Mechanistic comparison between Pd-catalyzed ligand-directed C-H chlorination and C-H acetoxylation

Article abstract of DOI:10.1021/ol901820w

This communication describes detailed Investigations of the mechanism of the Pd-catalyzed C-H chlorlnatlon and acetoxylatlon of 2-otolylpyrldlne. Under the conditions examined, both reactions proceed via rate-llmltlng cyclopalladatlon. However, substrate

Full text of DOI:10.1021/ol901820w

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4584-4587
Mechanistic Comparison between
Pd-Catalyzed Ligand-Directed C-H
Chlorination and C-H Acetoxylation
Kara J. Stowers and Melanie S. Sanford*
UniVersity of Michigan, Department of Chemistry, 930 North UniVersity,
Ann Arbor, Michigan 48109-1055
mssanfor@umich.edu
Received August 6, 2009
ABSTRACT
This communication describes detailed investigations of the mechanism of the Pd-catalyzed C-H chlorination and acetoxylation of 2-o-
tolylpyridine. Under the conditions examined, both reactions proceed via rate-limiting cyclopalladation. However, substrate and catalyst order
as well as Hammett data indicate that the intimate mechanism of cyclopalladation differs significantly between PdCl2-catalyzed chlorination
and Pd(OAc)2-catalyzed acetoxylation.
Palladium-catalyzed ligand-directed C-H bond functional-
ization has become a valuable synthetic method for the
selective oxidation of organic molecules.1 Over the past 5
years, numerous Pd-catalyzed reactions have been developed
for the directed oxygenation,2 halogenation,3 amination,4
sulfonylation,5 and arylation1b-e of both sp2 and sp3 C-H
bonds. Furthermore, these transformations have been applied
to structurally diverse organic scaffolds, including amino acid
derivatives2c and drug substrates.6
While significant progress has been made in the develop-
ment of new reactions, detailed mechanistic studies in this
area have received considerably less attention.7,8 An im-
proved mechanistic understanding could facilitate (i) the
development of new catalysts with improved catalytic activity
and substrate scope as well as (ii) the rational implementation
of strategies for controlling the chemo-, diastereo-, enantio-,
and site-selectivity of C-H functionalization reactions. This
communication describes an investigation of the mechanism
of pyridine-directed C-H bond chlorination with N-chloro-
succinimide (NCS). We report on the optimization of the
(1) For reviews, see: (a) Dick, A. R.; Sanford, M. S. Tetrahedron 2006,
62, 2439. (b) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.; Pham, Q. N.;
Lazareva, A. Synlett 2006, 3382. (c) Alberico, D.; Scott, M. E.; Lautens,
M. Chem. ReV. 2007, 107, 174. (d) Li, B. J.; Yang, S. D.; Shi, Z. J. Synlett
2008, 949. (e) Chen, X.; Engle, K. M.; Wang, D. H.; Yu, J. Q. Angew.
Chem., Int. Ed. 2009, 48, 5094.
(2) For examples, see: (a) Desai, L. V.; Hull, K. L.; Sanford, M. S.
J. Am. Chem. Soc. 2004, 126, 9542. (b) Giri, R.; Liang, J.; Lei, J. G.; Li,
J. J.; Wang, D. H.; Chen, X.; Naggar, I. C.; Guo, C.; Foxman, B. M.; Yu,
J. Q. Angew. Chem., Int. Ed. 2005, 44, 7420. (c) Reddy, B. V. S.; Reddy,
L. R.; Corey, E. J. Org. Lett. 2006, 8, 3391.
(5) Zhao, X.; Dimitrijevic, E.; Dong, V. M. J. Am. Chem. Soc. 2009,
131, 3466.
(3) For examples, see: (a) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am.
Chem. Soc. 2004, 126, 2300. (b) Giri, R.; Chen, X.; Yu, J. Q. Angew. Chem.,
Int. Ed. 2005, 44, 2112. (c) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford,
M. S. Tetrahedron 2006, 62, 11483. (d) Hull, K. L.; Anani, W. Q.; Sanford,
M. S. J. Am. Chem. Soc. 2006, 128, 7134. (e) Wan, X.; Ma, Z.; Li, B.;
Zhang, K.; Cao, S.; Zhang, S.; Shi, Z. J. Am. Chem. Soc. 2006, 128, 7416.
