Iron-catalyzed aerobic oxidative amidation of tertiary amines with carboxylic acids

Article abstract of DOI:10.1007/s11426-015-5368-z

An oxidative amidation of tertiary amines with carboxylic acids has been developed in the presence of FeCl₃·6H₂O as catalyst and oxygen as oxidant. A variety of tertiary amides were obtained in good to excellent yields from inexpensive and readily available reagents. The possible reaction pathways were investigated.

Full text of DOI:10.1007/s11426-015-5368-z

SCIENCE CHINA
Chemistry
• ARTICLES •
doi: 10.1007/s11426-015-5368-z
· SPECIAL ISSUE · CH bond activation
Iron-catalyzed aerobic oxidative amidation of tertiary amines with
carboxylic acids
Lina Ma, Yuanming Li & Zhiping Li*
Department of Chemistry, Renmin University of China, Beijing 100872, China
Received November 30, 2014; accepted December 23, 2014
An oxidative amidation of tertiary amines with carboxylic acids has been developed in the presence of FeCl3·6H2O as catalyst
and oxygen as oxidant. A variety of tertiary amides were obtained in good to excellent yields from inexpensive and readily
available reagents. The possible reaction pathways were investigated.
amidation, tertiary amine, carboxylic acid, iron catalysis, oxidation
(Strategy I) [7a]. Furthermore, the application of anhydrides
1 Introduction
as acylation reagents successfully overcomes the decar-
bonylation problem of aliphatic aldehydes in Strategy I
(Strategy II) [8a]. Recently, Bao and coworkers [9a] dis-
closed a novel reactions of perfluorophenyl carboxylates
with tertiary amines by using Pd(OAc)2 as catalyst and air
as oxidant (Strategy III). However, the use of the expensive
reagents limited the application of the method in amide
synthesis. Therefore, a practical method for amide bond
synthesis from tertiary amines is still highly desirable and
valuable [10,11]. Herein, we wish to report an oxidative
amidation of tertiary amines with carboxylic acids in the
presence of simple iron salt as catalyst and oxygen as oxi-
dant. The present study is complementary to amide synthesis
Amide bond formation is one of the most often used reac-
tions in the synthesis of natural products, pharmaceuticals
and fine chemicals [1], because amide groups were con-
tained in more than 25% of the known drugs contain in a
survey [2]. The traditional method for the synthesis of am-
ides is through the condensation of carboxylic acid and
amine. The aid of coupling reagents usually results in mild
reaction conditions and good yields. Recently, many cata-
lytic transformations for the amide bond formation have
been successfully developed, using alcohols [3], aldehydes
[4], nitriles [5] and aryl halides [6] as carbonyl sources.
Despite the rapid progress made using different carbonyl
sources in recently years, the development of amide for-
mation from tertiary amines is limited [7,8].
As tertiary amines are widely found in nature products
and easily available from chemical companies, the devel-
opment of amide formation from tertiary amines provides
an attractive alternative (Scheme 1) [9]. Recently, we have
demonstrated a new protocol for amide formation by an
unconventional oxidative amidation between tertiary amines
and aldehydes in the presence of a simple iron catalyst
*Corresponding author (email: zhipingli@ruc.edu.cn)
Scheme 1 Strategies for the amidation of tertiary amines.
© Science China Press and Springer-Verlag Berlin Heidelberg 2015
chem.scichina.com link.springer.com

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Ma et al. Sci China Chem June (2015) Vol.58 No.6
from tertiary amines, in which various carbonyl sources
could be applied for tertiary amide synthesis.
petroleum ether, v/v=1:2, Rf=0.3). 1H NMR (400 MHz,
CDCl3)  7.18 (d, J=7.8 Hz, 2H), 7.04 (d, J=7.6 Hz, 2H),
3.21 (s, 3H), 2.35 (s, 3H), 1.83 (s, 3H). 13C NMR (100 MHz,
CDCl3)  170.7, 142.0, 137.5, 130.2, 126.7, 37.1, 22.2,
20.9.
