Cobalt-catalyzed ortho-Alkylation of secondary benzamide with alkyl chloride through directed C-H bond activation

Article abstract of DOI:10.1021/ja1099853

Coupling of an alkyl chloride with a secondary benzamide derivative at the ortho-position can be achieved in good to excellent yield in the presence of a cobalt catalyst and cyclohexylmagnesium chloride in diethyl ether at room temperature. Cyclohexylmagnesium chloride formally acts to remove hydrogen atoms from the amide nitrogen and from the ortho-position and to generate the active cobalt species.

Full text of DOI:10.1021/ja1099853

Published on Web 12/15/2010
Cobalt-Catalyzed ortho-Alkylation of Secondary Benzamide with Alkyl
Chloride through Directed C-H Bond Activation
Quan Chen, Laurean Ilies, and Eiichi Nakamura*
Department of Chemistry, School of Science, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033
Received November 7, 2010; E-mail: nakamura@chem.s.u-tokyo.ac.jp
ortho-hydrogen atom,10 and a slight excess of CyMgCl was used
Abstract: Coupling of an alkyl chloride with a secondary benza-
mide derivative at the ortho-position can be achieved in good to
excellent yield in the presence of a cobalt catalyst and cyclo-
hexylmagnesium chloride in diethyl ether at room temperature.
Cyclohexylmagnesium chloride formally acts to remove hydrogen
atoms from the amide nitrogen and from the ortho-position and
to generate the active cobalt species.
to reduce Co(II)7 and also to compensate for side reactions such
as homocoupling and ꢀ-hydride elimination. All reagents are
mandatory for the success of the reaction. No conversion occurred
in the absence of either CyMgCl or DMPU.11 n-BuBr gave a much
lower yield than n-BuCl (see Supporting Information). Co(acac)3
and CoCl2 performed as efficiently as Co(acac)2, suggesting that
they are converted into the same catalytic species under the reaction
conditions. The reaction did not proceed at all in the absence of
the cobalt catalyst. Ni(acac)2 gave 4 in low yield, while
C-H bond activation of an aromatic compound leading to
regioselective formation of an aryl-aryl bond has received
considerable attention; however the corresponding alkyl-aryl bond
formation has met only with limited success.1 Furthermore, despite
potential use in medicinal and materials research, C-H bond
activation next to an amide group has been scarcely investigated,2
and to the best of our knowledge the alkylation of simpe benzamide
has not been reported.3 The reported methods typically require
precious metal catalysts and harsh reaction conditions, which led
us to study iron catalysis,4,5 especially C-H bond activation,6 and
now we disclose a new cobalt-catalyzed7 C-H bond activation.8,9
We report here that a cobalt-catalyzed coupling of a secondary
benzamide with an alkyl chloride in the presence of cyclohexyl-
magnesium chloride (CyMgCl) takes place at room temperature to
afford an ortho-alkylated benzamide in good to excellent yields.
The butylation of N-methyl-3-phenylbenzamide (1) with n-BuCl
shown in eq 1 is representative. 1 (0.50 mmol), Co(acac)2 (10 mol
%), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 12
equiv), and n-BuCl (1.2 equiv) were placed in a Schlenk tube, followed
by dropwise addition of a diethyl ether solution of CyMgCl (2.0 mol/
L, 0.75 mL) at 0 °C. The reaction mixture was stirred at room
temperature for 12 h and afforded selectively a 6-butylated product 3
in 81% isolated yield, accompanied by a dibutylated product 5 (<5%)
as detected by 1H NMR. Thus, the meta-phenyl group in 1 controlled
the alkylation to selectively occur on the less hindered position. When
an unsubstituted N-methylbenzamide 2 was used as a substrate, a
monoalkylated product 4 and a dialkylated product 6 were isolated in
63% and 22% yield, respectively. Thus, the combined yield based on
2 was 85% and that based on n-BuCl was 89%.
PdCl2(PPh3)2, Cu(OTf)2, and Fe(acac)3, among others, did not give
any desired product and the starting material was mostly recovered.
Table 1 summarizes the scope of the aromatic substrates. A
tertiary amide (entry 1) did not afford any alkylated products and
Table 1. Cobalt-Catalyzed ortho-Butylation of Benzamides and
Congeners with Butyl Chloridea
a The reaction was performed under the conditions shown in eq 1.
See the Supporting Information for details. The newly formed C-C
bond is shown in bold. b Isolated yield. The values in parentheses refer
to the 1H NMR yield. Most of the starting material was recovered when
