Rhodium-Catalyzed Alkylation of C?H Bonds in Aromatic Amides with Non-activated 1-Alkenes: The Possible Generation of Carbene Intermediates from Alkenes

Article abstract of DOI:10.1002/chem.201901300

The alkylation of C?H bonds (hydroarylation) in aromatic amides with non-activated 1-alkenes using a rhodium catalyst and assisted by an 8-aminoquinoline directing group is reported. The addition of a carboxylic acid is crucial for the success of this reaction. The results of deuterium-labeling experiments indicate that one of deuterium atoms in the alkene is missing, suggesting that the reaction does not proceed through the commonly accepted mechanism for C?H alkylation reactions. Instead the reaction is proposed to proceed through a carbene mechanism. The carbene mechanism is also supported by preliminary DFT calculations.

Full text of DOI:10.1002/chem.201901300

A Journal of
Accepted Article
Title: Rhodium-Catalyzed Alkylation of C-H Bonds in Aromatic Amides
with Unactivated 1-Alkenes : The Possible Generation of
Carbene Intermediates from Alkenes
Authors: Naoto Chatani, Takuma Yamaguchi, Satoko Natsui, Kaname
Shibata, Ken Yamazaki, Supriya Rej, and Yusuke Ano
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201901300
Link to VoR: http://dx.doi.org/10.1002/chem.201901300
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10.1002/chem.201901300
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COMMUNICATION
Rhodium-Catalyzed Alkylation of C-H Bonds in Aromatic Amides
with Unactivated 1-Alkenes : The Possible Generation of Carbene
Intermediates from Alkenes
Takuma Yamaguchi, Satoko Natsui, Kaname Shibata, Ken Yamazaki, Supriya Rej, Yusuke Ano, and
Naoto Chatani*
Abstract: Alkylation of C-H bonds (hydroarylation) in aromatic amides
with unactivated 1-alkenes using a rhodium catalyst and assistance
by an 8-aminoquinoline directing group are reported. The addition of
a carboxylic acid is crucial for the success of this reaction. The results
of deuterium-labelling experiments indicate that one of deuterium
atoms in the alkene is missing, suggesting that the reaction does not
proceed through commonly accepted mechanism for C-H alkylation
reactions. Instead the reaction is proposed to proceed through a
carbene mechanism. The carbene mechanism is also supported by
preliminary DFT calculations.
naphthylamide using various alkenes.14 We wish to report herein
on a more general range of hydroarylation of unactivated 1-
alkenes that involves the use of rhodium complexes as catalysts
in conjunction with an 8-aminoqunolinyl group as the directing
group (Scheme 1). A mechanism involving the generation of a
carbene intermediate form an alkene is proposed, based on the
results of deuterium labeling experiments and preliminary DFT
studies.
R
O
O
[Rh(OAc)(cod)]2
o-MeC6H4COOH
N
N
H
H
N
toluene
160 °C
N
R
H
The direct functionalization of C-H bonds has emerged as a
valuable tool for sustainable organic synthesis.1 A wide variety of
functionalization reactions of C-H bonds with various nucleophiles,
electrophiles, radicals, and other reagents has been reported to
date. Among them, the alkylation of C-H bonds (hydroarylation of
alkenes) is the most direct and atom-economical route for
preparing alkyl-substituted aromatic compounds, because all of
the atoms of the substrates and alkenes are incorporated into the
desired products. A pioneering example of this type of reaction
was reported by Murai and coworkers in 1993, who reported on
the RuH2(CO)(PPh3)3-catalyzed ortho-alkylation of aromatic
ketones with alkenes.2 This represents the first effective example
of chelation-assisted C-H functionalization. Since then, a number
of examples of the hydroarylation of alkenes has been reported.3
However, most are limited to reactions with activated alkenes,
such as α,β-unsaturated carbonyl compounds, styrene derivatives,
and norbornene, or non-isomerizable alkenes, such as ethylene,
tert-butylethylene, and vinylsilanes. The hydroarylation of simple
unactivated 1-alkenes that are applicable to a wide range of
substrates continues to remain a challenging issue.3-8 In most
cases, the hydroarylation of unactivated 1-alkenes is applicable
only to the reactive heteroaromatic C-H bonds or to a limited
range of 1-alkenes.
R = alkyl
Scheme 1. Alkylation of C-H Bonds with Unactivated 1-Alkenes.
We initiated our study by investigating the reaction of the aromatic
amide 1a (0.3 mmol) with 1-hexene (0.6 mmol) in the presence of
