pubs.acs.

org/joc

Mechanistic Analysis of Azine N-Oxide Direct Arylation:

Evidence for a Critical Role of Acetate in the Pd(OAc)2 Precatalyst
Ho-Yan Sun, Serge I. Gorelsky, David R. Stuart, Louis-Charles Campeau,* and
Keith Fagnou†
Center for Catalysis Research and Innovation, Department of Chemistry, University of Ottawa 10 Marie Curie,
Ottawa, Ontario, Canada K1N 6N5. †Deceased November 11, 2009

louis-charles_campeau@merck.com
Received September 15, 2010

Detailed mechanistic studies on the palladium-catalyzed direct arylation of pyridine N-oxides are
presented. The order of each reaction component is determined to provide a general mechanistic picture.
The C-H bond cleaving step is examined in further detail through computational studies, and the
calculated results are in support of an inner-sphere concerted metalation-deprotonation (CMD)
pathway. Competition experiments were conducted with N-oxides of varying electronic characters,
and results revealed an enhancement of rate when using a more electron-deficient species, which is in
support of a CMD transition state. The effect of base on reaction rate was also examined and it was
found that a carboxylate base was required for the reaction to proceed. This led to the conclusion that
Pd(OAc)2 plays a pivotal role in the reaction mechanism as more than merely a precatalyst, but also
as a source of acetate base required for the C-H bond cleavage step.

Introduction for the coupling of electron-rich,2 -neutral,3 and -poor4 arenes

(Scheme 1). While these reactions are synthetically useful, the
The formation of carbon-carbon bonds via direct aryla-
development of novel catalysts which show increased reac-
tion has undergone significant advances in recent years with
tivity at lower temperatures and catalyst loadings still re-
efforts focused toward expanding substrate scope and novel
mains a challenge. A better mechanistic understanding of
catalyst development.1 In light of these studies, direct aryla-
direct arylation is crucial to the development of new catalysts
tion of aryl halides has become an attractive alternative to
as there are relatively few of these studies published to
the use of stoichiometric organometallic reagents in the pre-
date.2,5-7 Such studies would be useful when developing new
paration of biaryl compounds. Our group and others have
reactions, allowing for improvements to be made to existing
been successful in developing a range of methods allowing
reaction conditions and in the development of specially

(1) For comprehensive reviews on direct arylations, see: (a) Ackermann, (4) (a) Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc.
L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792. (b) Campeau, 2005, 127, 18021. (b) Campeau, L.-C.; Stuart, D. R.; Leclerc, J.-P.; Bertrand-
L.-C.; Stuart, D. R.; Fagnou, K. Aldrichim. Acta 2007, 40, 35. (c) Alberico, D.; Laperle, M.; Villemure, E.; Sun, H.-Y.; Lasserre, S.; Guimond, N.; Lecavallier,
Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (d) Modern Arylation M.; Fagnou, K. J. Am. Chem. Soc. 2009, 131, 3291.
Methods; Ackermann, L., Ed.; Wiley-VCH: Weinheim, Germany, 2009. (5) (a) Garcia-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren,
(2) (a) Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan, A. M. J. Am. Chem. Soc. 2006, 128, 1066. (b) Garcı́a-Cuadrado, D.; de Mendoza,
V. Org. Lett. 2004, 6, 1159. (b) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. P.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2007,
Chem. Soc. 2005, 127, 8050. (c) Chuprakov, S.; Chernyak, N.; Dudnik, A. S.; 129, 6880.
Gevorgyan, V. Org. Lett. 2007, 9, 2333. (6) (a) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, B.
(3) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am. Chem. Bull. Chem. Soc. Jpn. 1998, 71, 467. (b) Yanagisawa, S.; Sudo, T.; Noyori, R.;
Soc. 2006, 128, 8754. Itami, K. J. Am. Chem. Soc. 2006, 128, 11748.

