The nickel(II)-catalyzed direct benzylation, allylation, alkylation, and methylation of C-H bonds in aromatic amides containing an 8-aminoquinoline moiety as the directing group

Article abstract of DOI:10.1246/bcsj.20140387

Direct alkylation via the cleavage of the ortho C-H bonds by a nickel-catalyzed reaction of aromatic amides containing an 8-aminoquinoline moiety as the directing group with alkyl halides is reported. Various alkyl halides, including benzyl, allyl, alkyl,

Full text of DOI:10.1246/bcsj.20140387

Selected Paper
The Nickel(II)-Catalyzed Direct Benzylation, Allylation, Alkylation,
and Methylation of C-H Bonds in Aromatic Amides Containing
an 8-Aminoquinoline Moiety as the Directing Group
Yoshinori Aihara, Jendrik Wuelbern, and Naoto Chatani*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871
E-mail: chatani@chem.eng.osaka-u.ac.jp
Received: December 13, 2014; Accepted: January 5, 2015; Web Released: January 16, 2015
Direct alkylation via the cleavage of the ortho C-H bonds by a nickel-catalyzed reaction of aromatic amides
containing an 8-aminoquinoline moiety as the directing group with alkyl halides is reported. Various alkyl halides,
including benzyl, allyl, alkyl, and methyl halides (or pseudo halides) participate as electrophilic coupling partners. The
reaction shows a high functional group compatibility. The reaction proceeds in a highly regioselective manner at the less
hindered C-H bonds in the reaction of meta-substituted aromatic amides, irrespective of the electronic nature of the
substituent. The mechanism responsible for the C-H alkylation reaction is discussed based on the results obtained in a
variety of mechanistic experiments.
Transition-metal-catalyzed direct C-H bond functionaliza-
tion has emerged as a powerful method for the construction
of organic molecules, and numerous reports on the formation
of C-C bonds via C-H bond cleavage have been appeared,
especially direct arylation with aryl halides or aryl metal
reagents.1 Compared to arylation reactions, examples of the
direct alkylation of C-H bonds to afford alkylated arenes
remain limited, because of the resistance of alkyl halides
toward oxidative addition and the fact that the resulting alkyl
metal complexes are susceptible to β-hydride elimination.2
Conventional approaches to the synthesis of alkylated arenes
rely on Friedel-Crafts-type reactions or SEAr type reactions,
both of which have some limitations including i) a low func-
tional group tolerance, ii) low regioselectivities, and iii) the
formation of a mixture of normal and branched products.3
Numerous efforts have been made to address these limitations,
and transition-metal-catalyzed direct alkylation with alkyl
halides has emerged as an alternative method for the synthesis
alkylated arenes. Due to those efforts, direct alkylations using
alkyl halides as the alkylating reagent with Pd,4 Ru,5 Fe,6 and
Co7 catalysts have been developed over the past few years.
In 2013, our group also reported the first example of the
nickel(II)-catalyzed direct alkylation of ortho C-H bonds in
aromatic amides with primary alkyl halides,8 by taking advan-
tage of a bidentate directing group.1m After this paper appeared,
other groups have expanded the substrate scope and limitations,
such as the direct alkylation of C(sp3)-H bonds,9a alkylation
with secondary alkyl halides,9b and phosphates9c as alkylating
reagents by utilizing the same chelation system. In this
manuscript, we report the full details of the nickel(II)-catalyzed
direct benzylation, allylation, alkylation, and methylation of
C-H bonds in aromatic amides, and we also discuss the
mechanism for this reaction, based on competition reactions,
deuterium labeling experiments, detailed product distributions,
and radical clock experiments.
Results and Discussion
Our group has focused on the use of bidentate directing
groups, such as 2-pyridylmethylamine10 and 8-aminoquino-
line8,11 in a catalytic functionalization of C-H bonds. To
expand the utility of the present chelation system, we examined
the reaction of 1a with butyl bromide. Fortunately, the alkyl-
ation of C-H bonds with alkyl halides was successful, when an
8-aminoquinoline chelation system was used. When the amide
1a was reacted with butyl bromide under optimal conditions
for arylation reactions with phenyl iodide,11h no reaction took
place (Entry 1 in Table 1). However, the addition of PPh3
dramatically improved the product yield to 41% NMR yield,
along with 54% of unreacted 1a being recovered (Entry 3). The
product yield was significantly affected by the nature of the
base used (Entries 3-8). The use of PCy3 gave 2a in 26% NMR
yield (Entry 9). The use of 2 equivalents of butyl bromide
improved the product yield to an isolated yield of 88%
(Entry 12). Some Ni(II) complexes could also be used as cata-
lysts (Entries 13-15). Similar to the arylation of C-H bonds,11h
the Ni(0) complex was also found to show catalytic activity. In
all cases, the starting amide 1a was recovered when the product
yield of 2a was low. No by-products were detected in the
reactions.
