Amidation via ligand-free direct oxidative C(sp3)-H/N[sbnd]H coupling with Cu-CPO-27 metal-organic framework as a recyclable heterogeneous catalyst

Article abstract of DOI:10.1016/j.tet.2016.10.059

A copper-based metal-organic framework Cu-CPO-27 was synthesized, and used as a recyclable catalyst for the amidation of unactivated alkanes by benzamides via direct oxidative C(sp³)-H/N[sbnd]H coupling under ligand-free conditions. Using a catalytic amount of the Cu-CPO-27 for the transformation, high yields of N-cyclohexyl benzamides were achieved. The Cu-CPO-27 was more catalytically active than other Cu-MOFs such as Cu₃(BTC)₂, Cu(BDC), Cu(EDB), Cu₂(BPDC)₂(BPY), Cu₂(BDC)₂(DABCO), and Cu₂(EDB)₂(BPY). The Cu-CPO-27 also exhibited advantages as compared to several copper-based salts, including Cu(OAc)₂, CuCl₂, CuBr, CuI, CuCl, Cu(NO₃)₂, and CuSO₄. The Cu-CPO-27 catalyst could be reused several times for the amidation transformation while its catalytic activity was not decreased significantly. To the best of our knowledge, the amidation of unactivated alkanes by benzamides via direct oxidative C(sp³)-H/N[sbnd]H coupling was not previously performed under heterogeneous catalysis conditions.

Full text of DOI:10.1016/j.tet.2016.10.059

Accepted Manuscript
3
Amidation via ligand-free direct oxidative C(sp )-H/N–H coupling with Cu-CPO-27
metal-organic framework as a recyclable heterogeneous catalyst
Thanh T. Hoang, Hanh T.H. Nguyen, Tien T. Le, Dung T. Le, Thanh Truong, Nam
T.S. Phan
PII:
S0040-4020(16)31118-8
10.1016/j.tet.2016.10.059
TET 28200
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 May 2016
Revised Date: 12 October 2016
Accepted Date: 24 October 2016
Please cite this article as: Hoang TT, Nguyen HTH, Le TT, Le DT, Truong T, Phan NTS, Amidation
3
via ligand-free direct oxidative C(sp )-H/N–H coupling with Cu-CPO-27 metal-organic framework as a
recyclable heterogeneous catalyst, Tetrahedron (2016), doi: 10.1016/j.tet.2016.10.059.
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ACCEPTED MANUSCRIPT
Amidation via ligand-free direct oxidative C(sp3)-H/N-H coupling with Cu-CPO-27
metal-organic framework as a recyclable heterogeneous catalyst
Thanh T. Hoang, Hanh T. H. Nguyen, Tien T. Le, Dung T. Le, Thanh Truong, Nam T. S.
Phan*
Department of Chemical Engineering, HCMC University of Technology, VNU-HCM,
268 Ly Thuong Kiet, District 10, Ho Chi Minh City, Viet Nam
*Email: ptsnam@hcmut.edu.vn
Ph: (+84 8) 38647256 ext. 5681
Fx: (+84 8) 38637504
O
O
NH2
Cu-CPO-27
di-tert-butyl peroxide
N
H
+

ACCEPTED MANUSCRIPT
Amidation via ligand-free direct oxidative C(sp3)-H/N-H coupling with Cu-CPO-27 metal-
organic framework as a recyclable heterogeneous catalyst
Thanh T. Hoang, Hanh T. H. Nguyen, Tien T. Le, Dung T. Le, Thanh Truong, Nam T. S. Phan*
Department of Chemical Engineering, HCMC University of Technology, VNU-HCM,
268 Ly Thuong Kiet, District 10, Ho Chi Minh City, Vietnam
*Email: ptsnam@hcmut.edu.vn
Tel: (+84 8) 38647256 ext. 5681
Fax: (+84 8) 38637504
Abstract
A copper-based metal-organic framework Cu-CPO-27 was synthesized, and used as a recyclable
catalyst for the amidation of unactivated alkanes by benzamides via direct oxidative C(sp3)-H/N-
H coupling under ligand-free conditions. Using a catalytic amount of the Cu-CPO-27 for the
transformation, high yields of N-cyclohexyl benzamides were achieved. The Cu-CPO-27 was
more catalytically active than other Cu-MOFs such as Cu3(BTC)2, Cu(BDC), Cu(EDB),
Cu2(BPDC)2(BPY), Cu2(BDC)2(DABCO), and Cu2(EDB)2(BPY). The Cu-CPO-27 also
exhibited advantages as compared to several copper-based salts, including Cu(OAc)2, CuCl2,
CuBr, CuI, CuCl, Cu(NO3)2, and CuSO4. The Cu-CPO-27 catalyst could be reused several times
for the amidation transformation while its catalytic activity was not decreased significantly. To
the best of our knowledge, the amidation of unactivated alkanes by benzamides via direct
oxidative C(sp3)-H/N-H coupling was not previously performed under heterogeneous catalysis
conditions.
Keywords: Cu-CPO-27; coupling; amidation; oxidative; ligand-free.
1