8180 J. Org. Chem. 2010, 75, 8180–8189 Published on Web 11/05/2010 DOI: 10.1021/jo101821r
r 2010 American Chemical Society
Sun et al.
JOC Article
SCHEME 1. The Evolution of Cross-Coupling Methods ligand on the precatalyst in the active catalyst formed in
direct arylation. These studies have led to the advancement
of a catalytic cycle for direct arylation of pyridine N-oxide.
The most discussed mechanisms of direct arylation are the
carbopalladation or Heck-type pathway,7 the oxidative in-
sertion pathway,8-10 the electrophilic palladation or electro-
philic aromatic substitution (SEAr) pathway,2,6 and the
concerted metalation-deprotonation (CMD) pathway3,5,11
(Scheme 2).
The Heck-type pathway (path A) is characterized by syn-
addition of a palladium-carbon bond across a double bond
of the aromatic coupling partner. While anti-β-hydride elim-
ination is a high-energy process, the formation of a π-allyl
species is often proposed, which could then isomerize to
allow for a lower energy syn-β-hydride elimination.7a
Less described in the literature is the oxidative addition of
a Pd(II) species to a Pd(IV) species through an insertion into a
C-H bond of an aromatic coupling partner (path B). A
double reductive elimination would then afford the biaryl
product as well as regenerate the catalytically active Pd(0)
species.
To date, the most commonly suggested hypothesis for the
mechanism of direct arylation is electrophilic palladation
(path C). Originally proposed for the arylation of electron-
rich heteroaromatics, this has since been referenced numer-
ous times for other direct arylation reactions.2,6,12 An elec-
trophilic palladation or electrophilic aromatic substitution
(SEAr) type process would involve a rate-determining nu-
cleophilic attack by the arene on an electrophilic Pd(II)-aryl
species followed by rapid deprotonation of the resulting
Wheland intermediate. Subsequent reductive elimination
designed catalysts to reveal the necessary reactivity for an of the biaryl from Pd(II) would form the desired carbon-
even broader range of direct C-H bond transformations in carbon bond as well as regenerate the active catalyst.
organic synthesis. Our group and others have found computationally that
Of the studies directed toward elucidating the mechanism for simple or electron-deficient aromatics, a CMD pathway
of direct arylation, computational studies have been promi- (path D) is the lowest energy process, which was consistent
nently featured while little experimental evidence in support with experimental observations.3,4,13,14 In a CMD pathway,
of the various proposals has been brought forth. Electro- the Pd-C bond formation occurs concurrently with the
philic, nucleophilic, and electron-neutral palladium aryl species cleavage of the C-H bond of the arene to afford a Pd(II)
have all been suggested to interact with aromatic substrates diaryl species. This is then followed by reductive elimination
of varying electronic characters. Moreover, few if any of of the biaryl product, regenerating the active catalyst. While
these studies deal with the relationship between precatalyst convincing computational evidence has been reported,11
and active catalyst. Studies of this kind have been crucial to there have been very few reports of in-depth experimental
the development of very active catalysts in other palladium- support for a CMD mechanism.
catalyzed processes. In our previous report of this chemistry,
we related the preliminary findings of experimental results Results and Discussion
aimed at elucidating the mechanism of the C-H bond
1. Kinetics. The generally accepted mechanism for palladium-
cleaving process.4 Herein we describe a detailed investigation
catalyzed direct arylation of aryl halides and simple arenes
of the possible modes of C-H bond cleavage in the direct
is shown in Scheme 3. The active Pd(0) catalyst undergoes
arylation of pyridine N-oxides. Coupled with detailed kinetic
oxidative insertion into the aryl halide, followed by C-H bond
studies and other key experimental evidence, DFT calculations
cleavage of the simple arene. Reductive elimination provides the
were performed for the four most commonly proposed mecha-
nisms for direct arylation. Stoichiometric studies have also
(8) Okazawa, T.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem. Soc.
been used to elucidate the role of base in this transformation 2002, 124, 5286.
and have led to an unexpected and critical role of the acetate (9) Campo, M. A.; Huang, Q.; Yao, T.; Tian, Q.; Larock, R. C. J. Am.
Chem. Soc. 2003, 125, 11506.
(10) Capito, E.; Brown, J. M.; Ricci, A. Chem. Commun. 2005, 1854.
(7) (a) McClure, M. S.; Glover, B.; McSorley, E.; Millar, A.; Osterhout, (11) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008,
M. H; Roschanger, F. Org. Lett. 2001, 3, 1677. (b) Glover, B.; Harvey, K. A.; 130, 10848.
Liu, B.; Sharp, M. J.; Tymoschenko, M. F. Org. Lett. 2003, 5, 301. (c) Li, W.; (12) Zhao, X.; Yeaung, C. S.; Dong, V. M. J. Am. Chem. Soc. 2010, 132,
Nelson, D. P.; Jensen, M. S.; Hoerrner, R. S.; Javadi, G. J.; Cai., D.; Larsen, 5837.
R. D. Org. Lett. 2003, 5, 4835. (d) Wang, J.-X.; McCubbin, J. A.; Jin, M.; (13) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am. Chem. Soc.
Laufer, R. S.; Mao, Y.; Crew, A. P.; Mulvihill, M. J.; Snieckus, V. Org. Lett. 2005, 127, 13754.
2008, 10, 2923 and references cited therein. (14) Biswas, B.; Sugimoto, M.; Sakaki, S. Organometallics 2000, 19, 3895.

J. Org. Chem. Vol. 75, No. 23, 2010 8181

JOC Article Sun et al.

