Copper-catalyzed amidation of benzoic acids using tetraalkylthiuram disulfides as amine sources

Article abstract of DOI:10.1080/00397911.2017.1330960

A facile method for the copper-catalyzed synthesis of N-substituted benzamides was explored. In the presence of CuBr and di-tert-butyl peroxide, various N-substituted benzamides were prepared through amidation of benzoic acid by using commercially available and cheap tetraalkylthiuram disulfides as amine sources. With this protocol, a series of 14 N-substituted benzamides were furnished in good to excellent yields. The broad substrate scope and good to excellent yield show its practical synthetic value in organic synthesis.

Full text of DOI:10.1080/00397911.2017.1330960

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Copper-catalyzed amidation of benzoic acids using
tetraalkylthiuram disulfides as amine sources
Meng-Tian Zeng, Wan Xu, Min Liu, Xing Liu, Cai-Zhu Chang, Hui Zhu & Zhi-
Bing Dong
To cite this article: Meng-Tian Zeng, Wan Xu, Min Liu, Xing Liu, Cai-Zhu Chang, Hui Zhu & Zhi-
Bing Dong (2017): Copper-catalyzed amidation of benzoic acids using tetraalkylthiuram disulfides
as amine sources, Synthetic Communications, DOI: 10.1080/00397911.2017.1330960
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1330960
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SYNTHETIC COMMUNICATIONS®
https://doi.org/10.1080/00397911.2017.1330960
Copper-catalyzed amidation of benzoic acids using
tetraalkylthiuram disulfides as amine sources
Meng-Tian Zeng, Wan Xu, Min Liu, Xing Liu, Cai-Zhu Chang, Hui Zhu, and
Zhi-Bing Dong
School of Chemistry and Environmental Engineering, Wuhan Institute of Technology, Wuhan, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 22 April 2017
A facile method for the copper-catalyzed synthesis of N-substituted
benzamides was explored. In the presence of CuBr and di-tert-butyl
peroxide, various N-substituted benzamides were prepared through
amidation of benzoic acid by using commercially available and cheap
tetraalkylthiuram disulfides as amine sources. With this protocol, a
series of 14 N-substituted benzamides were furnished in good to
excellent yields. The broad substrate scope and good to excellent
yield show its practical synthetic value in organic synthesis.
KEYWORDS
Amidation; benzamide;
copper bromide; di-tert-
butyl peroxide;
tetraalkylthiuram disulfide
GRAPHICAL ABSTRACT
Introduction
As popular structural units, amides are widely existed in biological active molecules,
polymers and pharmaceuticals.[1] N-substituted benzamides are important core structural
units in some therapeutic agents, for example, 2,6-dialkoxybenzamide derivatives (a) with
potent dopamine-receptor-blocking activities as potential neuroleptic agents,[2] biaryl
carboxylamides (b) as retinoid-related orphan receptor gamma inverse agonists,[3] 4-(4-
(2-hydroxybenzoyl)aminophenyl)butyric acid (c) was found to be efficacious to promote
peroral delivery[4] of variety of therapeutic proteins such as salmon calcitonin, insulin,
and recombinant human growth hormone (Fig. 1).
In the last two decades, several methods were reported for the preparation of benzamides.
For example, the direct carbamoylation of aryl halides catalyzed by Pd catalyst,[5] Ru[6] or
Cu[7] catalyzed oxidative coupling reaction of carboxylic acid with N-substituted formamides,
aerobic oxidative transformation of primary alcohols, and amines to amides promoted by
Au[8] catalyst in water- or metal-free condition,[9] oxidative synthesis from methylarenes
using Zn[10] or Fe[11] and so on. However, some reported routes are limited by toxicity
CONTACT Zhi-Bing Dong
dzb04982@wit.edu.cn
School of Chemistry and Environmental Engineering, Wuhan
Institute of Technology, Wuhan 430205, P. R. China.
Color versions of one or more of the figures in this article can be found online at www.tandfonline.com/lsyc.
Supplemental data (full experimental detail, 1H NMR and 13C NMR spectra) for this article can be accessed on the
publisher’s website.
© 2017 Taylor & Francis

