Exploration of Cu-catalyzed regioselective hydrodehalogenation of o-haloanilides using EtOH as hydrogen source

Article abstract of DOI:10.1016/j.jorganchem.2021.121844

In present work, we have explored a Cu(acac)₂/vasicine-catalyzed regioselective hydrodehalogenation methodology of o-haloanilides using EtOH as hydrogen source and solvent. The catalytic system could selectively dehalogenate 2-Br and 2-I, and features regioselective, efficient and functional group tolerance.

Full text of DOI:10.1016/j.jorganchem.2021.121844

Journal of Organometallic Chemistry 943 (2021) 121844
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Communication
Exploration of Cu-catalyzed regioselective hydrodehalogenation of
o-haloanilides using EtOH as hydrogen source
Min-Xin Li1, Mei-Ling Li1, Yan-Ling Tang, Yun Sun∗, Lu Qu, Feng Huang, Ze-Wei Mao∗
School of Chinese Materia Medica, Yunnan University of Chinese Medicine, Kunming650500, China
a r t i c l e i n f o
a b s t r a c t
Article history:
In present work, we have explored a Cu(acac)2/vasicine-catalyzed regioselective hydrodehalogenation
methodology of o-haloanilides using EtOH as hydrogen source and solvent. The catalytic system could
selectively dehalogenate 2-Br and 2-I, and features regioselective, efficient and functional group tolerance.
Received 11 February 2021
Revised 8 April 2021
Accepted 14 April 2021
Available online 18 April 2021
© 2021 Elsevier B.V. All rights reserved.
Keywords:
Cucatalyzed
Regioselective
Hydrodehalogenation
o-Haloanilides
Organic halides, an important class of compounds, are widely
used as solvents and intermediates inorganic chemistryas well as
industrial applications [1]. However, organichalides are classified as
environmental pollutants because they are difficult to be degraded,
especially aromatic halides. The researchers have found that the
conversion of C-X (X=halogen atom) bond to C-H bond could
greatly improve the degradability. Therefore, the dehalogenation of
aromatic halides has great potential for environmental pollution
control [2]. In recent years, transition metal-catalyzed the hydrode-
halogenation of aryl halides represents an efficient approach to
transform C-X bonds into C-H bonds [3]. For example, Bhattachar-
jya et al have reported aligand-free Pd-catalyzed hydrodehalogena-
tion of aryl halides in the presence oftetramethyldisiloxane [4]. Xia
et al have developed a simple Ru-catalyzed hydrodehalogenationof
organic halides in 2-propanol [5]. Parveen et al have explored re-
gioselective CuI-catalyzed hydrodehalogenationof aromatic α- and
β-halo carbonylcompounds [6].
used [8]. For instance, Zhang et al have improved Pd(OAc)2/Ph3P-
catalyzed dehalogenation of 2-bromoacetanilides with alcohols as
hydrogen donors (Scheme 1,a) [8a]. Wu et al have reported an
efficient hydrodehalogenation of N-(2-bromophenyl)pivalamide us-
ing Pd(OAc)2-XantPhos catalyst (Scheme 1,b) [8b]. Li et al have
found that o-iodobenzanilide could be converted to benzanilide us-
ing Pd/C as the catalyst withoutthe addition of a ligand under hy-
drogen (Scheme 1,c) [8c]. In former wok, we have developed a
practical hydrodehalogenation methodology of o-haloanilides us-
ing PdCl2/dppap in water, which could selectively dehalogenate Cl
and Br but not I atom (Scheme 1,d) [8d]. Although many strate-
gies have been achieved for the dehalogenation of o-haloanilides
by Pd-catalyzed processes, there are obvious limitations: (1) high-
cost and toxic solvents, (2) poor selectivity to Cl, Br and I, (3) lim-
ited scope of substrates.Therefore, there is still worthwhile to ex-
plore an efficient, low cost and regioselective catalyticstrategy for
hydrodehalogenation of o-haloanilides.
o-Haloanilides are important organic intermediates in synthe-
sis, and functionalization of C-X bond can form 2-amination, ben-
zoxazoles and benzimidazoles by C-O, C–C and C-N cross cou-
pling reactions [7]. Recently, transition metal-catalyzed hydrode-
halogenation of o-haloanilides has attracted more attention, which
could contribute to deeper recognition of C-X activation. Among
the related studies, palladium is the most widely transition metal
used in catalytic hydrodehalogenation, and very few other metal is
Copper as a cheap metal is widely used in transition metal-
catalyzed coupling reactions, such as Sonogashira, Ullmann and
Chan-Lam coupling [9]. According to the literature, we find that
o-haloanilides can be convert to benzoxazoles and benzimida-
zoles by Cu(II)-catalyzed formation of C-O and C–N bond, respec-
tively [7,10]. This shows that Cu(II) salts can activate the C-X bon-
dof o-haloanilides, and hydrodehalogenation of o-haloanilides is
likely to be achieved using Cucatalyst.To the best of our knowl-
edge, there is no report on Cu(II)-catalyzed hydrodehalogenation
of o-haloanilides in green solvent so far. Vasicine, a bioactive al-
kaloid isolated from the medicinal plant [11], has been used as
catalyst in methodology in recent years [12]In present work, we
have explored an efficient and regioselective Cu(acac)2/vasicine-
∗
Corresponding authors.
E-mail addresses: 41546147@qq.com (Y. Sun), maozw@ynutcm.edu.cn (Z.-W.
Mao).
1
These authors contributed equally to this work.
https://doi.org/10.1016/j.jorganchem.2021.121844
0022-328X/© 2021 Elsevier B.V. All rights reserved.

