Selective synthesis of (Z)-4-aryl-5-[1-(aryl)methylidene]-3-bromo-2(5H)-furanones

Article abstract of DOI:10.1016/S0040-4020(01)01017-1

4-Aryl-3-bromo-2(5H)-furanones have been selectively synthesized in satisfactory yields by treatment of easily available 3,4-dibromo-2(5H)-furanone either with arylboronic acids in the presence of Ag₂O and a catalytic amount of PdCl₂(MeCN)₂ or with aryl(trialkyl)stannanes in the presence of a catalyst precursor consisting of AsPh₃ and a Pd(II) or a Pd(0) compound. These monobromo derivatives have been then used as precursors to a variety of (Z)-4-aryl-5-[1-(aryl)methylidene]-3-bromo-2(5H)-furanones including the compound with the structure corresponding to that reported for naturally occurring rubrolide N. The structure and stereochemistry of these synthetic compounds have been unambiguously established by NMR techniques.

Full text of DOI:10.1016/S0040-4020(01)01017-1

TETRAHEDRON
Pergamon
Tetrahedron 57 +2001) 9997±10007
Selective synthesis of
ꢀZ)-4-aryl-5-[1-ꢀaryl)methylidene]-3-bromo-2ꢀ5H)-furanones
a,p
a
b
Fabio Bellina, Chiara Anselmi, Stephane Viel, Luisa Mannina and Renzo Rossi
b,c
a,p
Â
aDipartimento di Chimica e Chimica Industriale, University of Pisa, Via Risorgimento 35, I-56126 Pisa, Italy
bIstituto di Chimica Nucleare, CNR, Area delle Ricerca di Roma, Via Salaria Km 29.3, I-00016 Monterotondo Stazione, Roma, Italy
c
Á Á
Facolta di Scienze M.F.N., Universita del Molise, Via Mazzini 8, I-86170 Isernia, Italy
Received 27 August 2001; accepted 25 October 2001
AbstractÐ4-Aryl-3-bromo-2+5H)-furanones have been selectively synthesized in satisfactory yields by treatment of easily available
3,4-dibromo-2+5H)-furanone either with arylboronic acids in the presence of Ag2O and a catalytic amount of PdCl2+MeCN)2 or with
aryl+trialkyl)stannanes in the presence of a catalyst precursor consistingof AsPh and a Pd+II) or a Pd+0) compound. These monobromo
3
derivatives have been then used as precursors to a variety of +Z)-4-aryl-5-[1-+aryl)methylidene]-3-bromo-2+5H)-furanones includingthe
compound with the structure correspondingto that reported for naturally occurringrubrolide N. The structure and stereochemistry of these
synthetic compounds have been unambiguously established by NMR techniques. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
We speculated that readily available 3,4-dibromo-2+5H)-
furanone +4) might be an ideal starting material to access
either 1l or the related compounds 3a±h if it was possible
to achieve a regioselective arylation of 4 at the bromine-
bearingcarbon atom 4 of this dibromo derivative. On the
other hand, 4 represents the cyclic analogof methyl + Z)-2,3-
dibromopropenoate +5) +Fig. 3) and similarly to this last
compound it might exhibit regioselectivity in Pd-catalyzed
cross-coupling reactions with organometallic reagents.6,7
Rubrolides are a family of biologically active marine
ascidian +tunicate) metabolites which have been isolated
from Ritterella rubra1 and Synoicum blochmanni +Fig. 1).2
Rubrolides A +1a) to H +2b) are potent antibiotics and show
moderate but selective inhibition of protein phosphatases 1
and 2A.1 On the other hand, rubrolides K +1i), I +1g), M +1k)
and L +1j) show signi®cant cytotoxicity against P-388
suspension culture of mouse limphoid neoplasm, the
monolayer cultures of human lungcarcinoma +A-549),
human colon carcinoma +HT-29) and human melanoma
+MEL-28).2 Ef®cient and selective procedures for the
synthesis of rubrolides, which are unsubstituted at the
3-position of their 2+5H)-furanone ring, have been
reported.3±5 Nevertheless, no synthetic route toward rubro-
lides which contain an halogen atom in their 3-position have
been reported to date.
Thus, we anticipated that 4 would be able to react with an
equimolar amount of an arylmetal derivative in the presence
of a suitable Pd-catalyst to give selectively the correspond-
ing4-aryl-3-bromo-2+5 H)-furanone 6. The synthesis of
Recently, in connection with an ongoing project directed
towards the development of concise and ef®cient procedures
for the selective synthesis of natural products and their
analogs which are potentially cytotoxic against human
tumor cell lines, we decided to develop a general procedure
for the synthesis of rubrolide N +1l) and some related
substances of general formula 3 +Fig. 2) and to evaluate
the cytotoxic activities of these compounds.
Keywords: furanones; couplingreactions; boron and compounds; tin and
compounds; biologically active compounds.
p
Correspondingauthors. Tel.: 139-50-918282; fax: 139-50-918260;
e-mail: bellina@dcci.unipi.it
Figure 1. Chemical structures of rubrolides.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020+01)01017-1

9998
F. Bellina et al. / Tetrahedron 57 62001) 9997±10007
Figure 2. Chemical structures of compounds 3a±h.
Based on our success with Pd+PPh3)4 as catalyst in Negishi-
type reactions of compound 5 or the correspondingethyl
ester,6,10 we then investigated a similar protocol for the
synthesis of a typical 4-aryl-3-bromo-2+5H)-furanone 6
startingfrom 4. However, we observed that reaction of
this dibromide with 1.2 equiv. of phenylzinc bromide +8)
in THF or in a 1:1 mixture of THF and DMF at 208C, in
the presence of 5 mol% Pd+PPh3)4, did not produce the
required compound 6a. It should be noted that compound
4 was completely consumed in this reaction and that the
crude reaction mixture proved to contain a signi®cant
amount of biphenyl +9).
Figure 3. Chemical structures of compounds 4, 5 and 6.
rubrolide N +1l) and the structural analogs 3a±h might then
be completed by subsequent appendage of a 1-+aryl)methy-
lidene substituent at C-5 of compounds 6, which we envi-
saged to perform by a furanolate chemistry similar to that
previously employed to synthesize rubrolides C and E start-
ingfrom 4-+4-methoxyphenyl)-2+5 H)-furanone.4
On the other hand, no better result was obtained when 4 was
reacted with 3.0 equiv. of 8 at 658C in a mixture of THF and
DMF, in the presence of a catalytic amount of Pd+PPh3)4.
The results obtained in the study of the synthesis of 4-aryl-3-
bromo-2+5H)-furanones 6 startingfrom 48 and the use of
these monobromo derivatives as precursors to +Z)-4-aryl-
5-[1-+aryl)methylidene]-2+5H)-furanones such as com-
pound 1l and the related substances 3a±h form the subject
of this paper. We will also report that the NMR parameters
of 1l prepared from 4 did not match those described in the
literature for the naturally occurringcompound with the
surmised structure of rubrolide N.2 Finally, we will report
the results of tests to evaluate the cytotoxic activities
exhibited by some +Z)-4-aryl-5-[1-+aryl)methylidene]-
2+5H)-furanones prepared from 4 against the National
Cancer Institute +NCI) 3-cell and 60-cell line panels.
An initial attempt to prepare selectively 6a by a Suzuki-type
reaction proved also to be unsuccessful.11 In fact, treatment
of 4 with 1.2 equiv. of phenylboronic acid +10a) in a mixture
of toluene and EtOH at 208C for 3 h, in the presence of
2.1 equiv. of Na2CO3 and 5 mol% Pd+PPh3)4 provided a
reaction mixture which did not contain either 6a or
unreacted 4. Instead, this mixture contained a small
amount of 3,4-diphenyl-2+5H)-furanone +11) together with
unreacted 10a. On the other hand, the product of the reac-
tion of 4 with 1.3 equiv. of 10a, which was performed in
dioxane for 21 h at 808C, in the presence of 3.0 equiv. of
K3PO4 and 3 mol% Pd+PPh3)4, proved to be constituted of a
complex mixture in which 9 was one of the major com-
ponents and compounds 6a and 11 were in a ca. 1:1 molar
ratio. Nevertheless, we were grati®ed to ®nd that
compounds 6 could be regioselectively prepared using a
procedure similar to that we recently developed for the
synthesis of 4-alkyl-3-bromo-2+5H)-furanones from 4.7a In
fact, when 4 was reacted with 1.1 equiv. of an arylboronic
acid 10 in THF under re¯ux for 18±26 h, in the presence of
3.0 equiv. of Ag2O, 5 mol% PdCl2+MeCN)2 and 20 mol%
AsPh3, the required cross-coupled product 6 was obtained in
yields ranging from 66 to 79% +Scheme 2, Table 1).
