On-water chemistry: Copper-catalyzed straightforward synthesis of benzo[b]furan derivatives in neat water

Article abstract of DOI:10.1021/ol060274c

A more sustainable protocol leading to 2-alkyl- or 2-aryl-substituted benzo[b]furans is reported, involving a copper-TMEDA complex which catalyzes the transformation of readily available ketone derivatives into the corresponding benzofurans in good to excellent yields. The reaction is accomplished using water as the solvent without organic cosolvents, and one example of catalyst reutilization is also presented.

Full text of DOI:10.1021/ol060274c

ORGANIC
LETTERS
2006
Vol. 8, No. 7
1467-1470
On-Water Chemistry: Copper-Catalyzed
Straightforward Synthesis of
Benzo[b]furan Derivatives in Neat Water§
Mo´nica Carril, Raul SanMartin,* Imanol Tellitu, and Esther Dom´ınguez*
Kimika Organikoa II Saila, Zientzia eta Teknologia Fakultatea,
Euskal Herriko Unibertsitatea, P.O. Box 644, 48080 Bilbao, Spain
raul.sanmartin@ehu.es
Received February 1, 2006
ABSTRACT
A more sustainable protocol leading to 2-alkyl- or 2-aryl-substituted benzo[b]furans is reported, involving a copper−TMEDA complex which
catalyzes the transformation of readily available ketone derivatives into the corresponding benzofurans in good to excellent yields. The reaction
is accomplished using water as the solvent without organic cosolvents, and one example of catalyst reutilization is also presented.
In recent years, amid growing concern about the development
of more environmentally friendly protocols in organic
chemistry, water has become the solvent of choice to
successfully perform many organic transformations.1 The
advantages derived from the use of water, instead of organic
solvents, are clear in terms of safety, cost, and reduced
toxicity. Furthermore, the insolubility of organic compounds
in water causes them to react on its surface, thereby giving
rise to the term “on-water” chemistry, which implies that
hydrogen-bond-type interactions are responsible for rate
accelerations and greater selectivities observed in aqueous
reaction media compared with organic ones.1
The properties of water, either as a solvent or as an
additive, have been extensively applied to different types of
organic transformations including coupling reactions cata-
lyzed by transition metals, thus broadening the scope of on-
water chemistry and its contribution to green chemistry.2
Examples of such transformations include the palladium-
catalyzed coupling reactions enhanced by the presence of
small amounts of water such as in our recently reported route
to the antiepileptic drug Trileptal.3 In connection with this
previous work and continuing with our research on the
synthesis of valuable heterocycles through direct arylations
in the absence of transmetalating agents, we report here the
first copper-catalyzed synthesis of benzo[b]furan derivatives
accomplished in aqueous media,4 as well as a recovery and
reutilization of the copper catalyst.
Benzo[b]furans are of great interest because of their
applications in pharmacology and their wide distribution in
nature.5 For instance, 2-arylbenzofurans and their derivatives
exhibit a broad range of biological activities, such as their
antineoplastic,6 antiviral,7 antioxidative,8 and antiinflamma-
(3) Carril, M.; SanMartin, R.; Churruca, F.; Tellitu, I.; Dom´ınguez, E.
Org. Lett. 2005, 7, 4787.
§ Dedicated to the memory of Prof. Marcial Moreno Man˜as.
(1) (a) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H.
C.; Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3275 and references
therein. (b) Li, C.-J. Chem. ReV. 2005, 105, 3095.
(2) For a review on palladium-catalyzed reactions in aqueous media,
see: (a) Genet, J. P.; Savignac, M. J. Organomet. Chem. 1999, 576, 305.
For other metal-catalyzed protocols, see: (b) Willis, M. C.; Taylor, D.;
Gillmore, A. T. Org. Lett. 2004, 6, 4755. (c) Sanz, R.; Castroviejo, M. P.;
Ferna´ndez, Y.; Fan˜anas, F. J. J. Org. Chem. 2005, 70, 6548. (d) Nakamura,
I.; Mizushima, Y.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 15022.
(4) While this work was being carried out, an elegant protocol for the
synthesis of benzo[b]furans based on copper catalysis has been recently
reported, but in the absence of water (DMF was the solvent employed).
See: Chen, C.-Y.; Dormer, P. G. J. Org. Chem. 2005, 70, 6964.
(5) (a) Lipshutz, B. H. Chem. ReV. 1986, 86, 795. (b) Fuerst, D. E.; Stoltz,
B. M.; Wood, J. L. Org. Lett. 2000, 2, 3521.
(6) Navarro, E.; Alonso, S. J.; Trujillo, J.; Jorge, E.; Pe´rez, C. J. Nat.
Prod. 2001, 64, 134.
(7) Kraus, G. A.; Kim, I. Org. Lett. 2003, 5, 1191.
(8) Lu, H.; Liu, G.-T. Planta Med. 1992, 58, 311.
10.1021/ol060274c CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/04/2006

