Palladium-catalyzed ortho-halogenations of acetanilides with N-halosuccinimides via direct sp2 C–H bond activation in ball mills

Article abstract of DOI:10.3762/bjoc.14.31

A solvent-free palladium-catalyzed ortho-iodination of acetanilides using N-iodosuccinimide as the iodine source has been developed under ball-milling conditions. This present method avoids the use of hazardous organic solvents, high reaction temperature,

Full text of DOI:10.3762/bjoc.14.31

Palladium-catalyzed ortho-halogenations of acetanilides with
N-halosuccinimides via direct sp2 C–H bond activation
in ball mills
Zi Liu1, Hui Xu1 and Guan-Wu Wang*1,2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 430–435.
1Hefei National Laboratory for Physical Sciences at Microscale and
Department of Chemistry, University of Science and Technology of
China, Hefei, Anhui 230026, P. R. China and 2State Key Laboratory
of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu
730000, P. R. China
doi:10.3762/bjoc.14.31
Received: 20 November 2017
Accepted: 13 February 2018
Published: 16 February 2018
Email:
This article is part of the Thematic Series "Mechanochemistry".
Guest Editor: J. G. Hernández
Guan-Wu Wang* - gwang@ustc.edu.cn
* Corresponding author
© 2018 Liu et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
acetanilide; ball milling; C–H activation; halogenation;
mechanochemistry; N-halosuccinimide; palladium catalysis
Abstract
A solvent-free palladium-catalyzed ortho-iodination of acetanilides using N-iodosuccinimide as the iodine source has been de-
veloped under ball-milling conditions. This present method avoids the use of hazardous organic solvents, high reaction temperature,
and long reaction time and provides a highly efficient methodology to realize the regioselective functionalization of acetanilides in
yields up to 94% in a ball mill. Furthermore, the current methodology can be extended to the synthesis of ortho-brominated and
ortho-chlorinated products in good yields by using the corresponding N-halosuccinimides.
Introduction
Aryl halides have been widely utilized in organic syntheses, metal-catalyzed cross-coupling reactions, a series of halogena-
which give access to a range of complex natural products [1,2]. tions at the ortho-position of the directing groups have been
However, traditional halogenations of aromatic compounds by disclosed [5-18]. Nevertheless, from the viewpoint of green
direct electrophilic halogenation [3] and Sandmeyer reaction [4] chemistry, the reduction or even elimination of organic sol-
have several drawbacks such as low regioselectivities, compli- vents, shorter reaction times, simplification of work-up proce-
cated reaction procedures and even a risk of danger. Thus, it is dures and improvement of product yields are highly demanding.
necessary to discover new approaches to the regioselective con- In recent years, the application of mechanochemical techniques
struction of C–X bonds. With the development of transition- in organic syntheses has attracted increasing attention [19-28].
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Beilstein J. Org. Chem. 2018, 14, 430–435.
A few mechanochemical ortho-C–H bond activation reactions 3 h. Unfortunately, the desired iodinated product was not
under the catalysis of rhodium and palladium salts have been re- detected (Table 1, entry 1). Then, various acids were examined