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1. Introduction
Amidation reactions are frequently used in the synthesis of numerous nitrogen-containing
pharmaceutical candidates and agrochemicals as well as many fine chemicals and synthetic
polymers.1-3 Although amides could be achieved by using the reaction between amines and
carboxylic acids or acid chlorides,4-6 these traditional synthetic methods require the preparation
of prefunctionalized starting materials, thus raising atom-economical and environmental
concerns.7-9 Several synthetic routes have been explored for the amide bond formation from a
variety of starting material sources in the presence of metal catalysts.10,2,11-13 Apparently, organic
transformations via the direct activation of C-H bonds would offer shorter and more efficient
synthetic procedures.14-16 In 2014, Hartwig and co-workers reported the first example of a
homogeneous copper-catalyzed amidation of unactivated alkanes by benzamides via direct
oxidative C(sp3)-H/N-H coupling using CuI and 4,7-dimethoxyphenanthronline ligand as catalyst
17
system and di-tert-butyl peroxide as oxidant.
Recently, Cheng and co-workers also
demonstrated a copper-catalyzed oxidative C(sp3)-H/N-H coupling of aryl amides with alkanes
to form the corresponding N-alkylated amides using Cu(acac)2 complex as catalyst and di-tert-
butyl peroxide as oxidant.18 To improve green aspects of the transformation, heterogeneous
catalysts should be explored, as they would offer several advantages in terms of recyclability and
reusability.19,20 At the same time, the contamination of the desired products with hazardous and
harmful metals would be minimized when the catalyst could be recycled and reused.21
Metal-organic frameworks (MOFs) are crystalline, sponge-like materials consisting of metal-
connecting points and organic ligands.22-26 With these structures, MOFs offer several advantages
2

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over conventional crystalline materials.27-32 During the last decade, potential applications of
MOFs have been explored in many fields, including gas storage, gas separation, energy
technologies, sensors, optics, drug storage and delivery, heavy metal ion extraction, and
catalysis.33-38 Although a very large number of MOFs have been mentioned in the literature,
many of them have been investigated for application in gas capture and storage, and only a small
number of them have been used for catalytic applications.39-43 In MOF structures, the opportunity
for high dispersion and high loading of catalytically active sites could be maximized as each
organic linker or each metal in the framework could be useful for catalysis.44-47 During the last
few years, a large number of organic reactions using MOFs as heterogeneous catalysts or catalyst
supports have been reported.48-53 Among many famous MOFs, copper-based frameworks have
offered high activity in numerous organic transformations.54-62 In this work, we wish to present
the amidation of unactivated alkanes by benzamides via direct oxidative C(sp3)-H/N-H coupling
using a copper-based metal-organic framework Cu-CPO-27 as a recyclable heterogeneous
catalyst under ligand-free conditions. The catalyst could be reused several times for the
amidation transformation while its catalytic activity was not decreased significantly. To the best
of our knowledge, this ligand-free copper-catalyzed amidation reaction was not previously
performed under heterogeneous catalysis conditions.
2. Results and discussion
O
O
Cu-CPO-27
N
NH2
+
H
di-tert-butyl peroxide
Scheme 1. The direct oxidative C(sp3)-H/N-H coupling reaction between cyclohexane and
benzamide using Cu-CPO-27 catalyst.
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The metal-organic framework Cu-CPO-27 was synthesized from 2,5-dihydroxyterephthalic acid
and copper nitrate trihydrate following a literature procedure,63,64 and was characterized by a
variety of different techniques (Fig. S1 – Fig. S7). The Cu-CPO-27 was used as catalyst for the
direct oxidative C(sp3)-H/N-H coupling reaction between cyclohexane and benzamide to form N-
cyclohexyl benzamide as the principal product (Scheme 1). Initial studies addressed the effect of
temperature on the yield of N-cyclohexyl benzamide. In the first example of a homogeneous
copper-catalyzed amidation of unactivated alkanes by benzamides via direct oxidative C(sp3)-
o
H/N-H coupling, Hartwig and co-workers carried out the reaction at 100 C 17. However, Cheng
o
and co-workers carried out the same transformation at 115 C.18 The reaction was conducted
with 10 mol% catalyst loading, using 93 equivalents of cyclohexane for 10 h, in the presence of
o
o
o
4 equivalents of di-tert-butyl peroxide as oxidant, at room temperature, 80 C, 100 C, 105 C,
110 oC, and 120 oC, respectively. It was found that the coupling reaction could not proceed at 80
oC or lower temperature, with no trace amount of N-cyclohexyl benzamide being detected after
10 h. The best yield of N-cyclohexyl benzamide was achieved for the reaction conducted at 110
o
oC (entry 4, Table 1). It was observed that performing the transformation at higher than 110 C
was not necessary as the yield of N-cyclohexyl benzamide was not improved any further (Fig.
S8).
Similar to other coupling reactions via C-H bond activation,14-16 the presence of an oxidant
should be necessary for the direct oxidative C(sp3)-H/N-H coupling reaction between
cyclohexane and benzamide. We decided to explore the impact of different oxidants on the yield
of N-cyclohexyl benzamide, having used di-tert-butyl peroxide (DTBP), tert-butyl
hydroperoxide (TBHP) in water, tert-butyl hydroperoxide (TBHP) in decane, dibenzoyl peroxide
4

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(DBP), dilauroyl peroxide (DLP), hydrogen peroxide, K2S2O8, tert-butyl peroxide benzoate
(TBPB), and cumyl hydroperoxide (CHP) as oxidant, respectively. Interestingly, it was found
that di-tert-butyl peroxide was the only oxidant that should be used, achieving 94% yield after 10
h (entry 14, Table 1). Other oxidants were found to be totally inactive for the transformation,
with no trace amount of N-cyclohexyl benzamide being detected after 10 h (Fig. S9). Hartwig
and co-workers previously pointed out that the oxidant was crucial for this transformation, and
di-tert-butyl peroxide was the oxidant of choice.17 Cheng and co-workers also demonstrated that
the combination of a copper complex and di-tert-butyl peroxide led to the formation of the
C(sp3)-H/N-H coupling products in high yields.18
Table 1. Screening the reaction conditions regarding temperature, oxidant, oxidant amount,
cyclohexane amount, and catalyst concentration.
Entry Temperature
(oC)
Oxidant
Oxidant
Cyclohexane
Catalyst
GC
Yield
(%)
0
amount
amount
(equiv.)
93
concentration
(equiv.)
(mol%)
10
1
2
3
4
5
80
DTBP
DTBP
DTBP
DTBP
DTBP
4
4
4
4
4
100
105
110
120
93
10
11
93
10
60
93
10
94
93
10
94
6
7
110
110
TBHP
(water)
TBHP
4
4
93
93
10
10
1
1
5

