Cobalt-catalyzed chemoselective insertion of alkene into the ortho C-H bond of benzamide

Article abstract of DOI:10.1021/ja200645w

Insertion of 1-alkene, 2-alkene, and styrene into the ortho C-H bond of benzamide in the presence of an inexpensive cobalt catalyst, DMPU as a crucial ligand, and cyclohexylmagnesium chloride proceeds smoothly at 25 °C to selectively give the ortho-alkylated product. Notable features of this reaction include the structural variety of the alkene and the amide substrate and the tolerance of functional groups such as halide, olefin, ester, and amide groups.(Figure Presented)

Full text of DOI:10.1021/ja200645w

COMMUNICATION
pubs.acs.org/JACS
Cobalt-Catalyzed Chemoselective Insertion of Alkene into the Ortho
CÀH Bond of Benzamide
Laurean Ilies, Quan Chen, Xiaoming Zeng, and Eiichi Nakamura*
Department of Chemistry, School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
S Supporting Information
b
benzamide 2 in quantitative yield. On the other hand, (E)-3-
octene did not give the alkylation product at all under otherwise
identical conditions.
Under these conditions, a tertiary amide such as N,N-
dimethylbenzamide was entirely unreactive, and 2-phenylpyri-
dine and an acetophenone imine that previously served as
excellent substrates8 gave the expected octylation products in
only <10% yield, suggesting that the deprotonated amide func-
tions as a crucial directing group. N-Phenylacetamide did not
react under the present conditions.
ABSTRACT: Insertion of 1-alkene, 2-alkene, and styrene
into the ortho CÀH bond of benzamide in the presence of
an inexpensive cobalt catalyst, DMPU as a crucial ligand, and
cyclohexylmagnesium chloride proceeds smoothly at 25 °C
to selectively give the ortho-alkylated product. Notable
features of this reaction include the structural variety of the
alkene and the amide substrate and the tolerance of func-
tional groups such as halide, olefin, ester, and amide groups.
The key reaction parameters were optimized for a less reactive
substrate, N-methyl-1-naphthalenecarboxamide (3), using 1.2
equiv of 1-octene and 10 mol % Co(acac)3 in the presence of a
variety of alkyl Grignard reagents and ligands in diethyl ether
at 25 °C for 12 h. The alkylation took place exclusively at the
2-position. Representative data are summarized in Table 1.
Comparison of entries 1 and 2 indicates the necessary presence
of DMPU,11,13 as no desired product was obtained in its absence.
The conditions in eq 1 utilizing 1.5 equiv of CyMgCl gave N-
methyl-2-octyl-1-naphthalenecarboxamide (4) in 80% yield
(73% isolated yield) together with 19% recovery of the starting
amide 3 (entry 2). The use of only 1.2 equiv of Grignard reagent
still furnished the product in 69% yield (entry 3), indicating that
the reaction is essentially catalytic for the Grignard reagent (1
equiv of CyMgCl is consumed to deprotonate the NH of the
amide). Thus, 1-octene is formally inserted between the ortho
carbon and hydrogen atoms of the carboxamide. This is contrary
