A new route to 5-aryl and 5-heteroaryl-2-pyrones via Suzuki coupling of a 2-pyrone-5-boronate ester

Article abstract of DOI:10.1055/s-2003-36789

The synthesis of the 2-pyrone-5-boronate ester 5 is described along with its palladium-catalysed coupling reactions with a range of aryl and heteroaryl halides and triflates.

Full text of DOI:10.1055/s-2003-36789

LETTER
253
A New Route to 5-Aryl and 5-Heteroaryl-2-pyrones via Suzuki Coupling of a
2-Pyrone-5-boronate ester
A
N
ew Route to
d
5-Aryl and
w
5-Heteroaryl-2-py
a
r
ones rd C. Gravett,a Philip J. Hilton,b Keith Jones,*a Jean-Marie Pérona
a
School of Chemical and Pharmaceutical Sciences, Kingston University, Kingston-upon-Thames, Surrey, KT1 2EE, UK
Fax +44(20)85477562; E-mail: keith.jones@kingston.ac.uk
b
St. Thomas’ Hospital, London SE1 7EH, UK
Received 12 November 2002
aryl halides using Pd(0) catalysis.10 Under the conditions
reported by Masuda, reaction of 4 with 5-bromo-2-pyrone
3 gave little or no product. However, changing the catalyst
to PdCl2(PPh3)2 and carrying out the reaction in refluxing
toluene gave the desired pinacolboronate 5 in 83% yield
as a stable, crystalline solid.11
Abstract: The synthesis of the 2-pyrone-5-boronate ester 5 is
described along with its palladium-catalysed coupling reactions
with a range of aryl and heteroaryl halides and triflates.
Key words: Suzuki coupling, palladium, boron, heterocycles,
pyrone
The 2-pyrone unit is an important feature of a number of
natural products which display a wide range of biological
activity.1 A number of simple 2-pyrones, including 5-phe-
nyl-2-pyrone, have been investigated for their binding and
inactivation of α-chymotrypsin.2 More recently, phenyl-
substituted 2-pyrones have been shown to be potent HIV-
1 protease inhibitors.3 In addition to biological activity, 2-
pyrones have been used in the preparation of other ring
systems. Reaction with ammonia is a well-established
route to pyridones.4 Diels–Alder reactions of 2-pyrones
can lead to a variety of products depending on the dieno-
phile and whether cycloaddition is followed by extrusion
of carbon dioxide.4 Cycloadditions not involving carbon
dioxide extrusion have been utilised in the synthesis of
shikimate-derived compounds5 as well as in the synthesis
of a tricylic portion of the gibberellic acids.6 A recent pa-
per reported the synthesis of 5-aryl-2-pyrones using a Su-
zuki coupling reaction of 5-bromo-2-pyrone and their
subsequent Diels–Alder reactions.7 As we have developed
a new 2-pyrone-5-boronate ester and demonstrated its
utility in the synthesis of bufadienolide-related steroids,8
we wanted to explore the use of this reagent in the prepa-
ration of 5-aryl and 5-heteroaryl-2-pyrones.
Scheme 1
Reaction of 5 with a variety of aryl and heteroaryl halides
and triflates was explored to define the usefulness of this
boronate reagent (Table 1). All reactions were conducted
using a slight excess of the boronate 5 in dry DMF as sol-
vent, with PdCl2(dppf) as catalyst and using crushed po-
tassium phosphate as base at 60 °C.12 As can be seen from
entries 1–3, aryl bromides, iodides and triflates are all
equally effective under these conditions giving rise to 5-
phenyl-2-pyrone in very good yield. Entry 4 demonstrates
that benzene rings substituted with electron-withdrawing
groups are also good substrates whilst entry 5 indicates
that electron-donating substituents only lower the yield
slightly. The attempted double coupling of 1,4-di-iodo-
benzene (entry 6) failed to give more than a trace of bis-
coupled product and instead the mono-coupled product
was isolated in 70% yield. This is in contrast to the Stille
coupling of 5-trimethylstannyl-2-pyrone with 1,4-di-io-
dobenzene reported by Meinwald in which a 68% yield of
the bis-coupled product was obtained.13 This could be
caused by decomposition of the pyrone boronate during
the reaction even though 2.2 molar equivalents were used.
Boronate 5 reacted cleanly with 3-bromothiophene to give
the coupled product in 82% yield (entry 7). Our interest in
the free-radical chemistry of 2-haloindoles and subse-
quent carbon-carbon bond formation at the 2-position of
indoles14 prompted us to explore the Suzuki reaction of 5
with a range of 2-bromoindoles (entries 8–10). Reaction
with N-phenylsulfonyl-2-bromoindole gave coupled
product in 42% yield after purification. N-Unsubstituted
In designing a suitable pyrone boron derivative for Suzuki
coupling reaction, we were mindful of the ready cleavage
of the pyrone ring under aqueous base conditions. Conse-
quently, we turned our attention to preparing a 5-boronate
ester substituted 2-pyrone as pinacol boronate esters have
found use in palladium-catalysed coupling reactions.9 In
our hands, the best synthesis of 5-bromo-2-pyrone 3 in-
volved photochemically-initiated bromination of 2-py-
rone 1 to give the 5,6-dibromo-2-pyrone 2 followed by
dehydrobromination using triethylamine to give 3 in 60%
overall yield (Scheme 1). Masuda and co-workers have
reported the coupling of pinacolborane 4 with a range of
Synlett 2003, No. 2, Print: 31 01 2003.
Art Id.1437-2096,E;2002,0,02,0253,0255,ftx,en;D26202ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