the yield was low. c 20 mol % of catalyst was used. d 2.5 equiv of
n-BuCl, 4.0 equiv of cyclopentylmagnesium chloride, and 18 equiv of
DMPU were used.
The optimum conditions for the reaction of 2 with n-BuCl (1.2
equiv) call for the use of 3 equiv of CyMgCl, DMPU (12 equiv to
2), and a catalytic amount of Co(acac)2 (10 mol %) in diethyl ether
at room temperature. A 2 equiv amount of CyMgCl is formally
necessary to deprotonate the amide nitrogen and to remove the
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428 J. AM. CHEM. SOC. 2011, 133, 428–429
10.1021/ja1099853  2011 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Cobalt-Catalyzed ortho-Alkylation of
took part in the reaction to give the desired compound, suggesting
considerable synthetic potential for this method.
N-Methyl-3-Phenylbenzamide with Various Alkyl Chloridesa
In summary, we have developed a cobalt-catalyzed directed
activation of an ortho C-H bond of a secondary benzamide, which
results in regioselective coupling with an alkyl chloride. This
reaction represents a rare example of the cobalt-catalyzed introduc-
tion of a saturated hydrocarbon group directly to an aromatic group
through C-H bond activation, especially to a benzamide substrate.
An intricate reaction mechanism yet to be investigated allowed us
to couple the benzamide and the primary alkyl chloride directly
without preparing the corresponding alkyl anion separately.15 The
mild reaction conditions and the use of an inexpensive ligand,
DMPU, are additional attractive features. Benzamide is a functional
group of established importance, and the present alkylation method
will be useful in various fields including medicinal and organo-
electronics applications. Finally, this finding will contribute to the
expansion of the repertoire of cobalt catalysis that has received
considerable attention in recent years.7
Acknowledgment. We thank MEXT (KAKENHI Specially
Promoted Research for E.N., No. 22000008; Strategic Promotion
of Innovative Research and Development from Japan Science and
Technology Agency, JST) and the Global COE Program for
Chemistry Innovation and the University of Tokyo ASATSU-DK
China Scholarship.
Supporting Information Available: Experimental procedures and
data of the new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
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a The reaction was performed under the conditions shown in eq 1.
See the Supporting Information for details. The newly formed C-C
bond is shown in bold. b Isolated yield. The values in parentheses refer
to the 1H NMR yield. c 1.2 equiv of each alkyl chloride was used. d 2.0
equiv of the alkyl chloride was used.
resulted largely in the recovery of the starting material, indicating
that a deprotonated amide acts as a directing group. N-Phenylamide
gave the butylated product in low yield (entry 2), together with the
recovery of the starting material. The alkylation of the anilide ring12
was not observed. The selective 6-butylation of the 3-phenyl
substrate (Vide supra, entry 3) suggests steric control. The reaction
tolerates the presence of MeO and F groups (entries 6 and 7). In
contrast to its R ) H counterpart 2, which predominantly gave the
monobutylated product 4 (entries 4 and 5), 4-fluorobenzamide tends
to give the dibutylated product, and the use of excess BuCl (2.5
equiv) and of cyclopentylmagnesium chloride (4.0 equiv) gave the
dibutyl compound in 88% yield (entry 7). 1-Naphthylamide (entry
8) and N-methylisonicotinamide2e (entry 9) also serve as a substrate
of this reaction. The latter selectively undergoes dibutylation
reaction (entry 9), similarly to the 4-fluoro substrate.
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reactions gave a monoalkylated product accompanied by a trace
or undetectable amount of the dialkylated product. The use of
cyclohexyl chloride (in combination with CyMgCl) resulted largely
in the recovery of the starting amide (entry 1). The reaction of
t-BuCl gave an isobutylated product (entry 2) suggesting ꢀ-elimina-
tive rearrangement of a σ-cobalt intermediate13 or intermediacy of
a π-complex.14 A competition experiment using an equimolar
mixture of n-BuCl and t-BuCl (entry 3) gave predominantly the
product from t-BuCl (i.e., the isobutylated product), suggesting a
radical-like activation of the alkyl chloride. Alkyl chlorides bearing
trimethylsilyl, acetal, and pyrrole groups (entries 5-7) smoothly
(14) We are grateful to a reviewer who pointed out this possibility.
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