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(decane)
8
110
110
110
110
110
110
110
DBP
DLP
4
4
4
4
4
4
4
93
93
93
93
93
93
93
10
10
10
10
10
10
10
1
1
9
10
11
12
13
14
H2O2
1
K2S2O8
TBPB
CHP
1
1
1
DTBP
94
15
16
17
18
19
110
110
110
110
110
DTBP
DTBP
DTBP
DTBP
DTBP
0
1
2
3
4
93
93
93
93
93
10
10
10
10
10
0
18
47
67
94
20
21
22
23
24
110
110
110
110
110
DTBP
DTBP
DTBP
DTBP
DTBP
4
4
4
4
4
23
46
10
10
10
10
10
73
91
93
94
88
70
93
115
25
26
110
110
DTBP
DTBP
4
4
93
93
0
0
2.5
80
6

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27
28
29
110
110
110
DTBP
DTBP
DTBP
4
4
4
93
93
93
5
85
94
94
7.5
10
Furthermore, it was observed that the amount of di-tert-butyl peroxide displayed a profound
impact on the yield of N-cyclohexyl benzamide, having performed the coupling reaction in the
presence of 1, 2, 3, and 4 equivalents of di-tert-butyl peroxide as oxidant, respectively. It was
found that the reaction using 1 equivalent of di-tert-butyl peroxide proceeded with difficulty,
affording only 18% yield of N-cyclohexyl benzamide after 10 h. As expected, increasing the
amount of the oxidant led to higher yields for the transformation. Up to 94% yield of N-
cyclohexyl benzamide was achieved after 10 h in the presence of 4 equivalents of the oxidant
(entry 19, Table 1). No product was generated in the absence of the oxidant (Fig. S10). Another
factor that should be considered is the reactant molar ratio. The transformation could occur under
solvent-free conditions, when a large excess of cyclohexane was employed as the reaction
medium. It was found that 94% yield was achieved for the reaction using 93 equivalents of
cyclohexane (entry 23, Table 1). Increasing the amount of cyclohexane to 115 equivalents
caused a drop in the reaction rate, though an 88% yield of N-cyclohexyl benzamide was still
obtained after 10 h. Decreasing the amount of cyclohexane to 23 equivalents also expressed a
negative effect on the reaction, providing only 73% yield after 10 h (Fig. S11). This could be
rationalized based on the fact that the mass transfer phenomenon would be of importance for the
reaction using heterogeneous catalysts.
Another factor that would express a considerable impact is the catalyst loading. It was noted that
the coupling reaction between cyclohexane and benzamide could occur readily utilizing a
7

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catalytic amount of the Cu-CPO-27. The reaction utilizing 2.5 mol% catalyst could afford 80%
yield of N-cyclohexyl benzamide after 10 h. Increasing the catalyst concentration to 7.5 mol%
led to 94% yield after 10 h (entry 28, Table 1). Employing more than 7.5 mol% catalyst was
noticed to be unnecessary as the yield of N-cyclohexyl benzamide was not improved any further
(Fig. S12). It must be emphasized that no reaction occurred in the absence of the catalyst,
proving the requirement of utilizing the Cu-MOF as catalyst for the generation of N-cyclohexyl
benzamide. In the first report of a homogeneous copper-catalyzed amidation between
cyclohexane and benzamide, Hartwig and co-workers employed 2.5 mol% CuI catalyst in the
presence of 4,7-dimethoxyphenanthronline ligand.17 Cheng and co-workers implemented the
same transformation deploying 10 mol% Cu(acac)2 complex as catalyst.18 The fact that the
coupling reaction between cyclohexane and benzamide could proceed to produce N-cyclohexyl
benzamide in the presence of a framework catalyst without any added ligand would offer an
advantage.
To underline the advantages of utilizing the Cu-CPO-27 as catalyst for the direct oxidative
C(sp3)-H/N-H coupling reaction between cyclohexane and benzamide, the catalytic activity of
the Cu-CPO-27 was compared with that of other Cu-MOFs including Cu3(BTC)2, Cu(BDC),
Cu2(BPDC)2(BPY), Cu2(BDC)2(DABCO), Cu2(EDB)2(BPY), and Cu(EDB) [BTC =
benzenetricarboxylate; BDC = benzenedicarboxylate; BPDC = biphenyl-4,4’-dicarboxylate;
BPY
=
4,4’-bipyridine; DABCO
=
1,4-diazabicyclo[2.2.2]octane; EDB
=
4,4’-
ethynyldibenzoate]. It was observed that the reaction using Cu3(BTC)2 catalyst could proceed to
86% yield after 10 h. Indeed, the famous Cu3(BTC)2 was previously used as catalyst in many
copper-catalyzed organic transformations. Cu(BDC) was also found to be active for the
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transformation, affording 84% yield after 10 h. Similarly, the Cu(EDB)-catalyzed direct
oxidative coupling reaction produced N-cyclohexyl benzamide in a yield of 87% after 10 h.
Cu2(EDB)2(BPY) was more catalytically active than Cu(EDB), with 89% yield of N-cyclohexyl
benzamide being observed after 10 h. However, Cu2(BPDC)2(BPY) offered lower activity,
though the reaction still afforded 74% yield after 10 h. It was found that the direct oxidative
coupling reaction using Cu2(BDC)2(DABCO) catalyst proceeded with difficulty, and only 33%
yield was detected after 10 h. Among these Cu-MOFs, Cu-CPO-27 offered the best performance,
with 94% yield of N-cyclohexyl benzamide being achieved after 10 h (Fig. 1).
100
80
60
40
20
0
Catalyst
Fig. 1. Yields of N-cyclohexyl benzamide with different different Cu-MOFs as catalyst. The
reaction was carried out at 110 oC for 10 h, using 93 equivalents of cyclohexane, in the presence
of 4 equivalents of di-tert-butyl peroxide, at 7.5 mol% catalyst loading.
9