With the optimized reaction conditions in hand, we exam-
ined the scope of the substrate in the reaction. Table 2 shows
the results for reactions of various aromatic amides with butyl
bromide under the standard reaction conditions. A variety of
functional groups were found to be tolerated and, even the
438 | Bull. Chem. Soc. Jpn. 2015, 88, 438–446 | doi:10.1246/bcsj.20140387
© 2015 The Chemical Society of Japan

Table 1. The Nickel-Catalyzed Butylation of 1a with Butyl
Bromide
Table 2. The Ni-Catalyzed Butylation of C-H Bonds in
Aromatic Amidesa)
cat. Ni 10 mol%
ligand 20 mol%
base 2 equiv
O
O
Amide
Productb)
N
N
+
BuBr
H
H
O
O
N
N
toluene 1 mL
H
Bu
R
R
140 °C, 24 h
N
H
N
H
1a 0.3 mmol
0.45 mmol
2a
N
N
Bu
Entry Catalyst
Ligand
Base
Yields (2a/1a)a)
R = OMe (1b)
2b
2c
2d
2e
2f
2g
2h
2i
74% (89%)c)
72% (85%)c)
75%
1
2
3
4
5
6
7
8
9
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
none
none
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PCy3
DMF
NaHCO3
0%/101%
0%/92%
41%/54%
79%/15%
3%/109%
0%/90%
5%/101%
OCH2Ph (1c)
OSiMe2But (1d)
Me (1e)
Ph (1f)
Cl (1g)
I (1h)
C(O)CH3 (1i)
CF3 (1j)
Na2CO3
NaHCO3
Na2CO3
Li2CO3
K2CO3
NaOAc
2,6-lutidine 0%/105%
Na2CO3
Na2CO3
92%d)
81%d)
92%e)
68%e)
75%d)
26%/63%
0%/95%
2j
95%d)
10 Ni(OTf)2
O
O
1.5 mmol
DMSO
1.5 mmol
N
N
H
11 Ni(OTf)2
Na2CO3
0%/97%
H
N
N
N
N
N
Bu
4 79%d)
12b) Ni(OTf)2
13 Ni(OAc)2
14 NiCl2
15 [NiBr2(dme)] PPh3
16 [Ni(cod)2] PPh3
PPh3
PPh3
PPh3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
91% (88%)/0%
70%/19%
66%/31%
76%/10%
51%/35%
3
O
O
MeO
MeO
MeO
MeO
N
N
H
H
N
Bu
a) NMR yields. The number in parenthesis is the isolated yield
of 2a. b) BuBr (0.6 mmol) was used.
5
6 92%
O
O
AcO
AcO
N
N
H
iodide remained intact, as in 2h. The reaction of meta-
substituted substrates resulted in alkylation to proceed exclu-
sively at the less hindered C-H bonds, irrespective of the
electronic nature of the substituent. In general, electron-
withdrawing groups tended to give butylation products in
higher yields. The addition of NaI was found to improve the
product yields in some cases.
H
N
Bu
7
8 52%
O
O
N
N
H
H
N
F
F
Bu
9
O
10 87%
This C-H bond alkylation reaction was also found to be
applicable to α,β-unsaturated amides, as shown in Table 3. The
cyclic amides, 17, 19, and 21 gave the corresponding butyl-
ation products in good yields. However, in the case of the
acyclic amide 23, a mixture of stereoisomers 24, was produced,
with the E-isomer being favored. The reaction was limited
to trisubstituted α,β-unsaturated amides, suggesting that the
presence of the substituent at the α-carbon is an important
factor in terms of the reactivity of the substrates. In fact, reac-
tions of 25 and 27 failed to give the corresponding butylation
products.
O
N
N
H
H
N
N
N
S
S
Bu
11
12 50%
O
O
N
N
H
H
N
N
N
Bu
Me
Me
13
14 76%d),f)
A variety of alkyl halides were also found to be applicable
to this reaction, as shown in Table 4. Octyl iodide as well as
octyl bromide gave the octylation product 29 in high yield.
