2,3-Disubstituted benzofuran and indole by copper-mediated C-C bond extension reaction of 3-zinciobenzoheterole

Article abstract of DOI:10.1021/ol060896y

A metalative 5-endo-dig cyclization reaction of 2-ynylphenoles or anilines effected by BuLi and ZnCl₂ produces 3-zinciobenzoheteroles in excellent yield. These intermediates have been transmetalated to the corresponding cuprates and allowed to react with electrophiles to produce a variety of 2,3-disubstituted benzofurans and indoles.

Full text of DOI:10.1021/ol060896y

ORGANIC
LETTERS
2
006
Vol. 8, No. 13
803-2805
2
,3-Disubstituted Benzofuran and Indole
2
by Copper-Mediated C
−C Bond
Extension Reaction of
3-Zinciobenzoheterole
Masaharu Nakamura,*,† Laurean Ilies, Saika Otsubo, and Eiichi Nakamura*
Department of Chemistry, The UniVersity of Tokyo, Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
masaharu@scl.kyoto-u.ac.jp; nakamura@chem.s.u-tokyo.ac.jp
Received April 13, 2006
ABSTRACT
2
A metalative 5-endo-dig cyclization reaction of 2-ynylphenoles or anilines effected by BuLi and ZnCl produces 3-zinciobenzoheteroles in
excellent yield. These intermediates have been transmetalated to the corresponding cuprates and allowed to react with electrophiles to produce
a variety of 2,3-disubstituted benzofurans and indoles.
2
,3-Disubstituted benzofurans and indoles form the core of
with other carbon electrophiles that would offer more diverse
synthetic possibilities. In addition, the reaction using Et Zn
numerous natural products and have considerable pharma-
cological potential. We previously reported a new method
for preparation of this class of compounds by zinc-mediated
cyclization of 2-ynylphenol or aniline (1), followed by
palladium-catalyzed C-C bond extension. In this previous
2
method, we relied largely on Et Zn to obtain the crucial zinc
intermediate, bis(benzofuran-3-yl)zinc or (benzofuran-3-yl)-
ethylzinc, that shares the same organometallic core structure
with 2 except the chlorine ligand on the metal atom. While
such intermediates smoothly underwent Pd-catalyzed reac-
tions with aryl and alkenyl halides, they resisted reaction
2
1
2
gave 5-10% recovery of the protio product 4 (E ) H), which
is due to the fast, sluggish cyclization, causing in situ
competitive protonation of the zinc intermediate by 1. In this
Letter, we report a more synthetically useful procedure that
allows quantitative generation of the 3-zinciobenzoheterole
2 and subsequent copper-mediated coupling with a variety
of carbon electrophiles to give 2,3-disubstituted benzofurans
and indoles.
3
4
A hint of the solution was already provided in our previous
2
synthesis of indoles, where ZnCl
2
instead of Et
2
Zn tends to
give better results. Optimization of the reaction conditions
†
PRESTO, Japan Science and Technology Corporation (JST).
(
1) (a) Katritzky, A. R. ComprehensiVe Heterocyclic Chemistry; Perga-
mon Press: Oxford, 1984, Vol. 4, Part 3, p 658. (b) Williams, A. Furans,
Synthesis and Applications; Noyes Data Corporation: Park Ridge, NJ, 1973;
pp 1-303.
(4) Metallobenzofuran. (a) Hg: Larock, C. R.; Harrison, L. W. J. Am.
Chem. Soc. 1984, 106, 4218-4227. (b) Li: Gilman, H.; Melstrom, D. S. J.
Am. Chem. Soc. 1948, 70, 1655-1657. 3-Metalloindole. (a) Li: Saulnier,
M. G.; Gribble, G. W. J. Org. Chem. 1982, 47, 757-761. (b) Zn: Amat,
M.; Hadida, S.; Pshenichnyi, G.; Bosch, J. J. Org. Chem. 1997, 62, 3158-
3175. (c) Hg: Ramachandran, L. K.; Witkop, B. Biochemistry 1964, 3,
1603-1611. (d) B: Zheng, Q.; Yang, Y.; Martin, A. R. Tetrahedron Lett.
1993, 34, 2235-2238. (e) Mg: DeGraw, J. I.; Kennedy J. G.; Skinner, W.
A. J. Heterocycl. Chem. 1966, 3, 67-69. (f) Sn: Ciattini, P. G.; Morera,
E.; Ortar, G. Tetrahedron Lett. 1994, 35, 2405-2408. (g) Sn: Hodson, H.
F.; Madge, D. J.; Slawin, A. N. Z.; Widdowson, D. A.; Williams, D. J.
Tetrahedron 1994, 50, 1899-1906.
(2) Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E. Angew. Chem.,
Int. Ed. 2006, 45, 944-947.
(3) Benzofuran: (a) Hu, Y.; Zhang, Y.; Yang, Z.; Fathi, R. J. Org. Chem.
2
002, 67, 2365-2368. (b) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli,
F.; Moro, L. Synlett 1999, 1432-1434. (c) Arcadi, A.; Cacchi, S.; Del
Rosario, M.; Fabrizi, G.; Marinelli, F. J. Org. Chem. 1996, 61, 9280-
9
288. (d) Kondo, Y.; Shiga, F.; Murata, N.; Sakamoto, T.; Yamanaka, H.
Tetrahedron 1994, 50, 11803-11812. Indole: (e) Battistuzzi, G.; Cacchi,
S.; Fabrizi, G. Eur. J. Org. Chem. 2002, 2671-2681 and references therein.
1
0.1021/ol060896y CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/01/2006

