (100) [Mϩ], 421 (17) phenyl)methylidene]-3-chloro-4-(4-hydroxyphenyl)-2(5H)-furanone
[Mϩ], 228 (13), 211 (34), 119 (22). IR (KBr disk): ν˜ ϭ 1769, 1607,
1498, 1253, 1179, 1009, 839 cmϪ1 1H NMR (200 MHz, CDCl3): 2.13 mmol) was added to a solution of 14e (0.10 g, 0.24 mmol) in
(Rubrolide M) (14a): A 1  solution of BBr3 in CH2Cl2 (2.13 mL,
.
δ ϭ 3.90 (s, 3 H), 3.94 (s, 3 H), 6.90 (d, J ϭ 8.8 Hz, 1 H), 7.07 (m, dry CH2Cl2 (8 mL) stirred at Ϫ78 °C. The mixture was warmed to
2 H), 7.49 (m, 2 H), 7.77 (dd, J ϭ 8.8, 2.2 Hz, 1 H), 7.91 (d, J ϭ room temperature and stirred for 23 h. Water (10 mL) was then
2.2 Hz, 1 H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 55.4, 56.3,
added and the mixture was extracted with EtOAc (4 ϫ 25 mL).
2298
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 2290Ϫ2302

Mucochloric Acid: A Useful Synthon for the Selective Synthesis of Furanones
FULL PAPER
The organic extract was washed with brine (15 mL), dried and con-
centrated under reduced pressure, and then the solid residue was
purified by MPLC on silica gel with a mixture of CHCl3 and meth-
anol (96:4) as eluent. The chromatographic fractions containing
14a were collected and concentrated under reduced pressure and
the solid residue was recrystallised from a mixture of ethanol and
water (ca. 5:1) to give pure 14a (92 mg, 97%) as a yellow solid; m.p.
227Ϫ230 °C. IR (KBr disk): ν˜ ϭ 3473, 1750, 1611, 1509, 1246,
CDCl3): δ ϭ 70.3, 125.7, 127.0 (2 C), 128.2 (2 C), 128.3, 128.5 (2
C), 128.8 (2 C), 129.7, 130.0, 130.3, 155.6, 172.8 ppm. C16H12O2
(236.27): calcd. C 81.34, H 5.12; found C 81.27, H 5.06. Compound
4c was also synthesized in 60% yield by Pd-catalysed reaction be-
tween 12 and tributyl(phenyl)tin (20a) according the above re-
ported procedure (Table 4, Entry 3).
3,4-Bis(4-methoxyphenyl)-2(5H)-furanone (4d): The crude product
obtained from the Pd-catalysed reaction between 12 and 4-meth-
oxyphenylboronic acid (18d) according to the above reported pro-
cedure (Table 4, Entry 2) was purified by MPLC on silica gel, with
a mixture of CH2Cl2 and hexane (90:10, ϩ 1% EtOAc) as eluent,
to give 4d (0.52 g, 67%) as a pale-yellow solid; m.p. 151Ϫ152 °C
(m.p.[61] 144Ϫ146 °C). EI-MS: m/z (%) ϭ 297 (22) [Mϩ ϩ1], 296
(100) [Mϩ], 239 (68), 224 (18), 219 (71), 135 (90), 121 (11). IR (KBr
1
1163, 837 cmϪ1. H NMR (200 MHz, [D6]DMSO): δ ϭ 6.29 (s, 1
H), 7.06 (m, 3 H), 7.53 (m, 2 H), 7.74 (dd, J ϭ 8.8, 2.2 Hz, 1 H),
8.06 (d, J ϭ 2.2 Hz, 1 H), 9.29 (br. s, 2 H) ppm. 13C NMR
(50 MHz, [D6]DMSO): δ ϭ 110.7, 113.4, 116.7 (2 C), 116.9, 117.5,
119.8, 127.3, 131.8 (2 C), 132.4, 136.2, 146.3, 150.8, 155.9, 160.3,
164.6 ppm. C17H10BrClO4 (393.61): calcd. C 51.87, H 2.56; found
C 51.79, H 2.44.
1
disk): ν˜ ϭ 1731, 1604, 1507, 1255, 1017, 962, 843 cmϪ1. H NMR
Demethylation of 14f. Synthesis of (Z)-3-Chloro-4-(3-chloro-4-
hydroxyphenyl)-5-[1-(4-hydroxyphenyl)methylidene]-2(5H)-furanone
(200 MHz, CDCl3): δ ϭ 3.82 (s, 3 H), 3.83 (s, 3 H), 5.13 (s, 2 H),
6.80Ϫ6.95 (m, 4 H), 7.38 (m, 2 H) ppm. 13C NMR (50 MHz,
(14j): A 1  solution of BBr3 in CH2Cl2 (3.71 mL, 3.71 mmol) was CDCl3): δ ϭ 55.2, 55.3, 70.3, 114.1 (2 C), 114.3 (2 C), 122.7, 123.2,
added to a solution of 14f (0.20 g, 0.53 mmol) in dry CH2Cl2 123.7, 128.9 (2 C), 130.5 (2 C), 154.4, 159.7, 161.1, 173.9 ppm.
