Para-Selective Alkylation of Benzamides and Aromatic Ketones by Cooperative Nickel/Aluminum Catalysis

Article abstract of DOI:10.1021/jacs.6b08767

We report a method that ensures the selective alkylation of benzamides and aromatic ketones at the para-position via cooperative nickel/aluminum catalysis. Using a bulky catalyst/cocatalyst system allows reactions between benzamides and alkenes to afford the corresponding para-alkylated products. The origin of the high para-selectivity has also been investigated by density functional theory calculations.

Full text of DOI:10.1021/jacs.6b08767

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Article
para-Selective alkylation of benzamides and aromatic
ketones by cooperative nickel/aluminum catalysis
Shogo Okumura, Shu-Wei Tang, Teruhiko Saito, Kazuhiko Semba, Shigeyoshi Sakaki, and Yoshiaki Nakao
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b08767 • Publication Date (Web): 19 Oct 2016
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Journal of the American Chemical Society
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para-Selective Alkylation of Benzamides and Aromatic Ketones by
Cooperative Nickel/Aluminum Catalysis
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Shogo Okumura,† Shuwei Tang,‡ Teruhiko Saito,† Kazuhiko Semba,† Shigeyoshi Sakaki,‡,* and Yoshi-
aki Nakao†,*
†Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan and ‡Fukui
Institute for Fundamental Chemistry, Kyoto University, Sakyo-ku, Kyoto 606-8103, Japan
ABSTRACT: We report a method that ensures the selective alkylation of benzamides and aromatic ketones at the para-position via
cooperative nickel/aluminum catalysis. Using a bulky catalyst/co-catalyst system allows reactions between benzamides with al-
kenes to afford the corresponding para-alkylated products. The origin of the high para-selectivity has also been investigated by
density functional theory calculations.
a Transition metal catalysis for ortho-alkylation: emerging protocols (refs 5&6)
The introduction of alkyl groups on a benzene ring is a fun-
damentally important transformation. Among various possible
O
O
ways to alkylate the aromatic core, the alkylation reaction
using alkenes serves as an ideal transformation in terms of
atom-economy1 as well as the availability of alkene feedstock
in the chemical industry. For example, around 70% of benzene
is supplied for the alkylation reaction with ethylene and pro-
pylene to produce ethylbenzene and cumene, which are further
converted to styrene and phenol/acetone, respectively, on in-
dustrial scales.2 The alkylation of substituted benzenes, in
particular electron-poor ones such as aromatic carbonyl com-
pounds, still suffers from systematic drawbacks. The electron-
withdrawing carbonyl groups limit the scope of alkyl groups
that can be introduced at the meta-position by acid-catalyzed
aromatic electrophilic substitutions using reactive alkylating
agents such as alkyl ethers.3 Recent advances in metal-
catalyzed direct C–H alkylation4 have made the introduction
of both linear5 and branched6 alkyl groups at the ortho-
position possible (Eq. 1), predominantly via the coordination
of the carbonyl group to a metal catalyst. Conversely, to the
best of our knowledge, the only examples that provide an ef-
fective para-selective alkylation of electron-deficient arenes