tory properties.9 As a result, a number of routes leading to
differently substituted benzo[b]furans have been described
in the literature, although currently no general synthetic
methodology exists.10
In the course of our ongoing investigations into the
synthesis of several N-heterocyclic compounds, we found
that when the copper-catalyzed N-arylation reaction between
deoxybenzoin 1 and benzylamine was tested, instead of the
expected product 2, 2-arylbenzo[b]furan 3 was isolated in
66% yield (Scheme 1). This unexpected result, due to an
Scheme 1
Figure 1. Copper source and base screening for the ring closure
of 1 performed in neat water.
a double role for the 1,2-diamines. On one hand, they might
be acting as ligands,11 and on the other, they might be
coordinating to the copper facilitating the formation of enol-
type intermediates through a coordination to the oxygen, as
shown in Scheme 2. Thus, having determined that the
intramolecular O-arylation process probably catalyzed by
copper, prompted us to search for a general methodology
(based on copper catalysis) for constructing the benzo[b]-
furan framework. In addition, given the previously mentioned
advantages provided by the use of aqueous media, we
decided to investigate whether water would be effective as
a solvent for performing such reactions.
Scheme 2. Mechanistic Pathway Proposal
To optimize the process, we chose deoxybenzoin 1 as the
model compound and the efficiency of different copper
sources and bases was then tested. Because water was
present, we considered that water-soluble inorganic bases,
such as K3PO4, would be suitable to effect the reaction.
However, neither K3PO4 nor the commonly used organic base
triethylamine provided benzofuran 3 in more than 12% yield
(Figure 1), with significant amounts of unreacted substrate
1 being recovered from the reaction mixture.
Interestingly, shifting to different 1,2-diamine derivatives
resulted in a clear improvement of the yields, as shown in
Figure 1. This fact, along with the colors observed during
the course of the reaction (violet and green for the Cu/
DMEDA and Cu/TMEDA systems, respectively), suggested
combination of CuI and TMEDA was the most efficient of
these two reagent systems, providing the benzofuran 3 in
91% yield, we subsequently directed efforts toward optimiz-
ing the reaction conditions.
(9) (a) Sun, M.; Zhao, C.; Gfesser, G. A.; Thiffault, C.; Miller, T. R.;
Marsh, K.; Wetter, J.; Curtis, M.; Faghih, R.; Esbenshade, T. A.; Hancock,
A. A.; Cowart, M. J. Med. Chem. 2005, 48, 6482. (b) Inoue, M.; Carson,
M. W.; Frontier, A. J.; Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123,
1878.
(10) The most common approach to these heterocycles consists of the
palladium-catalyzed cyclization of the corresponding 2-(1-alkynyl)phenols.
See: (a) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 10292
and references therein. For other methodologies, see: (b) Kraus, G. A.;
Schroeder, J. D. Synlett 2005, 2504. (c) Katritzky, A. R.; Ji, Y.; Fang, Y.;
Prakash, I. J. Org. Chem. 2001, 66, 5613. (d) For a recent contribution of
our group to the synthesis of 2,3-diarylbenzofurans and phenanthrofurans
based on a palladium-catalyzed tandem C-/O-arylation, see: Churruca, F.;
SanMartin, R.; Tellitu, I.; Dom´ınguez, E. Eur. J. Org. Chem. 2005, 12,
2481.
Remarkably, when the catalyst loading was decreased from
8.5 mol % to 5.6 mol %, only slightly lower yields of product
were obtained, and the reaction proceeded smoothly even
with less than 2 mol % of CuI. However, the presence of
catalyst, even in small amounts, was absolutely necessary
for the reaction to occur. In addition, it was observed that a
decrease in temperature from 120 °C to 60 °C resulted in
(11) Such complexes have been previously reported for being involved
in other copper-catalyzed coupling reactions and are probably responsible
for the color of the solution. See: Kaplars, A.; Huang, X.; Buchwald, S. L.
J. Am. Chem. Soc. 2002, 124, 7421.
1468
Org. Lett., Vol. 8, No. 7, 2006

