Synthetic and mechanistic studies of Pd-catalyzed C-H arylation with diaryliodonium salts: Evidence for a bimetallic high oxidation state Pd intermediate

Article abstract of DOI:10.1021/ja904116k

This contribution describes the substrate scope and mechanism of Pd-catalyzed ligand-directed C-H arylation with diaryliodonium salts. This transformation was applied to the synthesis of a variety of different biaryl products, using directing groups inclu

Full text of DOI:10.1021/ja904116k

Published on Web 07/21/2009
Synthetic and Mechanistic Studies of Pd-Catalyzed C-H
Arylation with Diaryliodonium Salts: Evidence for a Bimetallic
High Oxidation State Pd Intermediate
Nicholas R. Deprez and Melanie S. Sanford*
Department of Chemistry, UniVersity of Michigan, 930 North UniVersity AVenue,
Ann Arbor, Michigan 48109
Received May 21, 2009; E-mail: mssanfor@umich.edu
Abstract: This contribution describes the substrate scope and mechanism of Pd-catalyzed ligand-directed
C-H arylation with diaryliodonium salts. This transformation was applied to the synthesis of a variety of
different biaryl products, using directing groups including pyridines, quinolines, pyrrolidinones, and
oxazolidinones. Electronically and sterically diverse aryl groups (Ar) were transferred in high yield using
iodine(III) reagents of general structure [Mes-I-Ar]BF4. Mechanistic investigations have been conducted
that establish the kinetic order of the catalytic reaction in each component, determine the resting state of
the catalyst and the iodine(III) reagent, quantify the electronic influence of the arylating reagent on the
reaction rate, and establish the intra- and intermolecular 1° H/D kinetic isotope effect. On the basis of
these studies, this transformation is proposed to proceed via turnover-limiting oxidation of the Pd dimer
[Pd(N∼C)(OAc)]2 (N∼C ) 3-methyl-2-phenylpyridine) by [Mes-I-Ph]BF4. This mechanism implicates a
bimetallic high oxidation state Pd species as a key catalytic intermediate. The significance of this and
other aspects of the proposed mechanism are discussed in detail.
Introduction
More recent efforts have begun to explore metal-catalyzed
C-H arylation as an alternative strategy for the construction
of biaryls.2-6 This approach is attractive because it allows direct
replacement of an Ar-H bond with an Ar-Ar′ bond, eliminat-
ing the need for a preinstalled functional group. In addition,
appropriate ligands can be used to direct highly site selective
C-H arylation within complex organic molecules. In recent
years, there has been a flurry of activity in this field, and ligand-
directed C-H arylation methods have been reported with
various late transition-metal catalysts.2-6
Our group has been particularly interested in developing Pd-
catalyzed ligand-directed C-H arylation reactions using
[Ar-IIII-Ar′]X reagents.5,6 These iodine(III) compounds were
selected on the basis of significant evidence that they could
Biaryls are important synthetic targets, as they serve as key
structural motifs of diverse natural products, pharmaceuticals,
agrochemicals, and conjugated materials. The most common
method for forming biaryl linkages involves transition metal-
catalyzed cross coupling (e.g., Suzuki-Miyaura, Stille, Hiyama,
Sonogashira, Kumada, and Negishi reactions).1 While these
transformations have found widespread application, they suffer
from the disadvantage that they require the use of two
prefunctionalized starting materials. As such, each coupling
reagent must be independently prepared, which adds one or more
additional steps to a synthetic sequence.
(1) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b) Farina,
V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1. (c)
Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (d) Suzuki, A.
J. Organomet. Chem. 1999, 576, 147. (e) Beletskaya, I. P.; Cheprakov,
A. V. Chem. ReV. 2000, 100, 3009. (f) Kotha, S.; Lahiri, K.; Kashinath,
D. Tetrahedron 2002, 58, 9633. (g) Denmark, S. E.; Sweis, R. F. Acc.
Chem. Res. 2002, 35, 835. (h) Muci, A. R.; Buchwald, S. L. Top.
Curr. Chem. 2002, 219, 131. (i) Negishi, E.; Anastasia, L. Chem. ReV.
2003, 103, 1979.
(3) For examples of ligand-directed Ar-H oxidative coupling, see: (a)
Hull, K. L.; Lanni, E. L.; Sanford, M. S. J. Am. Chem. Soc. 2006,
128, 14047. (b) Xia, J. B.; You, S. L. Organometallics 2007, 26, 4869.
(c) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904.
(d) Li, B. J.; Tian, S. L.; Fang, Z.; Shi, Z. J. Angew. Chem., Int. Ed.
2008, 47, 1115. (e) Brasche, G.; Garc´ıa-Fortanet, J.; Buchwald, S. L.
Org. Lett. 2008, 10, 2207.