involve the introduction of a limited number of cyclic alkyl
groups via nucleophilic substitution with radical species gen-
erated from cycloalkanes as reaction solvents in the presence
of a ruthenium catalyst and di-tert-butyl peroxide.7 Here, we
demonstrate an effective direct para-alkylation of benzamides
and aromatic ketones with alkenes by cooperative nick-
el/Lewis acid (LA) catalysis (Eq. 2). We chose this catalytic
system with the expectation that the coordination of the car-
bonyl groups to the LA would enhance the reactivity of the
electron-deficient arenes towards the electron-rich nickel(0)
catalyst. Moreover, we speculated that the steric repulsion
between the nickel catalyst and the LA should increase the
para-selectivity relative to reactions at ortho- and meta-
positions. Progress in para-selective direct arene C–H func-
tionalizations still remain limited; reported examples are either
restricted to electron-rich arenes,8–14 to specific arenes with
bulky substituents15,16 or to substrates with a directing group.17
R2
+
(1)
R1
R2
R1
Transition metal
catalysis
or
O
R1
via
R1
O
[M]
H
R2
b Cooperative Ni/Al catalysis for para-alkylation: elusive protocols (this work)
O
O
R2
(2)
+
R1
R1
Cooperative Ni/Al
catalysis
R2
via
R1
O
[Ni]
H
[Al]
We have previously reported that the direct alkylation of
pyridine derivatives with alkenes proceeds selectively at the
C-4 position of the pyridine moiety by cooperative catalysis
using bis(1,5-cyclooctadiene)nickel [Ni(cod)2], N-heterocyclic
carbene (NHC) as a ligand for nickel, and the bulky LA co-
catalyst (2,6-t-Bu2–4-Me–C6H2O)2AlMe (MAD).18 As a start-
ing point for this investigation, we used the same catalyst sys-
tem using L1 [1,3-bis(2,6-diisopropylphenyl)imidazo-2-
ylidene] as
a ligand for the reaction between N,N-
diethylbenzamide (1a) and 1-tridecene (2a). However, the
corresponding para- and meta-alkylbenzamides (3aa and
3’aa) were obtained only in low yield (4%) and moderate re-
gioselectivity (3aa/3’aa = 61:39; entry 1, Table 1). We then
decided to screen both potential ligands and LAs, and
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Page 2 of 7
Table 2. Substrate Scope for the para-Selective Alkylation of
Benzamides
Table 1. Conditions for the Alkylation of N,N-
Diethylbenzamide (1a) with 1-Tridecene (2a)
1
2
3
4
O
O
O
Et2N
R12N
R2
Et2N
Et2N
5
6
7
8
Ni(cod)2 (10 mol%)
L6 (10 mol%)
MAD (40 mol%)
Ni(cod)2 (10 mol%)
Ligand (10 mol%)
Lewis acid (100 mol%)
O
1a
1a
(1.0 mmol)
+
C11H23
(0.20 mmol)
3aa
+
R12N
R2
+
O
150 °C, 18 h
R3
R3
150 °C, 18 h
C11H23
C11H23
3
9
2
2a
(3.0 mmol)
+ regioisomer(s)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(0.60 mmol)
3'aa
O
O
R1
H
Me Ph
OMe Ph
Me m-tol L4
OMe p-tol L5
OMe 3,5-xyl L6
R2
L
R2
R2
R2
Et2N
Et2N
R2
Me
L1
L2
L3
OH
N
N
C11H23
O
O
3aaa
67%, 92:8
Al
3aba,b
63%, 90:5:5
R1
R1
R2
R2
R2
R2
O
O
MAD
entry ligand
Lewis acid
MAD
MAD
MAD
MAD
MAD
MAD
AlMe3
none
yield (%)a
3aa/3’aa a
61:39
66:34
64:36
81:19
60:40
93:7
Et2N
Et2N
1
2
3
4
5
6
7
8
4
40
60
4
44
86
34
7
L1
L2
L3
L4
L5
L6
L6
L6
R
3acc
63%, 91:9
R = Me: 3ad,d 96%, 94:6
(CH2)2OSiMe2 Bu: 3ae,a 97%, 97:3
t
O
O
Et2N
Et2N
81:19
58:42
SiMeR2
,
,
3aha b e
R = Me: 3af, 60%, 94:6
OSiMe3: 3ag, 95%, 96:4
O
a Determined by gas chromatography analysis using n-dodecane
as an internal standard and not corrected for response factors of
minor isomers.
