One-pot synthesis of benzofurans via palladium-catalyzed enolate arylation with o-bromophenols

Article abstract of DOI:10.1021/ol801510n

(Chemical Equation Presented) A one-pot synthesis of benzofurans which utilizes a palladium-catalyzed enolate arylation is described. The process demonstrates broad substrate scope and provides differentially substituted benzofurans in moderate to excelle

Full text of DOI:10.1021/ol801510n

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4211-4214
One-Pot Synthesis of Benzofurans via
Palladium-Catalyzed Enolate Arylation
with o-Bromophenols
Christian Eidamshaus and Jason D. Burch*
Merck Frosst Canada, 16711 Trans Canada Hwy., Kirkland, QC, Canada H9H 3L1
jason_burch@merck.com
Received July 3, 2008
ABSTRACT
A one-pot synthesis of benzofurans which utilizes a palladium-catalyzed enolate arylation is described. The process demonstrates broad
substrate scope and provides differentially substituted benzofurans in moderate to excellent yields. The utility of the method is further
demonstrated by the synthesis of the natural product eupomatenoid 6 in three steps.
The benzofuran scaffold is ubiquitous in the realms of
pharmacologically active agents and in isolated natural
products. Prescribed agents featuring this nucleus include
the antidepressant (-)-BPAP1 and the antiarrythmic Amio-
darone.2 Some benzofuran derivatives are also known as
5-lipoxygenase inhibitors,3 angiotensin II inhibitors,4 calcium
entry blockers,5 and antitumor agents.6 Benzofuran-contain-
ing natural products include frondosin B7 and the eupo-
matenoid family.8 Thus synthetic access to benzofurans is
of considerable interest, and numerous approaches to this
scaffold have been disclosed in the literature.9 Many of these
methods rely on harsh conditions with limited functional
group tolerability. Recent approaches have focused on the
use of relatively mild, transition-metal-catalyzed processes
such as the Heck10 and Sonagashira11 reactions. In general,
however, these approaches require multiple steps and
yield benzofurans of limited structural diversity. Herein we
disclose a one-pot approach to benzofurans using readily
available ketones and o-bromophenols as starting materials.
The palladium-catalyzed enolate arylation reaction pio-
neered by Buchwald and Hartwig is a powerful method for
the construction of R-aryl ketones that has demonstrated
excellent substrate scope.12 Recently, Willis and co-workers
have used this reaction for the construction of benzofurans
using o-bromoiodobenzene as the electrophilic reaction
partner. In this case, ring closure is accomplished by
a palladium-catalyzed O-arylation of the enol.13 While this
process could occur in theory via a sequential one-pot
process, this was only possible for a single ketone; all other
(1) Shimazu, S.; Takahata, K.; Katsuki, H.; Tsunekawa, H.; Tanigawa,
A.; Yoneda, F.; Knoll, J.; Akaike, A. Eur. J. Pharmacol. 2001, 421, 181–
189.
(2) Singh, B. M.; Vaughan Williams, E. M. Br. J. Pharmacol. 1970,
139, 255–264.
(9) For a review of the chemistry and synthesis of benzofurans, see:
Hou, X.-L.; Yang, Z.; Wong, H. N. C. Furans and Benzofurans. In Progress
in Heterocyclic Chemistry; Gribble, G. W., Gilchrist, T. L., Eds.; Pergamon:
Oxford, England, 2002; Vol. 14, pp 139-179.
(3) Ohemeng, K. A.; Apollina, M. A.; Nguyen, V. N.; Schwender, C. F.;
Singer, M.; Steber, M.; Ansell, J.; Argentieri, D.; Hageman, W. J. Med.
Chem. 1994, 37, 3663–3667.
(4) Kiyama, R.; Homna, T.; Hayashi, K.; Ogawa, M.; Hara, M.;
Fujimoto, M.; Fujishita, T. J. Med. Chem. 1995, 38, 2728–2741.
(5) Kozikowsky, A. P.; Ma, D.; Du, L.; Lewin, N. E.; Blumberg, P. M.
J. Am. Chem. Soc. 1995, 117, 6666–6672.
(10) Zhang, H.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem., Int. Ed.
2004, 43, 6144–6148.
(11) (a) Colobert, F.; Castanet, A.-S.; Abillard, O. Eur. J. Org. Chem.
2005, 3334–3341. (b) Anderson, K. W.; Ikawa, T.; Tundel, R. E.; Buchwald,
S. L. J. Am. Chem. Soc. 2006, 128, 10694–10695.
(6) Gangjee, A.; Devraj, R.; McGuire, J. J.; Kisliuk, R. L. J. Med. Chem.
1995, 38, 3798–3805.
(12) (a) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am.
Chem. Soc. 2000, 122, 1360–1370. (b) Hamann, B. C.; Hartwig, J. F. J. Am.
Chem. Soc. 1997, 119, 12382–12383.
(7) Patil, A. D.; Freyer, A. J.; Killmer, L.; Offen, P.; Carte, B.; Jurewicz,
A. J.; Johnson, R. Tetrahedron 1997, 53, 5047–5060.
(8) Bowden, B. F.; Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1972, 25,
2659–2669.
(13) Willis, M. C.; Taylor, D.; Gillmore, A. T. Tetrahedron 2006, 62,
11513–11520.
10.1021/ol801510n CCC: $40.75
Published on Web 08/29/2008
2008 American Chemical Society