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100
80
60
40
20
0
Catalyst
Fig. 2. Yields of N-cyclohexyl benzamide with different copper salts as catalyst. The reaction
was carried out at 110 oC for 10 h, using 93 equivalents of cyclohexane, in the presence of 4
equivalents of di-tert-butyl peroxide, at 7.5 mol% catalyst loading.
To further emphasize the advantages of employing the Cu-CPO-27 catalyst for the direct
oxidative C(sp3)-H/N-H coupling reaction between cyclohexane and benzamide to form N-
cyclohexyl benzamide, we also performed the reaction in the presence of several copper-based
salts. Among these copper-based catalysts, Cu(acac)2 complex exhibited highest activity for the
direct oxidative coupling reaction, with 97% yield being achieved after 10 h. Indeed, Cheng and
co-workers previously demonstrated a copper-catalyzed oxidative C(sp3)-H/N-H coupling of aryl
amides with alkanes to form the corresponding N-alkylated amides using Cu(acac)2 complex as
18
catalyst . CuI, CuBr, and CuCl were also noted to be active for the transformation, producing
10

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N-cyclohexyl benzamide in a yield of 94%, 89%, and 87%, respectively, after 10 h. Copper(II)
salts offered lower catalytic activity for the reaction than copper(I) salts, affording 80%, 73%,
and 62% yields, respectively, for the case of CuCl2, Cu(NO3)2, and CuSO4. Similarly, the
reaction using Cu(OAc)2 could proceed to 62% yield after 10 h (Fig. 2). We also explored the
catalytic activity of other salts for the direct oxidative C(sp3)-H/N-H coupling reaction between
cyclohexane and benzamide, including Co(NO3)2, Fe(NO3)3, Ni(NO3)2, Zn(NO3)2, and CoCl2.
However, it was found that the reaction using Co(NO3)2 as catalyst afforded less than 10% yield
after 10 h, while no product was detected for the case of Ni(NO3)2, CoCl2, Fe(NO3)3 and
Zn(NO3)2 (Table S1).
100
80
60
40
20
0
Mechanistic studies
Fig. 3. Mechanistic studies for the direct oxidative C(sp3)-H/N-H coupling reaction. The reaction
was carried out at 110 oC for 10 h, using 93 equivalents of cyclohexane, in the presence of 4
equivalents of di-tert-butyl peroxide, at 7.5 mol% catalyst loading.
11

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To understand the mechanism of the direct oxidative C(sp3)-H/N-H coupling reaction between
cyclohexane and benzamide to generate N-cyclohexyl benzamide, further mechanistic studies
were then performed. In the first experiment series, (2,2,6,6-tetramethylpiperidin-1-yl)oxy
(TEMPO) as antioxidant was added to the mixture at the beginning of the reaction. It was
observed that the transformation was affected by the radical trapping reagent. Indeed, using 1
equivalent of TEMPO, 90% yield of N-cyclohexyl benzamide was obtained after 10 h. It should
be noted that up to 94% yield was achieved in the absence of the antioxidant. Increasing the
amount of TEMPO to 2 equivalents significantly affected the transformation, and only 33% yield
was observed after 10 h. It was found that no reaction occurred in the presence of 3 equivalents
of TEMPO, with no trace quantity of N-cyclohexyl benzamide being recorded after 10 h. It could
be proposed that the interaction of the radicals in the catalytic cycle with TEMPO would stop the
coupling reaction. Moreover, it was observed that air should be required for the transformation.
In the second experiment series, the reaction was carried out under argon for 10 h. Under this
condition, only 40% yield of N-cyclohexyl benzamide was observed after 10 h, though 4
equivalents of di-tert-butyl peroxide as oxidant was present in the reaction mixture. It should be
noted that the reaction could proceed to 94% yield after 10 h under air (Fig. 3). These
observations would suggest that both di-tert-butyl peroxide and molecular oxygen in the air
could play an important role in the catalytic cycle of the direct oxidative C(sp3)-H/N-H coupling
reaction. In the third experiment series, the Cu-CPO-27 was soaked in pyridine as the catalyst
poison, and then evacuated under vacuum prior to use. It was found that 55% yield of N-
cyclohexyl benzamide was obtained after 10 h. This could be rationalized based on the fact that
the strong interaction of pyridine with the copper sites would deactivate the Cu-MOF catalyst. 65
With all of these results and based on a previous report, 18 the mechanism of the direct oxidative
12

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C(sp3)-H/N-H coupling reaction between cyclohexane and benzamide to form N-cyclohexyl
benzamide was proposed (Scheme 2).
tBuOOtBu
tBuO
O
NH2
tBuOH
Cu(III)
tBuO
tBuOH
O
NH
Cu(II)
O
O
N
H
N
H
Scheme 2. Proposed reaction mechanism.
When an organic transformation is carried out under heterogeneous catalysis conditions, the
leaching test should be explored. In several cases, the transformation would proceed under both
heterogeneous and homogeneous catalysis conditions.66 In order to check if active copper species
dissolved from the solid Cu-CPO-27 catalyst contributed to the formation of N-cyclohexyl
benzamide in the direct oxidative C(sp3)-H/N-H coupling reaction between cyclohexane and
benzamide, a control experiment was carried out. Apparently, if N-cyclohexyl benzamide was
still produced after the Cu-CPO-27 catalyst was isolated from the mixture, the direct oxidative
C(sp3)-H/N-H coupling reaction was not occurring under real heterogeneous catalysis conditions.
13