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M.-T. ZENG ET AL.
Figure 1. Examples of N-substituted benzamide groupings present in therapeutic agents.
issues,[12] expensive metal,[13] and stoichiometric amount of activating reagent.[14] As far as
we know, the synthesis of benzamide using market available tetraalkylthiuram disulfides
which could be served as cheap amine sources has not been reported. Although dimethylfor-
mamide (DMF) were served as starting material reacting with tetramethylthiuram disulfide
(TMTD) to furnish N-substituted benzamide,[7] the reported methods suffered from big
excess of DMF (4–10 equiv.), ligand loading, argon protection, and normal isolation yield.
Hereby, we present practical protocol to prepare a series of N-substituted benzamides
through amidation of benzoic acids using tetraalkylthiuram disulfides as amine sources,
which could be an alternative way for the construction of this important block.
Results and discussion
For initial studies, we selected benzoic acid (1a) and TMTD (2a) as substrate for model
reaction under various conditions (Table 1). For the first trial, N,N-dimethylbenzamide could
not be detected with no adding of oxidant and catalyst (Table 1, entries 1–3), while target
compound was obtained with good yield (80%) when both oxidant and catalyst was added
(entry 4). Subsequently, a broad screening of copper, palladium, and nickel catalysts was per-
formed (entries 14–19). It revealed that palladium and nickel salts were not (or less) effective,
but copper catalysts could catalyze the model reaction well to give N,N-dimethylbenzamide
with reasonable yields (entries 4–13) and CuBr was the best one (entry 11). Oxidants which
might promote the reaction were screened, for example, H2O2, KMnO4, FeCl3, PhI(OAc)2,
and di-tert-butyl peroxide (DTBP) (entries 20–23, 11). The results showed that DTBP was
the best oxidant for the model reaction. Solvent (entries 24–28, 11) and temperature (entries
29–30, 11) were further probed, and it showed that ethyl acetate (EtOAc) was the best solvent
and 120 °C was the most suitable temperature (entry 11). In addition, examination of CuBr
loading showed that increasing the CuBr (15% mmol) led to almost no yield change, but
decreasing the CuBr (5% mmol) led to significant yield decrease (31–32). The check for
the loading of DTBP showed that 2 equiv is reasonable (entries 11, 33–35).
Under the optimized reaction conditions, various functionalized benzoic acid
derivatives (1a–1i) and tetraalkylthiuram disulfides (2a–2c) reacted smoothly, providing
the corresponding N-substituted benzamides smoothly (shown in Table 2). The substrate
expansion experiment exhibited that benzoic acid with the electron-withdrawing (1b–1d)
or electron-donating groups (1e) could react with TMTD (2a) well, giving 75–92% isolated
yields (entries 2–5). The benzoic acid bearing multiple functional groups (1f) is also
suitable to furnish the desired product with excellent 89% yield (entry 6). 2-Naphthoic acid
(1g) or 2-biphenylcarboxylic acid (1h) reacted with TMTD produced the target products

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Table 1. Optimization of the reaction conditionsa.
Entry
Catalyst (mmol%)
Oxidant (equiv.)
Solvent
Temp. (°C)
Yieldb (%)
1
—
—
—
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
DMF
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
130
110
120
120
120
120
0
0
2
DTBP
3
CuI
—
0
4
CuI
DTBP (4.0)
DTBP (4.0)
DTBP (4.0)
DTBP (4.0)
DTBP (4.0)
DTBP (4.0)
DTBP (4.0)
DTBP (4.0)
DTBP (4.0)
DTBP (4.0)
DTBP (4.0)
DTBP (4.0)
DTBP (4.0)
DTBP (4.0)
DTBP (4.0)
DTBP (4.0)
H2O2 (4.0)
KMnO4 (4.0)
FeCl3 (4.0)
PhI(OAc)2 (4.0)
DTBP (4.0)
DTBP (4.0)
DTBP (4.0)
DTBP (4.0)
DTBP (4.0)
DTBP (4.0)
DTBP (4.0)
DTBP (4.0)
DTBP (4.0)
DTBP (3.0)
DTBP (2.0)
DTBP (1.0)
80
5
CuCl2
CuBr2
CuO
68
6
75
7
54
8
Cu(OAc)2
CuSO4
Cu(OTf)2
CuBr
56
9
53
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31c
32d
33
34
35
69
83
CuCl
79
Cu2O
Pd(OAc)2
PdCl2
PdBr2
Pd(PPh)4
NiCl2
NiBr2
CuBr
52
20
Trace
Tarce
Trace
Trace
Trace
0
CuBr
Trace
0
CuBr
CuBr
15
CuBr
30
CuBr
DMSO
DMAC
PhCH3
PhNO3
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
41
CuBr
36
CuBr
47
CuBr
39
CuBr
79
CuBr
58
CuBr
81
CuBr
49
CuBr
82
CuBr
81
CuBr
EtOAc
120
59
DTBP, di-tert-butyl peroxide; EtOAc, ethyl acetate; DMSA, dimethylacetamide; DMSO, dimethyl sulfoxide; DMF, dimethylformamide.
Bold values represent the best reaction conditions obtained.
aReaction conditions: 1a (1.1 mmol), 2a (1.0 mmol), [Cat.] (10 mmol%), solvent (2.0 mL) for 10–12 h.
bIsolated yield.
cCuBr loading: 15 mmol%.
dCuBr loading: 5 mmol%.
with 74 and 79% yield, respectively (entries 7, 8). We also studied the scope of tetraalk-
ylthiuram disulfides. By treating substituted benzoic acid with tetraethylthiuram disulfide
(2b) or tetrabutylthiuram disulfide (2c) under the standard conditions (entries 9–14), the
desired amidation products (3i–3n) could be successfully afforded in good or excellent
yield (80–95%). In general, this reaction was not affected by the electronic property on
the aromatic ring and the steric hindrance from N-substituted amine group, showing its
good substrate suitability.
The reaction mechanism is not clear at this stage, we speculate that the reaction proceed
through copper-catalyzed oxidative decarboxylation (de-carbonylsulfide, –COS) manner,[6]
the further details and the related applications for this protocol are under research in our lab.

