A facile and efficient synthesis of 2-imidazolines from aldehydes using hydrogen peroxide and substoichiometric sodium iodide

Article abstract of DOI:10.1055/s-0030-1259992

The reaction of aldehydes with ethylenediamine for the preparation of 2-imidazolines has been studied using hydrogen peroxide as an oxidant in the presence of sodium iodide and anhydrous magnesium sulfate. A mild, green, and efficient method is established to carry out this reaction in high yield. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1259992

PAPER
1599
A Facile and Efficient Synthesis of 2-Imidazolines from Aldehydes Using
Hydrogen Peroxide and Substoichiometric Sodium Iodide
E
G
fficient
S
ynthesis
u
of 2-Imidaz
o
olines from
A
-
ldehyde
y
s
i Bai,* Kai Xu, Guo-feng Chen, Yong-hui Yang, Tian-yu Li
Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Environmental Science, Hebei University,
Baoding 071002, P. R. of China
Fax +86(312)5937102; E-mail: gybai@hbu.edu.cn
Received 26 January 2011; revised 17 March 2011
been drastically reduced; hydrogen peroxide being used
as the major oxidant with only a small amount of sodium
iodide as catalyst.
Abstract: The reaction of aldehydes with ethylenediamine for the
preparation of 2-imidazolines has been studied using hydrogen per-
oxideas an oxidant in the presence of sodium iodide and anhydrous
magnesium sulfate. A mild, green, and efficient method is estab-
lished to carry out this reaction in high yield.
Initially, the synthesis of 2-phenylimidazoline from benz-
aldehyde and ethylenediamine was carried out with differ-
Key words: 2-imidazoline, hydrogen peroxide, aldehydes, ethyl- ent hydrogen peroxide systems. The reaction mixtures
enediamine, environmentally friendly process
were first analyzed by gas chromatography. Unfortunate-
ly, 2-phenylimidazoline could not be detected in the reac-
tion mixtures when hydrogen peroxide was used alone or
The synthesis of 2-imidazolines has attracted much inter- with ceric ammonium nitrate (CAN) as the oxidant
est, not only because they are important intermediates, (Table 1, entries 1, 3). Only the Schiff base from the reac-
chiral ligands, and chiral auxiliaries in organic reactions,1 tion of benzaldehyde and ethylenediamine was obtained
but also because they have found wide applications in when hydrogen peroxide was used alone, suggesting that
many biological areas including antidiabetic and antipar- hydrogen peroxide is not suitable for the transformation of
2
asitic activities. Nitriles are generally employed as the the Schiff base intermediate to 2-imidazoline. On the oth-
3
starting materials to prepare these compounds, but this er hand, benzoic acid was the only product when hydro-
method has shortcomings, such as high reaction tempera- gen peroxide/CAN system was used as the oxidant.
tures, acidic conditions, and the use of highly toxic cya- However, some other hydrogen peroxide systems such as
nide. An alternative method, using carboxylic acids and
derivatives as the starting substrates, gives 2-imidazolines Table 1 Preparation of 2-Phenylimidazoline from Benzaldehyde
4
a
with low yields or requires extended reaction times. Re- and Ethylenediamine
cently, aldehydes and ethylenediamine have been used as
N
starting materials in the preparation of 2-imidazolines.5
Ishihara has communicated that the synthesis can be per-
formed by the reaction of aldehydes with ethylenediamine
in the presence of 1.25 equivalents of molecular iodine.5a
H N
O
2
H2O2, catalyst
t-BuOH
Ph
N
H
Ph
H
H2N
1
2
Fujioka used 1.05 equivalents of N-halosuccinimides Entry
Catalyst
none
KI
Yield (%)b
5b
(
X = Cl, Br, and I) and Sayama used 2–3 equivalents of
1
2
3
4
5
6
7
8
0
21
0
pyridinium hydrobromide perbromide in the same con-
5
e
version. However, these methods are restricted by the
use of expensive and environmentally unfriendly halide
reagents (iodine, NBS/NIS/NCS, or pyridinium hydrobro-
mide perbromide) as oxidants. This shortcoming has lim-
ited their practical application and there has been great
demand for the use of a green oxidant.
CAN
NaIc
6
NaI
33
29
5
NaId
NaIc,e
NaIe
Against this context, our interest has centered on hydro-
gen peroxide, which is a universal, ecologically clean, and
convenient reagent for a series of oxidations in organic
6
synthesis. In this paper, we report our studies on the ef-
31
0
fective and green synthesis of 2-imidazolines from alde-
hydes and ethylenediamine via a new hydrogen peroxide
oxidation system. In this system, the use of halides has
9
NaIc,f
a
Reaction conditions: benzaldehyde (1 mmol), ethylenediamine (1.1
mmol), t-BuOH (10 mL), catalyst (0.4 mmol), 80 °C.
b
Determined by GC.
c
H O was added in one portion.