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o
The reaction was carried out at 110 C for 10 h, using 93 equivalents of cyclohexane, in the
presence of 4 equivalents of di-tert-butyl peroxide as oxidant, at 7.5 mol% loading of Cu-CPO-
27 catalyst. After the reaction, the Cu-MOF catalyst was isolated from the reaction mixture. The
reaction solution was transferred to a new flask, and fresh reagents were then added to the
o
solution. The resulting mixture was stirred for 10 h at 120 C. It was found that no further yield
of N-cyclohexyl benzamide was detected in the absence of the solid Cu-CPO-27 catalyst (Fig. 4).
This observation would indicate that the direct oxidative C(sp3)-H/N-H coupling reaction
between cyclohexane and benzamide to form N-cyclohexyl benzamide could only proceed in the
presence of the solid Cu-CPO-27 catalyst.
100
80
60
7.5 mol% catalyst
Leaching test
40
20
0
0
2
4
6
8
10
Time (h)
Fig. 4. The leaching test showed that N-cyclohexyl benzamide was not produced in the absence
of catalyst. The reaction was carried out at 110 oC for 10 h, using 93 equivalents of cyclohexane,
in the presence of 4 equivalents of di-tert-butyl peroxide, at 7.5 mol% catalyst loading.
14

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100
80
60
40
20
0
1
2
3
4
5
6
7
Run
Fig. 5. Catalyst reusability investigation. The reaction was carried out at 110 oC for 10 h, using
93 equivalents of cyclohexane, in the presence of 4 equivalents of di-tert-butyl peroxide, at 7.5
mol% catalyst loading.
For environmentally benign chemistry, issues that should be considered when using solid
catalysts for organic transformations are the ease of separation as well as the deactivation and
reusability of the catalysts. Although several copper salts exhibited high activity in the direct
oxidative C(sp3)-H/N-H coupling reaction between cyclohexane and benzamide, these catalysts
could not be reused. The catalyst was therefore investigated for reusability in the direct oxidative
C(sp3)-H/N-H coupling reaction over 7 successive runs. After the first run, the Cu-MOF catalyst
was separated from the reaction mixture by simple centrifugation, washed with copious amounts
of DMF and cyclohexane to remove any physisorbed reagents, dried at 150 oC under vacuum for
2 h, and reused in further reactions under identical conditions to those of the first run. It was
observed that the catalyst could be reused many times in the direct oxidative C(sp3)-H/N-H
15

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coupling reaction between cyclohexane and benzamide while its catalytic activity was not
decreased significantly. Indeed, an 86% yield of N-cyclohexyl benzamide was still observed in
the 7th run (Fig. 5). Moreover, XRD (Fig. 6) and FT-IR (Fig. 7) results of the reused catalyst after
the 7th run also indicated that the framework could be maintained in the direct oxidative C(sp3)-
H/N-H coupling reaction.
2000
1500
1000
500
b)
a)
0
5
10
15
20
25
30
2-Theta Scale
Fig. 6. X-ray powder diffractograms of the fresh (a) and reused (b) catalyst.
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b)
a)
4000
3500
3000
2500
2000
1500
1000
500
Wavenumber (cm-1)
Fig. 7. FT-IR spectra of the fresh (a) and reused (b) catalyst.
Table 2. The direct oxidative C(sp3)-H/N-H coupling reaction using Cu-CPO-27 catalyst a
Entry
Reactant 1
Reactant 2
Products
Isolated
yields
(%)
O
O
NH2
1
90
N
H
17

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O
O
NH2
2
92
N
H
Cl
Cl
O
O
NH2
3
4
87
65
N
H
O
O
O
O
NH2
N
H
O
O
O
NH2
N
5
63
H
O
O
NH2
NH2
6
7
65
62
N
H
O
N
H
O
O
NH2
8
9
47
51
N
H
O
O
NH2
N
H
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O
O
NH
N
10
82
O
O
O
O
S NH2
O
11
12
73
55
S
N
O
H
O
O
NH2
N
H
N
N
O
O
NH
O
N
13
14
78b
O
O
O
60b
NH
O
N
O
O
O
S NH2
O
S
15
16
66b
53b
N
O
H
O
O
S NH2
O
S
N
O
H
a
o
The reaction was carried out at 110 C for 10 h, using 93 equivalents of cyclohexane, in the
presence of 4 equivalents of di-tert-butyl peroxide, at 7.5 mol% catalyst loading.
b 0.001 mol% tBuOK was required.
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The study was then extended to the direct oxidative C(sp3)-H/N-H coupling reaction between
different benzamides and cycloalkanes (Table 2). The products were purified by column
chromatography. It was found that N-cyclohexylbenzamide could be achieved with an isolated
yield of 90% (entry 1). Similarly, 92% yield of 4-chloro-N-cyclohexylbenzamide was obtained
for the coupling reaction of 4-chlorobenzamide with cyclohexane (entry 2). It was found that
benzamides containing electron-donating groups were less reactive in the direct oxidative C(sp3)-
H/N-H coupling reaction. The coupling reaction of 4-methoxybenzamide with cyclohexane
afforded 87% yield of N-cyclohexyl-4-methoxybenzamide (entry 3), while 65% yield of N-
cyclohexyl-4-methylbenzamide was observed for the case of 4-methylbenzamide (entry 4).
Similarly, the transformation using Cu-CPO-27 catalyst produced 63% yield of N-cyclohexyl-3-
methylbenzamide (entry 5) and 65% yield of N-cyclohexyl-2-methylbenzamide (entry 6).
Moreover, cyclooctane and cycloheptane were noticed to be less reactive towards the direct
oxidative C(sp3)-H/N-H coupling reaction than cyclohexane, with 62% yield of N-
cyclooctylbenzamide (entry 7) and 47% yield of N-cycloheptylbenzamide (entry 8), respectively,
being obtained. The reaction of a benzamide containing an n-hexyl substituent with cyclohexane
also occurred under these conditions, affording N-cyclohexyl-4-hexylbenzamide in 51% yield
(entry 9).
To expand the scope of the research, the direct oxidative C(sp3)-H/N-H coupling reaction was
also performed with different nitrogen reactants. The reaction between phthalimide and
cyclohexane proceeded to give 82% yield of N-cyclohexyl phthalimide (entry 10). Indeed, Cheng
and co-workers previously demonstrated this transformation using Cu(acac)2 complex as catalyst
and di-tert-butyl peroxide as oxidant.18 Furthermore, benzenesulfonamide was found to able to
20

