Oxidative C-H activation/C-C bond forming reactions: Synthetic scope and mechanistic insights

Article abstract of DOI:10.1021/ja051402f

This paper describes a new palladium-catalyzed method for C-H activation/carbon-carbon bond formation with hypervalent iodine arylating agents. This transformation has been applied to a variety of arene and benzylic substrates containing different directing groups (pyridines, quinolines, oxazolidinones, and amides) and proceeds with high levels of regiocontrol. Mechanistic experiments provide preliminary evidence in support of an unusual mechanism for this transformation involving a Pd(II)/Pd(IV) catalytic cycle. Copyright

Full text of DOI:10.1021/ja051402f

Published on Web 05/03/2005
Oxidative C-H Activation/C-C Bond Forming Reactions: Synthetic Scope
and Mechanistic Insights
Dipannita Kalyani, Nicholas R. Deprez, Lopa V. Desai, and Melanie S. Sanford*
Department of Chemistry, UniVersity of Michigan, 930 North UniVersity AVenue, Ann Arbor, Michigan 48109-1055
Received March 4, 2005; E-mail: mssanfor@umich.edu
Table 1. Palladium-Catalyzed Phenylation of C-H Bondsa
Palladium-catalyzed reactions for the formation of C-CAr bonds
are widely used in organic synthesis. The vast majority of these
transformations (e.g., Stille, Suzuki-Miyaura, Sonogashira, Hiya-
ma, and Negishi reactions) involve coupling of an aryl halide with
an organometallic fragment.1 The disadvantage of this approach is
that it requires the use of two functionalized starting materials,
which can be challenging and/or expensive to access in the context
of complex molecule synthesis. An alternative strategy for C-CAr
bond construction would involve Pd-mediated C-H activation
followed by functionalization of the resulting Pd-aryl/alkyl species
with an appropriate arylating reagent. The development of such
C-H activation/arylation reactions, particularly with broad scope,
high functional group tolerance, and mild reaction conditions,
represents an area of significant current interest,2-5 as such
transformations promise to facilitate selective construction of
carbon-carbon bonds at late stages in the synthesis of drug
molecules and/or natural products.
We recently reported Pd-catalyzed ligand-directed C-H activa-
tion/oxygenation reactions6 and proposed that they proceed via C-O
bond forming reductive elimination from Pd(IV) acetate intermedi-
a Conditions: 1 equiv of substrate, 1.1-2.5 equiv of [Ph2I]BF4, 5 mol
% Pd(OAc)2 in AcOH, AcOH/Ac2O, C6H6, or toluene, 100 °C, 8-24 h.
ates of general structure B (eq 1). We reasoned that C-H activation/
C-CAr bond forming processes could be available via an analogous
mechanistic pathway involving Pd(IV) aryl intermediate C (eq 1).7
We further hypothesized that, by analogy to the oxygenation
reactions (which use PhI(OAc)2 as a stoichiometric oxidant), iodine-
(III) arylating agents might be used to access C.7,8 The resulting
C-H activation/arylation reactions would be of significant synthetic
utility; furthermore, they would be highly mechanistically unusual,
as Pd-catalyzed C-CAr bond forming processes almost universally
proceed via Pd(0)/(II) catalytic cycles.1,9,10
Our initial investigations focused on the Pd-catalyzed C-H
activation/arylation of 2-phenyl-3-methylpyridine (1) with iodine-
(III) reagent [Ph2I]BF4. We were pleased to find that 5 mol % Pd-
(OAc)2 catalyzes the formation of monophenylated product 1a in
a variety of common organic solvents, including AcOH, CH2Cl2,
and C6H6, and under optimized conditions (5 mol % Pd(OAc)2,
1.1 equiv of [Ph2I]BF4, AcOH, 100 °C), 1a is obtained in 88%
isolated yield (Table 1, entry 1).4 Importantly, this transformation
is very practical; it does not require the use of strong bases or
expensive ligands and is conducted in the presence of ambient air/
moisture. Directed C-H activation/phenylation also proceeds in
good yield with a variety of alternative arene (entries 2-4, 7-13)
and benzylic (entries 5 and 6) substrates. Diverse heterocycles,
including pyridines, quinolines, pyrrolidinones, and oxazolidinones,
are effective directing groups, and a wide variety of functionalities,
including ethers, amides, enolizable ketones, aldehydes, aryl halides,
b With 2 equiv of substrate, 1.0 equiv of [Ph2I]BF4. c NaHCO3 (1.5-2.0
equiv) added. d Approximately 16% of 6a was formed in the absence of
Pd(OAc)2. e The balance of material was starting material (12) and/or starting
material and diarylated product (4 and 7).