2 Experimental
2.2.3 N-methyl-N-(p-tolyl)propionamide (3c)
2.1 General information
Isolated by flash column chromatography (ethyl acetate/
petroleum ether, v/v=1:2, Rf=0.3). 1H NMR (400 MHz,
CDCl3)  7.21 (d, J=8.0 Hz, 2H), 7.06 (d, J=8.1 Hz, 2H),
3.24 (s, 3H), 2.37 (s, 3H), 2.08 (q, J=7.4 Hz, 2H), 1.04 (t,
J=7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) 174.2, 141.6,
137.6, 130.3, 127.0, 37.3, 27.4, 21.0, 9.7.
1H NMR spectra were recorded on Bruker 400 MHz spec-
trometer (Switzerland) and the chemical shifts were report-
ed in parts per million () relative to internal standard TMS
(0 ppm) for CDCl3. The peak patterns are indicated as fol-
lows: s, singlet; d, doublet; dd, doublet of doublet; t, triplet;
m, multiplet; q, quartet. The coupling constants, J, are re-
ported in Hertz (Hz). 13C NMR spectra were obtained at
Bruker 100 MHz and referenced to the internal solvent sig-
nals (central peak is 77.0 ppm in CDCl3). CDCl3 was used
as the NMR solvent. Mass spectra were obtained on a VG
ZAB-HS mass spectrometer. APEX II (Bruker Inc., Swit-
zerland) was used for HR-MS and ESI-MS. IR spectra were
recorded by a Nicolet 5MX-S infrared spectrometer (Ther-
mo Electron, USA). Flash column chromatography was
performed over silica gel 200–300. All reagents were
weighed and handled in air at room temperature. Unless
otherwise noted, all reactions were performed under a ni-
trogen atmosphere. All reagents were purchased from Alfa
(USA), Acros (Belgium), Aldrich (USA), and TCI (Japan)
and used without further purification.
2.2.4 N-methyl-N-(p-tolyl)benzamide (3d)
Isolated by flash column chromatography (ethyl acetate/
petroleum ether, v/v=1:2, Rf=0.3). 1H NMR (400 MHz,
CDCl3)  7.33–7.27 (m, 2H), 7.23 (m, 1H), 7.17 (m, 2H),
7.01 (d, J=8.1 Hz, 2H), 6.91 (d, J=8.2 Hz, 2H), 3.47 (s, 3H),
2.26 (s, 3H). 13C NMR (100 MHz, CDCl3)  170.6, 142.3,
136.2, 129.8, 129.7, 129.4, 128.6, 127.6, 126.6, 38.4, 20.9.
2.2.5 N,4-dimethyl-N-(p-tolyl)benzamide (3e)
Isolated by flash column chromatography (ethyl acetate/
petroleum ether, v/v=1:2, Rf=0.3). 1H NMR (400 MHz,
CDCl3)  7.20 (d, J=8.1 Hz, 2H), 7.01 (d, J=8.2 Hz, 2H),
6.96 (d, J=7.9 Hz, 2H), 6.92 (d, J=8.3 Hz, 2H), 3.46 (s, 3H),
2.27 (s, 3H), 2.23 (s, 3H). 13C NMR (100 MHz, CDCl3) 
170.7, 142.5, 139.6, 136.1, 132.9, 129.7, 128.8, 128.3,
126.6, 38.6, 21.3, 20.9.
2.2 Synthesis and characterization of the products 3
To a mixture of amine 1 (0.5 mmol), pivalic anhydride (1.0
mmol), carboxylic acid 2 (1.0 mmol), and FeCl3·6H2O (0.1
mmol), toluene (2.0 mL) was added under nitrogen at room
temperature. Nitrogen flow was closed and oxygen was then
introduced into the Schlenk tube via a needle from an oxy-
gen balloon. The resulting mixture was stirred under 85 °C
for 24 h. The temperature of reaction was cooled to room
temperature and the solvent was evaporated in vacuo. The
residue was purified by flash column chromatography on
silica gel with ethyl acetate/petroleum ether (v/v=1:10) as an
eluent to afford the pure product 3 [8].
2.2.6 N-methyl-4-nitro-N-(p-tolyl)benzamide (3f)
Isolated by flash column chromatography (ethyl acetate/
petroleum ether, v/v=1:2, Rf=0.3). 1H NMR (400 MHz,
CDCl3)  8.02 (d, J=8.6 Hz, 2H), 7.45 (d, J=8.6 Hz, 2H),
7.02 (d, J=7.8 Hz, 2H), 6.91 (d, J=7.8 Hz, 2H), 3.49 (s, 3H),
2.27 (s, 3H). 13C NMR (100 MHz, CDCl3)  168.3, 147.8,
142.2, 141.1, 137.2, 130.1, 129.4, 126.6, 122.9, 38.2, 20.8.