cases required ring closure in a separate operation. Further,
only bromoiodobenzene was used as the electrophilic partner,
thus limiting structural diversity of the benzenoid portion of
the benzofurans accessible by this method. While related,
our approach (Scheme 1) is fundamentally different in that
Buchwald examples, aryldialkylphosphines were preferred,15
and in this case rac-2-(di-tert-butylphosphino)-1,1′-binaphthyl
8 (rac-DTBPB) was the optimal ligand. Conversion could be
increased to 97% by the use of 1.5 equiv of ketone and 2.7
equiv of base.
Optimization of solvent (Table 2) revealed that the reaction
could be carried out in a variety of higher boiling ethereal
Scheme 1. One-Pot Approach to Benzofurans
Table 2. Optimization of Reaction Solvent
entry
solvent
conversion (%)a
cyclization will occur via an acid-catalyzed process. The
broad availability of o-bromophenols should allow access
to benzofurans of wide structural diversity.14
For optimization of the arylation process, unsubstituted
o-bromophenol and propiophenone were selected as the reaction
partners. An initial ligand screen was carried out (Table 1), and
1
2
3
4
5
6
7
8
toluene
THF
DME
dioxane
DMF
DMA
tBuOH
DCE
97
85
78
84
54
37
45
0
a Measured by HPLC analysis; see Supporting Information for further
details.
Table 1. Optimization of Phosphine Ligand
solvents (DME, THF, dioxane) in addition to toluene,
although in slightly diminshed conversions. Polar aprotic
solvents, such as DMF and DMA, or protic solvents (tBuOH)
resulted in significantly diminished conversion, and dichlo-
roethane was not acceptable.
A reaction temperature screen was then undertaken from
room temperature to 110 °C. It was found that at tempera-
tures lower than 80 °C, reaction times were exceedingly long.
At temperatures above 80 °C, conversion rates were in-
creased, but several unidentified minor side products were
formed.
Finally, a variety of bases other than sodium tert-butoxide
were tested in this process, such as inorganic (K2CO3, K3PO4,
NaH, CsOH), hindered pyridyl (2,6-di-tert-butyl-4-meth-
ylpyridine), and amide (NaHMDS) bases. Unfortunately, no
conversion to the desired product was observed in all cases.
With an optimal set of catalysis conditions selected, we
were then poised to test the one-pot process and to evaluate
the substrate scope of this reaction. Gratifyingly, treatment
of the reaction mixture from the arylation process with a
1:1 mixture of CH2Cl2 and trifluoroacetic acid (TFA) at room
temperature cleanly provided the desired benzofurans, which
could then be isolated by simple filtration through a plug of
silica. Further, it was found that the arylation process could
be run under microwave irradiation without a reduction in
a Measured by HPLC analysis; see Supporting Information for further
details.
(14) A recent ACD search revealed >1300 commercially available ortho-
bromophenols.
it was found that the reaction was quite sensitive to the steric
constraints of the phosphine ligand. As with several of the
(15) PPh3, BINAP and dppf provided no conversion to the desired aryl
ketone.
4212
Org. Lett., Vol. 10, No. 19, 2008

