NBu4NI-catalyzed unexpected amide bond formation between aldehydes and aromatic tertiary amines

Article abstract of DOI:10.1039/c3ra40298c

A novel and practical amide bond formation method has been developed without the need for any metals. This method provides a novel route for amide bond formation, in the presence of an nBu₄NI/TBHP catalyst system, from readily available aldehydes and aromatic tertiary amines.

Full text of DOI:10.1039/c3ra40298c

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nBu4NI-catalyzed unexpected amide bond formation
between aldehydes and aromatic tertiary amines3
Cite this: RSC Advances, 2013, 3, 3869
Wen-Peng Mai,* Ge Song, Jin-Wei Yuan, Liang-Ru Yang, Gang-Chun Sun,* Yong-
Mei Xiao, Pu Mao and Ling-Bo Qu
Received 21st January 2013,
Accepted 21st January 2013
DOI: 10.1039/c3ra40298c
www.rsc.org/advances
A novel and practical amide bond formation method has been
developed without the need for any metals. This method provides
a novel route for amide bond formation, in the presence of an
nBu4NI/TBHP catalyst system, from readily available aldehydes
and aromatic tertiary amines.
aldehydes.15 Herein, we report a new amide bond formation
technique which is catalyzed by nBu4NI, using TBHP as an
oxidant, from readily available aldehydes and aromatic tertiary
amines (Scheme 1). This method offers a new and alternative
approach to amide bond formation without any metal catalysts.
Our investigation started with treating benzaldehyde (1a) and
N,N-dimethylaniline (2a) under our previously reported catalyst
system14 to synthesize a-ketoamide through radical oxidative
coupling. However, an unexpected compound N-methyl-
N-phenylbenzamide (3aa) was obtained instead of our desired
product a-ketoamide. This was an unexpected process, so we
chose 1a and 2a as model substrates to optimize the reaction
conditions. A series of reaction conditions are summarized in
Table 1. As shown in Table 1, PhI(OAc)2 was not an effective
catalyst when using TBHP as the oxidant (Table 1, entry 1). No
product was detected employing I2 as catalyst (Table 1, entry 3). To
our delight, KI displayed catalytic effect in this transformation
with 42% product yield (Table 1, entry 2). A more soluble catalyst
nBu4NI was examined because KI has low solubility in DCE at 90
uC (Table 1, entries 4–11). We performed the reaction with a 1 : 1
(1a : 2a) ratio of substrates to obtain a modest yield (Table 1, entry
4). When the amount of 2a was increased, the reaction showed
lower activation under the same conditions (Table 1, entry 5).
Nevertheless, the reaction proceeded more smoothly when the
amount of substrate 1a was increased (Table 1, entries 6 and 7).
We found 1a reacted with 2a at 90 uC in DCE to afford the desired
product in 72% yield when the ratio was 2 : 1 (1a : 2a) (Table 1,
entry 8). However, continuing to increase the ratio of 1a : 2a was
not favourable for this transformation (Table 1, entry 9). Among
The amide bond is one of the key structural units in a wide range
of biological compounds, such as peptides, proteins, natural
products and pharmaceuticals, and is also widely employed in
synthetic polymers.1 As a result, the development of efficient
amide syntheses has attracted considerable interest.