While no reaction took place in the case of octyl chloride, it is
noteworthy that the addition of NaI (2 equivalents) dramatically
improved the product yield to 88% isolated yield. This effect of
NaI was also observed in the case of other sterically demand-
ing alkyl halides or some functionalized alkyl halides. When
phenethyl bromide was used as the coupling partner, the corre-
sponding product 34 was obtained in 57% yield, however the
yield was improved to 88% isolated yield when 2 equivalents
of NaI was added.12 The use of 3-methylbutyl bromide and
O
Bu
O
N
N
H
H
N
N
MeO
MeO
Bu
15
16 88%d),f)
a) Reaction conditions: amide (0.3 mmol), BuBr (0.6 mmol),
Ni(OTf)2 (0.03 mmol), PPh3 (0.06 mmol), and Na2CO3 (0.6
mmol) in toluene (1 mL) at 140 °C for 24 h. b) Isolated yields.
c) NaI (0.6 mmol) was used as an additive. d) Run at 160 °C.
e) BuI (0.6 mmol) was used instead of BuBr. f) BuBr (1.2
mmol) was used.
Bull. Chem. Soc. Jpn. 2015, 88, 438–446 | doi:10.1246/bcsj.20140387
© 2015 The Chemical Society of Japan | 439

Table 3. The Ni-Catalyzed Butylation of C-H Bonds in
α,β-Unsaturated Amidesa)
Table 4. The Ni-Catalyzed Alkylation of C-H Bonds in
Aromatic Amides with Functionalized Alkyl Halidesa),b)
Ni(OTf)2
PPh3, Na2CO3
RBr
Amide
Productb)
O
H
O
Q
O
O
N
H
N
H
toluene, 140 °C, 24 h
N
N
H
N
H
1a
R
N
N
N
N
N
N
N
Bu
O
O
O
17
18 81%
Q
N
Q
Q
N
N
H
O
O
O
O
O
O
H
H
Oct
3
3
N
H
N
H
CN
OMe
N
N
N
29 Oct I 88%
Oct Br 92%
Oct Cl 0% (88%)
O
Bu
30 77%
31 91%
19
20 67%
O
O
O
Q
N
Q
N
Q
N
H
N
H
N
H
H
H
O
O
Bu
3
3
21
22 72%
Ph
CO2Me
O
TIPS
32 60% (76%)
33 (62%)
34 57% (88%)
N
H
N
H
O
O
O
Q
N
Q
N
H
Q
N
Bu
H
H
23
24 54% (E:Z = 85:15)
O
OBn
N
H
N
H
N
35 47% (81%)
36 72% (92%)
37 35% (70%)
Ph
Ph
Bu
O
O
O
25
26 0%
Q
N
Q
N
Q
N
H
O
H
H
N
H
N
H
CF3
N
tBu
tBu
Bu
27
28 0%
38 trace (44%)
39 trace (45%)
40 (67%)
a) Reaction conditions: amide (0.3 mmol), BuBr (0.6 mmol),
Ni(OTf)2 (0.03 mmol), PPh3 (0.06 mmol), and Na2CO3 (0.6
mmol) in toluene (1 mL) at 140 °C for 24 h. b) Isolated yields.
a) Reaction conditions: amide 1a (0.3 mmol), RBr (0.6 mmol),
Ni(OTf)2 (0.03 mmol), PPh3 (0.06 mmol), and Na2CO3 (0.6
mmol) in toluene (1 mL) at 140 °C for 24 h. b) Isolated yields.
The number in the parenthesis is the yield using NaI (0.6
mmol).
cyclopentylmethyl bromide in the absence of NaI resulted in
essentially no reaction, but the yields of 38 and 39 were
improved to 44% and 45% yields, respectively, when NaI was
added.
generated by a Finkelstein reaction under the conditions in the
reaction with NaI.
To examine the effect of NaI in more detail, the reaction of
1a with 4-phenylphenethyl bromide (41-Br) was carried out in
the absence of NaI (Scheme 1). The corresponding alkylation
product 42 was formed in 43% yield, along with 33% of 1a and
53% of 41-Br being recovered, and only a 3% NMR yield of
4-phenylstyrene (based on the bromide 41-Br) was formed.
However, when 1a was reacted with 41-Br in the presence
of NaI, 42 was produced in 88% isolated yield, with a 10%
yield of 4-phenylstyrene. These results suggest that β-hydride
elimination leading to the formation of 4-phenylstyrene is not
the cause of the low conversion in the reaction without NaI.