SCHEME 2. The Four Possible Mechanisms of Direct Arylation

desired biaryl product and regenerates the active Pd(0) catalyst. the catalyst resting state is at the Pd(0) species, then first-
With the goal of obtaining a more detailed understanding of the order behavior in the aryl halide, palladium catalyst, and the
catalytic cycle, and more specifically the intimate role of each of pyridine N-oxide may be expected. However, if the catalyst
the primary reaction components, the order for each reagent in was saturated as a Pd(II) species formed after oxidative
the coupling of 4-nitropyridine N-oxide and 5-bromo-m-xylene addition, the aryl bromide would then be expected to exhibit
was obtained.15 Using either Pd(OAc)2 and tri-tert-butylpho- zero-order behavior, while first-order behavior may still be
sphonium tetrafluoroborate salt or Pd(PtBu3)2 as the catalyst,
the concentration of each reaction component was varied and SCHEME 3. General Mechanism for the Palladium-Catalyzed
the progression of the reaction at 110 °C was monitored. The Direct Arylation of Simple Arenes
initial time (t0) of each kinetic run corresponded to the time at
which the reaction flask was placed into the oil bath, which
was preheated to 110 °C. During the course of the reaction,
aliquots of the reaction mixture were removed, at which
point the N-oxide readily precipitated from solution, thus
stopping the reaction. The solvent was then removed and
the resulting samples were analyzed by NMR spectroscopy
for the formation of product with trimethoxybenzene as an
internal standard.
There are several mechanistic scenarios to be considered
for the direct arylation of pyridine N-oxides. One possible
scenario involves oxidative addition as the rate-determining
step of the reaction. In this case, one would expect to observe
a first-order behavior in both aryl bromide and palladium
catalyst, while zero-order behavior in pyridine N-oxide would
be observed. If the C-H bond cleavage step were to be rate
determining, two possible scenarios may be anticipated; if

(15) The choice of substrate was mainly guided for analytical simplicity as
all analyses was done with 1H NMR.

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JOC Article

FIGURE 1. Log plot of the initial rate dependence on the concentration of (a) 5-bromo-m-xylene, (b) 4-nitropyridine N-oxide, (c) Pd(PtBu3)2,
and (d) PtBu3.

established for both the Pd catalyst and the N-oxide. The same The rate-constant’s dependence on catalyst concentration
observed kinetic consequences could be expected if reductive was determined by using Pd(PtBu3)2 as the catalyst in order
elimination was the rate-determining step, but these two cases to eliminate catalyst preactivation. PivOH (30 mol %) was
may be distinguished by looking for the presence or absence consequently added to account for the acetate that is normally
of a significant kinetic isotope effect at the C2 position of the in solution when Pd(OAc)2 is used. The reaction rate was
N-oxide (vide infra). measured over a range of catalyst loadings of Pd(PtBu3)2,
The order in 5-bromo-m-xylene was determined by plot- varying from 1 mol % to 20 mol %. This order was deter-
ting the log of the initial rate versus the log of the concentra- mined with respect to an aryl bromide concentration of 0.3 M
tion, using 5 mol % of Pd(OAc)2 as the precatalyst (Figure 1a). and an N-oxide concentration of 0.6 M, and a slope of 0.56
A slope of 0.04 was obtained revealing that varying the was obtained from the kinetic plot (Figure 1c), which is
concentration of the aryl halide from 0.2 to 0.6 M has no ef- consistent with half-order behavior in catalyst. This behavior
fect on the reaction rate, thus establishing zero-order behav- has been associated with systems in which the catalyst
ior in this system. The zero-order dependence in 5-bromo- resting state is a dimer, while the active form of the catalyst is
m-xylene is indicative of a fast oxidative addition in which a monomer.17 According to the zero-order dependence on
the palladium catalyst is saturated as a Pd(II)-aryl species and aryl bromide and first-order dependence on the N-oxide, the
thus ruling out the possibility of oxidative insertion being the dimeric resting state should be found between the oxidative
rate-determining step. addition and arene metalation steps.
The order in 4-nitropyridine N-oxide was also determined Finally, the order in ligand was determined, also using
in a similar manner by varying its concentration from 0.1 to 5 mol % of Pd(PtBu3)2 as the catalyst. No change in rate was
0.8 M (Figure 1b). A slope of 1.16 was obtained indicating a observed over a range of ligand concentrations from a 1:2 Pd:
first-order behavior in pyridine N-oxide. A first-order depen- ligand ratio to a 1:6 ratio (Figure 1d), thus establishing a
dence on pyridine N-oxide suggests that a single molecule of zero-order behavior in this system. It has been previously
the N-oxide participates at the transition state of the reaction, determined that the oxidative addition product of Pd(PtBu3)2
which is consistent with arene metalation or reductive elimina- into the C-Br bond of an aryl bromide is a T-shaped complex
tion being the rate-determining step. Reductive elimination bearing a single phosphine ligand and a free coordination site,18
was discarded as a possible rate-determining step due to the
observation of a significant kinetic isotope effect (KIE) in a (17) (a) Fairlie, D. P.; Bosnich, B. Organometallics 1988, 7, 946.
side-by-side comparison of rates (kH/kD = 3.3) using pyridine (b) Van Strijdonck, G. F. P.; Boele, M. D. K.; Kamer, P. C. J.; de Vries,
J. G.; van Leeuwen, P. W. N. M. Eur. J. Inorg. Chem. 1999, 1073. (c) Kina, A.;
N-oxide or pyridine N-oxide-d5 as the starting azine.16 Hiroshi, I.; Hayashi, T. J. Am. Chem. Soc. 2006, 128, 3904. (d) Collum, D. B.;
McNeil, A. J.; Ramirez, A. Angew. Chem., Int. Ed. 2007, 46, 3002. (e) Shen,
Z.; Dornan, P. K.; Khan, H. A.; Woo, T. K.; Dong, V. M. J. Am. Chem. Soc.
(16) For results from a one-pot KIE experiment, please see ref 4a. 2009, 131, 1077.