2
2
SYNTHESIS 2011, No. 10, pp 1599–1603
x
x.
x
x
.
2
0
1
1
d
e
f
At 50 °C.
Advanced online publication: 05.04.2011
DOI: 10.1055/s-0030-1259992; Art ID: H30011SS
Georg Thieme Verlag Stuttgart · New York
Ultrasound 40 KHz was used at 50 °C for 3 h.
Microwave 150 W was used at 50 °C for 20 min.
©

1
600
G.-y. Bai et al.
PAPER
hydrogen peroxide with potassium iodide (entry 2) and Table 2 The Effect of Anhydrous Magnesium Sulfate and Sodium
hydrogen peroxide with sodium iodide (entry 5) were Iodidea
found to have better oxidative performance in this reac-
tion. In particular, hydrogen peroxide with sodium iodide
showed the highest activity among these systems.
Entry
MgSO (g)
NaI (mmol)
Yield (%)b
4
1
2
3
4
5
6
7
8
9
0
0.4
0.6
0.8
1.0
0.4
0
33
69
74
61
79
0
In the optimization, several solvents, including tert-butyl
alcohol, ethyl acetate, ethanol, and water were tested and
the best result was achieved using tert-butyl alcohol.
Moreover, the manner of addition of the hydrogen perox-
ide was also studied. A slow addition of hydrogen perox-
ide gave higher yields than addition as a single portion
0
0
0
0.25
0.50
0.50
0.50
0.50
0.50
0.50
0.75
1.00
(
entries 4, 5).
Application of ultrasound and microwave heating can of-
7
0.2
0.4
0.6
0.8
1.0
0.4
0.4
77
94
96
97
97
87
86
ten cut down the reaction time dramatically. Unfortunate-
ly, the results showed that both ultrasound (entries 7, 8)
and microwave (entry 9) confer no great advantage to this
reaction compared with the traditional heating method.
The effect of temperature was also examined and a higher 10
yield was obtained at 80 °C than at 50 °C or at reflux.
Thus, the ratios of the reactants were optimized at 80 °C
to maximize the yield of the reaction. A ratio of 1:1.1:0.8 12
for benzaldehyde/ethylenediamine/sodium iodide was
found to be optimum for the reaction and the yield of 2-
phenylimidazoline under these conditions was 74%
1
1
1
3
a
Reaction conditions: benzaldehyde (1 mmol) and ethylenediamine
(
1.1 mmol) in t-BuOH (10 mL), 80 °C.
Determined by GC.
(
Table 2, entry 3), although still lower than our expecta-
b
tions. The main reason for this result was attributed to the
water generated in situ from the formation of the Schiff
base intermediate and the decomposition of hydrogen per- nylimidazoline. Noticeably, the yield increased greatly
oxide, preventing the desired transformation. Therefore, from 74% to 97% on adding 0.50 gram of anhydrous mag-
we attempted several methods to remove the water includ- nesium sulfate to the original system (entries 3, 10) and it
ing azeotropic removal with toluene, and addition of dif- is the best result among all the runs. On the other hand, the
ferent types of drying agents such as molecular sieves yield was also 94% on reducing the amount of sodium io-
type 4Å, anhydrous magnesium sulfate, and anhydrous dide to 0.4 mmol (entry 8) and so we opted to use 0.4
sodium sulfate. It was found that addition of a small mmol of sodium iodide as the appropriate amount for the
amount of anhydrous magnesium sulfate could markedly purpose of green synthesis.
