Fe-catalyzed esterification of amides via C-N bond activation

Article abstract of DOI:10.1039/c7ra12152k

An efficient Fe-catalyzed esterification of primary, secondary, and tertiary amides with various alcohols for the preparation of esters was performed. The esterification process was accomplished with FeCl3$6H2O, which is a stable, inexpensive, environmentally friendly catalyst with high functional group tolerance.

Full text of DOI:10.1039/c7ra12152k

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Fe-catalyzed esterification of amides via C–N bond
activation†
Cite this: RSC Adv., 2018, 8, 4571
Xiuling Chen, * Siying Hu, Rongxing Chen, Jian Wang, Minghu Wu, Haibin Guo
and Shaofa Sun*
Received 6th November 2017
Accepted 6th January 2018
An efficient Fe-catalyzed esterification of primary, secondary, and tertiary amides with various alcohols for
DOI: 10.1039/c7ra12152k
the preparation of esters was performed. The esterification process was accomplished with FeCl
3 2
$6H O,
which is a stable, inexpensive, environmentally friendly catalyst with high functional group tolerance.
rsc.li/rsc-advances
The amide bond is not only employed as an important natural the reaction was limited to only tertiary amides; primary or
peptide skeleton in biological systems, but also as a versatile secondary amides were not compatible with this catalytic
1,2
functional group in organic transformations. Among amide oxidation system.
3,4
transformations, transamidation and esterication of amides
5–11
have attracted widespread attention from organic chemists.
In contrast to transamidation of amides, esterication of
amides is relatively difficult because of the low nucleophilicity
of alcohols compared with amines. To overcome this short-
(1)
12
coming, various processes for the esterication of amides have
6
been developed, such as using an activating agent, employing
We initially selected benzamide 1a and ethanol 2a as model
substrates to screen the reaction conditions, and the results are
summarized in Table 1. First, in the presence of FeCl , ethyl
2
benzoate 3a was afforded in 31% yield (Table 1, entry 1). Next,
our catalyst-screening results showed that various iron
3 3 4 2 3 2
complexes such as FeCl , FeBr , FeSO $7H O, FeCl $6H O, and
7
8
twisted amides, and forming intramolecular assisted groups.
For increasing the synthetic exibility of esterication of
amides, new catalytic systems Zn(OTf) and Sc(OTf) were
developed by Mashima and Williams for the esterication of
2
3
9
amides. Shimizu et al. reported CeO
2
catalyzed esterication of
10
amides. Off late, progress of the signicant Ni-catalyzed
Fe(NO
3
)
3
$9H
2
O could catalyze the reaction (Table 1, entries 2–
11
esterication of amides has gained precedence. Although
this approach produces satisfactory yield, the drawbacks such
as the use of an expensive catalyst, generation of reagent waste,
high temperature and the limited scope of the substrate still
persists. Herein, under mild reaction conditions, we report
a novel and efficient Fe-catalyzed esterication of amides for the
synthesis of esters (eqn (1)). Compared to conventional
methods, this esterication procedure is distinguished by using
a stable, inexpensive, environment-friendly catalyst, i.e., FeCl3-
6
), and FeCl $6H O was the best catalyst for this reaction as
3
2
ethyl benzoate 3a was afforded in 35% yield (Table 1, entry 6).
2
Other metal complexes such as CuCl , PdCl , and NiCl $6H O
did not improve the efficiency of this transformation (Table 1,
entries 7–9). In the absence of an iron complex, this reaction
could not work and the product was not detected (Table 1, entry
2
2
2
1
0). Next, in the presence of FeCl
additives on the reaction was investigated (Table 1, entries 11–
8). Among the tested additives, the stronger bidentate ligands
3 2
$6H O, the inuence of
1
$
6H O with a low toxicity solvent. The catalytic system has wide
2
such as 1,10-phenanthroline or 2,2-bipyridine did not show any
efficiency, while hydrochloric acid gave the best reactive activity
as ethyl benzoate 3a was obtained in 91% yield (Table 1, entry
functional group compatibility. The reactions of several
primary, secondary, and tertiary amides with various alcohols
have been well tolerated in this process. Moreover, esters were
also as effective as esterication reagents for the esterication
of amides by the acyl–acyl exchange process. In the course of
our present study, a Co-catalyzed amide C–N cleavage to form
2 4 3
18). In general, H SO or HNO was used as a catalyst for
esterication; however, they did not efficiently promote the
reaction under the present system (Table 1, entries 16–17). In
the absence of FeCl $6H O, the product 3a was afforded in 35%
3 2
yield (Table 1, entry 19). For the solvents investigated (Table 1,
entries 20–23), n-hexane was the best choice (Table 1, entry 18).
