Copper-catalyzed direct amination of benzylic hydrocarbons and inactive aliphatic alkanes with arylamines

Article abstract of DOI:10.1039/d0ob00491j

A new synthetic method toward direct C-N bond formation through saturated C-H amination of benzylic hydrocarbons and inactive aliphatic alkanes with primary aromatic amines under an inexpensive catalyst/oxidant (Cu/DTBP) system has been developed. Both aminopyridines and anilines could react smoothly with primary and secondary benzylic C-H substrates or cyclohexane to form the corresponding aromatic secondary amines in moderate to good yields. This protocol has the advantages of wide functional group tolerance and use of readily available raw materials.

Full text of DOI:10.1039/d0ob00491j

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Copper-catalyzed direct amination of benzylic
hydrocarbons and inactive aliphatic alkanes with
arylamines
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Hua Yao, Bo Xie, Xiaoyang Zhong, Shengzhou Jin, Sen Lin*, and Zhaohua Yan*
coupling reactions have been developed for the construction
of aromatic amines5. Such as Ullman cross-coupling6,
Abstract ： A new synthetic method toward direct C–N bond
formation through saturated C–H amination of benzylic
hydrocarbons and inactive aliphatic alkanes with primary
aromatic amines under an inexpensive catalyst/oxidant
(Cu/DTBP) system has been developed. Both aminopyridines and
anilines could react smoothly with primary and secondary
benzylic C–H substrates or cyclohexane to form the
corresponding aromatic secondary amines in moderate to good
yield. This protocol has the advantages of wide functional group
tolerance and using of readily available raw materials.
Buchwald–Hartwig
amination7 [Scheme
1,
(a)],
hydroamination8, hydroaminomethylation9 and hydrogen
borrowing methodology10 [Scheme 1, (b)]. However, all
these transformations have in common the need for a reactive
Scheme 1
. Synthesis of aromatic secondary amines
Previous works
R2
Pd or Cu catalyst
base
R1
R1
R1
(a)
(b)
+
+
NH2
OH
Y
Y
N
H
R2
R2
Y
Y
X
R2
R1
catalyst
Amines are a class of important compounds that find wide
application in indispensable areas of life such as
pharmaceuticals, agrochemicals, dyes ， and functional
materials1. Due to their interesting physiological activities,
especially their extremely important pharmacophore in many
bioactive compounds, secondary amines have received
extensive attention in the field of drug discovery2. Traditional
methods of preparation of secondary amines involve treating
primary amines with halogenated hydrocarbons3 or using
various reductants to completely reduce the imines4, but these
transformations are often problematic due to the harsh
reaction conditions, generally low yields and poor chemical
selectivity. To overcome these deficiencies, metal-catalyzed
NH2
N
H
This work
Cu (60 mol %)
DTBP (2 equiv)
R1
H3C
R1
+
R2
Y
N
R2
(c)
120 °C, 12 h
Y
NH2
H
X = F, Cl, Br, I
Y = C, N
functional group may leading to potential environmental
problems. It would be highly attractive to direct amination of
the unfunctionalized starting materials such as aromatic
hydrocarbon, aliphatic hydrocarbon , or other C (sp3)−H
bond containing compounds，since formally only H2O will
be formed as a byproduct of this transformation. Within this
contribution, we herein report a general method of copper-
catalyzed direct amination of C (sp3)–H with aromatic amines
to afford the corresponding aromatic secondary amines
[Scheme 1, (c)]. Both anilines and aminopyridines can react
Department of Chemistry, Nanchang University, No. 999, Xuefu Rd. Nanchang,
330031, P. R. China. E-mail: senlin@ncu.edu.cn, yanzh@ncu.edu.cn
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Journal Name
smoothly with primary and secondary benzylic C–H Cu(OAc)2, Cu powder and CuSCN were emplVoieyweAdrticlienOntlhinee
substrates in moderate to good yields.
reaction (Table 1, entries 2-6). The reDsuOlIt:s10s.1h0o3w9/eDd0OtBh0a0t4C91uJ
powder showed the best results for this reaction. Other metal
catalysts (such as Fe salts, Ni salts and Ag salts) exhibited
less efficient or no catalytic activity under the same
conditions (Table 1, entries 7-10). Meanwhile, several
oxidants (such as TBHP, BPO, TBPB, etc.) were filtrated for
a
Table 1.
