Rhodium(I)-catalyzed cyclization reaction of o-alkynyl phenols and anilines. Domino approach to 2,3-disubstituted benzofurans and indoles

Article abstract of DOI:10.1021/ol9001174

A rhodium-catalyzed cyclization of o-alkynylphenols and anilines followed by intermolecular conjugate addition that succeeds with alkyl and aryl alkynes is reported. In this reaction, 2,3-disubstituted benzofurans or indoles are obtained in one pot in good to excellent yields.

Full text of DOI:10.1021/ol9001174

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1329-1331
Rhodium(I)-Catalyzed Cyclization
Reaction of o-Alkynyl Phenols and
Anilines. Domino Approach to
2,3-Disubstituted Benzofurans and
Indoles
Naohiro Isono and Mark Lautens*
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto,
Toronto, Ontario, Canada M5S 3H6
mlautens@chem.utoronto.ca
Received January 19, 2009
ABSTRACT
A rhodium-catalyzed cyclization of o-alkynylphenols and anilines followed by intermolecular conjugate addition that succeeds with alkyl and
aryl alkynes is reported. In this reaction, 2,3-disubstituted benzofurans or indoles are obtained in one pot in good to excellent yields.
Substituted benzofuran and indole skeletons are widely found
in bioactive compounds of medicinal interest.1 Transition
Scheme 1. Synthesis of 2,3-Disubstituted Benzofuran and Indole
metal catalyzed annulation of o-alkynylphenols or anilines
has been used to prepare these heterocycles, but limited
methods exist to prepare the 2,3-disubstituted derivatives.2,3
Benzofuran or indole annulation with rhodium catalysts have
been reported4 including a recent disclosure from Trost on
the rhodium-catalyzed cycloisomerization to form indoles,
benzofurans, and enol lactones.5 Using [Rh(cod)Cl]2/(4-
FC6H4)3P, he reported that terminal alkynes cyclize, but
substrates bearing an internal alkyne fail to react. We report
a general method to prepare both benzofurans and indoles
including the 2,3-disubstituted derivatives via a cyclization/
addition cascade using Rh(I), BINAP (Scheme 1).
(1) Benzofuran: Keay, B. A.; Dibble, P. W. In ComprehensiVe Hetero-
cyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon Press: Oxford, UK, 1996; Vol. 2, p 395. Indole: Gribble, G. W.;
In ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon Press: Oxford, UK, 1996; Vol. 2, p 207.
(2) For reviews, see: Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104,
2285, and references therein.
(3) Leading references: (a) Kondo, Y.; Shiga, F.; Murata, N.; Sakamoto,
T.; Yamanaka, H. Tetrahedron 1994, 50, 11803. (b) Arcadi, A.; Cacchi,
S.; Del Rosario, M.; Fabrizi, G.; Marinelli, F. J. Org. Chem. 1996, 61,
9280. (c) Nakamura, I.; Mizushima, Y.; Yamamoto, Y. J. Am. Chem. Soc.
2005, 127, 15022. (d) Fu¨rstner, A.; Davies, P. W. J. Am. Chem. Soc. 2005,
127, 15024. (e) Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E. Org.
Lett. 2006, 8, 2803, and references therein.
(4) For a recent example of benzofuran synthesis via dealkylation-
cyclization by a rhodium catalyst: (a) Oppenheimer, J.; Johnson, W. L.;
Tracey, M. R.; Hsung, R. P.; Yao, P.-Y.; Liu, R.; Zhao, K. Org. Lett. 2007,
9, 2361. Intramolecular hydroamination: (b) Liu, Z.; Hartwig, J. F. J. Am.
Chem. Soc. 2008, 130, 1570. Amino-Claisen rearrangement of N-propargyl
anilines: (c) Saito, A.; Kanno, A.; Hanzawa, Y. Angew. Chem., Int. Ed.
2007, 46, 3931.
(5) Trost, B. M.; McClory, A. Angew. Chem., Int. Ed. 2007, 46, 2074.
10.1021/ol9001174 CCC: $40.75
Published on Web 02/23/2009
2009 American Chemical Society

