Elements of regiocontrol in palladium-catalyzed oxidative arene cross-coupling

Article abstract of DOI:10.1021/ja0745862

By changing the stoichiometric oxidant and modifying the indole N-substituent in palladium-catalyzed oxidative arene cross-coupling reactions, both C2 and C3 oxidative indole arylation can be achieved in high yield. High regioselectivity can also be achieved with the benzene component, and the use of this methodology with pyrrole substrates is illustrated. A mechanistic hypothesis for the change in C2/C3 selectivity is advanced. Copyright

Full text of DOI:10.1021/ja0745862

Published on Web 09/19/2007
Elements of Regiocontrol in Palladium-Catalyzed Oxidative Arene
Cross-Coupling
David R. Stuart, Elisia Villemure, and Keith Fagnou*
Center for Catalysis Research and InnoVation, UniVersity of Ottawa, Department of Chemistry, 10 Marie Curie,
Ottawa, Ontario, Canada K1N 6N5
Received June 22, 2007; E-mail: keith.fagnou@uottawa.ca
Table 1. Regioselectivity in Oxidative Arene Cross-Couplinga
An increasing emphasis on waste minimization has prompted
research aimed at replacing common synthetic techniques with
greener alternatives. In biaryl synthesis, direct arylation1,2 is an
emerging alternative to Suzuki and Stille couplings;3 however, a
more efficient strategy would involve the direct catalytic cross-
coupling of two arenes without recourse to stoichiometric activating
groups (eq 1).4-7 This last approach presents several new challenges,
mol %
Pdb
oxidant
(equiv)b
additive
time
(h)
%
entry
(mol %)b
indole
convc
2:3:4c
1d
10 Cu(OAc)2(3) 3-nitropyridine (10)
CsOPiv (40)
10 AgOAc (2.2) 3-nitropyridine (10)
CsOPiv (40)
10 AgOAc (2.2) 3-nitropyridine (10)
CsOPiv (40)
1a
5
24
24
100 8.9:1:0.26
32 1:4:0
78 1:8.7:0.3
2
3
1a
1b
including the avoidance of unwanted arene homocoupling and the
need to achieve/manipulate regioselectivity on both substrates.
While much has been learned about regioselectivity in catalytic
direct arene functionalizations, the ability to manipulate this
character has been achieved in only a few instances.8
Herein, we demonstrate that high regiocontrol can be acheived
to access both C3 and C2 arylindoles in Pd-catalyzed oxidative
cross-coupling reactions. We also show that regioselectivity can
occur at the benzene component, and we can validate the use of
this methodology with pyrrole substrates. These findings should
further encourage the development of these reactions as a tool for
the synthesis of biaryl molecules, and the observations regarding
regiocontrol may warrant consideration in other PdII-catalyzed
processes.9
4
5
6
7
8
9
10
5
2
20
AgOAc (3)
AgOAc (3)
none
none
none
none
none
none
none
none
1b
1b
1b
1b
1b
1b
1b
3
15
3
3
3
99
87
18
45
61
1:25:0.7
1:14:0.4
1.1:1:0
1.3:1:0
3.7:1:0
99:1:0
50
100
300
20
none
none
none
3
3
100
15
CsOAc (200)
1:99:0
a Conditions: Pd(TFA)2, oxidant, 3-nitropyridine, cesium pivalate, PivOH
(6 equiv), and 1a/b were added to a screw-capped vial followed by the
addition of benzene (30-60 equiv; see SI) and heating to 110 °C. b Relative
to 1. c Determined by GC/MS. d Microwave heating.
Scheme 1. Reactions of Pyrrolesa
Following our success with Pd-catalyzed C3-selective indole/
benzene cross-couplings involving a stoichiometric copper(II)
oxidant,6a a range of other terminal oxidants were examined (Table
1). Interestingly, AgOAc produced an inversion in selectivity
compared to Cu(OAc)2, favoring C2 arylation in a 1:4 ratio (entry
1 vs 2).10 With the goal of optimizing the reaction for C2 arylation,
we determined that removal of the additives and changing from
N-acetyl to N-pivalyl indole results in 100% conversion and a
1:25 C3/C2 ratio (entry 4). Under these conditions, 2 mol % Pd is
sufficient to achieve 87% conversion with a 1:14 C3/C2 ratio
after 15 h (entry 5). We also note the formation of some benzene
homocoupling appearing once the indole conversion exceeds 90%.