improve the yield. Thus, addition of anhydrous magne-
The color of the reaction mixture quickly changed to deep
sium sulfate to a mixture of benzaldehyde and ethylenedi-
yellow, as iodine was initially generated after the addition
amine in the presence of hydrogen peroxide and sodium
of hydrogen peroxide to the mixture, and then slowly dis-
iodide was examined in detail for the synthesis of 2-phe-
appeared. A detailed mechanism of the reaction is pro-
N
O
H2O2, NaI
Ph
N
Ph
C
H
t-BuOH, 80 °C
H
1
2
H2N
H2N
H2O
H
N
HI
NaOH
Ph
H
5
N
N
Ph
NH2
H2O
I
H
removed by MgSO4
3
NaI
HN
I2
Ph
N
H2O2
H
4
Scheme 1 Proposed mechanism for the synthesis of 2-phenylimidazoline in the H O /NaI/MgSO system
2
2
4
Synthesis 2011, No. 10, 1599–1603 © Thieme Stuttgart · New York

PAPER
Efficient Synthesis of 2-Imidazolines from Aldehydes
1601
posed based on the above experimental phenomenon and Table 3 2-Imidazolines Prepareda
results, as shown in Scheme 1. Firstly, the intermediate 4
Entry Aldehyde
Product
Yield (%)b,c
96
is formed via cyclization of the Schiff base intermediate 3,
obtained from the corresponding aldehyde and ethylene-
diamine without any catalyst, as Fujioka has described.5b
Then, 4 reacts with the in situ generated iodine, from the
oxidation of sodium iodide by hydrogen peroxide, to form
H
N
O
1
N
O
O
5
c
5d
the key intermediate 5, as Gogoi and Ishihara have de-
scribed, which then eliminates hydrogen iodide to gener-
ate the desired imidazoline. The hydrogen iodide is
neutralized by sodium hydroxide, which is the by-product
of the reaction of sodium iodide and hydrogen peroxide,
to regenerate the sodium iodide catalyst and water. Final-
ly, the water is removed by anhydrous magnesium sulfate
and the hydrogen peroxide oxidation process can recycle
effectively.
H
N
2
O
quant
97
O
O
N
H
N
O
3
O2N
2
O N
N
O2N
O2N
H
N
4
O
74
N
The ineffectiveness of the ultrasound and microwave irra-
diation can be ascribed to the fact that both can accelerate
the decomposition of hydrogen peroxide rather than its re-
action with sodium iodide.
NO2
NO2
H
N
5
O
62
99
98
N
Based on the above results, a series of aldehydes were
treated with ethylenediamine in the presence of hydrogen
peroxide/sodium iodide/anhydrous magnesium sulfate
under the same conditions to provide the corresponding 2-
imidazolines in moderate to excellent yields, as shown in
Table 3.
H
O
N
6
Cl
Cl
Cl
N
Cl
H
N
7
O
N
As listed in Table 3, it can be seen that most of the reac-
tions between the aldehydes with ethylenediamine with
the hydrogen peroxide/sodium iodide/anhydrous magne-
sium sulfatesystem proceeded smoothly to give the corre-
sponding 2-imidazolines in good yields. Reactions of
substrates possessing both electron-withdrawing (entries
Cl
Cl
H
N
8
O
89
88
N
Cl
Cl
H
N
9
O
3
, 6) and electron-donating (entries 2, 10, 11) groups pro-
Cl
Cl
N
ceeded well, with the yields all above 91%. Thus, elec-
tronic effects seem not to be prominent in this reaction.
Moreover, steric effects on the benzene ring were also
perceived. The o-substituted aldehydes (entries 5, 8) gave
rather lower yields than the m- and p-substituted alde-
hydes (entries 4, 7 and entries 3, 6), suggesting that the
main effect is steric factor rather than electronic.
H
O
N
1
0
1
94
91
N
H
N
O
1
MeO
MeO
N
In summary, the hydrogen peroxide/sodium iodidesystem
has been employed as a novel, mild, and efficient means
a
Reaction conditions: aldehyde (1 mmol), ethylenediamine (1.1
mmol), NaI (0.4 mmol), and MgSO (0.5 g) in t-BuOH (10 mL),
4
for the preparation of 2-imidazolines from aldehydes and 80 °C.
b
Isolated yield.
ethylenediamine in excellent yields in the presence of an-
hydrous magnesium sulfate. In addition, the reactions pro-
ceed under environmentally friendly conditions.
c
All the products were confirmed by mp, H NMR, 13C NMR, and IR
1
data (see experimental), which corresponded to the reported materi-
als.
5
c,h,8–12
Sonication was performed in Kunshan KQ-300VDE ultrasonic
cleaner, the microwave reactions were carried out in DISCOVER S-
Class chemical synthesis system of CEM Corporation. Flash col-
umn chromatography was performed on silica 200–300 mesh. Melt-
ing points were measured with a XT-4 melting point apparatus and
are uncorrected. Reaction mixtures were analyzed by gas chroma-
tography using a 30 m SE-30 capillary column. IR spectra were re-
the internal standard. Mass spectra were recorded on Bruker APEX-
Ultra 7.0-T spectrometer.
