An economical access to 3,4-diaryl-2(5H)-furanones and 4-aryl-6-methyl- 2(2H)-pyranones by pd-catalyzed Suzuki-type arylation of 3-aryl-4-tosyloxy-2(5H) -furanones and 6-methyl-4-tosyloxy-2(2H)-pyranones, respectively

Article abstract of DOI:10.1002/ejoc.200900581

Both symmetrical and unsymmetrical 3,4-diaryl-substituted 2(5H)-furanones have been efficiently synthesized using an inexpensive procedure involving the Pd(OAc)₂/PCy₃-catalyzed Suzuki-type arylation of readily available 3-aryl-4-tosy

Full text of DOI:10.1002/ejoc.200900581

FULL PAPER
DOI: 10.1002/ejoc.200900581
An Economical Access to 3,4-Diaryl-2(5H)-furanones and
4-Aryl-6-methyl-2(2H)-pyranones by Pd-Catalyzed Suzuki-Type Arylation of
3-Aryl-4-tosyloxy-2(5H)-furanones and 6-Methyl-4-tosyloxy-2(2H)-pyranones,
Respectively
Fabio Bellina,*[a] Chiara Marchetti,[a] and Renzo Rossi*[a]
Keywords: Synthetic methods / C–C coupling / Palladium / Cross-coupling / Heterocycles
Both symmetrical and unsymmetrical 3,4-diaryl-substituted
of this arylation protocol have also been used for the high
2(5H)-furanones have been efficiently synthesized using an
yielding synthesis of 4-aryl-6-methyl-2(2H)-pyranones from
inexpensive procedure involving the Pd(OAc)2/PCy3-cata- 6-methyl-4-tosyloxy-2(2H)-pyranone.
lyzed Suzuki-type arylation of readily available 3-aryl-4-tos-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
yloxy-2(5H)-furanones as the key step. The mild conditions
Germany, 2009)
tested tumor cell lines and strongly inhibited tubulin poly-
merization at doses as low as 1 m.[10f] Thus, a number of
methods have been developed for the synthesis of com-
pounds 1.[10g,10k,14] However, these methods are limited by
the use of not readily available starting materials,[10j,14a,14b]
toxic reagents and synthetic intermediates,[14c,14e] multiple
palladium-catalyzed cross-coupling reactions,[10g,14c,14e,14f]
or a very large molar excess of Grignard reagents.[14d]
Therefore, we recently decided to develop a new procedure
for accessing compounds 1 from commercially available
starting materials via a chemistry free from the above men-
tioned limitations, involving Suzuki-type reactions of 3-
aryl-4-tosyloxy-2(5H)-furanones 3, a class of activated tos-
ylates, with arylboronic acids 4 as a key step.
Introduction
Five-membered heterocycles with two aryl groups on ad-
jacent positions include a very large number of biologically
active compounds[1] such as cyclooxygenase-2 (COX-2) in-
hibitors,[2] anticoccidial agents,[3] cannabinoid CB1 receptor
antagonists,[4] ligands for the Niemann Pick C1 Like 1
(NPC1L1) protein,[5] antagonists for the human CCK1 re-
ceptor,[6] inhibitors of transforming growth factor-beta,[7]
p38α MAP kinase,[8] and HMG-CoA reductase,[9] and sub-
stances with potent cytotoxic activity against human cancer
cell lines.[10]
Among these heterocycles, unsymmetrical 3,4-diaryl-sub-
stituted 2(5H)-furanones 1 represent a class of compounds
that has received considerable attention because of their
biological properties. One of these compounds is Rofecoxib
(Vioxx®) (1a) (Figure 1), a COX-2 inhibitor,[11] which was
withdrawn from the market in 2004 following the detection
of an increase in cardiovascular events.[12] Additional bioac-
tive diaryl-substituted heterocycles of this class include
compound 1b[10h] and 1c[10f] (Figure 1), which are (Z)-re-
stricted analogues of combretastatin A-4 (2) (Figure 1), a
potent inhibitor of tubulin polymerization which displays
potent cytotoxic activity against a variety of tumor cell lines
and tumors.[1a,1c,13] Compound 1b proved to be more cyto-
toxic than 2 against the NCI 60 human tumor cell lines
panel[10h] and 1c was shown to be remarkably potent in all
Figure 1. Chemical structures of compounds 1a–c and 2.
