Iodine-catalyzed efficient amide formation from aldehydes and amines

Article abstract of DOI:10.1016/j.tetlet.2015.11.027

An efficient iodine-catalyzed radical oxidative amidation of aldehydes with amines has been developed. This methodology was employed to prepare amides in good to excellent yields with the advantages of wide functional group tolerance and operational simplicity.

Full text of DOI:10.1016/j.tetlet.2015.11.027

Tetrahedron Letters xxx (2015) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Iodine-catalyzed efficient amide formation from aldehydes
and amines
b
a,
Peng Wang a, , Jiaxuan Xia , Yueqing Gu
⇑
⇑
a Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 210009 Nanjing, China
b School of Pharmacy, China Pharmaceutical University, 210009 Nanjing, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient iodine-catalyzed radical oxidative amidation of aldehydes with amines has been developed.
This methodology was employed to prepare amides in good to excellent yields with the advantages of
wide functional group tolerance and operational simplicity.
Received 26 September 2015
Revised 3 November 2015
Accepted 9 November 2015
Available online xxxx
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Amide
Iodine
Catalyst
Aldehyde
Amine
Introduction
mation with good atom-economic and cheap starting materials
superior to other methods mentioned above, the application of
The amide bond is one of the most important functional groups
in modern chemistry, with application in a number of natural
products, pharmaceuticals, and polymer syntheses (Fig. 1).1–3 In
the past decades, various kinds of approaches have been reported
for amide synthesis, including the condensation between car-
boxylic acid derivatives with amines, which is the most commonly
used method in the formation of amides. However, many draw-
backs, such as low atom economy, high waste pollution, and poor
functional group tolerance etc. restrict its application range.4
Recently, some alternative methods have been figured out to
address these problems, for example rearrangement of aldoximes
and ketoximes, coupling of nitriles with alcohols or amines, palla-
dium-catalyzed aminocarbonylation, and N-arylation or N-alkeny-
lation of amides.5–16 Oxidative amidation is one example of the
versatile methods.
Oxidative amidation of aldehydes into amides has been known
since the early 1980s. As shown in Scheme 1, the general reaction
mechanism of this transformation is initiated by the coupling of
aldehyde with amine to form the hemiaminal intermediate, which
was subsequently oxidized to the amide product.17,18 To date,
increasing attention is being devoted to this transformation. Sev-
eral reaction systems including palladium, copper, lanthanide,
and iron catalysts have been reported.19–22 In spite of this transfor-
metal catalysts raises a whole new set of issues. Hence, with a good
capacity for electron transfer processes, inexpensive and environ-
mentally friendly iodine has recently been reported to serve as
an alternative catalyst for transition metals in many reactions.23,24
In fact, iodine catalysis has been widely applied in the direct
oxidation functionalization of carbonyl compounds. Recently,
many C–N bond formation reactions of carbonyl compounds have
been reported under iodine-catalyzed oxidation conditions.25–28
Wang and co-workers29 reported the iodine-catalyzed synthesis
of N,N-dimethyl aryl amides from benzylic alcohols and dimethyl-
formamide, via a radical pathway. Although it is a fundamentally
different approach to amide synthesis, the scope of amide was lim-
ited to N,N-dimethyl aromatic amides. Therefore, the development
of alternative methods to amide bond formation utilizing iodine as
catalyst remains an area of active research. During the last few
years, our group has been involved in the development of oxida-
tion-related reactions employing various oxidation systems.30
Herein, we developed an efficient iodine-catalyzed oxidative ami-
dation of aldehydes into amides, utilizing TBHP as an oxidant.
Results and discussion
In a pilot experiment, morpholine 1a (1 mmol) reacted with
N-chlorosuccinimide (NCS, 1.1 mmol) in acetonitrile at room tem-
perature. Then the corresponding N-chloromorpholine was
⇑
Corresponding authors.
http://dx.doi.org/10.1016/j.tetlet.2015.11.027
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
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P. Wang et al. / Tetrahedron Letters xxx (2015) xxx–xxx
O
OH
HO
O
O
HO
O
OH
H
O
O
O
N
F
N
H
O
O
O
O
O
OH
OH
NH
O
Taxol
Atorvastatin (Lipitor)
O
H
O
N
N
N
N
N
O
O
O
N
HN
O
N
O
O
HN
HN
N
H
N
H
N
OH
O
O
N
O
N
N
N
N
O
Imatinib (Gleevec)
Ciclosporine (Restasis)
Figure 1. Some important pharmaceutical molecules containing the amide bond.
H
N
OH
O
Oxidising
Agent
O
O
R1
R2
R1
1. NCS, CH3CN, rt, 3h
O
R1
R1
O
R2
R3
N
R2
R3
N
R2
R1
N
H
R3
H
R3
N
2.
, I2, TBHP, reflux
R2
R3
H
Scheme 1. The general reaction mechanism of amides from aldehydes and amines.
O
O
N
N
N
O
O
O
H3CO
H3COOC
Cl
Cl
Br
2a
85%
2b
81%
2c
85%
O
Table 1
Optimization study for the synthesis of amide 2a from anisaldehyde and morpholinea
O
O
N
N
N
Ph
O
1. NCS, CH3CN, rt, 3h
O
O
HN
O2N
Ph
N
O
2d
80%
O
2e
73%
O
2f
80%
O
2. anisaldehyde, initiator,
oxidant, reflux