Rather, the low yield of 42 in the reaction of 1a with 41-Br can
be attributed to the low reactivity of the C-Br bond in 41-Br.
In support of this, essentially the same results were obtained in
the reaction of 1a with 41-I, the corresponding iodide 41-I is
The reaction of 1a with a secondary halide, such as
cyclopentyl bromide under reaction conditions suitable for
primary halides gave only a trace amount of the alkylation
product 43. After optimization of the reaction conditions, and
using IMesMe and PPh3 as the ligand, the product yield was
improved to 51% (Scheme 2).13
Several studies were carried out, in an attempt to obtain
information regarding the mechanism for the reaction. We
hypothesized that the alkylation products are formed via the
addition of C-H bonds to alkenes which may involve the
generation of an alkyl halide via dehydrobromination under the
reaction conditions employed. However, when 1a was reacted
with 1-octene, the expected alkylation product 29 was not
detected (Scheme 3). Because the PPh3 is essential for the
alkylation reaction to proceed, a quaternary phosphonium
440 | Bull. Chem. Soc. Jpn. 2015, 88, 438–446 | doi:10.1246/bcsj.20140387
© 2015 The Chemical Society of Japan

X
41
Ph
O
H
Ni(OTf)2
PPh3
Na2CO3
10 mol%
20 mol%
2 equiv
O
R
N
H
N
N
H
N
toluene, 140 °C, 24 h
1a
42
recovery
of 41
42
Ph
X = Br (41-Br)
43% (33%)a
53%
(based on 41)
3%
(based on 41)
X = Br with NaI 88% (9%)a
X = I (41-I)
86% (9%)a
15%b
(based on 41)
trace
10%
(based on 41)
5%
(based on 41)
aThe number in parenthesis is the recovery of 1a.
bThe corresponding iodide 41-I was obtained.
Scheme 1. The effect of NaI.
Ni(OTf)2
10 mol%
Ni(OTf)2
PPh3
Na2CO3
BuBr
10 mol%
20 mol%
2 equiv
IMesMe HCl 20 mol%
CD3
O
PPh3
NaOtBu
20 mol%
23 mol%
2 equiv
D
D
2 equiv
N
H
toluene, 140 °C, 8 h
N
Na2CO3
O
D
O
H
D
CD3
O
CD3
O
Br
N
H
1a-d7
2 equiv
N
H
D
D
Q
D
D
Q
N
N
H
N
H
N
toluene, 140 °C, 24 h
Me Me
+
Bu
H/D
1a
43 51%
D
D
IMesMe
=
25%
49% (H)
70%
N
N
Mes
Mes
CD3
O
CD3
O
D
Scheme 2. The Ni-catalyzed alkylation with secondary alkyl
halide.
D
Q
D
D
without BuBr
N
H
N
H
N
D
H/D
Ni(OTf)2
PPh3
10 mol%
20 mol%
2 equiv
PPh3 57% (H)
none 59% (H)
D
D
1a-d7
88%
O
H
O
Na2CO3
Scheme 4. Deuterium labeling experiments.
Hex
2 equiv
N
H
N
H
N
toluene, 140 °C, 24 h
N
Oct
The deuterated amide 1a-d7 was reacted with BuBr for 8 h
1a
29 trace
under otherwise standard reaction conditions (Scheme 4). As
observed in the case of arylation,11h a significant amount of
H/D exchange at the ortho position (the d-content decreased
from >98% to 51% (49%H)) and on the amide nitrogen in the
recovered amide was observed. A significant amount of H/D
exchange occurred, even in the absence of BuBr, indicating that
the cleavage of C-H bonds is reversible. These results indicate
that the cleavage of C-H bonds is not likely the rate deter-
mining step in the reaction. It was also found that the presence
of PPh3 had no effect on the H/D exchange reaction.
Ni(OTf)2
PPh3
Na2CO3
BuPPh3Br
10 mol%
20 mol%
2 equiv
O
H
O
2 equiv
N
H
N
H
N
toluene, 140 °C, 24 h
N
Bu
1a
2a 5%
Scheme 3. Alkylation sources.
bromide is also another candidate for the use of an alkylation
reagent. However, the corresponding butylation product 2a was
formed in only 5% yield. These results indicate that neither the
olefin nor the quaternary phosphonium bromide is involved in
this alkylation and that the alkyl halides themselves function as
the coupling partner.
