The nBu4NI catalysed oxidative benzoic acid amide formation from aryl acetaldehydes and amines in aqueous solution

Article abstract of DOI:10.3184/174751913X13791657394773

A metal-free amide synthesis from aryl acetaldehydes and secondary aromatic amines via a carbon degradation process using nBu₄NI/TBHP system in aqueous solution is described. This protocol has not been reported previously. Both substrates are cheap and readily available.

Full text of DOI:10.3184/174751913X13791657394773

630 RESEARCH PAPER
OCTOBER, 630–632
JOURNAL OF CHEMICAL RESEARCH 2013
The nBu4NI catalysed oxidative benzoic acid amide formation from aryl
acetaldehydes and amines in aqueous solution
Ge Song, Gangchun Sun, Yamin Tang and Wenpeng Mai*
Chemistry and Chemical Engineering School, Henan University of Technology, Henan Province, Zhengzhou 450001, P.R. China
A metal-free amide synthesis from aryl acetaldehydes and secondary aromatic amines via a carbon degradation process using
nBu4NI/TBHP system in aqueous solution is described. This protocol has not been reported previously. Both substrates are
cheap and readily available.
Keywords: amine, phenylacetaldehyde, aqueous solution, metal-free amide synthesis
The amide bond is the key backbone in a wide range of biological
compounds, such as proteins, peptides and pharmaceuticals
and is also found applied in polymers.1–4 As a result, the
development of efficient amide syntheses has stimulated
considerable attention. The amide bond is typically synthesised
by acylation of amines (primary or secondary) with carboxylic
acids or acid chlorides. This suffers from harsh conditions
and the formation of byproducts (Scheme 1). Other synthetic
methods have been developed for amide synthesis, such as a
modified Staudinger reaction,5 the aminocarbonylation of
aryl halides,6 Schmidt and Beckmann rearrangements,7 direct
amide synthesis from amines and alcohols,8 amidation of
nitriles,9 rearrangement of oximes,10 carbonylation of alkynes,11
iodonium-promoted α-halo nitroalkane amine coupling and
C–H oxidative amidation.12,13 Although great advances have
been achieved in this field, most of them are catalysed by
metals such as, Ru, Pd and Rh,14–16 so the transformations have
not been applied effectively in industry. Recently, we have
reported a new method for amide bond formation using aryl
aldehydes and tertiary amines as substrates without the need of
metals.17 A similar method for the synthesis of α-ketoamides via
amide bond formation without metals was also reported by our
group.18 This was more atom economic and made use of cheap
and abundant starting materials. As a logical extension of these
catalytic methods, we now report a new amide bond formation
from aryl acetaldehydes and secondary aromatic amines which
is catalysed by nBu4NI using TBHP as an oxidant in aqueous
solution (Scheme 2). This method provides a novel approach to
amide bond formation without any metal catalyst.
HN
O
Catalyst
Oxidant
O
+
N
Solvent
H
a
1
3
a
2
Scheme 2 Reaction sequence.
Treatment of a mixture of 1a (120 mg, 1.0 mmol), 2a (107 mg,
1.0 mmol), I2 (0.2 mmol), TBHP (4.0 mmol) in 3 mL CH3CN/
H2O at 90 °C in air for 15 h provided no product (Table 1, entry
1). KIdisplayedacatalyticeffectinthistransformationwith46%
product yield (Table 1, entry 3). This was an unexpected result
because the phenyl acetaldehyde lost a carbon in the process.
We next tested CuI as catalyst under the same conditions, but
the yield decreased to 26% (Table 1, entry 4). When nBu4NI
was examined as catalyst, TBHP as oxidant, the desired product
was increased to 60% yield in CH3CN/H2O (Table 1, entry 5).
However, the yields decreased respectively in acetone/H2O or
DCE/H2O using nBu4NI as catalyst (Table 1, entries 6 and 11).
As shown in Table 1, nBu4NBr was not an effective catalyst
using TBHP as oxidant (Table 1, entry 2). It showed that iodide
anion played an important role in this reaction. Other oxidants
such as DTBP, BPO, H2O2 and K2S2O8 were also tested in this
transformation under the same conditions, but none of them
showed any activation (Table 1, entries 7–10).
Under the optimised reaction conditions, the reactions
between different aryl acetaldehydes and aromatic secondary
amines were examined and the results are summarised in
Table 2. As shown in Table 2, both electron-poor and electron-
rich aryl acetaldehydes reacted efficiently with N-methylaniline
(2a), N-ethylaniline (2b), N-4-dimethylaniline (2c) and 4-chloro-
N-methylaniline (2d) to give the corresponding products (3–12)
in moderate yields. For example, phenyl acetaldehyde (1a)
We first selected 2-phenylacetaldehyde (1a) and
N-methylaniline (2a) as substrates to develop the reaction
conditions in the absence of metals. The reaction conditions
and results are summarised in Table 1.