(4) For other proposals of Pd-catalyzed ligand-directed C-H arylation
via a PdII/IV mechanism, see ref 5a and: (a) Shabashov, D.; Daugulis,
O. Org. Lett. 2005, 7, 3657. (b) Zaitsev, V. G.; Shabashov, D.;
Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154. (c) Reddy, B. V. S.;
Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8, 3391. (d) Giri, R.;
Maugel, N.; Li, J. J.; Wang, D. H.; Breazzano, S. P.; Saunders, L. B.;
Yu, J. Q. J. Am. Chem. Soc. 2007, 129, 3510. (e) Chiong, H. A.; Pham,
Q. N.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 9879. (f)
Thirunavukkarasu, V. S.; Parthasarathy, K.; Cheng, C. H. Angew.
Chem., Int. Ed. 2008, 47, 9462. (g) Yang, F.; Wu, Y.; Zhu, Z.; Zhang,
J.; Li, Y. Tetrahedron 2008, 64, 6782. (h) Yang, F.; Wu, Y.; Li, Y.;
Wang, B.; Zhang, J. Tetrahedron 2009, 65, 914.
(2) For recent reviews that discuss C-H arylation, see: (a) Campeau, L. C.;
Fagnou, K. Chem. Commun. 2006, 1253. (b) Daugulis, O.; Zaitsev,
V. G.; Shabashov, D.; Pham, Q. N.; Lazareva, A. Synlett 2006, 3382.
(c) Yu, J. Q.; Giri, R.; Chen, X. Org. Biomol. Chem. 2006, 4, 4041.
(d) Godula, K.; Sames, D. Science 2006, 312, 67. (e) Alberico, D.;
Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174. (f) Beccalli,
E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. ReV. 2007,
107, 5318. (g) Ackermann, L. Synlett 2007, 507. (h) Fairlamb, I. J. S.
Chem. Soc. ReV. 2007, 36, 1036. (i) Campeau, L. C.; Fagnou, K. Chem.
Soc. ReV. 2007, 36, 1058. (j) Catellani, M.; Motti, E.; Della Ca, N.
Acc. Chem. Res. 2008, 41, 1512. (k) Kakiuchi, F.; Kochi, T. Synthesis
2008, 3013. (l) Li, B. J.; Yand, S. D.; Shi, Z. J. Synlett 2008, 949.
(m) McGlacken, G. P.; Bateman, L. M. Chem. Soc. ReV. 2009, DOI:
10.1039/b805701j.
(5) (a) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am.
Chem. Soc. 2005, 127, 7330. (b) Deprez, N. R.; Kalyani, D.; Sanford,
M. S. J. Am. Chem. Soc. 2006, 128, 4972.
9
11234 J. AM. CHEM. SOC. 2009, 131, 11234–11241
10.1021/ja904116k CCC: $40.75  2009 American Chemical Society

Pd-Catalyzed C-H Arylation with Diaryliodonium Salts
A R T I C L E S
a
Table 1. Products of Pd-Catalyzed Directed C-H Phenylation with [Ph2I]BF4
a Conditions: 1 equiv of substrate, 1.1-2.5 equiv of [Ph2I]BF4, 5 mol % of Pd(OAc)2 in AcOH, AcOH/Ac2O, benzene, or toluene, 100 °C, 8-24 h.
b The balance of material was starting material (entry 11) or a mixture of starting material and diarylated product (entries 3 and 6). c Conditions: 2 equiv
of 8-methylquinoline, 1 equiv of [Ph2I]BF4. d Approximately 16% of the product in entry 5 was formed in the absence of Pd(OAc)2. e 1.2-2 equiv of
NaHCO3 was added.
promote biaryl formation via an unusual PdII/IV catalytic cycle.7,8
We anticipated that a PdII/IV pathway for C-H arylation would
be highly complementary to related reactions in the literature,
particularly those involving more common Pd0/II mechanisms.
For example, PdII/IV sequences should tolerate important func-
tional groups (e.g., aryl halides and enolizable ketones) that can
be reactive with the low-valent Pd intermediates and/or strong
bases often required in Pd0/II processes. In addition, high
oxidation state Pd species are known to be stable toward air
and moisture,7,8 obviating the need for special glassware and/
or for rigorous purification of solvents and reagents. Finally,
since PdII/IV-catalyzed reactions remain relatively rare,2,4-8 we
reasoned that mechanistic studies could provide novel insights
that might be broadly applicable to this class of transformations.
We report herein a detailed investigation of the substrate
scope and mechanism of Pd(OAc)2-catalyzed ligand-directed
C-H arylation with [Ar-I-Ar′]BF4.5a Studies of reaction order
in each component, Hammett analysis, kinetic isotope effect
data, and equilibrium investigations have all been used to
interrogate the resting state of the catalyst and the oxidant under
the reaction conditions. These investigations provide strong
evidence for oxidation as the turnover-limiting step and suggest
the formation of a dimeric high oxidation state Pd complex as
a key catalytic intermediate. The potential implications of these
findings are discussed.