(15 mL) that was stirred at Ϫ78 °C. The mixture was warmed to C18H16O4 (296.32): calcd. 72.96, H 5.44; found C 72.90, H 5.41.
room temperature, stirred for 20 h and then worked up according
Synthesis of Unsymmetrical 3,4-Diaryl-2(5H)-furanones 4 by Pd-
to the same procedure used for the preparation of 14a. The crude
Catalysed Reaction of 4-Aryl-3-chloro-2(5H)-furanones 13 with Ar-
ylboronic Acids 18 or Aryl(tributyl)tin Reagents 20: A flame-dried
reaction vessel, flushed with argon, was charged with a compound
13 (1.3 mmol), an arylboronic acid 18 (1.95 mmol), KF (0.11 g,
reaction product was purified by MPLC on silica gel, with a mix-
ture of CHCl3 and methanol (96:4) as eluent, to give 14j (0.18 g,
98%) as a yellow solid; m.p. 266Ϫ270 °C. IR (KBr disk): ν˜ ϭ 3418,
1728, 1603, 1444, 1282, 1163, 829 cmϪ1 1H NMR (200 MHz,
.
3.90 mmol), [Pd2(dba)3] (29 mg, 0.032 mmol), a 1  toluene solu-
tion of tBu3P (0.065 mL, 0.065 mmol) and de-aerated toluene
(8 mL), and the mixture, which was periodically monitored by GLC
and TLC, was stirred at 85 °C until compound 13 was completely
consumed. The mixture was then cooled to room temperature, di-
luted with EtOAc (150 mL) and filtered through Celite. The filtrate
was concentrated under reduced pressure and the solid residue was
purified by recrystallisation or by MPLC on silica gel. This pro-
cedure was used to prepare compounds 4e, 4f, 4g and 4h (Entries
1, 2, 4 and 5, respectively, Table 5). On the other hand, compounds
[D6]DMSO): δ ϭ 6.24 (s, 1 H), 6.89 (m, 2 H), 7.18 (d, J ϭ 8.4 Hz,
1 H), 7.39 (dd, J ϭ 8.4, 1.8 Hz, 1 H), 7.58 (d, J ϭ 1.8 Hz, 1 H),
10.15 (br. s, 1 H), 10.98 (br. s, 1 H) ppm. 13C NMR (50 MHz,
[D6]DMSO): δ ϭ 114.7, 115.1, 115.8 (2 C), 116.8, 119.0, 120.1,
123.5, 129.2, 130.4, 132.7 (2 C), 143.4, 148.6, 154.9, 158.9,
163.8 ppm. C17H10Cl2O4 (349.16): calcd. C 58.48, H 2.89; found C
58.32, H 2.77.
Synthesis of Symmetrical 3,4-Diaryl-2(5H)-furanones 4 by Pd-Cata-
lysed Reaction of 12 with Arylboronic Acids 18 or Aryl(tributyl)tin
Reagents 20: A flame-dried reaction vessel, flushed with argon, was 4f and 4a were synthesized by cross-coupling reactions of 13d and
charged with 12 (2.40 g, 2.61 mmol), an arylboronic acid 18 13e with 1.5 equiv. of 18f and 18a, respectively, in toluene at 85 °C
(7.83 mmol), KF (0.45 g, 7.83 mmol), [Pd2(dba)3] (59 mg, in the presence of 1 mol % [chloro(di-2-norbornylphosphanyl)(2Ј-
0.065 mmol), a 1  toluene solution of tBu3P (0.13 mL, 0.13 mmol)
and de-aerated toluene (10 mL), and then the mixture, which was
periodically monitored by GLC and TLC, was stirred at 85 °C for
the period of time indicated in Table 4. After completion of the
reaction, the mixture was cooled to room temperature, diluted with
EtOAc (150 mL) and filtered through Celite. The filtrate was con-
centrated under reduced pressure and the residue was purified by
MPLC on silica gel. This procedure was used to prepare com-
pounds 4c and 4d (Table 4, Entries 1 and 2). Compound 4c was
also prepared by reaction of 12 (0.19 g, 1.27 mmol) with tributyl-
(phenyl)tin (20a, 1.40 g, 3.81 mmol), KF (0.29 g, 5.08 mmol),
[Pd2(dba)3] (29 mg, 0.032 mmol), a 1  toluene solution of tBu3P
(0.063 mL, 0.063 mmol) and de-aerated toluene (6.5 mL) at 95 °C
for 114 h, followed by purification by MPLC on silica gel (Table 4,
Entry 3).
dimethylamino-1,1Ј-biphenyl-2-yl)palladium()] and 3.0 equiv. of
KF (Table 5, Entries 3 and 8). Moreover, as shown in Entries 6 and
7 of Table 5, compounds 4i and 4a were synthesized by Pd-cata-
lysed reactions of 13d and 13e, respectively, with aryltin reagents
20f and 20a, respectively. The following procedure was used: A
flame-dried reaction vessel, flushed with argon, was charged with
a compound 13 (3.54 mmol), an aryl(tributyl)tin reagent 20
(5.32 mmol), [Pd(OAc)2] (29.8 mg, 0.18 mmol), Cy3P (99.3 mg,
0.35 mmol), KF (0.41 g, 7.10 mmol) and de-aerated toluene
(18 mL). The resulting mixture was maintained at 95 °C for the
period of time indicated in Table 5 and then it was cooled to room
temperature, diluted with EtOAc (100 mL) and stirred at room
temperature for 4.5 h in the presence of KF (3.08 g, 53.1 mmol).