M.-X. Li, M.-L. Li, Y.-L. Tang et al.
Journal of Organometallic Chemistry 943 (2021) 121844
Table 1
Optimization of hydrodehalogenation of 1aa.a,b
Yield (%)
2a
Entry
[Cu]
L
Base
3a
1
2
3
4
5
CuBr2
L1
L2
L3
L4
L5
Et2NH
Et2NH
Et2NH
Et2NH
Et2NH
-
-
-
-
-
32
48
trace
35
44
6
Cu(OAc)2 L1
Et2NH
Et2NH
Et2NH
Et2NH
Et2NH
-
-
-
-
-
43
62
38
26
52
7
L2
L3
L4
L5
8
9
10
11
12
13
14
15
CuSO4
L1
L2
L3
L4
L5
Et2NH
Et2NH
Et2NH
Et2NH
Et2NH
-
-
-
-
-
12
34
trace
31
26
Scheme 1. Hydrodehalogenation of o-haloanilides.
16
17
18
19
20
Cu(OTf)2 L1
Et2NH
Et2NH
Et2NH
Et2NH
Et2NH
trace
70
78
34
81
60
L2
L3
L4
L5
-
-
-
15
21
22
23
24
25
Cu(acac)2 L1
Et2NH
Et2NH
Et2NH
Et2NH
Et2NH
-
49
L2
L3
L4
L5
-
57
-
20
trace
86
67
trace
26
27
28
29
Cu(acac)2 L5
K3PO4
K2CO3
Et3N
-
trace
70
-
trace
22
68
DIPA
42
a
All the reactions were carried out using 1aa (1.0 mmol), 1aa/Cu/ L(1.0:0.05:0.1),
base (2.0 mmol), EtOH (5 mL) in a sealed tube at 100 °C for 12 h.
b
Isolated yields.
(Table 1, Entry 1-15). To our delight, hydrodehalogenationof 1aa
could beproceeded under Cu(OTf)2-L5 catalytic system, and 2a
was prepared in 15% yield (Table 1, Entry 20). Furthermore, when
Cu(acac)2 was used, the yield of 2a was obviously raised to 86% us-
ing vasicine as ligand (Table 1, Entry 25). The results revealed that
Cu/vasicine-catalyzed hydrodehalogenation of o-haloanilides could
be taken place in EtOH. In order to investigate the effect of dif-
ferent bases on hydrodehalogenation of 1aa, another four other
bases were tested to check and identify this reaction conditions.
These bases did not contribute to hydrodehalogenation and the re-
sults were obviously unsatisfactory. Among them, only diisopropy-
lamine (DIPA) could lead to 2a in low yield (22%). Thus, it was
clear that Cu(acac)2-vasicine catalyst was beneficial to regioselec-
tive hydrodehalogenation of o-haloanilides.
Scheme 2. Contrast experiments of hydrodehalogenation.
catalyzed hydrodehalogenation of o-haloanilides using EtOH as hy-
drogen source.
Initially, N-(2-bromophenyl)benzamide (1aa) was chosen as
a
model substrate to identify the optimal hydrodehalogena-
tion conditions including Cu sources, ligands and bases, the re-
sults were summarized in Table 1. Firstly, 1aa transformation
was carried out using different Cu sources (CuBr2, Cu(OAc)2,
CuSO4, Cu(OTf)2, Cu(acac)2), ligands (L1-L5) in presence of Et2NH
in EtOH (Table 1, Entry 1-25). The results showed that N-(2-
bromophenyl)benzamides easily yielded to benzoxazoles through
Cu-catalyzed intramolecular O-arylation. When CuBr2, Cu(OAc)2
or CuSO4 was introduced, only benzoxazole 3a was formed and
no title product 2a was obtained in presence of five ligands
Following to probe the influence of the amount of Cu(acac)2-
vasicine catalyst, we paid attention to catalytic amount and sol-
vents based on o-bromobenzamide (1aa). As shown in Table 2,
2

