Published on Web 03/03/2007
Palladium-Catalyzed Methylation and Arylation of sp2 and sp3 C-H Bonds in
Simple Carboxylic Acids
Ramesh Giri, Nathan Maugel, Jiao-Jie Li, Dong-Hui Wang, Steven P. Breazzano,
Lindsey B. Saunders, and Jin-Quan Yu*
Department of Chemistry MS015, Brandeis UniVersity, Waltham, Massachusetts 02454-9110
Received January 13, 2007; E-mail: yu200@brandeis.edu
Palladium-catalyzed cross-coupling reactions are among the most transformation. Thus, stirring sodium toluate 1a with 0.5 equiv of
widely used carbon-carbon bond-forming reactions in organic syn- benzoquinone, 1 equiv of Ag2CO3,13 3 equiv of MeB(OH)2 and 10
thesis.1 Extensive development of a wide range of ligands has mol % Pd(OAc)2 in tert-amyl alcohol or tert-BuOH at 100 °C for
allowed the use of ArCl,2a-c alkyl halides,2d and sterically hindered 3 h affords ortho methylated product 1b in 50% isolated yield (eq
2,6-substituted ArX2e as coupling partners. The decarboxylative 3). Arylation of 1a using a phenylboronate 2 as the coupling partner
Heck or Suzuki coupling using ArCOOH is another practically proceeds under similar conditions at 120 °C to give ortho arylated
appealing approach since carboxylic acids are readily available.3 product 1c in 45% isolated yield (eq 3). Based on our previous
The potential of Pd-catalyzed C-H activation reactions for develop- studies,4b this catalytic reaction most likely proceeds via a PdII/Pd0
ing synthetically useful carbon-carbon bond forming reactions catalysis. Although the role of sodium counterions remains to be
prompted our initial efforts to couple sp2 and sp3 C-H bonds in elucidated, we haVe shown that the preformed palladium toluate14
oxazoline and pyridine substrates with organotin and organoboron in the absence of sodium counterions is not reactiVe. This led us
reagents.4,5 However, these types of substrates seriously restrict the to hypothesize that the electronically enriched carbonyl instead of
substrate scope since the oxazolines require installation and removal the O-anion of the sodium carboxylate binds the PdII in the C-H
and pyridines lack versatility for further synthetic manipulations. cleavage step.
Considering the broad utility of hydroxyl and carboxyl func-
tionalities as directing groups in asymmetric catalysis,6 the use of
simple functional groups to direct C-H activation/C-C coupling
processes could prove fruitful in developing C-C bond forming
reactions.7 Carboxyl-directed lactonization of sp3 C-H bonds
catalyzed by K2PtCl4 has been previously observed by Sen, Sames,
Guided by the mechanism of the Suzuki coupling reaction, we
and others.8 Ortho alkenylation of benzoic acid catalyzed by Pd-
reasoned that the yield could be further improved by employing a
(OAc)2 has been reported by Miura.9 Despite these significant
suitable base to enhance the transmetalation step in the coupling
advances, Pd-catalyzed C-H activation/C-C coupling reactions
reaction. We screened a wide range of bases and found that
using a carboxyl group (eqs 1,2) have not been developed. In
K2HPO4 increases the yields of 1b and 1c to 75% and 63%, respec-
particular, Pd-catalyzed coupling of sp3 -C-H bonds in aliphatic
tively (Table 1, entries 1, 3). Since the presence of K2HPO4 leads
acids with organometallic reagents is an unanswered challenge and
to the in situ formation of carboxylates, benzoic acids instead of
yet a significant goal from the viewpoint of synthetic applications.
sodium carboxylates are used as substrates under these new
Herein, we report the first catalytic protocol for the coupling of
conditions.
both o-C-H bonds in benzoic acids and -C-H bonds in aliphatic
Although the arylation of benzoic acid gives a mixture of mono-
acids with organoboron reagents via PdII/Pd0 catalysis. The general-
and diarylated compounds in 50% yield (3:2 ratio), we found that
ity of this newly observed Pd-insertion into -C-H bonds was
the meta substituted benzoic acids lead to regioselective arylation,
further demonstrated by -arylation of aliphatic acids using ArI in
albeit in lower yields (Table 1, entries 4-6). The tolerance of OMe
which PdII/PdIV catalysis is likely responsible.10-11
and CO2Me groups allows for the preparation of a wide range of
1,2,4-substituted arenes.