2.2.7 N-methyl-N-(p-tolyl)cyclopentanecarboxamide (3g)
Isolated by flash column chromatography (ethyl acetate/
petroleum ether, v/v=1:2, Rf=0.3). 1H NMR (400 MHz,
CDCl3)  7.21 (d, J=8.1 Hz, 2H), 7.10 (d, J=8.2 Hz, 2H),
4.32 (m, 1H), 4.08–3.99 (m, 1H), 3.86–3.75 (m, 1H), 3.24 (s,
3H), 2.38 (s, 3H), 2.10–1.96 (m, 2H), 1.91–1.68 (m, 2H).
13C NMR (100 MHz, CDCl3)  172.8, 140.5, 137.8, 130.2,
127.2, 74.7, 69.4, 37.7, 30.1, 25.9, 21.0.
2.2.1 N-methyl-N-(p-tolyl)hexanamide (3a)
Isolated by flash column chromatography (ethyl acetate/
petroleum ether, v/v=1:2, Rf=0.4). 1H NMR (400 MHz,
CDCl3)  7.21 (d, J=8.0 Hz, 2H), 7.05 (d, J=8.2 Hz, 2H),
3.24 (s, 3H), 2.38 (s, 3H), 2.06 (t, J=7.6 Hz, 2H), 1.63–1.49
(m, 2H), 1.27–1.05 (m, 4H), 0.83 (t, J=7.0 Hz, 3H). 13C
NMR (100 MHz, CDCl3)  173.4, 141.6, 137.4, 130.2,
127.0, 37.2, 33.9, 31.4, 25.2, 22.3, 21.0, 13.8 (see the
Supporting Information online).
2.2.8 N-methyl-N-(p-tolyl)cyclopentanecarboxamide (3h)
Isolated by flash column chromatography (ethyl acetate/
petroleum ether, v/v=1:2, Rf=0.3). 1H NMR (400 MHz,
CDCl3)  7.20 (d, J=8.1 Hz, 2H), 7.04 (d, J=8.1 Hz, 2H),
3.21 (s, 3H), 2.38, (s, 3H), 2.28–2.33 (m, 1H), 1.41–1.57 (m,
1H), 0.90–1.01 (m, 1H). 13C NMR (100 MHz, CDCl3) 
2.2.2 N-methyl-N-(p-tolyl)acetamide (3b)
Isolated by flash column chromatography (ethyl acetate/

Ma et al. Sci China Chem June (2015) Vol.58 No.6
3
182.1, 141.6, 137.5, 130.3, 126.9, 41.3, 37.5, 28.8, 26.9, 25.3.
tanoic acid 2a was chosen as a model reaction to establish
the reaction conditions (Table 1). First, a variety of metal
salts were screened by the use of oxygen as oxidant (Entries
1–6). FeCl3·6H2O was found to be the best catalyst for the
present oxidative amidation (Entry 1). The increasing
amount of 2a further improved the yield of 3a to 67% yield
(Entry 7). Next, the effect of solvents was investigated and
other tested solvents such as DCE, H2O and MeCN obvi-
ously retarded the efficiency of the desired transformation
(Entries 8–10). Importantly, a 51% yield of 3a was still
achieved even in the presence of 2 mol% of FeCl3·6H2O
(Entry 11). Finally, a 71% yield of 3a was obtained when
the reaction time was prolonged to 24 h (Entry 12). It is
worth mentioning that only trace amount of 3a (<5%) was
observed in the absence of iron catalyst, indicating that iron
catalyst is important in this reaction (Entry 13).