[a] Dipartimento di Chimica e Chimica Industriale, University of
Pisa,
In this paper we provide an account on the results of
this investigation. Moreover, we describe that the protocol
developed for efficiently performing the cross-coupling be-
tween 3 and 4 was also successfully used for the preparation
of a variety of 4-aryl-6-methyl-2(2H)-pyranones 6 from the
corresponding 4-tosylate 5 (Figure 2).
Via Risorgimento 35, 56126 Pisa, Italy
Fax: +39-0502219260
E-mail: bellina@dcci.unipi.it
rossi@dcci.unipi.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900581.
Eur. J. Org. Chem. 2009, 4685–4690
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4685

F. Bellina, C. Marchetti, R. Rossi
Table 1. Synthesis of 3-aryltetronic acids 9a–c.
FULL PAPER
Entry
7
Ar1
9
Yield (%)
1
2
3
7a
7b
7c
Ph
9a
9b
9c
63
50
53
3,4,5-(MeO)3C6H2
4-CF3C6H4
Figure 2. Chemical structures of compounds 3, 4, 5 and 6a,b.
It should be noted that, recently, it has been reported
that some compounds of type 6 show antimicrobial ac-
tivity.[15] In particular, 6a was found to exhibit promising
inhibitory activity against Fusarium oxysporum and 6b dem-
onstrated modest inhibitory activity against Scizosaccharo-
myces pombi.[15]
responding boronic acids, which are often employed as
starting materials for the synthesis of these salt,[21] we pre-
ferred to use arylboronic acids as organometallic partners
of the Suzuki-type cross-coupling reactions.
Thus, a set of experiments was performed using 3a and
phenylboronic acid (4a) as model substrates. As shown in
Table 2, a variety of catalyst systems, bases and solvents
were screened for the reaction of 3a with 4a.
This screening was necessary as it has previously been
reported that the PdCl2(PPh3)2-catalyzed reaction of 3a
with arylboronic acids in THF at 60 °C in the presence of
an aqueous solution of KF as the base gives only a trace
amount of the required arylated products.[18e]
Results and Discussion
We planned the synthesis of compounds 1 according to
the retrosynthetic sequence illustrated in Scheme 1 in which
commercially available methyl arylacetates 7 and methyl hy-
droxyacetate (8) were the starting materials.
At first, we obtained a very disappointing result when
the reaction of 3a with 1.5 equiv. of 4a was performed un-
der experimental conditions very similar to those success-
fully employed by Wu, Zhang and Gao[17b] for the reaction
of 4-tosyloxy-2(5H)-furanone with arylboronic acids, i.e.
using a RhCl(PPh3)2/dppf catalyst system and CsF as base
in a mixture of toluene and water (Table 2, entry 1). An
unsatisfactory result was also obtained when the reaction of
3a with 4a was carried out under experimental conditions
(Table 2, entry 2) similar to those used by Zhang and co-
workers[14f] for the Suzuki-type arylation of halogenated
2(5H)-furanones. However, better results were obtained
Scheme 1. Retrosynthesis of compounds 1.
Thus, a tandem process, which combines a transesterifi- when diphosphanes with a wide bite angle, such as dppf
cation and a subsequent Dieckmann condensation was em- (Table 2, entry 3) or Xantphos (Table 2, entry 4), were em-
ployed to prepare 3-aryltetronic acids 9 from 7 and 8 ac- ployed as ancillary ligands for palladium in place of PPh3.
cording to a procedure very recently reported in the litera- On the contrary, the use of (S)-BINAP, which has a bite
ture.[16] As shown in Table 1, treatment of methyl arylacet- angle (93°) lower than those of dppf and Xantphos (99°
ates 7a–c with 1.2 equiv. of 8 in refluxing THF in the pres- and 111°, respectively),[22] led to the formation of traces of
ence of 2.2 equiv. of tBuOK gave compounds 9a–c in 50– the required derivative 1d (Table 2, entry 5).
63% yield.
