Nickel-Catalyzed Cross-Dehydrogenative Coupling of α-C(sp3)-H Bonds in N-Methylamides with C(sp3)-H Bonds in Cyclic Alkanes

Article abstract of DOI:10.1021/acs.orglett.8b02736

A nickel-catalyzed cross-dehydrogenative coupling reaction of α-C(sp³)-H bonds in N-methylamides with C(sp³)-H bonds from cyclic alkanes has been developed, which offers a cheap transition-metal-catalyzed C-H activation method for amides without the requirement for any extraneous directing group. This new strategy is highly selective and tolerates a variety of functional groups. Mechanistic investigations into the reaction process are also described in detail.

Full text of DOI:10.1021/acs.orglett.8b02736

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nickel-Catalyzed Cross-Dehydrogenative Coupling of α‑C(sp3)−H
Bonds in N‑Methylamides with C(sp3)−H Bonds in Cyclic Alkanes
Ze-Lin Li,† Kang-Kang Sun,† and Chun Cai*,†,‡
†Chemical Engineering College, Nanjing University of Science and Technology, Nanjing 210094, People’s Republic of China
‡Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Lu, Shanghai 20032, People’s Republic of China
S
* Supporting Information
ABSTRACT: A nickel-catalyzed cross-dehydrogenative cou-
pling reaction of α-C(sp3)−H bonds in N-methylamides with
C(sp3)−H bonds from cyclic alkanes has been developed,
which offers a cheap transition-metal-catalyzed C−H
activation method for amides without the requirement for
any extraneous directing group. This new strategy is highly
selective and tolerates a variety of functional groups.
Mechanistic investigations into the reaction process are also
described in detail.
Scheme 1. Representative Examples of Activation of N−H
and C−H Bonds in Amides
ryl amides and sulfonamides are privileged structural
Amotifs that have found widespread application in
agrochemicals, pharmaceuticals, natural products, dyes, poly-
mers, and drugs.1 For example (Figure 1), chlorantraniliprole
(1) is an efficient insecticide and BMS-193884 (2) is a
modulator of vascular tone, cell proliferation, and hormone
production.
simple alkanes was provided by Cheng and co-workers;2g this
reaction employs simple alkanes without prefunctionalization
and does not require strong base. Furthermore, Bolm’s team2d
developed an iron-catalyzed hetero-cross-dehydrogenative
coupling reaction of sulfoximines with diarylmethanes,
showing a new route to N-alkylated sulfoximines which are
otherwise difficult to prepare. On the other hand, much effort
has been put into the selective C−H activation of aryl rings to
achieve regioselectivity. As a representative example, a ligand-
promoted rhodium(III)-catalyzed ortho C−H activation of
amides was reported in 2017 by Yu,3a which has overcome the
limitations of palladium(II)-catalyzed C−H amination reac-
tions. Almost at the same time, Bolm’s team3b described a
procedure for the direct mechanochemical rhodium(III)-
Figure 1. Drugs containing the aryl amide and sulfonamide functional
groups.
Over the past decade, transition-metal-catalyzed C−H/N−
H activation of aryl amides has emerged as a new and efficient
procedure for the synthesis of selectively substituted amides.
Traditional methods can be roughly divided into the following
two categories: N−H/C−H activation coupling in −NHR2
and selective C−H activation in aryl3−5(Scheme 1).
Examples include work in N−H/C−H activation coupling
by Hartwig’s group,2c who established a set of rare copper-
catalyzed reactions of alkanes with simple amides, sulfona-
mides, and imides, which achieved the functionalization at
secondary C−H bonds over tertiary C−H bonds and even
occur at primary C−H bonds. Then an efficient oxidative
C(sp3)−H/N−H coupling of sulfoximines and amides with
Received: August 26, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02736
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
catalyzed ortho C−H bond activation of amides with 1,4,2-
dioxazol-5-ones as the nitrogen source which avoided the use
of solvents and additional heating. In 2015,4e Kanai’s group
established a meta-selective C−H borylation, directed by a
secondary interaction between ligand and substrate, which
showed good control of the regioselectivity. In addition, a free-
radical-promoted para-selective C−H silylation of amides using
hydrosilanes was described by Liu et al.;5c this cross-
dehydrogenative silylation enables both electron-rich and
electron-poor aromatics to afford the desired arylsilanes with
unique selectivity. Although all of the previously developed
methodologies for the functionalization of amides were
efficient and regioselective, C(sp3)−H activation in the N-
methylamides still poses a significant challenge.