J. Org. Chem. Vol. 75, No. 23, 2010 8183

JOC Article Sun et al.

SCHEME 4. Free Energy Diagram (ΔGq298K, kcal 3 mol-1 in a solvent correction for toluene.24 The initial structures for
toluene) for the Relevant Intermediates, Transition States, and all calculations are pyridine N-oxide (A) and a palladium(II)
Products in the Oxidative Insertion Pathway species (B, F, or F0 ) coordinated by one PMe3 ligand after
oxidative insertion into the C-Br bond of bromobenzene. In
the case of species F the bromide has been replaced by a bi-
carbonate anion while species F0 contains an acetate anion in
place of bromide. The relative geometry between the aryl
group and the other anionic ligand is denoted as trans where
the cis isomer is only marginally higher in energy.
Among the processes examined, the C-H oxidative inser-
tion pathway (Scheme 4) was found to be the highest in
energy, thus making it an unlikely candidate as the acting
mechanism of the reaction. This pathway was found to
proceed through transition state C having an energy of
56.6 kcal/mol and the resulting pentacoordinate Pd(IV) inter-
mediate D has an energy of 51.7 kcal/mol. Reductive elim-
ination of HBr gives the common intermediate E having an
energy of 36.8 kcal/mol. The Heck-type pathway (Scheme 5)
is only slightly lower in energy than the C-H oxidative inser-
tion pathway having a transition state (G) with an energy of
53.4 kcal/mol, though this results in an intermediate H with a
relatively low lying energy of 16.6 kcal/mol.
SCHEME 5. Free Energy Diagram (ΔGq298K, kcal 3 mol-1 in
toluene) for the Relevant Intermediates, Transition States, and
Products in the Heck-Type Pathway

and as such, the arene metalation transition state should

have at most one bound phosphine ligand. Additionally, the
zero-order dependence on phosphine ligand supports the
arene metalation transition state containing a single phos-
phine ligand and hence it is unlikely that dissociation of PtBu3
from Pd occurs before the rate-determining step of the reaction.
With a basic understanding of the catalytic cycle, the mech-
anism of the C-H bond cleavage was investigated in greater
detail through both computational and experimental studies.
2. Computational Analysis. Quantum chemical19 density
functional theory20 calculations were used to assist in differ-
entiating among the four possible mechanistic scenarios and
determining the lowest energy pathway for the C-H bond
cleavage step. All computations were performed at the
Hybrid B3LYP level21 with a TZVP22 basis set for all atoms
except palladium, for which a DZVP23 basis set was used.
The ligand (either PMetBu2 or PtBu3) in the reaction was ap-
proximated with PMe3 in all computations in order to reduce
computational time. This is a commonly used technique3,5,11
and was not expected to change the qualitative findings of the
calculations. Energy diagrams show the relative Gibbs Free
Energies for the various transition states, intermediates, and
products involved in each of the potential mechanisms. When investigating the CMD pathway two variants must
Calculations were performed in both the gas phase and with be considered: an inner-sphere mechanism and an outer-
sphere mechanism (Figure 2).3,5,11,25,26 An inner-sphere
mechanism is characterized by an internal base coordinated
(18) Stambuli, J. P.; B€
uhl, M.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124,
9346. to palladium participating in the CMD process. This base
(19) Ziegler, T.; Autschbach, J. Chem. Rev. 2005, 105, 2695.
(20) (a) Hohenburg, P.; Kohn, W. Phys. Rev. B 1964, 136, 864. (b) Kohn,
W.; Sham, L. J. Phys. Rev. A 1965, 140, 1133. (24) Foresman, J. B.; Keith, T. A.; Wiberg, K. B.; Snoonian, J.; Frisch,
(21) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785. M. J. J. Phys. Chem. 1996, 100, 16098.
(22) Schafer, A.; Huber, C.; Ahlrichs, R. J. Chem. Phys. 1994, 100, 5829. (25) Pascual, S.; de Mendoza, P.; Braga, A. A. C.; Maseras, F.; Echavarren,
(23) Godbout, N.; Salahub, D. R.; Andzelm, J.; Wimmer, E. Can. J. A. M. Tetrahedron 2008, 64, 6021.
Chem. 1992, 70, 560. (26) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496.

8184 J. Org. Chem. Vol. 75, No. 23, 2010

Sun et al.
JOC Article
SCHEME 7. Free Energy Diagram (ΔGq298K, kcal 3 mol-1 in
toluene) for the Relevant Intermediates, Transition States, and
Products in the Inner- and Outer-Sphere CMD Pathways, Using
Acetate As the Base

FIGURE 2. Inner- and outer-sphere mechanisms for the concerted

metalation-deprotonation process.