79%, 95:5
O
Et2N
Et2N
found that the use of bulky NHC ligands such as L219 in-
creased the yield to 40% (entry 2, Table 1), and that the use of
the equally bulky and more electron-donating NHC ligand
L320 furnished a yield of up to 60% (entry 3, Table 1). How-
ever, for both ligands, no improvement regarding the selectivi-
ty was observed. We therefore turned our attention to the tun-
ing of steric effects via the modulation of the terminal phenyl
groups in L2 or L3. A significant increase in regioselectivity
(3aa/3’aa = 81:19) was observed for L4 carrying m-tolyl
groups (entry 4, Table 1), whereas p-tolyl groups in L5 did not
affect the 3aa/3’aa ratio (entry 5, Table 1). Ultimately, the
best performance was observed for L6 with 3,5-xylyl groups,
which resulted in a para-selective (3aa/3’aa = 93:7) alkylation
in 86% combined yield (entry 6, Table 1). The use of sterically
undemanding AlMe3 as a co-catalyst proved to be detrimental
for the reaction yield (entry 7, Table 1), while the absence of
an aluminum-based LA resulted in both poor yield and regi-
oselectivity (entry 8, Table 1). Combined, these observations
indicate that the steric factors associated with ligand and co-
catalyst most likely play a key role in the control of the regi-
oselectivity.
C6H13
,
3aia
34%, >99:1
3aja f
85%, 95:5
(pin)B
O
N
O
N
O
Me
[Si]
[Si]
[Si] = SiMe(OSiMe3)2
3bg
3cg
54%, 93:7
94%, 96:4
O
O
F
F
Et2N
Et2N
[Si]
3dg
[Si]
[Si]
3ega,e
74%, >99:1
97%, 98:2
O
[Si]
O
Et2N
MeO
Et2N
a
3fg
3gga,e
62%, 97:3
O
O
47%, 78:10:7:5
O
N
Et2N
Et2N
N
Using the Ni(cod)2/L6 system in combination with the co-
catalyst MAD, we carried out the alkylation of 1a with a varie-
ty of alkenes (Table 2). For example, using 2a on a preparative
scale (1.0 mmol) afforded a mixture of para- and meta-
alkylation products (3aa/3’aa = 92:8) in 67% yield. Al-
lyl(triethoxy)silane (2b) also reacted with 1a to give the corre-
sponding para-alkylation product, which was further subjected
to the Tamao–Fleming oxidation21 to give 3ab. 1-Alkenes that
contain bulky substituents such as vinylcyclohexane (2c), 3,3-
dimethyl-1-butene (2d), 5-(tert-butyldimethylsilyloxy)-3,3-
dimethyl-1-pentene (2e), trimethyl(vinyl)silane (2f), and
[Si]
[Si]
3hga,g
71%, 92:8
3igg,h
89%, >99:1
Yields were determined from the combined mass of the purified
product mixtures. The product ratios were determined by GC
analysis of the crudes. Run with 100 mol% MAD. Run with
allyl(triethoxy)silane followed by the Tamao–Fleming oxidation. c
Run with 5.0 mmol 2. d Run with 7.0 mmol 2d.e Run with 20
a
b
f
g
mol% Ni(cod)2/L6. Run with 5.0 mmol 2j. Run with toluene
(1.0 mL) as a solvent at 135 °C. h Run for 7.5 h.