In searching for milder and efficient reaction conditions
Compounds 9a, 9b and 9c were then reacted with than those above summarized, we decided to perform the
1.05 equiv. of p-toluenesulfonyl chloride in CH2Cl2 at room reaction between 3a and 4a in methanol at 60 °C using a
temperature in the presence of 1.2 equiv. of Et3N to provide catalyst system consisting of a 1:2 mixture of Pd(OAc)2 and
the corresponding 4-tosylate derivatives, 3a, 3b and 3c in the electron-rich ligand PCy3 and K2HPO4·3H2O or an
77, 82 and 75% yield, respectively.
aqueous solution of NaHCO3 as the base under experimen-
The possibility of using tosylates 3a–c as activated elec- tal conditions (Table 2, entries 6 and 7) similar to those re-
trophiles in efficient transition metal-catalyzed arylation re- ported by Wu, Zhang et al.[23] for the Suzuki-type reaction
actions with arylboronic acids 4 was next evaluated.[17–19] of 3-aryl- or 3-bromo-4-(tosyloxy)coumarins with aryl-
Since a large variety of arylboronic acids are commercially boronic acids, respectively. Good results were obtained in
available and potassium aryltrifluoroborates show, in gene- particular when the reaction was carried out using an aque-
ral, lower reactivity[20] and are more expensive than the cor- ous solution of NaHCO3 as base. Under these experimental
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Eur. J. Org. Chem. 2009, 4685–4690

Pd-Catalyzed Suzuki-Type Arylation
Table 2. Optimization of the reaction conditions for the cross-coupling reaction between tosylate 3a and phenylboronic acid (4a).
Entry Transition metal compound (%) Ligand [mol-%]
Base [equiv.]
Solvent
Reaction conditions [°C/h] Yield (%)[a]
1
2[b]
3[b]
4[b]
5[b]
6
7
8
9
10
11
RhCl(PPh3)3 (2.0)
PdCl2(PPh3)2 (5.0)
PdCl2(dppf) (5.0)
PdCl2(PhCN)2 (5.0)
PdCl2(PhCN)2 (5.0)
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
Pd(OAc)2 (5.0)
dppf (2.0)
–
CsF (4.0)
CsF (3.0)
CsF (3.0)
CsF (3.0)
CsF (3.0)
toluene/H2O (1:1)
toluene/H2O (1:1)
toluene/H2O (1:1)
toluene/H2O (1:1)
toluene/H2O (1:1)
MeOH
50/28
60/25
–
12
23
53
trace
29
65
52
90
trace
trace
–
110/28
110/22
110/48
60/1.5
60/1.5
60/1.5
60/1.5
60/1.5
60/1.5
XantPhos (5.0)
(S)-BINAP (5.0)
PCy3 (10.0)
PCy3 (10.0)
PCy3 (10.0)
PCy3 (10.0)
PPh3 (10.0)
dppf (5.0)
K2HPO4·3H2O (3.0)
NaHCO3 1  in H2O (3.0)
K2HPO4 (3.0)
NaHCO3 (3.0)
NaHCO3 (3.0)
NaHCO3 (3.0)
MeOH
MeOH
MeOH
MeOH
Pd(OAc)2 (5.0)
MeOH
[a] Isolated yield based on tosylate 3a. [b] Reaction performed in the presence of 5 mol-% BnEt3NCl.
conditions compound 1d was isolated in 65% yield (Table 2,
entry 7).
We next found that, in contrast to what reported for the
arylation of 3-aryl-4-tosyloxycoumarins and 3-bromo-4-
(tosyloxy)coumarins,[23] the yield of 1d was improved when
the reaction between 3a and 4a was carried out in the pres-
ence of anhydrous inorganic bases. In fact, the use of anhy-
drous K2HPO4 instead of the corresponding hydrated salt
caused an increase of the yield from 29 to 52% (compare
entries 6 and 8 of Table 2). Moreover, a more remarkable
improvement of the yield of 1d was obtained when the Scheme 2. Attempted synthesis of 1d by direct arylation of 9a.