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react with cyclohexane, providing N-cyclohexylbenzenesulfonamide in 73% yield (entry 11).
Using the copper-based framework as catalyst, the coupling reaction between picolinamide and
cyclohexane could generate N-cyclohexylpicolinamide in 55% yield (entry 12). As mentioned in
Scheme 2, this direct oxidative C(sp3)-H/N-H coupling reaction involved the formation of a
cycloalkyl radical in the catalytic cycle. We then decided to explore the coupling transformation
with toluene as reactant instead of cyclohexane. Indeed, the benzylic methyl group should be
more ready to be activated in the presence of an oxidant. However, it was found that the reaction
could not proceed under the standard conditions, with the desired product being detected in trace
amount. Huang and co-workers previously conducted the reaction using CuCl catalyst, and
t
pointed out that the reaction was significantly accelerated in the presence of BuOK as a base. 67
t
Utilizing 0.001 mol% BuOK, the reaction between phthalimide and toluene afforded 78% yield
of N-benzyl phthalimide in the presence of the copper-based framework catalyst (entry 13).
Similarly, N-α-methylbenzylphthalimide was obtained in 60% yield via the reaction between
phthalimide and ethylbenzene (entry 14). Furthermore, N-benzylbenzenesulfonamide (entry 15)
and N-benzyl-p-toluenesulfonamide (entry 16) were produced in 66% and 53% yields,
respectively.
3. Conclusions
In summary, the Cu-CPO-27 was synthesized from 2,5-dihydroxyterephthalic acid and copper
nitrate trihydrate by a solvothermal method. The material could be employed as a recyclable
heterogeneous catalyst for the amidation of unactivated alkanes by benzamides via direct
oxidative C(sp3)-H/N-H coupling under ligand-free conditions. Using a catalytic amount of the
21

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framework for the transforamtion, high yields of N-cyclohexyl benzamides were achieved. The
oxidant exhibited a significant effect on the transformation, and di-tert-butyl peroxide was the
only oxidant that should be used. The Cu-CPO-27 was more catalytically active than other Cu-
MOFs such as Cu3(BTC)2, Cu(BDC), Cu(EDB), Cu2(BPDC)2(BPY), Cu2(BDC)2(DABCO), and
Cu2(EDB)2(BPY). The framework also exhibited advantages over several copper-based salts,
including Cu(OAc)2, CuCl2, CuBr, CuI, CuCl, Cu(NO3)2, and CuSO4 in terms of the catalytic
activity as well as the catalyst reusability. The catalyst could be reused several times while its
catalytic activity was not decreased significantly. The amidation of unactivated alkanes by
benzamides via direct oxidative C(sp3)-H/N-H coupling could only occur in the presence of the
solid Cu-MOF catalyst, and no contribution from leached copper sites present in the liquid phase,
if any, was detected.
4. Experimental
4.1. Preparation of the metal-organic framework Cu-CPO-27
All reagents and starting materials were obtained commercially from Sigma-Aldrich, Acros, and
Merck, and were used as received without any further purification unless otherwise noted. The
Cu-CPO-27 was synthesized following a literature procedure.63,64 In a typical experiment,
H2dhtp (H2dhtp = 2,5-dihydroxyterephthalic acid; 0.186 g, 0.97 mmol), and Cu(NO3)2.3H2O
(0.500 g, 2.07 mmol) were added to a mixture of DMF (DMF = N,N’-dimethylformamide; 20
mL), and water (1 mL). The resulting mixture was magnetically stirred for 10 min to produce a
clear solution, and was then equally split between three 10 mL vials. The vials were tightly
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o
capped and heated at 85 C for 18 h to obtain reddish crystals. After cooling the vials to room
temperature, the crystals were collected and washed in DMF (3 x 20 mL) for 3 days. The
frameworks were then soaked in methanol (3 x 20 mL) at room temperature for 3 days. The
framework was then heated on a Shlenk line under vacuum at 150 oC for 5 h, yielding 0.260 g of
product as reddish black crystals (60% based on 2,5-dihydroxyterephthalic acid).
4.2. General experimental procedure
In a catalytic reaction, a solution of benzamide (0.0242 g, 0.2 mmol) and diphenyl ether (0.034
mL, 0.2 mmol) in cyclohexane (1.5 mL) was added into a 10-mL screw tube containing the
catalyst and di-tert-butyl peroxide (0.147 mL, 0.8 mmol) as an oxidant. The catalyst
concentration was determined based on the copper/benzamide molar ratio. The reaction mixture
o
was magnetically stirred at 110 C for 10 h. Reaction yields were monitored by taking samples
and quenching with water (1 mL). The extraction was carried out using ethyl acetate (2 mL), and
the organic phase was dried over anhydrous Na2SO4, and analyzed by GC with reference to
diphenyl ether as an internal standard. Purification by column chromatography was implemented
1
to afford N-cyclohexyl benzamide. GC-MS, H NMR and 13C NMR analyses were also
conducted to confirm the structure of the product. To investigate the recyclability of Cu-CPO-27,
the catalyst was separated from the reaction mixture by simple centrifugation, washed with DMF
o
and dichloromethane, dried at 150 C under vacuum on a Shlenk line for 2 h, and reused in
further experiments. For the leaching test, after the first run, the catalyst was separated from the
reaction mixture. The reaction solution was transferred to a new 10-mL screw tube, and fresh
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reagents were then added to the solution. The resulting mixture was magnetically stirred for 10 h
at 120 oC, and the formation of N-cyclohexyl benzamide was analyzed by GC.
4.3. Characterization data of products
4.3.1. N-cyclohexyl benzamide
Prepared as shown in the general experimental procedure. Benzamide (0.0242 g, 0.2 mmol) and
cyclohexane (1.5 mL) was added into a 10-mL screw tube containing the catalyst (4 mg, 7.5
mol%) and di-tert-butyl peroxide (0.147 mL, 0.8 mmol). The reaction mixture was magnetically
o
stirred at 110 C for 10 h. Organic components were extracted into ethyl acetate (2 mL). The
product was purified on silica gel (230-400 mesh or 37-63 µm, ethyl acetate/hexane = 1:3 (v./v.),
TLC silica gel 60 F254, Rf = 0.47): white solid, 90% yield (36.5 mg), mp = 141-143 °C, literature
o
mp = 139-141 C.68 1H NMR (500 MHz, CDCl3) δ 7.76 – 7.74 (m, 2H), 7.49 – 7.41 (m, 3H),
6.03 (s, 1H), 3.98 (tt, J = 10.5, 4 Hz, 1H), 2.04 – 2.01 (m, 2H), 1.77 – 1.73 (m, 2H), 1.67 – 1.63
13
(m, 1H), 1.47 – 1.38 (m, 2H), 1.28 – 1.17 (m, 3H). C NMR (125 MHz, CDCl3, ppm) δ 166.6,
135.1, 131.2, 128.5, 126.8, 48.66, 33.2, 25.6, 24.9. GC-MS: m/z 203 (39%), 122 (88%), 105
(100%), 77(48%). N-cyclohexylbenzamide was previously reported.69,18,70,68
4.3.2. N-cyclohexyl-4-chlorobenzamide
Prepared as shown in the general experimental procedure. 4-Chlorobenzamide (0.0318 g, 0.2
mmol) and cyclohexane (1.5 mL) was added into a 10-mL screw tube containing the catalyst (4
24