ported [29-38]. Hernández and Bolm reported the rhodium-cata- because the addition of acids into the reaction system could
lyzed bromination and iodination of 2-phenylpyridine using promote the C–H bond halogenation according to the previous
N-bromosuccinimide (NBS) and N-iodosuccinimide (NIS), re- literature [46]. As desired, compound 2a was isolated in
spectively, as the halogen source [30]. However, the 87% yield when p-toluenesulfonic acid (PTSA) was employed
mechanochemical ortho-halogenation using the cheaper palla- (Table 1, entry 2). A control experiment was conducted for the
dium catalysts has not been reported yet. In continuing our reaction of 1a with NIS in the absence of Pd(OAc)2, yet still
interest in mechanochemistry [21,22,39-41] and C–H activa- with PTSA as the promoter, and no iodinated product was
tion reactions [42-44], we have independently investigated the furnished (Table 1, entry 3). The use of D-camphorsulfonic acid
solvent-free ortho-iodination of acetanilides under ball-milling (D-CSA) or mesitylenesulfonic acid dihydrate provided infe-
conditions [45]. In addition, the current reaction can be extend- rior results than that obtained in the presence of PTSA (Table 1,
ed to ortho-bromination and ortho-chlorination by using the entries 4 and 5 vs entry 2). Furthermore, no desired product was
corresponding N-halosuccinimides. Herein, we report these obtained when pyridine-2-sulfonic acid, 2-nitrobenzoic acid,
regioselective ortho-halogenations in detail.
2-aminoethanesulfonic acid or tungstophosphoric acid hydrate
(HPA) was used in the reaction (Table 1, entries 6–9). Thus, the
combination of Pd(OAc)2 with PTSA was essential for the reac-
Results and Discussion
To begin our study, N-(p-tolyl)acetamide (1a) was chosen as the tion to take place effectively. Subsequently, the ratio of sub-
model substrate to react with NIS using Pd(OAc)2 as the cata- strates was investigated, and the results demonstrated that the
lyst to optimize reaction parameters such as additive, reaction amount of both NIS and PTSA affected the product yield. De-
time and reagent ratio. The reaction of 1a (0.4 mmol) with NIS creasing or increasing the amount of PTSA was not beneficial
(0.4 mmol) was initially performed under the catalysis of to the reaction (Table 1, entries 10 and 11). When the amount of
Pd(OAc)2 (10 mol %) in a Spex SamplePrep 8000 mixer mill at NIS was increased from 1.0 equiv to 1.5 equiv and 2.0 equiv,
a frequency of 875 cycles per minute at room temperature for the yield of the iodinated product did not further go up (Table 1,
Table 1: Optimization of the reaction conditions.a
entry
ratio of reagentsb
additive
time (h)
yieldc (%)
1
2
1:0.1:1:0
1:0.1:1:2
1:0:1:2
–
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
2 h
4 h
N.R.
87
PTSA
3
PTSA
N.R.
62
4
1:0.1:1:2
1:0.1:1:2
1:0.1:1:2
1:0.1:1:2
1:0.1:1:2
1:0.1:1:2
1:0.1:1:1.5
1:0.1:1:2.5
1:0.1:1.5:2
1:0.1:2:2
1:0.1:1:2
1:0.1:1:2
D-CSA
5
mesitylenesulfonic acid dihydrate
56
6
pyridine-2-sulfonic acid
N.R.
N.R.
N.R.
N.R.
81
7
2-nitrobenzoic acid
8
2-aminoethanesulfonic acid
9
HPA
10
11
12
13
14
15
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
86
88
86
80
87
aUnless otherwise specified, all the reactions were carried out in a Spex SamplePrep 8000 mixer mill using 1a (0.4 mmol). bThe reagent ratio referred
to 1a:Pd(OAc)2:NIS:additive. cIsolated yield. N.R. = no reaction.
431