2. Results and discussion
3,4-Dibromo-2+5H)-furanone +4), which we used as a
startingmaterial for the synthesis of compounds 6, was
prepared from commercially available mucobromic acid
+7) by a procedure similar to that previously used for the
conversion of mucochloric acid to 3,4-dichloro-2+5H)-
furanone.9 Thus, a methanol solution of 7 was treated at
08C with 1.5 equiv. of NaBH4, added in portionwise
manner, and then with 1.0 equiv. of concentrated sulfuric
acid in methanol +Scheme 1). The crude reaction product
was recrystallized from hexane and Et2O to give dibromide
4 in 75% yield.
Interestingly, in all of the cases examined +entries 1±3,
Scheme 2. +a) 10 +1.1 equiv.), PdCl2+MeCN)2 +5 mol%), AsPh3 +20 mol%),
Ag2O +3.0 equiv.), THF, 658C, 18±26 h.
Scheme 1. +a) NaBH4 +1.5 equiv.), MeOH, 08C; +b) conc. H2SO4, 08C.

F. Bellina et al. / Tetrahedron 57 62001) 9997±10007
Table 1. Palladium-catalyzed cross-couplingreaction of 4 with arylboronic acids 10
9999
Entry
Arylboronic acid Ar
Reaction time +h)
Product 6
Isolated yield +%)
1
2
3
C6H5
3-Cl, 4-MeOC6H3
4-ClC6H4
18
21
26
6a
6b
6c
66
79
61
These reactions were performed in THF at 658C using1.1 equiv. of 10, 5 mol% PdCl2+MeCN)2, 20 mol% AsPh3 and 3.0 equiv. of Ag2O.
Table 1) this Ag2O-mediated Pd-catalyzed reaction did not
provide the 3,4-diaryl-2+5H)-furanones derived from the
cross-couplingat the bromine-bearingcarbon atoms C-3
and C-4 of 4. Instead, signi®cant amounts of biaryls 9,
which derived from homocouplingof compounds 10, were
found to be present in the crude reaction mixtures.
A plausibile mechanism of this process is presented in
Scheme 3. In particular, it is proposed that the catalytic
cycle of the cross-couplingreaction involves oxidative
addition of the C-4 carbon±bromine bond of 4 to a palla-
dium+0) species and that the resultingorganopalladium+II)
bromide A interacts with Ag2O and 10 to give the inter-
mediate B. Transmetalation of this intermediate with 10
followed by reductive elimination would then produce the
required derivative 6. The transmetalation from boron to
palladium, which produces D, could occur by prior boron
to silver+I) transmetalation, i.e. via C or directly from
complex B.
Similar mechanisms have been recently suggested either for
the Ag2O-mediated, Pd-catalyzed couplingof silanols with
aryl and alkenyl iodides12 or for the Pd-catalyzed coupling
of aryl and alkenyl iodides with boronic acids mediated by
copper+I) thiophene-2-carboxylate.13
We were also pleased to observe that compounds 6 could
also be regioselectively obtained in yields ranging from 58
to 76% by reaction of 4 with 1.0±1.1 equiv. of an aryl-
+trialkyl)stannane 12 in NMP at 208C in the presence of
the catalyst precursor consistingof 5 mol% PdCl +PhCN)2
2
and 10 mol% AsPh3 +catalyst A)14 or that obtained by treat-
ment of 2.5 mol% Pd2+dba)3 with 10 mol% AsPh3 +catalyst
B) +Scheme 4, Table 2).
Scheme 3. Plausible mechanism for the Ag2O-mediated Pd-catalyzed reac-
tion between 4 and 10.
Similarly to the above mentioned Ag2O-mediated Pd-
catalyzed reactions of 4 with 10, these cross-couplingreac-
tions did not afford any trace of the diarylated compounds
11, but provided signi®cant amounts of biaryls 9 derived
from homocouplingof 12 when catalyst A or B was used.
Another signi®cant feature of some of these reactions was
that, unexpectedly, the cross-couplingreactions of 4 with
aryl+trimethyl)stannanes 12b and 12c +entries 2 and 4, Table
Scheme 4. +a) 12 +1.1 equiv.), PdCl2+PhCN)2 +5 mol%), AsPh3 +10 mol%),
NMP, 208C; +b) 12 +1.0 equiv.), Pd2+dba)3 +2.5 mol%), AsPh3 +10 mol%),
NMP, 208C.
Table 2. Palladium-catalyzed cross-couplingreactions of 4 with aryl+trialkyl)stannanes 12
Entry
Organotin
Ar
Catalyst precursor
Reaction time +h)
6/9 molar ratio
Cross-coupled product
Isolated yield +%)
12
R
1
2
3
4
5
6
7
8
12a
12b
12a
12c
12d
12e
12f
C6H5
C6H5
C6H5
Bu
Me
Bu
Me
Bu
Bu
Bu
Bu
Cat A
Cat A
Cat B
Cat B
Cat B
Cat B
Cat B
Cat B
93
39
94
22
89
89
112
250
92/8
90/10a
92/8
6a
6a
6a
6d
6e
6f
76
70
67
59
68
58
73
62
4-MeSC6H4
4-MeOC6H4
3-FC6H4
4-MeC6H4
3-Cl, 4-MeOC6H3
91/9a
92/8
96/4b
93/7
6g
6c
12g
n.d.
All reactions were performed at 208C in the presence of 5 mol% PdCl2+PhCN)2 and 10 mol% AsPh3 +Cat A) or in the presence of 2.5 mol% Pd2+dba)3 and
10 mol% AsPh3 +Cat B).
a
The crude reaction product was also contaminated by 3-bromo-4-methyl-2+5H)-furanone +13). The desired monoarylated compound and 13 were in a ca.
84:16 molar ratio, respectively.
The crude reaction product was also contaminated by ca. 10% of 4.
b

10000
F. Bellina et al. / Tetrahedron 57 62001) 9997±10007
Figure 4. Chemical structures of compounds 13 and 6d.
2) furnished 3-bromo-4-methyl-2+5H)-furanone +13) in
addition to the desired compounds 6a and 6d, respectively
+Fig. 4).
Scheme 5. +a) TBDMSOTf +1.2 equiv.), i-Pr2EtN +3.0 equiv.), CH2Cl2,
208C, 2 h, then DBU +2.0 equiv.), 208C, 4 h.
17a and 17b, respectively +entries 1 and 2, Table 3),
compound 3e in 86% yield startingfrom 6d and 17a
+entry 3, Table 3), and compounds 3f and 3h in 99 and
24% yield startingfrom 6e and 17b and 17c, respectively
+entries 4 and 5, Table 3).
The required monobromo derivatives and compound 13
were found to be present in the crude reaction products of
these reactions in a ca. 84:16, molar ratio, respectively.
Puri®cation of these crude products by MPLC on silica
gel allowed us to isolate pure 6a and 6d in 70 and 59%
yield, respectively.
All these compounds were characterized by MS, IR and
NMR analyses as well as by elemental analysis. Moreover,
the structure and stereochemistry of 3a, 3c, 3f and 3h were
It should also be noted that preliminary tests indicated that
the regioselectivity of the cross-coupling reactions between
4 and organostannanes 12, which were carried out usingthe
catalyst precursor A, was higher than that obtained when
these reactions were performed usingcatalyst A and
10 mol% CuI. In fact, signi®cant amounts of symmetrically
3,4-diaryl substituted 2+5H)-furanones 11 were formed
under these last conditions.