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mg, 7.5 mol%) and di-tert-butyl peroxide (0.147 mL, 0.8 mmol). The reaction mixture was
o
magnetically stirred at 110 C for 10 h. Organic components were extracted into ethyl acetate (2
mL). The product was purified on silica gel (230-400 mesh or 37-63 µm, ethyl acetate/hexane =
1:3 (v./v.), TLC silica gel 60 F254, Rf = 0.5): white solid, 92% yield (43.7 mg), mp = 182-184 °C,
literature mp = 184-185 oC.71 1H NMR (500 MHz, CDCl3, ppm): δ 7.69 (d, J = 8.5 Hz, 2H), 7.39
(d, J = 8.5 Hz, 2H), 5.90 (d, J = 4.5 Hz, 1H), 3.93 – 3.99 (m, 1H), 2.04 – 2.01 (m, 2H), 1.78 –
13
1.74 (m, 2H), 1.64 – 1.68 (m, 1H), 1.48 – 1.39 (m, 2H), 1.27 – 1.20 (m, 3H). C NMR (125
MHz, CDCl3, ppm): δ = 165.5, 137.5, 133.5, 128.76, 128.3, 48.8, 33.2, 25.6, 24.9. GC-MS: m/z
239, 237 (13%, 39%, [M+]), 158, 156 (29%, 87%), 141, 139 (33%, 100%), 113, 111 (14%,
34%). N-cyclohexyl-4-chlorobenzamide was previously reported.69,18, 71
4.3.3. N-cyclohexyl-4-methoxybenzamide
Prepared as shown in the general experimental procedure. 4-Methoxybenzamide (0.0308 g, 0.2
mmol) and cyclohexane (1.5 mL) was added into a 10-mL screw tube containing the catalyst (4
mg, 7.5 mol%) and di-tert-butyl peroxide (0.147 mL, 0.8 mmol). The reaction mixture was
o
magnetically stirred at 110 C for 10 h. Organic components were extracted into ethyl acetate (2
mL). The product was purified on silica gel (230-400 mesh or 37-63 µm, ethyl acetate/hexane =
1:3 (v./v.), TLC silica gel 60 F254, Rf = 0.2): white solid, 87% yield (40.5 mg), mp = 160-162 °C,
o
literature mp = 160-161 C.72 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 8.5 Hz, 2H), 6.89 (d, J
= 8.5 Hz, 2H), 6.04 (d, J = 6.5 Hz, 1H), 3.98 – 3.92 (m, 1H), 3.83 (s, 3H), 2.02 – 1.99 (m, 2H),
13
1.76 – 1.72 (m, 2H), 1.66 – 1.62 (m, 1H), 1.45 – 1.36 (m, 2H), 1.27 – 1.17 (m, 3H). C NMR
(125 MHz, CDCl3, ppm): δ 166.2, 162.0, 128.6, 127.4, 113.6, 55.4, 48.6, 33.3, 25.6, 25.0. GC-
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MS: m/z 233 (28%, [M+]), 151 (42%), 135 (100%). N-cyclohexyl-4-methoxybenzamide was
previously reported.18,72
4.3.4. N-cyclohexyl-4-methylbenzamide
Prepared as shown in the general experimental procedure. 4-Methylbenzamide (0.0274 g, 0.2
mmol) and cyclohexane (1.5 mL) was added into a 10-mL screw tube containing the catalyst (4
mg, 7.5 mol%) and di-tert-butyl peroxide (0.147 mL, 0.8 mmol). The reaction mixture was
o
magnetically stirred at 110 C for 10 h. Organic components were extracted into ethyl acetate (2
mL). The product was purified on silica gel (230-400 mesh or 37-63 µm, ethyl acetate/hexane =
1:3 (v./v.), TLC silica gel 60 F254, Rf = 0.4): white solid, 65% yield (28.2 mg), mp = 147-149 °C,
literature mp = 151 oC.73 1H NMR (500 MHz, CDCl3) δ 7.65 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0
Hz, 2H), 6.04 (d, J = 5.9 Hz, 1H), 4.00 – 3.93 (m, 1H), 2.38 (s, 3H), 2.04 – 2.00 (m, 2H), 1.76 –
13
1.72 (m, 2H), 1.66 – 1.63 (m, 1H), 1.45 – 1.37 (m, 2H), 1.27 – 1.18 (m, 3H). C NMR (125
MHz, CDCl3) δ 166.6, 141.5, 132.3, 129.1, 126.8, 48.6, 33.3, 25.6, 24.9, 21.4. GC-MS: m/z 217
(38%, [M+]), 136 (63%), 119 (100%), 91 (40%). N-cyclohexyl-4-methylbenzamide was
previously reported.18,68,73
4.3.5. N-cyclohexyl-3-methylbenzamide
Prepared as shown in the general experimental procedure. 3-Methylbenzamide (0.0274 g, 0.2
mmol) and cyclohexane (1.5 mL) was added into a 10-mL screw tube containing the catalyst (4
mg, 7.5 mol%) and di-tert-butyl peroxide (0.147 mL, 0.8 mmol). The reaction mixture was
26