We next performed a competition experiment using an
excess amount of a 1:1 mixture of 1b and 1j in a reaction with
octyl bromide (Scheme 5). The findings indicate that 1j reacted
to give 45 as the major product. This result again indicates that
the presence of an electronic-withdrawing group on aromatic
amides facilitates the reaction.14
Bull. Chem. Soc. Jpn. 2015, 88, 438–446 | doi:10.1246/bcsj.20140387
© 2015 The Chemical Society of Japan | 441

O
H
O
H
Ni(OTf)2
PPh3, Na2CO3
Oct Br (0.4 mmol)
X
MeO
Q
F3C
Q
0.6 mmol
Ni(OTf)2 0.3 mmol
PPh3 0.6 mmol
N
H
N
H
+
O
O
O
H
toluene, 160 °C, 36 h
Q
Q
Q
Na2CO3 0.6 mmol
N
H
N
H
N
H
+
1b (0.5 mmol)
1j (0.5 mmol)
toluene 1 mL
140 °C, 24 h
Q = 8-quinolinyl
O
O
1a 0.3 mmol
MeO
Q
N
H
F3C
Q
N
+
H
Oct
Oct
X
yield
48
:
49
44 5%
45 67%
Br
I
88%
94%
18
11
:
:
1
1
Scheme 5. Competition experiment.
0.6 mmol
0.03 mmol
0.6 mmol
C12H25 Br 46
Ni Cat.
NaHCO3
X
O
H
O
Q
0.6 mmol
Q
N
H
N
H
Ni(OTf)2
PPh3
Na2CO3
0.3 mmol
0.6 mmol
0.6 mmol
O
O
O
toluene 1 mL, 140 °C, 20 h
C12H25
Q
Q
Q = 8-quinolinyl
Q
N
H
N
H
N
H
+
1a 0.3 mmol
47
toluene 1 mL
140 °C, 24 h
Q = 8-quinolinyl
H
recovery of
C10H21
47
C12H25 H
0.3 mmol
46
Ni(OTf)2 76% (19%)
[Ni(cod)2] 94% (trace)
53%/46
16%/46
3%/46
14%/46
trace
6%/46
X
yield
50
:
51
Br
I
81%
88%
2.9
2.0
:
:
1
1
aThe numer in parenthesis is the recovery of 1a.
Scheme 6. Product distribution.
Scheme 7. Radical clock experiments.
As shown in Table 1, both Ni(0) and Ni(II) complexes
showed a high catalytic activity. The product distribution was
examined in considerable detail in order to develop a better
understanding of the difference between the Ni(II)- and Ni(0)-
catalyzed reactions (Scheme 6). When Ni(OTf)2 was used as
the catalyst, the alkylation product 47 was produced in 76%
yield, along with 19% of 1a and 53% of the bromide 46 being
recovered. No evidence for β-hydride elimination leading to the
formation of dodecene was found. In contrast, the halide 46
was recovered only in 16%, and 14% yield of dodecane and
6% of dodecene were produced when the Ni(cod)2 catalyst
was used. In both cases, no dimerization of 46 leading to the
formation of tetracosane (C24H50) was observed.15
These results exclude the possibility of a Ni(0)/Ni(II)
catalytic cycle. However, a Ni(I)/Ni(III) catalytic cycle, which
involves a radical path cannot be excluded, based on the find-
ings reported herein. In fact, a Ni(I)/Ni(III) catalytic cycle was
proposed in the Ni-catalyzed alkylation of C(sp3)-H bonds.9a
In order to obtain mechanistic information regarding this,
reactions were run in the presence of radical scavengers. The
addition of TEMPO (2 equivalents) resulted in no detectable
products being formed. The alkylation product was not formed
and 1a was recovered in 79% NMR yield. We next used
GALVINOXYL (2 equivalents) in place of TEMPO. Again, a
reaction did not take place and 1a was recovered in 52% yield.
To gain more insights into the mechanism, radical clock
experiments were next carried out. The reaction of 1a with 6-
bromohex-1-ene gave the unrearranged product 48 selectively
(Scheme 7). Although the use of 6-iodohex-1-ene resulted in a
slight decrease in the ratio of 48/49, the unrearranged alkyl-
ation product 48 was still the major product. We next used
cyclopropylmethyl halides, since the cyclopropylmethyl radical
is known to undergo ring-opening faster than the cyclization of
the 5-hexenyl radical.16 The reaction with cyclopropylmethyl
bromide gave a mixture of the unrearranged product 50 and the
rearranged product 51 in a total isolated yield of 81% in favor
of the unrearranged product 50.