and benzylic hydrogens, are well tolerated. Activated arenes are
not required for efficient catalysis, and both electron-rich and
electron-poor aromatic rings (e.g., entries 9 and 2) are phenylated
in excellent yields. Notably, substrates containing meta arene
substituents (X) (entries 2, 3, 9, 10, and 13) react to form a single
detectable regioisomeric product (with the new C-C bond installed
para to X) regardless of the electronic nature of the substituent.
These results are particularly remarkable in substrates with m-OMe,
m-halide, and m-acetyl groups, where dual point chelation of Pd to
the primary directing group and to X might be expected to afford
the opposite isomer,11 and suggest that the regioselectivity of C-H
activation is predominantly controlled by sterics in these systems.5d,12
The observed regioselectivity makes this reaction a potentially
valuable complement to more traditional arene functionalization
methods such as directed ortho-metalation.13
We next sought to expand these transformations to the transfer
of diverse aryl groups, and initial studies toward this goal focused
on the Pd(OAc)2-catalyzed reaction of 1 with the mixed iodine-
(III) reagents [Ph-I-Ar]BF4 (eq 2a). These reactions were found
to afford the desired arylated products (1b-g), but only as mixtures
with the analogous phenylated compound 1a [in ratios ranging from
2.6:1 to 0.31:1 (1b-g: 1a); see Table S1]. We reasoned that a sub-
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10.1021/ja051402f CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Functionalization of 1 with Diverse Aryl Substituents
Using [Mes-I-Ar]BF4
initively excluded based on the current data. However, a recent re-
port by Canty,7 which demonstrates the direct stoichiometric oxida-
tion of electron-rich Pd(II) complexes to Pd(IV) phenyl adducts
with [Ph2I]OTf, provides additional support in favor of the former.
In summary, we have described a new Pd-catalyzed method for
C-H activation/C-C bond formation and have demonstrated its
high functional group tolerance, regioselectivity, and scope under
relatively mild conditions. Preliminary mechanistic experiments
have provided evidence in support of a rare Pd(II)/(IV) catalytic
cycle for this transformation. Current efforts are aimed at further
elucidating the mechanism and exploring the scope of these trans-
formations.
a
a Conditions: substrate 1 (0.12 M), [Mes-I-Ar]BF4 (1.1-1.3 equiv),
Pd(OAc)2 (5 mol %), AcOH, 12 h, 100 °C. b Reaction carried out at 120
°C.
Acknowledgment. We thank the University of Michigan, the
Camille and Henry Dreyfus Foundation, and the Arnold and Mabel
Beckman Foundation for financial support.
Supporting Information Available: Experimental details and
spectroscopic and analytical data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
stantial steric differentiation between the two aryl groups at iodine-
(III) might allow for the selective transfer of the smaller substituent;
as such, reactions between 1 and [Mes-I-Ar]BF4 were examined.14
Gratifyingly, these transformations proceeded cleanly to provide a
single arylated product in good to excellent isolated yield (eq 2b).