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o
magnetically stirred at 110 C for 10 h. Organic components were extracted into ethyl acetate (2
mL). The product was purified on silica gel (230-400 mesh or 37-63 µm, ethyl acetate/hexane =
1:3 (v./v.), TLC silica gel 60 F254, Rf = 0.4): white solid, 63% yield (27.3 mg), mp = 123-124 °C,
o
literature mp = 121-122 C.74 1H NMR (500 MHz, CDCl3) δ 7.57 (s, 1H), 7.53 – 7.51 (m, 1H),
7.28 (dd, J = 4.6, 2.0 Hz, 2H), 6.02 (d, J = 5.5 Hz, 1H), 3.97 (tdt, J = 11.9, 8.0, 3.9 Hz, 1H), 2.38
(s, 3H), 2.04 – 2.00 (m, 2H), 1.77 – 1.73 (m, 2H), 1.67 – 1.63 (m, 1H), 1.47 – 1.38 (m, 2H), 1.28
13
– 1.18 (m, 3H). C NMR (125 MHz, CDCl3) δ 166.8, 138.3, 135.1, 131.9, 128.4, 127.6, 123.8,
48.6, 33.2, 25.6, 24.9, 21.3. GC-MS: m/z 217 (46%, [M+]), 136 (78%), 119 (100%), 91 (53%).
N-cyclohexyl-3-methylbenzamide was previously reported. 74,75
4.3.6. N-cyclohexyl-2-methylbenzamide
Prepared as shown in the general experimental procedure. 2-Methylbenzamide (0.0274 g, 0.2
mmol) and cyclohexane (1.5 mL) was added into a 10-mL screw tube containing the catalyst (4
mg, 7.5 mol%) and di-tert-butyl peroxide (0.147 mL, 0.8 mmol). The reaction mixture was
o
magnetically stirred at 110 C for 10 h. Organic components were extracted into ethyl acetate (2
mL). The product was purified on silica gel (230-400 mesh or 37-63 µm, ethyl acetate/hexane =
1:3 (v./v.), TLC silica gel 60 F254, Rf = 0.4): white solid, 65% yield (28.2 mg), mp = 126-127 °C,
literature mp = 126-128 oC.76 1H NMR (500 MHz, CDCl3) δ 7.32 (d, J = 7.6 Hz, 1H), 7.28 (td, J
= 7.6, 1.0 Hz, 1H), 7.21 – 7.17 (m, 2H), 5.65 (s, 1H), 3.97 (tdt, J = 12.2, 8.2, 3.9 Hz, 1H), 2.43
(s, 3H), 2.06 – 1.99 (m, 2H), 1.77 – 1.70 (m, 2H), 1.68 – 1.61 (m, 1H), 1.43 (tt, J = 15.5, 3.4 Hz,
13
2H), 1.25 – 1.17 (m, 3H). C NMR (125 MHz, CDCl3) δ 169.3, 137.0, 135.7, 130.9, 129.6,
27

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126.6, 125.7, 48.5, 33.2, 25.6, 24.9, 19.6. GC-MS: m/z 217 (38%, [M+]), 136 (70%), 119
(100%), 91 (51%). N-cyclohexyl-2-methylbenzamide was previously reported.69,18,76
4.3.7. N-cyclooctylbenzamide
Prepared as shown in the general experimental procedure. Benzamide (0.0242 g, 0.2 mmol) and
cyclooctane (1.5 mL) was added into a 10-mL screw tube containing the catalyst (4 mg, 7.5
mol%) and di-tert-butyl peroxide (0.147 mL, 0.8 mmol). The reaction mixture was magnetically
o
stirred at 110 C for 10 h. Organic components were extracted into ethyl acetate (2 mL). The
product was purified on silica gel (230-400 mesh or 37-63 µm, ethyl acetate/hexane = 1:3 (v./v.),
TLC silica gel 60 F254, Rf = 0.5): white solid, 62% yield (28.6 mg), mp = 102 -104 °C. 1H NMR
(500 MHz, CDCl3) δ 7.74 (d, J = 7.2 Hz, 2H), 7.48 (t, J = 7.3 Hz, 1H), 7.42 (t, J = 7.4 Hz, 2H),
6.07 (s, 1H), 4.21 (td, J = 8.1, 4.0 Hz, 1H), 1.95 – 1.92 (m, 2H), 1.71 – 1.55 (m, 12H). 13C NMR
(125 MHz, CDCl3) δ 166.3, 135.2, 131.2, 128.5, 126.8, 49.9, 32.4, 27.2, 25.5, 23.8. GC-MS: m/z
231 (19%, [M+]), 122 (57%), 105 (100%), 77 (33%). N-cyclooctylbenzamide was previously
reported.69
4.3.8. N-cycloheptylbenzamide
Prepared as shown in the general experimental procedure. Benzamide (0.0242 g, 0.2 mmol) and
cycloheptane (1.5 mL) was added into a 10-mL screw tube containing the catalyst (4 mg, 7.5
mol%) and di-tert-butyl peroxide (0.147 mL, 0.8 mmol). The reaction mixture was magnetically
o
stirred at 110 C for 10 h. Organic components were extracted into ethyl acetate (2 mL). The
28