These conditions are compatible with a range of indole substrates
as illustrated in Table 2. Substituted benzenes may also be used
(entries 7-10). Importantly, high selectivity can also be obtained
for reaction at the more sterically accessible C-H bond of the
benzene component. Entries 9 and 10 illustrate the potential of this
approach; not only can high regioselectivity be achieved at both
arenes, but it can also be controlled to give a desired indole isomer.
Pyrroles can also be successfully coupled using a Pd catalyst and
a silver oxidant.11 In these cases, small amounts of pyrrole
dimerization is noticed (less than 10%), but synthetically useful
yields of the 2-phenylpyrrole products can be achieved (Scheme
1). Currently, high yields can be achieved in reactions with indole
with as few as 15 equiv of benzene, although more is commonly
employed.
a See the SI for experimental details.
The reason for the inversion in C2/C3 selectivity is a focus of
continuing investigation. The possibility of in situ indole metalation
by the CuII and AgI oxidants was ruled out by reacting the indole
with stoichiometric Cu(OAc)2 or Ag(OAc) in AcOD at 100 °C.
After 14 h of reaction time, the indole is quantitatively recovered
with no H/D exchange above that found in control experiments
performed in the absence of metals (less than 10% at C3).
More informative is the influence of Pd concentration and acetate
additives. For example, the C3 selectivity increases dramatically
when the Pd(TFA)2 loading is increased from 20 to 300 mol % in
the absence of oxidant under otherwise identical conditions (Table
9
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J. AM. CHEM. SOC. 2007, 129, 12072-12073
10.1021/ja0745862 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of the Pd-Catalyzed Indole/Benzene Cross-Couplinga
a Conditions: Pd(TFA)2 (5 mol %), AgOAc (3 equiv), PivOH (6 equiv), and the N-pivalylindole were added to a screw-capped vial followed by benzene
(approximately 60 equiv) and heating to 110 °C. b Determined by GC/MS. c Isolated yield. d Represents the ratio of C2/C3/double arylation. e Represents
the ratio of the major (isolated) isomer to other minor isomers detected by GC/MS. f 10 mol % Pd used. g Cu(OAc)2 used as the oxidant. See SI.
(2) For examples with indoles, see: (a) Deprez, N. R.; Kalyani, D.; Krause,
1, entries 6-9). Furthermore, the addition of 2 equiv of CsOAc to
reactions performed with 20 mol % Pd(TFA)2 in the absence of
A.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 4972. (b) Wang, X.;
Lane, B. S.; Sames, D. J. Am. Chem. Soc. 2005, 127, 4996. (c) Lane, B.
S.; Sames, D. Org. Lett. 2004, 6, 2897. (d) Wang, X.; Gribkov, D. V.;
Sames, D. J. Org. Chem. 2007, 72, 1476. (e) Lane, B. S.; Brown, M. A.;
Sames, D. J. Am. Chem. Soc. 2005, 127, 8050.
oxidants induces very high C2 selectivity (entry 10 vs 6).
Our rationale for the dramatic change in selectivity continues to
evolve. These studies indicate that it is the acetate base, when added
as a AgI or CsI salt, and not the metal counterion that imparts the
increased C2 selectivity to the Pd catalyst. This may be due to
carboxylate-induced cleavage of higher-order Pd clusters and the
formation of monomeric Pd species (vide infra). On the other hand,
when excess Cu(OAc)2 is added to a catalytic quantity of Pd(TFA)2,
mixed Pd-Cu clusters may be formed that exhibit pronounced C3
selectivity.12,13 The change in C3/C2 selectivity as a function of
[Pd] is indirect support for this hypothesis. At high [Pd], where
the presence of trinuclear Pd carboxylate clusters should be favored,
high C3 selectivity is observed. It is plausible that analogous mixed
Pd-Cu complexes may behave in a similar fashion.
(3) Hassan, J.; Se´vignon, M.; Gozzi, C.; Shulz, E.; Lemaire, M. Chem. ReV.
2002, 102, 1359.
(4) For recent examples of oxidative arene homocoupling, see: (a) Hull, K.