SCHEME 6. Free Energy Diagram (ΔGq298K, kcal 3 mol-1 in

toluene) for the Relevant Intermediates, Transition States, and
Products in the Inner- and Outer-Sphere CMD Pathways, Using
Bicarbonate As the Base

of HBr (Scheme 6). This pathway led to higher energy prod-

ucts than if bicarbonate was used as the base, and thus it
was discarded. Calculations were also performed with ace-
tate as the base. The relative energies of the transition states
reflected those found when bicarbonate was used as the base,
although the absolute values were found to be slightly lower
(Scheme 7).
Efforts were made to locate the transition state energy
leading to the Wheland intermediate in an SEAr type path-
way (Scheme 8) starting with F as the initial Pd(II) species.
However, only the intermediate I (18.9 kcal/mol), a η2
can be either the halide from the aryl halide or a carbonate/ π-complex having no cationic character on the aromatic ring,
carboxylate anion from a ligand exchange on palladium. Dif- could be located. Departing from intermediate I this reaction
ferentiated from this is the outer-sphere mechanism in which pathway converges with that of the inner-sphere CMD
the deprotonation is performed by an external base (a car- pathway at transition state J (34.9 kcal/mol). Formation of
bonate or carboxylate anion). the carbon-palladium bond and loss of H2CO3 yields products
Both CMD variants were found to be substantially lower K (15.9 kcal/mol). The possibility of an SEAr mechanism was
in energy than the alternate pathways (Schemes 6 and 7). thus discarded on the basis that no Wheland intermediate
Starting with species B and bicarbonate as the external base, or complex containing arene cationic character could be
the outer-sphere mechanism had a transition state L energy located computationally.
of 40.3 kcal/mol and the inner-sphere mechanism starting From these results, the inner-sphere CMD mechanism was
from F as the Pd(II) species had a transition state J energy of determined to be the most likely pathway for the C-H bond
32.4 kcal/mol. The inner-sphere mechanism with bromide as cleavage step in direct arylation. Computational results were
the base was found to have no thermodynamic barrier and also correlated to experimental findings to further support
arrives at the product E (36.8 kcal/mol) with subsequent loss the proposal for a CMD mechanism. An Arrhenius plot was
J. Org. Chem. Vol. 75, No. 23, 2010 8185
JOC Article Sun et al.

SCHEME 8. Relevant Intermediates, Transition States, and

Products in the SEAr Pathway

FIGURE 3. Arrhenius plot constructed for the coupling of 4-

constructed for the coupling between 4-nitropyridine N-oxide nitropyridine N-oxide.
and 5-bromo-m-xylene (Figure 3) and the Arrhenius energy
of activation was determined to be 18.5 kcal/mol. This value
is in good agreement with the calculated ΔEq of 17.6 kcal/mol
(at 298 K, in toluene), suggesting that the inner-sphere CMD
pathway is an energetically viable process.
The regioselectivity of the reaction was also examined and
proved to be particularly illustrative. Computationally, the
energies for arylation to take place at each position on the
pyridine N-oxide ring were calculated for the inner- and outer-
sphere mechanisms by using both carbonate and acetate as the
base (Figure 4). In both cases, the inner-sphere mechanism
was predicted to arylate preferentially at the C2 position,
followed by C4 and with arylation at the C3 position being
the highest in energy, while the outer-sphere mechanism
was predicted to have the opposite selectivity, favoring
arylation at the C4 position while arylation at the C2 position
was the highest energy process. Pyridine N-oxide is known
to be amphoteric acting as both a nucleophile and an elec-
trophile.27 The N-oxide moiety also imparts an increased
acidity of the C-H bonds at positions 2 and 4 on the pyri-
dine ring.28 While our initial hypothesis was that an in-
creased acidity of the C-H bond was a necessary compo- FIGURE 4. Free energy of activation (ΔGq298K, kcal 3 mol-1 in
nent for the CMD mechanism, recent computational results toluene) for the three possible sites of arylation via the inner- and
outer-sphere mechanisms.
from our group have shown that a more important factor is
electropositive character at the position ortho to the nitro- preferentially at the C6 position, suggesting that a steric bias
gen in the aromatic ring (as present at the C2 position for the less hindered site is controlling the regiochemical
of pyridine N-oxide).11 Experimentally, the regiochemical outcome of the reaction. A smaller C3 substituent, such as a
outcome for the direct arylation of pyridine N-oxide is such methoxy group, results in nonselective arylation when PtBu3
that only arylation at the C2 position is observed, which is in is used as the ligand, which is in agreement with a steric
agreement with calculated predictions for the inner-sphere argument for the selectivities observed, while selectivity for
mechanism. the C2 position is observed when the smaller PtBu2Me is
The inner-sphere CMD mechanism also accurately pre- used. This apparent ligand effect has been observed with
dicts the site selectivity for substituted pyridine N-oxides other pyridine N-oxide and aryl halide substrates,4b,29,30
(Table 1). When pyridine N-oxides bearing a phenyl or meth- and along with the observed zero-order in ligand during
ylester substituent at the C3 position are used, the regio- kinetic experiments, it is also in agreement with the phos-
selectivity is sterically controlled and arylation takes place phine ligand being present on the metal at the CMD step.

