Microwave assisted Suzuki reactions for the preparation of the antifungal 3-aryl-5-methyl-2,5-dihydrofuran-2-ones

Article abstract of DOI:10.1055/s-2005-862367

The Suzuki cross-coupling reaction of arylboronic acids with a bromo-furanone has been developed to prepare a series of substituted 2,5-dihydrofuran-2-ones related to the fungal metabolite, incrustoporin. A protocol of microwave heating was introduced to improve synthesis throughput. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-862367

538
LETTER
Microwave Assisted Suzuki Reactions for the Preparation of the Antifungal
3-Aryl-5-methyl-2,5-dihydrofuran-2-ones
P
reparation of the
h
Antifungal
r
3-Aryl-5
i
-methy
s
l-2,5-dihy
t
drofur
o
a
n-2-ones pher J. Mathews, John Taylor, Melloney J. Tyte, Paul A. Worthington*
Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42 6EY, UK
Fax +44(1344)455629; E-mail: paul.worthington@syngenta.com
Received 14 December 2004
involves esterification, allylation, hydrolysis and lactoni-
Abstract: The Suzuki cross-coupling reaction of arylboronic acids
with a bromo-furanone has been developed to prepare a series of
substituted 2,5-dihydrofuran-2-ones related to the fungal metabo-
lite, incrustoporin. A protocol of microwave heating was introduced
to improve synthesis throughput.
sation followed by phenylselenation, oxidation and syn-
elimination. We now wish to report the results of our
approach leading to a very efficient synthesis of these
compounds, which has enabled further investigations into
their antifungal properties.
Key words: antifungal compounds, arylations, catalysis, cross-
coupling, palladium, microwave heating
Natural products have played a significant role in the dis-
covery of new fungicides for use in crop protection. They
can either be used as commercial compounds per se (ex-
amples include streptomycin and validamycin A1) or as
leads for further chemical exploration. In recent years an
illustration of this latter approach, starting from the natu-
ral products pyrrolnitrin, the strobilurins and the oude-
mansins, has led to the development of a number of
important new fungicides.2
Scheme 1 Route to 3-aryl-5-methyl-2,5-dihydrofuran-2-ones.
As depicted in Scheme 1, our synthesis makes use of a mi-
crowave assisted palladium-catalysed Suzuki cross-cou-
pling reaction of 3-bromo-5-methyl-2(5H)-furanone (3)
with an arylboronic acid 4 to prepare a range of 3-aryl-5-
methyl-2,5-dihydrofuran-2-ones 5. This looked to be very
attractive since a wide selection of arylboronic acids is
available from commercial sources.9 Also, the key inter-
mediate bromo-furanone 3 can be prepared in four steps
starting from levulinic acid 6 (Scheme 2). This involved
an isomerisation of a-angelica lactone 7 to b-angelica
lactone 8 in the presence of triethylamine,10 followed by
bromination and dehydrobromination using the method of
Ortuno.11
Figure 1
The antibiotic incrustoporin (1), isolated from the fermen-
tation of the Basidiomycete Incrustoporia carneola
(strain 9170)3 was reported in 1995 to possess activity
against a wide range of phytopathogenic fungi as well as
having some cytotoxic activity (Figure 1). Two total syn-
theses have been published, by Mori4 and Rossi,5 but it re-
mains an attractive starting point for further chemical and
biological exploration. A series of racemic 3-phenyl-5-
methyl-2,5-dihydrofuran-2-ones 2 related to incrustopor-
in (1) are reported by Pour6–8 to be active against filamen-
tous fungi. The current route to these compounds starts
from the appropriately substituted phenylacetic acid and
Scheme 2 Reagents and conditions: (a) H3PO4; (b) Et3N, 100 °C, 4
h, 79%; (c) Br2, CCl4, reflux, 1.5 h; (d) Et3N, 20 °C, 2 h, 66% over two
steps.
An initial attempt to couple the bromo-furanone 3 with
phenylboronic acid, using Pd(Ph3P)4 catalyst in acetoni-
trile as solvent and sodium carbonate as the base, at a
temperature of 90 °C, resulted in decomposition and no
SYNLETT 2005, No. 3, pp 0538–0540
Advanced online publication: 04.02.2005
DOI: 10.1055/s-2005-862367; Art ID: D37404ST
© Georg Thieme Verlag Stuttgart · New York
1
6.
0
2.
2
0
0
5

LETTER
Preparation of the Antifungal 3-Aryl-5-methyl-2,5-dihydrofuran-2-ones
539
observable product. However, repeating the reaction in employed in this cross-coupling reaction and using caesi-
toluene at 140 °C and using potassium carbonate as the um carbonate as the base we obtained a similar product
base gave a 40% yield of the desired coupled product yield but in a much shorter time (compare entry 4 with 3).
(Table 1, entry 1). These conditions appear to be general Using these standard heating conditions, a range of aryl-
and they have enabled halogenated examples to be syn- boronic acids have been coupled with the bromo-furanone
thesised (entries 2 and 3) in 63% and 46% yields, respec- 3 (entries 5 and 6) in short reaction times of 2–3 minutes.
tively.
With the heteroaromatic boronic acids such as 2-benzo-
Microwave-assisted chemical synthesis is proving to be a furanboronic acid (entry 7) and 3-thiopheneboronic acid
powerful technique for increasing the throughput of (entry 9) the yields for the cross-coupling were low
chemical synthesis.12 The Suzuki reaction, which involves (13% and 17%, respectively) using conventional heating.
using elevated temperatures, has been adapted by micro- Employing microwave heating and using 1,2-dimethoxy-
wave heating to achieve faster reactions and cleaner prod- ethane (DME) as solvent, the yield with 2-benzofuranbo-
ucts.13 When microwave heating conditions were ronic acid was increased to 36% (entry 8). For 3- and 4-
Table 1 Sukuki Palladium-Catalysed Cross-Coupling Reaction of 3-Bromo-5-methyl-2(5H)-furanone (3) with Boronic Acids 4
Entry
1
ArB(OH)2
Base
Temp (°C)
140
Time
1 h
Yield of 5 (%)a
K2CO3
40
2
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
110
110
150
150
150
2 h
63
46
50
56
40
3
1.5 h
2 min
2 min
3 min
4b
5b
6b
7
K2CO3
K2CO3
K2CO3
140
150
110
1 h
13
36
17
8b,c
3 min
2 h
9
a Isolated yield.
b Microwave heating.
c DME as solvent.
Synlett 2005, No. 3, 538–540 © Thieme Stuttgart · New York