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methylbis(trimethylsilyloxy)vinylsilane (2g) all reacted with
1a to yield the corresponding para-alkylated benzamides
Table 3. Substrate Scope for the para-Selective Alkylation of
Aromatic Ketones
1
2
(3ac–3ag). Notably, with some of these bulky alkene sub-
strates, MAD can be used in catalytic amounts. The multi-
substituted double bonds of 2,4,4-trimethyl-1-pentene (2h) and
norbornene (2i) also engaged in the para-selective alkylation
of 1a (3ah and 3ai), whereas the internal double bond of 2-
octene (2j) was isomerized to the terminal position prior to
affording the linear para-alkylation product (3aj). Unfortu-
nately, styrene, cyclohexene, vinylboronate, and alkyl vinyl
ether derivatives did not engage in such alkylation reactions
(Table S1 of Supporting Information). Subsequently, we sur-
veyed the scope of benzamides using vinylsilane 2g, as this
should provide products with convertible silyl groups.22 Mor-
pholino(phenyl)methanone (1b), whose aminocarbonyl func-
tionality can be readily transformed to ketones by nucleophilic
carbonyl substitution reactions,23 afforded 3bg in excellent
yield and para-selectivity. Benzamide bearing an arylboronate
functionality (1c) also participated in the alkylation at the po-
sition para to the aminocarbonyl group to give 3cg. It is worth
noting that a fluorine substituent at the meta- or ortho-position
of 1a (1d and 1e, respectively) did not affect the para-
alkylation reaction, even though it has been shown to perturb
the selectivity of metal-catalyzed directed ortho-C–H alkyla-
tions.24,25 A modest, yet clear C6-selectivity was observed for
the alkylation of N,N-diethyl-1-naphthamide (1f). Moreover,
the selective C–C bond formation at the position para to the
aminocarbonyl group can be achieved in the presene of an-
other carbonyl group of ester 1g and sp2-hybridized nitrogen
of substituted pyridines 1h and 1i. The latter observation is
particularly worth noting as we previously demonstrated that
pyridines are alkylated at the C-4 position under similar reac-
tion conditions.18 This may be partly derived from the lowered
Lewis basicity of the sp2-nitrogen in 1h and 1i due to the pres-
ence of an electron-withdrawing aminocarbonyl group, be-
cause competitive reactions of 1h or 1i and pyridine with 2g
resulted preferentially in the C4-alkylation of pyridine (see
Supporting Information).
3
4
5
6
7
8
9
O
R1
R2
Ni(cod)2 (10 mol%)
L6 (10 mol%)
MAD (10 mol%)
O
4
(1.0 mmol)
+
R1
R2
toluene, 120 °C
R3
R3
5
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2.0 mmol)
+ regioisomer(s)
O
O
Me2N
C6H13 Me2N
5aka,b,c
45%, 97:3 (2 h)
5aca,b,c
63%, 98:2 (2 h)
O
O
Me2N
Me2N
SiMe3
5add
78%, 97:3 (18 h)
5afd
91%, 99:1 (36 h)
O
O
Me2N
[Si]
Me
[Si]
[Si] = SiMe(OSiMe3)2
5age
88%, 97:3 (12 h)
5bgf,g
52%, 99:1 (12 h)
O
O
Ph
[Si] tBuMe2SiO
[Si]
5cgf
66%, 95:5 (1 h)
5dgb
49%, 94:6 (2 h)
O
O
Aromatic ketones were also alkylated in excellent para-
selectivity (Table 3), whereas benzoates did not participate in
the para-alkylation reaction under these reaction conditions
(Table S2 of Supporting Information). The reaction of 4-
dimethylaminobenzophenone (4a) with 1-octene (2k) and
vinylcyclohexane (2c) proceeded in the presence of 20 mol%
Ni/L6 and 100 mol% MAD to give the corresponding alkyl-
ated arenes in 45% and 63% yield, respectively. As with the
case of alkylation of benzamides, sterically demanding alkenes
2d, 2f, and 2g reacted smoothly in the presence of a catalytic
amount of MAD. Subsequently, we examined the scope of
aromatic ketones using 2g as an olefin coupling partner. The
reaction of 4-methylbenzophenone (4b) in the presence of 40
mol% MAD at 150 °C for 18 h suffered from the formation of
side products, which were likely derived form nucleophilic
addition of the methyl group of MAD to the carbonyl moiety
of 4b. We thus performed the reaction in the presence of 10
mol% MAD at 100 °C to obtain the para-alkylation product in
52% yield with 99:1 regioselectivity and negligible amounts of
the byproducts. Benzophenones bearing 4-phenyl (4c) and 4-
siloxy (4d) groups gave the corresponding alkylated ketones
with high para-selectivity. Alkyl aryl ketones such as ethyl
phenyl ketone (4e), tert-butyl phenyl ketone (4f), and α-
substituted indanone (4g) gave respective alkylated arenes
with excellent para-selectivity. The use of 1 mol% MAD al-
[Si]
[Si]
5egh
59%, 99:1 (1.5 h)
5fg
56%, 98:2 (2 h)
O
O
F
[Si]
[Si]
5gg
5hgi
55%, 96:4 (1 h)
91%, >99:1 (2.5 h)
Yields were determined from the combined mass of the puri-
fied product mixtures. The product ratios were determined by GC
analysis of the crudes. a Run with 20 mol% Ni(cod)2/L6. b Run
with 100 mol% MAD. c Run at 150 °C. d Run with 40 mol%
MAD. e Run with 20 mol% MAD. Run with 3.0 mmol 2. g Run
f
at 100 °C. h Run with 5 mol% Ni(cod)2/L6 i Run with 1 mol%
MAD.