[Rh(OAc)(cod)]2 (2.5 mol%) as the catalyst in toluene (1 mL) at
160 °C for 12 h, which gave only trace amount of the expected
alkylation product 2a, with 84% of 1a being recovered (see Table
S1 in SI). It was found that the addition of carboxylic acid
improved the efficiency of the reaction. An extensive series of
carboxylic acids was screened and it was found that o-toluic acid
proved to be the optimal choice as the yield of 2a was dramatically
improved to 49% NMR yield. Various other reaction parameters
were examined in conjunction with the use of one equivalent of o-
toluic acid, and finally we find that the use of five equivalents of 1-
hexene gave the expected alkylation products 2a in 84% isolated
yield (linear/branch = 88/12).
Substrate scope with regards to the amide showed that, aromatic
amides possessing electron-donating, electron-withdrawing, and
ortho-substituents were all tolerated (Table 1). The reaction
shows a high functional group tolerance (2a-l). A bromide
remained intact, as in 2j, which provided the opportunity for further
functionalization via conventional cross-coupling methods. The
linear selectivity of the reaction was affected by the electronic
nature of the substituent. Electron-donating groups gave a higher
ratio of linear selectivity than electron-withdrawing groups. In the
case of the reaction of meta-substituted aromatic amides, the
more sterically accessible C-H bond underwent hydroarylation to
give the alkylation products. The reaction of 1,4-
dimethylbenzamide gave 2o in 56% with a high linear selectivity.
We recently reported on the Rh-catalyzed reaction of aromatic
amides that contain an 8-aminoquinoline directing group9 with
activated alkenes, such as acrylic esters,10 styrenes,11 α,β-
unsaturated lactones,12 maleimide,13a norbornene,13b and N-
vinylphthalimide.13c In a different system of picolinamide auxiliary,
we reported the alkylation reaction at C8-position of 1-
T. Yamaguchi, S. Natsui, K. Shibata, K. Yamazaki, Dr. S. Rej, Dr. Y.
Ano, Prof. Dr. N. Chatani
Department of Applied Chemistry
Faculty of Engineering, Osaka University
Suita, Osaka 565-0871 (Japan)
E-mail: chatani@chem.eng.osaka-u.ac.jp
Supporting information for this article can be found in XXXX.
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Table 1. Rh-Catalyzed Alkylation of Aromatic Amides with 1-Hexenea
2.5 mol %
Table 2. Rh-Catalyzed Alkylation of Aromatic Amides with 1-Alkenesa
2.5 mol %
[Rh(OAc)(cod)]2
2-MeC6H4COOH 0.3 mmol
O
O
[Rh(OAc)(cod)]2
2-MeC6H4COOH
0.3 mmol
O
O
Q
Q
R
N
N
Q
Q
H
+
R
H
N
N
toluene 1 mL
160 °C, 12 h
H
R
+
H
Bu
R
O
H
toluene 1 mL
160 °C, 12 h
H
Bu
1a
3
0.3 mmol
O
1.5 mmol
1
2
0.3 mmol
1.5 mmol
O
O
R
O
Q
N
Q
Q
N
N
H
Q
R
Q
H
H
N
H
N
H
4
Bu
Bu
3a 89% (89:11)
3b 87% (91:9)
3c
88% (89:11)
R = Me (2a) 84% (88:12)
R = OMe (2b)b 57% (90:10)
R = OMe (2f) 72% (92:8)
R = Me (2g) 85% (89:11)
O
O
O
Q
N
Q
N
Q
(2c)b 48% (88:12)
N
R = Ph
R = F
R = F
(2h) 85% (86:14)
H
H
H
(2d) 77% (83:17)
OAc
R = Cl
R = Br
(2i)
86% (80:20)
70% (75:25)
74% (78:22)
67% (71:29)
CN
CO2Me
3
2
2
R = CF3 (2e) 66% (64:36)
2j
(
)
3d
90% (86:14)
3e 87% (82:18)
3f 86% (86:14)
2k
R = OAc
R = CF3
(
)
O
O
Q
O
2l
)
(
Q
N
Q
N
CO2Et
CO2Et
Bu
N
H
H
H
O
Br
O
O
3
Q
N
41%b (85:15)
3i 78%c (82:18)
Q
N
Q
N
3h
3g
80% (90:10)
H
H
H
+
Bu
O
O
O
O
Bu
Bu
Q
Q
Q
Q
N
H
N
H
N
H
N
2ma 2mb
2o 56% (100:0)
/
= 68% (84:16) / 20%
Bu
+
H
O
O
O
O
O
3k 94%d
b
62%b
3l 82%d
3ja
3jb
16%
Q
N
Ph
Q
Ph
Q
N
N
H
a Isolated yield. b Isolated by column chromatography followed by GPC. c Alkene
(0.6 mmol) was used. d The ratio of linear and branched isomers could not be
determined.
H
+
H
Bu
Bu
Bu
2na 2nb
2p 66% (85:15)
/
= 78% (95:5) / 0%
a Isolated yield. b [Rh(OAc)(cod)]2 (0.015 mmol) was used.
To gain insights regarding the mechanism for the reaction,
deuterium labeling experiments were carried out (Scheme 2).
When 1a-d7 was reacted in the absence of an alkene for 2 h
(Scheme 2a),11 a significant amount of H/D exchange was
observed at the ortho-position on the benzene ring. These results
indicate that the cleavage of the ortho C-H bond is reversible.
Notably, H/D exchange was also observed at the benzylic position,
although no alkylation took place at these positions. To collect
additional mechanistic information regarding this alkylation
reaction, deuterium labeling experiments using 1a-d7 with 1-
dodecene was examined (Scheme 2b). A deuterium atom was