H3CO
1a
2a
O
N
Ph
N
Ph
Ph
N
Ph
Ph
Entry
Initiator
Oxidant
Time (h)
Yieldb (%)
Ph
Br
H3CO
1
2
3
4
5
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
—
—
TBAI
KI
TBPB
TBHP
TBHP
H2O2
CAN
Oxone
TBHP
TBHP
TBHP
TBHP
—
3
3
45
85
83
0
0
0
70
35
60
86
0
2g
87%
O
2h
89%
2i
80%
12
12
12
12
3
3
12
3
12
12
12
12
12
O
O
N
Ph
Ph
Ph
N
N
Ph
H
6
O
2k
75%
2l
79%
7c
8d
9e
10f
11
12
13
14
15
2j
87%
O
O
O
N
N
Ph
N
H
Ph
Ph
H
S
—
0
0
38
20
Cl
2m
78%
2n
81%
2o
80%
TBHP
TBHP
TBHP
O
N
Ph
Ph
a
Reaction conditions: morpholine 1a (1 mmol) and N-chlorosuccinimide (NCS)
(1.1 mmol) in 5 mL acetonitrile at room temperature for 3 h. To this reaction mix-
ture were added anisaldehyde (2 mmol), catalyst (20 mol %), and oxidant (5 mmol)
under reflux.
2p
76%
b
Isolated yield by column chromatography.
I2 (10 mol %).
TBHP (1 mmol).
At room temperature.
Scheme 2. Substrate scope for the synthesis of amides.
c
d
e
f
Under nitrogen.
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P. Wang et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
H
N
Cl
A
R1
R2
H
N
Cl
R1
R2
I
t-BuOO + H
I2
1/2
I
H
N
R1
R2
1/2 I2
t-BuOOH
t-BuO
O
B
R1
R3
N
or t-BuO
t-BuOO
R2
O
O
R3
R3
H
or
t-BuOOH
t-BuOH
C
Scheme 3. Proposed reaction pathway.
quantitatively formed after 3 h. This reaction mixture solution,
containing N-chloromine generated in situ, was directly treated,
without any purification, with anisaldehyde (2 mmol), iodine
(20 mol %), and tert-butyl peroxybenzoate (TBPB 5 mmol) under
reflux for 3 h, generating the amide 2a in only 45% yield (Table 1,
entry 1). By switching the oxidant from TBPB to tert-butyl
hydroperoxide (TBHP), the product amide 2a was obtained with
a significant improvement of yield to 85% (Table 1, entry 2).
Increasing the reaction time, even in reflux for 12 h, had a slight
influence in improving the yield (Table 1, entry 3). Other oxidants
such as H2O2, CAN, and oxone gave no product (Table 1,
entries 4–6). With respect to the amount of iodine in the proce-
dure, it was found that 20 mol % were optimal. The decrease in
the amount to 10 mol % was detrimental (Table 1, entry 7). Like-
wise, the decrease in the amount of TBHP from 5 equiv to 1 equiv
led to a collapse of the yield from 85% to 35% (Table 1, entry 8).
When the reaction was performed at room temperature with a
considerable lengthening of the reaction time, the amide was
achieved with a substantial yield reduction (Table 1, entry 9). No
obvious yield increase was observed under nitrogen (Table 1, entry
10). Moreover, no product formation was observed when perform-
ing the reaction without the oxidant (TBHP) or iodine (Table 1,
entries 11–13). Other initiators were also investigated. In compar-
ison with iodine, TBAI or KI resulted in lower yields of the product
2a (Table 1, entries 14 and 15). Therefore, the optimal reaction con-
ditions were iodine (20 mol %) as the catalyst, with TBHP (5 equiv)
as oxidant and CH3CN as solvent.
step is the formation of tert-butylperoxyl radical and iodide anion
from the reaction between TBHP with iodine. Then the intermedi-
ate A from N-chloroamine is transformed into an amino radical B
on the basis of the redox reaction of iodide. Moreover, the
tert-butoxyl radical is generated from TBHP in the presence of
iodide anion. Then the tert-butylperoxyl and/or tert-butoxyl radi-
cals grab hydrogen from the aldehyde to generate acyl radical C,
which subsequently could combine with the amino radial B to
form amides.
Conclusions
In conclusion, we have developed an efficient approach to the
synthesis of functionalized amides from aldehydes and amines.
Unlike the previous study that uses metal catalysts, the protocol
described herein uses a catalytic amount of iodine as catalyst
together with TBHP as an oxidant. This methodology can be
applied in preparing a wide range of amides directly from aromatic
and aliphatic aldehydes and variously substituted amines. Further
applications of this chemistry to synthesis of functionalized amides
are under current investigation.
Acknowledgements
We are grateful for the financial support from the NSFC
(National Nature Science Foundation of China, No. 81501529)
and Fundamental Research Funds for the Central Universities
(ZJ15011).
With the optimal conditions in hand, we next investigated the
scope of this reaction, as illustrated in Scheme 2. The aldehyde
bearing electron-donating substituent gave the desired product
in excellent yield (2a). It is worth noting that aldehydes containing
functional groups such as p-Cl, p-Br, and p-COOCH3 were all toler-
ated (2b–2d). Besides, the electron-withdrawing substituted alde-
hydes were also efficiently transformed into the desired products
in good yields (2e).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.11.
027.
Next, we conducted the reaction with a series of N,N-dialkyl-
amines showing excellent tolerance (2f–2k). These results
indicated that acyclic as well as cyclic amines were shown to be
effective in this reaction. Similarly, both electro-donating groups,
such as OMe, and withdrawing groups, such as acetyl, were well
tolerated providing the desired amides in satisfied yields. Further-
more, primary amines gave the corresponding N-mono-substituted
amides in good yields (2l–2n).
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