M.-X. Li, M.-L. Li, Y.-L. Tang et al.
Journal of Organometallic Chemistry 943 (2021) 121844
Table 2
Optimization of the reaction conditions.a,b
Yield (%)
Entry
Cu(acac)2
L5
Solvent
2a
3a
1
2
3
4
5
6
7
8
2 mol%
5 mol%
10 mol%
20 mol%
5 mol%
5 mol%
5 mol%
5 mol%
4 mol%
EtOH
EtOH
EtOH
EtOH
i-PrOH
CH3CN
THF
65
86
87
82
46
-
trace
trace
trace
trace
32
10 mol%
20 mol%
40 mol%
10 mol%
10 mol%
10 mol%
10 mol%
-
70c
-
H2O
-
58
a
The reactions were carried out using 1aa (1.0 mmol, Et2NH (2.0 mmol), solvent (5 mL) in sealed
tube at 100 °C for 12 h.
b
Isolated yields. cThe reaction was performed at 90 °C.
when 2 mol% Cu(acac)2 and 4 mol% L5 was used, the yield of 2a
was moderate (Table 2, Entry 1). To our surprise, increasing the
amount of Cu(acac)2 and L5 had positive effect on the reaction, and
the yield of 2a was improved to 87% (Table 2, Entry 3).However,
further increasing the amount of Cu catalyst from 10 mol% to 20
mol% was not beneficial to improve the yield of 2a under this con-
dition (Table 1, Entry 4). In addition, other solvents were checked
also. The results indicated that when the reaction was carried out
in i-PrOH,CH3CN,THF or H2O, 2a was obtained in 46% yield only in
i-PrOH. Moreover, 1aa did not give any product in CH3CN, and only
3a could be observed using THF (70% yield) or H2O (58% yield) as
solvent(Table 2, Entry 5-8). Therefore, the best hydrodehalogena-
tion of o-haloanilides was performed taking 5 mol% Cu(acac)2 and
10 mol% vasicine as the catalysts in presence of 2 eq. Et2NH in
EtOHfor 12 h at 100 °C.
With the optimal reaction conditions confirmed, a series of o-
haloanilides were investigated to check the scope and limits of
Cu-catalyzed hydrodehalogenation. First of all, 2-chloro-, 2-bromo-
and 2-iodoanilides (1a-1c) were tested to study the activity of cat-
alysts. It was gratifying that the hydrodehalogenation worked se-
lectively for Br, and I employingCu(acac)2/vasicine catalytic sys-
tem was sensitive to Br and I atoms selectively. For example, 2-
Br and 2-I could be hydrogenated in good yields (74-88%), but
2-chloroanilides were difficult to be hydrodehalogenated (Table 3,
2a-2c). Based on this, various substituted 2-bromoanilides and 2-
iodoanilides including electron donating groups (CH3, CH3O, X, etc)
and electron withdrawing groups (NO2, CF3) were performed un-
der standard reaction condition. On the whole, 2-iodoanilides gave
the corresponding products in higher yields than 2-bromoanilides,
and there was no obvious distinctions between EDG and EWG on
the acyl. For example, 2a, 2d, 2k, 2l, 2o, 2p and 2q were obtained
from corresponding o-haloanilides in good yields (80-90%). How-
ever, when EDG or EWG on the aniline units, the results were ob-
vious different, and EWG gave title products in higher yields than
EDG. For instance, 2r was formed in 63-68% yields, and 2s-2v were
formed in 88-93% yields, respectively (Table 3, Entry 18-23). In ad-
dition, only 2-Br and 2-I atoms can be hydrogenated, and others
could not be hydrogenated, which exhibits good regioselectivity.
On the other hand, the substituent position on aryl ring had ob-
vious influence on applicability. Especially, ortho substituted ben-
zoyl afforded lower yields than that of para or metaposition, such
as 2g and 2n. From above results, our improved protocol for Cu-
catalyzed hydrodehalogenation of o-haloanilides is significantly ef-
ficient and regioselective.
Scheme 3. Control reaction of mechanistic studies.
Besides, we have studied the applicability of reaction condi-
tions and substrates. 1ab was performed by copper iodide cat-
alytic conditions reported previously by Ahmed [6], but only trace
2a was obtained. In addition, substrates without bearing a neigh-
boring amide moiety were tested to verify substrate scope. How-
ever, 4a, 4b and 4c were not converted to hydrodehalogenation
product. Based on this, the present Cu(acac)2-vasicine catalyst was
regioselective and chemoselective for hydrodehalogenation of o-
haloanilides.
According to reported works, dehalogenation of aromatic
halides could be achieved using alcohol as hydrogen source in
most cases [8a-8c]. So we performed relative experiments to ex-
plore thepossible mechanism, and some control reactions were
carried out as shown in Scheme 3. Firstly, when no base was
added, only benzoxazole (3a, 25% yield)was formed (Scheme 3,a).
Then Et3N was used, the yield of 3a was up to 68% and a small
amount of title product 2a was observed (Scheme 3,b). How-
ever, when DIPA or Et2NH was used, the yield of 2a was up
to 86% (Scheme 3,c,d). This results of control reactions indicated
that secondary amines play vital role in hydrodehalogenation as
base, especial Et2NH as the best base, and EtOH participated
in Cu/vasicine-catalyzed hydrodehalogenation of o-haloanilides as
hydrogen source.Therefore, the possible mechanism of hydrode-
halogenation of o-haloanilides is shown in Scheme 4. Firstly, o-
3

