Cobalt-Catalyzed Monoselective Ortho-C-H Functionalization of Carboxamides with Organoaluminum Reagent

Article abstract of DOI:10.1021/acs.orglett.6b02860

A simple triphenylphosphine-ligated cobalt catalyst is reported for the direct ortho-C-H methylation and ethylation of aromatic, heteroaromatic, alkenyl, and even aliphatic carboxamides with inexpensive organoaluminum reagents in the presence of a cheap a

Full text of DOI:10.1021/acs.orglett.6b02860

Letter
pubs.acs.org/OrgLett
Cobalt-Catalyzed Monoselective Ortho-C−H Functionalization of
Carboxamides with Organoaluminum Reagent
†
†
Huiqiao Wang, Sheng Zhang, Zhiqiang Wang, Minghui He, and Kun Xu*
College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, Henan 473061, P. R. China
*
S Supporting Information
ABSTRACT: A simple triphenylphosphine-ligated cobalt cata-
lyst is reported for the direct ortho-C−H methylation and
ethylation of aromatic, heteroaromatic, alkenyl, and even
aliphatic carboxamides with inexpensive organoaluminum
reagents in the presence of a cheap alkyl chloride as oxidant.
This reaction shows monoselectivity in contrast with previously
established C−H methylation methodologies.
4
c,14
here has recently emerged an intense interest in the
oxidant.
Monomethylations were achieved with substrates
T
synthetic community to use inexpensive and abundant
possessing two accessible reaction sites tolerating various
functional groups and heterocycles. Selective mono-C−H
ethylation can also be achieved by using 1,10-phenanthroline
as the supporting ligand to suppress undesired β-hydride
elimination. This reaction provides an operationally simple and
economic method to methylate and ethylate C−H bonds and is
preferable, especially when monofunctionalization is required.
We commenced our experimentation by treating N-
first-row transition-metal catalysts to construct carbon−carbon
1
bonds through direct C−H activation. Among these metals,
cobalt has been demonstrated as a powerful catalyst to
2
,3
complete such transformations for alkylating a C−H bond
4
5
with both alkyl organometallics and alkyl electrophiles. As
pioneered by Nakamura and others, a cobalt catalyst can
catalyze the ortho-alkylation of benzamide substrate with
4a,b
Grignard reagent in the presence of an oxidant. Considering
their functional group compatibility, easy availability, and low
cost, organoaluminum reagents such as trimethylaluminum can
be considered as a suitable methyl donor for a C−H
methylation reaction, as recently demonstrated by Nakamura
(
quinolin-8-yl)benzamide 1a with trimethylaluminum 2 in
THF in the presence of 5 mol % of Co(acac) and 1.2 equiv of
3
DCB as oxidant (Table 1, entry 1). To our delight, we obained
the desired monomethylation product in 39% isolated yield
with monoselectivity. We considered that a ligand promotion
effect as observed in similar types of iron catalysis may increase
6
et al. in iron-catalyzed C−H activation. Because of the
importance of C−H methylation affecting protein−ligand
6
7
the yield of the desired product. By screening various ligands
binding in drug discovery and pharmacology studies, a call
(
entries 2−8), we found the simplest triphenylphosphine acts
for C−H methylation methodology has recently garnered8
as the most effective ligand for this reaction to give the desired
product in 91% isolated yield. The electronic effect on the
triarylphosphine ligand was studied, and the results showed that
the electron-deficient ligand gave decreased yields (p-F, 79%
compared with p-Me, 91%). Increasing the bulkiness of the
responses in the form of several methodologies by using Pd,
9
6,10
4a,11
Ni, Fe, and Co
as catalysts for the ortho-methylation of
benzoic acid derivatives. Although developed, among these
methods, for substrates possessing two accessible C−H bonds,
a mixture of mono- and dimethylation products was always
obtained, and monoselective C−H methylation of benzamides
15
phosphine ligand by increasing the cone angle decreased the
yield, demonstrating the sensitivity toward steric hindrance of
this reaction (P(o-Me-Ph) , PCy ). Bipyridine (Bpy) and 1,10-
6a
has not been well achieved.