to the related alkylation reaction with alkyl chloride that needed
more than 2 equiv of the Grignard reagent, which formally
accepts the NH proton and the ortho hydrogen atom.11 Cyclo-
pentylmagnesium chloride (CyptMgCl) (entry 4) and MeMgCl
(entry 5) performed similarly, but the latter also gave a small
amount of 2-methylated product. Me3SiCH2MgCl (entry 6) was
far less efficient.
ince the seminal work of Murai,1 ruthenium- and rhodium-
S
catalyzed CÀH bond activation of an aromatic compound
followed by insertion of an olefin has become a powerful syn-
thetic tool.2,3 The reaction generally requires the use of a
rare transition metal catalyst4 at high reaction temperature and
tolerates a rather limited range of olefins. We report here the
ortho alkylation of a secondary benzamide5 with a nearly stoi-
chiometric amount of 1-alkene, 2-alkene, or styrene via cobalt
-catalyzed CÀH bond activation in the presence of 1,3-dimethyl-
3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) and an essen-
tially catalytic amount of a Grignard reagent. The reaction
reported in this communication features the use of an inexpen-
sive cobalt catalyst,6,7 room-temperature conditions, and the
tolerance of aryl halide, olefin, ester, and amide groups. The
reaction allows the use of various simple and functionalized al-
kene substrates, including 1-alkene, 2-alkene, and styrene.8 The
reaction adds to the rapidly expanding repertoire of cobalt-
catalyzed CÀH bond activation reactions.9À11
6-Octylation of N-methyl-3-phenylbenzamide (1) with 1-oc-
tene is illustrative (eq 1). A diethyl ether solution of cyclohex-
ylmagnesium chloride (CyMgCl, 2.9 mL, 2.44 M, 7.1 mmol) and
then 1-octene (0.89 mL, 5.7 mmol) were added dropwise to a
mixture of Co(acac)3 (169 mg, 0.47 mmol), 1 (1.00 g, 4.7 mmol),
and DMPU (3.4 mL, 28 mmol) at 0 °C. The reaction mixture was
stirred at 25 °C for 12 h, and after workup, N-methyl-2-octyl-5-
phenylbenzamide (2) was obtained in 98% yield (1.50 g).
Notably, ligands commonly used for cobalt-catalyzed CÀH
bond activation, such as PCy3 (entry 7) and IMes HCl (entry 8)
3
previously used by Yoshikai,8 as well as PMePh210a (entry 9) and
TMEDA10c (entry 10) did not afford the desired product but
instead gave back the starting amide. Co(acac)2, CoCl2, or CoBr2
complexes used under otherwise the same conditions as in entry
2 gave 4 in lower yield (59, 31, or 15%, respectively), and the
absence of a cobalt catalyst resulted in complete recovery of the
starting material (see the Supporting Information for details).
Table 2 illustrates the scope of the aromatic amide in the
reaction with 1-octene. For all carboxamides, the reaction took
When (E)-2-octene was employed under similar conditions
(eq 1), the reaction took place at the terminal position, presum-
ably after olefin isomerization,12 to give the same 2-alkylated
Received: January 22, 2011
Published: March 23, 2011
r
2011 American Chemical Society
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|