Pd(OAc)2/PCy3-catalyzed reaction of 3a with 4a was car-
ried out in methanol at 60 °C in the presence of solid
NaHCO3 as the base (Table 2, entry 9). Compound 1d was
cleanly obtained in 90% isolated yield. On the contrary, the
chemically pure unsymmetrical 3,4-diaryl-substituted
2(5H)-furanones 1b, 1e, 1f, 1g, and 1h in 90, 54, 70, 83 and
use of ligands for palladium different from PCy3, such as
76% yield, respectively.
PPh3 and dppf, gave unsatisfactory results (Table 2, entries
10 and 11).
The preparation of 1a by reaction of 4-hydroxy-3-phenyl-
2(5H)-furanone (9a) with 1.2 equiv. of 4a in a 20:1 mixture
Table 3. Coupling of activated tosylates 3b and 3c with arylboronic
acids.
of THF and water at 60 °C for 1.5 h in the presence of
1.1 equiv. of p-toluenesulfonyl chloride, 3.0 equiv. of
Na2CO3 and 5 mol-% PdCl2 (Scheme 2), according to a re-
cently described protocol for the palladium-catalyzed direct
arylation of 4-hydroxycoumarins,[24] was also attempted.
Unfortunately, the reaction did not provide any trace of 1d
despite the absence of 9a in the crude reaction mixture.
Nevertheless, encouraged by the results obtained in entry
11 of Table 2, we next investigated the scope of this cross-
coupling reaction by using tosylates 3c and 3b, bearing aryl
moieties substituted with one electron-withdrawing and
three electron-donating groups, respectively, at their acti-
vated C-4 position and arylboronic acids 4b–e as substrates
under the experimental condition of this entry. The boronic
acids were characterized by electron-neutral, electron-rich
or electron-deficient aryl moieties. As shown in Table 3, the
examined reactions (entries 1–5) generated the desired
Entry
3
Ar1
4
Ar2
1
Yield (%)
1
2
3
4
5
3b 3,4,5-(MeO)3C6H2 4b
3b 3,4,5-(MeO)3C6H2 4c
3b 3,4,5-(MeO)3C6H2 4d
3c
3c
2-naphthyl
3-F,4-MeOC6H3
4-AcC6H4
4-MeOC6H4
2-naphthyl
1b
1e
1f
1g
1h
90
54
70
83
76
4-CF3C6H4
4-CF3C6H4
4e
4b
Eur. J. Org. Chem. 2009, 4685–4690
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4687

F. Bellina, C. Marchetti, R. Rossi
FULL PAPER
Finally, we turned our attention to the application of the
optimized reaction conditions used in entry 11 of Table 2
and entries 1–5 of Table 3 for the preparation of 4-aryl-6-
methyl-2(2H)-pyranones 6 from 6-methyl-4-tosyloxy-2(2H)-
pyranone (5) and arylboronic acids. Compound 5 was ob-
tained in 70% yield from commercially available 4-hydroxy-
6-methyl-2(2H)-pyranone (triacetic acid lactone) (10) (Fig-
ure 3) according to a literature procedure.[25]
Conclusions
Both symmetrical and unsymmetrical 3,4-diaryl-substi-
tuted 2(5H)-furanones, including 4-(2-naphthyl)-3-(3,4,5-
trimethoxyphenyl)-2(5H)furanone (1b), which was shown
to be highly cytotoxic against the NCI human tumor cell
lines panel,[10h] have been prepared in high yields via an
inexpensiveprocedureinvolvinganunprecedentedPd(OAc)2/
PCy3-catalyzed Suzuki-type cross-coupling reaction of aryl-
boronic acids containing electron-rich, electron-neutral and
electron-deficient aryl moieties with readily available 3-aryl-
4-tosyloxy-2(5H)-furanones as the key step. The mild exper-
imental reaction conditions of this procedure, in which
methanol is used as the solvent and NaHCO3 is employed
as the base, have also proven to be suitable for the high
yielding synthesis of 4-aryl-6-methyl-2(2H)-pyranones from
6-methyl-4-tosyloxy-2(2H)-pyranone. Investigations in
which the mild Pd(OAc)2/PCy3-catalyzed arylation pro-
cedure developed in this study is applied are in progress.