The mixture was then diluted with EtOAc (100 mL) and filtered
through Celite. The filtrate was washed with water (50 mL), dried
and concentrated under reduced pressure and the residue was puri-
fied by MPLC on silica gel.
3,4-Diphenyl-2(5H)-furanone (4c): The crude product obtained
from the Pd-catalysed reaction between 12 and phenylboronic acid
(18a) according to the above reported procedure (Table 4, Entry 1)
was purified by MPLC on silica gel, with benzene as eluent, to give
4c (0.39 g, 63%) as a yellow solid; m.p. 98Ϫ99 °C (m.p.[61]
4-Phenyl-3-(3,4,5-trimethoxyphenyl)-2(5H)-furanone
(4e):
The
crude product obtained from the reaction between 13a and 18f in
the presence of catalytic amounts of [Pd2(dba)3] and tBu3P
104Ϫ105). EI-MS: m/z (%) ϭ 236 (65) [Mϩ], 179 (100), 178 (67), (Table 5, Entry 1) was purified by MPLC on silica gel, with a mix-
165 (8), 131 (13), 105 (28), 76 (9). IR (KBr disk): ν˜ ϭ 1752, 1638,
ture of CH2Cl2 and hexane (95:5, ϩ 1% EtOAc) as eluent, to give
4e (0.18 g, 42%) as a pale-orange solid; m.p. 155Ϫ156 °C. EI-MS:
1159, 1062, 1029, 957, 789 cmϪ1 1H NMR (200 MHz, CDCl3):
.
δ ϭ 5.16 (s, 2 H), 7.28Ϫ7.49 (m, 10 H) ppm. 13C NMR (50 MHz, m/z (%) ϭ 327 (21) [Mϩ ϩ 1], 326 (100) [Mϩ], 311 (25), 269 (14),
Eur. J. Org. Chem. 2003, 2290Ϫ2302
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2299

F. Bellina, C. Anselmi, F. Martina, R. Rossi
193 (25), 152 (21), 105 (71). IR (KBr disk): ν˜ ϭ 1738, 1639, 1510, [Mϩ ϩ 1], 326 (66) [Mϩ], 269 (28), 191 (19), 163 (10), 135 (100),
FULL PAPER
1249, 1130, 1007, 769 cmϪ1
.
1H NMR (200 MHz, CDCl3): δ ϭ
121 (7). IR (KBr disk): ν˜ ϭ 1732, 1639, 1519, 1241, 1140, 1015,
3.73 (s, 6 H), 3.87 (s, 3 H), 5.17 (s, 2 H), 6.67 (s, 2 H), 5.38 (br. s, 829 cmϪ1. 1H NMR (200 MHz, CDCl3): δ ϭ 3.78 (s, 3 H), 3.82 (s,
5 H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 56.0, (2 C), 60.9, 70.5, 3 H), 3.91 (s, 3 H), 5.14 (s, 2 H), 6.89 (m, 4 H), 7.05 (d, J ϭ 8.0 Hz,
106.2 (2 C), 125.2, 125.8, 127.5 (2 C), 128.9 (2 C), 130.5 (2 C),
130.8, 138.4, 153.2, 155.8, 173.2 ppm. C19H18O5 (326.35): calcd. C 55.8 (2 C), 70.3, 111.3, 112.1, 114.2 (2 C), 122.0, 122.9, 123.2, 123.8,
1 H), 7.30 (m, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 55.3,
69.93, H 5.56; found C 69.87, H 5.48.
129.0 (2 C), 148.8, 149.2, 154.6, 161.2, 173.8 ppm. C19H18O5
(326.35): calcd. C 69.93, H 5.56; found C 69.83, H 5.50.
