Nickel-catalyzed sp3 C-H bond activation from decarboxylative cross-coupling of α,β-unsaturated carboxylic acids with amides

Article abstract of DOI:10.1055/s-0033-1341279

Nickel-catalyzed functionalization of C(sp³)-H bonds adjacent to a nitrogen atom in amides through decarboxylative cross-coupling of α,β-unsaturated carboxylic acids is reported. A possible reaction mechanism is proposed that involves radical intermediate species. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1341279

LETTER
▌1621
lNettierckel-Catalyzed sp3 C–H Bond Activation from Decarboxylative Cross-
Coupling of α,β-Unsaturated Carboxylic Acids with Amides
Nickel-Catalyzed sp3 C–H Bond Activation from Amides
Jia-Xiang Zhang,a Yan-Jing Wang,b Nai-Xing Wang,*a Wei Zhang,a Cui-Bing Bai,a Yi-He Li,a Jia-Long Wena
a
Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. of China
b
College of Sciences, Beijing University of Chemical Technology, Beijing 100029, P. R. of China
Fax +86(10)62554670; E-mail: nxwang@mail.ipc.ac.cn
Received: 10.03.2014; Accepted after revision: 07.04.2014
unsaturated carboxylic acids. To the best of our knowl-
edge, we present a precedent for a new oxidative function-
alization of C(sp3)–H bonds in amides, which is related
with decarboxylative cross-coupling (Scheme 1).
Abstract: Nickel-catalyzed functionalization of C(sp3)–H bonds
adjacent to a nitrogen atom in amides through decarboxylative
cross-coupling of α,β-unsaturated carboxylic acids is reported. A
possible reaction mechanism is proposed that involves radical inter-
mediate species.
Key words: C–H bonds activation, nickel, cross-coupling, amides,
radical reaction
O
H
TBHP
Ni(OAc)2⋅4H2O
O
CO2H
+
N
N
Ar
Ar
100 °C,16 h
O
17 examples
up to 80% yield
The development of methodologies for the efficient func-
tionalization of C–H bonds has become a hot topic in or-
ganic synthesis.1 One related area is decarboxylative
cross-coupling, which can afford the desired negative syn-
thon for use in organic synthesis. In this approach, stable
and inexpensive carboxylic acids can be used in place of
expensive and unstable organometallic reagents. More-
over, decarboxylative carbon–heteroatom cross-coupling
is a powerful method for the construction of C–C bonds
and C–H bond functionalization.2,3 Particularly, transi-
tion-metal-catalyzed activation of C(sp3)–H bonds adja-
cent to a heteroatom (often nitrogen or oxygen) has
attracted considerable attention, and remarkable progress
has been made in this field.4–7
Ar = Ph, 4-MeC6H4, 4-ClC6H4, 4-BrC6H4, 2-ClC6H4,
4-MeOC6H4, naphthyl, furan, thiophene
Scheme 1 Functionalization of sp3 C–H bonds adjacent to a nitrogen
atom in amides
Initially, cinnamic acid and N,N-dimethylacetamide
(DMA) were chosen as model substrates. The optimiza-
tion of reaction conditions is shown in the Table 1. It was
found that cinnamic acid did not react with DMA without
the catalyst or additive oxidant (entries 1 and 2); thus, cat-
alysts and additive oxidants were essential for the reac-
tions. The reaction of DMA and TBHP was also
conducted with a range of temperatures (entries 3–8) and
it was found that the yield could be increased to 80% by
performing the reaction at 100 °C. The yield was not im-
proved further by performing the reaction at higher tem-
peratures (entries 7 and 8). Moderate yield was obtained
through the use of DTBP (entry 9). When other oxidizing
agents such as N-bromosuccinimide (NBS) or 2,3-dichlo-
ro-5,6-dicyano-1,4-benzoquinone (DDQ) were used, no
product was obtained (entries 10 and 11). Furthermore,
only trace amounts of product was obtained by using
K2S2O8 as the oxidant in the reaction (entry 12). A range
of transition-metal salts were tested as catalysts for the re-
actions, and it was found that Ni(OAc)2·4H2O was most
efficient (entries 13–20). The optimized reaction condi-
tions were thus established to involve heating TBHP as
oxidizing agent and 10 mol% Ni(OAc)2·4H2O as catalyst
to 100 °C (entry 6).
In many oxidative coupling reactions, precious metals
such as palladium, rhodium, and ruthenium salts are used
as catalysts;8 however, the use of copper and iron salts has
also been developed.9,10 Recently, nickel-catalyzed oxida-
tive C–H functionalizations have been attracting increas-
ing attention.11 For example, Veiros reported the first C–
H activation of an acetonitrile ligand on a nickel center.11d
Lei’s group has demonstrated a nickel-catalyzed oxida-
tive arylation of C(sp3)–H bonds adjacent to the oxygen
atom of cyclic ethers.11e
However, the activation of C(sp3)–H bonds adjacent to the
nitrogen atom of amides has scarcely been investigated.12
Amides are important resources in organic synthesis, and
oxidative cross-coupling strategies that employ amides as
raw material could provide an important new synthetic
tool.13
To expand the scope of the system, a range of α,β-unsatu-
rated carboxylic acids were tested as substrates, and we
were pleased to find that the corresponding products were
all obtained in moderate to good yield (Figure 1). It is
noteworthy that α,β-unsaturated carboxylic acids substi-
tuted with electron-donating groups gave better yields.
The aryl group also affected the reaction yields. Several
α,β-unsaturated carboxylic acids connected to furan and
In this study, we report on the nickel-catalyzed function-
alization of C(sp3)–H bonds adjacent to the nitrogen atom
in amides through decarboxylative cross-coupling of α,β-
SYNLETT 2014, 25, 1621–1625
Advanced online publication: 14.05.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1341279; Art ID: st-2014-w0210-l
© Georg Thieme Verlag Stuttgart · New York

