Palladium-catalyzed methylation and arylation of sp2 and sp 3 C-H bonds in simple carboxylic acids

Article abstract of DOI:10.1021/ja0701614

The use of preformed sodium carboxylates as substrates led to the first observation of facile Pd-insertions into sp³ β-C-H bonds in simple aliphatic acids. Consequently, Pd-catalyzed methylation and arylation of o-C-H bonds in benzoic acids and β-C-H bonds in aliphatic acids using either a phenylboronate, methylboronic acid, or ArI have been achieved via a C-H activation/C-C coupling sequence. Copyright

Full text of DOI:10.1021/ja0701614

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
widely used carbon-carbon bond-forming reactions in organic syn-
thesis.1 Extensive development of a wide range of ligands has
allowed the use of ArCl,2a-c alkyl halides,2d and sterically hindered
2,6-substituted ArX2e as coupling partners. The decarboxylative
Heck or Suzuki coupling using ArCOOH is another practically
appealing approach since carboxylic acids are readily available.3
The potential of Pd-catalyzed C-H activation reactions for develop-
ing synthetically useful carbon-carbon bond forming reactions
prompted our initial efforts to couple sp2 and sp3 C-H bonds in
oxazoline and pyridine substrates with organotin and organoboron
reagents.4,5 However, these types of substrates seriously restrict the
substrate scope since the oxazolines require installation and removal
and pyridines lack versatility for further synthetic manipulations.
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,
and others.8 Ortho alkenylation of benzoic acid catalyzed by Pd-
(OAc)2 has been reported by Miura.9 Despite these significant
advances, Pd-catalyzed C-H activation/C-C coupling reactions
using a carboxyl group (eqs 1,2) have not been developed. In
particular, Pd-catalyzed coupling of sp3 â-C-H bonds in aliphatic
acids with organometallic reagents is an unanswered challenge and
yet a significant goal from the viewpoint of synthetic applications.
Herein, we report the first catalytic protocol for the coupling of
both o-C-H bonds in benzoic acids and â-C-H bonds in aliphatic
acids with organoboron reagents via PdII/Pd0 catalysis. The general-
ity of this newly observed Pd-insertion into â-C-H bonds was
further demonstrated by â-arylation of aliphatic acids using ArI in
which PdII/PdIV catalysis is likely responsible.10-11
transformation. Thus, stirring sodium toluate 1a with 0.5 equiv of
benzoquinone, 1 equiv of Ag2CO3,13 3 equiv of MeB(OH)2 and 10
mol % Pd(OAc)2 in tert-amyl alcohol or tert-BuOH at 100 °C for
3 h affords ortho methylated product 1b in 50% isolated yield (eq
3). Arylation of 1a using a phenylboronate 2 as the coupling partner
proceeds under similar conditions at 120 °C to give ortho arylated
product 1c in 45% isolated yield (eq 3). Based on our previous
studies,4b this catalytic reaction most likely proceeds via a PdII/Pd0
catalysis. Although the role of sodium counterions remains to be
elucidated, we haVe shown that the preformed palladium toluate14
in the absence of sodium counterions is not reactiVe. This led us
to hypothesize that the electronically enriched carbonyl instead of
the O-anion of the sodium carboxylate binds the PdII in the C-H
cleavage step.
Guided by the mechanism of the Suzuki coupling reaction, we
reasoned that the yield could be further improved by employing a
suitable base to enhance the transmetalation step in the coupling
reaction. We screened a wide range of bases and found that
K2HPO4 increases the yields of 1b and 1c to 75% and 63%, respec-
tively (Table 1, entries 1, 3). Since the presence of K2HPO4 leads
to the in situ formation of carboxylates, benzoic acids instead of
sodium carboxylates are used as substrates under these new
conditions.
Although the arylation of benzoic acid gives a mixture of mono-
and diarylated compounds in 50% yield (3:2 ratio), we found that
the meta substituted benzoic acids lead to regioselective arylation,
albeit in lower yields (Table 1, entries 4-6). The tolerance of OMe
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
â-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
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-
tions (see Supporting Information) led us to discover that the use
of sodium carboxylates as substrates was effective for the desired
Table 1. Ortho Methylation and Arylation of Benzoic Acidsa
a Conditions: 10 mol % Pd(OAc)2, 0.5 equiv of benzoquinone, 1 equiv
