Rhodium(III)-catalyzed intermolecular hydroarylation of alkynes

Article abstract of DOI:10.1021/ja103080d

The rhodium(III)-catalyzed hydroarylation of internal alkynes is described. Good yields are obtained for a variety of alkynes, and excellent regioselectivity is observed for unsymmetrically substituted alkynes. The reaction also gives good yields for a range of arenes. Preliminary mechanistic investigations suggest that this reaction proceeds through arene metalation with the cationic rhodium catalyst, which enables challenging intermolecular reactivity.

Full text of DOI:10.1021/ja103080d

Published on Web 05/04/2010
Rhodium(III)-Catalyzed Intermolecular Hydroarylation of Alkynes
Derek J. Schipper,* Marieke Hutchinson, and Keith Fagnou†
Centre for Catalysis Research and InnoVation, Department of Chemistry, UniVersity of Ottawa, 10 Marie Curie,
Ottawa, Ontario, Canada K1N 6N5
Received April 12, 2010; E-mail: dschi064@uottawa.ca
Table 1. Optimization of Hydroarylation Conditionsa
Transition-metal-catalyzed direct transformations of aromatic
C-H bonds represent a burgeoning field in organic chemistry
because it enables inherently efficient construction of organic
building blocks.1 Of these processes, alkyne hydroarylation has
received much attention in recent years because it allows for the
entry
solvent
acid
temp (°C)
% yieldb
atom-economical synthesis of functionalized alkenes directly from
simple arenes and alkynes.2 Hydroarylation of alkynes typically
occurs by two pathways (Scheme 1). The first proceeds through
activation of the alkyne by a cationic metal complex.2,3 The second
proceeds via activation of the arene by oxidative insertion of a
nucleophilic metal into a C-H bond.2,4 Although many intra- and
intermolecular examples have been reported, these pathways have
limited scope and utility since they usually necessitate the use of
electron-rich arenes, electron-deficient alkynes, or synthetically
restricted directing groups. Moreover, the products are often
obtained as regio- or stereoisomeric mixtures.
1
2
3
4
5
6
PhMe
PhMe
PhMe
PhMe
iPrOAc
iPrOAc
none
100
100
100
100
100
90
5
76
AcOH
PivOH
PivOH
PivOH
PivOH
90
0c
93
99 (99)
a Conditions: indole (1 equiv), alkyne (1.1 equiv), Cp*Rh(MeCN)3-
(SbF6)2 (5 mol %), and acid (5 equiv) were dissolved in the solvent and
b
heated at the indicated temperature for 15 h. 1H NMR yield of the major
product using 1,3,5-trimethoxybenzene as an internal standard. An isolated
yield is given in parentheses. c Using [Cp*RhCl2]2 as the catalyst.
Scheme 1. Intermolecular Hydroarylation of Alkynes
choice of the protecting group on indole was found to be crucial,
with N,N-dimethylcarbamoyl being optimal.9 We were pleased to
find that heating the coupling partners in toluene with the catalyst
afforded the desired product, albeit without catalyst turnover (entry
1). Superior catalytic efficiency was obtained when 5 equiv of acetic
acid were added to the reaction mixture (entry 2) and again upon
the use of pivalic acid (entry 3). Use of a related non-cationic
catalyst, [Cp*RhCl2]2,10 led to no reactivity (entry 4). A screen of
solvents revealed isopropyl acetate to be superior to toluene (entry 5).
Finally, lowering the temperature to 90 °C gave 3a in near quantitative
yield (entry 6).
Table 2 outlines the scope of the hydroarylation under our
optimized reaction conditions. Both electron-donating (3b) and
electron-withdrawing (3c, 3d) groups on the indole are tolerated,
as is a chloro-substituted substrate (3e). This catalyst system also
allows for the use of other heterocycles (3f-h), a range of different
types of directing groups (3h-k), and electron-rich (3i, 3j)11 and
electron-poor (3k) simply substituted benzenes in hydroarylation.