ing 2-substituted benzofurans in excellent yield (entries 5-7).
-Ethynylphenol 1d resisted cyclization, which stands in stark
contrast to the smoothness of the cyclization for an aniline
2
Scheme 1. Cyclization of 2-Ynylphenol (or aniline) 1 to
-Zinciobenzoheterole 2 and Trapping with Electrophiles
3
couterpart giving 4k in 99% yield. Poor stability of 3-met-
3
allobenzofuran compared with the indole counterpart could
explain the intolerance for another metal atom at position 2.
The reaction proceeded equally well with 2-ynylanilines
1h-j under similar conditions (entries 8-11). For substrate
1l (X ) NBn, R ) (E)-styryl), the yield was modest (entry
12) because of the instability of the starting material.
We tentatively attribute the large difference of the reactiv-
2
ity between Et Zn-generated bisphenoxyzinc and the BuLi/
ZnCl -generated phenoxyzinc chloride (2) to increased Lewis
2
acidity of the zinc atom. We also attribute the lack of
necessity to employ TMEDA to the presence of LiCl, whose
Cl anion acts as a ligand to the zinc atom and prevents the
formation of unproductive aggregates. We defer further
discussion until we obtain concrete pieces of structural and
mechanistic evidence.
allowed us to achieve the cyclization and the subsequent
transformations with much higher efficiency. Thus, we first
deprotonated acetylenic phenol 1a (X ) O, R ) Ph) with
2
BuLi (1.0 equiv), and then added ZnCl (1.0 equiv) to obtain
the corresponding zinc phenoxide as a clear homogeneous
solution. Removal of the solvent in vacuo followed by
addition of toluene and heating at reflux for 1 h resulted in
the formation of the zinc intermediate 2a that was isolated
quantitatively as its protonated form 4a (E ) H) (Table 1,
The zinc intermediate 2 was found to be a much more
2
useful intermediate than those reported earlier. In the
5
presence of CuCN‚2LiCl, 2 gave a variety of compounds,
most of which are unavailable by our previous method (Table
2
). 3-Allyl benzoheteroles 5 and 7 were obtained in quantita-
tive yield (entries 1 and 3). The butyl-substituted intermediate
b was slightly less reactive than the phenyl-substituted 2a,
2
Table 1. Cyclization of 2-Ynylphenol (or aniline) 1 into
Benzofuran (or indole) 4 (E ) H)a
but still gave the desired 3-allyl-2-butylbenzofuran 6 in good
yield (entry 2). The reaction with cinnamyl bromide was
time
(h)
b
N N
completely S 2 selective (entry 4), in contrast to the S 2′
entry
X
R
yield (%) (4)
5
,6
selectivity of less hindered zinc reagents. Coupling with
benzoyl chloride gave 3-aroyl benzoheteroles 9 and 10 in
good yield (entries 5 and 6). The method thus provides an
easy access to 2-substituted 3-aroyl benzofurans and indoles
1
2
3
4
5
6
7
8
9
O
O
O
O
O
O
O
NBn
NBn
NBn
NBn
NBn
Ph
1
1
48
2
1
1
1
1
2
16
2
100 (4a)
98 (4b)
98 (4c)
0 (4d)
100 (4e)
96 (4f)
86 (4g)
100 (4h)
97 (4i)
98 (4j)
99 (4k)
48 (4l)
n-Bu
t-Bu
c
H
(E)-styryl
2-thienyl
CH2OMOMd
Ph
7
that are useful for the pharmacological studies.
Copper-mediated 1,2-addition to benzaldehyde took place
to give the alcohol 11 in good yield (entry 7). When BF
3
‚
n-Bu
OEt was used as an additive, the first addition product
2
10
11
12
t-Bu
c
further reacted with the second equivalent of the benzofuranyl
cuprate 3a to yield an intriguing, highly substituted methane
derivative 12 (entry 8). Michael addition to 2-cyclohexen-
1-one in the necessary presence of chlorotrimethylsilane as
H
(E)-styryl
2
a
Reaction conditions: BuLi (1.0 equiv), 0 °C to room temperature, 30
min, then ZnCl2 (1.0 equiv), toluene, 120 °C. Isolated yield. c 2.0 equiv
b
d
of BuLi, ZnCl2 was used. MOM ) methoxymethyl.
8
an additive afforded the corresponding ketones 13-15 in
good yield (entries 9-11). Diethyl malonate also reacted
smoothly in the presence of chlorotrimethylsilane and
afforded the benzofuran esters 16 and 17 in excellent yield
entry 1). No starting material (1a) was recovered. An
additional merit is that the new procedure does not require
tetramethylethylenediamine (TMEDA) that was mandatory
(entries 12 and 13). The reaction with 3-iodo-2-cyclohexen-
1-one gave the conjugated ketone 18 in excellent yield (entry
2
in the Et Zn-mediated method.
1
4).
Cyclization of a hexynyl substrate 1b (X ) O, R ) n-Bu)
also took place quantitatively (entry 2), with 95% deuterium
(
5) Knochel, P.; Singer, R. D. Chem. ReV. 1993, 93, 2117-2188 and
references therein.
6) Nakamura, E.; Aoki, S.; Sekiya, K.; Oshino, H.; Kuwajima, I. J. Am.
Chem. Soc. 1987, 109, 8056-8066.
2
incorporation upon DCl/D O quenching (86% incorporation
(
by the Et Zn cyclization). 2-tert-Butylbenzofuran (4c) that
2
was obtained earlier in a modest 50% yield can now be
synthesized in quantitative yield (entry 3). Various other
(
7) (a) Twyman, L. J.; Allsop, D. Tetrahedron Lett. 1999, 40, 9383-
9384. (b) Yang, Z.; Liu, H. B.; Lee, C. M.; Chang, H. M.; Wong, H. N. C.
J. Org. Chem. 1992, 57, 7248-7257.
alkynyl phenols bearing styryl, thienyl, or CH
2
OMOM
(
8) Nakamura, E.; Kuwajima, I. J. Am. Chem. Soc. 1984, 106, 3368-
substituents (1e-g) reacted smoothly to give the correspond-
3370.
2804
Org. Lett., Vol. 8, No. 13, 2006