We next examined the effect of catalyst concentration on the
products formed in the reaction of 1a with 6-bromohex-1-ene.
If a radical chain mechanism were operative, then the 48/49
ratio would be expected to increase at higher catalyst concen-
trations because the radical would have less time to rearrange
before reacting with another nickel.17 In contrast, if a radical
chain were not involved, the 48/49 ratio would be expected to
be unchanged as a function of catalyst concentration. However,
the ratio was found to be constant, irrespective of the catalyst
concentration used (Scheme 8), suggesting that the radical
chain mechanism is not operative.
Although some mechanistic studies were performed, it
remains difficult to reach a firm conclusion regarding the
mechanism for this reaction, i.e., whether or not the reaction
proceeds via a radical mechanism, because of the inconclu-
sive results obtained. The results shown in Scheme 8 suggest
that free radical species are not involved in the reaction. The
possibility that the key intermediate has a radical character, but
that a radical species is not free, but instead remains in the
coordination sphere in a nickel center cannot be excluded.
The alkylation of C-H bonds essentially proceeds through a
mechanism similar to that proposed in the arylation of C-H
bonds (Scheme 9).11h,18 Amide A coordinates to NiX2 followed
by a ligand exchange with the generation of HX, which is
accelerated by Na2CO3, to give the nickel complex B. Complex
B then undergoes a reversible cyclometalation to give complex
C via a concerted metalation deprotonation (CMD) mechanism,
442 | Bull. Chem. Soc. Jpn. 2015, 88, 438–446 | doi:10.1246/bcsj.20140387
© 2015 The Chemical Society of Japan

O
H
O
O
Ni(OTf)2 X mol%
PPh3 0.6 mmol
Na2CO3 0.6 mmol
Q
Q
Q
N
H
N
H
N
H
+
toluene 1 mL
140 °C, 24 h
Q = 8-quinolinyl
1a 0.3 mmol
+
Br
0.6 mmol
X mol%
48
:
49
5 mol%
10 mol%
15 mol%
20
18
19
:
:
:
1
1
1
The ratio of product was determined by NMR.
Scheme 8. Dependence of the ratio of 48 and 49 on the concentration of nickel catalyst.
R
X + A H-X + R-H
TEMPO
Ni(OTf)2 10 mol%
1 equiv
CD3
O
D
CD3
O
H-Ni-X
B
D
D
Q
PPh3
Na2CO3
20 mol%
2 equiv
D
D
Q
N
R'
N
H
H
A
R-X
Ni(0)
toluene 1 mL
140 °C, 8 h
Q = 8-quinolinyl
H/D
H-X
O
R-Ni-X
D
O
R
D
62% (H)
H-X
R-H
N
Ni
R
N
H
N
N
F
Scheme 10. Effect of TEMPO on the H/D exchange.
A
NiX2
H-X
H-X
R-H
place to the same extent as that for the reaction in the absence
of TEMPO (Scheme 10). As shown in Scheme 4, the presence
of PPh3 also had no effect on the cleavage of C-H bonds,
indicating that the presence of PPh3 is essential for the oxida-
tive addition of an alkyl halide with a nickel center and but that
it is not involved in the cleavage of C-H bonds.
H-X
O
O
H
N
N
N
Ni
X
Ni
X
N
R
E
B
Na2CO3
Benzylation and Allylation. Benzyl and allyl bromides
were also found to participate as electrophilic counter part-
ners in the reaction (Table 5). Crotyl bromide was not a viable
reactant, but the reaction with 3-bromo-2-methylprop-1-ene
gave the corresponding allylation product 56 in good yield. The
regioselectivity was again controlled by steric factors. In all
cases, the less hindered C-H bonds reacted exclusively.
Methylation. It is important to note that the regioselective
methylation of C-H bonds is a research topic of considerable
interest in the area of pharmaceutical chemistry, because of
the well-known “magic methyl effect” which, in many cases,
greatly improves the biological activity of a drug.19 However,
examples of the methylation of C(sp2)-H bonds with methyl
halides (or pseudohalide) are very rare. Tremont reported that
acetanilides react with MeI in the presence of a stoichiometric
amount of Pd(OAc)2 resulting in methylation at the ortho
position.4a,20 A catalytic version was recently reported using
MeI as the methylation reagent.4c-4e,4i,4k,21 While organometal-
lic reagents,22 such as Me4Sn, MeB(OH)2, peroxides23 and
others24 can also be used in the methylation of C(sp2)-H bonds,
the methylation of C-H bonds continues to be a significant
challenge.