1
unambiguously assigned on the basis of their H and 13C
NMR spectra at 600 and 150 MHz, respectively, and by a
combination of NMR techniques, which included homo-
nuclear shift correlation +1H±1H COSY), nuclear Over-
hauser enhancement spectroscopy +NOESY), hetero-
nuclear multiple quantum coherence +HMQC) and hetero-
nuclear multiple bond correlation +HMBC). Unfortunately,
in the case of compound 3e the structural and stereo-
chemical assignments by NMR spectroscopy could not be
performed owingto the very low solubility of this substance
in solvents such as acetone-d6, CDCl3, C6D6, CD3OD and
DMSO-d6.
Havingset up two different protocols for the regioselective
synthesis of compounds 6, we examined the conversion of
these heterocyclic derivatives into a precursor to rubrolide
N, i.e. compound 3a, and some of its structural analogs of
general formula 3 which are characterized by methoxyaryl
moieties, by a procedure similar to that recently used to
prepare the dimethyl ethers 14 and 15 correspondingto
rubrolide C +1c) and rubrolide E +1e), respectively, starting
from 4-+4-methoxyphenyl)-2+5H)-furanone +16) +Fig. 5).4
Finally, we investigated the conversion of the methyl aryl
ether subunits of compounds 3a, 3c and 3f so prepared into
the correspondingphenol moieties and, ®rst of all, we tried
to prepare compound 1l from 3a. Thus, 5.0 equiv. of BBr3 in
CH2Cl2 were added to a CH2Cl2 solution of 3a maintained at
2788C and the resultingmixture was allowed to warm up to
208C, stirred at this temperature for 48 h and then hydro-
lyzed and extracted with CHCl3. A TLC analysis of the
dried organic extract showed the presence of two new
compounds. This extract was concentrated and the residue
was puri®ed by MPLC on silica gel. Concentration of the
®rst eluted chromatographic fractions followed by a puri®-
cation of the resultingproduct by a second MPLC on silica
Thus, a CH2Cl2 solution of a compound 6 was sequentially
treated with 1.2 equiv. of tert-butyldimethylsilyl tri¯uoro-
methanesulfonate +TBDMSOTf), 3.0 equiv. of diisopropyl-
ethylamine and 1.0 equiv. of an arylaldehyde 17.
After stirringfor 2 h at room temperature, the reaction
mixture was treated with 2.0 equiv. of 1,8-diaza-
bicyclo[5.4.0]undec-7-ene +DBU) at 208C for 4.5 h to give
stereoselectively the required compound 3 +Scheme 5).
Table 3. Synthesis of +Z)-4-aryl-5-[1-+aryl)methylidene]-2+5H)-furanones
3 by introduction of a1-+aryl)methylidene unit at the C-5 position of
compounds 6
This one-pot procedure was used to prepare compounds 3a
and 3c in 87 and 95% yield startingfrom aldehydes 6b and
Entry
Reagents
Compound 6 17
Product Isolated yield +%)
Aldehyde
R1
X
Z
1
2
3
4
5
6b
6b
6d
6e
6e
17a Br
17b
17a Br
17b
H
Me
Me
Me
Me
3a
3c
3e
3f
87
95
86
99
24
H
H
H
H
H
17c Br Br Me
3h
These syntheses were performed usingthe experimental conditions indi-
cated in Scheme 5.
Figure 5. Chemical structures of compounds 14, 15 and 16.

F. Bellina et al. / Tetrahedron 57 62001) 9997±10007
10001
similarly substituted aromatic moiety, the chemical shift
of C-17 is expected up®eld compared with that of C-15.
On the other hand, this interchange would lead to a better
agreement between the literature data and our assignments
even though not negligible differences should be still
present amongthe chemical shift values of the protons
+Dd,0.8 ppm) or of the carbon atoms +Dd,4 ppm) of the
aryl moiety linked to C-4 of synthetic 1l and of the natural
product. Thus, all these observations indicate that some
NMR assignments made in the literature for the natural
product with the surmised structure of rubrolide N2 are
incorrect and that probably the substituent at C-3 of the
naturally occurringcompound is a chlorine atom instead
of a bromine atom.
Scheme 6. +a) BBr3 +5.0 equiv.), CH2Cl2, 208C, 15±48 h, then H2O.
gel provided 3-bromo-4-+3-chloro-4-hydroxyphenyl)-5-[1-
+3-bromo-4-methoxy-phenyl)methylidene]-2+5H)-furanone
+3b) in 51% yield +Scheme 6).
It is worth mentioningthat the procedure, which was used to
prepare 1l from 3a, proved to be suitable for the preparation
of compounds 3d and 3g from 3c and 3f, respectively, in
almost quantitative yield +Scheme 5). On the contrary,
attempts to prepare 1l from 3a in high selectivity were
unsuccessful. In fact, demethylation of 3a either by treat-
ment with 7.0 equiv. of BBr3 in CH2Cl2 at 208C for 60 h and
at 358C for 6 h, followed by hydrolysis, or by reaction with
10.0 equiv. of AlCl3 and 12.0 equiv. of ethanethiol at room
temperature for 1 h, followed by hydrolysis with dilute
aqueous HCl,16 provided 1l contaminated by signi®cant
amounts of 3b.
On the other hand, concentration of the last eluted chroma-
tographic fractions of the ®rst MPLC on silica gel followed
by puri®cation of the resultingresidue by a second MPLC
on silica gel allowed us to obtain 1l in 47% yield +Scheme
6). The structure and stereochemistry of 3b and 1l were
con®rmed by their 1H and 13C NMR spectra and by a combi-
nation of NMR techniques which included NOESY, 1H±1H
COSY, HMQC and HMBC.
However, it was observed that several NMR parameters of
1l did not match those reported for the natural product with
the structure of rubrolide N.2 In fact, the chemical shift of
C-3 in synthetic 1l +dˆ107.9 ppm) was signi®cantly differ-
ent from that of the correspondingcarbon atom in the
natural compound +dˆ119.0 ppm).2 On the other hand, it
must be taken into account that: +i) the chemical shift for
C-3 either in a compound similar to 1l, i.e. 3a, or in
3-bromo-4-aryl-2+5H)-furanones such as 6a and 6f is
usually included between 107 and 110 ppm; +ii) unex-
pectedly, the chemical shift value reported for C-3 in
rubrolide N is very similar to the chemical shift values for
C-3 in rubrolides which are characterized by a chlorine atom
in their position 3 and are included in the range d 116.9±
118.5 ppm;2 +iii) C-3 of 3-chloro-4-phenyl-2+5H)-furanone,
which recently we selectively synthesized from 3,4-
dichloro-2+5H)-furanone,15 absorbs at 117.1 ppm. It should
also be noted that the assignments, which have been
reported in the literature for C-17 and C-15 of the naturally
occurringcompound with the surmised structure of rubro-
lide N +dˆ123.4 and 117.0 ppm, respectively),2 ought to be
interchanged. In fact, for compounds characterized by a
Finally, compounds 1l, 3a, 3d, 3e, 3f and 3g were evaluated
in the NCI 3-cell line, one dose primary anticancer assay at a
1.00£1024 M concentration. This 3-cell line panel consisted
of MCF7 +breast), NCI-H460 +lung) and SF-268 +CNS). The
results for each test agent are reported in Table 4 as the
percent of growth of the treated cells when compared to
the untreated control cells. The data summarized in Table
4 indicate that compounds 1l and 3d were highly cytotoxic
+entries 1 and 3). In fact, their values for the growth reduc-
tion of any one of the cell lines were negative numbers,
which indicate cell kill. On the contrary, compounds 3a,
3e, 3f and 3g were found to be inactive +entries 2, 4±6).