A range of alkynes are also compatible with the reaction, including
diaryl- (3g,k), electron-rich arene- (3l), alkenyl- (3m), cyclopropyl-
(3n), heterocyclic- (3o), and trimethylsilyl-substituted (3p) alkynes
as well as alkynes with ester (3q) and protected-alcohol (3r)
moieties.12 The dimethylcarbamoyl group can be easily removed
using KOH in EtOH/H2O at 90 °C.13
To probe the reaction mechanism, C2-deuterated 1a was
subjected to the reaction conditions (eq 1). At low conversion, no
deuterium incorporation in the product was observed.14 This
excludes the possibility of arene activation by oxidative insertion,
which should retain deuterium incorporation (Scheme 1). Also, a
decrease in deuterium incorporation in the starting material was
observed, suggesting an arene metalation/protodemetalation equi-
librium prior to reaction with the alkyne.15 Futhermore, the requisite
use of excess acid (Table 1, entry 1) suggests a protonation event
An alternative pathway is the activation of the arene with an
electrophilic metal, which could then undergo migratory insertion of
the alkyne followed by protodemetalation (Scheme 1). Although this
pathway holds promise for overcoming some of the limitations of
hydroarylation, only Pd(II) catalysis has shown efficacy with intramo-
lecular examples.5 In an elegant example, Gevorgyan reported the
hydroarylation of o-alkynyl biaryls.6 Li reported the hydroarylation
of N-arylpropiolamides under similar conditions.7 Although these
examples represent important advances, the development of novel
catalysts is still necessary to achieve elusive intermolecular reactivity.
Herein we report the Rh(III)-catalyzed intermolecular hydroarylation
of alkynes. Preliminary mechanistic investigations suggest that the
reaction proceeds through arene activation by the cationic metal
catalyst. This relatively unexplored pathway allows intermolecular
hydroarylation to proceed in high yields for a range of arenes and
internal alkynes and is highly regio- and stereoselective.
We recently reported Rh(III)-catalyzed transformations at aromatic
C-H bonds.8 Since indoles represent an important motif in medicinal
chemistry, this motif was selected along with Cp*Rh(MeCN)3(SbF6)2
and 1-phenyl-1-propyne (2a) for reaction development (Table 1). The
† Deceased November 11, 2009.
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6910 J. AM. CHEM. SOC. 2010, 132, 6910–6911
10.1021/ja103080d  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of the Rhodium-Catalyzed Hydroarylationa, b
reaction should be useful for rapid, atom-economical preparation
of organic building blocks. Furthermore, this novel reactivity for
the intermolecular hydroarylation of alkynes should have broader
implications for the development of related transformations.
Acknowledgment. We thank NSERC, the University of Ottawa,
Amgen, Eli Lilly, and Astra Zeneca for financial support. D.J.S.
thanks NSERC for a postgraduate scholarship (PGS-D). Prof. A. M.
Beauchemin and Dr. L.-C. Campeau are thanked for assistance with
manuscript preparation.
Supporting Information Available: Detailed experimental proce-
dures and characterization data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
References
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(b) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.; Pham, Q.-N.; Lazareva, A. Synlett
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Godula, K.; Sames, D. Science 2006, 312, 67. (e) Alberico, D.; Scott, M. E.;
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Aldrichimica Acta 2007, 40, 35. Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013.
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and references therein.
(3) For recent examples, see: (a) Hashimoto, T.; Izumi, T.; Kutubi, M. S.;
Kitamura, T. Tetrahedron Lett. 2010, 51, 761. (b) Menon, R. S.; Findlay,
A. D.; Bissember, A. C.; Banwell, M. G. J. Org. Chem. 2009, 74, 8901.
(c) Suarez-Pantiga, S.; Palomas, D.; Rubio, E.; Gonzalez, J. M. Angew.
Chem., Int. Ed. 2009, 48, 7857. (d) Zhang, X.; Teo, W. T.; Chan, P. W. H.
Org. Lett. 2009, 11, 4990.
(4) For recent examples, see: (a) Tsukada, N.; Mitsuboshi, T.; Setoguchi, H.;
Inoue, Y. J. Am. Chem. Soc. 2003, 125, 12102. (b) Nakao, Y.; Kanyiva,
K. S.; Oda, S.; Hiyama, T. J. Am. Chem. Soc. 2006, 128, 8146. (c) Nakao,
Y.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2008, 130, 2448. (d)
Kanyiva, K. S.; Nakao, Y.; Hiyama, T. Angew. Chem., Int. Ed. 2007, 46,
8872. (e) Lim, Y.-G.; Lee, K.-H.; Koo, B. T.; Kang, J.-B. Tetrahedron
Lett. 2001, 42, 7609. (f) Satoh, T.; Nishinaka, Y.; Miura, M.; Nomura, M.
Chem. Lett. 1999, 28, 615. (g) Kuninobu, Y.; Tokunaga, Y.; Kawata, A.;
Takai, K. J. Am. Chem. Soc. 2006, 128, 202.
a Conditions: arene (1 equiv), alkyne (1.1 equiv), Cp*Rh(MeCN)3(SbF6)2 (5
mol %), and pivalic acid (5 equiv) in iPrOAc (0.4 M) at 90 °C for 15 h.
b Isolated yields. c In 1,2-dichloroethane for 24 h. d Using 2 equiv of
arene and 1 equiv of alkyne. e Using 2.5 mol % Cp*Rh(MeCN)3(SbF6)2
in tAmOH (0.2 M) at 70 °C.
in the catalytic cycle, and the arene scope highlights the importance
of the presence of a directing group.