lowed the para-selective alkylation of 3-fluoroacetophenone
(4h), which was contaminated by the Aldol condensation un-
der the standard conditions with a higher loading of MAD.
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In order to gain an understanding of the reaction mechanism,
alkylation reactions using 1a and 1a-d5 were examined in par-
allel. The initial reaction rates were measured by gas chroma-
tography analysis and afforded a value of 3.7 for the kinetic
isotope effect (Figure S1 of Supporting Information). The
reaction between 1a-d5 and 2g for 3.5 h resulted in the loss of
deuterium exclusively at the para-position of 1a-d5 and in
partial deuteration of 2g at the α-position (Eq. 3). These ob-
servations implied rate-limiting and reversible C–H activation
exclusively at the para-position. Density functional theory
(DFT) calculations were then carried out on the alkylation
reaction of N,N-dimethylbenzamide with propene by (L6)Ni
and AlMe3, in order to develop a plausible catalytic cycle. The
obtained energy profile is displayed in Figure 1a with geomet-
rical changes (detailed changes are shown in Figure S2 and S3
of Supporting Information). Herein, bis(alkene)nickel complex
6 represents most likely a resting state of the catalytic cycle,
because this is the most stable in possible reactant complexes.
This species undergoes a ligand exchange reaction with N,N-
dimethylbenzamide coordinating to AlMe3, leading to the
formation of σ-complex 9 via mono-alkene complexes 7 and 8.
Cleavage of the coordinated C–H bond and formation of one
C–H and two C–Ni bonds should then proceed in a concerted
manner in one step to furnish an alkyl(aryl)nickel complex 10,
in which an agostic interaction between H and Ni is observed.
Then, geometric isomerization affords T-shaped al-
kyl(aryl)nickel intermediate 12 via its isomer 11, and reduc-
tive elimination under concomitant formation of a C–C bond
affords the alkylated arene–Ni complex 13. The proposed
catalytic cycle is consistent with a related mechanism for the
nickel-catalyzed alkylation of 1,3-bis(trifluoromethyl)benzene,
which was recently reported by Hartwig, Eisenstein, and
coworkers.26 In our theoretical study, the C–H activation step
exhibits the highest activation barrier and should thus be con-
sidered as the rate-determining step of the catalytic cycle,
which is supported by the observed kinetic isotope effect. The
theoretical and experimental results show that the para-
selectivity should thus be determined at the transition state
TS9–10. The present DFT calculations successfully show the
para-selectivity, which is enhanced by the presence of AlMe3;
66:34 without AlMe3 vs. para/meta = 98:2 with AlMe3. The
origin of the high para-selectivity in the presence of the alu-
minum Lewis acid cocatalyst can be explained in terms of
electronic and steric factors, as will be discussed below.
tron-rich nickel(0) center at the para-position rather than at the
meta-position. This notion was corroborated by the H NMR
1
1
2
3
4
5
6
7
8
analysis of the adduct 1a–AlMe3, which showed significant
shifts for the signals associated with the para-hydrogen to
lower field relative to those at the meta-position (see Support-
ing Information). The acceleration by AlMe3 can be explained
by the LUMO energy; the LUMO energy (–2.58 eV) of N,N-
dimethylbenzamide coordinating to AlMe3 is at lower energy
than that of N,N-dimethylbenzamide (–2.05 eV) as shown in
Figure 2. Because the LUMO consists of the σ* MO of the
aromatic ring and the C–H σ* antibonding MO, the stronger
CT to this LUMO leads to the easier C–H σ-bond cleavage.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Indeed,
the
electron
population
of
the
N,N-
dimethylbenzamide–AlMe3 moiety increases more than that of
N,N-dimethylbenzamide without AlMe3, in the reaction from 7
to 10 (see Figure S5 of Supporting Information). Accordingly,
it can be concluded that the aluminum Lewis acid accelerates
the C–H σ-bond cleavage particularly at the para-position.
