The role of reversible oxidative addition in selective palladium(0)- catalyzed intramolecular cross-couplings of polyhalogenated substrates: Synthesis of brominated indoles

Article abstract of DOI:10.1021/ja1052335

A Pd(0)-catalyzed C-N bond-forming reaction leading to the synthesis of brominated indoles is described. The use of the phosphine ligand PtBu ₃ is necessary for reactivity. It is proposed that the bulky ligand serves to prevent inhibition of th

Full text of DOI:10.1021/ja1052335

Published on Web 08/03/2010
The Role of Reversible Oxidative Addition in Selective Palladium(0)-Catalyzed
Intramolecular Cross-Couplings of Polyhalogenated Substrates: Synthesis of
Brominated Indoles
Stephen G. Newman and Mark Lautens*
Department of Chemistry, UniVersity of Toronto, Toronto, Ontario, Canada M5S 3H6
Received June 15, 2010; E-mail: mlautens@chem.utoronto.ca
Scheme 2. Ligand Effect in the Synthesis of 2-Bromoindole
Abstract: A Pd(0)-catalyzed C-N bond-forming reaction leading
to the synthesis of brominated indoles is described. The use of
the phosphine ligand PtBu3 is necessary for reactivity. It is
proposed that the bulky ligand serves to prevent inhibition of the
catalyst by facilitating reversible oxidative addition into the product
C-Br bond. Intramolecular coupling of a vinyl bromide in the
presence of an aryl iodide can take place, demonstrating
unprecedented levels of selectivity.
irreversible oxidative addition of active Pd(0) into the carbon-
bromide bond of 2a to form 3 was shutting down the catalytic cycle,
varying the phosphine ligand might allow regeneration of active
Pd(0). A ligand screen was carried out, with most classes giving
only trace amounts of product 2a (Scheme 2). To our delight, when
PtBu3 (protected as the BF4 salt) was used, a 64% yield was
obtained. The reaction was further optimized by changing the base
and Pd/L ratio, and the scope was evaluated. A broad range of
electron-poor, electron-rich, and sterically crowded gem-dibro-
moolefins underwent efficient C-N bond formation to form novel
2-bromoindoles (Table 1).5,6 Remarkably, iodoaniline 1l containing
three reactiVe carbon-halide bonds could be used to afford
dihalogenated indole 2l containing two reactiVe carbon-halide
bonds. To the best of our knowledge, this is the first report of
selective cross-coupling of a vinyl bromide in the presence of an
aryl iodide.
Palladium has recently played an increasingly important role in
the synthesis of heterocycles by catalyzing C-C and C-X bond-
forming reactions.1 Most reports on this topic include a diverse
range of substrates because of the high functional group tolerance
of palladium catalysis. Notably absent in the vast majority of such
scope evaluations is the presence of polyhalogenated substrates.
This leaves a significant gap in the scope of most palladium-
catalyzed heterocycle syntheses, despite the appeal of halogenated
products.2 A plausible explanation is that the Pd(0)/Pd(II) catalytic
cycle gets terminated upon oxidative addition to a nonproductive
carbon halide. Oxidative addition is generally considered to be an
irreversible step in cross-coupling reactions, so the formed arylpalla-
dium halide is a catalytic dead end. Herein, we present our findings
on how the use of the bulky phosphine ligand PtBu3 can help overcome
this problem for the synthesis of 2-bromoindoles and other heterocycles.
Cross-coupling of a vinyl bromide in the presence of an aryl iodide is
demonstrated, illustrating the power of this method.
When studying the synthesis of indoles from gem-dibromoolefins
such as 1a, we observed that an external nucleophile (e.g., a boronic
acid) was necessary for conversion of the starting material (Scheme
1).3 Mechanistic studies suggested the intermediacy of 2-bromoin-
dole 2a, but this product was never observed directly in the reaction,
even in the absence of boronic acid. We suspected that the active
Pd(0) catalyst was undergoing irreversible oxidative addition after
the first turnover to form catalytically inactive Pd(II) species 3.
The presence of a boronic acid or similar coupling partner is
necessary to liberate active Pd(0) and achieve catalyst turnover.
To explore the involvement of arylpalladium halide 3 in the
catalytic cycle, Pd(PtBu3)2 was mixed with an excess of indole 2a
in C6D6 until the starting complex was consumed, with the
generation of proposed oxidative addition product 3a and 1 equiv
Table 1. Palladium-Catalyzed Synthesis of 2-Bromoindoles
Scheme 1. Tandem Indole Synthesis through a Brominated
Intermediate
While oxidative addition of aryl bromides is generally irrevers-
ible, an exception was discovered by Hartwig and Roy,4 who
observed that treatment of an arylpalladium bromide with an excess
of PtBu3 could induce reductive elimination to give free Pd(0). If
a Reaction conditions: 1 (0.2 mmol), Pd(OAc)2 (5 mol %), PtBu3 ·HBF4
(6 mol %), and K2CO3 (0.4 mmol) in PhMe (0.5 mL) at room temperature
for 14 h. Isolated yields are reported. b Performed on 2 mmol scale with 10
mol % ligand. c For 24 h. d Using 10 mol % ligand.
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10.1021/ja1052335  2010 American Chemical Society

