OH-catalyzed amidation of azides and aldehydes: An efficient route to amides

Article abstract of DOI:10.1039/c6gc00402d

A [bmIm]OH-catalyzed amidation of azides and aldehydes is reported. This reaction is easily handled and proceeds under mild conditions. The overall transformation involves azide-enolate cycloaddition, which subsequently undergoes rearrangement to give amides. Importantly, the employment of ionic liquid makes this transformation green and practical.

Full text of DOI:10.1039/c6gc00402d

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[bmIm]OH-catalyzed amidation of azides and
aldehydes: an efficient route to amides†
Cite this: DOI: 10.1039/c6gc00402d
Lijun Gu,*a,b Wei Wang,a Jiyan Liu,a Ganpeng Lia and Minglong Yuan*b
Received 11th February 2016,
Accepted 15th February 2016
DOI: 10.1039/c6gc00402d
www.rsc.org/greenchem
A
[bmIm]OH-catalyzed amidation of azides and aldehydes is
Because of their versatile reactivity, organic azides are now
reported. This reaction is easily handled and proceeds under mild widely recognized as valuable intermediates and building
conditions. The overall transformation involves azide–enolate blocks for organic synthesis.5–9 A number of elegant methods
cycloaddition, which subsequently undergoes rearrangement to that use organic azides have recently been developed, particu-
give amides. Importantly, the employment of ionic liquid makes larly for the synthesis of nitrogen-containing compounds.10–13
this transformation green and practical.
Rh-,14 Au-,15 Ru-16 or base-mediated amidation reactions,17
using organic azides as starting materials, have been develo-
ped by several groups. Although these methods represent a
considerable advance, they still need toxic solvents, specific
directing groups or transition-metal-catalysts. Because of their
low melting points, negligible vapor pressures, and good
recyclability, ionic liquids (ILs) have been increasingly recog-
nized as environmentally-friendly materials for organic syn-
thesis.18 1-n-Butyl-3-methylimidazolium hydroxide ([bmIm]-
OH) has been used successfully as a catalyst for α-hydroxy-
lation of phosphonates by our own group.19 Recently, Rama-
chary developed a DBU-catalyzed azide–aldehyde [3 + 2]
cycloaddition reaction through the rapid elimination of water
at room temperature for the synthesis of 1,4-disubstituted
1,2,3-triazoles.20 Herein, we disclose our preliminary results on
the [bmIm]OH-promoted azide–aldehyde cycloaddition/
rearrangement reaction by releasing N2 gas for the synthesis of
amides, a transformation that to our knowledge has not pre-
viously been described (Scheme 1).21 Our new procedure does
not require high temperature, specific directing groups or tran-
sition-metal-catalysts and offers rapid access to amides from
readily available materials (Scheme 1).
Initially, we focused our efforts on optimizing the reaction
conditions for the synthesis of amides between phenyl azide
1a and cyclohexanecarbaldehyde 2a in [bmIm]OH. Treatment
of the phenyl azide 1a and cyclohexanecarbaldehyde 2a at
30 °C for 5 hours in DMSO with 10 mol% [bmIm]OH could
not give amide 3aa and 1,2,3-triazolines 4 was obtained in
98% yield. After workup with saturated NH4Cl, N-phenylcyclo-
hexanecarboxamide 3aa was obtained in 90% yield (Table 1,
entry 1). When the reaction was carried out under convention-
al heating, the yield decreased to 78% (Table 1, entry 2). A
lower loading of the catalyst also led to a decreased yield and
no reaction occurred in the absence of [bmIm]OH (Table 1,
Amides are fundamental molecules in organic synthesis and
in the chemical industry. As examples of their broad utility,
amide derivatives are used as fungicides, insecticides, and
plant virucides in agriculture, and also as antitumor agents in
medicine.1 The development of synthetic methods for the
preparation of amides has consequently received considerable
attention. Traditional approaches to amide synthesis involve
the condensation of carboxylic acids or activated carboxylic
acid derivatives (acid anhydrides and acid halides) with
amines, and the coupling of primary amides with organo-
halides.2 These traditional methods are, however, often unsuit-
able for use with labile substrates and/or suffer from a limited
substrate scope. They frequently involve multistep processes,
resulting in large amounts of unwanted byproducts and
additional purification steps, or require harsh conditions and
high pressures. Recently, activation of C–H bonds for the
straightforward construction of C–N bonds has received much
attention.3 Various amides have been successfully synthesized
by direct C–H activation and subsequent C–N bond formation.