Subsequently, the scope of the substrates were investi-
gated under the optimized reaction conditions (Tables 2 and
3). A range of carboxylic acids were examined and the re-
sults were shown in Table 2. To our satisfaction, both ali-
phatic and aromatic acids could be applied in this transfor-
mation. Good to excellent yields of aliphatic acids were
reacted efficiently with 1a (Entries 1 and 2). Moreover,
various benzoic acid derivatives also reacted smoothly with
1a (Entries 3–5). Benzoic acid with electron-donating group
reacted efficiently with 1a (Entry 4), whereas electron-
withdrawing groups on the benzene ring reduced the effi-
ciency of the oxidative amidation (Entry 5). Furthermore,
the reaction of tetrahydrofuran-2-carboxylic acid 2h with 1a
also led to the corresponding amide 3g, albeit in a lower
yield (Entry 6). And cyclohexanecarboxylic acid with 1a
2.2.9 N-(4-bromophenyl)-N-methylacetamide (3i)
Isolated by flash column chromatography (ethyl acetate/
petroleum ether, v/v=1:5, Rf=0.1). 1H NMR (400 MHz,
CDCl3)  7.51 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H),
3.20 (s, 3H), 1.84 (s, 3H). 13C NMR (100 MHz, CDCl3) 
170.1, 143.4, 132.8, 128.7, 121.2, 37.0, 22.3.
2.2.10 N-(4-(acetamidomethyl)phenyl)-N-methylacetamide
(3j)
Isolated by flash column chromatography (ethyl acetate/
1
petroleum ether, v/v=1:5, Rf=0.1). H NMR (400 MHz,
CDCl3) 7.34 (d, J=7.8 Hz, 2H), 7.16 (t, J=10.8 Hz, 2H),
6.54 (s, 1H), 4.45 (d, J=5.1 Hz, 2H), 3.20 (s, 3H), 2.03 (s,
3H), 1.82 (s, 3H). 13C NMR (100 MHz, CDCl3)  170.5,
170.2, 143.5, 138.2, 129.0, 127.1, 42.9, 37.1, 23.1, 22.3.
2.2.11 N-ethyl-N-phenylacetamide (3k)
Isolated by flash column chromatography (ethyl acetate/
petroleum ether, v/v=1:1, Rf=0.5). 1H NMR (400 MHz,
CDCl3)  7.40 (t, J=7.5 Hz, 2H), 7.32 (t, J=7.3 Hz, 1H),
7.13 (d, J=7.3 Hz, 2H), 3.72 (t, J=7.2 Hz, 2H), 1.79 (s, 3H),
1.08 (t, J=7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) 
169.9, 142.8, 129.6, 128.1, 127.8, 43.7, 22.8, 13.0.
2.2.12 N-(3-chlorophenyl)-N-methylacetamide (3l)
Isolated by flash column chromatography (ethyl acetate/
petroleum ether, v/v=1:1, Rf=0.4). 1H NMR (400 MHz,
CDCl3)  7.37–7.27 (m, 2H), 7.19 (s, 1H), 7.08 (d, J=7.4
Hz, 1H), 3.20 (s, 3H), 1.87 (s, 3H). 13C NMR (100 MHz,
CDCl3) 170.1, 145.6, 135.0, 130.6, 127.9, 127.4, 125.3,
77.3, 77.0, 76.7, 37.0, 22.4.
Table 1 Optimization of the reaction conditions a)
2.2.13 8-Acetyl-8-azabicyclo[3.2.1]octan-3-one (3m)
Isolated by flash column chromatography (ethyl acetate/
1
petroleum ether, v/v=1:1, Rf=0.3) [8]. H NMR (400 MHz,
CDCl3) 4.96–4.80 (m,1H), 4.44–4.33 (m, 1H), 2.76–2.62
(m, 1H), 2.58–2.47 (m, 1H), 2.46–2.27 (m, 2H), 2.22–1.93
(m, 5H), 1.83–1.71 (m, 1H), 1.70–1.59 (m, 1H). 13C NMR
(100 MHz, CDCl3) 207.1, 167.0, 54.3, 50.7, 49.5, 48.7,
29.8, 27.9, 21.5.
Cat.
2a (equiv.)
1.0
Solvent
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
DCE
3a (%) b)
61(60)
29(27)
51(51)
19(19)
39(37)
43(43)
67(66)
<5
Entry
1
FeCl3·6H2O
FeSO4·7H2O
FeCl3
2
1.0
3
1.0
4
FeCl2
1.0
2.2.14 N-methyl-N-phenylacetamide (3n)
5
CoCl2
1.0
6
CuCl2
1.0
Isolated by flash column chromatography (ethyl acetate/
1
7
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
2.0
petroleum etner, v/v=1:1, Rf=0.3) [8]. H NMR (400 MHz,
8
2.0
CDCl3)  7.39 (t, J=7.6 Hz, 2H), 7.31 (t, J=7.3 Hz, 1H),
7.16 (d, J=7.4 Hz, 2H), 3.24 (s, 3H), 1.84 (s, 3H). 13C NMR
(100 MHz, CDCl3) 170.4, 144.5, 129.6, 127.3, 127.0, 37.0,
22.3.