Table 2. Coupling of 3-Zinciobenzoheterole 2 with Various Electrophiles in the Presence of Cu(I)a
a
Reaction conditions: a mixture of 2 (1.0 mmol) in toluene (1.0 mL) was cooled to -78 °C and CuCN‚2LiCl in THF (1.0 M, 1.0 mL), additive (2.4
mmol), and electrophile (1.2 mmol) were successively added. The mixture was then warmed to the indicated temperature and stirred. When Me3SiCl was
used in situ as an additive, the reaction mixture was quenched with tetrabutylammonium fluoride (THF solution, 1.0 mol/L). Isolated yield based on 1.
Determined by H NMR.
b
c
1
In most of the cases, the only byproduct was 3-protonated
Acknowledgment. We thank the Ministry of Education,
Culture, Sports, Science, and Technology of Japan for
financial support, a scholarship (L.I.), a Grant-in-Aid for
Exploratory Research (KAKENHI 17655037), and for the
21st Century COE Program for Frontiers in Fundamental
Chemistry.
benzoheterole 4 (E ) H), which was recovered in 5-20%
yield. The new zincio intermediates also react with aryl and
alkenyl halides under palladium catalysis (data not shown)
and may be used as a general alternative to the previous
procedure.
In conclusion, we have developed a procedure for the
generation of 3-zincio-2-substituted benzoheteroles 2, which
is superior to the previous method for the lack of necessity
of the TMEDA additive, for the much higher yield of the
cyclization, and for the versatility of the zinc intermediates
for further synthetic elaborations.
Supporting Information Available: Details of the ex-
perimental procedure and spectral data for new compounds
PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(
OL060896Y
Org. Lett., Vol. 8, No. 13, 2006
2805