The substrate scope of esterication with alcohols was
investigated under the optimized reaction conditions. As shown
in Table 2, esterication of benzamide by primary alcohols,
13
esters was reported by Danoun et al. However, an additional
additive (Bipy) and Mn (3 equiv.) were needed and the scope of
Hubei University Of Science and Technology, China
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c7ra12152k
1
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a
a
Table 1 Optimization of the reaction conditions
Table 2 Esterification of primary amide with various alcohols
b
Entry
1
Alcohol
Products
Yield
b
Entry
Catalyst (20%)
Additive (40%)
Yield
1
2
3
4
5
6
7
8
9
FeCl
FeCl
2
—
—
—
—
—
—
—
—
31
31
25
20
20
35
Trace
Trace
Trace
—
Trace
Trace
Trace
Trace
22
Ethanol 2a
3a, 85%
3b, 88%
3
FeBr
FeSO
Fe(NO
FeCl $6H
CuCl
PdCl
3
4
$7H
2
O
3
)
3
$9H
2
O
3
2
O
O
2
3
4
5
n-Propanol 2b
n-Octanol 2c
2
2
Ni
2
Cl$6H
2
—
—
Pyridine
1,10-Phenanthroline
Formic acid
L-Proline
10
12
13
14
15
16
17
18
19
20
21
22
23
—
3c, 82%
3d, 91%
3e, 81%
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
—
3
3
3
3
3
3
3
$6H
$6H
$6H
$6H
$6H
$6H
$6H
2
2
2
2
2
2
2
O
O
O
O
O
O
O
H
2
SO
4
i-Propanol 2d
t-Butyl alcohol 2e
HNO
HCl
HCl
HCl
HCl
HCl
HCl
3
25
91
35
Trace
36
c
d
e
f
FeCl
FeCl
FeCl
FeCl
3
3
3
3
$6H
$6H
$6H
$6H
2
2
2
2
O
O
O
O
28
40
a
Reaction conditions: 1a (0.2 mmol), 2a (0.1 mL), catalyst (0.04 mmol,
0 mol%), H SO (concentrated, 0.24 mmol), HNO (concentrated, 0.24
2
2
4
3
6
Cyclohexanol 2f
3f, 80%
ꢀ
b
mmol), HCl (0.24 mmol, 36–38%), n-hexane (1.0 mL), 80 C, 14 h. GC
yield using hexadecane as internal standard. DMF was used as
a solvent. 1,4-Dioxane was used as solvent. Toluene was used as
3
solvent. CH CN was used as solvent.
c
d
e
f
7
8
9
Phenethanol 2g
Phenethanol 2h
Triuoroethanol 2i
3g, 83%
3h, 81%
3i, 81%
secondary alcohols, tertiary alcohols, and ring alcohols took
place smoothly, and the corresponding esters were afforded in
good to high yields. When primary alcohols 2a, 2b, 2c were used
as substrates, affording the ester products 3a–3c in high yields,
it should be noted that the reactivity of the alcoholysis of
amides was independent of the alkyl chain length (Table 2,
entries 1–3). Secondary alcohols 2d and tertiary alcohols 2e also
worked effectively as the substrates, producing the esters in 81–
91% yield (Table 2, entries 4–5). Treating 1a with cyclohexanol
2
f could afford the ester 3f in 80% yield (Table 2, entry 6).