2-Imidazolines; General Procedure
A mixture of aldehyde (1.0 mmol), ethylenediamine (1.1 mmol),
and t-BuOH (10 mL) was stirred for 20 min in a round-bottomed
flask (25 mL). NaI (0.06 g, 0.4 mmol) and anhyd MgSO (0.5 g)
4
1
13
corded on a Varian 640-FTIR spectrophotometer. H NMR and
C
were then added and this mixture was kept at 80 °C with stirring.
During this time aq 30% H O was added dropwise slowly until the
NMR spectra were recorded at 600 MHz and 150 MHz, respective-
2
2
ly, on a Bruker spectrometer in CDCl or DMSO-d using TMS as
color of I was not discharged. After workup, the reaction mixture
3
6
2
was quenched with sat. aq Na S O (2 mL) and the precipitate was
2
2
4
Synthesis 2011, No. 10, 1599–1603 © Thieme Stuttgart · New York

1
602
G.-y. Bai et al.
PAPER
1
collected by filtration. The products were purified by column chro-
H NMR (600 MHz, CDCl ): d = 7.79 (s, 1 H), 7.65 (d, J = 7.7 Hz,
3
matography on silica gel using EtOAc–Et N (100:1) as eluent
1 H), 7.42 (d, J = 8.0 Hz, 1 H), 7.34 (t, J = 7.9 Hz, 1 H), 4.75 (s, 1
3
(Table 3).
H), 3.80 (s, 4 H).
1
3
C NMR (150 MHz, CDCl ): d = 163.58, 134.48, 132.30, 130.59,
3
2
-Phenylimidazoline
1
29.72, 127.24, 125.07, 50.45.
9
Yield: 96%; mp 99–101 °C (Lit. mp 100–101 °C).
–
1
IR (KBr): 3196, 2925, 1604, 1507, 1266, 979, 694 cm .
2-(2-Chlorophenyl)imidazoline
Yield: 89%; mp 64 °C (Lit. mp 69–70 °C).
9
1
H NMR (600 MHz, CDCl ): d = 7.80 (d, J = 7.1 Hz, 2 H), 7.45 (t,
J = 7.3 Hz, 1 H), 7.40 (t, J = 7.4 Hz, 2 H), 5.06 (s, 1 H), 3.77 (s, 4
3
–
1
IR (KBr): 3139, 2933, 1612, 1502, 1278, 980, 766 cm .
H).
1
H NMR (600 MHz, CDCl ): d = 7.79 (dd, J = 7.6, 1.8 Hz, 1 H),
3
1
3
C NMR (150 MHz, CDCl ): d = 164.74, 130.56, 130.53, 128.41,
7.40 (dd, J = 8.0, 1.1 Hz, 1 H), 7.35 (td, J = 7.8, 1.8 Hz, 1 H), 7.30
(td, J = 7.5, 1.2 Hz, 1 H), 5.20 (s, 1 H), 3.94 (s, 2 H), 3.66 (s, 2 H).
3
1
26.96, 50.29.
1
3
C NMR (150 MHz, CDCl ): d = 163.54, 131.90, 131.32, 131.02,
3
2
-(1, 3-Benzodioxol-5-yl)imidazoline
1
30.49, 130.16, 126.94.
1
2
Yield: quant; mp 178–180 °C (Lit. mp 178 °C).
–
1
IR (KBr): 3174, 2928, 2788, 1580, 1035, 925, 825 cm .
2-(2,4-Dichlorophenyl)imidazoline
Yield: 88%; mp 98–100 °C (Lit. mp 111–112 °C).
9
1
H NMR (600 MHz, CDCl ): d = 7.31 (d, J = 1.7 Hz, 1 H), 7.28–
.23 (m, 1 H), 6.81 (d, J = 8.1 Hz, 1 H), 6.01 (s, 2 H), 4.66 (s, 1 H),
3
–
1
7
3
IR (KBr): 3134, 2923, 1606, 1504, 1051, 978, 800 cm .
.77 (s, 4 H).
1
H NMR (600 MHz, CDCl ): d = 7.76 (d, J = 8.4 Hz, 1 H), 7.42 (d,
3
1
3
C NMR (150 MHz, DMSO-d ): d = 162.48, 148.20, 146.52,
J = 2.0 Hz, 1 H), 7.29 (dd, J = 8.4, 2.0 Hz, 1 H), 5.16 (s, 1 H), 3.79
6
1
24.20, 120.92, 107.24, 106.53, 100.79, 48.99.
(s, 4 H).