Table 1. Cyclization of 2-Alkynlphenol 1 into Benzofuran 2a
Table 2. Synthesis of 2,3-Disubstituted Benzofurana
entry
R (1)
C6H5- (1a)
C6H5- (1a)
n-C4H9- (1b)
4-MeO-C6H4- (1c)
3-F-C6H4- (1d)
BzOCH2CH2- (1e)
product
% yieldb
entry EWG (4)
ligand
products % yieldb
5:6
1
2a
2a
2b
2c
2d
2e
95
92
88
92
90
97
1
CN (4a)
-
5a + 6a
5a + 6a
5b only
5c + 6c
5c + 6c
86
96
94
92
85
3.5:1
23:1
-
2c
3d
4d
5d
6d
2
CN (4a)
BINAP
3
COEt (4b)
CO2Et (4c)
CO2Et (4c)
-
-
-
4
2.4:1c
>20:1c
5d
a All reactions were run under the following conditions unless
a All reactions were run under the following conditions unless
otherwise noted: 1 (0.2 mmol), [Rh(CO)2acac] (10 mol %), BINAP (11
mol %) in toluene (1.5 mL) and H2O (0.2 mL). b Yields of isolated products.
c Dioxane-H2O (15:2) was used as a solvent. d [Rh(CO)2acac] (5 mol %)
and BINAP (5.5 mol %) were used.
otherwise noted: 1a (0.2 mmol), 4 (2.0 mmol), [Rh(cod)OH]2 (3 mol %) in
c
dioxane (2 mL) and H2O (0.1 mL). b Isolated yields. Determined by H
NMR spectroscopy. d 1a (0.2 mmol), 4c (0.4 mmol), [Rh(cod)OH]2 (3 mol
%) in DME (2 mL) and H2O (0.2 mL) at 85 °C.
1
unsaturated product 6c.8 By reducing the number of equiva-
lents of 4c to two, we observed that 5c was now formed
with much higher selectivity (>20:1 vs 2.4:1) and high yield.
We next investigated the scope of the reaction with respect
to the alkynyl phenols and electrophiles (Table 3). 2-Hexy-
nylphenol 1b gave the product in high yield. The reaction
tolerated a range of functional groups on the aromatic ring
(entries 2, 3, and 5-7).
We found that o-alkynylphenol 1 afforded 2-alkyl- or
arylbenzofuran 2 using Rh(I) and a bidentate ligand. The
reaction tolerated a range of functional groups on the alkyne.
The reaction of 1 in the presence of [Rh(CO)2acac] and BINAP
afforded the corresponding benzofurans 2a-2e in good yield
(Table 1). When the reaction was conducted in the presence of
D2O, deuterium incorporation on the C-3 of benzofuran 2a was
observed supporting the generation of rhodium benzofuran 3
after the cyclization reaction (Scheme 2). Recognizing the
possibility to construct a further carbon-carbon bond, we
decided to search for a competent electrophile that could
intercept 3.6,7
Scheme 3.
Synthesis of 2,3-Disubstituted Indolea
Scheme 2
.
Cyclization of 1a to Rhodium Benzofuran and
Trapping with D2O
When the reaction was carried out with 1a (R ) Ph) in
the presence of acrylonitrile (4a), 2,3-disubstituted benzo-
furans 5a and 6a were obtained in high yield. In this reaction,
a small amount of unsaturated product 6a was produced. The
selectivity was improved using BINAP as a ligand. As an
initial attempt, [Rh(CO)2acac] was used in an addition
reaction. However, 2a was mainly obtained even though a
trace amount of 5a was observed on 1H NMR. Other
electron-deficient alkenes could be used (Table 2). The
reaction of 1a with ethyl acrylate afforded 5c along with
a All reactions were run under the following conditions unless otherwise
noted: 7 (0.2 mmol), 4 (2.0 mmol), [Rh(cod)OH]2 (3 mol %) in dioxane (2
mL) and H2O (0.1 mL). b [Rh(cod)OH]2 (3 mol %) and BINAP (7 mol %)
were used. c An amount of 2 equiv of ethyl acrylate was used. The ratio
1
was determined by H NMR spectroscopy.
This reaction can also be adapted to the synthesis of indoles.
2-Substituted indole 8 was obtained from o-alkynyl aniline
derivative 7. In a labeling experiment, deuterium was incorpo-
(6) For reviews on rhodium-catalyzed 1,4-addition, see: (a) Fagnou, K.;
Lautens, M. Chem. ReV. 2003, 103, 169. (b) Hayashi, T.; Yamasaki, K.
Chem. ReV. 2003, 103, 2829. (c) Miura, T.; Murakami, M. Chem. Commun.
2007, 217
.
(7) For a recent example of a rhodium-catalyzed cascade reaction
consisting of ring expansion/1,4-addition: Matsuda, T.; Shigeno, M.;
(8) Lu reported that LiBr inhibited ꢀ-hydride elimination in a palladium-
catalyzed aminopalladation, addition reaction (ref 9a). In our case, there
was not an obvious effect with LiBr in the reaction.
Murakami, M. J. Am. Chem. Soc. 2007, 129, 12086
.
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Org. Lett., Vol. 11, No. 6, 2009