The focus is on large-scale syntheses of new unsymmetrical
3,4-diaryl-substituted 2(5H)-furanones that are suitable for
in vivo tests, more water-soluble, and possess higher cytoto-
xicity against human tumor cell lines than the furanone de-
rivatives tested so far.
Figure 3. Chemical structures of compounds 10 and 11.
As shown in Table 4, these palladium-catalyzed cross-
coupling reactions enabled the synthesis of compounds 6a–
d in high yields (entries 1,4).
Table 4. Coupling of 6-methyl-4-tosyloxy-2(2H)-pyranone (5) with
arylboronic acids.
Experimental Section
General Procedure for the Suzuki-Type Reaction between 3-Aryl-
4-tosyloxy-2(5H)-furanones 3 and Arylboronic Acids 4: A 3-aryl-4-
tosyloxy-2(5H)-furanone
3
(1.0 mmol), Pd(OAc)2 (11.2 mg,
0.05 mmol), PCy3 (28.0 mg, 0.1 mmol), NaHCO3 (252 mg,
3.0 mmol), and an arylboronic acid 4 (1.5 mmol) were placed in a
reaction vessel under a stream of argon. The reaction vessel was
fitted with a silicon septum, evacuated and back-filled with argon,
and this sequence was repeated thrice. Deaerated methanol (16 mL)
was added by syringe and the mixture was stirred under argon at
60 °C for 3 h. After this period of time, the reaction – monitored
by GLC and TLC analyses of a sample of the crude reaction mix-
ture after it had been diluted with AcOEt and filtered through Ce-
lite® – was complete. The reaction mixture was then allowed to cool
to room temperature and concentrated under reduced pressure. The
residue was diluted with AcOEt (25 mL), poured into water
(100 mL) and the resulting mixture was extracted with AcOEt
(4ϫ25 mL). The combined organic extracts were washed with
brine, dried and concentrated under reduced pressure. The resulting
solid residue was purified by MPLC or flash chromatography on
silica gel or by recrystallization. This procedure was employed to
prepare 3,4-diaryl-2(5H)-furanones 1b and 1d–h.
Entry
4
Ar
Reaction time [h] Product Yield (%)
1
2
3
4
4a
4e
4f
Ph
3
2
2
2
6a
6b
6c
6d
84
70
96
76
4-MeOC6H4
4-CF3C6H4
4-AcC6H4
4d
The results of this procedure for the synthesis of com-
pounds 6 thus proved to compete favourably with those re-
cently reported in the literature[15] in which these heterocy-
cle derivatives were synthesized in modest to high yields via
Suzuki-type reaction of arylboronic acids with 4-bromo-6-
methyl-2(2H)-pyranone (11) (Figure 3), obtained in 78%
yield by treatment of 10 with PBr3 in a mixture of Et2O
and DMF. Moreover, in this literature procedure the high-
est yields were obtained when a mixture of Pd(OAc)2 and 2-
(di-tert-butylphosphanyl)biphenyl, a quite expensive bulky 4-(2-Naphthyl)-3-(3,4,5-trimethoxyphenyl)-2(5H)-furanone (1b): The
ligand, was used as the catalyst precursor.[15] It is also worth
crude product obtained from the Suzuki-type reaction between 3-
(3,4,5-trimethoxyphenyl)-4-tosyloxy-2(5H)-furanone (3b) and 2-
naphthylboronic acid (4b) (Table 3, entry 1) was purified by
mentioning that yields of compounds 6 that are similar to
those reported in Table 4, have been recently obtained by
Suzuki-type cross-coupling of 5 with arylboronic acids in
recrystallization from a mixture of CH2Cl2 and petroleum ether to
give 1b (341 mg, 90%) as a colourless solid, m.p. 206 °C (ref.[10g]
the presence of a catalytic amount of a N-heterocycle car-
m.p. 199–202 °C). EI–MS: m/z (%) = 377 (26) [M+ + 1], 376 (100)
bene-derived nickel-pincer complex.[19a] However, this com-
1
[M+], 361 (11), 202 (11), 189 (10). H NMR (300 MHz, CDCl3): δ
plex is not commercially available and the cross-coupling
= 7.82 (m, 4 H), 7.55 (m, 2 H), 7.40 (m, 1 H), 6.73 (s, 2 H), 5.30
(s, 2 H), 3.89 (s, 3 H), 3.70 (s, 6 H) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 173.5, 155.7, 153.2 (2 C), 148.8, 134.0 (2 C), 133.1 (2
C), 128.6, 128.3, 127.9, 127.4, 127.1, 126.0, 125.5, 124.7, 106.6 (2
reactions catalyzed by this complex occur at higher tem-
peratures and with longer reaction times than those of our
mild procedure.