To the best of our knowledge, the aluminum reagent has not
been successfully applied as an alkyl donor in cobalt-catalyzed
C−H functionalizations. Inspired by the recent work by
3
3
phenanthroline (1,10-phen) were also suitable ligands for this
reaction (entries 8 and 9). For the cobalt source, cobalt(III)
6
Nakamura and co-workers, we hypothesized that trimethyla-
showed better performance than Co(II), and Co(acac) gave
3
luminum may act as a suitable methylating reagent in cobalt-
catalyzed C−H methylations, and different selectivity is
possibly achievable through the cooperation between cobalt
and Lewis acidic aluminum and also by fine-tuning of the
supporting ligand for cobalt. In this work, we reported that a
simple, inexpensive triphenylphosphine-ligated cobalt catalyst
was able to catalyze the selective ortho-monomethylation of
various arene, alkene, and even aliphatic carboxamides bearing
the best performance (entry 9 to entry 11). Dichloroalkane
acted as a good oxidant for this reaction; among them, 2,3-
dichlorobutane acted as the best oxidant (entries 13−16).
Using 1 atm of air as oxidant gave a low yield (40%, entry 17).
It should be noted that monomethylation was observed among
all of the entries in Table 1, indicating that monoselectivity may
12
13
an 8-aminoquinolynyl directing group with trimethylalumi-
num in the presence of only 1.2 equiv of dichloroalkane as
Received: September 22, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02860
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of the Reaction Conditions
Scheme 1. Substrate Scope of N-Quinolylbenzamides
entry
Co catalyst
ligand
PPh3
oxidant
yield (%)
39
1
2
3
4
5
6
7
8
9
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)2
Co(OAc)2
CoCl2
2,3-DCB
2,3-DCB
2,3-DCB
2,3-DCB
2,3-DCB
2,3-DCB
2,3-DCB
2,3-DCB
2,3-DCB
2,3-DCB
2,3-DCB
2,3-DCB
DCE
b
91 (58)
P(p-Me-C H )
91
79
80
6
5
3
P(p-F-C H )
6
5
3
P(o-Me-C H )
6
5
3
PCy3
1,10-Phen
Bpy
67
b
90 (87)
79
63
61
59
71
82
36
11
53
40
38
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
10
11
12
13
14
15
16
17
18
c
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
4
5
6
air
nitrogen
a
Reaction conditions: 1a (0.2 mmol), AlMe (0.4 mmol, 2 M in
3
toluene), Co catalysis (0.01 mmol), ligand (0.011 mmol), oxidant
0.24 mmol) in THF (0.5 mL) at 80 °C for 20 h; yields are isolated
(
a
Reaction conditions: 1 (0.2 mmol), AlMe3 (0.4 mmol, 2 M in
b
yields. The value in the parentheses represents the yield when 2 mol
toluene), Co(acac) (0.01 mmol), PPh (0.011 mmol), DCB (0.24
mmol) in THF (0.5 mL) at 80 °C for 20 h; yields are isolated yields.
c
3
3
%
of catalyst was used. 0.3 mmol of DCB was used.
originate from the Co−Al interaction with the directing group
but not be affected by the ligand and oxidant used.
By testing various benzamide substrates, we found the 8-
quinoline amide directing group is the most suitable directing
group for this transformation. Benzamide bearing a triazolyldi-
suggesting a C−H bond of higher acidity is more reactive. This
result is in accordance with the result of competition
experiments in Scheme 5a. For functional group tolerance,
ether (3e−f), tertiary amine (3g), fluoro (3i), chloro (3j), and
trifluoromethyl (3k,o) were all well tolerable. Because of the
mild nucleophilicity of trimethylaluminum, ester can also be
well tolerated (3p).The reaction is not sensitive to electronic
effects exerted by electron-donating and -withdrawing sub-
stituents on the arene, demonstrating that substrates possessing
dimethylamino (3g) and trifluoromethyl (3k,o) substituents
both gave good yields.
Besides arene carboxamides, heteroaromatic carboxamides
were also suitable substrates (Scheme 2). Pyridine (7) and
thiophene (8) carboxamides can be methylated with increased
catalyst loading. Cyclohexene carboxamide (9) and aliphatic
carboxamide (10) can also be successfully methylated. The
reaction can be easily scaled up to gram scale as demonstrated
by monomethylation of 4-(trifluoromethyl)benzamide in 87%
yield on a 5 mmol scale (Scheme 3).
16
methylmethyl (TAM) directing group, which was developed
by Ackermann, delivered the desired methylation product in
lower yield (76%) compared with 8-aminoquinoline (see the SI
for details).