Thus, these data seem to suggest that the presence either of
two phenol subunits or a chlorine atom at C-15 are neces-
sary for cytotoxicity of +Z)-4-aryl-5-[1-+aryl)methylidene]-
3-bromo-2+5H)-furanones. It should also be noted that
compounds 1l and 3d were further evaluated against the
NCI 60 cell line panel but showed limited cytotoxicity,
displayingaveraeg GI
1025 M, respectively.
values 1.70£1025 and 1.29£
50
Table 4. Results of the cytotoxicity tests for compounds 1l, 3a, 3d, 3e, 3f and 3g in the NCI 3-cell line, one dose primary anticancer assay
Entry
Compound
Growth percentages
MCF-7 +breast)
Activity
NCI-H460 +lung)
SF-268 +CNS)
1
2
3
4
5
6
1l
3a
3d
3e
3f
264
155
297
99
100
82
279
41
273
141
145
104
275
41
288
121
130
97
Active
Inactive
Active
Inactive
Inactive
Inactive
3g
In the protocol used, each cell line was inoculated and preincubated on a microtiter plate. Test agents were then added at a 1.00£1024 M concentration in
DMSO and the culture incubated for 48 h. End-point determinations were made with alamar blue. Results for each test are reported as the percent of growth of
the treated cells when compared to the untreated control cells.

10002
F. Bellina et al. / Tetrahedron 57 62001) 9997±10007
3. Conclusions
for APCI ionization. The experimental conditions used
included: discharge current, 3 mA +ionspray voltage read-
back, 5012 V); ori®ce voltage, 60 V +260 V in negative-ion
mode); scan range, m/zˆ400±600. IR spectra were recorded
on a Perkin±Elmer 1725 FT-IR spectrophotometer. NMR
spectra were recorded on a Varian Gemini 200 MHz
spectrometer or on a Bruker AMX 600 spectrometer using
TMS and CDCl31 as an internal standard, respectively.
Nevertheless, the H and 13C NMR spectra of 3b and 3d
were referenced to DMSO-d6 at d 2.50 ppm +down®eld to
TMS) and at d 40.40 ppm, respectively. On the other hand,
The results summarized earlier show that, when suitable
reaction conditions are employed, 3,4-dibromo-2+5H)-fura-
none +4) is able to undergo highly regioselective cross-
couplingreactions with arylboronic acids or aryl+trialkyl)-
stannanes to give 4-aryl-3-bromo-2+5H)-furanones 6 in
moderate to good yields. We have also shown that
compounds 6 represent useful precursors to +Z)-4-aryl-5-
[1-+aryl)methylidene]-3-bromo-2+5H)-furanones such as
compounds 1l and 3a±g, which represent a not previously
synthesized class of compounds with potential cytotoxic
activities. The structure and the stereochemistry of these
substances were unambiguously assigned by NMR tech-
niques. These assignments allowed us to conclude that the
structure reported in the literature for rubrolide N2 is incor-
rect. In fact, several NMR parameters of compound 1l,
which has the structure of rubrolide N, did not match
those reported for this natural product.2
1
the H NMR spectra of 1l and 3g were referenced to the
residual CHD2OD proton of CD3OD at 3.37 ppm down®eld
to TMS, whereas the 13C NMR spectra of these compounds
were referenced to CD3OD at 49.30 ppm. The structure of
compounds 6a, 6f, 1l, 3a±d and 3f±h was assigned on the
basis of the 1H and 13C NMR spectra of these compounds at
600 and 150 MHz, respectively, and by a combination of
1
NMR techniques which included H±1H COSY, NOESY
+mixingtime: 400 ms), HMQC and HMBC. All reactions
of air and water sensitive materials were performed in
¯ame-dried glassware under an atmosphere of nitrogen or
argon using standard syringe, cannula and septa techniques.
Solvents were dried and distilled before use. The following
compounds were prepared by published procedures:
PdCl2+PhCN)2,17 PdCl2+MeCN)2,18 3-chloro-4-methoxy-
phenylboronic acid +10b),19 4-methylthiophenyl-trimethyl-
stannane +12c),20 3-¯uorophenyltributylstannane +12e),21 4-
methoxyphenyltributylstannane +12d)22 and 4-tolyltributyl-
stannane +12f).23
Finally, it should be noted that two +Z)-4-aryl-5-[1-+aryl)-
methylidene]-3-bromo-2+5H)-furanones so prepared, which
are characterized by two phenol subunits and a chlorine
atom at C-15, were found to be signi®cantly active in the
NCI 3-cell line, one dose primary anticancer assay. Never-
theless, these compounds showed limited cytotoxicity
against the NCI 60 cell line panel.
We are currently investigating a protocol similar to that used
to prepare compounds 1l and 3a±g for the synthesis of
cytotoxic rubrolides, which are characterized by a chlorine
atom linked at C-3 of their 2+5H)-furanone ring.
4.1.1. 3,4-Dibromo-2ꢀ5H)-furanone ꢀ4). A stirred solution
of mucobromic acid +7) +28.67 g, 111.2 mmol) in methanol
+160 ml), which was cooled to 08C, was treated with NaBH4
+6.31 g, 166.7 mmol), added in a portionwise manner, and
the resultingmixture was stirred for 15 min at 0 8C. A solu-
tion of concentrated sulfuric acid +10.89 g, 111.2 mmol) in
methanol +55 ml), which was cooled to 08C, was then added
and the resultingmixture was stirred for 15 min. It was then
diluted with Et2O +1.5 l) and washed with brine +4£200 ml).
The organic phase was dried and concentrated under
reduced pressure and the solid residue was recrystallized
from a mixture of hexane and Et2O +1:1) to give 4
+20.20 g, 75% yield) as a colorless solid. Mp 90±918C.
MS, m/z +%): 244 +19) [M1], 242 +39) [M1], 240 +19)
4. Experimental
4.1. General
Meltingpoints and boilingpoints are uncorrected. Precoated
aluminum silica gel sheets Merck 60 F254 were used for TLC
analyses. GLC analyses were performed on a Dani GC 1000
instrument with a PTV injector, which was equipped with a
Dani data station 86.01. Two types of capillary columns
were used: an Alltech AT-1 bonded FSOT column
+30 m£0.25 mm i.d.) and an Alltech AT-35 bonded FSOT
column +30 m£0.25 mm i.d.). Puri®cations by MPLC on
silica gel +Merck silica gel 60, particle size 0.015±
0.040 mm) were performed on a BuÈchi B-680 system
usinga Knauer K-2400 differential refractometer as
detector. GLC/MS analyses were performed usinga
Q-mass 910 spectrometer interfaced with a Perkin±Elmer
gas-chromatograph. The ionspray mass spectra of
compound 1l and 3b were acquired usinga Perkin±Elmer
Sciex API III1 triple quadrupole mass spectrometer +Sciex,
Concord, Ont., Canada) equipped with a source for atmos-
pheric pressure ionization and an articulated ionspray
interface. The ESI spectra, in negative-ion mode, were
obtained under the followingconditions: ionspray voltage,
24.0 kV; ori®ce voltage, 260 V; scan range, m/zˆ400±
600; scan time, 4.73 s; no interscan delay; unit-mass reso-
lution. The APCI-MS spectra of compounds 3d±h were
registered on a quadrupole mass spectrometer equipped
with the Sciex API source and a heated nebulizer probe
1
[M1], 163 +86), 161 +100), 119 +19), 117 +17). H NMR
+200 MHz, CDCl3): d 4.90 +2H, s, H-5). Anal. Calcd for
C4H2Br2O2: C, 19.86; H, 0.84; Br, 66.07. Found: C, 19.67;
H, 1.02; Br, 66.18.