Table 3. Synthesis of 2,3-Disubstituted Benzofuran: Scope of o-Alkynylphenola
entry
R (1)
EWG (4)
products
% yieldb
5:6
1c
2c
3c
4
5
6
n-Bu (1b)
CN (4a)
CN (4a)
CN (4a)
COEt (4b)
COEt (4b)
COEt (4b)
COEt (4b)
5ba + 6ba
5ca + 6ca
5da + 6da
5bb
83
96
92
70
91
86
75
15:1
18:1
65:1
-
-
-
-
4-MeO-C6H4 (1c)
3-F-C6H4 (1d)
n-Bu (1b)
4-MeO-C6H4 (1c)
3-F-C6H4 (1d)
CHdCH2 (1f)
5cb
5db
5fb
7
a All reactions were run under the following conditions unless otherwise noted: 1 (0.2 mmol), 4 (2.0 mmol), [Rh(cod)OH]2 (3 mol %) in dioxane (2
mL) and H2O (0.1 mL). b Isolated yields. c [Rh(cod)OH]2 (3 mol %), BINAP (6.6 mol %) were used.
rated in the indole product using D2O. Using the same strategy
as for benzofurans, in situ trapping of the cyclized Rh-
intermediate could be carried out with electrophiles such as
acrylonitrile, ethyl vinyl ketone, and ethyl acrylate (Scheme 3).9
A plausible reaction mechanism is shown in Scheme 4.
Alkyne-coordinated rhodium A is generated from the substrate
and Rh(I). Then 3-rhodium benzofuran B is formed
benzofuran ring, the arylrhodium reacted with the tethered
R,ꢀ-unsaturated ester. The reaction of phenol 10 produced
tricyclic benzofuran 11 in 66% yield, along with protonated
product 12 in 9%.12
Scheme 5
.
Cascade Cyclization Reaction from o-Alkynylphenol
10
Scheme 4. Plausible Reaction Mechanism
In summary, we report a rhodium-catalyzed cyclization
of o-alkynylphenols and anilines followed by intermolecular
conjugate addition that succeeds with alkyl and aryl
alkynes.13 In this reaction, 2,3-disubstituted benzofurans or
indoles are obtained in one pot in good to excellent yields.
The rhodium-catalyzed reactions are convenient and atom-
economical. Further exploration of the reaction scope and
other types of cyclizations is currently under investigation.
Acknowledgment. We gratefully acknowledge NSERC
(Canada), Merck-Frosst, Otsuka Pharmaceutical Co., Ltd.
(Tokyo), and the University of Toronto for financial support.
via 5-endo cyclization. The key intermediate aryl rhodium B
then reacts with an electrophilic alkene, and after protonation,
the desired compound is obtained and Rh-hydroxide is regener-
ated.10,11 Trost proposed vinylidene intermediates in the
cycloisomerization of terminal alkynes.5 Such intermediates
are precluded in our substrates since the alkyne bears a
substituent.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Domino double intramolecular cyclization was also pos-
sible (Scheme 5). In this reaction, after construction of the
OL9001174
(11) A control experiment was conducted using the rhodium catalyst in
the presence of preformed benzofuran 2a and acrylonitrile. No addition
product was obtained, and the starting material was recovered in high yield.
(9) For a recent example of tandem intramolecular cyclization of
alkynylanilines and conjugate addition, see: (a) Pd: Shen, Z.; Lu, X
Tetrahedron 2006, 62, 10896. (b) Au: Alfonsi, M.; Arcadi, A.; Aschi, M.;
Bianchi, G.; Marinelli, F. J. Org. Chem. 2005, 70, 2265.
(10) Heating a dioxane solution of 1a and ethyl vinyl ketone at 90 °C
in the absence of the rhodium catalyst gave no 1,4-adduct product and
recovered 1a (100%).
(12) This reaction was carried out without water at 90 °C in 6 h. 11
was obtained in 11%, and 10 was recovered (49%).
(13) Following acceptance of this manuscript a recent paper appeared
on related reactions using Pd(II) catalysts: Martínez, C.; Álverez, R.
Aurrecoechea, J. M. Org. Lett. 2009, 11, 1083-1086.
Org. Lett., Vol. 11, No. 6, 2009
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