Manganese-catalyzed directed methylation of C(sp2)-H bonds at 25 °C with high catalytic turnover

Article abstract of DOI:10.1021/acs.orglett.7b02778

We report here a manganese-catalyzed C-H methylation reaction of considerable substrate scope, using MeMgBr, a catalytic amount of MnCl₂· 2LiCl, and an organic dihalide oxidant. The reaction features ambient temperature, low catalyst loading, typically 1%, high catalytic turnover reaching 5.9 × 10³, and no need for an extraneous ligand and illustrates a unique catalytic use of simple manganese salts for C-H activation, which so far has relied on catalysis by manganese carbonyls.

Full text of DOI:10.1021/acs.orglett.7b02778

Letter
pubs.acs.org/OrgLett
Manganese-Catalyzed Directed Methylation of C(sp2)−H Bonds at 25
°C with High Catalytic Turnover
Takenari Sato, Takumi Yoshida, Hamad H. Al Mamari,† Laurean Ilies,* and Eiichi Nakamura*
Department of Chemistry, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
S
* Supporting Information
ABSTRACT: We report here a manganese-catalyzed C−H methylation reaction
of considerable substrate scope, using MeMgBr, a catalytic amount of MnCl2·
2LiCl, and an organic dihalide oxidant. The reaction features ambient
temperature, low catalyst loading, typically 1%, high catalytic turnover reaching
5.9 × 103, and no need for an extraneous ligand and illustrates a unique catalytic
use of simple manganese salts for C−H activation, which so far has relied on
catalysis by manganese carbonyls.
iron catalyst selectively methylates the naphthalene ring via
bidentate chelation.10g,11 The C−H methylation12 is a trans-
formation found to be useful for probing the methyl effects in
pharmacology through late-stage synthetic elaboration13 and
has not been achieved to date using manganese catalysis.7
The gram-scale reaction of secondary benzamide 1 with
MeMgBr (4 equiv) in the presence of 0.1 mol % of MnCl2·
2LiCl and 1-bromo-2-chloroethane (2 equiv) as a mild oxidant
in THF at 25 °C for 24 h gave the desired product 2 in 90%
yield together with recovery of 1 in 10% (NMR); the product
was isolated in 68% yield after recrystallization (eq 1). The
reaction requires slightly more than the theoretical stoichiom-
etry of 3 equiv of MeMgBr, 1 equiv for methyl delivery, 2 equiv
for deprotonation, and a small portion for catalyst activation.
The reaction proceeded cleanly without formation of by-
products or of the 2,6-dimethylated product. With 1% catalyst
loading, the reaction gave 2 in 94% yield with recovery of 1 in
6% yield and with 0.01 mol % after 48 h gave the product in
59% yield with 41% recovery of the starting material. In this last
experiment, the reaction achieved a turnover number of 5.9 ×
103. Attempts to accelerate the reaction at a higher temperature
resulted in premature termination of the reaction.
espite the economic merits and lack of toxicity of
1,2
Dmanganese,
catalytic use of organomanganese species
has thus far found limited applications because of their low
reactivity.3 Among such applications, catalytic C(sp2)−H bond
activation4 has been explored with considerable success by the
use of manganese carbonyl complexes5,6 under high catalyst
loading (5−10%) and at high temperatures (60−120 °C),
except for an example of stoichiometric photochemical
borylation carried out at 25 °C.7,8 We report here a MnCl2·
2LiCl-catalyzed directed C(sp2)−H methylation9 with
MeMgBr,10 which takes place at ambient temperature without
an extraneous ligand, with catalyst loading of <1%, and a
maximum turnover number of 5.9 × 103. The reaction requires
much lower catalyst loading and proceeds at a lower reaction
temperature compared even with a recently reported10g iron-
catalyzed C−H methylation utilizing AlMe3. The reaction is
applicable to various substrates, such as aromatic, hetero-
aromatic, and olefinic secondary amides, and aromatics having
pyridine, oxazoline, pyrazole, nitrile, and methylsulfone as a
directing group. A striking difference between the manganese
and the iron catalysis is illustrated for the C−H activation of N-
(1-naphthyl)-2-picolinamide in Figure 1, where the manganese
system selectively methylates the pyridine ring, whereas the
First, we describe several key reaction parameters (details in
the Supporting Information). MeLi in place of MeMgBr gave
the desired product in low yield, and mono- and dimethylzinc
reagents were completely unreactive. Grignard reagents with a
longer alkyl chain than methyl underwent β-hydride
elimination14 and gave no C−H activation products. Phenyl-
magnesium bromide gave biphenyl,15 instead of the desired
Figure 1. Contrasting regioselectivity between manganese and iron
catalysis.10g
Received: September 5, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02778
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Letter
phenylated amide. Benzyl and allyl reagents did not give the
desired product at all. Various organic dihalides served as an
oxidant for the reaction, with 1-bromo-2-chloroethane being
the most efficient and readily available.