540
C. J. Mathews et al.
LETTER
Cross-Coupling Using Microwave Heating; Typical Procedure
A mixture of tetrakis(triphenylphosphine)palladium (25 mg), 3,4-
dichlorophenylboronic acid (0.75 mmol), 3-bromo-5-methyl-
2(5H)-furanone (0.45 mmol) and Cs2CO3 (1.3 mmol) in toluene (5
mL) was heated at 150 °C for 2 min in a sealed vial under micro-
wave irradiation.14 The toluene was removed and the residue taken
up in CH2Cl2, washed with H2O and dried over MgSO4. Removal of
the solvent gave a brown oil which was purified by HPLC to give
(3,4-dichlorophenyl)-5-methyl-2,5-dihydrofuran-2-one as a white
crystalline solid (55 mg, 50%, mp 110–111 °C).8
pyridineboronic acids no cross-coupled products could be
detected. However, as shown in Scheme 3, the trans-2-
phenylvinylboronic acid (9) could be coupled with 3 using
microwave heating to give 52% of the expected product
10. This result would suggest that the scope of the reaction
could be further extended.
References
(1) Worthington, P. A. Nat. Prod. Rep. 1988, 5, 47.
(2) Knight, S. C.; Anthony, V. M.; Brady, A. M.; Greenland, A.
J.; Heaney, S. P.; Murray, D. C.; Powell, K. A.; Schulz, M.
A.; Spinks, C. A.; Worthington, P. A.; Youle, D. Ann. Rev.
Phytopathol. 1997, 35, 349.
(3) Zapf, S.; Anke, T.; Sterner, O. Acta. Chem. Scand. 1995, 49,
Scheme 3 Reagents and conditions: Pd(PPh3)4, Cs2CO3, toluene,
microwave, 150 °C, 3 min.
233.
(4) Yajima, A.; Mori, K. Liebigs Ann. Chem. 1996, 1091.
(5) Rossi, R.; Bellina, F.; Biagetti, M.; Mannina, L.
Tetrahedron: Asymmetry 1999, 10, 1163.
In summary, we have developed a very simple and effi-
cient synthesis of the antifungal 3-aryl-5-methyl-2,5-di-
hydrofuran-2-ones 5 starting from readily available
starting materials. The reaction has been adapted for
microwave heating to enable the compound throughput to
be much improved and allow further biological investiga-
tions to be carried out.
(6) Pour, M.; Spulak, M.; Balsanek, V.; Kunes, J.; Buchta, V.;
Waisser, K. Bioorg. Med. Chem. Lett. 2000, 10, 1893.
(7) Pour, M.; Spulak, M.; Buchta, V.; Kubanova, P.;
Voprsalova, M.; Wsol, V.; Fakova, H.; Koudelka, P.;
Pourova, H.; Schiller, R. J. Med. Chem. 2001, 44, 2701.
(8) Pour, M.; Spulak, M.; Balsanek, V.; Kunes, J.; Kubanova,
P.; Buchta, V. Bioorg. Med. Chem. 2003, 11, 2843.
(9) Aldrich ChemFiles 2003, 3, 3.
(10) Helberger, J. H.; Ulubay, S.; Civelekoglu, H. Ann. Chem.
1949, 561, 215.
(11) Ochoa de Echaguen, C.; Ortuno, R. M. Tetrahedron 1994,
Cross-Coupling Using Conventional Heating; Typical
Procedure
50, 12457.
(12) Siu, J.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem.
2004, 2, 160.
(13) Bai, L.; Wang, J.; Zhang, Y. Green Chem. 2003, 5, 615.
(14) An automated SmithCreatorTM microwave system was used
(purchased from Personal Chemistry).
Tetrakis(triphenylphosphine)palladium (75 mg) was added to a
stirred mixture of 3,4-dichlorophenylboronic acid (2.0 mmol), 3-
bromo-5-methyl-2(5H)-furanone (1.3 mmol) and K2CO3 (2.8
mmol) in toluene (20 mL) under a nitrogen atmosphere and the mix-
ture was heated at 110 °C for 1.5 h. The toluene was removed and
the residue taken up in CH2Cl2, washed with H2O and dried over
MgSO4. Removal of the solvent gave a brown oil which was puri-
fied by HPLC to give 3-(3,4-dichlorophenyl)-5-methyl-2,5-dihy-
drofuran-2-one as a white crystalline solid (150 mg, 46%, mp 110–
111 °C).8
Synlett 2005, No. 3, 538–540 © Thieme Stuttgart · New York