4-(4-Methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)-2(5H)-furanone
(4f): The crude product obtained from the reaction between 13d
and 18f in the presence of KF and catalytic amounts of [Pd2(dba)3]
and tBu3P (Table 5, Entry 2) was purified by MPLC on silica gel,
with a mixture of CH2Cl2 and EtOAc (95:5) as eluent, to give 4f
(0.27 g, 58%) as a yellow solid; m.p. 139Ϫ141 °C. EI-MS: m/z
(%) ϭ 357 (2) [Mϩ ϩ 1], 356 (85) [Mϩ], 254 (1), 135 (100). IR (KBr
disk): ν˜ ϭ 1727, 1602, 1508, 1256, 1123, 1026, 838 cmϪ1. 1H NMR
(200 MHz, CDCl3): δ ϭ 3.77 (s, 6 H), 3.83 (s, 3 H), 3.88 (s, 3 H),
5.16 (s, 2 H), 6.67 (s, 2 H), 6.87 (m, 2 H), 7.33 (m, 2 H) ppm. 13C
NMR (50 MHz, CDCl3): δ ϭ 55.4, 56.0 (2 C), 60.8, 70.3, 106.2, (2
C), 114.2 (2 C), 122.8, 123.8, 125.9, 129.2 (2 C), 138.2, 153.4 (2 C),
155.4, 161.4, 173.7 ppm. C20H20O6 (356.37): calcd. C 67.41, H 5.66;
found C 67.40, H 5.59. This compound was also synthesized in
14% yield by reaction of 13d with 18f in toluene at 85 °C for 28 h
in the presence of KF, [chloro(di-2-norbornylphosphanyl)(2Ј-di-
methylamino-1,1Ј-biphenyl-2-yl)palladium()] (1 mol %) and KF
(3.0 equiv.) (Table 5, Entry 3).
4-(4-Methylthiophenyl)-3-phenyl-2(5H)-furanone (4a): The crude
product obtained from the reaction between 13e and 20a in the
presence of catalytic amounts of [Pd(OAc)2] and Cy3P (Table 5,
Entry 7) was purified by MPLC on silica gel, with a mixture of
toluene and EtOAc (95:5) as eluent, to give 4a (0.26 g, 26%) as a
yellow solid; m.p. 138Ϫ139 °C. EI-MS: m/z (%) ϭ 282 (57) [Mϩ],
225 (50), 178 (84), 177 (54), 165 (20), 149 (51), 105 (100). IR (KBr
disk): ν˜ ϭ 1749, 1339, 1158, 1083, 1033, 956, 7732 cmϪ1. 1H NMR
(200 MHz, CDCl3): δ ϭ 2.48 (s, 3 H), 5.14 (s, 2 H), 7.21 (d, J ϭ
8.4 Hz, 2 H), 7.34Ϫ7.45 (m, 7 H) ppm. 13C NMR (50 MHz,
CDCl3): δ ϭ 14.9, 70.3, 125.2, 125.6 (2 C), 126.7, 127.6 (2 C), 128.5,
128.7 (2 C), 129.2 (2 C), 130.3, 142.7, 155.3, 173.4 ppm. C17H14O2S
(282.36): calcd. C 72.31, H 5.00; found C 72.18, H 4.89. This com-
pound was also prepared in 25% yield by reaction of 13e with 18a
in the presence of KF and a catalytic amount of [chloro(di-2-nor-
bornylphosphanyl)(2Ј-dimethylamino-1,1Ј-biphenyl-2-
yl)palladium()] (Entry 8, Table 5).
4-(4-Hydroxyphenyl)-3-(3,4,5-trihydroxyphenyl)-2(5H)-furanone
(4j): A 1  CH2Cl2 solution of BBr3 (7.68 mL, 7.68 mmol) was
added over 15 min to a stirred solution of 4f (0.23 g, 0.64 mmol)
in dry CH2Cl2 (25 mL), which was cooled to Ϫ78 °C. The mixture
was warmed to room temperature and stirred for 24 h. Water
(30 mL) and CH2Cl2 (70 mL) were added and the organic phase
was separated. The aqueous phase was extracted with CH2Cl2 (2
ϫ 50 mL) and the collected organic extracts were washed with
water (3 ϫ 15 mL), dried and concentrated under reduced pressure
to give 4j (0.19 g, 99%) as a yellow solid. 1H NMR analysis showed
that this crude compound had chemical purity higher than 96%.
M.p. 255 °C (decomp.). IR (KBr disk): ν˜ ϭ 3400, 1701, 1608, 1446,
4-(3,4-Dimethoxyphenyl)-3-(3,4,5-trimethoxyphenyl)-2(5H)-
furanone (4g): The crude product obtained from the reaction be-
tween 13g and 18f in the presence of KF and catalytic amounts of
[Pd2(dba)3] and tBu3P (Table 5, Entry 4) was purified by MPLC on
silica gel, with a mixture of CH2Cl2 and EtOAc (85:15) as eluent,
to give 4g (0.29 g, 58%) as a light-brown solid; m.p. 118Ϫ120 °C.
APCI-MS: m/z (%) ϭ 387 [Mϩ]. IR (KBr disk): ν˜ ϭ 1731, 1646,
1519, 1240, 1131, 1025, 825 cmϪ1 1H NMR (200 MHz, CDCl3):
.
δ ϭ 3.60 (s, 3 H), 3.79 (s, 6 H), 3.86 (s, 3 H), 3.91 (s, 3 H), 5.20 (s,
2 H), 6.68 (s, 2 H), 6.85 (d, J ϭ 8.8 Hz, 1 H), 6.88 (d, J ϭ 2.2 Hz,
1 H), 6.98 (dd, J ϭ 8.8, 2.2 Hz, 1.H) ppm. 13C NMR (50 MHz,
CDCl3): δ ϭ 55.6, 55.9, 56.1 (2 C), 60.8, 70.3, 106.4 (2 C), 110.5,
110.9, 120.6, 122.9, 124.1, 126.0, 138.2, 148.8, 151.1, 153.4 (2 C),
155.4, 173.6 ppm. C21H22O7 (387.40): calcd. C 65.28, H 5.74; found
C 65.19, H 5.68.