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M.-T. ZENG ET AL.
Table 2. Synthesis of N-substituted benzamides from benzoic acids and tetraalkylthiuram disulfidesa.
Entry
1
Benzoic acid 1
Sulfur compound 2
Product 3
Yieldb (%)
81
2
3
4
75
91
78
5
92
6
7
89
74
8
9
79
95
(Continued)

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Table 2. Continued.
Entry
Benzoic acid 1
Sulfur compound 2
Product 3
Yieldb (%)
10
93
87
80
11
12
13
14
81
87
DTBP, di-tert-butyl peroxide; EtOAc, ethyl acetate.
aReaction conditions: 1 (1 mmol); 2 (1.1 mmol); CuBr (10% mmol); DTBP (2.0 equiv.) and EtOAc (2 mL) at 120 °C for 10–12 h.
bIsolated yield.
Conclusion
In summary, we described a facile and useful protocol for the formation of N-substituted
benzamides. In the presence of CuBr and DTBP, various benzoic acids reacted with
tetraalkylthiuram disulfides to give N-substituted benzamides with good to excellent yields.
The broad substrate scope, cheap amine sources (tetraalkylthiuram disulfides), and good to
excellent yield show its practical synthetic value in organic synthesis, and might afford an
alternative way for the construction of this important block in some potential biologically
or pharmaceutically active compounds.
Experimental
Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker AC 400 MHz
spectrometer (1H NMR at 400 Hz, 13C NMR at 100 Hz) in CDCl3 using tetramethylsilane
as an internal standard. Chemical shifts are given in ppm and coupling constants (J) are

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M.-T. ZENG ET AL.
given in Hz. Electrospray ionization–high-resolution mass spectra (ESI–HRMS) were
determined on an Ion Spec (7.0 T) spectrometer.
All reactions were performed under dried glassware with septums. All starting materials
were purchased from commercial suppliers and used without further purification
unless otherwise stated. Yield refers to isolated compounds estimated to be > 95% pure
1
as determined by H NMR and capillary GC analysis.
Typical procedure for the preparation of N-substituted benzamides in the
presence of CuBr and DTBP (TP)
Benzoic acid (1.0 mmol), TMTD (1.1 mmol), CuBr (10% mmol), DTBP (2.0 equiv.) were
added in dried seal tube equipped with a septum and magnetic stirrer bar, EtOAc
(2 mL) was then added. The mixture was stirred at 120 °C and checked by thin-layer
chromatography (TLC) until the starting material was finished (about 10–12 h). The
reaction was cooled down to room temperature, quenched with sat. NH4Cl solution
(5 mL), and then extracted with EtOAc (10 mL). The crude solution was dried over
anhydrous Na2SO4 and evaporated under vacuum. The residue was purified by flash
column chromatography to afford the desired product.
N,N-dimethylbenzamide (3a)
According to TP, the residue was purified by flash chromatography on silica gel (EtOAc/
petroleum ether ¼ 1:1.5) to give the target compound 3a (121 mg, 81%) as brown yellow
1
oil. H NMR (400 MHz, CDCl3) δ: 7.31 (s, 6H), 3.02 (s, 3H), 2.87 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ: 171.58, 136.27, 129.47, 128.30, 126.97, 39.50, 39.25. HRMS (ESI)
calcd for C9H11NO (149.0841), found: 149.0837.[6]
Acknowledgments
We thank the foundation support from National Natural Science Foundation of China (21302150),
Hubei Provincial Department of Education (D20131501), Scientific Research Foundation for the
Returned Overseas Chinese Scholars, State Education Ministry [2012]1707 and foundation of
High-end Talent Cultivation Program from Wuhan Institute of Technology. We also thank Prof.
AiwenLei at Wuhan University for his generous NMR analysis support.
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