Intramolecular cross-coupling of gem-dibromoolefins: A mild approach to 2-bromo benzofused heterocycles

Article abstract of DOI:10.1039/b912093a

Highly useful halogenated benzofurans and benzothiophenes are prepared from readily available gem-dibromoolefins using a mild, ligand-free copper catalyzed cross-coupling procedure.

Full text of DOI:10.1039/b912093a

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Intramolecular cross-coupling of gem-dibromoolefins: a mild approach
to 2-bromo benzofused heterocycleswz
Stephen G. Newman, Valentina Aureggi, Christopher S. Bryan and Mark Lautens*
Received (in College Park, MD, USA) 19th June 2009, Accepted 16th July 2009
First published as an Advance Article on the web 6th August 2009
DOI: 10.1039/b912093a
Highly useful halogenated benzofurans and benzothiophenes are
prepared from readily available gem-dibromoolefins using a
mild, ligand-free copper catalyzed cross-coupling procedure.
Halogenated heterocycles are of significant value in the
synthesis of natural and unnatural products due to their
reactivity and ease of derivatization.1 The most straight-
forward method for their synthesis is by treatment of the
unsubstituted parent substrate with an electrophilic halogen
Scheme
2
Protecting group-free synthesis of gem-dibromovinyl
source. For benzofused heterocycles such as benzofurans,
benzothiophenes, and indoles, this typically provides access
to 3-halogenated substrates, which have found frequent
application in organic synthesis.2 In contrast, 2-substituted
benzofused heterocycles are less accessible, typically requiring
lithiation,3 which introduces issues of regioselectivity,
scalability, and functional group compatibility. There is a
clear need for the development of milder conditions for the
formation of 2-halogenated benzofused heterocycles.
phenols.
gain access to desirable 2-bromobenzofused heterocycles by a
selective intramolecular cross-coupling procedure.
Our initial efforts focused on the synthesis of 2-bromo-
benzofurans. A very limited number of this family of
substrates have been previously reported, most of which are
synthesized through a lithiation protocol. While this method
has proven effective for unsubstituted benzofuran, it is
incompatible with substrates bearing substituents around the
aryl ring, especially base sensitive or ortho-directing groups.6
Previous studies in our lab used commercially available salicyl-
aldehyde 4 and derivatives as precursors to gem-dibromoolefin
5a by a 3-step route (Scheme 2). We believed that 5a and
derivatives could be used for the synthesis of 2-bromobenzo-
furans such as 6a. In the interest of making this route more
attractive, we first investigated the Ramirez olefination7
of salicylaldehydes, and identified protecting group-free
conditions. Preformation of 3 equivalents of the active
PPh3CBr2 ylid, followed by slow addition of NEt3 and salicyl-
aldehyde 4, provided gem-dibromoolefin 5a in 81% yield. The
use of excess ylid and the slow addition of reagents were
necessary for high yields. This protocol may be applicable
to the protecting group-free Ramirez olefination of other
aldehydes containing Lewis basic groups.
We and others have recently devoted attention to the
synthesis of 2-substituted indoles and other benzofused
heterocycles by tandem intra- and intermolecular cross-
coupling reactions of gem-dihaloolefins
1
(Scheme 1).4
Mechanistic studies suggest that the predominant reaction
pathway involves first an intramolecular carbon–heteroatom
coupling to form heterocycles 2, followed by intermolecular
cross-coupling (e.g. Suzuki, Sonagashira, Heck) to form
substrates 3.4e This is in contrast to the more commonly
observed selectivity for the cross-coupling of gem-dihaloolefins,
which typically react first at the (E)-halide.5 Interestingly, in
the absence of an external coupling partner, the proposed
intermediate 2 is not observed, instead providing only recovered
starting material. Herein, we report our findings on how to
With this improved starting material synthesis in hand, we
screened conditions for the selective intramolecular cross-
coupling reaction of phenol 5a to form benzofuran 6a. Studies
with palladium catalysis proved ineffective, often providing
recovered starting material or a complex mixture of products.
Conversely, the use of copper as a cross-coupling catalyst gave
cleaner reaction and enabled us to develop a highly effective
catalytic system.8 When phenol 5a was treated with K3PO4
and catalytic CuI at 80 1C in THF, 2-bromobenzofuran 6a was
formed with complete selectivity in 89% yield (Table 1, entry 1).
Many different copper species were effective catalysts, with
good conversion being obtained with 5 mol% CuI, CuCl2, and
Cu0 (powder). The choice of base was important, with organic
bases such as NEt3 giving reduced reactivity, and Cs2CO3
Scheme 1 Synthesis of 2-substituted heterocycles by tandem cross-
coupling.
Department of Chemistry, University of Toronto,
80 St. George Street, Toronto, Canada M5S 3H6.
E-mail: mlautens@chem.utoronto.ca; Fax: +1 416 946 8185;
Tel: +1 416 978 6083
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic
chemistry. Please see our website (http://www.rsc.org/chemcomm/
organic webtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: Experimental
procedures and characterization data. See DOI: 10.1039/b912093a
ꢀc
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5236 | Chem. Commun., 2009, 5236–5238