The para-selectivity also arises from a steric repulsion be-
tween the m-tolyl substituent of L6 and the aluminum Lewis
acid in TS9–10, which is larger in the case of the meta-C–H
functionalization. The coordination of AlMe3 group com-
pletely changes the orientation of the aminocarbonyl group of
N,N-dimethylbenzamide to avoid the steric repulsion with the
ligand substituents (Figure 3a vs Figure 3b). The extent of the
congested geometry is larger in the transition state of meta-
alkylation (Figure 3c) than in that of the para-alkylation (Fig-
ure 3b) in the presence of AlMe3; the distances between the
methyl groups of AlMe3 (Cα and Cβ) and that of L6 (C12) are
much shorter in the former than in the latter. The steric factor
should be more pronounced in the real catalytic system con-
taining bulkier MAD, and the para-selectivity should be in-
creased accordingly (entry 6 vs entry 7, Table 1), though the
values calculated for L6 and AlMe3 show merely small differ-
ences for the respective activation barriers. Ligands lacking
the methyl substituents in the m-tolyl group of L6 (C12), such
as L1–L3 and L5, thus show poor para-selectivity because
they do not induce this steric repulsion (entries 1–3 and entry
5 of Table 1). The absence of the aluminum Lewis acid co-
catalyst gives the worst selectivity and poor reactivity even
with L6 as a ligand due to the lack of both the electronic acti-
vation and the steric repulsion (entry 8, Table 1).
In summary, we have demonstrated that the challenging pa-
ra-selective alkylation of benzamides and aromatic ketones
can be accomplished effectively by a cooperative catalysis
based on a bulky NHC-ligated nickel catalyst and a bulky
aluminum co-catalyst. The experimentally obtained results are
fully supported by the results of theoretical calculations on
appropriate model compounds, and a plausible reaction mech-
anism including the origin of the high para-selectivity is pro-
posed.
Ni(cod)2 (10 mol%)
L6 (10 mol%)
MAD (100 mol%)
O
D
O
D
D
D
D
38% D
SiMe(OSiMe3)2
Et2N
Et2N
(3)
150 °C, 3.5 h
D
D
D
D
<5% D
1a-d5
(0.20 mmol)
3ag-d, 27%
+
2g
recovered:
(0.60 mmol)
O
D
14% D
D
<5% D
Et2N
+
SiMe(OSiMe3)2
D
D/H
<5% D
2g, 72% (NMR)
D
1a-d5, 65%
85% D
The activation energies are 35.4 and 37.3 kcal/mol for the
para- and meta-alkylation in the absence of AlMe3 (Figure 1b)
but they are 30.8 and 33.2 kcal/mol in the presence of AlMe3
(Figure 1a). These results clearly show that AlMe3 accelerates
the reaction. Qualitatively, N,N-dimethylbenzamide coordinat-
ing to AlMe3 should show higher reactivity towards an elec-
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a) with AlMe3
L6
1
2
3
4
5
6
7
8
R
L6
Ni
R
Ni
NMe2
O+
R
H
L6 Ni
L6
L6
R
R
Ni
Ni
TS9–10
–AlMe3
TS12–13
L6
H
30.8
33.2
R
11
26.7
24.6
29.7
31.6
R
10
25.6
27.4
Ni
L6
12
24.3
27.2
R
L6
Ni
8
Ni
H
21.8 (para)
12.5 (meta)
9
L6
7
Ni
16.6
18.1
R
L6
14.2
9
Ni
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
13
3.0
1.8
6
0.0
Ligand exchange
Isomerization
C–C reductive elimination
C–H activation
L6
b) without AlMe3
R
L6
Ni
R
Ni
H
L6
NMe2
O
TS15–16
R
L6
Ni
Ni
R
R
35.4
37.3
L6 Ni
H
TS18–19
L6
16
28.8
29.2
L6
Ni
30.0
35.9
R
R
18
26.2
26.9
Ni
R
17
L6
H
15
14
22.3
21.8
Ni
20.2 (para)
18.2 (meta)
L6
19.1
15.3
7
Ni
R
L6
14.2
Ni
19
6.0
2.8
6
0.0
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Changes in geometry and Gibbs energy in the alkylation of N,N-dimethylbenzamide catalyzed by (a) (L6)Ni/AlMe3 system and
(b) (L6)Ni system. Values in blue represent the energy changes in the para-alkylation and those in black for the meta-alkylation.