NaHCO3 +NaX
O
R
O
N
Ni
N
N
Ni
N
X
D
C
H-X = HI, NaHCO3, H2O, A
R
X
Scheme 9. Proposed reaction mechanism.
which is also accelerated by the presence of Na2CO3. The
oxidative addition of an alkyl halide to the complex C gives
the nickel(IV) species D. Complex D undergoes a reductive
elimination to give E, which is then protonated to afford the
alkylation product with the regeneration of the nickel(II)
catalyst. As shown in Scheme 4, C-H bond cleavage appears to
be reversible and does not appear to be the rate-determining
step in this reaction. As shown in Table 1, both Ni(II) and Ni(0)
complexes have high catalytic activities. Based on the results
shown in Scheme 6, even when Ni(0) is used as the catalyst
precursor, the nickel complexes are converted into Ni(II)
species and participate in the main catalytic cycle as the
complex B.
When 1a was reacted with methyl iodide under the standard
reaction conditions, which involve the use of 4 equivalents of
methyl iodide, the corresponding methylation product 57 was
obtained in 56% NMR yield, along with the N-methylation
product in 47% yield (Scheme 11). When MeOTs was used,
The findings clearly show that the presence of TEMPO had
no effect on the cleavage of C-H bonds. Thus, even in the
presence of TEMPO, an H/D exchange reaction of 1b took
Bull. Chem. Soc. Jpn. 2015, 88, 438–446 | doi:10.1246/bcsj.20140387
© 2015 The Chemical Society of Japan | 443

Ni(OTf)2
PPh3
Na2CO3
Me-X
10 mol%
20 mol%
2 equiv
Table 5. The Ni-Catalyzed Benzylation and Allylation of
C-H Bonds in Aromatic Amidesa)
O
H
O
N
H
Productb)
N
H
Amide
N
toluene, 140 °C, 24 h
N
Me
57
O
O
1a 0.3 mmol
R
R
N
H
N
H
MeI (1.2 mmol)
56% (NMR)
trace
N
N
MeOTs (1.2 mmol)
MeOTs (0.6 mmol)/
NaI (0.6mmol)
Ph
91%
R = OMe (1b)
Me (1e)
52b 66%
52e 60%
52g 55%
52j 65%
Scheme 11. Ni-catalyzed methylation.
Cl (1g)
CF3 (1j)
Table 6. The Ni-Catalyzed Methylation of C-H Bonds in
Aromatic Amidesa)
O
O
R
R
N
N
H
H
N
Amide
Productb)
N
O
O
R = OMe (1b)
Cl (1g)
53b 71%
53g 63%
53j 71%
R
R
N
H
N
H
CF3 (1j)
N
N
Me
O
O
R = OMe (1b)
Ph (1f)
58b 91%
MeO
MeO
MeO
MeO
58f 95%c),d)
58g 91%c),d)
58i 93%
N
N
H
H
N
Cl (1g)
C(O)CH3 (1i)
CF3 (1j)
N
58j 71%c),d)
5
O
54 70%
O
O
O
N
N
N
H
H
N
N
N
N
H
F
F
H
N
N
9
55 49%
Me
O
O
3
59 86%
N
N
H
O
O
H
N
MeO
MeO
MeO
MeO
N
H
N
H
N
1a
N
O
Me
56 88%
5
60 74%
O
a) Reaction conditions: amide 1a (0.3 mmol), bromides (0.6
mmol), Ni(OTf)2 (0.03 mmol), PPh3 (0.06 mmol), and Na2CO3
(0.6 mmol) in toluene (1 mL) at 140 °C for 24 h. b) Isolated
yields.
Q
Q
N
N
H
H
H
H
H
H
Me
H
H
H
O
61
62 65%c),e)
Me
Me
O
only a trace amount of 57 was obtained. However, the use of a
combination of methyl iodide/NaI dramatically increased the
product yield to 91% isolated yield.
Results for the methylation of various aromatic amides are
shown in Table 6. In the reaction of meta-substituted aromatic
amides, the less hindered C-H bonds were exclusively mono-
methylated, even though the methyl group is sterically less
bulky.
a) Reaction conditions: amide (0.3 mmol), MeOTs (0.6 mmol),
Ni(OTf)2 (0.03 mmol), PPh3 (0.06 mmol), Na2CO3 (0.6 mmol),
and NaI (0.6 mmol) in toluene (2 mL). b) Isolated yields.
c) At 160 °C. d) PPh3 (10 mol %) was used. e) Reaction condi-
tions: amide (0.15 mmol), MeOTs (0.3 mmol), Ni(OTf)2 (0.015
mmol), PPh3 (0.03 mmol), Na2CO3 (0.3 mmol), and NaI (0.3
mmol) in toluene (2 mL).