1622
J.-X. Zhang et al.
LETTER
1
thiophene structures generated the corresponding prod- In the H NMR spectra of purified products a–j and p,
ucts with moderate yields.
some peaks appeared as a set of two peaks instead of a sin-
gle peak; signal duplication was also observed for the cor-
responding 13C NMR spectra. Such extra peaks are
generated because the nitrogen atom in these compounds
is bonded to three different groups, and C–N bond rotation
leads to the emergence of rotamers8 and consequent split-
ting in the NMR spectra.14,15 It was found that when the
substituent on the nitrogen atom was smaller, splitting of
the NMR spectra was more obvious compared with the
NMR spectra of a and p. When the nitrogen atom was
fixed within a cyclic structure, the rotation of the C–N
bonds was reduced, and the splitting in the corresponding
NMR spectrum was weakened (see the NMR spectra of
k–o, Primary Data).
Other amides could also be used as reactants, including
1-(pyrrolidin-1-yl)ethanone, tert-butyl pyrrolidine-1-car-
boxylate, 1-(piperidin-1-yl)ethanone, and N,N-dimethyl-
formamide. Some other types of amides such as N-methyl-
formamide and N-methylacetamide were tested as the
substrates; however, only trace amounts of products were
found (Scheme 2). The unsymmetrical amide N-methyl-2-
pyrrolidinone (NMP) was also a suitable substrate for the
reaction; in this case, the major product was q, with only
trace amounts of the alternative product r being observed
(Scheme 2). It is notable that the selectivity toward the
CH2 group adjacent to the nitrogen atom in the ring pre-
dominated over the N-methyl group for NMP. All of the
new products were characterized by NMR and HRMS The reaction yield dropped in the presence of butylated
analysis.
hydroxytoluene (BHT). Moreover, no product was ob-
Table 1 Optimization of the Reaction Conditionsa
O
CO2H
O
Me
N
catalyst (10%)
additive (3 equiv), heat, 16 h
+
Me
N
O
Me
Entry
Catalyst
Additiveb
Temp. (°C)
Yield (%)
1
2
–
–
–
100
100
25
0
0
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
NBS
3
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
NiCl2·6H2O
0
4
60
45
75
80
78
70
50
0
5
90
6
100
120
150
100
100
100
100
100
100
100
100
100
100
100
100
7
8
9c
10
11
12
13
14
15
16
17
18
19
20
DDQ
0
K2S2O8
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
trace
70
60
50
55
45
40
43
45
NiSO4·6H2O
Cu(OAc)2
Cu(OAc)2·H2O
Co(OAc)2·4H2O
Zn(OAc)2·2H2O
Pb(OAc)2·3H2O
Mn(OAc)2·4H2O
a Reaction conditions: cinnamic acid (0.148 g, 1 mmol), catalyst (0.1 mmol, 10 mol%), additive (3 mmol).
b TBHP = tert-butyl hydroperoxide (70% in water).
c DTBP = di-tert-butylperoxide.
Synlett 2014, 25, 1621–1625
© Georg Thieme Verlag Stuttgart · New York