254
E. C. Gravett et al.
LETTER
indole (entry 9) also reacted in moderate yield whilst cou- catalyst (Scheme 2). Anisole derivative 7 (mp 95–97 °C)
pling with N-Boc-2-bromo-3-formylindole (entry 10) was isolated in 91% yield after purification. The Suzuki
gave the cleanest reaction but again only a moderate yield coupling of 5 with aromatic halides followed by hydroge-
of coupled product was isolated. It is likely that the sensi- nation provides a rapid and efficient way of introducing a
tivity of the 2-bromoindoles used contributes to the lower valerolactone residue onto an aromatic ring.
yields obtained. Finally, an attempt to produce a dimeric
2-pyrone by coupling 5 with its precursor failed to give
any coupled product (entry 11). Again, we believe this is
due to side reactions of the pyrone ring under the basic
conditions of the reaction.
Table 1 Suzuki Coupling Reactions of Boronate 5
Scheme 2
En- Reactant
try
Boronate Product
5 (mol
Yield
(%)
In summary, we have shown that boronate 5 is a useful
reagent for palladium-catalysed coupling reactions with
aryl and heteroaryl halides and triflates. It allows the
introduction of a 2-pyrone moiety into a wide variety of
aromatic systems and the facility with which the pyrone
can be reduced further adds to the utility of these products.
equiv)
1
2
3
4
1.1
1.1
1.1
1.3
82
74
80
78
Acknowledgement
We should like to thank the Special Trustees for St Thomas’ Hospi-
tal for financial support of this work.
References
5
6
1.3
2.2
66
70
(1) Dickinson, J. M. Nat. Prod. Rep. 1993, 10, 71.
(2) Boulanger, W. A.; Katzenellenbogen, J. A. J. Med. Chem.
1986, 29, 1159.
(3) Prasad, J. V. N. V.; Para, K. S.; Lunney, E. A.; Ortwine, D.
F.; Dunbar, J. B.; Ferguson, D.; Tummino, P. J.; Hupe, D.;
Tait, B. D.; Domagala, J. M.; Humblet, C.; Bhat, T. N.; Liu,
B.; Guerin, D. M. A.; Baldwin, E. T.; Erickson, J. W.;
Sawyer, T. K. J. Am. Chem. Soc. 1994, 116, 6989.
(4) Joule, J. A.; Mills, K. Heterocyclic Chemistry; Blackwell
Science: Oxford, 2000.
7
8
1.1
1.1
82
42
(5) Posner, G. H.; Wettlaufer, D. G. J. Am. Chem. Soc. 1986,
108, 7373.
(6) Markó, I. E.; Seres, P.; Evans, G. R.; Swarbrick, T. M.
Tetrahedron Lett. 1993, 34, 7305.
(7) Afarinkia, K.; Berna-Canovas, J. Tetrahedron Lett. 2000,
41, 4955.
(8) Gravett, E. C.; Hilton, P. J.; Jones, K.; Romero, F.
Tetrahedron Lett. 2001, 42, 9081.
(9) Henaff, N.; Whiting, A. Tetrahedron 2000, 56, 5193.
(10) Muarata, M.; Oyama, T.; Watanabe, S.; Masuda, Y. J. Org.
Chem. 2000, 65, 164.
(11) Preparation of(5): A mixture of 5-bromo-2-pyrone (13 g,
74 mmol), pinacolborane (16.2 mL, 14.7 g, 111 mmol),
triethylamine (31 mL, 22.1 g, 222 mmol) and PdCl2(PPh3)2
(1.56 g, 2.2 mmol) in dry tolune (100 mL) was heated to
reflux under a N2 atmosphere for 6 hours. After this time,