(f) Wang, X.; Mei, T. S.; Yu, J. Q. J. Am. Chem. Soc. 2009, 131, 7520.
(4) For examples, see: (a) Thu, H. Y.; Yu, W. Y.; Che, C. M. J. Am.
Chem. Soc. 2006, 128, 9048. (b) Jordon-Hore, J. A.; Johansson, C. C. C.;
Gulias, M.; Beck, E. M.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 16184.
(c) Mei, T. S.; Wang, X.; Yu, J. Q. J. Am. Chem. Soc. 2009, 131, 10806.
(6) Wasa, M.; Engle, K. M.; Yu, J. Q. J. Am. Chem. Soc. 2009, 131,
9886.
(7) (a) Hull, K. L.; Lanni, E. L.; Sanford, M. S. J. Am. Chem. Soc.
2007, 128, 14047. (b) Desai, L. V.; Stowers, K. J.; Sanford, M. S. J. Am.
Chem. Soc. 2008, 130, 13285. (c) Hull, K. L.; Sanford, M. S. J. Am. Chem.
Soc. 2009, 131, 9651. (d) Racowski, J. M.; Dick, A. R.; Sanford, M. S.
J. Am. Chem. Soc. 2009, 131, 10974. (e) Deprez, N. R.; Sanford, M. S.
J. Am. Chem. Soc. 2009, 131, 11234
.
(8) (a) Chiong, H. A.; Pham, Q. N.; Daugulis, O. J. Am. Chem. Soc.
2007, 129, 9879. (b) Li, J. J.; Giri, R.; Yu, J. Q. Tetrahedron 2008, 64,
6979. (c) Powers, D. C.; Ritter, T. Nat. Chem. 2009, 1, 302
.
10.1021/ol901820w CCC: $40.75
Published on Web 09/15/2009
 2009 American Chemical Society

catalyst, elucidation of the turnover-limiting step, and
mechanistic comparison to related Pd-catalyzed C-H ac-
etoxylation reactions.
Pd-catalyzed C-H chlorination has been proposed to
proceed by the general catalytic cycle outlined in Scheme
1.3,8c,9,10 This cycle begins with ligand directed C-H
began with conditions analogous to those in the literature: 5
mol % of Pd(OAc)2 and 1.2 equiv of NCS in CH3CN with
[1] ) 0.12 M.3c However, at this concentration the reactions
did not remain homogeneous, which led to inconsistent
kinetics; furthermore, when [1] was lowered, competing
formation of acetoxylated product 3 was observed,12 which
complicated kinetic analysis.
Based on these preliminary studies, we surveyed a variety
of alternative Pd sources (Table S2, Supporting Information)
and identified PdCl2 as an optimal catalyst for the chlorina-
tion of 1 in MeCN. Further optimization revealed that 5 mol
% of PdCl2 is required to achieve full conversion and that
the highest yield (80%) is obtained at concentrations between
0.048 and 0.024 M. Importantly, these conditions also
worked well for the Pd(OAc)2-catalyzed ortho-acetoxylation
of 1, providing 3 in 77% yield.
Scheme 1.
General Mechanism for C-H Chlorination9
With optimal conditions for the chlorination and acetoxy-
lation of 1 in hand,13 we first examined the intermolecular
kinetic isotope effect (KIE) for the two reactions. The Pd-
catalyzed functionalizations of 1 and 1-d1 were monitored
by GC, and the method of initial rates was used to determine
the rate at each [oxidant]. As shown in Table 1, a large
primary isotope effect was observed in both systems, with
kH/kD ) 4.4 ( 0.2 for chlorination and kH/kD ) 4.3 ( 0.5
for acetoxylation.14
activation (i), which is followed by two-electron oxidation
of the resulting palladacycle to a monomeric PdIV species
(or a closely related PdIII-PdIII dimer) (ii).8c Finally, C-Cl
bond-forming reductive elimination (iii) regenerates the
catalyst and releases the functionalized product. Previous
studies have demonstrated that electrophilic chlorinating
8c,10
reagents like N-chlorosuccinimide (NCS)10 and PhICl2
can promote the stoichiometric two-electron oxidation of
cyclometalated Pd(II) complexes, demonstrating the potential
viability of step (ii) of the proposed catalytic cycle. However,
detailed investigations of the turnover-limiting step, the
kinetic isotope effect, and the electronic requirements of
C-H chlorination have thus far not been explored.