Results and Discussion
Synthetic Scope. Initial studies examined the Pd(OAc)2-
catalyzed ortho-phenylation of 3-methyl-2-phenylpyridine (1)
with the hypervalent iodine reagent [Ph2I]BF4.5a This reaction
afforded the monophenylated product 2 in a variety of common
solvents, with the optimal conditions being 1.1 equiv of
[Ph2I]BF4 and 5 mol % of Pd(OAc)2 at 100 °C in AcOH (eq
1). Notably, this reaction proceeded efficiently in the presence
of ambient moisture and air, and no special purification of
solvents or reagents was required.
Numerous directing groups, including pyridines, quinolines,
pyrrolidinones, and oxazolidinones, were also effective at
promoting both aromatic and benzylic C-H phenylation with
[Ph2I]BF4 (Table 1).5a This transformation tolerated the presence
of enolizable ketones, aldehydes, ethers, amides, benzylic
hydrogens, and aryl halides within the organic substrate. Good
to excellent yields were obtained regardless of the electronic
nature of the aromatic compound. Further, excellent (>20:1) site
selectivity was observed when a meta-substituent was present
on the arene undergoing functionalization.9
To further expand the utility of this methodology, we explored
the installation of diverse arenes (Ar). We initially reasoned
that selective transfer of different aryl groups might be achieved
based on electronic preferences, and thus, a series of electroni-
cally unsymmetrical iodine(III) reagents [Ph-I-p-XC6H4]BF4
was examined. As summarized in Table 2, these reagents
underwent preferential transfer of the most electron-deficient
aromatic group; however, the levels of selectivity were only
modest, with ratios of 2:2-Ar ranging from 2.6:1 to 1:0.31.
(6) For other examples of the use of [Ar2I]X in C-H arylation, see: (a)
Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int. Ed. 2005, 44, 4046.
(b) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc.
2008, 130, 8172. (c) Phipps, R. J.; Gaunt, M. J. Science 2009, 323,
1593.
(7) (a) Bayler, A.; Canty, A. J.; Ryan, J. H.; Skelton, B. W.; White, A. H.
Inorg. Chem. Commun. 2000, 3, 575. (b) Canty, A. J.; Rodemann, T.
Inorg. Chem. Commun. 2003, 6, 1382. (c) Canty, A. J.; Patel, J.;
Rodemann, T.; Ryan, J. H.; Skelton, B. W.; White, A. H. Organo-
metallics 2004, 23, 3466. (d) Canty, A. J.; Rodemann, T.; Skelton,
B. W.; White, A. H. Inorg. Chem. Commun. 2005, 8, 55. (e) Canty,
A. J.; Rodemann, T.; Skelton, B. W.; White, A. H. Organometallics
2006, 25, 3996. (f) Chaudhuri, P. D.; Guo, R.; Malinakova, H. C. J.
Organomet. Chem. 2007, 693, 567.
(8) For other examples of the oxidation of PdII to PdIV with an iodine(III)
reagent, see: (a) Lagunas, M. C.; Gossage, R. A.; Spek, A. L.; van
Koten, G. Organometallics 1998, 17, 731. (b) Dick, A. R.; Kampf,
J. W.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 12790. (c)
Whitfield, S. R.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 15142.
(d) Racowski, J. M.; Dick, A. R.; Sanford, M. S. J. Am. Chem. Soc.
2009, ASAP article.
(9) Kalyani, D.; Sanford, M. S. Org. Lett. 2005, 7, 4149.
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A R T I C L E S
Deprez and Sanford
Table 2. Arylation of 3-Methyl-2-phenylpyridine
Table 4. Pd-Catalyzed Arylation of 2-Aryl Pyrrolidinones with
[Ar-I-Ar]BF4
entry
X
2:2-Ar
entry
X
Y
Z
yield (%)
1
2
3
4
5
CF3
F
CI
CH3
OMe
2.6 : 1
1 : 0.33
1 : 0.83
1 : 0.71
1 : 0.31
1
2
3
Me
H
Me
H
CF3
H
MeO
MeO
H
83
84
81
Scheme 1. Originally Proposed Catalytic Cycle for Pd-Catalyzed
C-H Arylation5a
Table 3. Pd-Catalyzed Arylation of 3-Methyl-2-Arylpyridines with
[Mes-I-Ar]BF4
entry
W
X
Y
Z
yield (%)
1
2
3
4
5
6
7
8
H
CF3
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
85
87
88
83
Cl
Me
OMe
C(O)Me
H
H
H
CF3
Cl
F
Me
OMe
84
81a
81
[Ph2I]BF4 cleanly afforded the ortho-arylated product 2 (eq 2).5a
In contrast, more traditional Pd0/II electrophiles like PhI and PhOTf
were ineffective phenylating reagents under both catalytic and
stoichiometric reaction conditions. Finally, Canty and Malinakova
have both demonstrated the stoichiometric oxidation of PdII model
complexes with [Ar2I]X reagents to form observable monomeric
PdIV species.7 On the basis of all of these results, the general
catalytic cycle shown in Scheme 1 was proposed, involving (i)
ligand-directed C-H activation to afford palladacycle A, (ii)
oxidation of A with [Ph2I]BF4 to generate a PdIV intermediate of
general structure B, and finally, (iii) C-C bond-forming reductive
elimination to afford the arylated product 2.