TLC analysis showed no remaining 5-bromo-2-pyrone. The
dark solution was filtered through a short plug of silica and
this was further eluted with dichloromethane (250 mL). The
solvent was removed under reduced pressure to give a dark
crystalline solid. Flash column chromatography using
dichloromethane as eluent gave the 2-pyrone-5-boronate 5
(13.6 g, 61.4 mmol, 83%) as a pale yellow crystalline solid,
mp 91–93 °C. This material was used in all coupling
reactions. An analytically pure sample with the same mp
could be obtained as white crystals by sublimation at 0.7 mm
9
10
11
1.3
1.3
1.3
44
48
0
As part of our studies on 2-pyrone substituted steroids re-
lated to bufadienolides, we were interested in reduction of
the pyrone ring to the saturated lactone. To this end, com-
pound 6 (entry 5, in Table 1) was reacted with hydrogen
at atmospheric pressure using 5% rhodium on alumina as
Synlett 2003, No. 2, 253–255 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Hg pressure. δH (CDCl3, 300 MHz) 1.29 (6 H, s), 6.27 (1 H,
dd, J = 9.6 and 1.2 Hz), 7.50 (1 H, dd, J = 9.6 and 2.1 Hz)
and 7.84 (1 H, dd, J = 2.1 and 1.2 Hz); δC (CDCl3, 75 MHz)
24.8, 84.5, 96.9, 115.6, 146.3 and 160.1; HRMS calcd for
C11H1511BO4: 222.1063; found: 222.1059. Anal. Calcd for
C11H15BO4: C, 59.50; H, 6.81. Found: C, 59.66; H, 6.83.
(12) Typical procedure for Suzuki coupling: Phenyl triflate (50
mg, 0.22 mmol), 2-pyrone-5-boronate 5 (55 mg, 0.25
mmol), and PdCl2(dppf) (20 mg, 0.022 mmol) were
A New Route to 5-Aryl and 5-Heteroaryl-2-pyrones
255
followed by washing with dichloromethane (30 mL). The
solvent was removed under reduced pressure to give a solid
that was further purified by flash column chromatography
(10% ethyl acetate in dichloromethane) to yield 5-phenyl-2-
pyrone (30.2 mg, 0.172 mmol, 80%). δH (CDCl3, 300 MHz)
6.38 (1 H, dd, J = 9, 1 Hz, H-3), 7.35 (5 H, m, aromatic-H),
7.56 (1 H, dd, J = 9, 3 Hz), 7.62 (1 H, dd, J = 3, 1 Hz); δC
(CDCl3, 75 MHz) 116.5, 120.6, 126.0, 128.4, 129.3, 133.5,
144.0, 148.3, 161.2; m/z 172 (M+, 90%), 144(38), 115(100),
89(12), 63(10). These data match those reported.7
dissolved in dry DMF (4 mL) under a N2 atmosphere. Finely
crushed K3PO4 (180 mg, 0.82 mmol) was added to the DMF
solution and this slurry was heated to 60 °C for 6 hours. The
DMF was removed under reduced pressure to give a dark
solid that was initially purified by dissolving in
(13) Liu, Z.; Meinwald, J. J. Org. Chem. 1996, 61, 6693.
(14) (a) Dobbs, A. P.; Jones, K.; Veal, K. T. Tetrahedron 1998,
54, 2149. (b) Fiumana, A.; Jones, K. Chem. Commun. 1999,
1761. (c) Fiumana, A.; Jones, K. Tetrahedron Lett. 2000, 41,
4209.
dichloromethane and filtering through a plug of silica,
Synlett 2003, No. 2, 253–255 ISSN 0936-5214 © Thieme Stuttgart · New York