(27) (a) Andersson, H.; Almqvist, F.; Olsson, R. Org. Lett. 2007, 9, 1335. (29) Schipper, D. J.; El-Salfiti, M.; Whipp, C. J.; Fagnou, K. Tetrahedron
(b) Taylor, E. C., Jr.; Crovetti, A. J. Organic Syntheses; Wiley: New York, 2009, 4977.
1963; Collect. Vol. IV, p 654; 1956; Vol. 36, p 53. (30) The regioselectivities for 3-fluoro- and 3-phenylpyridine N-oxide
(28) (a) Paudler, W. W.; Humphrey, S. A. J. Org. Chem. 1970, 35, 3467. have also been reproduced stoichiometrically with 2. See the Supporting
(b) Kreuger, S. A.; Paudler, W. W. J. Org. Chem. 1972, 37, 4188. Information.

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JOC Article
TABLE 1. Experimental and Computational Results for the Regio-
selectivity in the Direct Arylation of C3-Substituted Pyridine N-Oxides

calcd A:B exptl A:B exptl A:B

entry X= (L = PMe3) (L = PtBu3) (L = PtBu2Me)
1 Ph 1:11 1:10
2 CO2Me 1:4 1:7
3 OMe 6:1 1:1 5:1
4 NO2 9:1 4:1 6:1
5 CN 4:1 10:1 15:1
6 F 76:1 25:1

FIGURE 6. Hammett plot for the direct arylation of C4-substituted

pyridine N-oxides.

TABLE 2. Yields of a Stoichiometric Reaction between 1 and 4-

Nitropyridine N-Oxide, Using Different Bases

FIGURE 5. Computational and experimental results for competi-

tion experiments between pyridine N-oxides of different electronics.

In general, sterics seem to be the overriding factor in the

observed selectivity. However, when smaller substituents
are present subtle electronic factors come into play. This is entry K2CO3 KOPiv NMR Yield (%)a
exemplified by the inversed regioselectivity to the C2 posi- 1 none none 0
tion when a small C3 electron-withdrawing substituent, such 2 10 equiv none 5
3 none 10 equiv 29
as a nitro, cyano, or fluoro group, is present. The electron- 4 10 equiv 10 equiv 31
withdrawing substituent could impart an electropositive a
Trimethoxybenzene as internal standard.
character to the C2 position of the N-oxide through reso-
nance and inductive effects, thus stabilizing the developing F value suggests the enhancement of rate with increasing
negative charge of the CMD transition state that involves the electron-withdrawing ability of the substituent located at the
development of a negative charge at the C2 position. In all C4 position of the N-oxide, which is in support of the CMD
cases, the elaborated DFT model accurately predicts regio- pathway. An electron-withdrawing substituent would be
chemistry. expected to stabilize the development of a negative charge
Additionally, one-pot competition experiments and com- at the CMD transition state, and thus lower the energy of the
putational predictions of relative rates under a CMD mech- process.
anism were performed (Figure 5) and it was found that the 3. Base Effects. Further experiments were performed to
experimental values correlated well with the calculated ones. examine the nature of the base in the CMD process. The
It was seen that in all cases, the aryl bromide reacted most three-coordinate arylpalladium halide complex 1 (Table 2), a
readily with the more electron-deficient arene, which is con- possible intermediate in the catalytic cycle, was synthesized
trary to what would be expected if SEAr was the acting mech- according to a procedure reported by Hartwig et al.18 and
anism. The greater reaction rate of the methoxy-substituted was stoichiometrically reacted with 4-nitropyridine N-oxide
N-oxide over the methyl-substituted N-oxide is due to the in the presence of K2CO3 and/or KOPiv as a base. Reactivity
σ-withdrawing effect of the methoxy substituent to the meta was found to depend heavily on the presence of pivalate base
position of the arene, which is also reflected in the positive in the reaction mixture. While no product is observed in the
σmeta value of a methoxy substituent. The results of these absence of any base, surprisingly low reactivity was observed
competition experiments are also in agreement with the when using K2CO3 (Table 2, entries 1 and 2). However, in the
obtained Hammett plot, which provides a side-by-side com- presence of pivalate, with or without K2CO3, the desired
parison of the different N-oxides’ reaction rates (Figure 6). In coupling product is obtained in approximately 30% yield
the past, Hammett studies conducted for direct arylation (Table 2, entries 3 and 4).
reactions have generally resulted in negative F values, and The reaction rate was also found to depend heavily on the
this observation was commonly used as the main argument identity of the base present in the reaction mixture. Kinetic
in support of an SEAr mechanism for direct arylation.2 The experiments were run with Pd(PtBu3)2 as the catalyst in order
obtained Hammett plot gives a F value of þ1.53. The positive to eliminate catalyst preactivation as a potentially significant
J. Org. Chem. Vol. 75, No. 23, 2010 8187
JOC Article Sun et al.