C O M M U N I C A T I O N S
of PtBu3 (Scheme 3).7 Heating the reaction mixture in the presence
of excess base and 1a gave catalyst turnover, and indole 2a was
isolated in 77% yield, suggesting that 3a is a competent catalyst.
To evaluate the site selectivity of the oxidative addition of aniline
1a and indole 2a, the two were mixed with 1 equiv of Pd(PtBu3)2.
Formation of product 3a with no detectable reaction of aniline 1a
was observed, suggesting that oxidative addition preferentially occurs
into the carbon-bromine bond of 2a. These experiments support the
mechanism proposed in Scheme 4. An initial Pd(0)-catalyzed C-N
bond-forming reaction takes place to produce indole 2a,8 which then
undergoes preferential oxidative addition with Pd(0) to form Pd(II)
species 3. With most ligands, this complex is catalytically inactive. If
PtBu3 is used, free Pd(0) can be released and re-enter the catalytic
cycle. Reversible catalyst inhibition was enhanced in the synthesis of
polyhalogenated indoles 2k and 2l, which required extended reaction
times. Notably, although Hartwig published his findings in 2001, the
ability of PtBu3 to induce reductive elimination of arylpalladium
bromides has not been exploited in catalysis.9
that the origin of this effect is the reversibility of oxidative addition
into the carbon-bromine bond of the product, which has previously
been demonstrated only in stoichiometric reactions. This unique
mechanism allows for the selective cross-coupling of a vinyl bromide
in the presence of an aryl iodide. The use of PtBu3 as a ligand for
other coupling reactions of polyhalogenated substrates has been
demonstrated. Studies of the generality of this finding, analysis of other
bulky phosphine ligands, and mechanistic studies of the equilibrium
between Pd(0) and arylpalladium halide are currently underway.
Scheme 5. Selective Intramolecular Cross-Couplings Utilizing PtBu3
Scheme 3. Mechanistic Investigations
Acknowledgment. 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. We thank Johnson Matthey
for the donation of palladium catalysts. S.G.N. thanks NSERC for
a postgraduate scholarship.
To determine whether this finding was general, we explored other
intramolecular couplings of polyhalogenated substrates that our
group had previously found to be problematic. The synthesis of
dibromobenzofuran 6 had only been possible using copper catalysis
(Scheme 5).10 With Pd(OAc)2 and PtBu3 in toluene at 100 °C,
phenol 5 could now be converted to dibromobenzofuran 6 in 45%
yield. Use of similar ligands such as PCy3 and SPhos led mostly
to decomposition of the starting material.
Supporting Information Available: Experimental procedures and
spectral data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Scheme 4. Proposed Mechanism
References
(1) For an overview of the use of palladium catalysis in the synthesis of
heterocycles, see: (a) Zeni, G.; Larock, R. C. Chem. ReV. 2006, 106, 4644.
(b) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry; Pergamon:
New York, 2000. (c) Cacchi, S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873.
(2) Regioselectivity in palladium(0) oxidative additions to polyhalogenated
substrates is commonly observed when there is a strong electronic or steric
bias. For a recent review, see: Wang, J.-R.; Manabe, K. Synthesis 2009, 1405.
(3) Fang, Y.-Q.; Lautens, M. J. Org. Chem. 2008, 73, 538.
Similarly, Heck reaction of dibrominated substrate 7 led to no
coupling product under the previously optimized conditions in the
absence of an external coupling partner, presumably because of
irreversible oxidative addition.11 Use of the modified conditions
with PtBu3 allowed the formation of brominated Heck product 8
in 50% yield. Lastly, a literature search revealed a study by
Watanabe in which chloroindoles 10 and 11 could be prepared from
dichlorinated starting materials in 46 and 19% yield, respectively,
when PtBu3 was used.12 This study was published before Hartwig’s
work on stoichiometric reductive elimination, and the implication
of reversible oxidative addition was not recognized. While the yields
of these halogenated substrates were low, the sharp contrast
observed between PtBu3 and other phosphine ligands supports the
concept that the reversibility of oxidative addition plays an important
role in the palladium-catalyzed synthesis of brominated substrates.
Further understanding of this equilibrium may allow for a significant
improvement in the scope of numerous heterocycle syntheses.
In conclusion, we have demonstrated an unusual ligand effect in
the synthesis of brominated indoles. The bulky phosphine PtBu3 was
required for conversion of starting material to be observed. We propose
(4) (a) Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 1232. (b)
Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 13944. (c) Roy,
A. H.; Hartwig, J. F. Organometallics 2004, 23, 1533.
(5) While unprotected 2-bromoindoles are useful for numerous applications,
their syntheses are often difficult. See: (a) Bergman, J.; Venemalm, L. J.
Org. Chem. 1992, 57, 2495. (b) Techenor, M. S.; Trzupek, J. D.; Kastrinsky,
D. B.; Shiga, F.; Hwang, I.; Boger, D. L. J. Am. Chem. Soc. 2006, 128,
15683. There are also several bromoindole natural products. For an
overview, see: (c) Gribble, G. W. J. Nat. Prod. 1992, 55, 1353.
(6) Electron-rich 2-bromoindoles are unstable at room temperature and should
be stored in dilute Et2O under argon at-20 °C.
(7) While complex 3a could not be cleanly isolated, the chemical shift was
fully consistent with those of similar well-characterized complexes [e.g.,
the 31P chemical shifts of 3a and Pd(PtBu3)(o-tolyl)(Br) are δ 65.1 and
64.4, respectively]. See the Supporting Information and ref 4b.
(8) We believe both Z and E oxidative additions to 1a can lead to C-N bond
formation (see ref 3).
(9) The exceptionally bulky ligand tBu-Brettphos was recently used by
Buchwald to induce catalytic reductive elimination of aryl fluorides. See:
Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; Garcia-Fortanet, J.;
Kinzel, T.; Buchwald, S. L. Science 2009, 325, 1661.
(10) Newman, S. G.; Aureggi, V.; Bryan, C. S.; Lautens, M. Chem. Commun.
2009, 5236.
(11) Lautens, M.; Fang, Y.-Q. Org. Lett. 2003, 5, 3679.
(12) Watanabe, M.; Yamamoto, T.; Nishiyama, M. Angew. Chem., Int. Ed. 2000,
39, 2501.
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