Optimization of the reaction conditions
CH3
Cl
Cl
+
N
N
N
NH2
H
1a
2a
3a
Entry Catalyst (mol%)
Oxidant (eq.)
Solvent
Yieldb
Scheme 2.
Substrate scope of aminopyridines and other nitrogen-containing
heterocyclic compounds a,b
CH3
1
2
3
4
5
6
7
CuI (20)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
neat
neat
neat
neat
neat
neat
neat
31
29
38
35
51
34
19
Ar
NH
Cu (60 mol %)
DTBP (2 equiv)
CuBr (20)
CuCl2 (20)
Cu (OAc)2 (20)
Cu (20)
CuSCN (20)
FeCl2 (20)
Ar NH2
+
120 °C, 12 h
1
2a
3
NC
Cl
N
N
H
N
N
H
F
N
N
H
8
FeCl3 (20)
DTBP (2.0)
neat
trace
9
NiCl2 (20)
AgNO3 (20)
Cu (20)
DTBP (2.0)
DTBP (2.0)
TBHP (2.0)
BPO (2.0)
neat
neat
neat
neat
neat
neat
neat
DMSO
trace
trace
n.d.
3a,
75%
3c,
72%
3b,
77%
10
11
12
13
14
15
16
Br
I
Cu (20)
n.d.
N
N
H
N
N
H
N
N
H
Cu (20)
TBPB (2.0)
K2S2O8 (2.0)
DDQ (2.0)
DTBP (2.0)
n.d.
Cu (20)
n.d.
3f,
51%
3e,
68%
3d,
71%
CH3
N
Cu (20)
trace
trace
H3C
CH3
Cu (20)
17
18
19
20
Cu (20)
Cu (20)
Cu (20)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
DMF
DME
H2O
neat
trace
28
18
N
N
H
N
N
H
N
H
3g,
3i,
33%
32%
3h,
31%
trace
N
N
21
22
Cu (40)
Cu (60)
Cu (80)
Cu (60)
Cu (60)
Cu (60)
Cu (60)
Cu (60)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
neat
neat
neat
neat
neat
neat
neat
neat
63
72
71
n.d.
46
69
75
73
N
N
H
N
H
N
23
HN
3l,
46%
24
3k,
38%
3j,
29%
25
26
27c
28d
DTBP (1.0)
DTBP (3.0)
DTBP (2.0)
DTBP (2.0)
a
1
2a
(2.0 mL), Cu powder (0.3 mmol) and DTBP (1.0 mmol)
Conditions: (0.50 mmol),
120 °C, 12 h, under N2. b Isolated yield.
aConditions: 1a (0.50 mmol), 2a (1.0 mmol), solvent (2 mL), 10 h,
120 °C, under N2. b Isolated yield. c 12 h. d 14 h.
this transformation. It turned out that only DTBP exhibited
reaction activity to the transformation, and TBHP (tert-butyl
hydroperoxide) (70% in water), TBPB (tert-butyl
perbenzoate), BPO (benzoyl peroxide), DDQ (2,3-dichloro-
5,6-dicyano-1,4-benzoquin-one) and K2S2O8 did not trigger
the reaction (Table 1, entries 11-15). The reaction was carried
out in other solvents, whereas no reaction was observed in
DMSO and DMF, and reaction of DME and H2O afforded 3a
in lower yields (Table 1, entries 16-19). Increasing the
amount of Cu powder to 60% led to a higher yield of 72%
(Table 1, entry 20-22); further increasing it to 80% did not
improve the yield (Table 1, entries 23). The amount of the
oxidant was screened, results showed that 2.0 equiv of DTBP
provided 3a in better yield (Table 1, entry 22, 24, 25,26).