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Pd-Catalyzed Suzuki-Type Arylation
C), 70.6, 61.0, 56.1 (2 C) ppm. The spectroscopic data for this 99%
chemically pure compound were in agreement with those pre-
viously reported.[10g]
as eluent, to give 6d (174 mg, 76%) as a pale yellow solid, m.p.
175 °C. EI–MS: m/z (%) = 228 (34) [M+], 200 (26), 185 (100), 157
(10), 128 (13). 1H NMR (200 MHz, CDCl3): δ = 8.06 (m, 2 H),
7.67 (m, 2 H), 6.38 (s, 1 H), 6.33 (s, 1 H), 2.65 (s, 3 H), 2.35 (s, 3
H) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 197.1, 162.9, 162.7,
154.3, 140.2, 138.5, 129.1 (2 C), 127.0 (2 C), 109.3, 103.2, 26.7,
20.2 ppm. GLC analysis showed that 6c had chemical purity higher
than 98.7%. C14H12O3 (228.24): calcd. C 73.67, H 5.30; found C
73.63, H 5.21.
4-(3-Fluoro-4-methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)-2(5H)-
furanone (1e): The crude product obtained from the Suzuki-type
reaction between 3-(3,4,5-trimethoxyphenyl)-4-tosyloxy-2(5H)-fu-
ranone (3b) and (3-fluoro-4-methoxyphenyl)boronic acid (4c)
(Table 3, entry 2) was purified by MPLC on silica gel, with a mix-
ture of CH2Cl2 and AcOEt (93:7) as eluent, to give 1e (201 mg,
54%) as a pale orange solid, m.p. 124 °C. EI–MS: m/z (%) = 375
(23) [M+ + 1], 374 (100) [M+], 359 (15), 331 (11), 317 (11). 1H
NMR (200 MHz, CDCl3): δ = 7.13 (m, 2 H), 6.94 (m, 1 H), 6.65
(s, 2 H), 5.14 (s, 2 H), 3.90 (d, J = 5.4 Hz, 6 H), 3.80 (m, 6 H)
ppm. 13C NMR (50.3 MHz, CDCl3): δ = 173.4, 154.0, 153.6 (2 C),
149.8, 149.7, 138.8, 125.4, 125.3, 124.4, 124.3, 115.5, 115.1, 113.4,
106.5 (2 C), 70.2, 56.3, 56.2 (2 C) ppm. GLC analysis showed that
1e had chemical purity higher than 99 %. C20H19FO6 (374.36):
calcd. C 64.17, H 5.12; found C 64.09, H 5.07.
Supporting Information (see also the footnote on the first page of
this article): Experimental procedures and characterization for
compounds 1d, 1f, 1h, 3a–c, 5, 6a, 6b, and 9a–c.
[1] For reviews on this topic, see: a) N.-H. Nam, Curr. Med. Chem.
2003, 10, 1697–1722; b) F. Bellina, R. Rossi, Tetrahedron 2006,
62, 7213–7256; c) G. C. Tron, T. Pirali, G. Sorba, F. Pagliai, S.
Busacca, A. A. Genazzani, J. Med. Chem. 2006, 49, 3033–3044;
d) F. Bellina, S. Cauteruccio, R. Rossi, Tetrahedron 2007, 63,
4571–4624.
[2] a) Y. Leblanc, J. Y. Gautthier, D. Ethier, J. Guay, J. A. Mancini,
D. Riendeau, P. Tagari, P. J. Vickers, E. Wong, P. Prasit, Bioorg.
Med. Chem. Lett. 1995, 5, 2123–2128; b) J. J. Talley, Prog. Med.
Chem. 1999, 36, 201–234; c) A. Zarghi, P. N. Praven Rao, E. E.
