TBHP-mediated highly efficient dehydrogenative cross-oxidative coupling of methylarenes with acetanilides

Article abstract of DOI:10.3762/bjoc.12.217

A TBHP-mediated dehydrogenative cross-oxidative-coupling approach has been developed for the synthesis of N-arylbenzamides from methylarenes and acetanilides. This cross-coupling method is free of transition metal catalysts and ligands, and no extra organic solvents are required, which make it an useful and attractive strategy for the straightforward construction of C-N bonds. Besides, this conversion is an important complement to the conventional C-N forming strategies.

Full text of DOI:10.3762/bjoc.12.217

TBHP-mediated highly efficient dehydrogenative
cross-oxidative coupling of methylarenes with acetanilides
Cui Chen*, Weibing Liu and Peng Zhou
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 2250–2255.
College of Chemical Engineering, Guangdong University of
Petrochemical Technology, 2 Guandu Road, Maoming 525000, P. R.
China. Fax: +86-668-2923575; Tel: +86-668-2923444
doi:10.3762/bjoc.12.217
Received: 20 August 2016
Accepted: 11 October 2016
Published: 25 October 2016
Email:
Cui Chen* - cc161002@gdupt.edu.cn.
Associate Editor: J. A. Murphy
* Corresponding author
© 2016 Chen et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
dehydrogenative cross oxidative coupling; methyl arenes;
N-arylbenzamides; TBHP
Abstract
A TBHP-mediated dehydrogenative cross-oxidative-coupling approach has been developed for the synthesis of N-arylbenzamides
from methylarenes and acetanilides. This cross-coupling method is free of transition metal catalysts and ligands, and no extra
organic solvents are required, which make it an useful and attractive strategy for the straightforward construction of C–N bonds.
Besides, this conversion is an important complement to the conventional C–N forming strategies.
Introduction
Recently, amides have attracted more and more attention due to dehydrogenative cross-oxidative-coupling reactions between
their extensive utilization in pharmaceutical and agrochemical methylarenes and amines for the formation of amides are
applications [1-3], as well as for precursors in organic synthesis rather limited, and which would be an important complement
for the construction of natural products, polymers and organic to the conventional C–N forming strategies. Herein, we disclose
materials [4-6]. The database of medicinal chemistry indicates a dehydrogenative C–N cross-oxidative-coupling reaction
that around 25% of synthetic drugs contain the amide moiety of methylarenes with acetanilides, using TBHP as an
[7]. What is more, the amide motif has also served as pivotal oxidant to afford N-arylamides in moderate to good yields
intermediate to generate several other organic functionalities (Scheme 1).
[8,9]. To date, a large number of amidation reactions have been
established [10,11], such as the condensation of carboxylic acid Results and Discussion
derivatives with amines [12], the rearrangement of ketoximes We began by studying the reaction of toluene (1a) and
[13], the C–N cross coupling between aromatic amides or acetanilide (2a) as model substrates to identify the optimal
amines and aryl(pseudo)halides [14,15] or aldehydes [16-20]. conditions (Table 1). In the presence of I2 (0.1 equiv) and tert-
However, to the best of our knowledge, the studies of butyl hydroperoxide (TBHP, 2.0 equiv), the study commenced
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Scheme 1: Synthesis of N-arylamides.
to optimize the reaction time (Table 1, entries 1–3). The results occur in the absence of molecular iodine (Table 1, entry 14),
show that the reaction was completed after 24 h and led to the which indicates that molecular iodine is requisite for this
desired N-phenylbenzamide 3aa in 62% GC yield (Table 1, conversion. We were pleased to find that an excellent product
entry 2). Disappointingly, other peroxides like di-tert-butylper- yield of 86% was obtained (Table 1, entry 15) when increasing
oxide (DTBP), benzoyl peroxide, dicumyl peroxide (DCP), the loading of TBHP to 3.0 equivalents. However, decreasing
methyl ethyl ketone peroxide (MEKP), tert-butylperoxy the loading of TBHP to 1.0 equivalent led to a drastic drop in
benzoate (TBPB) and cumene hydroperoxide (CHP) proved the yield (Table 1, entry 16). It is worth mentioning that this
wholly ineffective for this conversion and no product was ob- conversion did not show any beneficial effect with nitrogen
served (Table 1, entries 4–9). Next, the effect of other iodine protection.
sources on the reaction was monitored. Pleasingly, ICl and NIS
afforded the desired product 3aa successfully, but led to a After identifying the optimized conditions, we next explored the
marked decrease in yield (Table 1, entries 10 and 11). When the substrate scope of this transformation. As detailed in Table 2, a
loading of I2 was increased to 1.0 equivalent, a pronounced wide variety of acetanilides having substituent groups such as
improvement in the reaction yield was observed (Table 1, entry methyl, methoxy, ethoxyl, chloro and cyano at different posi-