Despite these advances,4 versatile and efficient methods for
the direct construction of amides from readily available start-
ing materials, under metal-free and waste-free conditions,
remain highly desirable.
aKey Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs
Commission & Ministry of Education, Yunnan Minzu University, Kunming,
Yunnan 650500, China
bEngineering Research Center of Biopolymer Functional Materials of Yunnan,
Yunnan Minzu University, Kunming, Yunnan 650500, China.
E-mail: gulijun2005@126.com, yml@vip.163.com
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c6gc00402d
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Table 2 Scope of azides 1a
Entry
1
Azides 1
Product 3
Yieldb (%)
80
2
77
85
89
Scheme 1 Background and design of the [bmIm]OH-catalyzed amida-
tion of azides and aldehydes.
3
entries 3 and 4). No benefit was obtained by increasing the
reaction time (Table 1, entry 5). A series of solvents, including
DMF, toluene and ClCH2CH2Cl, were also tested, and the
results showed that they were less effective than DMSO
(Table 1, entry 1 versus entries 6–8). Replacement of [bmIm]-
OH with [bmIm]Cl did not deliver the desired product
(Table 1, entry 9).
After the standard reaction conditions had been deter-
mined, we next investigated the substrate scope of the reaction
by employing a variety of aryl azides 1 (Table 2). Aryl azides 1
with electron-donating substituents at the para position of the
phenyl ring, such as Me and MeO, worked well and afforded
the desired products 3ab–3ac in 80% and 77% yields, respecti-
vely (Table 2, entries 1 and 2). It was noted that the electron-
deficient aryl azides led to a higher reactivity than the
electron-rich aryl azides. Substrates with electron-withdrawing
groups such as halogen, CF3 and NO2 groups proceeded faster,
and the amidation was completed at a lower temperature com-
pared to phenyl azide 1a (Table 2, entries 1–7). Notably, substi-
4c
5c
6
91
84
82
7
8
82
86
77
9
10
11c
12
68
46
41
Table 1 Optimization of the reaction conditionsa
13d
Entry Variation from the “standard reaction conditions” Yieldb (%)
1
2
3
4
5
6
7
8
9c
None
At 110 °C
90
78
83
0
90
74
11
28
0
14
15
Trace
0
5 mol% [bmIm]OH
Without [bmIm]OH
6 h instead of 5 h
DMF instead of DMSO
Toluene instead of DMSO
ClCH2CH2Cl instead of DMSO
In [bmIm]Cl
a Reaction conditions: 1 (0.3 mmol), 2a (0.36 mmol), [bmIm]OH (10%
mol), 30 °C under an Ar atmosphere for 5 h, then workup with
saturated NH4Cl (10 mL) at 25 °C for 0.5 h. b Isolated yield. c 40 °C
instead of 30 °C for 6 h. d 50 °C instead of 30 °C for 6 h.
a Reaction conditions: 1a (0.3 mmol), 2a (0.36 mmol), [bmIm]OH
(10% mol), 30 °C under an Ar atmosphere for 5 h, then workup with
saturated NH4Cl (10 mL) at 25 °C for 0.5 h. b Isolated yield. c [bmIm]Cl:
1-butyl-3-methylimidazolium chloride.
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tuents at different positions on the phenyl moiety (para, meta,
and ortho positions) did not affect the reaction efficiency
(Table 2, entries 4, 7 and 8). Importantly, the halogen func-
tional groups, F and Cl, were compatible with the optimized
reaction conditions, thereby enabling subsequent modifi-
cations at the halogenated positions. The application of poly-
substituted aryl azide delivers the desired products in 86% Scheme 2 The large-scale reaction.
yield (Table 2, entry 9). Heterocyclic aryl azides 1k and 1l also
performed well in this [bmIm]OH-catalyzed amidation, giving
products 3ak and 3al in 77% and 68% yield, respectively.
