Cobalt-catalyzed coupling of alkyl grignard reagent with benzamide and 2-phenylpyridine derivatives through directed C-H bond activation under air

Article abstract of DOI:10.1021/ol2011264

Aromatic carboxamides and 2-phenylpyridine derivatives can be ortho-alkylated with Grignard reagents in the presence of a cobalt catalyst and DMPU as a ligand. The reaction proceeds smoothly at room temperature, using air as the sole oxidant. The dialkyla

Full text of DOI:10.1021/ol2011264

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3232–3234
Cobalt-Catalyzed Coupling of Alkyl
Grignard Reagent with Benzamide and
2-Phenylpyridine Derivatives through
Directed CꢀH Bond Activation under Air
Quan Chen, Laurean Ilies, Naohiko Yoshikai,† and Eiichi Nakamura*
Department of Chemistry, School of Science, The University of Tokyo, Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
nakamura@chem.s.u-tokyo.ac.jp
Received April 27, 2011
ABSTRACT
Aromatic carboxamides and 2-phenylpyridine derivatives can be ortho-alkylated with Grignard reagents in the presence of a cobalt catalyst and
DMPU as a ligand. The reaction proceeds smoothly at room temperature, using air as the sole oxidant. The dialkylated product is selectively
obtained when N-methylcarboxamide is employed as a substrate, whereas N-phenyl- or N-isopropylcarboxamide preferentially gives the
monoalkylated product.
Introduction of an alkyl group to an aromatic molecule
through transition-metal-catalyzed directed CꢀH bond
activation has recently emerged1 as an attractive method
for CꢀC bond formation. This approach allows the re-
gioselective introduction of a primary alkyl group, which is
prone to isomerization in FriedelꢀCrafts chemistry.2
However, this class of reactions still remains a challenge
for organic chemists3 because of the propensity of alkyl
organometallic reagents to undergo β-hydride elimination.
Successful examples4 include the directed alkylation of an
aromatic CꢀH bond with an alkylboron reagent or tetra-
alkyltin catalyzed by palladium at high temperature
(>100 °C) using Cu(II)/benzoquinone as an oxidant.5,6
We report herein that an inexpensive and benign cobalt
salt7ꢀ9 catalyzes an oxidative alkylation reaction of an
aromatic carboxamide or 2-phenylpyridine derivative with
an alkyl Grignard reagent in the presence of 1,3-dimethyl-
3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU).10 The
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† Present address: Division of Chemistry and Biological Chemistry,
School of Physical and Mathematical Sciences, Nanyang Technological
University, Singapore 637371.
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T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147–1169. (c) Chen, X.;
Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48,
5094–5115. (d) Handbook of CꢀH Transformations; Dyker, G., Ed.;
Wiley-VCH: Weinheim, 2005. (e) Kakiuchi, F.; Chatani, N. Adv. Synth.
Catal. 2003, 345, 1077–1101. (f) Shabashov, D.; Daugulis, O. J. Am.
Chem. Soc. 2010, 132, 3965–3972. (g) Ackermann, L.; Hofmann, N.;
Vicente, R. Org. Lett. 2011, 13, 1875–1877.
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ꢀ
(c) Gosmini, C.; Begouin, J.-M.; Moncomble, A. Chem. Commun.
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istry. A Century of Discovery; Marcel Dekker: New York, 1984.
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r
10.1021/ol2011264
Published on Web 05/24/2011
2011 American Chemical Society