Table 1 Effect of solvents, catalysts and oxidants in the new reactiona
R1
NH
Yield /%b
(RCO) O
+
2
Entry
Catalyst
Oxidant
Solvent
R2
O
+
R1
+
O
O
1
2
I
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
BPO
CH CN/H O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H22O
Ace3tone/H O
CH CN/H 2O
CH3CN/H2O
CH3CN/H2O
CH33CN/H22O
DCE/H2O
Trace
0
HN3
nBu42NBr
KI
NH
R2
R
R
con H2SO4
R
R
OH
O
R
3
46
26
60
35
0
R1
N
4
CuI
R2
5
nBu NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu4NI
nBu44NI
R1
6
NH
R2
RI
+
CO R1 NH2
+
7
X
OH
8
0
N
con H2SO4
9
K2S2O8
H2O2
0
R
R'
10
11
0
TBHP
53
aCatalyst (20 mol%), 1a (1.0 mmol), 2a (1.0 mmol) and oxidant (4.0 equiv.)
in 3 mL of the indicated solvent/H2O (1:1) at 90 °C for 15 h. TBHP, tert-
butyl-hydroperoxide, DTBP, tert-butyl-peroxide, BPO, benzoyl peroxide,
DCE, 1,2-dichloroethane.
Scheme 1 Overview of traditional methods of amide synthesis.
* Correspondent. E-mail: maiwp@yahoo.com
bIsolated yields.
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JOURNAL OF CHEMICAL RESEARCH 2013 631
Table 2 nBu4NI-catalysed amide bond formation of aryl acetaldehydes
(1) with N-substituted anilines (2)
key intermediate A which formed by benzyl C–H bond of
phenyl acetaldehyde reacting with tert-butylperoxy radical.
It decomposes to generate benzaldehyde B which was then
attacked by secondary amine to produce C. Finally, C was
oxidised to the amide product.
3
R
O
HN
2
nBu NI, 20%
4
TBHP, 4.0eq
R
O
1
N
1
R
2
+
R
R
H
3
CH CN/H O
R
3
2
In summary, we have developed a novel route to synthesise
amides from aryl acetaldehydes and aromatic secondary
amines. This protocol catalysed by nBu4NI via a carbon
degradation process in aqueous solution has never been reported
before. Both substrates are cheap and readily available. Further
investigations on this method are continuing in our laboratory.
1
2
O
O
O
N
N
1
1
R
R
N
4
5
6
7
R
= p-Cl, 64%
= p-CH , 52%
= p-Br, 52%
= p-Ph, 41%
1
1
1
1
8
9
10
R
= H, 69%
p-Cl, 73%
p-CH , 58%
1
R
R
R
3
3
60%
R
=
1
Experimental
R
=
1
3
All experiments were carried out using an ordinary flask in air.
Aldehydes, aromatic secondary amines, nBu4NI and TBHP (70%
in water) were purchased from commercial suppliers and used as
received unless otherwise noted. All solvents and other commercially
available reagents were purchased from Acros or TCI companies and
used directly. Reactions were monitored by TLC (Qingdao Haiyang
Chemical Co. Ltd. Silica gel 60 F254). Products were detected using
a UV-Vis lamp (254 nm). Column chromatography was performed
on Qingdao Haiyang Chemical Co. Ltd. Gel 60 (200–300 mesh).
NO
2
O
N
O
O
2
R
N
N
1
R
11
12
R
R
= p-CH , R = p-Cl, 55%
1
3
2
14 0%
13 trace
= p-Cl, R = p-CH , 66%
2 3
1
reacted with N-ethylaniline (2b) to form the amide product 8
in 69% yield. For N-substituted aniline, electron-withdrawing
or electron-donating group on phenyl ring made no difference
to the reaction. For example, N,4-dimethylaniline (2c) and
4-chloro-N-methylaniline (2d) reacted with different aryl
acetaldehydes under the optimised conditions, giving similar
yields. However, strong electron-withdrawing groups, such
as NO2, hindered the reaction severely and no product was
observed (Table 2, 14). In addition, the basicity of the aniline
also influenced the transformation, for example, diphenylamine
only gave a product in trace amounts (Table 2, 13).
The use of nBu4NI as catalyst, TBHP as oxidant for amide
bond formation has also been investigated in other reports,19,20
but application in carbon degradation reaction, there is no
relevant literature. Ishihara and other groups speculated on an
alternative mechanism that involves hypoiodite as the actual
oxidant.21,22 We have attempted to explain the degradation
process in this amide bond formation reaction. A possible
mechanism is outlined in Scheme 3 on the basis of the earlier
reports.18,20 As shown in Scheme 3, we considered that the
1
The H and 13C NMR spectras were obtained on a Bruker 400 MHz
1
NMR Fourier transform spectrometer. H NMR data was reported
as: chemical shift (δ ppm), multiplicity, coupling constant (Hz)
and integration. 13C NMR data was reported in terms of chemical
shift (δ ppm) multiplicity and coupling constant (Hz). The spectra
are referenced against the internal solvent (CDCl3, δH =7.26 ppm,
13C=77.0 ppm; DMSO-d6, δ 1H=2.50 ppm, 13C=40.0 ppm). Data
are reported as follows: s=singlet, d=doublet, t=triplet, q=quartet
and m=multiplet. ESI-MS spectra were recorded on a Bruker
Esquire 3000. High resolution mass spectra (HRMS) were obtained
on a Waters Micromass Q-Tof MicroTM instrument using the ESI
technique.