1
1251, 1182, 836 cmϪ1. H NMR (200 MHz, CDCl3): δ ϭ 5.23 (s,
2 H), 6.26 (s, 2 H), 6.76 (m, 2 H), 7.29 (m, 2 H), 8.25 (br. s, 1 H),
8.96 (br. s, 2 H), 10.06 (s, 1 H) ppm. 13C NMR (50 MHz, CDCl3):
δ ϭ 70.1, 107.9 (2 C), 115.5 (2 C), 120.9, 121.5, 122.2, 129.3 (2 C),
133.4, 146.1 (2 C), 155.3, 159.4, 173.5 ppm. C16H12O6 (300.27):
calcd. C 64.00, H 4.03; found C 63.87, H 3.91.
4-(2-Naphthyl)-3-(3,4,5-trimethoxyphenyl)-2(5H)-furanone (4h): The
crude product obtained from the reaction between 13h and 18f in
the presence of KF and catalytic amounts of [Pd2(dba)3] and tBu3P
(Table 5, Entry 5) was purified by recrystallisation from a mixture
of CH2Cl2 and hexane (ca. 1.5:1) to give 4h (0.19 g, 39%) as a light-
4-(3,4-Dihydroxyphenyl)-3-(3,4,5-trihydroxyphenyl)-2(5H)-furanone
(4k): A solution of compound 4g (0.18 g, 0.46 mmol) in dry
CH2Cl2 was treated with a 1  CH2Cl2 solution of BBr3 (6.97 mL,
6.97 mmol) at room temperature for 24 h according to the same
procedure used to prepare 4j from 4f. Usual workup provided 4k
(0.14 g, 99%) as a yellow solid. M.p. 260 °C (decomp.). IR (KBr
disk): ν˜ ϭ 3395, 1702, 1604, 1444, 1262, 1047, 801 cmϪ1. 1H NMR
(200 MHz, CDCl3): δ ϭ 5.18 (s, 2 H), 6.26 (s, 2 H), 6.71 (d, J ϭ
8.4 Hz, 1 H), 6.78 (dd, J ϭ 8.4, 1.8 Hz, 1 H), 6.84 (d, J ϭ 1.8 Hz,
1 H), 8.29 (s, 1 H), 8.94 (s, 2 H), 9.15 (s, 1 H), 9.56 (s, 1 H) ppm.
13C NMR (50 MHz, CDCl3): δ ϭ 70.1, 107.9(2 C), 114.9, 115.5,
119.6, 120.8, 121.9, 122.0, 133.3, 145.2, 146.0 (2 C), 147.9, 155.5,
173.6 ppm. C16H12O7 (316.27): calcd. C 60.76, H 3.82; found C
60.65, H 3.75.
brown solid; m.p. 199Ϫ202 °C. EI-MS: m/z (%) ϭ 377 (13) [Mϩ
1], 376 (55) [Mϩ], 319 (11), 221 (17), 202 (19), 155 (100), 101 (18).
IR (KBr disk): ν˜ ϭ 1733, 1640, 1581, 1243, 1130, 1030, 997 cmϪ1
ϩ
.
1H NMR (200 MHz, CDCl3): δ ϭ 3.70 (s, 3 H), 3.89 (s, 3 H), 5.30
(s, 2 H), 6.72 (s, 2 H), 7.40 (dd, J ϭ 8.8, 1.8 Hz, 1 H), 7.55 (m, 2
H), 7.82 (m, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 56.0 (2
C), 60.9, 70.5, 106.4 (2 C), 124.6, 125.4, 125.9, 126.9, 127.3, 127.7,
128.3, 128.5, 132.8, 133.1, 133.8, 133.9, 148.8, 153.3 (2 C), 155.5,
173.3 ppm. C23H20O5 (376.41): calcd. C 73.39, H 5.36; found C
73.45, H 5.31.
3-(3,4-Dimethoxyphenyl)-4-(4-methoxyphenyl)-2(5H)-furanone (4i):
The crude product obtained from the reaction between 13d and 20f
in the presence of KF and catalytic amounts of [Pd(OAc)2] and
Cy3P (Table 5, Entry 6) was purified by MPLC on silica gel, with
Acknowledgments
This work was supported by MIUR (Rome) and the University
a mixture of CH2Cl2 and EtOAc (97:3) as eluent, to give 4i (0.53 g, of Pisa. Grateful thanks are due to Mr. Piergiorgio Vergamini for
46%) as a beige solid; m.p. 103Ϫ105 °C. EI-MS: m/z (%) ϭ 327 (7)
recording IR spectra.
2300
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2290Ϫ2302

Mucochloric Acid: A Useful Synthon for the Selective Synthesis of Furanones
FULL PAPER
[1]
Cromlish, D. Ethier, J. F. Evans, A. W. Ford-Hutchison, J. Y.