Knaus, J. Pharm. Pharmaceut. Sci. 2007, 10, 159–167.
[3] G.-B. Liang, X. Qian, D. Feng, M. Fisher, T. Crumley, S. J.
Darkin-Rattray, P. M. Dulski, A. Gurnett, P. S. Leavitt, P. A.
Liberator, A. S. Misura, S. Samaras, T. Tamas, D. M. Schmatz,
M. Wyvratt, T. Biftu, Bioorg. Med. Chem. Lett. 2008, 18, 2019–
2022.
4-(4-Methoxyphenyl)-3[4-(trifluoromethyl)phenyl]-2(5H)-furanone
(1g): The crude product obtained from the Suzuki-type reaction
between 3-[4-(trifluoromethyl)phenyl]-4-tosyloxy-2(5H)-furanone
(3c) and (4-methoxyphenyl)boronic acid (4e) (Table 3, entry 4) was
purified by recrystallization from a mixture of CH2Cl2 and petro-
leum ether to give 1g (276 mg, 83%) as a pale yellow solid, m.p.
148 °C. EI–MS: m/z (%) = 335 (20) [M+ + 1], 334 (100) [M+], 305
1
(18), 277 (78), 262 (17). H NMR (300 MHz, CDCl3): δ = 7.65 (m,
2 H), 7.57 (m, 2 H), 7.26 (m, 2 H), 6.87 (m, 2 H), 5.19 (s, 2 H),
3.82 (s, 3 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 173.2, 161.9,
157.4, 134.5, 131.0, 130.3, 129.8 (2 C), 129.2 (2 C), 125.7 (2 C),
123.0, 122.5, 114.7 (2 C), 70.6, 55.4 ppm. GLC analysis showed
that 1g had chemical purity higher than 98.5%. C18H13F3O3
(334.29): calcd. C 64.67, H 3.92; found C 64.54, H 3.85.
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General Procedure for the Suzuki-Type Reaction between 6-Methyl-
4-tosyloxy-2(2H)-pyranone (5) and Arylboronic Acids: Compound 5
(280 mg, 1.0 mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol), PCy3 (28 mg,
0.1 mmol), NaHCO3 (252 mg, 3.0 mmol), and an arylboronic acid
4 (1.5 mmol) were placed in a reaction vessel under a stream of
argon. The reaction vessel was fitted with a silicon septum, evacu-
ated, and back-filled with argon, and this sequence was repeated
thrice. Deaerated methanol (10 mL) was added by syringe and the
mixture was stirred under argon at 60 °C for the period of time
reported in Table 4. After this period the reaction was complete.
The reaction mixture was then allowed to cool to room tempera-
ture, filtered through Celite®, and concentrated under reduced
pressure. The residue was purified by MPLC on silica gel. Com-
pounds 6a–d were prepared according to this general procedure.
6-Methyl-4-[4-(trifluoromethoxy)phenyl]-2(2H)-pyranone (6c): The
crude product obtained from the Suzuki-type reaction between 5
and [4-(trifluoromethoxy)phenyl]boronic acid (4f) (Table 4, entry 3)
was purified by MPLC on silica gel, with a mixture of toluene and
AcOEt (85:15) as eluent, to give 6c (259 mg, 96%) as a pale yellow
solid, m.p. 62 °C. EI–MS: m/z (%) = 270 (33) [M+], 243 (13), 242
1
(100), 199 (38), 69 (10). H NMR (200 MHz, CDCl3): δ = 7.61 (m,
2 H), 7.32 (m, 2 H), 6.33 (s, 1 H), 6.27 (s, 1 H), 2.33 (s, 3 H) ppm.
13C NMR (50.3 MHz, CDCl3): δ = 163.1, 162.7, 154.1, 150.9,
134.5, 128.4 (2 C), 123.0, 121.4 (2 C), 108.6, 103.2, 20.2 ppm. GLC
analysis showed that 6c had chemical purity higher than 99%.
C13H9F3O3 (270.20): calcd. C 57.79, H 3.36; found C 57.63, H 3.31.
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Eur. J. Org. Chem. 2009, 4685–4690
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4689

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Received: May 26, 2009
Published Online: August 6, 2009
4690
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4685–4690