(5) Fujiwara reported the first hydroarylation, which was initially thought to proceed
through arene metallation. See: (a) Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura,
T.; Fujiwara, Y. Science 2000, 287, 1992. (b) Jia, C.; Lu, W.; Oyamada, J.;
Kitamura, T.; Matsuda, K.; Irie, M.; Fujiwara, Y. J. Am. Chem. Soc. 2000, 122,
7252. However, futher mechanistic studies have suggested that the reaction
proceeds through a Friedel-Crafts-type reaction of a metal-activated alkyne.
See: (c) Tunge, J. A.; Foresee, L. N. Organometallics 2005, 24, 6440. (d)
Soriano, E.; Marco-Contelles, J. Organometallics 2006, 25, 4542.
(6) (a) Chernyak, N.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 5636. (b)
Chernyak, N.; Gevorgyan, V. AdV. Synth. Catal. 2009, 351, 1101.
(7) Jiang, T.-S.; Tang, R.-Y.; Zhang, X.-G.; Li, X.-H.; Li, J.-H. J. Org. Chem.
2009, 74, 8834.
The high selectivity for syn addition renders the possibility of
alkyne activation improbable (Scheme 1).3,16 However, it is
conceivable that syn addition arises from isomerization of the trans
addition product. A control experiment in which a 1:2.2 mixture
of E and Z isomers was exposed to the standard hydroarylation
conditions showed no alkene isomerization, ruling out the possibility
of alkene isomerization under these reaction conditions.
A proposed catalytic cycle that would explain both the decrease in
deuterium incorporation and the observed alkene geometry is shown in
Figure 1. First, reversible directed metalation with the rhodium(III) catalyst
occurs, with concomitant loss of a proton.17 The alkyne can then coordinate
to the rhodium center, after which migratory insertion occurs. Finally,
protonolysis yields the product and regenerates the catalyst.
(8) (a) Guimond, N.; Fagnou, K. J. Am. Chem. Soc. 2009, 131, 12050. (b)
Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.; Fagnou, K. J. Am.
Chem. Soc. 2008, 130, 16474.
(9) For a screen of indole protecting groups, see the Supporting Information.
(10) Satoh and Miura have shown [Cp*RhCl2]2 to be a useful catalyst for the
reaction of alkynes with a range of arenes: (a) Fukutani, T.; Umeda, N.;
Hirano, K.; Satoh, T.; Miura, M. Chem. Commun. 2009, 5141. (b) Umeda,
N.; Tsurugi, H.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2008, 47,
4019. (c) Ueura, K.; Satoh, T.; Miura, M. J. Org. Chem. 2007, 72, 5362.
(11) Use of the dimethylcarbamoyl protecting group in this case led to poor
conversion to product.
(12) Under the standard reaction conditions, terminal and dialkyl alkynes afforded
only trace amounts of product.
(13) See the Supporting Information for details.
(14) Under the same reaction conditions, using 1a and PivOD resulted in
deuterium incorporation at the alkene position. A control experiment
revealed no H/D exchange at the alkene of 3a under the reaction conditions.
(15) Under the standard reaction conditions in the absence of catalyst, no
deuterium loss was observed.
(16) For an example of reactivity of a cationic metal with alkynes, see: Burns,
R. M.; Hubbard, J. L. J. Am. Chem. Soc. 1994, 116, 9514.
(17) A competition between methoxyindole 1b and nitroindole 1c revealed a preference
for the more electron-rich arene (4:1 ratio), which is consistent with C-H bond
cleavage via electrophilic activation, as previously demonstrated for related systems.
See: (a) Li, L.; Brennessel, W. W.; Jones, W. D. Organometallics 2009, 28,
3492. (b) Davies, D. L.; Donald, S. M. A.; Al-Duaij, O.; Macgregor, S. A.; Polleth,
M. J. Am. Chem. Soc. 2006, 128, 4210. (c) Davies, D. L.; Donald, S. M. A.;
Macgregor, S. A. J. Am. Chem. Soc. 2005, 127, 13754.
Figure 1. Proposed catalytic cycle.
In conclusion, we have developed an intermolecular rhodium(III)-
catalyzed hydroarylation of alkynes. The reaction is applicable
across a range of both arenes and alkynes. Consequently, this
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