Synthesis of 3–12; general procedure
An 50 mL vial was charged with magnetic stirring bar,
arylacetaldehyde (1, 1.0 mmol), aromatic secondary amine (2,
1.0 mmol), nBu4NI (0.2 mmol), TBHP 70% in water (4.0 mmol),
followed by CH3CN/H2O (3/3 mL). After stirring at 90 °C for 15 h, the
reaction mixture was quenched with a saturated solution of Na2SO3
(to remove excess TBHP) and extracted with EtOAc (20 mL×2). The
combined organic phase was dried over anhydrous Na2SO4 and then
evaporated under reduced pressure. The isolated yield was obtained
by flash chromatography column on silica gel (gradient eluent of ethyl
acetate in petroleum: 10–25%, v/v).
1
N-Methyl-N-phenyl-benzamide (3):23,24 Yield 60%; yellow liquid; H
TBHP
I
+
tBuO
OH
[IO]
NMR (400 MHz, CDCl3) δ 7.27–7.32 (m, 2H), 7.21–7.26 (m, 6H), 7.04–
7.19 (m, 2H), 3.52 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.7, 144.9,
135.9, 129.6, 129.2, 128.7, 127.7, 126.9, 126.5, 38.41; HRMS [M+1]+,
calcd C14H14NO 212.1075; found: 212.1077.
1/2I2
4-Chloro-N-methyl-N-phenyl-benzamide (4):24 Yield 64%; yellow
liquid; 1H NMR (400 MHz, CDCl3) δ 7.24–7.28 (m, 4H), 7.14–7.21 (m,
3H), 7.04–7.06 (m, 2H), 3.51 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
169.5, 144.7, 135.7, 134.3, 130.3, 129.4, 128.0, 126.9, 126.8, 38.5; HRMS
[M+1]+: calcd C14H13ClNO 246.0686; found: 246.0685.
4-methyl-N-methyl-N-phenyl-benzamide (5):23 Yield 52%; yellow
liquid; 1H NMR (400 MHz, CDCl3) δ 7.14–7.28 (m, 5H), 7.05–7.07
(m, 2H), 6.97 (d, J=8.0 Hz, 2H), 3.51 (s, 3H), 2.28 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 170.7, 145.2, 139.8, 133.0, 129.1, 128.9, 128.4, 126.9,
126.3, 38.5, 21.3; HRMS [M+1]+: calcd C15H16NO 226.1232; found:
226.1240.
4-Bromo-N-methyl-N-phenyl-benzamide (6):25 Yield 52%; colourless
liquid; 1H NMR (400 MHz, CDCl3) δ 7.27–7.33 (m, 2H), 7.27 (d,
J=6.4 Hz, 2H), 7.19 (t, J=8.4 Hz, 3H), 7.05 (d, J=8.4 Hz, 2H), 3.51 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 169.5, 144.6, 134.8, 131.0, 130.4,
129.4, 126.9, 126.8, 124.1, 38.5; HRMS [M+1]+: calcd C14H13BrNO
290.0181; found: 290.0185.
+
tBuOOH
OH
H
2O
+
tBuOO
O
O
O
Ph
O
Ph
A
tBuO +CO
R1
R1
N
R2
NH
R2
O
Ph
H
O
Ph
H
B
C
O
R1
[IO]
Ph
N
D
R2
Scheme 3 Probable mechanism.
JCR1302043_FINAL.indd 631
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632 JOURNAL OF CHEMICAL RESEARCH 2013
Biphenyl-4-carboxylic acid methyl-phenyl-amide (7)24: Yield 41%;
pale yellow liquid; 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=7.2 Hz, 2H),
7.39–7.44 (m, 6H), 7.33–7.38 (m, 1H), 7.25–7.27 (m, 2H), 7.15–7.21 (m,
1H), 7.09–7.11 (m, 2H), 3.55 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.4,
145.0, 142.3, 140.1, 134.7, 129.4, 129.3, 128.8, 127.7, 127.1, 126.9, 126.5,
126.4, 38.5; HRMS [M+1]+: calcd C20H18NO 288.1388; found: 288.1381.
Received 5 July 2013; accepted 6 August 2013
Paper 1302043 doi: 10.3184/174751913X13791657394773
Published online: 7 October 2013
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NSFC (No. 21302042).
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