yield, which has the added benefit of shorter reaction times
(30 min versus 22 h).
Table 4 outlines the bromophenol substrate scope. As can
be seen from entries 1-6, electron-donating, halogen, and
To investigate the scope of the process, the reaction
between o-bromophenol and a series of ketones was
investigated. As can be seen in Table 3, the process allows
Table 4. Bromophenol Substrate Scope
Table 3. Ketone Substrate Scope
a Yield in parentheses are for microwave reactions; for further
information see Supporting Information. b Reactions performed at 100 °C.
aryl substitution is tolerated, although in general yields are
only moderate. Entry 6 also indicates that increased steric
hindrance adjacent to the cross-coupling site is acceptable.
Entries 7-9 demonstrate limitations to the current protocol:
electron-poor bromophenols, hydroxypyridines, and free
anilines are not successful in the palladium-catalyzed ary-
lation process and are recovered unreacted.
a Yields in parentheses are for microwave reactions; for further details
see Supporting Information. b Single regioisomer by NMR.
Eupomatenoid 6, first isolated in 1969 from the bark of
Eupomatia laurina R., shows a wide range of biological
activities.8 It was first synthesized in seven steps by
Stevenson,16 and subsequently two five-step syntheses fol-
lowed from Bach (25% overall yield)17 and Naito (52%
overall yield).18 Using the ketone arylation approach, we
a wide variety of substrate classes: aryl alkyl ketones
(entries 1-5), heteroaryl alkyl ketones (entry 6), dialkyl
ketones (entries 8-10), and cyclic ketones (entries 5,
7-10). Interestingly, for cases in which two regioisomers
are possible (entries 8 and 9) the reaction is completely
regioselective, providing only a single benzofuran by
NMR. One of these examples (entry 5) was scaled up to
preparative scale (10 mmol) without a significant decrease
in yield (see Supporting Information).
(16) Stevenson, R.; McKittrick, B. A. J. Chem. Soc., Perkin Trans. 1
1983, 475–482.
(17) Bach, T.; Bartels, M. Synthesis 2003, 925–939.
Org. Lett., Vol. 10, No. 19, 2008
4213

were able to complete a four-step, three-pot approach to this
natural product (Scheme 2). Subjection of 2-bromo-4-
for the one-pot process. Stille reaction with a 1-propenyl-
stannane using conditions developed by Fu,19 followed by
demethylation with ethanethiolate provided eupomatenoid 6
in 39% overall yield. Interestingly, although a commercially
available 1:1 cis:trans mixture of stannanes was used (in
excess), a 9:1 mixture of olefins was isolated, indicating the
trans-stannane couples at a significantly higher rate.
Scheme 2. Total Synthesis of Eupomatenoid 6
Acknowledgment. Drs. Austin Chen and David Powell
(Merck Frosst Canada) are gratefully acknowledged for the
careful editing of this manuscript.
Supporting Information Available: Experimental pro-
cedures for all benzofurans prepared and full characterization
data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL801510N
(18) Miyata, O.; Takeda, N.; Naito, T. Org. Lett. 2004, 6, 1761–1763.
(19) (a) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295–4298. (b)
Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 6343–
6348.
chlorophenol (37) and 4′-methoxypropiophenone (44) to our
optimized conditions provided benzofuran 45 in 45% yield
4214
Org. Lett., Vol. 10, No. 19, 2008