We next established the kinetic order in each reaction
component, starting with the oxidant. As shown in Figure 1,
Our mechanistic investigation focused on the Pd-catalyzed
functionalization of 2-o-tolylpyridine (1) with NCS and
PhI(OAc)2 to form 2 and 3, respectively (Table 1). Substrate
Table 1. Intermolecular Kinetic Isotope Effect Data
Figure 1. Order in oxidant for C-H chlorination (blue) and
acetoxylation (red).
for both NCS and PhI(OAc)2 the initial rate was independent
of [oxidant] over a wide range of concentrations (12-144 mM
or 0.5-3.0 equiv of oxidant relative to substrate).
entry
catalyst
oxidant
NCS
kH/kD
1
2
PdCl2
Pd(OAc)2
4.4 ( 0.2
4.3 ( 0.5
The kinetic order in palladium was next determined for
each transformation by varying the catalyst loading from 2.5
to 10 mol % ([Pd] ) 0.6-4.8 mM) under otherwise identical
conditions. As shown in Figure 2, chlorination showed a first-
order dependence on [Pd] over this catalytically relevant
concentration range. In contrast, for the C-H acetoxylation
reaction, a plot of initial rate versus [Pd] was clearly not
linear. A weighted nonlinear least-squares fit of the data to
PhI(OAc)2
1 possesses several desirable features. First, it undergoes
selective monofunctionalization. Second, it participates cleanly
in both C-H chlorination and C-H acetoxylation reactions,
thus allowing direct comparison of these two transformations.
Finally, the pyridine ring is readily modified, which facilitates
analysis of electronic effects in these systems.11 Our studies
(12) The OAc is presumably derived from the Pd(OAc)2 catalyst.
(13) The kinetic studies were run at different concentrations (0.024 M
for chlorination versus 0.048 M for acetoxylation) because the data for each
reaction was significantly more reproducible under these conditions.
However, the same kinetic orders and analogous Hammett trends were
observed for chlorination at 0.048 M. See the Supporting Information.
(14) Intermolecular primary KIE values between 3.58 and 1.85 were
observed in the Pd-catalyzed C-H acetoxylation of 2-benzylpyridines (ref
7b).
(9) The identity of the ancillary ligands in the catalytic intermediates is
not known; as a result, these ligands are represented as sticks.
(10) For the oxidation of a PdII model complex to PdIV with NCS, see:
Whitfield, S. R.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 15142
.
(11) 2-Benzylpyridines were used in a previous mechanistic study of
Pd-catalyzed C-H acetoxylation (ref 7b). However, these substrates reacted
with NCS to form undesired benzylic chlorination side products.
Org. Lett., Vol. 11, No. 20, 2009
4585

Very different F values were obtained for the two reactions,
with F ) -0.43 for chlorination and F ) +0.89 for
acetoxylation.15
The data presented here offer valuable insights into the
mechanistic similarities and differences between the Pd-
catalyzed chlorination and acetoxylation of substrate 1. The
large primary intermolecular KIE coupled with the zero-order
dependence on [oxidant] provide strong evidence that both
transformations proceed via turnover-limiting cyclopallada-
tion. This is in interesting contrast to the C-H arylation of
3-methyl-2-phenylpyridine with [Ar2I]BF4, which was pro-
posed to involve turnover-limiting oxidation of a cyclom-
etalated Pd(II) dimer.7e
While the rate-determining step appears to be the same in
both of the current systems, the different kinetic orders in
[Pd] and in [1] as well as the different Hammett F values
are consistent with different mechanisms for cyclopalladation
in the PdCl2 versus Pd(OAc)2-catalyzed reactions. Significant
literature precedent has shown that PdX2 (X ) OAc or Cl)
reacts rapidly and quantitatively with excess amine or
pyridine derivatives (L) to form monomeric complexes of
general structure Pd(X)2(L)2.16 For example, Pd(OAc)2(ba)2
(ba ) benzylamine) has been directly observed in the
Pd(OAc)2-mediated cyclometalation of benzylamine in
MeCN.17 As such, we propose that the catalyst resting state
during both C-H functionalizations is most likely Pd(X)2(1)2
(X ) Cl, 4; X ) OAc, 7) (Schemes 2 and 3).18
Figure 2. Order in [Pd] for C-H chlorination (blue) and acetoxy-
lation (red).
the equation: f(x) ) a[Pd]n provided an order (n) of 1.5 (
0.2 (Figure 2).