The initial explorations were completed by the inter-
molecular coupling of 5-amino-2-chloropyridine (1a) with
methyl-benzene (2a) as a model reaction under different
reaction conditions, including optimization of catalysts,
oxidants, reaction time, and solvents to yield desired
compound. The results are summarized in Table 1. The
reaction was initially carried out by using CuI and DTBP (Di-
tert-butyl peroxide) as a catalyst and an oxidant, respectively
(Table 1, entry 1). A small amount of the corresponding
product was obtained after heating at 120 °C for 10 h under
nitrogen atmosphere in the sealed tube. Encouraged by this
result, different kinds of Cu catalysts such as CuBr, CuCl2,
2 | J. Name., 2012, 00, 1-3
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When the reaction time was extended to 12 h, the yield of 3a without other substituents on the pyridine rings VwieewrAertiuclseeOdnlitnoe
increased to 75% (Table 1, entry 27), further increasing the participate in the reaction, and the reDsOulI:ts10.s1h0o39w/De0dOBth0a0t4921J-
reaction time to 14 h, there was a slight decrease in the yield aminopyridine was more suitable for our optimization
of 3a (Table 1, entry 28). On the basis of the results showed conditions.
Interestingly,
other nitrogen-containing
in Table 1, the reaction was carried out with 0.5 mmol of heterocyclic compounds such as aminopyrazine and 8-
aromatic amines, 2.0 mL of toluene substrates, 0.30 mmol of
Scheme 4.
Substrate Scope of benzylic hydrocarbons, aliphatic alkanes
and ethers a,b,e
Scheme 3. Substrate scope of anilines a,b
R3
R3
R1
R1
Br
CH3
Cu (60 mol %)
DTBP (2 equiv)
R1
H
R2
N
N
N
H
Cu (60 mol %)
DTBP (2 equiv)
R1
R2
R1
N
H
+
+
NH2
120 °C, 12 h
2
N
NH2
120 °C, 12 h
5
2a
4
N
H
NC
F3C
O2N
6
2b
7
Cl
F
N
H
N
H
N
H
N
N
H
N
N
H
N
N
H
5c,
66%
5a,
71%
5b,
70%
7a,
80%
7b,
7c,
82%
76%
Br
CN
61% for 5mmol-scale
Br
Cl
N
N
N
N
H
N
N
N
H
H
N
N
H
H
H
Cl
7e,
58%
5f,
7d,
7f,
52%
61%
31%
5e,
54%
5d,
64%
Cl
Br
Cl
Br
Cl
I
N
N
H
N
N
H
N
N
H
N
H
Br
N
H
N
H
e
7i,
54%
7g,
5%
7h,
69%
Cl
Cl
5h,
5k,
5i,
26%
45%
5g,
57%
N
N
H
N
N
H
N
N
H
H3C
MeO
7j,
7l,
NH
n.r.
58%
43%
7k,
55%
N
H
N
H
Cl
e
e
5l,
5j,
<5%
<5%
N
N
H
N
N
H
N
N
H
a
4
2a
(2.0 mL), Cu powder (0.3 mmol) and DTBP (1.0 mmol),
Conditions: (0.50 mmol),
120 °C, 12 h, under N2. b Isolated yield. e Detected by GC-MS.
7n,
33%
7m,
47%
7o,
46%
Br
Cl
Cu powder, and 1.0 mmol of DTBP at 120 °C for 12 h.
Cl
O
N
N
H
42%
N
N
O
With optimized conditions obtained, the scope of the
process was studied for the reaction of a series of substituted
aminopyridines with toluene as a representative example
(Scheme 2). The electronic effect of the substituent groups on
the pyridine rings had an obviously influence on the reactions.
Aminopyridines containing electron-withdrawing groups
such as halogen and -CN reacted with toluene affording the
corresponding aromatic secondary amines with yields
ranging from 68% to 77% (3a-3e). The reaction of
aminopyridines containing the electron-donating group
methyl was significantly reduced in the yield of the
N
N
H
n.d.
H
7p,
7q,
35%
7r,
N
N
H
O
7s,
n.d.
a
6
2
Conditions: (0.50 mmol), (2.0 mL), Cu powder (0.3 mmol) and DTBP (1.0 mmol),
120 °C, 12 h, under N2. b Isolated yield. e Detected by GC-MS.
aminoquinoline were adopted, the results showed that they
could react with methylbenzene smoothly and gave the
desired product in 38-46% yields (3k, 3l).