All reactions, including arylation, alkylation, benzylation,
allylation, and even methylation took place at the less hindered
C-H bonds in the reaction of meta-substituted aromatic amides.
To gain more insights into the mechanism, a deuterium label-
ing experiment using 1e-d7 was conducted (Scheme 12). The
findings showed that the hindered C-H bonds also undergo
H/D exchange to some extent, suggesting that the cleavage
of C-H bonds takes place, but that the oxidative addition of
halides or reductive elimination does not occur at the hindered
C-H bonds because of steric hindrance. Similar to the case
shown in Scheme 4, the presence of PPh3 also had no effect,
either on the efficiency of C-H bond cleavage or on the
regioselectivity of the cleavage of C-H bonds.
Conclusion
Regioselective alkylation at the ortho-position of aromatic
amides with alkyl halides (or pseudo halides) was achieved
444 | Bull. Chem. Soc. Jpn. 2015, 88, 438–446 | doi:10.1246/bcsj.20140387
© 2015 The Chemical Society of Japan

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PPh3 8% (H)
none 6% (H)
Ni(OTf)2 10 mol%
H/D
O
D
D
O
D
PPh3
Na2CO3
20 mol%
2 equiv
D3C
D
Q
D3C
D
N
H
N
H
toluene, 140 °C, 8 h
N
H/D
D
1e-d7
PPh3 52% (H)
none 51% (H)
Scheme 12. Deuterium labeling experiment using a meta-
substituted aromatic amide (1e-d7).
2
a) S. Messaoudi, J.-D. Brion, M. Alami, Eur. J. Org. Chem.
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using Ni catalysts in conjunction with an 8-aminoquinoline
directing group. Various groups, such as benzyl, allyl, alkyl,
and methyl groups can be introduced at the ortho position.
A variety of functional groups are tolerated in the reaction.
The reaction proceeds in a highly selective manner at the
less hindered C-H bonds in the reaction of meta-substituted
aromatic amides, irrespective of the electronic nature of the
substituents. Both Ni(II) and Ni(0) shows a high catalytic
activity, but, based on various mechanistic experiments, it
appears that that Ni(II) is the key catalytic species and Ni(0) is
converted to Ni(II) under the reaction conditions employed.
The proposed mechanism involves a Ni(II)/Ni(IV) catalytic
cycle. The key intermediate appears to have a radical character,
but the reaction probably does not proceed via a radical chain
mechanism. To reach a firm conclusion regarding the mecha-
nism for this reaction, further experiments and theoretical
studies will be required. A DFT calculation study is currently in
progress.
3
M. B. Smith, March’s Advanced Organic Chemistry:
Reactions, Mechanisms, and Structure, John Wiley & Sons, 2013.
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This work was supported, in part, by a Grant-in-Aid for
Scientific Research on Innovative Areas “Molecular Activation
Directed toward Straightforward Synthesis” from The Ministry
of Education, Culture, Sports, Science and Technology, and by
JST Strategic Basic Research Programs “Advanced Catalytic
Transformation Program for Carbon Utilization (ACT-C)”
from Japan Science and Technology Agency. This work was
supported by the JSPS Japanese-German Graduate Externship
from Japan Science and Technology Agency and the Deutsche
Forschungsgemeinschaft through the International Research
Training Group “Selectivity in Chemo- and Biocatalysis” (or
“Seleca”) Y.A. expresses his special thanks for a JSPS Research
Fellowship for Young Scientists.
6
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S. Asako, E. Nakamura, J. Am. Chem. Soc. 2014, 136, 13126.
c) B. M. Monks, E. R. Fruchey, S. P. Cook, Angew. Chem., Int. Ed.
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8
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Supporting Information
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Chem. Soc. 2009, 131, 6898. b) N. Hasegawa, V. Charra, S. Inoue,
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Experimental procedures and spectroscopic data for all
new compounds. This material is available electronically on
J-STAGE.
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446 | Bull. Chem. Soc. Jpn. 2015, 88, 438–446 | doi:10.1246/bcsj.20140387
© 2015 The Chemical Society of Japan