Journal of the American Chemical Society
COMMUNICATION
Table 1. Key Reaction Parameters for the Cobalt-Catalyzed
Reaction of N-Methyl-1-naphthalenecarboxamide (3) with
1-Octene To Give N-Methyl-2-octyl-1-naphthalenecarboxa-
mide (4)a
Table 2. Cobalt-Catalyzed Ortho Octylation of Benzamide
Derivatives with 1-Octene a
entry
RMgCl
ligand
4 (%)b
3 (%)b
1
2
CyMgCl
none
0
80
69
61
84
3
96
19
11
21
10d
89
95
96
90
98
CyMgCl
DMPU
DMPU
DMPU
DMPU
DMPU
PCy3
3
CyMgClc
CyptMgCl
MeMgCl
Me3SiCH2MgCl
CyMgCl
4
5
6
7
0
8
CyMgCl
IMes HCl
0
3
9
CyMgCl
PMePh2
0
10
CyMgCl
TMEDA
0
a The reaction conditions are described in eq 1 and the Supporting
Information. b 1H NMR yield in the presence of 1,1,2,2-tetrachlor-
oethane as an internal standard. c 1.2 equiv of CyMgCl was used instead
of the standard 1.5 equiv. d A 2-methylated product was also obtained in
<10% yield.
place exclusively at the ortho position, as illustrated already
for the formation of 2 and 4 (entries 1 and 2). N-Methyl-1-
pyrenecarboxamide also reacted smoothly at the ortho position
(entry 3), suggesting that the method may be useful in organic
semiconductor chemistry, where the introduction of long alkyl
chains increases the solubility of the compounds. When the
benzamide has two equally reactive ortho positions, double al-
kylation tends to predominate (entries 4À9). The reactions in
entries 5À9, in particular, gave the double alkylation product
exclusively when 2.2 equiv of 1-octene was used. When 1.2 equiv
of 1-octene was used in the reaction in entry 4, we still obtained
the dialkylation product (40%) together with the monoalkylation
product (39%) and recovery of the starting amide (15%). Thus,
we speculate that the second alkylation takes place quickly after
the first alkylation and that the cobalt catalyst is released from the
amide substrate only after the second alkylation is complete.3 In
contrast to previous studies,3,8 both electron-rich (entry 5) and
electron-deficient amides (entry 6) reacted equally well. The
chloride group in 4-chlorobenzamide was retained to give the
2,6-dioctyl product in 74% yield when MeMgCl was used (entry
7), while it was largely reduced when CyMgCl was used.
This contrast between the Me and Cy groups suggests that the
Cy group acts as a hydrogen donor. When we used MeMgCl,
even 4-bromobenzamide (entry 8) gave a modest yield (22%)
of the desired octylated product with retention of the bro-
mide group, together with debrominated products (18%). N-
Methylisonicotinamide14 reacted smoothly to give the dialky-
lated product exclusively (entry 9).
a The reaction was performed with 1.2 equiv of 1-octene under the
conditions described in eq 1 (see the Supporting Information for
details). b Isolated yield. Most of the amide starting material was
recovered when the yield was low. c 2.2 equiv of 1-octene was used.
d MeMgCl (1.5 equiv) was used instead of CyMgCl. e A dechlorinated
product was observed in trace amount (<5%). f 1H NMR yield;
debrominated products were observed in 18% yield.
Styrene gave a mixture of two regioisomers in a 2:1 ratio favoring
CÀC bond formation at the terminal position (entry 5). Like
2-octene, 1-phenyl-1-propene reacted predominantly at the
terminal position after isomerization of the olefin (entry 6).
In summary, we have developed a new cobalt-catalyzed CÀH
bond activation method for insertion of a nearly stoichiometric
amount of a simple or functionalized alkene into the ortho CÀH
bond of a secondary benzamide derivative in the presence of 1.5
equiv of CyMgCl. The unique features of the present conditions
include the structural variety of the alkene and the aromatic
carboxamide substrates that can be employed as well as the
tolerance of functional groups including bromide, chloride,
olefin, amide, and ester groups. The crucial role of DMPU for
the success of the reaction is notable and will be the subject of
further studies. The present olefin insertion reaction is synthe-
tically complementary to the iron-catalyzed CÀH bond functio-
nalization with organometallic coupling partners that we have
As illustrated in Table 3, we can employ a considerable variety
of olefinic substrates, including a wide variety of terminal and
internal alkenes as well as styrene and 1-phenyl-1-propene.
Trimethylvinylsilane, which has been a standard substrate since
Murai’s study, served as an excellent substrate (entry 1). 2-Sub-
stituted-1-alkenes reacted very smoothly in this reaction (entries
2 and 4), although they are generally poor substrates in Murai-
type reactions.3 The reaction tolerates the presence of functional
groups such as ester and olefin (entries 3 and 4). The internal
olefin in DL-limonene did not take part in the reaction, and the
product was expectedly a 57:43 diastereomeric mixture (entry 4).
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Journal of the American Chemical Society
COMMUNICATION
Table 3. Cobalt-Catalyzed Alkylation of N-Methyl-3-phenyl-
benzamide (1) with Various Olefins a
of Science for a Research Fellowship for Young Scientists
(P10033). Q.C. thanks the University of Tokyo for the Special
Scholarship for International Students.
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e
as a 57:43 mixture of diastereoisomers. Ratio of linear and branched
isomers, as determined by 1H NMR analysis.
been investigating for some time15,16 with the ultimate goal of
achieving sustainable and selective reactions for complex organic
synthesis.17
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
physical properties of the compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
nakamura@chem.s.u-tokyo.ac.jp
’ ACKNOWLEDGMENT
We thank MEXT (KAKENHI Specially Promoted Research,
22000008 to E.N.) and the Global COE Program for Chemistry
Innovation. X.Z. thanks the Japan Society for the Promotion
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