Copper-Catalyzed Ligand-Free Amidation of Benzylic Hydrocarbons and Inactive Aliphatic Alkanes

Article abstract of DOI:10.1021/acs.orglett.5b02063

An efficient copper-catalyzed amidation of benzylic hydrocarbons and inactive aliphatic alkanes with simple amides was developed. The protocol proceeded smoothly without any ligand, and a wide range of N-alkylated aromatic and aliphatic amides, sulfonamides, and imides were synthesized in good yields.

Full text of DOI:10.1021/acs.orglett.5b02063

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Ligand-Free Amidation of Benzylic Hydrocarbons
and Inactive Aliphatic Alkanes
Hui-Ting Zeng and Jing-Mei Huang*
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, Guangdong 510640, China
S
* Supporting Information
ABSTRACT: An efficient copper-catalyzed amidation of benzylic
hydrocarbons and inactive aliphatic alkanes with simple amides was
developed. The protocol proceeded smoothly without any ligand,
and a wide range of N-alkylated aromatic and aliphatic amides,
sulfonamides, and imides were synthesized in good yields.
a
Table 1. Optimization of the Reaction Conditions
itrogen-containing compounds have attracted much
Nattention owing to the high prevalence of C−N bonds
in pharmaceuticals, agrochemicals, polymers, etc.1 Presently,
C−H activation is noted as an efficient and highly atom-
economic method for the formation of various chemical
compounds. The amidation of sp3 C−H bonds of hydrocarbons
with amide compounds provides an efficient route to produce
N-alkyl amide derivatives. In the reported methods, the
amidations were usually performed by using nitrene-type
derivatives as the nitrogen sources.2,3 Recently, great progress
has been made in the direct amidation of C−H bonds by
employing a simple amide/imide via C−H/N−H cross-
coupling.4,5 Among them, secondary benzylic hydrocarbons
have often been used as good coupling partners.5a−g However,
the amidation of primary benzylic hydrocarbons as well as
inactive aliphatic alkanes is rare.5h−k Inspired by previous
works, we herein report a general method for the C−N bond
formation via C−H/N−H cross-coupling of amides/imides
with both primary benzylic hydrocarbons and inactive aliphatic
alkanes to afford the corresponding products in good yields.
To begin our study, we chose the benzamide 1a and toluene
2a as model substrates. The reaction was initially studied with
DTBP as an oxidant without any catalyst. No desired product
was detected after heating at 120 °C for 24 h under N2 in a
Schlenk tube (Table 1, entry 1). When Cu2O (10 mol %) was
used as the catalyst, product 3a was obtained in 57% yield
(entry 2). Encouraged by this result, a number of other Cu
catalysts, including CuI, CuCl, [MeCN]4Cu(I)PF6, CuCl2,
CuSO4·H2O, and Cu(OTf)2 were investigated (entries 3−8).
The results showed that CuCl displayed the highest catalytic
activity for this reaction (entry 4). Next, we screened other
oxidants, TBHP, DCP, and K2S2O8 were inefficient for the
coupling of primary benzylic C−H bonds with benzamide
(entries 9−11). When the reaction was performed under air,
the yield dropped to 25% (entry 12). Further, the effect of a
oxidant
additive
yield
b
entry
cat. (10 mol %)
Cu2O
(2 equiv)
(0.001 mol %)
(%)
1
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
TBHP
DCP
0
2
57
55
61
55
35
20
10
trace
trace
0
3
CuI
4
CuCl
5
[MeCN]4Cu(I)PF6
CuCl2
6
7
CuSO4·H2O
Cu(OTf)2
CuCl
8
9
10
11
12
13
14
15
16
17
18
CuCl
CuCl
K2S2O8
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
c
CuCl
25
d
CuCl
tBuOK
tBuOK
tBuOK
tBuOK
15
CuCl
84
e
CuCl
69
f
CuCl
74
tBuOK
0
CuCl
CuCO3·Cu(OH)2
84
a
Reaction conditions: 1a (0.5 mmol), 2a (2.0 mL), cat (10 mol %),
oxidant (1.0 mmol), additive (0.001 mol %), 120 °C, 24 h, under N2.
b
c
d
e
Isolated yield. Under air. tBuOK (20 mol %). tBuOK (0.002 mol
f
t
%). BuOK (0.0005 mol %).
when the base was reduced to a very small amount of 0.001 mol
%, an 84% yield of product was collected (entry 14). Slightly
increasing the amount of base resulted in a lower yield with
incomplete conversion of the starting materials (entry 15).
t
base (tBuOK) was studied. When 20 mol % of BuOK was
added, the product was obtained in 15% yield only, with most
of the starting materials recovered (entry 13). To our surprise,
Received: July 19, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02063
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
When the base was reduced to 0.0005 mol %, byproduct N-
methylbenzamide was detected in 15% yield and the desired
product was obtained in 74% yield (entry 16). These results
demonstrated that only a very small amount of base is needed
to promote this reaction and a higher loading of base led to a