SCHEME 9. Stoichiometric Reactivity of Complex 2

obtained yields were identical, revealing little dependence of the

FIGURE 7. Dependence of rate on the identity of the base used.
t
Conditions: ([, light blue) Pd(P Bu3)2, 2 equiv of K2CO3; (9, red) stoichiometric reaction on the presence of K2CO3 (Scheme 9).
5 mol % of Pd(PtBu3)2, 2 equiv of KOPic; (2, green) Pd(PtBu3)2, The yields of these stoichiometric reactions are comparable
2 equiv of K2CO3, 30 mol % of PivOH; and (b, dark blue) Pd(OAc)2, to that of the analogous catalytic reaction.35 These stoichio-
15 mol % of PtBu3 3 HBF4, 2 equiv of K2CO3. metric studies suggest that 2 is a likely intermediate in the
catalytic cycle. Furthermore, the observed identical yields
factor when measuring reaction rates. The rate of the reac- between the reactions run with and without K2CO3 are in
tion was observed to be slow when only one of K2CO3 or support of acetate, and not carbonate, performing the nec-
KOPiv was used, but when a combination of excess K2CO3 essary deprotonation at the CMD step.
with a substoichiometric amount of PivOH was used, the The participation of 2 in the catalytic cycle is further sup-
reaction rate increased approximately 6-fold and was com- ported by its ability to act as a competent catalyst as well as
parable to that of a reaction run under the standard reported by the similarity in initial rates between a reaction run with
conditions4 (Figure 7). The poor reactivity of a system using catalytic Pd(PtBu3)2 with PivOH and one run with a catalytic
only KOPiv as the base may be attributed to the eventual amount of 2 (Figure 8). A catalytic amount of KOPiv (5 mol %)
buildup of PivOH in the reaction mixture, which could result was added to the reaction run with 2 as the catalyst in order
in the proto-demetalation of a palladium aryl organometallic, to mimic the ratio of Pd to carboxylate base that is present
generating reduced arene and catalytically inactive Pd(II). when Pd(OAc)2 is used as the catalyst.
This effect may also be the result of excess carboxylate satu-
rating the catalyst and preventing its binding to the substrate.
Using K2CO3 with a substoichiometric amount of PivOH
would allow for the prevention of the buildup of acid by
allowing the PivOH that is formed to be deprotonated by the
K2CO3, thus regenerating the pivalate anion required for
another turn of the catalytic cycle. When using Pd(OAc)2 as
the catalyst, however, no pivalate additive was required to
achieve good reactivity, which alludes to a secondary role for
Pd(OAc)2.31 While Pd(OAc)2 has always been considered to
serve only as a precatalyst, these results are indicative of its
ability to act as a source of soluble carboxylate base to per-
form the deprotonation at the CMD step.32,33
To probe this hypothesis, the aryl palladium acetate
complex 2 was synthesized34 and reacted stoichiometrically
with 4-nitropyridine N-oxide in the presence and absence of
K2CO3. The conditions used were chosen to mimic the
conditions used in the catalytic reaction. In both cases, the

(31) While reactions having 10-30 mol % carboxylate have similar rates, FIGURE 8. Initial rate of a reaction run with a catalytic amount of
it was noticed that when >40 mol % carboxylate is present under the 2. Conditions: ([, blue) 1 equiv of bromobenzene, 2, 2 equiv of
standard conditions, a significant rate decrease is observed. K2CO3, 5 mol % of KOPiv; (9, red) 1 equiv of 5-bromo-m-xylene,
(32) To test this hypothesis, the rate of a reaction using a catalytic amount Pd(PtBu3)2, 2 equiv of K2CO3, 30 mol % of PivOH.
of KOAc was measured, but was found to be quite slow, likely due to the
insolubility of KOAc in the toluene. 4. Summary of Mechanistic Data and Proposed Catalytic
(33) When Pd(OPiv)2 was used in place of Pd(OAc)2 as the palladium
precatalyst, an activation period of ca. 20 min was observed. Once the Cycle. Given the mechanistic insight we obtained from the
formation of product began, however, the rate of the reaction paralleled results of the computational studies as well as the various
that of the reaction run with K2CO3 and catalytic PivOH. For kinetic
experiments with Pd(OPiv)2, see the Supporting Information.
(34) Barrios-Landeros, F. Oxidative Addition of Haloarenes by Pd(0) (35) Conditions: Bromobenzene (1 equiv), 4-nitropyridine N-oxide
Complexes of Bulky Alkyl Phosphines: Synthesis of Intermediates and (2 equiv), Pd(OAc)2 (5 mol%), PtBu3 3 HBF4 (15 mol%), K2CO3 (2 equiv),
Mechanistic Studies, Dissertation, Yale University, 2007. PhMe, 110 °C, 16 h. NMR yield of 62%.