NMe2
O
NMe2
O
H
H
Me3Al
LUMO (–2.05 ev)
LUMO (–2.58 ev)
Figure 2. LUMOs of N,N-dimethylbenzamide and its AlMe3 adduct whose geometries are taken to be the same as in the transition state for
C–H σ-bond cleavage
C10
C8
C3
C3
C6
C7
C5
C6
C5
C8
O1
C10
C8
C7
C6
C9
C7
C5
C3
Ni
C9
C9
C11
C11
Ni
H
Ni
C4
C4
C4
C1
C1
C1
Cβ
C2
Cα
C2
H
H
C2
C12
Al
Al
C12
Cα
Cβ
C2–H: 1.63 Å
C4–H: 1.74 Å
C2–H: 1.65 Å
C4–H: 1.60 Å
C2–H: 1.74 Å Cα–C12: 4.14 Å
C4–H: 1.74 Å Cβ–C12: 4.72 Å
Cα–C12: 3.87 Å
Cβ–C12: 3.73 Å
a) para-alkylation in the absence of AlMe3
(TS15–16 at para)
b) para-alkylation in the presence of AlMe3
(TS9–10 at para)
c) meta-alkylation in the presence of AlMe3
(TS9–10 at meta)
Figure 3. Transition states of the C–H σ-bond cleavage of N,N-dimethylbenzamide by (L6)Ni(propene)
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(21) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M. Organome-
tallics 1983, 2, 1694.
ASSOCIATED CONTENT
1
2
3
4
5
6
7
Supporting Information. Detailed experimental procedures in-
cluding spectroscopic and analytical data (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
(22) Hiyama, T. in Organometallics in Synthesis, Third Manual;
Schlosser, M. Ed.; John Wiley & Sons, 2013; 373.
(23) Martin, R.; Romea, P.; Tey, C.; Urpi, F.; Vilarrasa, J. Synlett
1997, 1414.
AUTHOR INFORMATION
Corresponding Author
(24) Sonoda, M.; Kakiuchi, F.; Kamatani, A.; Chatani, N.; Murai,
S. Chem. Lett. 1996, 25, 109.
sakaki.shigeyoshi.47e@st.kyoto-u.ac.jp
nakao.yoshiaki.8n@kyoto-u.ac.jp
8
9
(25) Aryl fluorides can be converted via C–F bond activation,
that could compensate for the limited functional group toler-
ance of the present para-alkylation protocols. Amii, H.;
Uneyama, K. Chem. Rev. 2009, 109, 2119.
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ACKNOWLEDGMENT
This article is dedicated to Professor Tamejiro Hiyama on the
occasion of his 70th birthday. This work was supported by the
CREST program “Establishment of Molecular Technology to-
wards the Creation of New Functions” Area from JST (Y.N. and
S.S.) and by Grant-in-Aids for Young Scientists (A) (25708006 to
Y.N.) and Research on Innovative Areas “Precise Formation of a
Catalyst Having a Specified Field for Use in Extremely Difficult
Substrate Conversion Reactions” (no. 15H05799 to Y.N.) from
MEXT.
(26) Bair, J. S.; Schramm, Y.; Sergeev, A. G.; Clot, E.; Eisen-
stein, O.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 13098.
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Ni + Al
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