Efforts were made to apply this methodology for the synthesis
of N-benzyl amides. It was found that the substrates 1m–1n
proceeded sluggishly to give the desired amides in low yields
(Table 2, entries 12 and 13). Unfortunately, aliphatic azides
and tosyl azides were not viable for this reaction (Table 2,
entries 14 and 15).
On the other hand, as shown in Table 3, different aldehydes
2 reacted with phenyl azide 1a to give the corresponding pro-
ducts in good to high yields. The reaction of cyclopentyl alde-
hyde 2b under the optimized standard conditions furnished
the corresponding amide in 92% yield. Apart from 2b, acyclic
aldehyde 2c smoothly reacted with 1a and led to the corres-
ponding product 3ca in 67% yield. When 2-phenylacet-
aldehyde 2d was employed, the reaction afforded the desired
amide 3da in 65% yield. To further explore the potential of our
methodology, α-unsubstituted aldehyde 2e was subjected to
the standard reaction conditions. The desired product was
isolated in good yield (69%). In addition, n-butylaldehyde 2f
could also provide the expected product 3fa in 54% yield.
To demonstrate the synthetic utility of the new method, the
reaction was carried out on
a gram scale (Scheme 2;
10.0 mmol of 1a in the presence of 12.0 mmol of 2a and
1 mmol [bmIm]OH in 20 mL of DMSO for 6 h, then workup
with saturated NH4Cl (40 mL) at 25 °C for 0.5 h). The reaction
could afford 1.70 g of 3aa in 84% yield. Therefore, this proto-
col could be used as a practical method to synthesize the pre-
cursors of some important bioactive molecules.
To gain insight into the course of the reaction, we con-
ducted a series of competition experiments. It has been
reported that the reaction of aldehydes with aryl azides gave
1,2,3-triazoles.20 We checked the possibilities of the formation
of 1,2,3-triazoles by the reactions given in Tables 1–3. No 1,2,3-
triazoles were found, which provided evidence that the reac-
tion does not proceed via a 1,2,3-triazole intermediate. The
reaction of phenyl azide 1a with cyclohexanecarbaldehyde 2a
in the presence of [bmIm]OH at 30 °C for 5 hours gave the
adduct 1,2,3-triazolines 4 in 98% yield. Importantly, 1,2,3-tri-
azolines 4 would release N2 gas to give amide 3aa in 90% yield
in the presence of saturated NH4Cl at 25 °C for 0.5 h. This
result implies that 1,2,3-triazolines 4 may be involved in this
process. Furthermore, when benzaldehyde 2g was employed as
the substrate, the reaction did not proceed (Scheme 3c), likely
owing to benzaldehyde 2g being a non-enolizable aldehyde.
Consequently, the working mechanism outlined in
Scheme 4 was proposed on the basis of the present results and
literature reports.20,21 With the aid of [bmIm]OH, cyclohexane-
Table 3 Scope of aldehydes 2a
Entry
1
Aldehydes 2
Product 3
Yieldb (%)
92
2
3
4
67
65
69
9
54
a Reaction conditions: 1a (0.3 mmol), 2 (0.36 mmol), [bmIm]OH (10%
mol), 30 °C under an Ar atmosphere for 5 h, then workup with
saturated NH4Cl (10 mL) at 25 °C for 0.5 h. b Isolated yield.
Scheme 3 Experiments for mechanistic studies.
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Scheme 4 Plausible mechanism.
carbaldehyde 2a generates enolate A, with subsequent cyclo-
addition to phenyl azide 1a to afford the intermediate 4, which
would then rearrange to amide 3aa with extrusion of N2 gas at
110 °C.
In summary, we have developed the IL-catalyzed amidation
of azides with aldehydes for the synthesis of amides, which
are valuable synthons for the chemical and pharmaceutical
industry. This protocol does not require an organic solvent or
any other catalyst and thus it provides a better and practical
alternative to the existing procedures. We believe that this
azide–aldehyde cycloaddition/rearrangement reaction mediated
by ILs will help chemists to design more and more interesting,
useful, and sustainable reactions in the near future.
We are grateful for the financial support from the Program
for Innovative Research Team (in Science and Technology) in
the University of Yunnan Province (IRTSTYN 2014–11) and The
Applied Basic Research Key Project of Yunnan (2013FA039).
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