reaction proceeds at room temperature in the presence of
air as the sole oxidant (eq 1). We also show that selectivity
toward mono- or dialkylation can be controlled by tuning
the directing group.
Table 2 summarizes the scope of the reaction with
benzamide derivatives. At least 2 equiv of the Grignard
reagent are necessary for deprotonation of the secondary
benzamide and for accepting the ortho-hydrogen atom.
The material balance for the benzamide was generally good,
and the starting material was recovered when the yield was
low. The byproducts were typically those produced by the
homocoupling and β-hydride elimination of the organo-
metallic reagent. As already discussed, the dialkyl product
3 was selectivelyobtainedinentry 1, and thisselectivity was
observed even when a smaller amount of the ethyl Grignard
reagent was used (entry 2). The preferred formation of the
dialkylation product of the N-methylamide substrate 1
suggests that the second alkylation takes place before the
cobalt species dissociates from the monoalkylated amide.
Note that the ortho-monoalkylated substrate 2 (entry 4)
reacted more slowly than the unsubstituted benzamide 1.
Dialkylzinc reagentscouldalsobeutilized(entry3), but the
reaction was slower and the monoalkylated product was
favored over the dialkylated product.
While cobalt/diamine-catalyzed directed oxidative ary-
lation of an arylpyridine with a zinc or Grignard reagent
has been recently reported,11 the use of alkyl Grignard
reagents possessing a β-hydrogen gave poor results. In
light of our recent finding that DMPU may serve to
stabilize alkylcobalt intermediates,12 we investigated the
cobalt-catalyzed reaction of N-methylbenzamide (1) with
EtMgCl in the presence of a cobalt catalyst and dry air as
an oxidant (Table 1). After considerable experimentation,
we found that the reaction of 1 with a THF solution of
EtMgCl (ca. 6 equiv) in the presence of Co(acac)2 (10 mol
%) and DMPU (30 equiv) in a Schlenck rection tube under
an atmosphere of dry air gives a dialkylated product 3 in
79% isolated yield and a trace amount (<2%) of the
monoalkylated product 2 (eq 1).
Substrates possessing an electron-donating or an elec-
tron-withdrawing substituent reacted smoothly to give the
corresponding diethylated products in good yield (entries 5
DMPU was crucial for achieving high yield and selec-
tivity (Table 1, entry 2). In its absence (entry 1), 2 and 3
were obtained unselectively in poor yield, together with the
recovery of the starting amide 1. Other Lewis basic ligands
such as tetramethylurea (TMU, entry 3), 1,3-dimethyl-2-
imidazolidinone (DMI, entry 4), and hexamethylpho-
sphoramide (HMPA, entry 5) performed less satisfacto-
rily. The diamines used previously11 as ligands for the
cobalt-catalyzed arylation of arylpyridine were inefficient
in this reaction (entries 6 and 7). High-purity (99.99%)
Co(acac)3 (entry 8) performed similarly to Co(acac)2 of
>98% purity, while the reaction did not proceed at all in
the absence of a catalyst (entry 9). Only a trace amount of
the products formed under nitrogen (entry 10).
Table 2. Cobalt-Catalyzed Oxidative Alkylation of Aromatic
Carboxamides with Grignard Reagentsa
Table 1. Reaction Conditions for the Cobalt-Catalyzed Alky-
lation of N-Methylbenzamide (1) with EtMgCla
entry
catalyst
ligand
2b (%)
3b (%)
1
2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)3
none
none
9
<2
5
11
80 (79)
50
DMPU
TMU
3
4
DMI
30
2
22
5
HMPA
TMEDAc
dtbpyd
DMPU
DMPU
DMPU
59
6
<2
<2
5
<2
7
<2
e
8
75
9
10 f
0
0
Co(acac)2
3
11
a Reaction conditions: 1 (0.50 mmol), cobalt catalyst (0.05 mmol),
EtMgCl, ligand (30 equiv) in THF under dry air at 25 °C for 12 h. b The
a For the reaction conditions, see eq 1 and the Supporting Informa-
tion. b Isolated yield. 1H NMR yield in parentheses. c 4.2 equiv. d Pre-
1
yield was determined by H NMR using 1,1,2,2-tetrachloroethane as an
internal standard. Isolated yield in parentheses. c 1 equiv; TMEDA = N,N,
N0,N0-tetramethylethylenediamine. d 10 mol %; dtbpy =4,40-di-tert-butyl-
2,20-bipyridyl. e 99.99% purity. f Performed under a nitrogen atmosphere.
pared in situ from ZnCl2 TMEDA and 2EtMgBr. e A product from the
3
defluorination of 3 was also observed in 12% yield. f 20 mol % of
Co(acac)2 was used.
Org. Lett., Vol. 13, No. 12, 2011
3233