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Table 1 Synthesis of benzofurans by intramolecular Ullmann couplinga
Scheme 3 Synthesis of benzothiophene precursors.
thiophenols 8 by nucleophilic aromatic substitution, Ramirez
olefination, and deprotection of commercially available
2-fluoro- and 2-chlorobenzaldehydes 7 (Scheme 3).12 Treatment
of these substrates with the conditions optimized for the
synthesis of benzofurans gave the corresponding 2-bromo-
benzothiophenes 8 in excellent yields (Table 2). Electron-
neutral (entry 1), -poor (entry 2), and -rich (entries 3 and 4)13
substrates smoothly underwent cross-coupling. Halogenated
derivatives could also be used with complete selectivity
(entries 5–8). Notably, gem-dichloroolefin 8i could be
converted to 2-chlorobenzothiophene 9i under the general
conditions (entry 9).
Entry
1
Substrate
Product
Yield (%)
93
2
3
89
95
4
89
Having developed a novel procedure for the synthesis of
halogenated benzofurans and benzothiophenes, we sought to
5
6
93
99
Table 2 Synthesis of benzothiophenes by intramolecular Ullmann
couplinga
7
96
Entry
1
Substrate
Product
Yield (%)
84
8
52b
a
Conditions: 5 mol% CuI, 2 equiv. K3PO4, 80 1C, 6 h, THF (0.2 M).
Purification by flash chromatography.
b
2
3
4
88
99
giving complex reaction mixtures. The choice of solvent and
temperature was also important, with several unidentified
by-products being formed at higher temperatures, especially
in non-polar solvents such as toluene.9 Of particular note is the
use of ligand-free conditions, which greatly simplifies the
reaction and work-up procedure, enabling purification to be
accomplished by simple filtration of the reaction mixture
through silica gel.10
74b
5
91
Following optimization, the scope of the reaction was
evaluated (Table 1). Subjecting a number of gem-dibromoolefins
with electron-withdrawing (entries 2 and 3) and -donating
(entries 4 and 5) substituents to the optimized reaction
conditions gave the expected 2-bromobenzofurans in excellent
yields. Halogen substituents on the aryl ring were also
tolerated, giving polyhalogenated benzofurans 6f and 6g
which may be useful for regioselective cross-coupling
6
7
82
91
8
96
(entries
6
and 7).11 More sterically encumbered tetra-
substituted olefin 5h could also undergo regioselective
cross-coupling to give 3-substituted benzofuran 6h (entry 8).
Following the study of benzofurans, we turned our
attention to the synthesis of benzothiophenes. Our lab has
recently developed a general methodology for the synthesis of
9
62b
a
Conditions: 5 mol% CuI, 2 equiv. K3PO4, 80 1C, 6 h, THF (0.2 M).
Purification by flash chromatography.
b
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Scheme 4 Preliminary finding on the synthesis of 2-bromoindoles.
extend this methodology to indoles. Unfortunately, applying
the general copper conditions to aniline 10a gave complete
recovery of starting material (Scheme 4). Increasing the
reaction temperature gave no conversion until approximately
130 1C, at which point starting material decomposed.
Exhaustive screening of bases, solvents, and ligands failed to
reveal effective conditions. Reinvestigation of palladium
catalyzed Buchwald–Hartwig conditions generally gave no
conversion of starting material. However, when P(t-Bu)3 was
used as a ligand, 2-bromoindoles 11a and 11b could be
obtained in 64% and 66% yield.14 Further studies into the
optimization, scope, and mechanism of this transformation
are currently underway.
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9 Reactions were performed in a sealed vessel. Refluxing THF or
MeCN were also effective solvents for cyclization if use of an open
vessel is desired, giving only slightly decreased yields.
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absence of ligand are rare, and often require polar, potentially
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In summary, we have developed a method for the synthesis
of a wide range of novel halogenated benzofused heterocycles.
gem-Dibromoolefins are used as readily accessible precursors,
ligand-free conditions were employed, and purification by
flash chromatography is unnecessary, making this method
highly efficient. We expect these substrates will become useful
building blocks for the synthesis of more complex hetero-
cycles, similar to the better known 3-halogenated isomers.
We gratefully acknowledge the financial support of the
Natural Sciences and Engineering Research Council of
Canada (NSERC), the University of Toronto, and
Merck-Frosst Canada for an industrial research chair.
S.G.N. thanks NSERC for a post-graduate scholarship
(CGS-M). V.A. thanks the Novartis Foundation for
postdoctoral funding.
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¨
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This journal is The Royal Society of Chemistry 2009
5238 | Chem. Commun., 2009, 5236–5238