Encouraged by these results, we attempted the coupling of
-C-H bonds in aliphatic acids with 2. The sodium carboxylate
of 6 was subjected to the arylation conditions in eq 3 to give
The formation of phenoxide in the presence of Cs2CO3 acceler-
ates both intra-12a and intermolecular12b ortho arylation of phenols
Table 1. Ortho Methylation and Arylation of Benzoic Acidsa
using a combination of Pd0 and ArI. This effect was attributed to
either an increase of the electron density of the phenyl ring or an
enhanced binding of the ArPdI species to the phenoxide. Inspired
by these observations, we focused on the development of Pd(OAc)2-
catalyzed C-H functionalization processes directed by carboxyl
groups. If successful, these types of processes could be applicable
to a wide range of simple substrates containing acidic protons. On
the basis of the Pd-catalyzed coupling protocols recently developed
in our laboratory,4b we began to search for coupling conditions using
simple carboxylic acids as substrates. Extensive screening of condi-
a
Conditions: 10 mol % Pd(OAc)2, 0.5 equiv of benzoquinone, 1 equiv
tions (see Supporting Information) led us to discover that the use
of Ag2CO3, 1.5 equiv of K2HPO4, 2 equiv of MeB(OH)2 or 1 equiv of 2,
b
of sodium carboxylates as substrates was effective for the desired tert-BuOH, 120 °C, 3 h. Yield at 100 °C.
9
3510 J. AM. CHEM. SOC. 2007, 129, 3510-3511 10.1021/ja0701614 CCC: $37.00 © 2007 American Chemical Society
C O MMU N I C A T I O N S
Table 2. -Arylation of Aliphatic Acids Using Ph-B(OR)2a
could also displace the iodide from the (R)(Ar)PdIVI intermediate
and increase the turnover number as observed.
In summary, we have observed the first example of Pd-insertion
into sp3 -C-H bonds in simple aliphatic acids. A promising
protocol for the coupling of sp2 and sp3 C-H bonds in simple
carboxylic acids with organoboron reagents has been established.
The potential of carboxyl-directed C-H activation in developing
C-C bond-forming reactions is also demonstrated by the arylation
of -C-H bonds in aliphatic acids using ArI. We are currently
optimizing the conditions to improve the yields of these reactions.
Acknowledgment. We thank Brandeis University for financial
a
Conditions: 10 mol % Pd(OAc)2, 1 equiv of 2, 0.5 equiv of benzo-
support and the Camille and Henry Dreyfus Foundation for a New
b
quinone, 1 equiv of Ag2CO3 and 1.5 equiv of K2HPO4. Yields of their
Faculty Award. We are also grateful to the Myron Rosenblum
methyl esters. Less than 2% diarylated products were observed in 6-10.
Endowed Fellowship to R.G and the NSF for a REU Fellowship
Table 3. -Arylation of Aliphatic Acids Using ArIa
to S.P.B.
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
yield yield
entry product (%)b entry product (%)b
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While the catalytic turnover remains to be improved, the observed
For a Pd-catalyzed arylation of sp3 C-H bonds in 2,4,6-tri-tert-
mono-selectivity is a highly desirable advantage. Benzylethers and
butylbromobenzene with PhB(OH)2 see: Barder, T. E.; Walker, S. D.;
Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685. (d)
esters were also tolerated (Table 2, entries 4-5), thus making this
For a Pd-catalyzed arylation of vinylic C-H bonds with PhB(OH)2 see:
protocol potentially applicable to organic synthesis. The preferential
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arylation of the cyclopropyl C-H bond is worth noting since
Dangel, B. D.; Johnson, J. A.; Sames, D. J. Am. Chem. Soc. 2001, 123,
examples of Pd insertion into methylene C-H bonds are still rare
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(9) Miura, M.; Tsuda, T.; Satoh, T.; Pivsa-Art, S.; Nomura, M. J. Org. Chem.
(entry 6).15
1998, 63, 5211.
Importantly, this coupling reaction provides the first example
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and ArI as the arylating reagent see: Zaitsev, V. G.; Shabashov, D.;
for carboxyl-directed Pd-insertion into sp3 -C-H bonds in simple
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PF6 see: (a) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J.
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and using PhI as the coupling partner led to mono- and diarylation
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(13) Ag2CO3 releases Ag+ and CO32- slowly during the reaction which appears
of aliphatic acid 6 in 40% combined yield (6a/6b ) 5:2). We further
to be important for the catalysis.
discovered that the use of 2 equiv of NaOAc as an additive
(14) Hermans, S.; Wenkin, M.; Devillers, M. J. Mol. Catal. A: Chem. 1998,
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substantially increases the combined yield of 6a and 6b to 70%
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(Table 3).18
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using MeI or ArX see: (a) Tremont, S. J.; Rahman, H. U. J. Am. Chem.
This arylation reaction most likely involves a COOH directed
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complex to (R)(Ar)PdIVI intermediate by ArI. The formation of
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diarylated products (Table 3) is consistent with the PdII/PdIV
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(17) For arylation of sp3 C-H bonds in 1-tert-butyl-2-iodobenzene see: Dyker,
pathway in which the PdII, unlike the Pd0 in the cross-coupling
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(18) The arylation of toluic acid 1 under the same conditions gives the ortho
arylated product in 95% yield.
arylation. Ag2CO3 is mainly responsible for the catalytic turnover
by converting PdI2 into the reactive PdII species.16a The excess AcO- JA0701614
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J. AM. CHEM. SOC. VOL. 129, NO. 12, 2007 3511


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