12). Further increasing the loading of I2 did not show any bene- tions were employed to react under the standard conditions. We
ficial effect (Table 1, entry 13). However, the reaction does not were pleased to find that all these tested substrates were suc-
Table 1: Optimization studiesa.
Entry
Catalyst (0.1 equiv)
Oxidant (2.0 equiv)
Time (h)
Yield (%)b
1
2
I2
I2
TBHP
TBHP
12
24
36
24
24
24
24
24
24
24
24
24
24
24
24
24
47
62
62
0
3
I2
TBHP
4
I2
DTBP
5
I2
benzoyl peroxide
DCP
0
6
I2
0
7
I2
MEKP
TBPB
0
8
I2
0
9
I2
CHP
0
10
11
12c
13d
14
15c,e
16c,f
ICl
NIS
I2
TBHP
31
39
71
71
–
TBHP
TBHP
I2
TBHP
–
TBHP
I2
TBHP
86
37
I2
TBHP
aUnless otherwise specified, all the reactions were carried out on 2a 0.25 mmol scale, catalyst 0.1 equivalents, oxidant 2.0 equivalents, toluene
2.0 mL; bGC yield; ciodine 1.0 equivalents; diodine 1.5 equivalents; eTBHP 3.0 equivalents; fTBHP 1.0 equivalent.
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cessfully converted into the desired N-arylbenzamides 3. a drastic drop in yield as compared to para-cyano- and para-
Notably, this conversion appears quite sensitive with respect to chloro-substituted acetanilides (Table 2, entries 5–8). As well as
the nature (electron-donating or electron-withdrawing) and po- ortho-methyl- and ortho-chloro-substituted substrates also led
sitions of the substituent groups under the stipulated conditions. to a marked decrease in yield as compared to their correspond-
para-Methoxy- and para-ethoxy-substituted acetanilides led to ing para-substituted substrates (Table 2, entries 2, 3, 5, and 9).
Table 2: Scope of the N-arylamidesa.
Entry
1
2
3
Yield(%)b
80
2
3
4
75
72
81
5
6
7
83
63
62
8
9
85
71
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Beilstein J. Org. Chem. 2016, 12, 2250–2255.
Table 2: Scope of the N-arylamidesa. (continued)
10
59
66
65
57
69
11
12
13
14
15
51
aUnless otherwise specified, all the reactions were carried out on 2 1.0 mmol scale, 1 2.0 mL; bisolated yield.
To further extend the adaptability of this transformation, other ed that the mechanism may involve a radical pathway. To our
methyl arenes were also checked under the standard conditions. delight, reactions using benzaldehyde and 1-(iodomethyl)benz-
Pleasingly, m-xylene and p-xylene afforded the desired product ene as the surrogates of toluene afforded 3aa in excellent yields.
3 successfully, but in lower yields (Table 2, entries 10 and 11). These results evidence that either 1-(iodomethyl)benzene or
In the same manner, we next investigated the reactions of benzaldehyde may be the reaction intermediates derived in situ
p-xylene with N-phenylacetamide, N-p-tolylacetamide, N-(4- from toluene.
methoxyphenyl)acetamide, N-(2-chlorophenyl)acetamide and
The mechanism for this conversion is unclear. Based on litera-
ture reports and our present experimental results, a plausible
reaction mechanism has been proposed in Scheme 3 and exem-
plified by the formation of 3aa. Initially, toluene (1a) reacted
with molecular iodine and TBHP to produce the 1-(iodo-
methyl)benzene (4) and benzaldehyde (5) [21,22]. Intermediate
6 was generated from the coupling of 2a with intermediate 4
[22], by eliminating a molecule of HI. According to the results
N-(3-chlorophenyl)acetamide under the standard conditions.
Gratifyingly, all the tested acetamides reacted with p-xylene
successfully, offering the desired N-arylbenzamides in moder-
ate yields, from 51% to 69% (Table 2, entries 12–14). It is note-
worthy that the reactions did not result in the desired product
when using aniline and diethylamine as the partners of
acetanilide.
In order to gain insight into the nature of this conversion, two of the control experiments, intermediate 6 also could be ob-
experiments were conducted (Scheme 2). With the addition of tained from the reaction of benzaldehyde with 2a under the
Na2CO3 (sodium carbonate) into the reaction between 1a and standard conditions. Then, intermediate 6 underwent a se-
2a, the yield of 3aa decreased dramatically to 37%, which con- quence of steps including fast oxidation and dehydration to give
firmed that Na2CO3 has an inhibitory effect for this transfor- N-acetyl-N-phenylbenzamide (8) under the stipulated condi-
mation. At the same time, the radical scavenger TEMPO tions, similar to the report of An [23]. Finally, the acidic hydro-
(2,2,6,6-tetramethylpiperidinoxyl) completely inhibited the lysis of N-acetyl-N-phenylbenzamide (8) furnished the final
reaction and almost no product was obtained. The result indicat- product N-phenylbenzamide (3aa).
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Beilstein J. Org. Chem. 2016, 12, 2250–2255.
Scheme 2: Control experiments.
Supporting Information
Supporting Information File 1
Full experimental details and copies of NMR spectral data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-12-217-S1.pdf]
Acknowledgements
We thank the Guangdong Provincial Department of Science and
Technology (No.916014) and the Department of Education of
Guangdong Province (No.916021) for financial support.
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In conclusion, a dehydrogenative C–N cross oxidative coupling
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