4.2. Palladium-catalyzed reaction between 4 and
arylboronic acids 10
A mixture of compound 4 +2.42 g, 10.0 mmol), an aryl-
boronic acid 10 +11.0 mmol), PdCl2+CH3CN)2 +0.13 g,
0.5 mmol), AsPh3 +0.61 g, 2.0 mmol) and Ag2O +6.95 g,
30.0 mmol) was placed in a reaction vessel under argon
atmosphere and then deaereated. Deaereated THF +40 ml)
was added and the reaction mixture, which was periodically
monitored by GLC and TLC, was stirred under re¯ux. On
completion of the reaction the mixture was cooled to room
temperature, diluted with EtOAc +250 ml) and ®ltered over
Celite. The ®ltrate was concentrated under reduced pressure

F. Bellina et al. / Tetrahedron 57 62001) 9997±10007
10003
and the residue was puri®ed by MPLC on silica gel and/or
by recrystallization. This procedure was used to prepare
compounds 10a, 10b and 10c. The reaction time of these
preparations and the isolated yields of compounds 10 so
prepared are reported in Table 1.
as a colorless liquid. Bp 1488C/0.1 mbar. MS, m/z +%): 375
+75), 373 +60), 319 +41), 317 +35), 261 +75), 260 +100), 154
+37). IR +®lm): n 1577, 1488, 1462, 1288, 1252, 1067, 1027,
804, 701 cm21. 1H NMR +200 MHz, CDCl3): d 7.39 +1H, d,
Jˆ1.5 Hz, H-2), 7.28 +1H, dd, Jˆ7.7, 1.5 Hz, H-6), 6.91
+1H, d, Jˆ7.7 Hz, H-5), 1.61±1.25 +12H, m, Sn±C±CH2±
CH2±), 1.04 +6H, t, Jˆ7.9 Hz, Sn±CH2±), 0.89 +9H, t, Jˆ
7.2 Hz, Sn±C±C±C±CH3). Anal. Calcd for C19H30ClOSn:
C, 52.87; H, 7.71. Found: C, 53.14; H, 7.45.
4.2.1. 3-Bromo-4-phenyl-2ꢀ5H)-furanone ꢀ6a). The crude
reaction product, which was obtained from the reaction of
phenylboronic acid +10a) with 4 accordingto Section 4.2
+entry 1, Table 1), was puri®ed by MPLC on silica gel, using
a mixture of benzene and EtOAc +99:1) as eluant, to give
compound 6a in 66% yield as a colorless solid. Mp 105±
1078C. MS, m/z +%): 240 +20) [M1], 238 +21) [M1], 211
+41), 209 +46), 105 +46), 102 +100). IR +KBr): n 1752, 1602,
4.3. Palladium-catalyzed reaction between 4 and
arylꢀtrialkyl)stannanes 12
The preparation of compounds 6 by the title reaction was
performed usingone of the followingPd-catalyst pre-
cursors: that consistingof a mixture of PdCl 2+PhCN)2
+0.192 g, 0.50 mmol) and AsPh3 +0.307 g, 1.00 mmol) +cata-
lyst A); or that consistingof a mixture of Pd 2+dba)3 +0.229 g,
0.25 mmol) and AsPh3 +0.307 g, 1.00 mmol) +catalyst B).
One of these catalyst precursors was sequentially treated
with a deaereated solution of 4 +10.0 mmol) in NMP
+15 ml) and a deaereated solution of an aryl+trialkyl)stan-
nane 12 +10.0±11.0 mmol) in NMP +10 ml). The resulting
mixture, which was periodically monitored by GLC and/or
TLC analysis, was stirred at room temperature for the period
of time reported in Table 2. After completion of the reaction
the mixture was poured into a saturated aqueous NH4Cl
solution +150 ml) and extracted with EtOAc +4£80 ml).
The organic extract, which was obtained from reactions
involvingaryl+tributyl)stannanes, was then stirred for
4.5 h at 208C with a 8 M aqueous KF solution +200 ml),
®ltered over Celite and the ®ltrate was extracted with
EtOAc +3£60 ml). The organic extract was washed with
water +80 ml), dried, ®ltered, concentrated under reduced
pressure and the residue was analyzed by GLC/MS. In the
case of the residues obtained from reactions involvingaryl-
+tributyl)stannanes, this analysis showed the presence of
three major products, i.e. the required cross-coupled
products 6, the homocouplingcompounds 9 derived from
the organostannanes, and AsPh3. On the other hand, in the
case of the residues obtained from reactions involvingaryl-
+trimethyl)stannanes 12b and 12c +entries 2 and 4, Table 2),
GLC/MS analysis also showed the presence of signi®cant
amounts of a compound havinga MS spectrum correspond-
ingto that of 3-bromo-4-methyl-2+5 H)-furanone +13). The
residues were then puri®ed by MPLC on silica gel and/or by
recrystallization. This general procedure was used to
prepare compounds 6a, 6c, 6d, 6e, 6f and 6g. Table 2
summarizes the reaction time and the catalyst precursor
used for these preparations, the molar ratios between the
required compounds 6 and the homocouplingproducts
derived from organostannes 12, and the isolated yields
of compounds 6 so obtained. It should be noted that the
physical and spectral properties of so prepared 6a and 6c
proved to be in agreement with those of the same
compounds obtained by Pd-catalyzed reaction of 4 with
10a and 10c, respectively.
1338, 1190, 1029, 984, 766, 749, 692 cm21 1H NMR
.
+600 MHz, CDCl3): d 7.84 +2H, dd, Jˆ8.3, 1.5 Hz, H-7
and H-11), 7.56 +1H, m, H-9), 7.53 +2H, m, H-8 and
H-10), 5.20 +2H, s, H-5). Anal. Calcd for C10H7BrO2: C,
50.24; H, 2.95. Found: C, 50.44; H, 3.11. GLC analysis
showed that 6a had chemical purity higher than 98%.
4.2.2.
3-Bromo-4-ꢀ3-chloro-4-methoxyphenyl)-2ꢀ5H)-
furanone ꢀ6b). The crude reaction product, which was
obtained from the reaction of 3-chloro-4-methoxyphenyl-
boronic acid +10b) with 4 accordingto Section 4.2 +entry
2, Table 1), was recrystallized from a mixture of CH2Cl2 and
hexane to give 6b in 78% yield as a colorless solid. Mp
162±1648C. MS, m/z +%): 307 +3) [M1], 306 +20) [M1],
305 +22) [M1], 304 +100) [M1], 302 +74) [M1], 275 +57),
166 +78). IR +KBr): n 1759, 1598, 1510, 1260, 1193, 1035,
1
988, 831, 702 cm21. H NMR +200 MHz, CDCl3): d 7.90
+1H, d, Jˆ2.2 Hz, H-7), 7.82 +1H, dd, Jˆ8.8, 2.2 Hz, H-11),
7.05 +1H, d, Jˆ8.8 Hz, H-10), 5.16 +2H, s, H-5), 3.99 +3H, s,
OCH3). Anal. Calcd for C11H8BrClO3: C, 43.53; H, 2.66.
Found: C, 43.23; H, 2.48. GLC analysis showed that 6b had
chemical purity higher than 98%.
4.2.3. 3-Bromo-4-chlorophenyl-2ꢀ5H)-furanone ꢀ6c). The
crude reaction product, which was obtained from the reac-
tion of 4-chlorophenylboronic acid +10c) with 4 according
to Section 4.2 +entry 3, Table 1), was recrystallized from a
mixture of CHCl3 and hexane to give 6c as a beige solid. Mp
173±1758C. Puri®cation of the mother liquor of this recrys-
tallization by MPLC on silica gel, using a mixture of CHCl3
and hexane +50:50) as eluant, allowed to obtain a further
amount of 6c in 61% overall yield. MS, m/z +%): 194 +61),
167 +32), 165 +100), 138 +22), 137 +37), 136 +52), 75 +27). IR
+KBr): n 1744, 1611, 1491, 1443, 1192, 1061, 1036, 990,
1
824 cm21. H NMR +200 MHz, CDCl3): d 7.80 +2H, m,
Harom), 7.50 +2H, m, Harom), 5.18 +2H, s, H-5). Anal. Calcd
for C10H6BrClO2: C, 43.91; H, 2.21. Found: C, 44.22; H,
2.45. 1H NMR analysis showed that 6c had chemical purity
higher than 96%.
4.2.4. 3-Chloro-4-methoxyphenyltributylstannane ꢀ12g).
Chlorotributylstannane +16.33 g, 50.2 mmol) was added
dropwise to a 0.81 M THF solution of 3-chloro-4-methoxy-
phenylmagnesium bromide +71 ml, 57.5 mmol) and the
resultingmixture was re¯uxed for 19 h. It was then cooled
to room temperature, poured into water +300 ml) and
extracted with Et2O +4£60 ml). The dried organic extract
was concentrated under reduced pressure and the residue
was fractionally distilled to give 12g +18.84 g, 87% yield)
4.3.1. 3-Bromo-4-methylthiophenyl-2ꢀ5H)-furanone ꢀ6d).