Finally, the order in substrate 1 was examined, using
0.25-2.5 equiv of 1 relative to oxidant ([1] ) 6-120 mM).
Again, the chlorination and acetoxylation reactions showed
different results (Figure 3). For chlorination, a plot of initial
Figure 3. Order in [1] for C-H chlorination (blue) and acetoxy-
lation (red).
Scheme 2. Two Possible Mechanisms for the Turnover-Limiting
Step of C-H Chlorination (1 ) 2-o-Tolylpyridine)
rate versus [1] showed that the rate was independent of [1].
In contrast, the acetoxylation reactions showed an inverse
first-order dependence on [1].
To gain insight into the electronic requirements of these
reactions, we next probed the initial rate of C-H function-
alization with a series of electronically different 2-o-
tolylpyridines. As shown in Figure 4, Hammett plots for both
In the chlorination reaction, the observed zero-order
dependence on [1] suggests that cyclometalation at
(15) Interpretation of the Hammett data is somewhat complicated by
the conjugated biaryl system in 1, since substitution of Y and Z can influence
the electronics of both the pyridine (which binds to the metal) and the ortho-
C-H bond (which undergoes activation). We note that the observed F value
for C-H acetoxylation (+0.89 in MeCN) is reasonably similar to that
reported for benzylpyridines (+1.40 in benzene, ref 7b), where the pyridine
and aryl group are electronically isolated. Thus, we hypothesize that the
effect observed here is predominantly due to pyridine electronics.
(16) For examples, see: (a) Deeming, A. J.; Rothwell, I. P. J. Organomet.
Chem. 1981, 205, 117. (b) Ryabov, A. D.; Sakodinskaya, I. K.; Yatsimirsky,
A. K. J. Chem. Soc., Dalton Trans. 1985, 2629. (c) Ryabov, A. D. Chem.
ReV. 1990, 90, 403, and references therein.
Figure 4. Hammett plot for C-H chlorination (blue) and C-H
(17) Kurzeev, S. A.; Kazankov, G. M.; Ryabov, A. D. Inorg. Chim.
Acta 2002, 340, 192.
acetoxylation (red).
(18) A dimeric resting state followed by C-H activation at a dimeric
intermediate is also possible based on the kinetic data for C-H chlorination.
However, literature reports suggest that dimeric complexes like Pd2(X)4(L)2
only predominate in solution under conditions where L:[Pd] < 2:1. Vicente,
J.; Saura-Llamas, I. Comments Inorg. Chem. 2007, 28, 39.
C-H chlorination and C-H acetoxylation showed a modest
correlation with the σ values of the Y and Z substituents.
4586
Org. Lett., Vol. 11, No. 20, 2009

dependence on [Pd] in this system.21 The Hammett F value
of +0.89 is fully consistent with this mechanistic proposal,
as electron-withdrawing substituents on the pyridine ligand
should both increase both Keq values and also render
complexes 8 and 9 more reactive toward electrophilic C-H
activation (thereby increasing both k1 and k2).7b,19b,c Notably,
mechanisms similar to both c17 and d18 have been proposed
for the stoichiometric cyclometalation of benzylamine at
Pd(OAc)2 in MeCN.17
Scheme 3. Possible Competing Mechanisms for the
Turnover-Limiting Step of C-H Acetoxylation
(1 ) 2-o-Tolylpyridine)
There are several important ramifications of these studies.