and 6). As with the unsubstituted benzamide 1, the mono-
alkylated product was observed in a trace amount (<2%)
for the electron-deficient substrate (entry 6), whereas 7%
of the monoalkylated product was observed for the elec-
tron-rich substrate (entry 5).
Table 3. Cobalt-Catalyzed Oxidative Alkylation of Arylpyri-
dine Congeners with EtMgCla
Interestingly, we could suppress the formation of the
dialkylated product by the choice of a suitable organic
substituent on the amide nitrogen atom. Thus, N-phenyl-
or N-isopropylamides (entries 7 and 8) yielded the desired
monoalkylated product together with a trace amount
(<5%) of a dialkylated product. Notably, a tertiary amide
(entry 9) did not react at all, suggesting the importance of
the anionic nitrogen atom.
A variety of alkyl Grignard reagents could be utilized
under the standard conditions as illustrated for the reac-
tion with N-methyl-1-naphthalenecarboxamide (entries
10ꢀ14). Methyl and ethyl Grignard reagents took part in
the reaction in good yield (entries 10 and 11), whereas the
isobutyl Grignard reagent gave a lower yield (entry 12).
Octyl Grignard reagent introduced the octyl group in 49%
yield (entry 13). Secondary alkyl Grignard reagents such as
cyclohexylmagnesium chloride (entry 14) did not afford
the desired product. Note that in all of these cases, no
products arising from the activation of the potentially
reactive C(8)ꢀH bond were observed.
a Reaction conditions: pyridine substrate (0.50 mmol), Co(acac)2
(13 mg, 0.05 mmol), DMPU (1.21 mL, 10.0 mmol), and EtMgCl (1.6
mmol) in THF under dry air at 25 °C for 12 h. See the Supporting
Information for details. b Isolated yield. 1H NMR yield in parentheses.
To our satisfaction, arylpyridines reacted with EtMgCl
in excellent yield under similar conditions (Table 3), indi-
cating that the anionic nitrogen ligand is not mandatory
for the reaction to take place smoothly. 2-Phenylpyridine
largely gave the monoalkylated product (entry 1), and this
propensity to monoalkylation stands in contrast to the N-
methylbenzamide reaction described above. The second
ortho-alkylation is slow but takes place in high yield, as
shown in entry 2. 2-(3-Tolyl)pyridine (entry 3) reacted at
the less hindered side in 87% yield. Benzo[h]quinoline
(entry 4) could also be alkylated in high yield.
In summary, we have shown that a cobalt catalyst can
introduce a β-hydrogen-possessing alkyl anion into the
ortho-position of a secondary benzamide or 2-phenylpyr-
idine derivative through directed CꢀH bond activation.
The key in controlling the reactivity of the alkylcobalt
species was the utilization of DMPU as a crucial ligand.
The present reaction is a rare example of oxidative CꢀH
bond functionalization using an inexpensive and nontoxic
catalyst under mild conditions (25 °C),13 under atmo-
spheric air as the sole oxidant. The mono- vs dialkylation
selectivity and the high reactivity of arylpyridine deriva-
tives suggest that this reaction may be mechanistically
different from the previously reported coupling with alkyl
chlorides,12a where arylpyridines were largely unreactive.
The reaction adds to the rapidly increasing repertoire of
catalytic CꢀH activation of benzamide derivatives,14
which are a common structural motif in natural products
and bioactive compounds, and have also recently emerged
as a scaffold of interest for materials science.
Acknowledgment. We thank MEXT (KAKENHI Spe-
cially Promoted Research for E.N., No. 22000008) and the
Global COE Program for Chemistry Innovation. Q.C.
thanks the University of Tokyo for the Special Scholarship
for International Students.
Supporting Information Available. Experimental pro-
cedures and physical properties of the compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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