C(O)Me
CHO
H
H
H
H
H
H
81
88
72
9
H
H
10
11
12
13
14
15
OMe
OMe
OMe
OMe
OMe
81b
79b
79b
78b
56b,c
a Reaction carried out at 120 °C. b Traces of the Mes addition
product were observed, but selectivity was generally >12:1. See
Supporting Information for further details. c With 2 equiv of [Mes-I-
(p-MeOC6H4)]BF4.
We next sought to sterically differentiate the two Ar groups
on iodine(III), reasoning that smaller groups should transfer
more rapidly. Gratifyingly, the mesityl/aryl-substituted reagents
[Mes-I-Ar]BF4 reacted to transfer the smaller Ar group with
high selectivity. As summarized in Tables 3 and 4, pyridine and
pyrrolidinone products containing both electron-rich and electron-
deficient Ar could be prepared in high yield using these reagents.
Many substituents were tolerated on the aryl ring being transferred,
including enolizable ketones, ethers, benzylic hydrogens, and
halogens. Further, these reagents were effective for the selective
installation of relatively large aryl groups such as o-tolyl.
Mechanistic Investigations. We next sought to gain a detailed
mechanistic understanding of this Pd-catalyzed C-H arylation.
Our previous investigations showed that the reaction is unaf-
fected by the addition of 500 equiv of Hg0 or 25 mol % of the
free radical inhibitors MEHQ and galvinoxyl.5a These results
suggest against mechanisms involving palladium nanoparticles10
or free radical intermediates.11 In addition, palladacycle 3 was
shown to be an effective catalyst, with a comparable kinetic profile
to Pd(OAc)2. Further, the stoichiometric reaction between 3 and
These preliminary studies left several key outstanding ques-
tions regarding the C-H arylation mechanism. For example,
the turnover-limiting step of this catalytic cycle remained to be
established. In addition, detailed information about the ligand
environment of the proposed PdIV intermediate B was not
available from the initial investigations. Finally, the effect of
electronic modification of the oxidant on the rates of these reactions
was poorly understood. To gain further mechanistic insights, we
(10) Heck reactions catalyzed by palladacycles were originally proposed
to proceed via a PdII/IV catalytic cycle; however, more recent studies
have shown the reactions are most likely catalyzed by Pd0 nanopar-
ticles. For a review, see: Weck, M.; Jones, C. W. Inorg. Chem. 2007,
46, 1865.
(11) Kraatz, H. B.; van der Boom, M. E.; Ben-David, Y.; Milstein, D. Isr.
J. Chem 2001, 41, 163.
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Pd-Catalyzed C-H Arylation with Diaryliodonium Salts
A R T I C L E S
Figure 2. Plot of initial rate (∆[2]/∆t) versus [Pd]2 showing second-order
kinetics in [Pd].
Figure 1. Plot of initial rate (∆[2]/∆t) versus [IIII] showing first-order
kinetics in IIII reagent.
have undertaken detailed studies to establish (1) the kinetic order
in each component of the catalytic reaction, (2) the resting state of
the catalyst and iodonium reagent, (3) the electronic influence of
the iodonium reagent on the reaction rate, and (4) the intra- and
intermolecular 1° H/D kinetic isotope effects.
Kinetic Order of the Reaction. We first sought to determine
the turnover-limiting step of this transformation by establishing
the kinetic order of C-H arylation in each reaction component.
These studies focused on the Pd(OAc)2-catalyzed ortho-pheny-
lation of 3-methyl-2-phenylpyridine (1) with [Mes-I-Ph]BF4
(4).12 We first examined the order of this transformation in the
IIII reagent by combining 3-methyl-2-phenylpyridine (250 mM),
Pd(OAc)2 (5 mM), and varying concentrations of 4 (75.2 to
175.2 mM) in AcOH at 110 °C. The reactions were monitored
by gas chromatography, and the initial rates method was used
to determine the rate at each [IIII]. As shown in Figure 1, a plot
of initial reaction rate (∆[2]/∆t) versus [IIII] was linear, indicating
a first-order dependence on the IIII reagent.13 This result suggests
that the iodine(III) oxidant is involved in the turnover-limiting
step. Notably, this is in contrast to most other Pd-catalyzed
ligand-directed C-H functionalization reactions, where cyclo-
palladation is typically rate limiting.14
The order in [Pd] was next determined using an analogous
procedure, with 3-methyl-2-phenylpyridine (250 mM),
[Mes-I-Ph]BF4 (100 mM), and varying concentrations of
[Pd(OAc)2] (3.8 to 10 mM) in AcOH at 110 °C.12 The data
from these experiments were subjected to a nonlinear least-
squares fit to the equation: f(x) ) a[Pd]n. This fit provided an
order (n) of 2.09 ( 0.08 (Supporting Information, Figure S7),
which was also reflected in a linear plot of initial rate versus
[Pd]2 (Figure 2). This second-order dependence on [Pd] is
consistent with a monomeric catalyst resting state that is in
equilibrium with a dimeric active catalyst (Vide infra).