Conventionally, the amide bond is typically synthesized by
acylation of amines (primary or secondary amines) with carboxylic
acids or acid chlorides.2 To avoid highly hazardous reagents and
improve atom economy, many synthetic routes have been
developed as alternative methods for amide synthesis, such as
the aminocarbonylation of aryl halides,3 modified Staudinger
reaction,4 Schmidt and Beckmann rearrangements,5 direct amide
synthesis from amines and alcohols,6 amidation of nitriles,7
rearrangement of oximes,8 carbonylation of alkynes,9 iodonium-
promoted a-halo nitroalkane amine coupling10 and C–H oxidative
amidation.11 Although great advances have been achieved in this
field, there still remains some room for improvement. Direct
oxidative amidation of aldehydes with amines is an attractive
method with potential industrial applications. Although this
process has achieved significant progress recently and a variety
of reaction systems have been developed for this transformation,
most of them are catalyzed by metals such as Ru, Y, Pd, Rh etc.,12
so the transformation still suffers from drawbacks, such as using
expensive transition metal catalysts. Recently, a new method for
amide bond formation has been reported via C–H bond activation
without metal by Wan13a and Wang.13b A similar method for the
synthesis of a-ketoamides via amide bond formation without
metal has also been reported by our group.14 More recently, Li
et al. reported the iron-catalyzed amidation of tertiary amines with
School of Chemistry and Chemical Engineering, Henan University of Technology,
Lianhua Street, Zhengzhou 450001, China. E-mail: maiwp@yahoo.com;
sungangchun@163.com; Fax: +86-371-67756715; Tel: +86-371-67756718
Scheme 1 Synthesis of amides via aldehydes and aromatic tertiary amines.
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Electronic supplementary information (ESI) available: See DOI: 10.1039/c3ra40298c
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Table 1 Optimization of reaction conditionsa
Table 2 nBu4NI-catalyzed synthesis of amides from aldehydes with aromatic
tertiary aminesa,b
Entry Catalyst (20 mol%) Oxidant(4.0 eq) Solvent Yield (%)b
1
2
PhI(OAc)2
KI
I2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
H2O2
DTBP
TBHP
—
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
trace
42
0
40
33
50
57
72
60
0
3
4c
5d
6e
7f
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
—
8g
9h
10
11
12
13
0
0
0
nBu4NI
a
Reaction conditions: 1a (2.0 mmol), 2a (1.0 mmol), DCE (3 mL),
under an air atmosphere, 10 h, 90 uC. TBHP: tert-butyl
hydroperoxide 70% in water, DTBP: di-tert-butyl peroxide 98%, H2O2
b
c
d
30% in water. Isolated yield. 1a : 2a = 1 : 1. 1a : 2a = 1 : 1.5.
e
f
g
h
1a : 2a = 1.2 : 1. 1a : 2a = 1.5 : 1. 1a : 2a = 2 : 1. 1a : 2a =
2.5 : 1.
the oxidants tested, H2O2 and DTBP showed no activation in this
reaction (Table 1, entries 10 and 11). In addition, the reaction was
unsuccessful in the absence of nBu4NI or TBHP (Table 1, entries
12 and 13). It indicated that both catalyst and oxidant were
important in this transformation.
With the optimal conditions in hand, the scope of the
transformation was investigated and the results are summarized
in Table 2. As shown in Table 2, the aldehydes with weak electron-
withdrawing groups gave modest yields (Table 2, 3ba and 3da).
Unfortunately, aryl aldehydes which have strong electron-with-
drawing groups, such as F, NO2 and CF3 were not suitable for this
protocol (see ESI ). However, electron-rich aryl aldehydes all
3
provided the corresponding amides smoothly. Electron-donating
groups, such as t-Bu, Me and Ph attached to the phenyl rings of
aryl aldehydes exhibited good reactivity (Table 2, 3ca, 3ea, 3ja and
3ee). For example, when 4-(tert-butyl) benzaldehyde (1e) reacted
with N,N-dimethylaniline (2a), amide 3ea was obtained in 83%
yield and [1,19-biphenyl]-4-carbaldehyde (1j) also provided a high
yield (75%). Likewise, product 3ee could be obtained in 86% yield
when 4-(tert-butyl) benzaldehyde (1e) reacted with amine 2e. To
our delight, furfural and its derivatives also provided the
corresponding products in moderate yields (Table 2, 3fa, 3gd,
3hc, 3ha and 3gb). Nevertheless, the investigation of other
heteroaryl aldehydes, such as picolinaldehyde and 1H-indole-3-
a
Reaction conditions: aldehydes (2.0 mmol), amines (1.0 mmol),
nBu4NI (20 mol%), TBHP (4.0 mmol), DCE (3 mL), 90 uC, 10 h.
b
e
c
d
Isolated yield. EtOAc instead of DCE as the solvent. 5 h.