Gauthier, R. Gordon, J. Guay, M. Gresser, S. Kargman, B.
Kennedy, Y. Leblanc, S. Leger, J. Mancini, G. P. O’Neill, M.
S. Miao, R. J. Andersen, J. Org. Chem. 1991, 56, 6275Ϫ6280.
B. S. Davidson, C. M. Ireland, J. Nat. Prod. 1990, 53,
1036Ϫ1038.
[2]
[3]
[4]
[5]
[6]
´
Ouellet, M. D. Percival, H. Perrier, D. Riendeau, I. Rodger, P.
`
J. J. Ortega, E. Zubia, J. M. Ocan˜a, S. Naranjo, J. Salva, Tetra-
´
Tagari, M. Therien, P. Vickers, E. Wong, L.-J. Xu, R. N.
hedron 2000, 56, 3963Ϫ3967.
Young, R. Zamboni, S. Boyce, N. Rupniak, M. Forrest, D. Vi-
sco, D. Patrick, Bioorg. Med. Chem. Lett. 1999, 9, 1773Ϫ1778.
M. A. Rahim, P. N. Praveen Rao, E. E. Knaus, Bioorg. Med.
Chem. Lett. 2002, 12, 2753Ϫ2756.
R. T. Lalonde, H. Perakyla, G. P. Cook, C. W. Dence, Environ.
Toxicol. Chem. 1990, 9, 687Ϫ691.
J. P. Surivet, J. M. Vatele, Tetrahedron Lett. 1996, 37,
4373Ϫ4376.
[35]
[36]
[37]
[38]
F. Bohlmann, G. Brindöpke, R. C. Rastogi, Phytochemistry
1982, 21, 695Ϫ699.
J. H. Jung, S. Pummangura, S. Chaichantipyuth, C. Patarapan-
ich, P. E. Fanwick, C.-J. Chang, J. L. McLaughlin, Tetrahedron
1990, 46, 5043Ϫ5054.
D. Kuhnt, T. Anke, H. Besl, M. Bross, R. Herrmann, U. Mo-
cek, B. Steffan, W. Steglich, J. Antibiot. 1990, 43, 1413Ϫ1420.
T. E. Janini, P. Sampson, J. Org. Chem. 1997, 62, 5069Ϫ5073.
R. Grigg, P. Kennewell, V. Savic, Tetrahedron 1994, 50,
5489Ϫ5494.
P. Forgione, P. D. Wilson, A. A. Fallis, Tetrahedron Lett. 2000,
41, 17Ϫ20.
For a review, see: Y. S. Rao, Chem. Rev. 1976, 76, 625Ϫ694.
For a review, see: D. W. Knight, Contemp. Org. Synth. 1994,
1, 287Ϫ315.
For some preliminary results, see: F. Bellina, C. Anselmi, R.
Rossi, Tetrahedron Lett. 2002, 43, 2023Ϫ2027.
[7]
For the Pd-catalysed self-coupling of arylboronic acids, see: M.
[8]
[9]
´
Moreno-Man˜as, M. Perez, R. Pleixats, J. Org. Chem. 1996,
61, 2346Ϫ2351.
[39]
For some previous examples of regioselective Pd-catalysed
monoarylation reactions of dichloroheterocycles by Suzuki-
[10]
type reactions, see: [39a] B. Jiang, C. G. Jang, Heterocycles 2000,
[39b]
[11]
[12]
53, 1489Ϫ1498.
829Ϫ831.
Y. Gong, H. W. Pauls, Synlett 2000,
[39c]
A. J. Cocuzza, F. W. Hobbs, C. R. Arnold, D.
R. Chidester, J. A. Yarem, S. Culp, L. Fitzgerald, P. J. Gilligan,
Bioorg. Med. Chem. Lett. 1999, 9, 1057Ϫ1062. [39d] S. Gronow-
itz, A.-B. Hornefeldt, V. Kristjansson, T. Musil, Chem. Scr.
1986, 26, 305Ϫ309.
J. Zhang, P. G. Blazecka, D. Belmont, J. G. Davidson, Org.
Lett. 2002, 4, 4559Ϫ4561.
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
For
141Ϫ152.
a review, see: R. Brückner, Chem. Commun. 2001,
For a review, see: E-i. Negishi, M. Kotora, Tetrahedron 1997,
53, 6707Ϫ6738.
[40]
[41]
For a review, see: R. Rossi, F. Bellina, Targets Heterocycl.
Chem. 2002, 5, 169Ϫ198.
For a review, see: N. B. Carter, A. E. Nadany, J. B. Sweeney, J.
Chem. Soc., Perkin Trans. 1 2002, 2324Ϫ2342.
M. Biagetti, F. Bellina, A. Carpita, R. Rossi, Tetrahedron Lett.
2003, 44, 607Ϫ610.
R. Rossi, A. Carpita, F. Bellina, P. Stabile, L. Mannina, Tetra-
hedron 2003, 59, 2067Ϫ2081.
M. Biagetti, F. Bellina, A. Carpita, P. Stabile, R. Rossi, Tetra-
hedron 2002, 58, 5023Ϫ5028.