lower yields of target benzofuran 3 (91% vs 33%) together
with unreacted substrate 1 (Figure 2).
Table 1. Preparation of Differently Substituted Benzo[b]furans
Figure 2. Catalyst loading and temperature screening.
It can be concluded that the optimal reaction conditions
for the target O-arylation reaction involved stirring the
substrate 1 in water at 120 °C in the presence of 8.5 mol %
of CuI and 3.5 equiv of TMEDA (Figures 1 and 2).
To determine the scope of the chosen reaction conditions,
we decided to apply this methodology to the synthesis of
different benzo[b]furans, as shown in Table 1. Substituent
variations in the bromoaryl moiety allowed us to study the
electronic requirements of the reaction. In this regard, the
heterocyclization was disfavored by the presence of electron-
donating methoxy substituents para to the bromo with, for
example, benzofuran 11 only being obtained in 21% yield
(Table 1, entry 5). In contrast, nonsubstituted aryl bromides
(Table 1, entries 1, 3, and 6) or those bearing fluorine atoms
(Table 1, entry 2) had a beneficial effect on the reaction
outcome, affording the corresponding benzofurans in good
to excellent yields.
Surprisingly, the proposed methodology worked extremely
well when the substrate contained a free primary amine
substituent, despite such moieties being known to readily
couple with aryl bromides in the presence of copper
catalysts.12 In our case, however, the competitive N-arylation
process was not observed and benzofuran 7 was selectively
obtained in 99% yield (Table 1, entry 3).
Furthermore, the presented method is not limited to the
use of deoxybenzoin derivatives as substrates, though the
presence of the second aryl ring seems to facilitate the
process, given that the alkyl ketones 8 and 14 afforded
benzofuran 9 and 15, respectively, in slightly lower yields
(Table 1, entries 4 and 7) than those observed for the above
assayed arylated systems. Although the optimized experi-
mental conditions proved suitable for the ring closure of a
series of 2-bromo derivatives, when the corresponding
2-chloro analogues were employed as starting materials, only
traces of the desired benzofurans were detected by GC-MS.
Because the isolation of the so-obtained benzofurans was
easily accomplished by extraction with dichloromethane, an
attempt to reuse the copper catalyst, dissolved in the aqueous
layer, was an appealing goal to study. Thus, after performing
a Isolated yields.
the reaction on substrate 12 and workup, the remaining green
aqueous solution, presumably containing the copper-
TMEDA complex, was again used to perform a second run
of the same reaction. Remarkably, benzofuran 13 was
obtained in only slightly lower yield for the second run (78%
vs 83%), as shown in Table 1 (entry 6). The addition of an
extra amount of TMEDA was required for the second run,
otherwise only traces of the benzofuran 13 were detected.
This fact strengthens the previous hypothesis that TMEDA
plays a double role in the reaction; though a portion behaves
as a ligand linked to the copper atom (forming the water-
soluble complex), the remainder of the TMEDA is consumed
as a base and therefore must be replaced.
Finally, although still preliminary, it should be pointed
out that the reported process has been scaled up to 1 g in
the case of ketone 6, providing the corresponding benzofuran
7 in 93% yield.
To sum up, we have developed an environmentally
friendlier route to benzo[b]furan derivatives based on a
(12) (a) Kwong, F. Y.; Kaplars, A.; Buchwald, S. L. Org. Lett. 2002, 4,
581. (b) Gujadhur, R.; Venkataraman, D.; Kintigh, J. T. Tetrahedron Lett.
2001, 42, 4791.
Org. Lett., Vol. 8, No. 7, 2006
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copper-catalyzed ring-closure reaction performed in water.
The benefits derived from the use of such a benign solvent
are clear in terms of lack of toxicity, safety, cost, and
availability, properties that make water a desirable medium
for every organic transformation. Furthermore, the on-water
methodology described here delivers a range of benzo[b]-
furans in good to excellent yields starting from readily
available substrates. In addition, the easy isolation of the
target compounds, by simple extraction with dichloro-
methane, allows the reutilization of the water solution
containing the copper catalyst, thereby providing environ-
mental and economic advantages over previously reported
protocols.
Acknowledgment. This research was supported by the
University of the Basque Country (Project UPV 41.310-
13656) and the Spanish Ministry of Education and Science
(MEC CTQ2004-03706/BQU). M.C. also thanks the Ministry
of Education and Science (MEC) for a predoctoral scholar-
ship.
Supporting Information Available: Experimental pro-
cedures and characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL060274C
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