detected only at the α-position of 5, and no D-incorporation was
observed at the β-position of 5. The deuterium labeling
experiment using 1a with 1-dodecene-d3 was examined (Scheme
2c). The obtained result differed from the predicted one, as in 6.
Hence, proton atoms were incorporated into both the α and β
position of the methylene carbons in nearly a comparable ratio
(1.02 H and 1.11 H) in 7. Thus, one of the deuterium atoms at the
terminal carbon of the original alkenes was missing, we
anticipated that an unusual mechanism may involve. As shown in
Table 1, the linear selectivity of the reaction was affected by the
electronic nature of the substituent on the arene moiety. For
instance, in the case of an electron-donating group, such as an
MeO group, the major isomer was the linear product (2b, a
selectivity in excess of 90%). In contrast, in the case of an
electron-withdrawing group, such as a CF3 group, selectivity was
low (71:29), with the linear isomer 2e being slightly favored. We
were interested to determining whether both isomers are formed
The scope of the 1-alkenes was examined with 1a (Table 2).
Alkenes containing acetoxy, cyano, ester, bromide and ketone
groups underwent hydroarylation in acceptable yields. In the
reaction with 2-methyl-1,5-hexadine and 4-vinyl-1-cyclohexene,
the di-substituted alkene moiety remained intact to give
selectively 3g or 3l, respectively. It was found that an internal
alkene, 2-hexene failed to give the corresponding alkylation
products.
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through the same mechanism. Therefore, in the reaction of 1e and
1-dodecene-d3, the two regioisomers, 8 and 9 were separated in
A proposed mechanism is shown in Scheme 3, based on the
above experiments. The coordination of a quinoline nitrogen atom
in 1 to a rhodium center followed by the oxidative addition of the
N-H bond gives complex A.15 The insertion of an alkene into a H-
Rh bond in complex A then gives complex B, which, after the
elimination of DX, affords the carbene complex C.16 The migratory
insertion of the ortho C-H bond into a carbene moiety in complex
C through the oxidative addition of the ortho C-H bond followed
by a 1,2 hydride migration gives E,17,18 which undergoes reductive
elimination followed by protonation to give the linear product with
the regeneration of the Rh(I) species. The reaction involves the
generation of a rhodium carbene complex from an alkene, a rare
occurrence.19,20 In sharp contrast, the results obtained from the
deuterium labeling experiment shown in Scheme 2d are
consistent with a branched isomer being formed through a
completely different mechanism. The coordination of a quinoline
nitrogen atom in 1 to a rhodium center followed by ligand
exchange gives complex F, which could also be formed by the
elimination of HX from complex A. The oxidative addition of the
ortho C-H bond to a rhodium center followed by the insertion of
an alkene into a H-Rh bond (hydrometalation) in complex G gives
complex H. An alternative mechanism involves formation of
complex G from A via a CMD mechanism. Reductive elimination
followed by protonation gives the branched product with the
regeneration of the Rh(I) species. We have no concise
explanation for why linear and branched isomers are formed
through different mechanisms. The corresponding formation of a
1
2
pure form, and H and H NMR spectra of these isomers were
obtained (Scheme 2d). Expectedly, the linear isomer 8 gave the
same result as that observed for 7. In sharp contrast, no proton
atom was observed at the benzylic position (0.06 H) in the
branched isomer 9 and nearly 1 H was detected at the methyl
group. These results suggest that the branched isomer formed
through the conventional mechanism, such as hydrometalation,
but that the linear isomer formed through a different mechanism.
Kinetic isotopic effect (KIE) experiments indicate that the
cleavage of a C-H bond is not a rate limiting step (Scheme 2e).
a) Deuterium Labeling Experiment without alkene
0.42 H
no alkene
[Rh(OAc)(cod)]2
2.5 mol %
PivOH 0.3 mmol
CD3
O
CD3
O
D
D
D
D
D
N
N
H
H
N
N
toluene 1 mL
160 °C, 2 h
D
D
H
D
1a-d7
0.53 H
0.3 mmol
0.90H
1a-
b) Deuterium LabelingExperiment for the Reaction of
d7 with 1-Dodecene
CD3
O
[Rh(OAc)(cod)]2 2.5 mol %
2-MeC6H4COOH 0.3 mmol
toluene 1 mL
D
D
Q
N
H
C10H21
+
D
160 °C, 2 h
0.86 H
O
CD3
D
1a-d7 0.3 mmol
CD3
O
D
D
Q
0.6 mmol
N
D
D
Q
H
carbene from a branched intermediate would be highly
N
H
H
H

