3-Zinciobenzofuran and 3-zincioindole: Versatile tools for the construction of conjugated structures containing multiple benzoheterole units

Article abstract of DOI:10.1002/anie.200502920

(Chemical Equation Presented) Closing the ring: Thermally stable but reactive 3-zinciobenzofurans and indoles were synthesized by metalative cyclization of 2-ynyl phenols or anilines. Furthermore, a variety of extended π-conjugated molecules were obtained by Pd-catalyzed cross-coupling reactions of these heterocycles with mono- or polyhalo-substituted arenes and alkenes (R²Hal_n; see scheme; Bn = benzyl).

Full text of DOI:10.1002/anie.200502920

Communications
Heterocycles
DOI: 10.1002/anie.200502920
3-Zinciobenzofuran and 3-Zincioindole: Versatile
Tools for the Construction of Conjugated
Structures Containing Multiple Benzoheterole
Units**
Masaharu Nakamura,* Laurean Ilies, Saika Otsubo,
and Eiichi Nakamura*
Functionalized benzoheteroles, such as benzofuran and
indole, form the core of natural products and serve as
promising units in materials science.[1] In the latter applica-
tions, conjugated compounds containing one or more benzo-
heterole units are attracting particular attention.[2] A poten-
tiallygeneral approach to this class of compounds is the
cyclization of a metal 2-ynyl phenolate or 2-ynyl anilide 1 to a
3-metallobenzoheterole intermediate 2 that reacts further
with an electrophile to produce the corresponding heterole 3
(Scheme 1). We report herein the virtuallyquantitative
Scheme 1. Cyclization of a 2-alkynyl phenol or aniline to a 3-zincioben-
zoheterole. Bn=benzyl;E + =electrophile.
cyclization of 1 into a zinc compound 2 and its use in the
concise synthesis of a variety of new benzoheterole conju-
gated systems (cf. Table 2). Such a cyclization has been known
for the synthesis of some 3-metallobenzofuran intermediates
(metal = Li, Hg,[3] and Pd[4]), but not in the indole series.[5] The
value of the present zinc-mediated chemistryresides in the
high yield of the cyclization and the versatility of the resulting
zinc compounds 2 in synthesis of a library of new multiple
benzoheterole conjugated systems.
The incorporation of a zinc atom to obtain 2, which is
stable yet reactive in the presence of a catalyst, was critical to
[*] Prof. Dr. M. Nakamura, L. Ilies, S. Otsubo, Prof. Dr. E. Nakamura
Department of Chemistry
The University of Tokyo
and Nakamura Functional Carbon Cluster Project ERATO
Japan Science and Technology Agency
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-5800-6889
E-mail: masaharu@chem.s.u-tokyo.ac.jp
nakamura@chem.s.u-tokyo.ac.jp
[**] We thank the Ministry of Education, Culture, Sports, Science, and
Technology of Japan for financial support, a scholarship (L.I.) and
for the 21st Century COE Program for Frontiers in Fundamental
Chemistry.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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success, as it was for the addition of a zinc enamide and
enolate to an unactivated alkene or alkyne.[6] Deprotonation
of a 2-alkynyl phenol 1a–f with 0.5 equivalents of Et2Zn
followed byheating in the presence of a catalytic amount of
N,N,N’,N’-tetramethylethylenediamine (TMEDA) in reflux-
ing toluene effected smooth cyclization into 2-substituted
benzofurans 3a–f (E = H), which were isolated after quench-
ing the reaction mixture with aqueous ammonium chloride.
We observed 97% deuterium incorporation (R = Ph) after
quenching the reaction mixture with deuterium chloride. The
reaction afforded 2-aryl, heteroaryl, vinyl, and alkoxymethyl
benzofurans in almost quantitative yields (Table 1, entries 1–
6), except stericallyhindered 2- tert-butylbenzofuran (3c),
which was obtained in 50% yield. Zinc phenoxides are known
tion with iodobenzene and (E)-bromostyrene took place
quantitativelyto give 2,3-diphenylbenzofuran ( 4)[12] and 2-
phenyl-3-(E)-phenylethenylbenzofuran (10; entries 1 and 7,
respectively). The synthetic merit of the zinc methodology is
demonstrated in the reactions with polyhaloarenes, which
afforded compounds inaccessible byknown methods. For
example, two or three benzofuran moieties can be introduced
in a single step to a benzene ring to yield molecules containing
seven and ten aromatic rings (5 and 7, 87 and 74% yield of the
isolated products, respectively; entries 2 and 4). Molecular-
modeling studies suggest intrinsic nonplanarityof these
compounds owing to the steric repulsion of substituents on
the benzofuran rings, which makes a chiral propeller con-
formation for tribenzofuran 7 favorable (see the Supporting
Information). The present method provides easyaccess to
asymmetrically substituted compounds, such as 6, byusing
two different zinc benzofuran compounds. Thus, zinc inter-
mediates 2a and 2e were treated sequentiallywith 1-bromo-
4-iodobenzene to give a mixed-furan compound 6 in 82%
yield (entry 3). Similarly, we synthesized 8 and 9 with
benzofuran-thiophene-benzofuran alternating units in 89
and 67% yield, respectively (entries 5 and 6) by starting
with 2,5-diiodothiophene. 1,2-Dibromoethene afforded an