With these optimized reaction conditions in hand, we then
investigated the reaction scope (Scheme 1). We first focused on
methylation of para-substituted benzamides in which two C−H
bonds are available. The previous iron-catalyzed system
reported by Nakamura et al. delivers mainly dimethylated
6
products for these substrates, but monomethylation was
achieved when cobalt was used as catalyst. This reaction is
also suitable for meta-substituted benzamide to deliver
monomethylated product, but for ortho-substituted benzamides,
such as o-toluamide, no reaction occurred (3v). The substrate
limitation of refraining from use of ortho-substituted benzamide
is accordance with the monoselectivity observed for this
reaction, showing the high sensitivity toward ortho-steric
hindrance. Although the reaction is sensitive to ortho-steric
hindrance, it is interesting to observe that this reaction is
amenable to meta-substitution. For 3,5-dimethylbenzamide (1t)
and 3,5-dimethoxybenzamide (1u), monomethylations were
still observed in high yields to give 2,3,5-trisubstituted
benzamides. For 3-fluorobenzamide (1m), the methylation
reaction occurred at the ortho-position of the fluoro substituent,
Ethylation was also successfully achieved by using
triethylaluminum. For ethylation, triphenylphosphine gave a
low yield, probably due to the undesired β-hydride elimination.
By using 1,10-phenanthroline, β-hydride elimination was
suppressed by saturating the coordinate site of Co (Scheme
4). Ethylation reaction shows exclusive monoselectivity, while
in the previous reports mixtures of mono- and diselectivity were
6b
obtained. For higher trialkylaluminums, such tripropylalumi-
B
DOI: 10.1021/acs.orglett.6b02860
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Methylation of Other Types of Carboxamides.
shows C−H on the electron-deficient arene (more acidic)
reacted faster than the one on the electron-rich arene (Scheme
5
a). Second, parallel KIE experiments reveal that C−H
activation is the rate determining step in this transformation
Scheme 5b; see the SI for details). Third, addition of a radical
(
scavenger such as 1,1-diphenylethylene has no adverse effect on
the reaction outcome (Scheme 5c). These initial mechanistic
experiments suggest that C−H activation may proceed through
a deprotonation-type mechanism by Co−Me species rather
than electrophilic attack by Co(III) to activate C−H bond. The
results of the radical scavenger experiments ruled out a radical
pathway for C−H activation, supporting the reaction through a
cobaltocycle intermediate.
a
Reaction conditions: 1 (0.2 mmol), AlMe3 (0.4 mmol, 2 M in
toluene), Co(acac) (0.02 mmol), PPh (0.022 mmol), DCB (0.24
3,11
3
3
Compared with other Co-catalyzed C−H activations,
mmol) in THF (0.5 mL) at 80 °C for 20 h; yields are isolated yields.
b
although the origin of the monoselectivity of this reaction
cannot be clearly revealed, we can conclude at this stage that
this monoseletivity maybe ascribed to the interaction of Lewis
acidic aluminum with the directing group as shown in a
proposed model in Figure 1. The cobalt may coordinate with
The temperature was 70 °C.
Scheme 3. Gram-Scale Synthesis
Scheme 4. Ethylation with Triethylaluminum
Figure 1. Rationalization of the observed selectivity for mono-
methylation.
the two nitrogen atoms, and aluminum may coordinate to the
iminolized C−O bond to exert steric bulkiness, preventing
formation of the second metallocycle.
In conclusion, we reported a simple triphenylphosphine-
ligated cobalt catalyst for the direct ortho-C−H methylation of
aromatic, heteroaromatic, alkenyl, and even aliphatic carbox-
amides with trimethylaluminum in the presence of a cheap alkyl
chloride as oxidant. This reaction shows excellent mono-
selectivity, in contrast with previously established C−H
methylation metholodologies. By tuning the supporting ligand
for cobalt to 1,10-phenanthroline, C−H ethylation can be
achieved in an excellent monoselective fashion. The method
may find utility for C−H methylation and ethylation for
pharmacology research, especially when monoselectivity is
required.
num and triisobutylaluminum, the reaction failed to give the
desired alkylation products, probably due to steric hindrance.
Some initial experiments were carried to gain mechanistic
information on this transformation (Scheme 5). First, a
competition reaction using 4-OMe and 4-CF substrates clearly
3
Scheme 5. Mechanistic Studies
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02860.
1
Experimental procedures, characterization data, and H
and 13C NMR of new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: xukun@nynu.edu.cn.
Author Contributions
†
H.W. and S.Z. contributed equally to this work.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.6b02860
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
13) For reviews, see: (a) Daugulis, O.; Roane, J.; Tran, L. D. Acc.
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21602119, U1504208) and acknowledge financial support
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DOI: 10.1021/acs.orglett.6b02860
Org. Lett. XXXX, XXX, XXX−XXX