unfavorable compared to B, because it would lead to a more
strained carbene complex and in addition, the Cα-H bond would
be less acidic making the elimination of DX unlikely. Thus, the
linear and branched isomers are formed through different
mechanisms because a branched carbene intermediate cannot
be generated.

D
H
D
C10H21
D
C10H21
1.28 H
4 (predicted)
5
38%
1.96 H
c) Deuterium Labeling Experiment for the Reaction of 1a with 1-Dodecene-d3
[Rh(OAc)(cod)]2 2.5 mol %
2-MeC6H4COOH 0.3 mmol
O
D
Q
D
O
1
N
C10H21
HX
+
toluene 1 mL
160 °C, 2 h
H
D
NHQ
O
H
D
linear isomer
RhX
1
O
Q
1a 0.3 mmol
0.6 mmol
H
D
N
R
Q
N
H

H
D
HX
HX
1.02 H
D
O
O

C10H21
H
O
N
Rh
F
N
D
C10H21
1.11 H
N
7 51%
X Rh
N
N
6
(predicted)
H
Rh
N
H
D
HX
A
H
D
D
d) Deuterium LabelingExperiment for the Reaction of 1e with 1-Dodecene-d3
E
D
R
D
O
[Rh(OAc)(cod)]2 2.5 mol %
2-MeC6H4COOH 0.3 mmol
CF3
O
D
R
O
N
Rh
H
Q
D
N
C10H21
+
N
N
H
toluene 1 mL
160 °C, 2 h
O
D
D
G
X Rh
N
H
D
O
N
D
D
D
O
CF3
O
CF3
1e
Rh
N
H
D
0.3 mmol
0.6 mmol
D
N
D
H
Q
Q
R
B
Rh
N
H
D
N
N
R
H
D
H
H
+
R
D
Me
C10H21
~1.0H