First, it is clear that the ligand environment at Pd during
C-H activation is significantly different in these two
transformations. If this result proves general, it has potential
implications for diastereoselectivity in the C-H function-
alization of chiral substrates upon changing the catalyst/
oxidant combination. In addition, the structures of the key
intermediates (as well as the possibility of competing
mechanisms) should inform the selection of chiral ligands
for asymmetric C-H functionalization reactions. Finally, the
development of more highly active C-H chlorination and
acetoxylation catalysts will require accelerating the cyclo-
metalation step of the catalytic cycle. Because most ancillary
ligands decrease the rate of directed C-H activation relative
to that with simple Pd salts, this is a particularly challenging
problem that will likely require the design of novel ligands.
In summary, this paper describes the mechanism of Pd-
catalyzed directed C-H chlorination and acetoxylation of
1. Under the conditions examined, both reactions proceed
via turnover-limiting cyclopalladation. However, kinetic
order and Hammett data indicate that the intimate mechanism
of C-H activation differs significantly between PdCl2-
catalyzed chlorination and Pd(OAc)2-catalyzed acetoxylation.
Ongoing work seeks to further explore the proposed mech-
anisms computationally as well as exploit the current results
for the development of new C-H functionalization catalysts.
Pd(Cl)2(1)2 (4) proceeds by either (a) direct C-H activation
via a five-coordinate transition state such as 519 or (b) pre-
equilibrium chloride dissociation followed by C-H activation
at cationic complex 6.20 Paths a and b are both consistent
with the observed kinetic orders of 1 in [Pd] and 0 in [1].18
Furthermore, both mechanisms have been proposed for
related cyclometalation reactions in the literature.19,20 We
tend to favor path b, as it offers a better explanation for the
Hammett F value of -0.43. The latter can be rationalized
on the basis of increased lability of Cl- (at complex 4) and
MeCN (at complex 6) with more electron-releasing pyridine
ligands. This would lead to an increase in both Keq and k2,
thereby affording faster reactions with electron rich pyridines.
For the acetoxylation reaction, the observed inverse first-
order dependence on [1] implicates pre-equilibrium dissocia-
tion of 1 from Pd(OAc)2(1)2 prior to C-H activation. As
shown in Scheme 3, this could generate monomeric species
Pd(OAc)2(1)(MeCN) (8) (path c) or an acetate-bridged dimer
such as Pd2(OAc)4(1)3 (9) (path d), and cyclometalation could
then occur at either of these intermediates. Path c is expected
to show a first order dependence on [Pd], while path d should
be second order in [Pd] (Scheme 3). We propose that these
(or other closely related) competing first- and second-order
mechanisms are likely responsible for the observed 1.5 order
Acknowledgment. We thank the NIH NIGMS (GM-
073836) for support of this research. K.J.S. also acknowl-
edges Novartis for a graduate fellowship. Finally, we thank
Frontier Scientific for a generous gift of 2-methylboronic
acid.
Supporting Information Available: Experimental details
and spectroscopic data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(19) For examples of cyclometalation mechanisms analogous to path a,
see ref 16c as well as: (a) Yatsimirsky, A. K. Zh. Neorg. Khim. 1979, 24,
2711. (b) Yagyu, T.; Aizawa, S.; Funahashi, S. Bull. Chem. Soc. Jpn. 1998,
71, 619. (c) Yagyu, T.; Iwatsuki, S.; Aizawa, S.; Funahashi, S. Bull. Chem.
Soc. Jpn. 1998, 71, 1857. (d) Martin-Matute, B.; Mateo, C.; Cardenas, D. J.;
Echavarren, A. M. Chem.sEur. J. 2001, 7, 2341.
OL901820W
(21) An alternative explanation would be that the catalyst resting state
is a mixture of monomeric and dimeric Pd species (see ref 8c for a similar
proposal). However, we believe that this is unlikely, as literature precedent
suggests that the reaction between a large excess of 1 and Pd(OAc)2 to
form Pd(OAc)2(1)2 should to be fast and essentially quantitative, particularly
at 70 °C. See refs 16-18.
(20) For examples of cyclometalation mechanisms analogous to path b,
see: (a) Alsters, P. L.; Engel, P. F.; Hogerheide, M. P.; Copijn, M.; Spek,
A. L.; van Koten, G. Organometallics 1993, 12, 1831. (b) Otto, S.; Chanda,
A.; Samuleev, P. V.; Ryabov, A. D. Eur. J. Inorg. Chem. 2006, 2561, and
references therein.
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