Palladium-catalyzed alkylation of sp2 and sp3 C-H bonds with methylboroxine and alkylboronic acids: Two distinct C-H activation pathways

Article abstract of DOI:10.1021/ja0646747

Palladium-catalyzed alkylations of sp² and sp³ C-H bonds with either methylboroxine or alkylboronic acids were developed. Ag₂O or AgCO₃ is used as a crucial oxidant and promoter for the transmetalation step. Ether, ester, alcohol, and alkene functional groups are tolerated. A new C-H activation pathway differing from the cyclometalation process is elucidated using methylboroxine as the coupling partner. Copyright

Full text of DOI:10.1021/ja0646747

Published on Web 09/08/2006
Palladium-Catalyzed Alkylation of sp2 and sp3 C-H Bonds with
Methylboroxine and Alkylboronic Acids: Two Distinct C-H Activation
Pathways
Xiao Chen, Charles E. Goodhue, and Jin-Quan Yu*
Department of Chemistry MS015, Brandeis UniVersity, Waltham, Massachusetts 02454-9110
Received July 1, 2006; E-mail: yu200@brandeis.edu
Table 1. Methylation of sp2 C-H Bonds with Methylboroxinea
The development of C-H activation/C-C bond forming reac-
tions catalyzed by transition metals has received much attention
recently.1 A wide range of efficient Ru- and Rh-catalyzed alkyla-
tions and arylations of aryl C-H bonds have been achieved with
olefins or aryl organometallic reagents.2,3 Pd-catalyzed alkenylation
of aryl C-H bonds via PdII/Pd0 catalysis has been reported.4
Significant results have also been obtained using Ar2I+X- or ArX
as the arylating reagents for sp2 5a,b and sp3 C-H bonds5c-e
involving PdII/PdIV catalysis. An alternative strategy involving C-H
activation by an intramolecular ArPdX moiety has been developed.6
In this context, an impressive example of arylation of sp3 C-H
bonds via Suzuki-Miyaura coupling has been achieved.7
We have recently initiated efforts to develop protocols for the
coupling of C-H bonds with organometallic reagents assisted by
a directing group (DG) (eq 1), which provided the first example
for Pd-catalyzed alkylation of sp2 C-H bonds.8 In this alkylation
reaction, the organotin reagents were added batch-wise to minimize
the undesired homocoupling reaction, which constitutes a practical
drawback. The toxicity of organotin reagents also limits the
a 10 mol % of Pd(OAc)2, 1 equiv of benzoquinone, 1 equiv of Cu(OAc)2,
applications. Furthermore, catalytic coupling of sp3 C-H bonds
2 equiv of methylboroxine, 100 °C, 24 h, CH2Cl2, air. b 10% dimethylated
with organotin reagents could not be achieved. Herein, we describe
a one-pot procedure for the coupling of sp2 and sp3 C-H bonds
with nontoxic and readily available methylboroxine and alkyl-
product was isolated.
Table 2. Methylation of sp3 C-H Bonds with Methylboroxinea
boronic acids using pyridine (Py) as a directing group.
The remarkable progress made in Pd-catalyzed alkyl-alkyl
Suzuki cross-coupling reactions with boronic acids9 indicates that
a C-H activation/C-C coupling sequence with organoboron re-
agents outlined in eq 1 is plausible in principle.10 However, the
execution of the sequential steps in a catalytic cycle represents a
formidable challenge for the following reasons: (1) PdII-catalyzed
homocoupling11a of organometallic reagents is faster than C-H acti-
vation; (2) the palladacycle formed from the C-H activation step
catalyzes homocoupling of the organometallic reagents11b if the
subsequent transmetalation and reductive elimination is not suf-
ficiently fast. Our strategy is to identify promoters for each step to
overcome the undesired homocoupling of the organoboron reagents.
Screening of coupling partners and reaction conditions using
2-phenylpyridine 1 as the substrate established that the combination
of Pd(OAc)2, methylboroxine (see eq 4), Cu(OAc)2, and benzoqui-
none provided a promising solution to this challenging problem
(Table 1). Functional groups attached to the aryl rings, such as MeO,
vinyl, and CF3, were tolerated (entries 2, 4, and 6), while a CHO
group decreased the yield (entry 5). Methylated product 12a was
also isolated in 36% yield using pyrazole as a directing group (entry
12).
a 10 mol % of Pd(OAc)2, 2 equiv of benzoquinone, 2 equiv of Cu(OAc)2,
2 equiv of methylboroxine, 100 °C, 24 h, HOAc, O2.
rather than CH2Cl2/air (Table 2). Ether, alcohol, and ester substrates
(entries 6-8) are compatible with this reaction. It is worth noting
that alkylation of the methylene group was also shown to be possible
(entry 9), albeit in lower yield. Unfortunately, the coupling of either
substrate 1 or 13 with ethyl- or butylboroxines as coupling partners
failed to give any desired alkylation products under various
conditions.
Importantly, the coupling of sp3 C-H bonds with methylboroxine
was also achieved by running the reaction in acetic acid/O2 (1 atm)
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C O M M U N I C A T I O N S
Table 3. Alkylation of C-H Bonds with Boronic Acidsa
process (eq 2). For the reaction with methylboroxine, we propose
that the methylboroxine coordinates with the pyridyl group first,
and the chelation of the oxygen atom in the methylboroxine with
Pd(OAc)2 directs the C-H cleavage (eq 4).15 The subsequent
intramolecular transmetalation is highly efficient, not requiring a
promoter (eq 4).
In summary, we have developed the first protocol for PdII-cata-
lyzed alkylations of sp2 and sp3 C-H bonds with either methyl-
boroxine or alkylboronic acids. Mechanistic investigations alluded
to an unusual methylboroxine-assisted C-H activation pathway.
We are currently exploring this new C-H activation pathway.
Acknowledgment. We thank Brandeis University and the U.S.
National Science Foundation (NSF CHE-0615716) for financial
support, and the Camille and Henry Dreyfus Foundation for a New
Faculty Award.
a 10 mol % of Pd(OAc)2, 1 equiv of Ag2O, 0.5 equiv of benzoquinone,
3 equiv of boronic acid, 100 °C, 6 h, tert-amyl alcohol, air.
To solve this problem, we turned to boronic acids. The reaction
of 1 with ethylboronic acids under the conditions described in Table
1 resulted in full recovery of the starting material. The stoichiometric
reaction of the dimeric palladacycle prepared from 1 with ethyl-
boronic acid gives 1b in less than 5% yield, indicating that
transmetalation is problematic. Screening a wide range of bases,
oxidants, and solvents established that the alkylation reaction
proceeds smoothly in the presence of Ag2O (or Ag2CO3) and
benzoquinone using t-amyl alcohol as the solvent (see Supporting
Information). Ag2O plays a dual role as an efficient promoter for
the transmetalation12 and co-oxidant13 with benzoquinone. Benzo-
quinone is crucial for the reductive elimination step.8 We were
pleased to find that this new protocol allowed the coupling of both
sp2 and sp3 C-H bonds with other boronic acids, including
cyclopropylboronic acid, thereby substantially expanding the scope
of C-H activation/C-C coupling reactions (Table 3). It should be
noted that the formation of dialkylated products was not observed
in entries 1-10. Interestingly, while Cu(OAc)2 is an efficient
oxidant with methylboroxine, the coupling reactions with boronic
acids were severely suppressed.14
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.
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)
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respectively, suggesting that C-H cleavage is the rate-limiting step
in both reactions (see Supporting Information).
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