Table 1. Optimization of the Reaction Conditions
Most recently, a protecting-group-free approach for the α-
functionalization of cyclic secondary amines was introduced by
Seidel and co-workers,6a who made a breakthrough in α-
C(sp3)−H bond functionalization. Similarly previous work that
used early-transition-metal (Ti, Zr, Ta, Ir)6 catalysts has been
largely limited to alkenes. The catalytic CDC (cross
dehydrogenative coupling) reaction between unactivated
C(sp3)−H bonds and versatile C(sp3)−H bonds, however,
remains a challenging issue, especially the use of a cheap
transition-metal catalytic system. Nickel7 is one of the most
abundant, inexpensive, environmentally friendly metals and
plays a very important role in the field of C−H activation.
Inspired by this, we herein report the first example of a
nickel-catalyzed highly selective cross-dehydrogenative cou-
pling (CDC) of α-C(sp3)−H bonds in N-methylamides with
the C(sp3)−H bonds of cyclic alkanes that proceeds without
any extraneous directing group. Compared with previous
research studies, this transformation (1) achieves a highly
selective CDC of C(sp3)−H bonds with C(sp3)−H bonds, (2)
tolerates a variety of functional groups and is solvent-free, (3)
employs a cheap transition-metal catalytic system, (4) does not
require an extraneous directing group to be used, thus avoiding
the preparation of raw materials and waste of resources, and
(5) has its mechanistic details described herein.
We initiated our studies by exploring reaction conditions for
the cross-dehydrogenative coupling of C(sp3)−H bonds in N-
methylbenzamide 1a with the C(sp3)−H bonds of cyclohexane
2a. Initially, a number of Ni catalysts were surveyed, including
NiCl2, Ni(OAc)2, Ni(OTf)2, and Ni(acac)2 (Table 1, entries
1−4). The results showed that NiCl2 displayed the highest
catalytic activity for this reaction (entry 1). Thereafter, we
explored various additives, with A5 and A8 furnishing
particularly effective catalysts (entries 5−13). In addition, we
explored the influence of peroxide on the yield (entries 14−
16). Unfortunately, TBHP (tert-butyl hydroperoxide) and
DCP (dicumyl peroxide) were inefficient for the coupling.
DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) operated
similarly. As to the nature of the bases, the most effective C−H
alkylation was accomplished with Cs2CO3 (entries 17−20).
Notably, decreasing the reaction temperature (entries 21 and
22) reduced the yield. Next, we explored the influence of
reaction time on yield, and the results showed that 24 h was
the best (entries 23 and 24). Finally, optimizations in various
solvents were conducted (entries 25−28), with cyclohexane
proving the most suitable for this transformation. Polar
solvents such as DMF and DMSO would compete with the
reaction between 1a and 2a and thus inhibited the formation
of desired products. On the other hand, cyclohexane (1 or 5
b
entry
cat.
NiCl2
additive peroxide
base
yield (%) of 3a
1
2
3
4
5
6
7
8
A1
A1
A1
A1
A2
A3
A4
A5
A6
A7
A8
A9
A10
A5
A5
A5
A5
A5
A5
A5
A5
A5
A5
A5
A5
A5
A5
A5
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
TBHP
DCP
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NaHCO3
tBuOK
Cs2CO3
Zn(OTf)2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
42
33
trace
16
36
0
40
58
27
31
Ni(OAc)2
Ni(OTf)2
Ni(acac)2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
9
10
11
12
13
14
15
16
17
18
19
20
49
10
trace
11
trace
trace
trace
22
71
0
32
0
37
60
0
DDQ
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
c
21
22
23
24
25
26
27
28
d
e
f
g
h
0
0
i
j
k
17
a
Reaction conditions: 1a (0.5 mmol), 2a (1.5 mL), cat. (15 mol %),
additive (30 mol %), peroxide (2 equiv), base (1 equiv), 130 °C, 24 h.