Encouraged by the above research，we decided to study
the amination of toluene with anilines and aliphatic amines.
As showed in Scheme 3, anilines bearing strong electron-
withdrawing groups, such as -NO2, -CF3，and -CN reacted
with toluene to offer the corresponding products in good
yields (5a-5d). The reaction of anilines with bromo and iodo
functional groups afforded the corresponding aromatic
ammoniation products (3g-3i).
Additionally
，
different positions of Methyl substituents in the pyridine
ring did not appear to have a significant effect on the reaction
yields. 2-aminopyridine (3f) and 3-aminopyridine (3j) which
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secondary amines in 45%-57% yields (5e-5h). Aniline ammoniation products in
Journal Name
47% and 33%Vie(w7Amrtic,le O7nnlin)e.
reacted with toluene giving 5i in a low yield of 26%. 4- Cyclohexane could react with aminopyDriOdIi:n1e0s.10s3m9/oDo0tOhBly00, 4a9n1dJ
methylaniline and 4-methoxyaniline were unsuccessful it worked with 5-amino-2-chloropyridine, 5-amine-2-
substrates (5j, 5k), which may be due to the electron donor bromopyridine, and 2-aminopyridine to give the
nature of the -Me and -OMe. Additionally, our optimized corresponding products in yields of 35%-46% (7o-7q), thus
reaction conditions may not be suitable for aliphatic amines, providing
a great opportunity for further synthetic
and cyclopentylamine failed to react with toluene to produce manipulations. Unlike primary benzylic hydrocarbons or
a,b
Scheme 5.
Substrate scope of benzylic hydrocarbons
R3
Scheme 6
. Control experiments for investigation of the mechanism
R3
R1
Cu (60 mol %)
R1
H
CH3
DTBP (2 equiv)
+
Cl
Cu (60 mol %)
DTBP (2 equiv)
R2
N
H
R2
Cl
NH2
120 °C, 12 h
+
N
N
N
H
4
8
2
120 °C, 12 h
+
N
NH2
O
BHT (2 equiv)
O2N
O2N
F3C
2a
1a
3a
, n.d.
9
detected by GC-MS
N
H
N
H
N
CH3
Cl
Cu (60 mol %)
DTBP (2 equiv)
H
Cl
8a,
75%
8b,
72%
8c,
70%
+
NH2
N
H
120 °C, 12 h
Ph2C=CH2 (2 equiv)
+
N
O2N
O2N
O2N
Cl
F3C
1a
2a
3a
, n.d.
N
H
N
N
H
10
H
detected by GC-MS
CH3
Cu (60 mol %)
DTBP (2 equiv)
Cl
8d
, 18%
Cl
8e,
66%
8f,
63%
+
N
N
120 °C, 12 h
TEMPO (2 equiv)
N
NH2
H
N
H
1a
3a,
n.d.
2a
8g,
32%
inactive aliphatic alkanes, the amination of sp3C−H bonds in
ethers such as 1,4-dioxane (7r) and anisole (7s) were failed
under the optimized reaction conditions.
a
4
2
Conditions: (0.50 mmol), (2.0 mL), Cu powder (0.3 mmol) and DTBP (1.0 mmol),
120 °C, 12 h, under N2. b Isolated yield.
corresponding secondary amine compound (5l).
Substrate scope studies were also carried out on other
Finally, a gram-scale reaction was explored, 5mmol of 1a
benzylic hydrocarbons, inactive aliphatic alkanes and ethers reacted with 10.0 mL of p-xylene, 3.0 mmol of Cu powder,
with aromatic amines. Results were disclosed in Scheme 4 and 10.0 mmol of DTBP at 120 °C for 12 h, and the product
and Scheme 5. The presence of electron-donating group -Me was produced in 61%.
at the para or ortho positions of toluenes could make them
In order to gain further insight into the plausible reaction
react smoothly with aminopyridine derivatives and aniline pathway, control experiments were conducted (Scheme 6).