ethylene-linked benzofuran 11 and a highlyconjugated
benzofuran 12 in high yield (entries 8 and 9). The olefin
geometryin the starting dibromide was retained in the
product. Some of these compounds show intense fluorescence
both in solution and in the solid state because of the extended
conjugation and nonplanarity; this property will be an
interesting future subject of materials-related studies.
Table 1: Cyclization of a 2-alkynyl phenol or aniline to form a benzo-
heterole 3 (E=H).
Entry
X
R
1
t
Yield [%][a]
Product
1
2
3
4
5
6
7
O
O
O
O
O
O
Ph
nBu
tBu
1a
1b
1c
1d 1 h
1e
1 h
1 h
3 days 50
94
99
3a
3b
3c[b]
3d
3e
3 f
E-styryl
2-thienyl
99
93
98
99
3 h
1 h
1 h
CH2OMOM[c] 1 f
NBn Ph
1g
3g
[a] Yield of the isolated product. [b] Starting material 1c was recovered in
31% yield. [c] MOM=methoxymethyl.
to form oligomeric aggregates,[7] and therefore TMEDA is
thought to activate the aggregate bypartiallybreaking the
coordination between the oxygen and zinc atoms. We have so
far been unable to cyclize either phenol 1, in which R = H,
likelybecause of the high acidityof the free acetylenic proton,
or the phenol in which R = Me3Si, as it resists cyclization and
premature loss of the silyl group results. We have previously
shown that a silicon group retards the reaction taking place
Next, we examined the scope of this coupling protocol for
the 3-zincioindole reagent (Table 2, entries 10–12). Coupling
of the zinc intermediate 2g with 1,4-diiodobenzene and 2,5-
diiodothiophene in the presence of the Pd0 catalyst gave the
conjugated bisindoles 13 and 14 in excellent yield. We could
also synthesize a indole-thiophene-benzofuran ternary com-
pound 15 byallowing zinciobenzofuran 2a and zincioindole
2g to react sequentiallyin one pot with 2-bromo-5-iodothio-
phene (entry12).
In conclusion, we have developed an efficient and general
synthetic method for 3-metallated 2-substituted benzoheter-
oles and their use in the preparation of molecules containing
multiple benzofuran and indole units. The rather low
reactivityof the zinc phenoxides in the absence of TMEDA
is probablydue to the propensityof zinc phenoxides to form
coordinativelysaturated oxygen-bridged aggregates, in con-
trast to the corresponding zinc anilides. The high reactivityof
the 3-metallobenzoheterole reported above suggests that
other the standard techniques in organozinc chemistry[13]
could contribute to expanding the utilityof our heteroar-
omatic zinc reagents. The nonplanar, multiaromatic ring
systems suggest their potential as new chiral scaffolds to be
exploited in asymmetric synthesis. We expect the present
methodology to be applicable to other heterocyclic systems,
such as benzothiophenes and benzosiloles, and to provide a
varietyof new compounds for various applications.
[8]
with such regiochemistry.
A slightlymodified method was found to be useful for the
indole synthesis. Deprotonation of N-benzyl-protected
alkynyl aniline 1g with butyllithium,[9] followed bytreatment
with zinc chloride and heating for one hour in toluene
quantitativelygenerated 2-substituted 3-zincioindole, which
was quenched with ammonium chloride to give 2-phenyl-
indole in 99% yield (Table 1, entry 7). When the reaction
mixture was quenched with deuterium chloride, 95% deute-
rium incorporation at the mechanisticallyexpected 3 position
was observed. TMEDA was not necessaryfor the cyclization
of indoles, presumablybecause the corresponding zinc
anilides tend not to form unreactive aggregates like the
related zinc phenoxides.[10]
The zinc intermediate 2 is a useful building block for the
construction of various conjugated structures with 2,3-disub-
stituted benzoheteroles as a keystructural motif. After
screening several catalyst systems, we found that various
aryl and alkenyl halides readily couple with 2 in the presence
of [Pd2(dba)3]·CHCl3 (dba = dibenzylideneacetone; 5 mol%)
and P(tBu)3 (20 mol%; Table 2).[11] The reactions of the 3-
zinciobenzofuran intermediate are described first: The reac-
Received: August 17, 2005
Published online: December 30, 2005
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Communications
Table 2: Conjugated compounds obtained by Pd-catalyzed coupling with halides.
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1
Phenol
Electrophile
Coupling product
Yield [%][a]
99
1a
4
5
2
3
1a
87
1a
1e
6
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82[b]
4
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74
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8
1a
1a
10
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94
92
9
1d
12
13
88
93
10
1g
1g
11
12
14
15
91
48
1a
1g
[a] Yield of the isolated products. [b] Symmetric coupling products were obtained in about 15% yield
(GC analysis). [c] 10 mol% of palladium and 40 mol% of P(tBu)3 were used. [d] E/Z=43:57, as
determined by H NMR spectroscopic analysis.
1
[9] Diethylzinc is too weak as a base to deprot-
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Keywords: benzoheterole · conjugation · cyclization ·
heterocycles · palladium · zinc
.
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