Figure 3. Plot of initial rate (∆[2]/∆t) versus [1]-3 showing inverse third-
order kinetics in 1.
Finally, the order of the reaction in 3-methyl-2-phenylpyridine
(1) was examined, using [Mes-I-Ph]BF4 (100 mM) and
Pd(OAc)2 (5 mM) along with [1] ranging from 202 to 304 mM
in AcOH at 110 °C.12 Qualitative experiments revealed that the
reaction rate slowed dramatically with increasing [1], suggesting
an inverse order dependence on the substrate. The quantitative
rate data (initial rate versus [1]) were subjected to a nonlinear
least-squares fit to the equation: f(x) ) a[1]n, which revealed
an inverse third-order dependence on 1 (n ) -3.1 ( 0.2,
Supporting Information, Figure S10). As shown in Figure 3,
this is also reflected in the linear fit of the plot of initial rate
versus [1]-3. This result indicates that 3 equiv of 1 must be lost
(14) (a) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer,
P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am. Chem. Soc.
2002, 124, 1586. (b) Zaitsev, V. G.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 4156. (c) Giri, R.; Chen, X.; Yu, J. Q. Angew. Chem., Int.
Ed. 2005, 44, 2112. (d) Wang, D. H.; Hao, X. S.; Wu, D. F.; Yu,
J. Q. Org. Lett. 2006, 8, 3387. (e) Chen, X.; Goodhue, C. E.; Yu,
J. Q. J. Am. Chem. Soc, 2006, 128, 12634. (f) Chiong, H. A.; Pham,
Q. N.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 9879. (g) Xia, J. B.;
You, S. L. Organometallics 2007, 26, 4869. (h) Desai, L. V.; Stowers,
K. J.; Sanford, M. S. J. Am. Chem. Soc. 2008, 130, 13285.
(12) All of the order studies were conducted under conditions where [1] >
([4] + [Pd]). When [1] < ([4] + [Pd]), the kinetics become much
more complex, and the order in [1] deviates from inverse third order
(see Supporting Information p S16). This is expected based on the
proposed mechanism, since under these conditions, the resting state
of the oxidant is a mixture of 8 and 4.
(13) Further confirmation of a first order dependence was provided by an
non-linear least squares fit to the eq: f(x) ) a[4]n. This provided n )
1.12 ( 0.08 and a ) 6 ( 1 × 10-4
.
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J. AM. CHEM. SOC. VOL. 131, NO. 31, 2009 11237

A R T I C L E S
Deprez and Sanford
odonium salts.16 In a particularly relevant example, Ochiai has
Scheme 2. Observation of 7 Under the Catalytic Reaction
Conditions
1
shown by H NMR spectroscopy that [Ph2I]BF4 forms a 1:1
complex with pyridine (Keq ) 20.2 M-1 at 24 °C in CH2Cl2).16d
Discrete “bound” and “free” adducts were not observed due to
fast exchange on the NMR time scale. Instead, the binding
interaction was monitored by changes in the chemical shifts
associated with pyridine resonances at varying relative concen-
trations of pyridine and [Ph2I]BF4.
We conducted an analogous set of studies to examine the
interaction between 1 and [Mes-I-Ph]BF4 (4) under our
catalytic conditions (110 °C in AcOH). First, we used a Job
plot to establish the stoichiometry of complexation. A series of
solutions with a constant total concentration ([1] + [4] ) 23.6
mM in CD3CO2D), but with varied mole fractions of the two
1
components, were examined by H NMR spectroscopy at 110
°C.17 The chemical shift of H(4) of 1 moved downfield as the
mole fraction of 4 increased, and the change in chemical shift
relative to free 1 (∆δΗ(4)) was used to construct a Job plot
(Figure 4). This plot showed a maximum at ꢀ ) 0.5, indicating
that complexation between 1 and 4 occurs with a 1:1
stoichiometry.18,19 These data implicate the formation of iodi-
ne(III) adduct 8 under the catalytic reaction conditions (eq 4).
Figure 4. Job plot of ∆δH(4) ·ꢀ (mole fraction of substrate) versus ꢀ at 110 °C.
in order to progress from the resting state to the transition state
of the reaction.