The crude reaction product, which was obtained by Pd-
catalyzed reaction between 4 and 4-methylthiophenyl-
trimethylstannane +12c) +entry 4, Table 2), was puri®ed by
MPLC on silica gel, using a mixture of CHCl3, petroleum

10004
F. Bellina et al. / Tetrahedron 57 62001) 9997±10007
ether and EtOAc +70:30:1) as eluant. The chromatographic
fractions containingthe required compound 6d were
concentrated under reduced pressure band the solid residue
was recrystallized from a mixture of CH2Cl2 and hexane to
give pure 6d in 59% yield as a colorless solid. Mp 144±
1468C. MS, m/z +%): 207 +16), 206 +100), 177 +49), 148
+81), 134 +49), 133 +49), 102 +45). IR +KBr): n 1768,
+15.03 g, 53.5 mmol), anhydrous K2CO3 +powder, 325
mesh, 37.03 g, 267.9 mmol) and methyl iodide +76.61 g,
539.9 mmol) in acetone +225 ml) was stirred under re¯ux
for 6 h. After cooling, the mixture was ®ltered and the
®ltrate was concentrated under reduced pressure. The
solid residue was recrystallized from hexane to give 17c
+13.38 g, 85% yield) as a colorless crystalline solid. Mp
1
1
1605, 1593, 1192, 1060, 1041, 990, 820 cm21. H NMR
88±898C +lit24 mp 928C). H NMR +200 MHz, CDCl3): d
+200 MHz, CDCl3): d 7.78 +2H, m, Harom), 7.32 +2H, m,
Harom), 5.18 +2H, s, H-5), 2.54 +3H, s, SCH3). Anal. Calcd
for C11H9BrO2S: C, 46.33; H, 3.18. Found: C, 46.56; H,
3.17.
9.85 +1H, s, CHO), 8.03 +2H, s, Harom), 3.97 +3H, s, OCH3).
The spectral properties of this compound were in agreement
with those previously reported.24
4.4. General procedure for the synthesis of ꢀZ)-4-aryl-5-
[1-ꢀaryl)methylidene]-3-bromo-2ꢀ5H)-furanones 3
starting from compounds 6 and arylaldehydes 17
4.3.2. 3-Bromo-4-ꢀ4-methoxyphenyl)-2ꢀ5H)-furanone ꢀ6e).
The crude reaction product, which was obtained by Pd-
catalyzed reaction between 4 and 4-methoxyphenyltributyl-
stannane +12d) +entry 5, Table 2), was puri®ed by MPLC on
silica gel, using a mixture of CHCl3, petroleum ether and
EtOAc +70:30:1) as eluant. The chromatographic fractions
containingthe required compound 6e were concentrated
under reduced pressure and the solid residue was recrystal-
lized from a mixture of CH2Cl2 and hexane to give pure 6e
in 68% yield as a colorless solid. Mp 133±1348C. MS, m/z
+%): 270 +6) [M1], 268 +7) [M1], 159 +11), 152 +100), 132
+40), 102 +12), 77 +14). IR +KBr): n 1752, 1605, 1513, 1276,
A solution of a compound 6 +3.3 mmol) in CH2Cl2 +20 ml)
was sequentially treated with tert-butyldimethylsilyl tri-
¯uoromethanesulfonate +1.04 g, 3.9 mmol), diisopropyl-
ethylamine +1.72 ml, 9.9 mmol) and an arylaldehyde 17
+3.9 mmol) and the resultingmixture was stirred for 2 h at
room temperature under argon. 1,8-Diazabicyclo[5.4.0]-
undec-7-ene +1.0 g, 6.6 mmol) was then added and the
mixture, which was periodically monitored by TLC analy-
sis, was stirred at room temperature for 4.5 h. It was then
diluted with CH2Cl2 +100 ml) and washed with 3 M HCl
+2£50 ml). The aqueous phase was extracted with CH2Cl2
+3£50 ml) and the collected organic extracts were washed
with brine +5£50 ml) until neutrality, dried and concentrated
under reduced pressure. The solid residue was puri®ed by
recrystallization or by MPLC on silica gel. This procedure
was employed to prepare compounds 3a, 3c, 3e, 3f and 3h.
The results of the preparation of these compounds are
summarized in Table 3.
1
1262, 1182, 1060, 989, 826 cm21. H NMR +200 MHz,
CDCl3): d 7.85 +2H, m, Harom), 7.01 +2H, m, Harom), 5.18
+2H, s, H-5), 3.89 +3H, s, OCH3). Anal. Calcd for
C11H9BrO3: C, 49.10; H, 3.37. Found: C, 49.28; H, 3.52.
4.3.3. 3-Bromo-3ꢀ¯uorophenyl)-2ꢀ5H)-furanone ꢀ6f). The
crude reaction product, which was obtained by Pd-catalyzed
reaction between 4 and 3-¯uorophenyltributylstanne +12e)
+entry 6, Table 2), was puri®ed by MPLC on silica gel, using
a mixture of toluene and EtOAc +99:1) as eluant, to give
pure 6f in 58% yield as a pale yellow solid. Mp 109±1118C.
MS, m/z +%): 258 +3) [M1], 256 +3) [M1], 229 +8), 227 +10),
123 +27), 120 +100), 99 +30). IR +KBr): n 1751, 1608, 1582,
4.4.1. ꢀZ)-3-Bromo-4-ꢀ3-chloro-4-methoxyphenyl)-5-[1-
ꢀ3-bromo-4-methoxyphenyl)methylidene]-2-ꢀ5H)-fura-
none ꢀ3a). The crude reaction product, which was obtained
from the reaction of 6b with 3-bromo-4-methoxybenzalde-
hyde +17a) accordingto Section 4.4 +entry 1, Table 3), was
recrystallized from a mixture of CH2Cl2 and hexane to give
pure 3a in 87% yield as a yellow solid. Mp 225±2278C. MS,
m/z +%): 502 +43) [M1], 501 +51) [M1], 500 +89) [M1], 364
+19), 226 +37), 193 +68), 178 +35), 156 +39), 119 +100). IR
+KBr): n 1778, 1606, 1499, 1291, 1272, 1003, 822, 750,
1
1439, 1157, 1071, 1033, 986, 801 cm21. H NMR +600
MHz, CDCl3): d 7.61 +1H, ddd, Jˆ9.1, 2.7, 1.8 Hz, H-7),
7.58 +1H, dd, Jˆ8.2, 1.8 Hz, H-11), 7.51 +1H, ddd, Jˆ8.2,
8.2, 5.5 Hz, H-10), 7.26 +1H, ddd, Jˆ8.2, 8.2, 2.7 Hz, H-9),
5.17 +2H, s, H-5). Anal. Calcd for C10H6BrFO2: C, 46.72; H,
2.35. Found: C, 46.93; H, 2.41.
1
711 cm21. H NMR +600 MHz, CDCl3): d 7.93 +1H, d,
4.3.4. 3-Bromo-4-ꢀ4-tolyl)-2ꢀ5H)-furanone ꢀ6g). The
crude reaction product, which was obtained by Pd-catalyzed
reaction between 4 and 4-tolyltributylstannane +12f) +entry
7, Table 2), was recrystallized from a mixture of CHCl3 and
petroleum ether to give pure 6g as a pale yellow solid. Mp
169±1718C. Puri®cation of the mother liquor of this recrys-
tallization by MPLC on silica gel, using a mixture of toluene
and EtOAc +98:2), as eluant, allowed to obtain a further
amount of pure 6g in 73% overall yield. MS, m/z +%): 254
+10) [M1], 252 +8) [M1], 225 +14), 223 +11), 143 +39), 119
+29), 116 +100). IR +KBr): n 1747, 1607, 1445, 1191, 1061,
Jˆ2.1 Hz, H-8), 7.79 +1H, dd, Jˆ8.7, 2.1 Hz, H-12), 7.75
+1H, d, Jˆ2.1 Hz, H-14), 7.42 +1H, dd, Jˆ8.5, 2.1 Hz,
H-18), 7.10 +1H, d, Jˆ8.5 Hz, H-17), 6.91 +1H, d, Jˆ
8.7 Hz, H-11), 6.01 +1H, s, H-6), 4.01 +3H, s, H-19), 3.94
+3H, s, H-20). 13C NMR +150 MHz, CDCl3): d 164.96 +C-2),
157.12 +C-10), 156.92 +C-16), 152.21 +C-4), 146.84 +C-5),
135.81 +C-8), 131.66 +C-12), 130.91 +C-14), 129.07 +C-18),
126.79 +C-7), 123.57 +C-13), 121.97 +C-15), 113.00 +C-6),
112.43 +C-9), 112.41 +C-17), 112.17 +C-11), 108.11 +C-3),
56.58 +C-20), 56.57 +C-19). Anal. Calcd for C19H13Br2ClO4:
C, 45.59; H, 2.62. Found: C, 45.27; H, 2.66.