Beilstein J. Org. Chem. 2018, 14, 430–435.
entries 12 and 13). The iodination was slightly less efficient for acetanilides was tolerable, and products 2e–i were isolated in
a shorter time of 2 h (Table 1, entry 14), and prolongation of the 51–94% yields (Table 2, entries 5–9), highlighting the func-
reaction time from 3 h to 4 h did not lead to a superior result tional group compatibility of the current protocol. The presence
(Table 1, entry 15).
of an acetyl group at the para-position of the phenyl ring of
acetanilide 1j decreased the yield of the corresponding product
To demonstrate the generality of this protocol, the regioselec- 2j to 11% (Table 2, entry 10). Unfortunately, substrates bearing
tive iodination of a series of acetanilides was then examined in a strong electron-donating methoxy group and a strong electron-
the presence of Pd(OAc)2 and PTSA under the ball-milling withdrawing nitro group could not afford any desired products,
conditions (Table 2). Gratifyingly, the ortho-iodinated and the reason is not quite clear right now.
acetanilides were obtained in moderate to good isolated yields.
Both p-Me and m-Me-substituted acetanilides provided prod- In an aim to investigate the influence of the milling frequency,
ucts 2a and 2b in excellent yields of 87% and 80%, respective- the model reaction of 1a with NIS was conducted by employ-
ly (Table 2, entries 1 and 2). As expected, 3,4-dimethylac- ing different types of mixer mills with different milling frequen-
etanilide underwent iodination successfully at the less sterically cies. Ortho-iodized acetanilide 2a was furnished in 90% yield
hindered ortho-position and gave product 2c in 85% yield after milling for 2 h by using a Retsch MM 200 mixer mill
(Table 2, entry 3). The unsubstituted acetanilide provided the (30 Hz, Scheme 1a). At a milling frequency of 50 Hz in a Spex
desired product 2d in 77% yield (Table 2, entry 4). It is worth SamplePrep 5100 mixer mill, the iodination was accomplished
mentioning that the presence of a potentially reactive group, within 1.5 h to afford the corresponding product 2a in 92%
such as fluoro, chloro, and bromo substituents in the yield (Scheme 1b). According to the above experimental results,
Table 2: Substrate scope.a
entry
1
substrate 1
product 2b
yieldc (%)
87
1a
1b
1c
1d
2a
2b
2c
2d
2e
2
3
4
5
80
85
77
94
1e
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Beilstein J. Org. Chem. 2018, 14, 430–435.
Table 2: Substrate scope.a (continued)
6
71
74
51
70
1f
2f
2g
2h
2i
7
8
9
1g
1h
1i
10
11
1j
2j
aAll the reactions were carried out in a Spex SamplePrep 8000 mixer mill using 1 (0.4 mmol), NIS (0.4 mmol), Pd(OAc)2 (10 mol %) and
PTSA (0.8 mmol) for 3 h. bProperly characterized by 1H NMR, 13C NMR, and HRMS spectral data. cIsolated yield.
it could be concluded that the higher milling frequency had a for 3 h provided the desired product 2a in only 49% yield,
beneficial effect on the reaction efficiency in terms of product which was inferior to those obtained by our mechanochemical
yield and reaction time.
approaches (Scheme 2).
Scheme 2: Palladium-catalyzed ortho-iodination of 1a in toluene.
The plausible mechanism is proposed and depicted in
Scheme 3. The addition of PTSA was essential for the present
reaction. It is believed the more active Pd(OTs)2 is formed in
situ from Pd(OAc)2 and TsOH [46,47]. The formed Pd(OTs)2
inserts into the ortho C–H bond of the anilides after coordina-
tion to the oxygen atom of the amide moiety, affording the
species A. Oxidative addition of the species A with NIS gener-
ates the Pd(IV) complex B. Finally, the iodinated product is
provided by reductive elimination along with regeneration of
Pd(OTs)2 in the presence of TsOH.
Scheme 1: The influence of the milling frequency on the reaction of 1a
with NIS.
To illustrate the superiority of the ball-milling technique, the
reaction was also investigated in an organic solvent. The reac-
tion of 1a with NIS conducted in toluene at room temperature
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Beilstein J. Org. Chem. 2018, 14, 430–435.
Scheme 3: Plausible mechanism.
It was intriguing to find that N-bromosuccinimide (NBS) and simple operation and environmentally friendliness. In addition,
N-chlorosuccinimide (NCS) could also be used as reaction part- the present protocol can be extended to the synthesis of ortho-
ners to react with the representative acetanilide 1a under iden- brominated and chlorinated acetanilides delivering good yields
tical ball-milling conditions. The corresponding ortho-bromi- by using the corresponding N-halosuccinimides.
nated and ortho-chlorinated products 3a and 4a were obtained
in 73% and 77% yields, respectively (Scheme 4).
Supporting Information
Supporting Information File 1
Experimental, analytical data and NMR spectra of 2a–j, 3a
and 4a.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-31-S1.pdf]
Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (No. 21372211).
ORCID® iDs
Guan-Wu Wang - https://orcid.org/0000-0001-9287-532X
Scheme 4: Palladium-catalyzed ortho-bromination and chlorination of
1a in a ball mill.
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