M.-X. Li, M.-L. Li, Y.-L. Tang et al.
Journal of Organometallic Chemistry 943 (2021) 121844
Table 3
Scope of hydrodehalogenation of o-haloanilides.a,b
Table 3
(continued)
Entry
1
2
Yield
12
13
X=Br, 83%
X=I, 84%
1
X=Cl, 10%
X=Br, 86%
X=I, 88%
X=Br, 75%
X=I, 80%
2
3
X=Cl, 8%
X=Br, 78%
X=I, 82%
14
15
X=Br, 69%
X=I, 73%
X=Br, 86%
X=I, 90%
X=Cl,
trace
X=Br, 74%
X=I, 81%
16
17
X=Br, 82%
X=I, 86%
4
5
X=Br, 82%
X=I, 85%
X=Br, 81%
X=I, 85%
X=Br, 78%
X=I, 85%
18
19
20
21
22
X=Br, 63%
X=I, 68%
6
7
X=Br, 74%
X=I, 76%
X=Br, 91%
X=I, 93%
X=Br, 68%
X=I, 70%
X=Br, 88%
X=I, 89%
8
9
X=Br, 73%
X=I,76%
X=Br, 85%
X=I, 86%
X=Br, 75%
X=I, 77%
X=Br, 92%
X=Br, 87%
10
11
X=Br, 77%
X=I, 83%
23
a
Reaction were carried out using 1 (1.0 mmol), Cu(acac)2 (0.05 mmol), vasicine
(0.1 mmol), Et2NH (2.0 mmol), water (5 mL) in sealed tube at 100 °C for 12 h.
b
Isolated yield.
X=Br, 80%
X=I, 82%
(continued on next column)
4

M.-X. Li, M.-L. Li, Y.-L. Tang et al.
Journal of Organometallic Chemistry 943 (2021) 121844
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.jorganchem.2021.
121844.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/
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5