1
1032, 986, 813, 752 cm21. H NMR +200 MHz, CDCl3): d
7.75 +2H, m, Harom), 7.30 +2H, m, Harom), 5.17 +2H, s, H-5),
2.42 +3H, s, CH3). Anal. Calcd for C11H9BrO2: C, 52.22; H,
3.58. Found: C, 52.47; H, 3.84.
4.4.2. ꢀZ)-3-Bromo-4-ꢀ3-chloro-4-methoxyphenyl)-5-[1-
ꢀ4-methoxyphenyl)methylidene]-2ꢀ5H)-furanone ꢀ3c). The
crude reaction product, which was obtained by reaction of
6b with 4-methoxybenzaldehyde +17b) accordingto Section
4.4 +entry 2, Table 3), was puri®ed by recrystallization from
4.3.5. 3,5-Dibromo-4-methoxybenzaldeyde ꢀ17c).
stirred mixture of 3,5-dibromo-4-hydroxybenzaldehyde
A

F. Bellina et al. / Tetrahedron 57 62001) 9997±10007
10005
a mixture of CH2Cl2 and hexane to give 3c in 95% yield as a
yellow solid. Mp 184±1868C. MS, m/z+%): 424 +28) [M1],
422 +100) [M1], 420 +81) [M1], 326 +5), 285 +35), 178 +5),
148 +15). IR +KBr): n 1763, 1600, 1498, 1297, 1273, 1174,
CHCl3, hexane and EtOAc +60:40:1) as eluant, to give
compound 3e in 24% yield as a yellow amorphous solid.
Mp 175±1788C. APCI-MS, m/z: [M1H]1ˆ543. IR +KBr):
n 1780, 1608, 1508, 1471, 1259, 1180, 1026, 982,
1
1
1019, 872 cm21. H NMR +600 MHz, CDCl3): d 7.75 +2H,
831 cm21. H NMR +600 MHz, CDCl3): d 7.91 +2H, m,
m, H-8 and H-12), 7.56 +1H, d, Jˆ2.2 Hz, H-14), 7.43 +1H,
dd, Jˆ8.5, 2.2 Hz, H-18), 7.10 +1H, d, Jˆ8.5 Hz, H-17),
6.92 +2H, m, H-9 and H-11), 6.08 +1H, s, H-6), 4.01 +3H,
s, H-19), 3.85 +3H, s, H-20). 13C NMR +150 MHz, CDCl3):
d 165.11 +C-2), 160.93 +C-10), 156.63 +C-16), 152.15 +C-4),
145.91 +C-5), 132.77 +C-8 and C-12), 130.78 +C-14), 128.92
+C-18), 125.37 +C-7), 123.29 +C-15 or C-13), 122.07 +C-13
or C-15), 114.59 +C-6), 114.53 +C-9 and C-11), 112.18
+C-17), 107.11 +C-3), 56.37 +C-19), 55.41 +C-20). Anal.
Calcd for C19H14BrClO4: C, 54.12; H, 3.35. Found: C,
53.87; H, 3.16. GLC analysis showed that 3c had chemical
purity higher than 97%.
H-8 and H-12), 7.47 +2H, m, H-14 and H-18), 7.07 +2H,
m, H-15 and H-17), 5.97 +1H, s, H-6), 3.91 +3H, s, H-20),
3.90 +3H, s, H-19). 13C NMR +150 MHz, CDCl3): d 164.58
+C-2), 161.53 +C-16), 154.78 +C-10), 153.17 +C-4), 148.52
+C-5), 134.41 +C-8 and C-12), 131.32 +C-7), 130.59 +C-14
and C-18), 120.61 +C-13), 118.65 +C-9 and C-11), 114.59
+C-15 and C-17), 110.56 +C-6), 108.53 +C-3), 60.80 +C-20),
55.51 +C-19). Anal. Calcd for C19H13Br3O4: C, 41.87; H,
1
2.40. Found: C, 41.80; H, 2.25. H NMR analysis showed
that compound 3h had chemical purity higher than 97%.
4.4.6. Demethylation of 3a: synthesis of ꢀZ)-3-bromo-4-
ꢀ3-chloro-4-hydroxyphenyl)-5-[1-ꢀ3-bromo-4-methoxy-
phenyl)methylidene]-2ꢀ5H)-furanone ꢀ3b) and ꢀZ)-3-
bromo-4-ꢀ3-chloro-4-hydroxyphenyl)-5-[1-ꢀ3-bromo-4-
hydroxyphenyl)methylidene]-2ꢀ5H)-furanone ꢀ1l). To a
solution of 3a +1.00 g, 2.0 mmol) in dry CH2Cl2 +40 ml),
which was stirred at 2788C, was added a 1 M solution of
BBr3 in CH2Cl2 +10 ml, 10.0 mmol) over 15 min. The reac-
tion mixture was allowed to warm up to room temperature
and stirred at this temperature for 48 h. Water +20 ml) and
CHCl3 +100 ml) were sequentially added and the organic
phase was separated. The aqueous phase was extracted
with CHCl3 +5£20 ml) and Et2O +40 ml). The collected
organic extracts were washed with brine +2£25 ml), dried
and concentrated under reduced pressure. The solid residue
was puri®ed by MPLC on silica gel using a mixture of
CHCl3 and methanol +96:4) as eluant. Concentration of
the ®rst eluted chromatographic fractions allowed to 3b
+0.50 g, 51% yield) as a yellow solid. Mp 243±2458C.
ESI-MS, m/z: [M2H]2ˆ483. IR +KBr): n 3321, 1724,
4.4.3. ꢀZ)-3-Bromo-4-ꢀ4-methylthiophenyl)-5-[1-ꢀ3-bromo-
ꢀ3e).
4-methoxyphenyl)methylidene]-2ꢀ5H)-furanone
The crude reaction product, which was obtained by reaction
of 6d with 3-bromo-4-methoxybenzaldehyde +17a) accord-
ingto Section 4.4 +entry 3, Table 3), was recrystallized from
a mixture of benzene and hexane to give 3e in 86% yield as a
yellow crystalline solid. Mp 245±2468C. APCI-MS, m/z:
[M1H]1ˆ481. IR +KBr): n 1765, 1595, 1487, 1266,
1
1224, 1093, 1054, 995, 818 cm21. H NMR +200 MHz,
DMSO-d6): d 8.09 +1H, d, Jˆ2.0 Hz, H-8), 7.83 +1H, dd,
Jˆ8.8, 2.0 Hz, H-12), 7.50 +4H, m, H-13, H-14, H-17 and
H-18), 7.21 +1H, d, Jˆ8.8 Hz, H-11), 6.31 +1H, s, H-6), 3.90
+3H, s, H-20), 2.56 +3H, s, H-19). It should be noted that a
complete structural and stereochemical assignment for 3e
by NMR spectroscopy could not be performed owingto the
very low solubility of this substance in solvents such as
acetone-d6, CDCl3, C6D6, CD3OD and DMSO-d6. Anal.
Calcd for C19H14Br2O3S: C, 47.33; H, 2.93. Found: C,
47.78; H, 2.73. TLC analysis showed that 3e was chemically
pure.