Table 1. Manganese-Catalyzed Methylation of Secondary
Carboxamides with MeMgBr
a
We used the MnCl2·2LiCl complex as the catalyst of choice
because of its ease of handling and high solubility,3 whereas a
variety of Mn(II) or Mn(III) catalyst precursors served equally
well as catalyst. The reaction did not proceed at all in the
absence of manganese. In control experiments using a
stoichiometric amount of Mn(acac)2 and Mn(acac)3, however,
we found a clear difference between them (eq 2). In the
presence of the oxidant (1-bromo-2-chloroethane), both
precursors functioned equally well. Without the oxidant, on
the other hand, Mn(acac)2 gave no 2, while Mn(acac)3 gave it,
albeit in a rather low yield of 17%, suggesting that the Mn(II)
species does not take part in C−H activation while Mn(III)
does, and the function of the oxidant is to regenerate the
reactive Mn(III) species. Notably, no deuterium incorporation
in the recovered starting material (1) took place in any of these
reactions upon quenching the reaction mixture with deuterium
oxide.
Table 1 shows that a variety of arene, heteroarene, and alkene
carboxamides can be methylated with MeMgBr (4 equiv) in the
presence of 1 mol % of MnCl2·2LiCl at 25 °C. In entries 1 and
3, we show that the reaction of N-phenylbenzamide and N-
methylbenzamide (MeMgBr (3.1 equiv) and 1-bromo-2-
chloroethane (2 equiv)) for 24−48 h effectively and selectively
methylated one of the two available ortho positions. The N-
phenyl substituent made the reaction slower and more
selective, presumably by weaker coordination to the active
species. By use of excess reagents, MeMgBr (5.5 equiv) and 1-
bromo-2-chloroethane (3 equiv), we methylated both of the
ortho positions in 83% yield (entry 2). When benzamide has a
m-methyl group (entry 4), the monomethylation reaction with
excess reagents took place selectively in 69% yield in the ortho
position distant from the m-methyl group. The second ortho
methylation on the m-methyl side was very slow to give doubly
methylated compound in 6% yield. In the presence of m-CF3 in
place of CH3 (entry 5), ortho methylation distant from the m-
CF3 group was the only reaction observed. The reaction of m-
fluorobenzamide was faster than the above reactions and
afforded the dimethylated product selectively in 73% yield
(entry 6). Despite the large size of the bromo group, m-
bromobenzamide gave a doubly ortho-methylated product in
64% yield together with monomethylated product in 16% yield
(entry 7). We observed neither dehydrobromination nor
methylation through bromo substitution, illustrating the
tolerance of the bromide group. An m-methoxy group (entry
8) gave an almost 1:1 mixture of mono- and disubstituted
products.
a
Reaction conditions: the reaction was performed on a 0.5 mmol scale
using MnCl2·2LiCl (1 mol %), MeMgBr (4 equiv; unless otherwise
noted below), and 1-bromo-2-chloroethane (2 equiv) at 25 °C for 24
h. See the SI for details. Yield of the isolated product. Recovered
starting material was in some cases difficult to separate from the
product, and the yield shown in parentheses was determined by H
b
1
c
NMR using 1,1,2,2-tetrachloroethane as an internal standard. 48 h.
d
MeMgBr (5.5 equiv) and 1-bromo-2-chloroethane (3 equiv), 48 h.
e
f
g
MeMgBr (3.1 equiv). MnCl2·2LiCl (0.1 mol %). Reaction
performed on a 0.2 mmol scale using 10 mol % of catalyst.
The scope of the amide substrates was further investigated by
the use of 4 equiv of MeMgBr, which predominantly afforded a
monomethylated product. 3,5-Dimethylbenzamide suffering
from steric hindrance (entry 9) afforded the monomethylated
B
DOI: 10.1021/acs.orglett.7b02778
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Organic Letters
Letter
product in 84% yield. Ortho-substituted substrates (entries 10
and 11) underwent methylation at the opposite ortho site in
high yield.
the manganese catalytic species and delivers the methyl group
to the ortho position.
Solid mechanistic information not being available, we only
suggest a plausible catalytic cycle (Figure 2). Based on the
The present catalytic system is also useful for ortho
methylation of heteroaromatic substrates. Thus, thiophene-2-
carboxamide (entry 12), indole-2-carboxamide (entry 13), and
isonicotinamide (entry 14) afforded the monomethylated
product in good yield. Entry 15 illustrates the insensitivity of
the manganese system to bidentate coordination as discussed in
Figure 1. Even upon increasing the amount of MeMgBr to 6
equiv, we could not observe any methylation at the naphthalene
ring. Also, a substrate possessing a bidentate directing group
such as N-(2-quinolyl)benzamide was unreactive under the
manganese catalysis conditions. Alkeneamides also reacted well
(entries 16 and 17), and an acyclic alkeneamide (entry 16)
reacted stereospecifically to give the Z-product.