Isolated yield. 120 °C. 100 °C. 12 h. 36 h. 2a (1 equiv), DMF
(1.5 mL). 2a (5 equiv), DMF (1.5 mL). 2a (5 equiv), DMSO (1.5
b
c
d
e
f
g
h
i
j
k
mL). 2a (5 equiv), benzene (1.5 mL). Determined by GC−MS.
equiv) is transferred from liquid to gas under our procedure,
thus resulting in a decrease of yield.
With the optimal reaction conditions in hand, we examined
a series of substituted amides to establish the scope.
Gratifyingly, this transformation showed excellent tolerance
B
DOI: 10.1021/acs.orglett.8b02736
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
for various benzamides and provided the corresponding
alkylation products in good to excellent yields. As can be
seen from Scheme 2, substituted substrates with electron-
Scheme 3. Nickel-Catalyzed Cross-Dehydrogenative
Coupling of α-C(sp3)−H Bonds in Sulfonamides and
a
C(sp3)−H Bonds from Cyclohexane
Scheme 2. Nickel-Catalyzed Cross-Dehydrogenative
Coupling of α-C(sp3)−H Bonds in Amides and C(sp3)−H
a
Bonds from Cyclohexane
a
Reaction condition: amides (0.5 mmol), 2a (1.5 mL), NiCl2 (15 mol
%), additive A5 (30 mol %), DTBP (2 equiv), Cs2CO3 (1 equiv), 130
°C, 24 h.
expected, most substituted amides underwent the reaction to
give good yields of the corresponding alkylation products
(Scheme 4). Unfortunately, octane (5j) and dioxane (5o) did
not couple well under the standard conditions (checked by
GC−MS).
Scheme 4. Nickel-Catalyzed Cross-Dehydrogenative
Coupling of α-C(sp3)−H Bonds in Amides and C(sp3)−H
a
Reaction condition: amides (0.5 mmol), 2a (1.5 mL), NiCl2 (15 mol
a
Bonds from Other Cyclic Alkanes
%), additive A5 (30 mol %), DTBP (2 equiv), Cs2CO3 (1 equiv), 130
°C, 24 h.
donating groups, such as Me and OMe, produced the desired
products in 70% and 65% yields, respectively (3b,c).
Meanwhile, benzamides bearing electron-withdrawing groups,
such as F, Cl, and Br produced the desired products in good
yields (3d−f). Moreover, when ortho-substituted benzamides
(3g−h) and meta-substituted benzamides (3i−k) were applied
in the reaction under standard conditions, the alkylation
proceeded smoothly to generate the desired products, which
showed that the regiochemistry of the substituent on the
benzamides did not have a significant effect on the reaction
yields. To our delight, 2,4-dichloro-N-methylbenzamide (3l)
and 3,4-dichloro-N-methylbenzamide (3m) also reacted with
cyclohexane to afford the corresponding products in good
yields. N-Ethyl-2-phenylacetamide was well tolerated too (3n).
When heterocyclic amide (3o), methanamide (3p), and
benzylamine (3q) were applied in the reaction under standard
conditions, the alkylation reaction did not proceed smoothly. It
is worth noting that methyl benzoate was tolerated well in this
procedure (3r). Encouraged by the above results, we
investigated the use of this catalytic system for other amides
(Scheme 3). The benzenesulfonamides with electron-donating
(4a,b) or electron-withdrawing (4c−e) substituents afforded
the desired products in satisfactory yield (54−66%). Other
benzenesulfonamides including ortho-substituted N-methyl-1-
phenylmethanesulfonamide (4f−h) and N-methyl-1-phenyl-
methanesulfonamide (4i) also worked well.
a
Reaction condition: amides (0.5 mmol), 2a (1.5 mL), NiCl2 (15 mol
%), additive A5 (30 mol %), DTBP (2 equiv), Cs2CO3 (1 equiv), 130
°C, 24 h. 140 °C.
b
Some experiments were investigated to gain insight into the
reaction mechanism. First, under the standard conditions, 4
equiv of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxyl), BHT
(butylated hydroxytoluene), or 1,1-diphenylethene were added
to the alkylation reaction as radical scavengers. The cross-
dehydrogenative coupling process (Scheme 5, S21, S22, and
The success of the benzamides and other amides encouraged
us to extend this procedure to other cyclic alkanes. As
C
DOI: 10.1021/acs.orglett.8b02736
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
S23) was completely inhibited as expected (determined by
GC−MS), indicating that the alkylation might be proceeding
through a radical pathway.