M. Biagetti, F. Bellina, A. Carpita, S. Viel, L. Mannina, R.
Rossi, Eur. J. Org. Chem. 2002, 1063Ϫ1076, and references
cited therein.
F. Bellina, M. Biagetti, A. Carpita, R. Rossi, Tetrahedron Lett.
2001, 42, 2859Ϫ2863.
For some previous examples of Pd-catalysed regioselective
Stille-type reactions involving heterocyclic dichlorides, see: [41a]
J. M. J. Nolsoe, L.-L. Gundersen, F. Rise, Acta Chem. Scand.
[41b]
1999, 53, 366Ϫ372.
G. Langli, L.-L. Gunderrsen, F. Rise,
[41c]
Tetrahedron 1996, 52, 5625Ϫ5638.
Chem. Scand. 1990, 44, 927Ϫ931.
T. Benneche, Acta
A. J. Majeed, O. An-
[41d]
tonsen, T. Benneche, K. Undheim, Tetrahedron 1989, 45,
993Ϫ1006. [41e] Y. Kondo, R. Watanabe, T. Sakamoto, H. Yam-
[41f]
anaka, Chem. Pharm. Bull. 1989, 37, 2814Ϫ2816.
J. Sol-
berg, K. Undheim, Acta Chem. Scand. 1989, 43, 62Ϫ68.
T. Staroske, L. Hennig, P. Welzel, H-J. Hofmann, D. Müller, T.
Häusler, W. S. Sheldrick, S. Zillikens, B. Gretzer, H. Pusch, H.
G. Glitsch, Tetrahedron 1996, 52, 12723Ϫ12744.
Y. Kim, N.-H. Nam, Y.-J. You, B.-Z. Ahn, Bioorg. Med. Chem.
Lett. 2002, 12, 719Ϫ722.
[42]
[21]
[22]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
F. Bellina, M. Biagetti, A. Carpita, R. Rossi, Tetrahedron 2001,
57, 2857Ϫ2863.
R. Rossi, F. Bellina, E. Raugei, Synlett 2000, 1749Ϫ1752.
F. Bellina, C. Anselmi, S. Viel, L. Mannina, R. Rossi, Tetra-
hedron 2001, 57, 9997Ϫ10007.
´
´
M. Therien, J. Y. Gauthier, Y. Leblanc, S. Leger, H. Perrier, P.
Prasit, Z. Whang, Synthesis 2001, 1778Ϫ1779.
V. R. Pattabiraman, S. Padakanti, V. R. Veeramaneni, M. Pal,
K. R. Yeleswarapu, Synlett 2002, 947Ϫ951.
[23]
[24]
[25]
R. Mahon, A. M. E. Richecoeur, J. B. Sweeney, J. Org. Chem.
1999, 64, 328Ϫ329.
T. Joh, K. Doyama, K. Onitsuka, T. Shiohara, S. Takahashi,
Organometallics 1991, 10, 2493Ϫ2498.
V. K. Ahluwalia, M. Bhupinder, K. Rakesh, Synth. Commun.
F. Bellina, C. Anselmi, R. Rossi, Tetrahedron Lett. 2001, 42,
3851Ϫ3854.
[26]
[27]
F. Bellina, R. Rossi, Synthesis 2002, 2729Ϫ2732.
G. Engel, M. Teuber, in MycotoxinsϪProduction, Isolation,
Separation and Purification (Ed.: V. Betina), Elsevier, Amster-
dam, 1984, pp. 291Ϫ314.
J. Boukouvalas, N. Lachance, M. Ouellet, M. Trudeau, Tetra-
hedron Lett. 1998, 39, 7665Ϫ7668.
A. Evidente, G. Randazzo, A. Ballio, J. Nat. Prod. 1986, 49,
593Ϫ601.
J. Boukovalas, F. Maltais, N. Lachance, Tetrahedron Lett. 1994,
35, 7897Ϫ7900.
X. Yang, Y. Shimizu, J. R. Steiner, J. Clardy, Tetrahedron Lett.
1989, 19, 619Ϫ626.
[28]
[29]
[30]
[31]
[32]
[33]
For leading references on Pd-catalysed Suzuki-type reactions
[49a]
of unactivated or deactivated aryl and vinyl chlorides, see:
A. F. Littke, G. C. Fu, Angew. Chem. Int. Ed. 2002, 41,
[49b]
´
R. B. Bedford, S. L. Hazelwood (nee Welch),
4176Ϫ4211.
[49c]
M. E. Limmert, Chem. Commun. 2002, 2610Ϫ2611.
G. Y.
Li, J. Org. Chem. 2002, 67, 3643Ϫ3650. [49d] L. Botella, C. Na-
´
A.
[49e]
jera, Angew. Chem. Int. Ed. 2002, 41, 179Ϫ181.
1993, 34, 761Ϫ764.
Schnyder, A. F. Indolese, M. Studer, H.-U. Blase, Angew. Chem.