1
0
Ethane-1,2-diol 2j
3j, 85%
Alcoholysis products 3g and 3h were obtained from corre-
sponding alcohols (Table 2, entries 7–8). Substrate alcohol
having triuoromethyl also participated in this catalytic reac-
tion to form the ester 3i in high yield (Table 2, entry 9). More-
a
Reaction conditions: 1a (0.2 mmol), 2a (0.1 mL), 2b–2j (0.24 mmol),
$6H O (0.04 mmol, 20 mol%), HCl (0.24 mmol, 36–38%), n-
FeCl
3
2
ꢀ
b
over, when ethane-1,2-diol was treated with 1a, only one product hexane (1.0 mL), 80 C, 14 h. Isolated yield.
3j was obtained (Table 2, entry 10).
We then examined the generality of amides and the results
are compiled in Table 3. Under the optimized conditions, both alkoxy, hydroxyl, amino, halide, and nitro remained intact
electron-rich and electron-decient group substituted benza- during the reaction. 2-Naphthamide also served as an efficient
mide could undergo C–N bond cleavage and esterication by substrate and could react with 2a, furnishing the ester 3r in 86%
ethanol to afford the corresponding ester products in high yield. Interestingly, heteroaryl substituted esters 3s and 3t were
yields (Table 3, entries 1–7). Various functional groups such as obtained from the reaction of 2-thiophenecarboxamide and 3-
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a
Table 3 Esterification of different amides with ethanol
Table 3 (Contd.)
b
b
Entry
1
Amides
Products and yield
Entry
Amides
Products and yield
3k, 86%
13
3w, 81%
a
3 2
Reaction conditions: 1b–1n (0.2 mmol), 2a (0.1 mL), FeCl $6H O
2
3
4
5
6
7
3l, 85%
3m, 78%
3n, 75%
3o, 86%
3p, 84%
3q, 90%
(0.04 mmol, 20 mol%), HCl (0.24 mmol, 36–38%), n-hexane (1.0 mL),
ꢀ
b
8
0 C, 14 h. Isolated yield.
indoleacetamide with 2a using the present reaction conditions,
indicating that this method will be an efficient approach to
introduce an aromatic heterocycle into functional molecules.
Substrates containing alkynes such as cinnamamide (1l) could
also react with ethanol smoothly to give an esterication
product 3u with 88% yield. The reaction was not sensitive to the
steric environment of the amide moiety; when meta- and ortho-
substituted amides 1m and 1n were subjected to the reaction
system, the corresponding ester products were obtained in high
yields.
In addition to alcohols, esters were also used as substrates
for esterication of amides through the acyl–acyl exchange
process under the optimal reaction conditions. As shown in
Table 4, in the current catalytic system, formate, acetate and
benzoate also served as efficient substrates and could react with
amides, furnishing the corresponding esters in high yield
14
(Table 4, entries 1–7).
The substrate scope of this iron-catalyzed esterication of
secondary and tertiary amides with alcohols was investigated.
Remarkably, when a secondary amide, viz., N-methylbenzamide
8
9
3r, 86%
3s, 84%
3t, 55%
(1o) and a tertiary amide, viz., N,N-diethylbenzamide (1p) were
used as substrates, the corresponding esters 3a and 3v were
afforded in high yield (Scheme 1).
In addition to aromatic primary, secondary and tertiary
amides, the esterication of aliphatic primary, secondary and
tertiary amides was also investigated under the optimal reaction
conditions, the corresponding esters were afforded in good to
excellent yield and the results are shown in Scheme 2. 2-Phe-
nylacetamide (1q) participated in this catalytic reaction to form
the ester 3y in 86% yield. N-Acetylaniline 1r and N,N-dime-
thylformamide 1s were also applicable to this catalytic system,
1
0
1
1
3u, 88%
3v, 85%
1
and transformed into the corresponding esters 3z and 3z in
79% and 82% yield respectively.
To demonstrate the effect of iron salt in the current catalytic
system, several control experiments were carried out as shown
in Scheme 3. When 1 equivalent FeCl $6H O was used as the
1
2
3
2
catalyst in the absence of HCl, 3a was obtained in 90% yield.