Scheme 7. Control Experiment
Scheme 5. Control Experiment
presence of alkylation product when 2 equiv of DTBP was
used (determined by GC−MS), suggesting that this reaction is
not an oxidant-catalyzed cross-dehydrogenative coupling
process. On the other hand, when we changed the material
from 1a to 6a, the alkylation reaction could not be carried out
(determined by GC−MS).
Meanwhile, an intermolecular competing kinetic isotope
effect (KIE) experiment was carried out (Scheme 8). As is
Subsequently, other experiments were also conducted. For
example, when the reaction was run without catalyst, no
product was obtained (Scheme 6, S31), revealing that NiCl2
Scheme 8. KIE Experiment
Scheme 6. Control Experiment
depicted, a significant KIE was observed with KH/KD = 4.76.
(The KIE was determined by 1H NMR spectroscopy by
analyzing the ratio of 3a vs 3a-D.) This result indicates that
C(sp3)−H bond cleavage of cyclohexane may be the rate-
determining step of this procedure.
On the basis of the above experiments and previous work,8 a
plausible reaction mechanism for this Ni-catalyzed cross
dehydrogenative coupling is presented in Scheme 9. First,
Scheme 9. Proposed Reaction Mechanism
was necessary for this procedure. Meanwhile, when the
reaction was run without additive, only 11% yield product
was obtained (Scheme 6, S32). Additive A5, triphenylphos-
phonium bromide, might activate the catalyst to facilitate the
reaction; on the other hand, it might serve as a phase-transfer
catalyst to facilitate the reaction too. In addition, the procedure
did not proceed well under DTBP-free conditions or N2
atmosphere (determined by GC−MS), suggesting that the
procedure is very dependent on DTBP and O2 plays a role in
oxidation to a certain extent (Scheme 6, S33 and S35). Notably,
less than a 10% yield of the alkylation product was observed
without base (Scheme 6, S34), showing that Cs2CO3 has a
significant effect on deprotonation. In order to further explore
the reaction process, control experiments were carried out in
Scheme 7. On the one hand, we have not detected the
NiCl2 complexation facilitates enolation to give I. The Ni(II)
complex then oxidatively adds into the proximal NMe group to
give II, which undergoes E1cb elimination to provide III.
Subsequently, the latter reacts with cycloalkyl radical to give
IV. Finally, H atom abstraction and protonation of V give the
product 3a. It is worth mentioning that one of the side
D
DOI: 10.1021/acs.orglett.8b02736
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(3) For selected references on ortho C−H activation in amides, see:
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cyclohexane radicals, and the yield of 1,1′-bi(cyclohexane) was
11% under the optimal reaction conditions (determined by
GC−MS).
In summary, the first example of nickel-catalyzed cross-
dehydrogenative coupling of α-C(sp3)−H bonds in N-
methylamides and C(sp3)−H bonds from cyclic alkanes is
described here. In this procedure, no extraneous directing
groups are used, thus avoiding a waste of resources. This new
protocol is highly selective and tolerates a variety of functional
groups. Mechanistic investigations toward the CDC reaction
process were also presented.
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.8b02736.
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B.; Chai, Li.; Liu, Z. Q. Org. Lett. 2017, 19, 5573.
Experimental procedures and characterization data for
all products (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: c.cai@njust.edu.cn.
ORCID
̈
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Chun Cai: 0000-0002-5755-9361
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̈
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We gratefully acknowledge Natural Science Foundation of
Jiangsu Province (BK 20131346, BK 20140776) for financial
support. This work was also supported by the National Natural
Science Foundation of China (21476116, 21402093) and the
Chinese Postdoctoral Science Foundation (2015M571761,
2016T90465).
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DOI: 10.1021/acs.orglett.8b02736
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