Pd(0)/PR3-catalyzed intermolecular arylation of sp3 C-H bonds

Article abstract of DOI:10.1021/ja903573p

(Figure Presented) Pd(0)-catalyzed intermolecular arylation of sp ³ C-H bonds has been achieved using PR₃/Arl. This protocol can be used to arylate a variety of aliphatic carboxylic acid derivatives, including a number of bioactive d

Full text of DOI:10.1021/ja903573p

Published on Web 07/06/2009
Pd(0)/PR3-Catalyzed Intermolecular Arylation of sp3 C-H Bonds
Masayuki Wasa, Keary M. Engle, and Jin-Quan Yu*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
Received May 2, 2009; E-mail: yu200@scripps.edu
Table 1. Directing Group Screeninga b
,
Palladium-catalyzed arylation of C-H bonds using Pd(0)/PAr3/
ArI has attracted a great deal of attention during the past several
decades.1-3 Compared to Pd(II)-catalyzed oxidative C-H func-
tionalization processes, arylation using this type of catalytic system
accommodates phosphine and NHC ligands and does not require a
co-oxidant, both of which can be significant practical advantages.
Despite pioneering efforts to apply this arylation reaction to sp3
C-H bonds, to date, only a few examples of alkyl C-H activation
by an intramolecular ArPdBr species have been reported by Dyker
and others (eqs 1-3, Scheme 1).4,5 Herein we report an example
of Pd(0)-catalyzed intermolecular arylation of ꢀ-C-H bonds in a
wide range of amide substrates (eq 4, Scheme 1). The development
of a simple and readily removable amide directing group was crucial
for enabling facile C-H activation under our reaction conditions.
Moreover, the use of CsF as the base allowed the substrate scope
to be expanded to include amides that contain R-hydrogen atoms.
a Conditions: 0.2 mmol of substrate, 10 mol % Pd(OAc)2, 20 mol %
ligand, 3.0 equiv of CsF, 3.0 equiv of aryl iodide, 100 mg of 3 Å MS, 1
mL of toluene, 100 °C, N2, 24 h. b Yield was determined by 1H NMR
analysis of crude product using CH2Br2 as the internal standard.
Scheme 1. Pd(0)-Catalyzed Arylation of C-H Bonds
Table 2. Ligand Screeninga
Previously, we have reported various auxiliary approaches for
ꢀ-C-H functionalization of aliphatic acid derivatives using Pd(II)/
Pd(IV) and Pd(II)/Pd(0) catalysis.6 In particular, the excellent
observed reactivity of O-methyl hydroxamic acids for ꢀ-C-H
activation prompted us to test whether intermolecular arylation of
ꢀ-C-H bonds could be achieved using this substrate and an ArI/
Pd(0)/PPh3 catalytic system. During our preliminary screening,
however, we found that the N-H bond of the CONHOMe moiety
readily underwent Buchwald-Hartwig amination with ArI. We
hypothesized that by reducing the nucleophilicity of the amide N-H
bond we could suppress the amination pathway. To this end, we
examined the effect of replacing the N-OMe group with a wide
range of N-aryl groups (Table 1) and screened each of these
substrates with a variety of different bases and ligands. Among
the bases tested, only CsF was found to be effective for arylation
with substrates that contained R-hydrogen atoms, although sub-
strates that did not contain R-hydrogen atoms worked well with
Cs2CO3 (see Supporting Information). With guidance from previous
studies,1-4 we screened an array of different phosphine ligands
(Table 2). Overall, we found that the desired ꢀ-C-H arylation
reaction proceeded best using CONH-C6F5 directing group, with
Buchwald’s Cyclohexyl JohnPhos ligand and CsF as base. Notably,
the use of Fu’s strategy for improving the stability of the phosphine
ligands by forming the HBF4 salt7 allowed our reaction to be
performed without using stringent air-sensitive techniques.
a The reaction conditions are identical to those described in Table 1.
Using this newly developed protocol, a wide range of R-methylated
carboxylic acids (after first being converted to the corresponding
amides) were arylated in excellent yields. ꢀ-Arylation of amide 2,
which contains a quaternary R-carbon atom, gave the monoarylated
product 2a in 78% yield. Αmides with tertiary and secondary R-carbon
atoms were also arylated in good yields (1a and 3a-6a), although
the arylation of ꢀ-methylene C-H bonds in a pentanoic acid derived
substrate gave only trace amount of product. Since amides 1 and 3
are derived from abundant and cheap feedstock chemicals (propanoic
and isopropanoic acid, respectively), this arylation process provides a
potential method for installing these prevalent three- and four-carbon
units onto advanced arene precursors in synthesis. Functional groups
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10.1021/ja903573p CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
such as protected amines, ethers, and ketones were tolerated (5a, 7a,
9a, and 10a). The directing group in the product can be removed
through either hydrolysis with 2 N KOH in ethylene glycol at 80 °C
or treatment with MeI/Na2CO3 followed by 2 N HCl at 24 °C.
The potential of this new catalytic reaction for application in a host
of different settings, including drug diversification, was further
demonstrated by the arylation of amides 7-11 derived from the drugs
gemfibrozil, ibuprofen, ketoprofen, fenoprofen, and flurbiprofen (Table
3). Strategically, the ability to functionalize selectively inert methyl
groups in biologically active molecules is of great importance in drug
discovery.
The mechanistic implications of this intermolecular C-H activation
reaction merit discussion. The data in Table 1 show that an acidic
N-H bond in the directing group is essential for reactivity. The fact
that amination of the ArI is not observed in the presence of well-
established ligands for amination is inconsistent with the involvement
of a Pd-NCOAr species A (Figure 1). We propose that the C-H
activation precursor B bears a coordination mode analogous to that of
the complex involved in ortho-C-H cleavage of phenyl acetic acid
substrates by Pd(OAc)2 (Figure 1).8 At this stage, the mechanism at
play in the subsequent C-H cleavage step in our system has yet to be
fully elucidated. For instance, it is unclear whether the phosphine ligand
remains bound to the Pd(II) center during this process. Furthermore,
the question of whether classical oxidative addition or proton abstrac-
tion by an external F- is the operative pathway also warrants further
investigation (Figure 1).
Table 3. ꢀ-Arylation of Carboxylic Acid-Derived Amidesa
Figure 1. Possible coordination modes.
In summary, we have developed a novel protocol for intermolecular
arylation of sp3 C-H bonds. This reaction provides a simple method
for ꢀ-arylation of carboxylic acids. Studies to develop an enantiose-
lective version of this reaction are currently underway in our laboratory.
Acknowledgment. We gratefully acknowledge The Scripps
Research Institute, the National Institutes of Health (NIGMS, 1 R01
GM084019-02), Amgen, and Eli Lilly for financial support. We thank
the A. P. Sloan Foundation for a fellowship (J.-Q.Y.) and the National
Science Foundation, the Department of Defense, and the Skaggs
Oxford Scholarship program for predoctoral fellowships (K.M.E.).
Supporting Information Available: Experimental procedure and
characterization of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
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a The reaction conditions are the same as described in Table 1.
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a The reaction conditions are identical to those described in Table 1.
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