This result indicated that the catalytic cycle of the iron salt was
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a
Table 4 Expanded substrate scope of amides and esters
b
Entry
1
Amides
Esters
Products and yield
1a
Scheme 2 Reaction of aliphatic amides 1q, 1r and 1s with different
alcohols.
2
3
4
1a
1a
1a
5
6
1b
1c
Scheme 3 Control experiments.
ferrocene as the catalyst, indicating that the iron salt catalyst
showed low efficiency in the presence of the stronger ligand.
Thus, it was deduced that free Fe(II or III) was effective for this
reaction.
7
1h
a
Reaction conditions: 1a–1h (0.2 mmol), 2k, 2l (0.1 mL), 2m–2o (0.24
$6H O (0.04 mmol, 20 mol%), HCl (0.24 mmol, 36–38%),
mmol), FeCl
n-hexane (1.0 mL), 80 C, 14 h. Isolated yield.
3
2
ꢀ
b
hindered in the present reaction conditions. When the stronger
bidentate ligands such as 2,2-bipyridine was used, 3a was not
obtained and trace amounts of 3a were detected on using
Scheme 1 Reaction of secondary and tertiary amides 1o and 1p with Scheme 4 Plausible reaction mechanism for Fe-catalyzed esterifica-
ethanol. tion of amides by alcohols.
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5
d
According to the reported literature and our experimental
results, the catalytic reaction pathways for the Fe-catalyzed
esterication of amides by alcohols are proposed as shown in
Scheme 4. The rst step is the generation of the amidate
complex A, which can be formed from free Fe(III) and amide 1.
The complex A reacts with alcohol 2 to produce an unstable
intermediate B. The interaction between the alcohol oxygen and
the carbonyl results in cyclic intermediate C, which is in equi-
librium with its isomer D. Intermediate E can also be produced
from D via C–N bond cleavage. Through the reaction of HCl and
a new molecule amide, intermediate E produces the desired
ester 3, ammonium chloride (colorless crystal, which was
detected aer the reaction), and the amidate complex A.
3 For reviews in C–N bond activation, see: (a) K. Ouyang,
W. Hao, W.-X. Zhang and Z. Xi, Chem. Rev., 2015, 115,
12045; (b) Q. Wang, Y. Su, L. Li and H. Huang, Chem. Soc.
Rev., 2016, 45, 1257.
4 For a review about amide reactivity see: (a) M. C. Whisler,
S. MacNeil, V. Snieckus and P. Beak, Angew. Chem., Int. Ed.,
2004, 43, 2206; (b) V. Snieckus, Chem. Rev., 1990, 90, 879;
(c) V. Pace, W. Holzer and B. Olofsson, Adv. Synth. Catal.,
2014, 356, 3697.
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M. Q. Tran, L. Ermolenko and A. Al-Mourabit, Org. Lett.,
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and S. S. Stahl, J. Am. Chem. Soc., 2009, 131, 10003; (c)
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5, 1496; (d) L. Becerra-Figueroa, A. Ojeda-Porras and
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S. Shi, M. Achtenhagen, R. Liu and M. Szostak, Org. Lett.,
2
In summary, we have discovered a simple, useful and general
method for the esterication of amides using inexpensive and
readily available iron salts as catalysts. The reaction shows high
substrate tolerance as a wide range of aromatic or aliphatic
primary, secondary and tertiary amides can be effectively used
to produce corresponding esters in good to excellent yields. In
addition to alcohol, esters were also used as substrates for
esterication of amides through the acyl–acyl exchange process.
The present ndings not only provide a general and concise
method for Fe-catalyzed amide C–N bond cleavage, but also
open an avenue for the preparation of esters.
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Conflicts of interest
There are no conicts to declare.
Acknowledgements
Financial support by Natural Science Foundation of China
2
012, 51, 10325; (g) M. Hutchby, C. E. Houlden,
(21603068) and research fund for the doctoral program (2016-
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8
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