The equilibrium constant for the reaction in eq 4 was next
established by measuring δH(4) while titrating in increasing
[Mes-I-Ph]BF4 in CD3CO2D at 110 °C (Figure 5). The
resulting curve was fitted to a 1:1 binding model,20 and the
nonlinear least-squares fit afforded an equilibrium constant of
111 ( 18 M-1. This value of Keq is consistent with complex 8
(eq 4) as the resting state of the oxidant under the catalytic
conditions.12
Catalyst Resting State. We next sought to probe the resting
state of the [Pd] under the reaction conditions. Since complex
3 was previously shown to serve as an effective catalyst for
C-H arylation and underwent stoichiometric reaction with
[Ph2I]BF4 to afford 2 (eq 2),5a we hypothesized that 3 might be
a catalytic intermediate. When dimer 3 was combined with 20
equiv of 1 at 110 °C in AcOH (mimicking the catalytic reaction
conditions, but in the absence of oxidant), only the correspond-
ing monomer 7 (which shows a diagnostic broad resonance at
1
6.2 ppm) was observed by H NMR spectroscopy (Scheme 2
and Supporting Information, Figure S19).15 This is consistent
with a literature report by Ryabov showing that the closely
related dimer 5 reacts with 2-phenylpyridine to form monomer
6 with Keq of 33 ( 2 M-1 at 70 °C in AcOH (eq 3).15 When
the catalytic reaction between Pd(OAc)2 (0.0027 mmol), 1 (0.05
mmol), and 4 (0.025 mmol) was monitored by 1H NMR
spectroscopy at 110 °C, an identical broad signal at 6.2 ppm
was observed throughout this transformation (Scheme 2 and
Supporting Information, Figure S19). These experiments col-
lectively suggest that the resting state of the Pd during the
catalytic cycle is monomer 7 (Scheme 2).
Figure 5. δH(4) as a function of [IIII] at 110 °C. The line depicts a
nonlinear least-squares fit to a 1:1 binding model, which showed that Keq
) 111 ( 18 M-1
.
Hammett Study. The rate of the Pd(OAc)2-catalyzed reaction
between 3-methyl-2-phenylpyridine (1) and [Mes-I-p-
XC6H4]BF4 was next examined as a function of the substituent
Oxidant Resting State. Several literature reports have dem-
onstrated that pyridine derivatives can coordinate to diaryli-
(15) Ryabov, A. D. Inorg. Chem. 1987, 26, 1252.
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Pd-Catalyzed C-H Arylation with Diaryliodonium Salts
A R T I C L E S
Scheme 3. Proposed Mechanism for C-H Arylation of 3-Methyl-2-phenylpyridine
X. Substrate 1 (100 mM) was combined with Pd(OAc)2 (5 mM)
and the appropriate oxidant [Mes-I-(p-XC6H4)]BF4 (200 mM)
in AcOH at 80 °C, and the initial reaction rate was measured
with each iodine(III) reagent. A Hammett plot of the resulting
data provided a F value of +1.7 ( 0.2 (Figure 6). This indicates
that C-H arylation is strongly accelerated by electron-
withdrawing groups on the iodine(III) reagent.21
were determined. As shown in eq 5, the intramolecular 1° kH/
kD for substrate 1-d4 was 2.5 ( 0.2, based on 1H NMR
spectroscopic analysis of the isolated product. This is similar
to that seen in other Pd-catalyzed ligand-directed C-H func-
tionalization reactions, which typically show 1° intramolecular
KIE values ranging from 2.2 to 6.7.22
The intermolecular kinetic isotope effect was determined by
comparing the initial reaction rate of 3-methyl-2-phenylpyridine
(1) to that of 3-methyl-2-(d5)-phenylpyridine (1-d5) (eq 6). In
this system, kH/kD was determined to be 1. The observed lack
of an intermolecular KIE implies that C-H bond cleavage
occurs after the rate-determining step of the reaction.
Figure 6. Hammett plot for Pd-Catalyzed C-H arylation of 1 with
[Mes-I-Ar]BF4.
Kinetic Isotope Effect. Finally, the 1° intra- and intermolecular
kinetic isotope effects (kH/kD) for this C-H phenylation reaction
(16) (a) Weiss, R.; Seubert, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 891.
(b) Zhdankin, V. V.; Koposov, A. Y.; Yashin, N. V. Tetrahedron Lett.
2002, 43, 5735. (c) Ochiai, M.; Suefuji, T.; Miyamoto, K.; Shiro, M.
Chem. Commun. 2003, 1438. (d) Suefuji, T.; Shiro, M.; Yamaguchi,
K.; Ochiai, M. Heterocycles 2006, 67, 391.
(21) Ansyln, E. K.; Dougherty, D. A. Modern Physical Organic Chemistry;
University Science Books: Sausalito, CA, 2006; p 447.
(17) A Job plot at 80 °C also displayed a maximum at 0.5 and is available
in the Supporting Information.
(22) For recent selected examples of intramolecular kinetic isotope effects
in Pd-catalyzed ligand-directed C-H functionalization reactions, see
refs 14b, d, e, and f as well as: (a) Cai, G.; Fu, Y.; Li, Y.; Wan, X.;
Shi, Z. J. Am. Chem. Soc. 2007, 129, 7666. (b) Shi, Z.; Li, B.; Wan,
X.; Cheng, J.; Fang, Z.; Cao, B.; Qin, C.; Wang, Y. Angew. Chem.,
Int. Ed. 2007, 46, 5554. (c) Li, J. J.; Giri, R.; Yu, J. Q. Tetrahedron
2008, 64, 6979. (d) Kirchberg, S.; Vogler, T.; Studer, A. Synlett 2008,
2841.