1
1592, 1493, 1300, 1257, 1057, 1034, 1018 cm21. H NMR
+600 MHz, DMSO-d6): d 10.94 +1H, s, H-19), 8.09 +1H, d,
Jˆ2.1 Hz, H-8), 7.84 +1H, dd, Jˆ8.7, 2.1 Hz, H-12), 7.58
+1H, d, Jˆ2.2 Hz, H-14), 7.39 +1H, dd, Jˆ8.3, 2.2 Hz,
H-18), 7.21 +1H, d, Jˆ8.7 Hz, H-11), 7.17 +1H, d, Jˆ
8.3 Hz, H-17), 6.32 +1H, s, H-6), 3.90 +3H, S, H-20). 13C
NMR +150 MHz, DMSO-d6): d 165.33 +C-2), 157.06
+C-10), 156.00 +C-16), 153.12 +C-4), 147.12 +C-5), 135.67
+C-8), 132.74 +C-12), 131.45 +C-14), 130.26 +C-18), 127.60
+C-7), 121.04 +C-15), 120.82 +C-13), 117.78 +C-17), 113.84
+C-11), 113.16 +C-6), 111.90 +C-9), 107.85 +C-3), 57.36
+C-20). Anal. Calcd for C18H11Br2ClO4: C, 44.44; H, 2.28.
Found: C, 44.15; H, 1.99.
4.4.4. ꢀZ)-3-Bromo-4-ꢀ4-methoxyphenyl)-5-[1-ꢀ4-meth-
oxyphenyl)methylidene]-2ꢀ5H)-furanone ꢀ3f). The crude
reaction product, which was obtained by reaction of 6e with
17b accordingto Section 4.4 +entry 4, Table 3), was recrys-
tallized from a mixture of CH2Cl2 and hexane to give pure 3f
in 99% yield as a yellow amorphous solid. Mp 148±1508C.
APCI-MS, m/z: [M1H]1ˆ387. IR +KBr): n 1771, 1604,
1
1514, 1504, 1258, 1176, 1022, 989, 828 cm21. H NMR
+600 MHz, CDCl3): d 7.74 +2H, m, H-8 and H-12), 7.49
+2H, m, H-14 and H-18), 7.07 +2H, m, H-15 and H-17),
6.91 +2H, m, H-9 and H-11), 6.11 +1H, s, H-6), 3.90 +3H,
s, H-19), 3.85 +3H, s, H-20). 13C NMR +150 MHz, CDCl3):
d 165.45 +C-2), 161.26 +C-16), 160.77 +C-10), 153.49 +C-4),
146.24 +C-5), 132.67 +C-8 and C-12), 130.66 +C-14 and
C-18), 125.55 +C-7), 121.29 +C-13), 114.51 +C-6), 114.47
+C-15 and C-17), 114.41 +C-9 and C-11), 106.32 +C-3),
55.47 +C-19), 55.39 +C-20). Anal. Calcd for C19H15BrO4:
C, 58.93; H, 3.91. Found: C, 58.59; H, 4.18.
Concentration of the last eluted chromatographic fractions
allowed to obtain compound 1l +0.45 g, 47% yield) as a
yellow solid. Mp 219±2238C. ESI-MS, m/z: [M2H]2ˆ
469. IR +KBr): n 3360, 1746, 1603, 1497, 1410, 1280,
1
1193, 1005, 753 cm21. H NMR +600 MHz, CD3OD): d
8.04 +1H d, Jˆ2.2 Hz, H-8), 7.66 +1H, dd, Jˆ8.4, 2.2 Hz,
H-12), 7.61 +1H, d, Jˆ2.2 Hz, H-14), 7.41 +1H, dd, Jˆ8.4,
2.2 Hz, H-18), 7.16 +1H, d, Jˆ8.4 Hz, H-17), 6.97 +1H, d,
Jˆ8.5 Hz, H-11), 6.18 +1H, s, H-6). 13C NMR +150 MHz,
CD3OD): d 166.80 +C-2), 157.45 +C-10), 157.03 +C-16),
154.45 +C-4), 147.89 +C-5), 136.96 +C-8), 133.15 +C-12),
132.20 +C-14), 130.57 +C-18), 127.45 +C-7), 122.73 +C-15
or C-13), 122.36 +C-13 or C-15), 118.28 +C-17), 117.76
4.4.5. ꢀZ)-3-Bromo-5-[1-ꢀ3,5-dibromo-4-methoxyphenyl)-
methylidene]-4-ꢀ4-methoxyphenyl)-2ꢀ5H)-furanone ꢀ3h).
The crude reaction product, which was obtained by reaction
of 6e with 17c accordingto Section 4.4 +entry 5, Table 3),
was puri®ed by MPLC on silica gel, using a mixture of

10006
F. Bellina et al. / Tetrahedron 57 62001) 9997±10007
+C-11), 114.78 +C-6), 111.81 +C-9), 107.86 +C-3). Anal.
Calcd for C17H9Br2ClO4: C, 43.21; H, 1.92. Found: C,
42.97; H, 1.88.
protein-bindingdye. Results of each test aegnt were
reported as the percent of growth of the treated cells when
compared to the untreated control cells. Table 4 summarizes
the results of the assays performed. Compounds 1l and 3d
were also evaluated against the NCI 60 cell line panel25 at
®ve concentrations at 10-fold dilutions. A 48 h continuous
drugexposure protocol was used, and a sulforhodamine B
protein assay was used to evaluate cell viability or growth.
4.4.7. Demethylation of 3c: synthesis of ꢀZ)-3-bromo-4-
ꢀ3-chloro-4-hydroxyphenyl)-5-[1-ꢀ4-hydroxyphenyl)-
methylidene]-2ꢀ5H)-furanone ꢀ3d). A solution of com-
pound 3c +0.50 g, 1.2 mmol) in CH2Cl2 +15 ml) was
reacted with a 1 M CH2Cl2 solution of BBr3 +6.0 ml,
6.0 mmol) at room temperature for 17 h accordingto the
same procedure used to prepare 1l from 3a. The crude reac-
tion product, which was obtained after usual work up, was
puri®ed by MPLC on silica gel, using a mixture of CHCl3
and methanol +96:4) as eluant, to give 3d +0.45 g, 99%
yield) as a yellow solid. Mp 284±2858C. APCI-MS, m/z:
[M11]1ˆ393; [M2H]2ˆ391. IR +KBr): n 3462, 3235,
Acknowledgements
Á
We wish to thank the Ministero dell'Universita e della
Ricerca Scienti®ca e Tecnologica +MURST) and the
University of Pisa for ®nacial support. We are also grateful
Professor Annalaura Segre for the use of NMR facilities of
the Servizio NMR dell'Area della Ricerca di Roma +CNR)
and to Professor Piero Salvadori for the use of the Perkin
Elmer Sciex API III1 triple quadrupole mass spectrometer.
We wish also to thank Mr Piergiorgio Vergamini for record-
ingIR spectra and Dr Angela Cuzzola for recordingthe ion
spray MS spectra and the APCI-MS spectra.
1733, 1601, 1277, 1172, 1031, 840 cm21 1H NMR
.
+600 MHz, DMSO-d6): d 10.93 +1H, s, H-19), 10.11 +1H,
s, H-20), 7.68 +2H, m, H-8 and H-12), 7.58 +1H, d, Jˆ
2.1 Hz, H-14), 7.38 +1H, dd, Jˆ8.4, 2.1 Hz, H-18), 7.17
+1H, d, Jˆ8.4 Hz, H-17), 6.84 +2H, m, H-9 and H-11),
6.22 +1H, s, H-6). 13C NMR +150 MHz, DMSO-d6): d
165.58 +C-2), 160.06 +C-10), 155.91 +C-16), 153.31 +C-4),
145.76 +C-5), 133.76 +C-8 and C-12), 131.42 +C-14), 130.20
+C-18), 124.61 +C-7), 121.10 +C-13), 121.02 +C-15), 117.78
+C-17), 116.91 +C-9 and C-11), 115.48 +C-6), 106.47 +C-3).
Anal. Calcd for C17H10BrClO4: C, 51.87; H, 2.56. Found: C,
51.65; H, 2.28.
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selectively ethyl +Z)-2-bromo-3-phenylpropenoate from ethyl