As summarized in Table 2, both electron-poor (entries 2-4) and
electron-rich (entries 5-7) Ar groups were coupled efficiently, and
benzylic C-H bonds as well as aryl ethers and halides were well
tolerated on the arene component. Furthermore, even sterically
hindered aryl substituents, such as ortho-tolyl (entry 6), could be
transferred with good selectivity and yield using this approach.
References
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(2) For recent examples of Pd(0)/(II)-catalyzed C-H activation/arylation of
activated arenes/heterocycles, see: (a) Lane, B. S.; Sames, D. Org. Lett.
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Lett. 2002, 4, 1783. (b) Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.;
Miyano, S.; Inoue, Y. Org. Lett. 2001, 3, 2579.
(5) For other examples of C-H activation/C-C bond forming reactions,
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(b) Thalji, R. K.; Ellman, J. A.; Bergman, R. G. J. Am. Chem. Soc. 2004,
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(8) For the use of iodine(III) arylating agents in Pd(II)/(0) C-C bond forming
reactions, see: Zhdankin, V. V.; Stang, P. J. Chem. ReV. 2002, 102, 2523.
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Our efforts next turned to investigation of the mechanism of these
C-H activation/arylation reactions. Specifically, we sought to probe
the possible intermediacy of cyclopalladated complex A and Pd-
(IV) species C (eq 1) in the catalytic cycle. First, we replaced [Ph2I]-
BF4 with Ph-I or Ph-OTf, electrophiles that are well-known to
undergo rapid oxidative addition to Pd(0), and found that <1% of
phenylated product 1a is formed under our catalytic conditions.
Next, we prepared cyclopalladated complex 14 (eq 3) and found
that it catalyzes the phenylation of 1 at a rate approximately identical
to that of Pd(OAc)2. In addition, 14 undergoes stoichiometric
reaction with [Ph2I]BF4 to afford phenylated product 1a (eq 3);7,15
in contrast, <1% of 1a is formed in analogous reactions between
14 and Ph-I or Ph-OTf.
Further studies revealed that the reaction of 1 with [Ph2I]BF4/5
mol % Pd(OAc)2 is unaffected by the addition of ∼500 equiv of
metallic Hg (a potent poison for heterogeneous catalysis)10 or 25
mol % MEHQ or galvinoxyl (well-known free radical inhibitors),
suggesting that neither Pd nanoparticles nor free radicals are par-
ticipants in the reaction pathway.10 In sum, these experiments pro-
vide compelling evidence against a traditional Pd(0)/(II) catalytic
cycle and are consistent with C-H activation to form a cyclomet-
alated Pd(II) intermediate followed by either (i) oxidation of Pd(II)
to Pd(IV) by [Ph2I]BF4 and subsequent C-C bond forming reduc-
tive elimination (eq 1) or (ii) direct electrophilic cleavage of the
Pd(II)-carbon bond by [Ph2I]BF4 (without a change of oxidation
state at the metal). Both mechanisms are highly unusual in Pd-
catalyzed C-C bond forming reactions,9,10 and neither can be def-
(12) Maleczka, R. E.; Shi, F.; Holmes, D.; Smith, M. R., III. J. Am. Chem.
Soc. 2003, 125, 7792.
(13) Snieckus, V. Chem. ReV. 1990, 90, 879.
(14) Similar steric effects have been observed in Cr-catalyzed aldehyde
arylation. Chen, D.; Ochiai, M. J. Org. Chem. 1999, 64, 6804.
(15) The stoichiometric reaction between 14 and [Ph2I]BF4 produces 1a in
quantitative yield in the presence of 2.5 equiv of a free arylpyridine
substrate, such as 3. Without the addition of 3, 1a is produced in modest
(∼20%) yield along with a complex mixture of high MW organic products
(see Supporting Information for more details). The role of the external
ligand 3 is not entirely clear (and is currently under investigation), but it
may serve as a trap for highly reactive cationic Pd species generated after
C-C bond forming reductive elimination.
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