(18) Blanda, M. T.; Horner, J. H.; Newcomb, M. J. Org. Chem. 1989, 54,
4626.
(19) Job, A. Ann. Chem. 1928, 9, 113.
(20) (a) Funasaki, N.; Ishikawa, S.; Neya, S. Bull. Chem. Soc. Jpn. 2002,
75, 719. (b) Bisson, A. P.; Hunter, C. A.; Morales, J. C.; Young, K.
Chem. Eur. J. 1998, 4, 845. (c) Fielding, L. Tetrahedron 2000, 56,
6151.
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A R T I C L E S
Deprez and Sanford
Summary of Mechanistic Data. The data assembled above
allow us to formulate a complete mechanistic picture of the
catalytic C-H arylation reaction. As shown in Scheme 3, we
propose that the resting state of the catalyst is the monomeric
PdII species 7, and the resting state of the oxidant is the pyridine-
coordinated iodine(III) reagent 8. This proposal is consistent
both with the values of Keq from eq 3 and Figure 5, as well as
with the direct observation of 7 under the catalytic reaction
conditions (Scheme 2). To enter the catalytic cycle, free oxidant
4 is generated by dissociation of 1 equiv of 1 from 8. In addition,
the Pd dimer 3 is formed by the combination of 2 equiv of
monomer 7, with concomitant dissociation of 2 equiv of 1. The
reaction between 3 and 4 to afford high oxidation state dimeric
intermediate 9 is then proposed to be the turnover-limiting step
of the catalytic cycle, which is followed by C-C bond
formation, ligand exchange, and cyclometalation to return to
the catalyst resting state. The rate equation shown in eq 7 can
be derived on the basis of the proposed mechanism, and
application of the pre-equilibrium approximation for [3] and
[4] affords the rate expression shown in eq 8.
Figure 8. Related PdIII∼PdIII and PtIII∼PtIII complexes from the literature.
acetate-bridged PdII complexes with PhICl2 (Figure 8).25-27
Similar PtIII-PtIII dimers have also been formed by reaction of
monomeric PtII starting materials with hypervalent iodine(III)
reagents, including PhICl2,28 PhI(OAc)2 (10),29 and [Ph-I-R]OTf
(R ) CCSi(Me)3) (12) (Figure 8).30
rate ) k3[3][4]
k1k2k3[7]2[8]
(7)
rate )
(8)
k-1k-2[1]3
Notably, if intermediate 9 is a PdIII-PdIII dimer (9b), this
complex could undergo direct C-C bond-forming reductive
elimination (similar to that depicted in Scheme 3)27 or could
disproportionate to PdIV and PdII species (either acetate-bridged
or unbridged) prior to C-C coupling from PdIV.28,30 In both
formulations of the proposed intermediate (9a and 9b), the
second Pd center effectively serves as an ancillary ligand to
the metal complex that mediates C-C bond formation. As such,
an attractive strategy for the development of second-generation
C-H arylation catalysts with improved activity and selectivity
would involve tuning this organometallic ligand.
The proposed mechanism is supported by all of the data
presented above. For example, eq 8 predicts that the reaction
will be first order in [IIII], second order in [Pd], and inverse
third order in 1, consistent with the experimental observations.
In addition, the Hammett F value of 1.7 ( 0.2 is consistent
with oxidative addition as the turnover-limiting step. This value
is comparable to that observed in Pd0/II oxidative addition
reactions.23 Finally, the observation of an intra- but not an
intermolecular kinetic isotope effect is consistent with C-H
activation occurring during the catalytic cycle but after the
turnover-limiting step.
It is also interesting to compare the turnover-limiting step of
C-H arylation with [Ar2I]BF4 to that of C-H acetoxylation
with PhI(OAc)2.14h Remarkably, although both reactions utilize
an iodine(III) oxidant and proceed under nearly identical
conditions (catalytic Pd(OAc)2, 100-110 °C in AcOH), the
turnover-limiting steps are different. As described above, C-H
arylation involves turnover-limiting oxidation. In contrast, Pd-
catalyzed C-H acetoxylation shows a zero-order dependence
on PhI(OAc)2 and a large intermolecular 1° H/D kinetic isotope
effect, suggesting that cyclopalladation is the turnover-limiting
step.31 These results have important implications for the
application of iodine(III) reagents in other Pd-catalyzed reac-
tions. For example, PhI(OAc)2 has been used to intercept Pd-
alkyl intermediates formed via aminopalladation,32 acetoxyp-
alladation,33 or carbopalladation34 to generate diverse products.
There are several notable features of the mechanism proposed
in Scheme 3. First, the observed second-order dependence on
[Pd] implicates bimetallic acetate-bridged Pd complex 9 as a
key intermediate in this process. This dimer can be viewed as
a PdIV species attached to a bridging PdII complex (as drawn in
Scheme 3 and also 9a in Figure 7). Alternatively, if there is
significant bonding between the two Pd centers, this may be
considered a PdIII-PdIII dimer (9b, Figure 7). This latter
(25) Cotton, F. A.; Koshevoy, I. O.; Lahuerta, P.; Murillo, C. A.; Sanau,
M.; Ubeda, M. A.; Zhao, Q. J. Am. Chem. Soc. 2006, 128, 13674.