of Ag2CO3, 1.5 equiv of K2HPO4, 2 equiv of MeB(OH)2 or 1 equiv of 2,
tert-BuOH, 120 °C, 3 h. b Yield at 100 °C.
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J. AM. CHEM. SOC. 2007, 129, 3510-3511
10.1021/ja0701614 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
a
could also displace the iodide from the (R)(Ar)PdIVI intermediate
and increase the turnover number as observed.
Table 2. â-Arylation of Aliphatic Acids Using Ph-B(OR)2
In summary, we have observed the first example of Pd-insertion
into sp3 â-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 â-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
support and the Camille and Henry Dreyfus Foundation for a New
Faculty Award. We are also grateful to the Myron Rosenblum
Endowed Fellowship to R.G and the NSF for a REU Fellowship
to S.P.B.
a Conditions: 10 mol % Pd(OAc)2, 1 equiv of 2, 0.5 equiv of benzo-
quinone, 1 equiv of Ag2CO3 and 1.5 equiv of K2HPO4. b Yields of their
methyl esters. Less than 2% diarylated products were observed in 6-10.
Table 3. â-Arylation of Aliphatic Acids Using ArIa
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
(%)b
entry
product
(%)b entry
product
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1
R ) Me, Ar ) Ph
6a/6b, 5:2
70
72
5
6
7
8
R ) rBu,, Ar ) Ph
62
45
42c
8a/8b, 4:1
2
3
4
R ) Et, Ar ) Ph
R ) (CH2)3OBn, Ar ) Ph
9a/9b, 5:1
R ) (CH2)2CO2Me, Ar ) Ph
10a/10b, 5:1
R ) (CH2)2CO2Me, Ar ) p-MePh 43
10c/10d, 5:1
7a/7b, 4:1
R ) rPr, Ar ) pMePh 60
12a/12b, 3:1
R ) nPr, Ar ) p-BrPh 63
12c/12d, 3:1
a Conditions: 10 mol % Pd(OAc)2, 2 equiv of aryl iodide, 2 equiv of
Ag2CO3, 1 equiv of K2HPO4, and 2 equiv of NaOAc. b Yields of their
methyl esters. c 10b was not isolated. The yield is based on 10a.
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predominantly the monoarylated product 6a in 30% isolated yield.
The use of Ag2O or AgOAc in place of Ag2CO3 as an oxidant
afforded less than 5% of 6a. The presence of Na2CO3 results in a
complete loss of reactivity with aliphatic acids. However, the
potassium carboxylate of 6 generated in situ using K2HPO4 affords
6a in 38% isolated yield (Table 2, entry 1).
While the catalytic turnover remains to be improved, the observed
mono-selectivity is a highly desirable advantage. Benzylethers and
esters were also tolerated (Table 2, entries 4-5), thus making this
protocol potentially applicable to organic synthesis. The preferential
arylation of the cyclopropyl C-H bond is worth noting since
examples of Pd insertion into methylene C-H bonds are still rare
(entry 6).15
Importantly, this coupling reaction provides the first example
for carboxyl-directed Pd-insertion into sp3 â-C-H bonds in simple
aliphatic acids. To demonstrate the generality of this C-H cleavage
reactivity in C-C bond forming reactions, we carried out arylation
reactions using ArI as the arylating reagents.15-17 We found that
alteration of our coupling protocol by omitting the benzoquinone
and using PhI as the coupling partner led to mono- and diarylation
of aliphatic acid 6 in 40% combined yield (6a/6b ) 5:2). We further
discovered that the use of 2 equiv of NaOAc as an additive
substantially increases the combined yield of 6a and 6b to 70%
(Table 3).18
This arylation reaction most likely involves a COOH directed
Pd insertion into C-H bonds and subsequent oxidation of the RPdII-
complex to (R)(Ar)PdIVI intermediate by ArI. The formation of
diarylated products (Table 3) is consistent with the PdII/PdIV
pathway in which the PdII, unlike the Pd0 in the cross-coupling
protocol, remains bound to the carboxylate and results in further
arylation. Ag2CO3 is mainly responsible for the catalytic turnover
by converting PdI2 into the reactive PdII species.16a The excess AcO-
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S. J. Am. Chem. Soc. 2003, 125, 1698. (b) For an example of Rh-catalyzed
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a
Pd-catalyzed arylation of sp3 C-H bonds in 2,4,6-tri-tert-
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and ArI as the arylating reagent see: Zaitsev, V. G.; Shabashov, D.;
Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154.
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PF6 see: (a) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J.
Am. Chem. Soc. 2005, 127, 7330. (b) Daugulis, O.; Zaitsev, V. G. Angew.
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to be important for the catalysis.
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