9
2.0
H2O
15(15)
10(10)
51(50)
71(71)
<5
10
11 c)
12 d)
13
2.0
MeCN
PhMe
PhMe
PhMe
2.0
2.0
2.0
3 Results and discussion
a) Conditions: 1a (0.5 mmol), cat. (0.1 mmol), pivalic anhydride (1.0
mmol), O2 balloon, and solvent (2 mL); unless otherwise noted; b) detected
by 1H NMR and based on 1a, isolated yields were given in parentheses; c)
FeCl36H2O (0.01 mmol); d) 24 h.
The reaction of 4-methyl-N,N-dimethylaniline 1a with hep-

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Ma et al. Sci China Chem June (2015) Vol.58 No.6
Table 3 Amidation of tertiary amines with acetic acid a)
Table 2 Amidation of carboxylic acid with 1a a)
a) Conditions: 1 (0.5 mmol), pivalic anhydride (1.0 mmol), 2a (1.0
mmol), FeCl3·6H2O (0.01 mmol), PhMe (2 mL) under oxygen; unless
otherwise noted; b) isolated yields; c) pivalic anhydride (2.0 mmol), 2a
(2.0 mmol).
a) Conditions: 1a (0.5 mmol), pivalic anhydride (1.0 mmol), 2 (1.0
mmol), FeCl3·6H2O (0.01 mmol), PhMe (2 mL) under oxygen; unless
otherwise noted; b) isolated yields.
role of pivalic anhydride was studied. The amide 3a was not
detected by H NMR in the absence of pivalic anhydride
1
(Eq. (2)). Furthermore, when 2.0 equivalent of benzoic
pivalic anhydride 5 [13] was added into the reaction under
our standard conditions, the desired product 3d was ob-
tained in a 50% yield (Eq. (3)). The results indicated that a
mixed anhydride like 5 generated by the reaction of carbox-
ylic acid 2 with pivalic anhydride in situ acts an active acyl-
ation reagent.
gave 51% yield of 3h (Entry 7).
Furthermore, other tertiary amine derivatives were inves-
tigated by the use of acetic acid 2b as a model acylation
reagent under the optimized conditions (Table 3). Aniline
with electron-withdrawing and electron-donating group
such as 1b and 1c reacted smoothly with 2a (Entries 1 and
2). Importantly, N,N-diethylaniline 1d also reacted with 2a
smoothly to give the corresponding tertiary amide in a 53%
yield (Entry 3). Substituent at meta-phenyl ring reduced the
efficiency of the reaction due to the dimerization of 1e (En-
try 4). To our delight, the reaction of tropinone with acetic
acid gave a 55% yield of 3l (Entry 5). However, the reaction
of N,N-dimethylaniline 1g with 2b led to 3n and 4 in 13%
and 51% yields, respectively (Eq. (1)) [12]:
(2)
(3)
Accordingly, a tentative mechanism for the present trans-
formation is proposed (Scheme 2). The oxidation of amine 1
gives amine radical A. Followed by the deprotonation, an
(1)
In order to clarify the possible reaction pathways, the

Ma et al. Sci China Chem June (2015) Vol.58 No.6
5
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amidation of tertiary amines with carboxylic acids.
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[9b,9c], followed by the reduction to furnish a peroxide
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via the elimination of D. Then the secondary amine G is
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is formed by carboxylic acids with pivalic anhydride to give
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catalyst most likely also plays an important role as Lewis
acid catalyst for the formation of the mixed anhydride in the
last step, because ferric iron salts showed higher activity
than ferrous irons (Table 1, Entries 1–4); (2) the rapid reac-
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4 Conclusions
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Supporting information
The supporting information is available online at chem.scichina.com and
link.springer.com/journal/11426. The supporting materials are published as
submitted, without typesetting or editing. The responsibility for scientific
accuracy and content remains entirely with the authors.
This work was financially supported by the Fundamental Research Funds
for the Central Universities, the Research Funds of Renmin University of
China (10XNL017).
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