L.; Lanni, E. L.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 14047 and
refs therein. (b) Takahashi, M.; Masui, K.; Sekiguchi, H.; Kobayashi, N.;
Mori, A.; Funahashi, M.; Tamaoki, N. J. Am. Chem. Soc. 2006, 128,
10930. (c) Mukhopadhyay, S.; Rothenberg, G.; Lando, G.; Agbaria, K.;
Kazanci, M.; Sasson, Y. AdV. Synth. Catal. 2001, 343, 455. With other
catalysts: (d) Li, X.; Hewgley, J. B.; Mulrooney, C. A.; Yang, J.;
Kozlowski, M. C. J. Org. Chem. 2003, 68, 5500 and refs therein.
(5) For lead examples dealing with oxidative cross-coupling and stoichiometric
Pd, see: (a) Itahara, T. J. Chem. Soc., Chem. Commun. 1981, 254. (b)
Itahara, T. J. Org. Chem. 1985, 50, 5272.
(6) For recent Pd-catalyzed reactions, see: (a) Stuart, D. R.; Fagnou, K.
Science 2007, 317, 1172. (b) Dwight, T. A.; Rue, N. R.; Charyk, D.;
Josselyn, R.; DeBoef, B. Org. Lett. 2007, 9, 3137. (c) Li, R.; Jiang, L.;
Lu, W. Organometallics 2006, 25, 5973.
(7) (a) Smrcˇina, M.; Lorenc, M.; Hanusˇ, V.; Sedmera, P.; Kocˇovsky, P. J.
Org. Chem. 1992, 57, 1917. (b) Ding, K.; Xu, Q.; Wang, Y.; Liu, J.; Yu,
Z.; Du, B.; Wu, Y.; Koshima, H.; Matsuura, T. J. Chem. Soc., Chem.
Commun. 1997, 693.
(8) For examples where substrate or solvent modification can result in a
dramatic change in selectivity, see: (a) Grimster, N. P.; Gauntlett, C.;
Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem., Int. Ed. 2005, 44, 3125.
(b) Beck, E. M.; Grimster, N. P.; Hatley, R.; Gaunt, M. J. J. Am. Chem.
Soc. 2006, 128, 2528. See also ref 2e.
(9) For illustrative recent examples employing metal oxidants, see: (a) Chen,
X.; Li, J.-J.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc.
2006, 128, 78. (b) Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem.
Soc. 2006, 128, 12634. (c) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am.
Chem. Soc. 2006, 128, 9084. (d) Pei, T.; Wang, X.; Widenhoefer, R. A.
J. Am. Chem. Soc. 2003, 125, 648. See also refs 8a,b and 4c.
(10) A previous report describes stoichiometric Pd(OAc)2 giving a 22% yield
of the C2 isomer. In our hands, these conditions give 50-100% conversion
and a C3/C2 ratio of 1.5:1. See ref 5a.
These results point to new opportunities for control of reactivity/
selectivity in Pd-catalyzed oxidative cross-coupling reactions and
may have broader impact in PdII catalysis. They also support the
potential of this approach in the synthesis of biaryl molecules.
Acknowledgment. We thank NSERC and the University of
Ottawa for support of this work. The Research Corporation,
Boehringer Ingelheim (Laval), Merck Frosst Canada, Merck Inc.,
and Astra Zeneca Montreal are thanked for additional unrestricted
research support. D.R.S thanks NSERC for a postdoctorate scholar-
ship.
Supporting Information Available: Experimental procedures and
spectroscopic characterization of all new products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(11) For a stoichiometric precedent with similar substrates, see ref 5b.
(12) (a) Sloan, O. D.; Thornton, P. Inorg. Chim. Acta 1986, 120, 173. (b)
Brandon, R. W.; Claridge, D. V. J. Chem. Soc., Chem. Commun. 1968,
677.
(13) (a) Orito, K.; Horibata, A.; Nakamura, T.; Ushito, H.; Nagasaki, H.;
Yuguchi, M.; Yamashita, S.; Tokuda, M. J. Am. Chem. Soc. 2004, 126,
14342. (b) Chen, X.; Li, J.-J.; Hao, X. S.; Goodhue, C. E.; Yu, J.-Q. J.
Am. Chem. Soc. 2006, 128, 78.
References
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