TBHP (6.0 mmol).
yields (49%–77%). Furthermore, as for aromatic tertiary amines,
they could also proceed smoothly in the reaction if R2 was an
electron-donating group. However, no desired product was
observed when R2 was CN. When changing the N-substituent of
amines, the transformation was still successful. For example, the
desired products were obtained in moderate yields using N-ethyl-
N-methylaniline (2f) as the substrate (Table 2, 3af and 3bf).
However, when R1 was phenyl, it influenced the reaction efficiency
remarkably (3ah). It indicated that the N-substituent (R1) of the
amines played an important role in the reaction. Unfortunately,
N-methyl dialkyl tertiary amines, such as 1-methylpiperidin-4-one,
carbaldehyde in this reaction was unsuccessful (see ESI ). It is
3
notable that a double bond in the substrates could be tolerated
under the oxidative conditions. For example, cinnamaldehyde (1i),
a-methylcinnamaldehyde (1m), trans-2-pentenal (1l) and (E)-4-
styrylbenzaldehyde (1k) all performed well under the optimal
conditions and gave the desired amides in moderate to good
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Scheme 2 nBu4NI-catalyzed amide synthesis from aldehydes and N-methylaniline.
Scheme 3 Proposed preliminary mechanism.
4-methylmorpholine and 1-methylpiperidine were all ineffective in
oxidized to species B or C and its mechanism has been proposed
in previous work17 (Scheme 3, eqn (b)). The intermediate D is
formed via two SET processes which have been established in
other reports.16a–c,18 Then, N-oxide A reacts with intermediate D to
form E, E produces intermediate D and secondary amine F via an
autocatalytic deoxygenative demethylation process.16a–c In the end,
the secondary amine F reacts with the aldehyde under oxidative
conditions to form the final product G (Scheme 3, eqn (e)).
In summary, we have developed a novel method for the direct
synthesis of amides, which are important structural units in many
biological compounds, from aldehydes and aromatic tertiary
amines. This transformation, catalyzed by nBu4NI, includes the
demethylation of tertiary amines and dehydrogenation of alde-
hydes in the absence of metal. Both substrates were cheap and
readily available. Further investigations on this transformation are
ongoing in our laboratory.
the reaction under the current conditions (see ESI ).
3
To our surprise, when 2-phenylacetaldehyde (1n) was investi-
gated under the optimal conditions, it showed an interesting
result (eqn (1)). Two carbons disappeared during this transforma-
tion and product 3aa was obtained in good yield.
ð1Þ
To gain insight into the mechanism of this novel reaction,
some control experiments were performed. Gratifyingly, the
reaction could also proceed to afford the desired amides under
the optimal conditions when N-alkylaniline reacted with aldehydes
(Scheme 2, eqn (2)). For example, N-methylaniline or
N-ethylaniline reacted with benzaldehyde to obtain the corre-
sponding products in 53% and 75% yields, respectively (Scheme 2,
eqn (2)), but diphenylamine failed in this reaction (Scheme 2, eqn
(2)). These investigations indicated that demethylation of the
aromatic tertiary amine was involved in the reaction process when
tertiary amines were used as substrates. To our disappointment,
no product was observed when 1-methylpiperazine was used as
the substrate to react with benzaldehyde. This experiment
displayed that alkyl secondary amines were ineffective in this
transformation (Scheme 2, eqn (4)). Otherwise, the reaction of
N-methyl-N-phenylformamide with benzaldehyde provided no
product under the optimized conditions (Scheme 2, eqn (3)).
This result confirmed that the demethylation process was not via
Acknowledgements
We gratefully acknowledge NSFC (No. 21172055).
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