LETTER
Nickel-Catalyzed sp3 C–H Bond Activation from Amides
1623
O
O
O
O
Ni(OAc)2⋅4H2O (10%)
CO2H
CO2H
Me
Me
N
H
H
+
+
H
H
N
TBHP (3 equiv)
100 °C,16 h
Me
Me
O
O
Ni(OAc)2⋅4H2O (10%)
N
H
N
H
TBHP (3 equiv)
100 °C,16 h
trace
O
O
O
CO2H
Ni(OAc)2⋅4H2O (10%)
Me
N
H
+
N
H
TBHP (3 equiv)
100 °C,16 h
trace
+
O
O
O
O
Ni(OAc)2⋅4H2O (10%)
CO2H
O
+
Ph
Ph
N
N
Me
N
TBHP (3 equiv)
100 °C,16 h
Ph
Me
r trace
q 70%
Scheme 2 Reactions of cinnamic acid reacted with some types of amides
served in the presence of radical inhibitor 2,2,6,6-tetra- tion of the double bond of salts of Ni(II) carboxylate to
methylpiperidine-1-oxyl (TEMPO). These results produce intermediate B. A hydroxyl radical, generated
indicate that the reaction likely follows a radical addition– from homolysis of TBHP, then adds to B to generate the
elimination process in the activation of C–H bonds medi- aryl α-hydroxylalkylated product and eliminate carbon di-
ated by TBHP.16–18
oxide and Ni(II). Finally, the desired product is generated
upon oxidation.
A possible reaction mechanism is proposed in Scheme 3.
Thus, the reaction of N,N-dimethylacetamide with the ini- In conclusion, we have developed the nickel-catalyzed ac-
tiator TBHP affords radical A, which adds to the α-posi- tivation of C(sp3)–H bonds adjacent to a nitrogen atom in
O
O
O
O
O
O
O
O
N
N
N
N
Me
Me
Me
Me
Br
Cl
d 75%
a 80%
b 80%
c 75%
O
O
O
O
O
O
O
O
MeO
MeO
N
N
N
N
Me
Me
Me
Me
MeO
Cl
g 65%
h 65%
e 83%
f 70%
O
O
O
O
O
O
N
N
N
N
S
Me
O
Me
O
H
O
i 40%
j 45%
l 65%
k 70%
O
O
O
O
O
N
N
N
N
O
O
O
Me
Cl
O
m 65%
p 75%
n 70%
o 70%
O
O
N
Me
q 70%
Figure 1 Products obtained
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1621–1625

1624
J.-X. Zhang et al.
LETTER
O
O
O
H
cat. Ni(II)
TBHP
CO2H
Ar
+
Ar
N
N
Me
Me
TBHP
cat. Ni(II)
TBHP
cat. Ni (II)
O
•
Ni (II)
N
COO
N
OH
O
2
•OH
Me
Ar
addition
A
Ni(II)
Ar
N
•
CO2
O
Ar
CO2, Ni(II)
elimination
Me
addition
2
Me
B
Scheme 3 Proposed reaction mechanism
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Acknowledgment
This work was supported financially by the Natural Science Foun-
dation of China (21172227) and by the National 973 Program Foun-
dation (No. 2010CB732202).
Primary Data for this article are available online at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000083 and can be cited using the following DOI:
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Synlett 2014, 25, 1621–1625
© Georg Thieme Verlag Stuttgart · New York

LETTER
Nickel-Catalyzed sp3 C–H Bond Activation from Amides
1625
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(19) Typical Procedure: To a mixture of cinnamic acid (0.148 g,
1 mmol), Ni(OAc)2·4H2O (25 mg, 0.1 mmol), and N,N-
dimethylacetamide (2 mL), tert-butyl hydroperoxide (0.39
g, 3 mmol, 70% in water) was added at r.t. dropwise. The
resulting mixture was heated to 100 °C for 16 h, then the
mixture was added to dichloromethane (40 mL) and washed
with water and saturated brine. The organic solution was
dried with anhydrous magnesium sulfate and the desired
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