DX
O
O
R
R
C
0.06 H
1.05 H
0.87H
NHQ
N
C10H21
17%

D
carbene intermediate
Rh
N
H
D
8
9
H
D
16%
RhX
R
H
D
D
D
e) Kinetic Isotopic Effect (KIE) Determination
branched isomer
Scheme 3. A Proposed Mechanism.
[Rh(OAc)(cod)]2 2.5 mol %
2-MeC6H4COOH 0.3 mmol
1a
0.3 mmol
or
kH
kD
= 1.08
C10H21
0.6 mmol
+
toluene 1 mL
160 °C, 2.5 h
1a-d7 0.3 mmol
Scheme 2. Deuterium Labeling Experiments and KIE study.
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In order to elucidate the complexity of the reaction mechanism,
we conducted preliminary density functional theory (DFT)
calculations for both the linear- and branched-selective pathways
(Figure 1).21 The efficiency of the reaction with unactivated 1-
alkenes were low in the absence of a carboxylic acid (see SI),
indicating that ligand exchange between acetate and the added
carboxylic acid is essential. Therefore, the models we selected for
the computation used 2-methyl benzoate as a ligand, which was
optimized as the optimal additive for the alkylation with 1-hexene.
The initial N-H oxidative addition to the Rh atom through TS1 has
a barrier of 7.8 kcal/mol to give the Rh-H species Int2. Alkene
coordination to Int2 leads to the formation of either Int3_L which
is a precursor to a linear isomer as in Figure 1, or to Int3_B which
is a precursor of a branched isomer. Each alkene coordination
type was investigated, and only the more stable intermediates and
transition states are described. For a linear selective pathway, a
facile insertion of an alkene into the Rh-H bond is observed to give
Int4_L. Subsequent deprotonation of the alkyl group to give Rh
carbene intermediate Int5_L would then proceed. The calculated
energy barrier for the generation of the Rh carbene through
TS3_L is 27.7 kcal/mol. After the dissociation of the carboxylic
acid, the C-H oxidative addition to the Rh atom, followed by 1,2-
hydride migration is found to proceed rapidly due to low activation
energy. The final reductive elimination process through TS6_L
from Int7_L requires a large energy of 30.1 kcal/mol, indicating
that this step is the rate determining step, hence the proposed Rh
carbene generation mechanism is confirmed as being acceptable.
G (kcal/mol)
Me
O
N
Me
O
Rh
N
Me
O
N
O
Bu
N
H
TS3_L
Me
Bu
O
Rh
N
Me
O
O
Ar
Rh
N
H
Me
O
N
25.1
N
H
TS4_L
Rh
N
O
Bu
20.7
TS6_L
TS6_L
TS3_L
Rh
N
N
Bu
H
ArCO2H
17.8
H
O
Rh
N
Me
Bu
O
Int3_L
TS4_L
O
O
TS5_L
Ar
Bu
10.9
N
Rh
TS1
12.8
H
10.0
Int6_L
Ar
N
O
TS2_L
Int5_L
7.8
TS5_L
O
TS1
Me
O
Ar
2.1
Int3_L
1.8
TS2_L
0.0
N
Bu
-2.6
Int4_L
Int1
Rh
N
-5.7
Int8_L
Me
Me
O
O
Me
O
H
N
Int5_L
-9.4
Bu
-11.2
Int2
N
O
Rh
N
Int7_L
O
Rh
N
O
Me
N
Me
O
OCOAr
Rh
N
N
Ar
Int1
Bu
N
H
O
Int4_L
Rh
N
Rh
N
Bu
O
Int7_L
Int8_L
Bu
Int2
Ar
Figure 1. Reaction Energy Profile for the Linear-Selective Pathway of the Rh-Catalyzed C-H Alkylation with 1-Hexene Calculated at the RB3PW91/6-311+G(d,p)-
SDD/SMD(toluene)// RB3LYP-D3/6-31G(d)-SDD Level of Theory (Ar = 2-MeC6H4).
reaction is proposed to proceed through a carbene mechanism.
The generation of a carbene complex from a simple alkene is very
rare.20 It is recognized that the main role of the directing group is
to accelerate the reaction by allowing the catalyst to come into
closer proximity to the C-H bond. However, our findings clearly
indicate that the directing group can also have an effect on
changing the reaction mechanism. A more detailed mechanistic
study is currently under process.
In summary, this reaction represents a rare example of C-H
alkylation with unactivated 1-alkenes, with the formation of a C-C
bond between the ortho-position of an aromatic amide and the
terminal carbon of the alkenes. The presence of a carboxylic acid
is required to proceed the reaction efficiently, however the role of
the carboxylic acid is unclear at this time. The most important
finding involves that the results of deuterium-labeling experiments
indicate that one of deuterium atoms in the alkene is missing. The
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Acknowledgements
This work was supported by JST Strategic Basic Research
Programs “Advanced Catalytic Transformation Program for
Carbon Utilization (ACT-C)” from JST (JPMJCR12YS) and Grant
in Aid for Specially Promoted Research by MEXT (17H06091).
K.S. expresses his special thanks for
Fellowship for Young Scientists.
a JSPS Research
Keywords: C-H activation • Rh catalyst • unactivated 1-alkene •
Quinolinamide • Rh-carbene
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COMMUNICATION
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10.1002/chem.201901300
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Takuma Yamaguchi, Satoko Natsui,
Kaname Shibata, Ken Yamazaki,
Supriya Rej, Yusuke Ano, and Naoto
Chatani*
Page No. – Page No.
Title
Alkylation reactions of C-H bonds (hydroarylation) in aromatic amides with
unactivated 1-alkenes using a rhodium catalyst and assisted by an 8-aminoquinoline
directing group are reported. Deuterium labelling experiments and prliminary DFT
studies has been carried out, which states the reaction is proposed to proceed
through a unusual carbene mechanism.
For internal use, please do not delete. Submitted_Manuscript
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