Substrates possessing other directing groups, such as pyridine
(Table 2, entry 1), oxazoline (entry 2), and pyrazole (entry 3),
Table 2. Manganese-Catalyzed Methylation of Various
a
Substrates with MeMgBr
Figure 2. Plausible catalytic cycle of manganese-catalyzed methylation.
stoichiometric experiments using Mn(II) and Mn(III) catalyst
precursor (eq 2) and the lack of chelation control (Figure 1),
we surmise that the C−H bond activation step involves a
methylmanganese(III) ate complex18 such as A, where the four
covalent bonds formed on the metal center leave no room for
additional coordination as seen in the iron(III) catalysis (Figure
1). An electron-rich intermediate such as A may be responsible
for the facile cleavage of the C−H bond at ambient
temperature; such an intermediate would not be available
starting from the manganese carbonyl complexes used in the
previous examples of manganese catalysis, which require
heating to remove carbonyl for activation.5,6 Complex A then
undergoes deprotonative cyclometalation to generate mangana-
cycle B together with methane. A KIE experiment for parallel
reactions gave a value of 2.0 (SI), indicating that C−H cleavage
is the turnover-limiting step. Complex B then undergoes
reductive elimination to create the C−C bond. The lack of
deuterium incorporation as shown in eq 2 suggests that B is
short-lived and produces a manganese(I) intermediate C as
soon as it is formed. C is then oxidized by dihalide and
undergoes ligand exchange with the starting material to
regenerate the manganese(III) complex A. In light of the
single-electron transfer reactivity of inorganic Mn(III)19 and of
methylmanganese(II) ate,20 C−H cleavage through a radical
mechanism cannot be ruled out; however, such a mechanism is
inconsistent with the faster reaction of electron-deficient
substrates and the observed KIE.21
a
Reaction conditions: the reaction was performed on a 0.5 mmol scale
using MnCl2·2LiCl (5 mol %), MeMgBr (4.5 equiv), and 1-bromo-2-
chloroethane (3 equiv) at 25 °C for 48 h. See the SI for details. Yield
of the isolated product. Recovered starting material was in some cases
difficult to separate from the product, and the yield shown in
parentheses was determined by H NMR using 1,1,2,2-tetrachloro-
ethane as an internal standard. 40 °C. MeMgBr (5.5 equiv). 2,3-
Dibromobutane was used instead of 1-bromo-2-chloroethane.
b
1
c
d
e
also took part in the ortho methylation. However, the reaction
required larger catalyst loading (5 mol %), probably because of
the weaker binding of these nonacidic substrates to the
manganese catalytic species. Interestingly, benzonitrile (entry
4) gave a methylated acetophenone, probably through the
initial addition of MeMgBr to generate a magnesium imide,
which next directed the ortho methylation.16 Methyl phenyl
sulfone (entry 5) also participated in the C−H activation
reaction.17 In light of the lack of reactivity of diphenyl sulfone,
we suggest that the anion of the methyl sulfone coordinates to
In summary, we have developed a manganese-catalyzed C−H
methylation reaction of considerable substrate scope, in some
cases complementary to other metal catalysts.10 Featuring low
catalyst loading and high catalytic turnover without the use of
an external ligand, the reaction illustrates a unique catalytic use
of manganese salts for C−H activation, which so far has relied
on catalysis by manganese carbonyls.
C
DOI: 10.1021/acs.orglett.7b02778
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02778.
■
S
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Experimental procedures and physical properties of the
compounds (PDF)
X-ray data for the product in Table 1, entry 15 (CCDC
1560075) (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: laur@chem.s.u-tokyo.ac.jp.
*E-mail: nakamura@chem.s.u-tokyo.ac.jp.
ORCID
Eiichi Nakamura: 0000-0002-4192-1741
Present Address
†(H.H.A.M.) Department of Chemistry, College of Science,
Sultan Qaboos University, P.O. Box 36, Al Khoudh 123,
Muscat, Sultanate of Oman.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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̈
We thank Dr. Rui Shang for helpful discussions (University of
Tokyo), Yuki Itabashi for crystallographic analysis (University
of Tokyo), and MEXT for financial support (Japan Agency for
Science and Technology; CREST; JPMJCR14L4, and Grant-in-
Aid no. 15H05754 to E.N.). H.A.M. thanks the Office of
International Cooperation at Sultan Qaboos University for an
official visit to the University of Tokyo.
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