8188 J. Org. Chem. Vol. 75, No. 23, 2010

Sun et al.
JOC Article
SCHEME 10. Proposed Catalytic Cycle for the Direct Aryla- of pyridine N-oxides. The data obtained from these studies
tion of Pyridine N-Oxides via a CMD Transition State allowed for the proposal of a revised catalytic cycle, which
points to CMD being the rate-limiting step in the process.
The critical role of the base in the CMD process was investi-
gated in further detail in both catalytic and stoichiometric
variations of the transformation. The observed dependence
of reactivity on the presence of soluble carboxylate indicates
that the acetate from the Pd(OAc)2 precatalyst is acting as
the deprotonating agent at the CMD step. This observation
is also in accord with the prevalence of Pd(OAc)2 being used
as a precatalyst in direct arylation reactions and should
be considered in the development of new direct arylation
processes.

Experimental Section
General Procedure for the Direct Arylation of Pyridine N-
Oxides with Aryl Bromides. Pyridine N-oxide (3 equiv), K2CO3
(2 equiv) PtBu3 3 HBF4 (6-15 mol %), and Pd(OAc)2 (5 mol %)
were weighed into a round-bottomed flask equipped with a
Teflon stir bar. The flask was fitted with a reflux condenser and
the reaction vessel was then evacuated and refilled with argon
(repeat 3 times). A solution of 5-bromo-m-xylene (1 equiv) in
toluene (0.3 M with respect to aryl bromide) was purged with
experiments performed, we are able to propose a revised argon (10-15 min) and added to the reaction flask. The flask
catalytic cycle for the direct arylation of pyridine N-oxides was placed in an oil bath and heated to 110 °C with constant
(Scheme 10). The results from the kinetic experiments sug- stirring. The reaction was allowed to heat at 110 °C overnight
gest a fast oxidative addition of the aryl halide into a Pd(0) after which the flask was removed from the oil bath and allowed
species after which the catalyst is saturated as a Pd(II) species. to cool to room temperature. The reaction was then filtered
According to the observed half-order dependence on catalyst through Celite (washing with CH2Cl2) and the filtrate was
concentration, this Pd(II) species could possibly exist as an concentrated under reduced pressure then loaded onto a short
inactive dimer that is in equilibrium with the less favored silica gel column for chromatography.
active monomeric form of the catalyst.36 Stoichiometric 2-(3,5-Dimethylphenyl)-4-nitropyridine N-oxide: 1H NMR
studies with different palladium complexes have pointed to (400 MHz, CDCl3, 293 K) δ 8.36 (1H, d, J = 7.2 Hz), 8.26
(1H, d, J= 3.2 Hz), 8.02 (1H, dd, J=3.2, 7.2 Hz), 7.39 (2H, s),
the involvement of an acetate at the transition state as the 7.16 (1H, s), 2.40 (6H, s); 13C NMR (100 MHz, CDCl3, 293 K) δ
deprotonating agent. The reaction likely proceeds via an 150.8, 142.0, 141.3, 138.4, 132.5, 130.6, 126.7, 121.6, 118.3, 21.4;
κ2-bound acetate on the palladium metal 2 from which the HRMS calcd for C13H12N2O3 (Mþ) 244.0848, found 244.0846;
pyridine N-oxide can displace one of the acetate oxygens and IR (vmax/cm-1) 3106, 3085, 3055, 2917, 2859, 1520, 1341, 1278;
coordinate to the metal center.37 The reaction is then pro- mp 174-175 °C.
posed to proceed through a 6-membered inner-sphere CMD
transition state, generating the palladium biaryl species that
Acknowledgment. This paper is dedicated in memory of
goes on to the reductive elimination step to give product and
Keith Fagnou. H.-Y.S. thanks the Canadian Government
regenerate the Pd(0) catalyst. The acetic acid generated in this
for a PGS-M scholarship. L.-C.C. and D.R.S. thank the
process is likely deprotonated by the carbonate base in the
Canadian Government for PGS-D scholarships. This re-
reaction mixture, which regenerates the acetate required for
search was funded in part by NSERC, the Research Corpo-
another turnover of the catalytic cycle.
ration (Cottrell Scholar Award; K.F.), the Ontario govern-
ment (Premier’s Research Excellence Award, K.F.), and the
Conclusion
University of Ottawa. We thank Tom K. Woo for computing
In conclusion, we have examined through kinetic and facilities use funded by the CFI and the ORF. The authors
computational analysis the mechanism of direct arylation also thank Prof. John F. Hartwig and Prof. Melanie S. Sanford
for helpful discussions during the preparation of this paper.
(36) Efforts to isolate and characterize the dimeric resting state of the
catalyst were unfruitful. However, as both the Pd-Br (1) and Pd-OAc (2) are
known to be monomeric, we suspect the involvement of pyridine N-oxide in Supporting Information Available: Detailed experimental
the dimeric form.
(37) It is likely that the inital coordination of pyridine N-oxide occurs via
procedures for kinetics as well as results of DFT calculations.
oxygen; for references on O-bound Pd complexes, see: Cho, S. H.; Hwang, This material is available free of charge via the Internet at http://
S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254. pubs.acs.org.

J. Org. Chem. Vol. 75, No. 23, 2010 8189