(26) Cotton, F. A.; Gu, J.; Murillo, C. A.; Timmons, D. J. J. Am. Chem.
Soc. 1998, 120, 13280.
Figure 7. Two possible formulations for intermediate 9: PdIV/PdII (9a)
versus PdIII∼PdIII (9b).
(27) Powers, D. C.; Ritter, T. Nat. Chem. 2009, 1, 302.
(28) Baxter, L. A. M.; Heath, G. A.; Raptis, R. G.; Willis, A. C. J. Am.
Chem. Soc. 1992, 114, 6944.
possibility is particularly interesting given the proximity of the
palladium centers in crystal structures of 5.24 In addition, Cotton
and more recently Ritter have reported the formation of related
symmetrical PdIII-PdIII dimers 11 and 13 by oxidation of
(29) Dick, A. R.; Kampf, J. W.; Sanford, M. S. Organometallics 2005, 24,
482.
(30) Canty, A. J.; Gardiner, M. G.; Jones, R. C.; Rodemann, T.; Sharma,
M. J. Am. Chem. Soc. 2009, 131, 7236.
(23) Stille, J. K.; Lau, K. S. Y. Acc. Chem. Res. 1977, 10, 434.
(24) (a) Thu, H. Y.; Yu, W. Y.; Che, C. M. J. Am. Chem. Soc. 2006, 128,
9048. (b) Kim, M.; Taylor, T. J.; Gabba¨ı, F. P. J. Am. Chem. Soc.
2008, 130, 6332.
(31) Our initial report on the mechanism of Pd-catalyzed C-H acetoxylation
used benzylpyridines as substrates (ref 14h). However, recent studies
have shown analogous order and KIE data with 2-phenylpyridine
derivatives. Stowers, K. J.; Sanford, M. S. manuscript in preparation.
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11240 J. AM. CHEM. SOC. VOL. 131, NO. 31, 2009

Pd-Catalyzed C-H Arylation with Diaryliodonium Salts
A R T I C L E S
A key feature of these transformations is that the oxidation of
PdII by PhI(OAc)2 is faster than competing ꢁ-hydride elimina-
tion. The current results suggest that analogous oxidations of
PdII-alkyl species with [Ar2I]BF4 will be significantly slower,
which may result in undesired competing processes. Thus, we
anticipate that new and more reactive arylating reagents may
be required to access chemistry similar to that of PhI(OAc)2.
can potentially be viewed as a mixed-valent PdIV/PdII species
or as a PdIII∼PdIII dimer. The observed kinetics have important
implications for future applications of this chemistry; for
example, the second-order dependence on catalyst and inverse
third-order dependence on substrate suggest that these trans-
formations will be highly sensitive to reaction concentration and
stoichiometry, an important consideration upon scale-up or
-down. In addition, the intermediacy of the dimeric species 3
and 9 suggests that catalyst activity and selectivity may be tuned
by modification of the tethered metal center. Finally, these
investigations raise the larger question of whether similar
dimeric intermediates may be involved in other Pd-catalyzed
C-H functionalization reactions. Ongoing investigations in our
laboratory are seeking to address all of these issues, and the
results will be reported in due course.
Conclusions
In summary, this paper describes detailed synthetic and
mechanistic investigations of Pd-catalyzed C-H arylation
reactions. The turnover-limiting step of the catalytic cycle
involves oxidation of Pd dimer 3 with [Mes-I-Ph]BF4 (4) to
form a dimeric high oxidation state Pd intermediate (9), which
(32) (a) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc. 2005,
127, 7690. (b) Streuff, J.; Ho¨velmann, C. H.; Nieger, M.; Mun˜iz, K.
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Soc. 2008, 130, 763.
Acknowledgment. We acknowledge the NIH NIGMS (GM-
073836) for support of this research. In addition, we thank Dr.
Eugenio Alavarado for assistance with NMR spectroscopy and Jim
Windak for assistance with mass spectrometry.
(33) Li, Y.; Song, D.; Dong, V. M. J. Am. Chem. Soc. 2008, 130, 2962.
(34) (a) Tong, X.; Beller, M.; Tse, M. K. J. Am. Chem. Soc. 2007, 129,
4906. (b) Welbes, L. L.; Lyons, T. W.; Cychosz, K. A.; Sanford, M. S.
J. Am. Chem. Soc. 2007, 129, 5836. (c) Liu, H.; Yu, J.; Wang, L.;
Tong, X. Tetrahedron Lett. 2008, 49, 6924. (d) Yin, G.; Liu, G. Angew.
Chem., Int. Ed. 2008, 47, 5442. (e) Lyons, T. W.; Sanford, M. S.
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K.; Hatanaka, M.; Sasai, H. J. Am. Chem. Soc. 2009, 131, 3452.
Supporting Information Available: Experimental details and
spectroscopic and analytical data for new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JA904116K
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