suppression of this reaction (entries 13, 15). When the reaction
was performed without CuCl, the reaction did not proceed
offered product 3o in an excellent yield of 92%. Unfortunately,
a low yield was obtained with p-toluenesulfonamide, and the
remaining compositions of the reaction mixture were N-benzyl-
N-methyl-p-toluenesulfonamide and N-methyl-p-toluenesulfon-
amide.
Substrate scope studies were also carried out on other
benzylic hydrocarbons and inactive aliphatic alkanes with
benzamide. Results were disclosed in Scheme 2. First, p-, m-,
t
(entry 17). It showed that BuOK might have worked as a
promoter to assist copper to catalyze this reaction. It was
interesting to find that 0.001 mol % of CuCO3·Cu(OH)2 could
also promote the reaction to produce 3a in the same yield of
84% (entry 18). CuCO3·Cu(OH)2 might have acted as a base,
which assisted the promotion of this reaction.
Scheme 2. Substrate Scope of Primary Benzylic
Hydrocarbons and Inactive Aliphatic Alkanes
a
With the optimized reaction conditions in hand, we then
explored the substrate scope. As shown in Scheme 1, a wide
Scheme 1. Substrate Scope of Amides, Sulfonamides, and
a
Imides
a
Conditions: 1a (0.5 mmol), 2 (2 mL), CuCl (10 mol %), DTBP (1.0
b
t
mmol), BuOK (0.001 mol %), 120 °C, 24 h, under N2. DTBP (1.5
c
mmol), 36 h. The ratio and yield were determined by 1H NMR of the
crude reaction mixture with CH3NO2 as the internal standard.
a
Conditions: 1 (0.5 mmol), 2a (2.0 mL), CuCl (10 mol %), DTBP
t
and o-xylenes were explored (4a−4c). They underwent the
reaction to give good yields of the corresponding amidation
products (67−82%). To our delight, mesitylene could couple
with benzamide to give an excellent yield of 92% (4d). A series
of halogen-containing toluene were tested. The results showed
that halogens could be well tolerated in this N-alkylation
reaction (4e−4i), providing a great opportunity for further
synthetic manipulations. p-Fluorotoluene gave a lower yield
than other halogen-containing toluene. Cyclohexane was
selected as the model inactive aliphatic alkane, and it worked
as a good partner with benzamide, p-toluenesulfonamide, and
phthalimide to give the corresponding products in yields of
80%, 70%, and 71%, respectively (4j−4l). Compared to
primary benzylic hydrocarbons or inactive aliphatic alkanes, a
lower yield was obtained with a secondary benzylic hydro-
carbon (31%, 4m), and the yield of a tertiary benzylic
(1.0 mmol), BuOK (0.001 mol %), 120 °C, 24 h, under N2.
range of amides could afford the corresponding products in
moderate to good yields. Benzamides containing electron-
donating groups such as Me and OMe underwent the reaction
to give good yields (3b−3d). Halide substituents could be well
tolerated (3e−3g). Additionally, benzamides bearing strong
electron-withdrawing groups, such as CF3 and NO2, produced
the amidation products in slightly lower yields (3h−3i).
Besides aromatic amides, aliphatic amides were also suitable
for this method (3j−3n). Caprolactam could be smoothly
transformed to the corresponding product 3n in 70% yield.
Notably, the long-chain lauroicacidamide gave a satisfactory
yield of 68% (3l). We also applied the optimal conditions to the
coupling of imides and sulfonamides with toluene. Phthalimide
B
DOI: 10.1021/acs.orglett.5b02063
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
hydrocarbon was at a trace level (4n). Next, the selectivity of
primary and secondary benzylic hydrocarbons was tested using
4-ethyltoluene. The result showed that the ratio of 4o and 4o′
was 2:1. Additionally, our optimized reaction conditions were
not suitable for intramolecular amidation, as 2-methyl-
benzamide failed to produce isoindolin-1-one with most of
the starting materials recovered in the solvent of benzene.
To study the mechanism, control experiments were carried
out (Scheme 3). When 2 equiv of 2,2,6,6-tetramethylpiperidine-
details and possible synthetic applications are currently
underway in our laboratory.
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.5b02063.
Experimental procedures and spectroscopic data (PDF)
Scheme 3. Radical Trapping Experiments
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: chehjm@scut.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Grant Nos. 21172080 and 21372089) for financial
support.
1-oxyl (TEMPO) was added to the reaction under the standard
conditions, no desired product was detected in the reaction
mixture of eqs 1 and 2. Notably, the radical scavenger
completely suppressed the reaction, and the reaction mixture
of eq 2 offered product 5a (determined by GC−MS), which
implied a radical process was involved in the amidation
coupling.
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