1
3
C NMR (150 MHz, CDCl ): d = 162.59, 136.40, 132.65, 132.22,
3
2
-(4-Nitrophenyl)imidazoline
1
29.99, 128.94, 127.32, 50.44.
5
c
Yield: 97%; mp 232–234 °C (Lit. mp 231 °C).
–
1
IR (KBr): 3176, 2937, 1581, 1520, 1336, 1108, 858 cm .
2-(4-Methylphenyl)imidazoline
8
1
Yield: 94%; mp 178–180 °C (Lit. mp 181 °C).
H NMR (600 MHz, CDCl ): d = 8.27 (d, J = 8.8 Hz, 2 H), 7.95 (d,
3
–
1
J = 8.8 Hz, 2 H), 4.80 (s, 1 H), 4.07 (s, 2 H), 3.65 (s, 2 H).
IR (KBr): 3136, 2925, 1600, 1494, 1271, 985, 827 cm .
1
3
1
C NMR (150 MHz, DMSO-d ): d = 162.65, 148.85, 136.89,
H NMR (600 MHz, CDCl ): d = 7.68 (d, J = 8.1 Hz, 2 H), 7.21 (d,
6
3
1
28.81, 123.94, 49.97.
J = 7.9 Hz, 2 H), 3.77 (s, 4 H), 2.38 (s, 3 H).
1
3
C NMR (150 MHz, DMSO-d ): d = 164.01, 140.27, 129.18,
6
2
-(3-Nitrophenyl)imidazoline
1
28.36, 127.49, 49.97, 21.41.
9
Yield: 74%; mp 158–159 °C (Lit. mp 156–157 °C).
–
1
IR (KBr): 3145, 2933, 1597, 1521, 1348, 860, 698 cm .
2-(4-Methoxyphenyl) imidazoline
Yield: 91%; mp 136–138 °C (Lit. mp 136–138 °C).
5
h
1
H NMR (600 MHz, CDCl ): d = 8.59 (s, 1 H), 8.31 (d, J = 8.5 Hz,
H), 8.18 (d, J = 7.8 Hz, 1 H), 7.61 (t, J = 8.0 Hz, 1 H), 4.88 (s, 1
3
–
1
1
IR (KBr): 3128, 2859, 1607, 1492, 1252, 1029, 839 cm .
H), 3.86 (s, 4 H).
1
H NMR (600 MHz, CDCl ): d = 7.73 (d, J = 8.9 Hz, 2 H), 6.91 (d,
3
1
3
C NMR (150 MHz, CDCl ): d = 162.62, 148.19, 133.04, 132.24,
J = 8.9 Hz, 2 H), 4.72 (s, 1 H), 3.84 (s, 4 H), 3.77 (s, 3 H).
13
3
1
29.58, 125.20, 121.90, 50.44.
C NMR (150 MHz, CDCl ): d = 164.36, 161.44, 128.52, 123.03,
3
1
13.72, 55.32, 50.55.
2
-(2-Nitrophenyl)imidazoline
1
0
Yield: 62%; mp 96–98 °C (Lit. mp 98 °C).
–
1
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
IR (KBr): 3160, 2929, 1603, 1525, 1363, 1267, 849 cm .
1
H NMR (600 MHz, CDCl ): d = 7.95 (d, J = 8.1 Hz, 1 H), 7.65 (s,
H) 7.64 (s, 1 H), 7.60–7.53 (m, 1 H), 4.72 (s, 1 H), 3.79 (s, 4 H).
3
1
1
3
Acknowledgment
C NMR (150 MHz, CDCl ): d = 162.43, 148.24, 132.93, 130.58,
3
1
30.47, 127.41, 124.09, 50.76.
The authors thank Professor L. M. Harwood for his assistance.
Financial support by the National Natural Science Foundation of
China (20806018) and the Science Project of the Hebei Education
Department (ZD200910) is gratefully acknowledged.
2
-(4-Chlorophenyl)imidazoline
1
1
Yield: 99%; mp 188 °C (Lit. mp 188 °C).
–
1
IR (KBr): 3108, 2922, 1601, 1465, 1270, 837, 728 cm .
1
H NMR (600 MHz, CDCl ): d = 7.72 (d, J = 8.5 Hz, 2 H), 7.38 (d,
3
References
J = 8.5 Hz, 2 H), 4.73 (s, 1 H), 3.77 (s, 4 H).
1
3
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–
1
IR (KBr): 3148, 2928, 1604, 1273, 979, 758, 707 cm .
Synthesis 2011, No. 10, 1599–1603 © Thieme Stuttgart · New York

PAPER
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