G. R. Pettit, S. B. Singh, M. R. Boyd, E. Hamel, R. K. Pettit,
J. M. Schmidt, F. Hogan, J. Med. Chem. 1995, 38, 1666Ϫ1672.
It should be noted that combretastatin A-4 and its (Z)-config-
ured acyclic analogues are prone to isomerise to the corre-
sponding (E) stereoisomers during storage and administration
and that these (E) stereoisomers exhibit a dramatic reduction
in both cytotoxicity and tubulin activity: N.-H. Nam, Y. Kim,
Y.-J. You, D.-H. Hong, H.-M. Kim, B.-Z. Ahn, Bioorg. Med.
Chem. Lett. 2001, 11, 3073Ϫ3076.
Int. Ed. 2002, 41, 3668Ϫ3671. [49f] A. Fürstner, A. Leitner, Syn-
[49g]
lett 2001, 290Ϫ292.
Lett. 2001, 42, 547Ϫ551.
Nolan, Org. Lett. 2001, 3, 1077Ϫ1080.
Trudell, Tetrahedron Lett. 2000, 41, 595Ϫ598.
A. E. Sutton, J. Clardy, Tetrahedron
[49h]
G. A. Grasa, A. C. Hillier, S. P.
[49i]
C. Zhang, M. L.
[49j]
A. F. Littke,
C. Dai, G. C. Fu, J. Am. Chem. Soc. 2000, 122, 4020Ϫ4028.
[49k]
J. P. Wolfe, S. L. Buchwald, Angew. Chem. Int. Ed. 1999,
[49l]
38, 2413Ϫ2416.
A. F. Littke, G. C. Fu, Angew. Chem. Int.
Ed. 1998, 37, 3387Ϫ3388.
For leading references on Pd-catalysed Stille-type reactions,
[34]
[50]
P. Prasit, Z. Wang, C. Brideau, C.-C. Chan, S. Charleson, W.
Eur. J. Org. Chem. 2003, 2290Ϫ2302
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2301

F. Bellina, C. Anselmi, F. Martina, R. Rossi
FULL PAPER
[55]
see: [50a] A. F. Littke, L. Schwarz, G. C. Fu, J. Am. Chem. Soc.
J. J. Li, M. B. Norton, E. J. Reinhard, G. D. Anderson, S. A.
Grefıgory, P. C. Isakson, C. M. Koboldt, J. L. Masferrer, W. E.
Perkins, K. Seibert, Y. Zhang, B. S. Zweifel, D. B. Reitz, J.
Med. Chem. 1996, 39, 1846Ϫ1856.
J. K. Stille, A. M. Echavarren, R. M. Williams, J. A. Hendrix,
Org. Synth. 1993, 71, 97Ϫ106.
J. L. Wardell, S. Ahmed, J. Organomet. Chem. 1974, 78,
[50b]
`
2002, 124, 6343Ϫ6348.
R. B. Bedford, C. S. J. Cazin, S. L.
´
Hazelwood (nee Welch), Chem. Commun. 2002, 2608Ϫ2609.
[50c]
A. F. Littke, G. C. Fu, Angew. Chem. Int. Ed. 1999, 38,
[56]
[57]
[58]
2411Ϫ2413.
[51]
Very recently, some symmetrical 3,4-diaryl-2(5H)-furanones
have been synthesized in high yields by reaction of 12 with
arylboronic acids 18 (3.0 equiv.) in toluene and water under
reflux in the presence of CsF (4.0 equiv.), [PdCl2(PPh3)2] (5
mol %) and BnEt3NϩClϪ (5 mol %); see ref.[40]
N.-H. Nam, Y. Kim, Y.-J. You, D.-H. Hong, H.-M. Kim, B.-
Z. Ahn, Bioorg. Med. Chem. Lett. 2002, 12, 1955Ϫ1958.
M. Cushman, D. Nagarathnam, D. Gopal, H. M. He, C. M.
Lin, E. Hamel, J. Med. Chem. 1991, 34, 2579Ϫ2588.
A. Monks, D. Scudiero, P. Skehan, R. Shoemaker, K. Paull, D.
Vistica, C. X. Hose, J. Langley, P. Cronise, A. Vaigro-Wolff, M.
Gray-Goodrich, H. Campbell, J. Mayo, M. Boyd, J. Natl. Can-
cer Inst. 1991, 83, 757Ϫ766.
395Ϫ404.
H. Morimoto, H. Shimadzu, E. Kushiyama, H. Kawanishi, T.
Osaka, Y. Kawase, K. Yasuda, K. Kikkawa, R. Yamauchi-
kohno, K. Yamada, J. Med. Chem. 2001, 44, 3355Ϫ3368.
R. Rossi, F. Bellina, A. Carpita, F. Mazzarella, Tetrahedron
1996, 52, 4095Ϫ4110.
C. Weisemann, G. Schmidtberg, B. Gunther, H. Albert, J. Or-
ganomet. Chem. 1988, 361, 299Ϫ307.
[52]
[53]
[54]
[59]
[60]
[61]
D. K. Dikhsit, S. Singh, M. M. Singh, V. P. Kamboj, Indian J.
Chem. Sect. B 1990, 29, 954Ϫ960.
Received February 14, 2003
2302
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 2290Ϫ2302