derivatives afforded the amination products in good yields The reactions were suppressed in the presence of butylated
(7a-7e, 8a, 8b, 8c). A significant negative effect occurred by hydroxytoluene (BHT), ethene-1,1-diyldibenzene and
-Cl substituents in the toluenes, providing only low 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) under the
conversions under standard conditions (7f, 7g, 8d). standard conditions. As expected, the formation of 3a was
Mesitylene can react with aromatic primary amines to obtain inhibited in the reactions, and the benzyl radical was captured
corresponding aromatic secondary amines in moderate yields by BHT and ethene-1,1-diyldibenzene offered products 9 and
(7h, 7i, 8e, 8f). It is noteworthy that ethylbenzene and 10 (detected by GC−MS). These results illustrated that the
propylbenzene were well-tolerated in this protocol, reaction possibly proceeds through a radical pathway.
ethylbenzene could couple with aminopyridines to give yield
On the basis of these preliminary results above, together
of 43-58% (7j-7l), however, the yield of this reaction with previous studies11, a plausible mechanism is depicted in
t
decreased significantly in the case of p-nitroaniline, 4-nitro- Scheme 7 . Initially, homolysis of DTBP can produce BuO
N-(1-phenylethyl)aniline (8g) was obtained with a yield of radical A, benzyl radical B would be generated by abstracting
32%, propylbenzene coupled with 5-amino-2-chloropyridine hydrogen from toluene by A. Reaction of arylamines with
and 2-aminopyridine afforded the corresponding copper produce intermediate C in the presence of DTBP.
4 | J. Name., 2012, 00, 1-3
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Intermediate C combined with the benzyl radical B to (1) (a) G. Guillena, D. J.Ramjn, M. Yus, Hydrogen
View Article Online
DOI: 10.1039/D0OB00491J
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Scheme 7. Possible mechanism.
CH3
Movassaghi, Biogenetically-Inspired Total Synthesis of
tBuOH
Epidithiodiketopiperazines and Related Alkaloids. Acc.
.
CH2
2a
tBuO
Chem. Res., 2015, 48, 1159-1171; (c) K. Okano, H.
.
tBuOOBut
Tokuyama, T. Fukuyama, Copper-mediated aromatic
amination reaction and its application to the total synthesis of
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A
B
I
Cl
NH Cu
tBuOH
N
C
Cl
tBuOOBut
+
NH2
II
N
Cl
NH Cu CH2
Cu
N
1a
D
Cl
N
N
H
3a
Conclusions
In general, we have developed an effective method of
copper-catalyzed direct amination of benzylic hydrocarbons
and inactive aliphatic alkanes with aromatic amines. Copper
powder was used as an effective promoter in this kind of
transformation. A range of anilines, aminopyridines and
other nitrogen-containing heterocyclic compounds are
suitable substrates for this transformation to product target
coupling products in moderate to good yields. This reaction
provides a potential route for the selective coupling C−N
functionalization from the simple substrates to functionalized
aromatic secondary.
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AUTHOR INFORMATION
Corresponding Authors
*Email: senlin@ncu.edu.cn
*Email: yanzh@ncu.edu.cn
Author Contribution
Hua Yao and Bo Xie contributed equally to this work.
NOTES
The authors declare no competing financial interest.
ACKNOWLEDGMENT
(3) (a) A. R. Katritzky, O. Mteh-Cohn, C. W. Reea,
Comprehensive Organic Functional Group Transformation.
Pergamon Press: New York, 1995, 2, 30. (b) R. N. Salvatore,
C. H. Yoon, K.W. Jung, Synthesis of secondary amines.
Tetrahedron, 2001, 57, 7785-7811. (c) D.M. Roundhill,
We thank the National Natural Science Foundation of China (No.
21362022) and The Natural Science Foundation of Jiangxi
Province (No. 20192BAB203006) for financial support.
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DOI: 10.1039/D0OB00491J
R3
R3
R1
H
R2
Y
Y
N
H
R2
R1
Cu
+
H
Y
NH2
DTBP
R1
N
H
Y = C, N
direct amination of C (sp3)-H
wide functional group tolerance
low-cost catalyst
48 examples up to 82%