An efficient one-pot synthesis of 2-oxazolines with molecular iodine under ultrasound irradiation

Article abstract of DOI:10.1007/s11164-015-1961-1

A series of 2-oxazolines were prepared by the condensation of aldehydes with 2-aminoethanol in the presence of molecular iodine and potassium carbonate in t-BuOH at 35-40 °C under ultrasound irradiation. The easy work-up procedure and moderate to good yie

Full text of DOI:10.1007/s11164-015-1961-1

Res Chem Intermed
DOI 10.1007/s11164-015-1961-1
An efficient one-pot synthesis of 2-oxazolines
with molecular iodine under ultrasound irradiation
Nan Xiao1 Sen Hao Wang2 Ai Ying Zhang1
•
•
•
Hong Yang Li1 Peng Wang1 Wei Li1
Bao Hua Chen1 Guo Feng Chen1 Na Li1
•
•
•
•
•
Received: 6 November 2014 / Accepted: 14 February 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract A series of 2-oxazolines were prepared by the condensation of alde-
hydes with 2-aminoethanol in the presence of molecular iodine and potassium
carbonate in t-BuOH at 35–40 °C under ultrasound irradiation. The easy work-up
procedure and moderate to good yields are the advantages of this methodology.
Keywords 2-Oxazolines Á Iodine Á Aromatic aldehydes Á 2-Aminoethanol Á
Ultrasound
Introduction
2-Oxazoline derivatives are important members of the five-membered heterocycles
which are frequently found in the structures of many biologically active natural
products and some drug-like compounds (Fig. 1) exhibiting cytotoxic, neuropro-
tective, antibiotic and antifungal properties [1]. In addition, 2-oxazolines derivatives
are also valuable intermediates in organic synthesis [2, 3], excellent catalyst ligands
[4–6], chiral auxiliaries [7, 8], protecting groups [9, 10], and monomers in
polymerization reactions [11]. Due to their pharmaceutical and synthetic material
applications, the preparation of 2-oxazoline derivatives has been holding the
Electronic supplementary material The online version of this article (doi:10.1007/s11164-015-1961-1)
contains supplementary material, which is available to authorized users.
&
Guo Feng Chen
chenguofeng@hbu.edu.cn; chenguofeng@hbu.cn
1
Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and
Environmental Science, Hebei University, Wusi East Road No. 180, Baoding 071002,
People’s Republic of China
2
College of Materials Science and Engineering, Beijing University of Chemical Technology,
Beijing 100029, People’s Republic of China
123

N. Xiao et al.
N
O
O
O
H
N
O
OMe
HO
N
N
O
N
H
O
OMe
OMe
H
H
H
O
2-Indolyloxazoline
Rilmenidine
Deflazacort
Fig. 1 Examples of oxazole-containing bioactive molecules
fascination of many synthetic chemists all these years. The reaction of carboxylic
acids [12–17] or acid derivatives like ester [18–22] with 2-aminoethanol is the most
common method for the synthesis of oxazolines. In addition, other substrates such
as imidate hydrochlorides [23], N-(2-hydroxyethyl) amides [24–29], ortho esters
[30], imino ether hydrochlorides [31], aldehydes [32–37] and nitriles [38–46] have
been used to prepare the oxazolines. Despite the potential applications of the
reported procedures in the synthesis of 2-oxazoline derivatives, some of them
suffered from one or more shortcomings such as prolonged reaction times,
expensive catalysts, hazardous reaction conditions, tedious work-up procedures and
lack of general applicability. The limitations of the currently available methods have
led to calls for the development of mild and practical value methods.
In recent years, the application of molecular iodine as an efficient catalyst in
organic synthesis has received more and more attention. Molecular iodine has
several advantages as it is inexpensive, readily available, less toxic than alternatives,
and a moisture-stable catalyst for organic transformations. Many organic reactions
using molecular iodine as catalyst are often associated with mild conditions, short
reaction times and simple work-up procedures [47–53].
On the other hand, ultrasound irradiation has been considered as an important
technique in organic synthetic chemistry. In recent years, a large number of organic
reactions have been carried out in high yields, short reaction times and mild
conditions under ultrasound irradiation, especially in heterocyclic compounds
synthesis [54–56].
In continuation of our interest in the synthesis of heterocyclic compounds under
ultrasound [57–61], here we wish to report an efficient method for the synthesis of
2-oxazolines using molecular iodine and potassium carbonate under ultrasound
irradiation (Scheme 1 and 2).
Cl
O
O
I2/K2CO3, air
Cl
+
HO
NH2
t-BuOH, 35-40 oC, u.s.
N
3a
1a
2
Scheme 1 Symthesis of 2-(4-chlorophenyl)-4,5-dihydrooxazole (3a)
123

An efficient one-pot synthesis of 2-oxazolines
O
I2/K2CO3, air
R
+
HO
NH2
RCHO
t-BuOH, 35-40 oC, u.s.
N
2
1 (a-k)
3 (a-k)
Scheme 2 Synthesis of 2-oxazolines
Experimental
Apparatus, materials and characterization
All materials were commercial reagent grade and used as received. The solvents
were dried and distilled before use. Melting points were determined on a TECH X-4
melting point apparatus, and the thermometer was uncorrected. All the reactions
were monitored by thin-layer chromatography (TLC) on silica-gel GF254 glass
plates under ultraviolet light (254 nm) and all yields refer to isolated products.
Optical rotations were measured on an Autopol IV Automatic Polarimeter using a
sodium lamp operating at 589 nm. The 1H NMR (600 MHz) and 13C NMR
(150 MHz) were recorded on a Bruker AVANCE III 600 spectrometer with
tetramethylsilane (TMS) as the internal standard and CDCl3 as solvent, and
chemical shifts (d) were reported in parts per million (ppm) relative to TMS. Mass
spectrometric data were determined on Shimadzu LCMS-2010EV or a Bruker apex
ultra 7.0 T spectrometer (the accuracy was 1 ppm). The Shanghai Branson-BUG25-06
or BUG40-06 ultrasonic cleaner (with a frequency of 25 or 40 kHz and a nominal
power 250 W) was used for sonication.
Typical procedure for preparation of 2-oxazolines
A 50-mL conical flask was charged with aromatic aldehydes (1, 1 mmol), t-BuOH
(20 mL) and 2-aminoethanol (2, 4 mmol), then anhydrous K2CO3 (414 mg,
3 mmol) and I2 (762 mg, 3 mmol) were added to the above solution, respectively.
Table 1 The effect of I2, aminoethanol and temperature on the yield of 3a under ultrasound
Entry
I2 (equiv.)
Aminoethanol (equiv.)
T (°C)
Isolated yield (%)
1
2
3
4
5
6
7
8
1.0
2.0
3.0
3.0
3.0
3.0
3.0
3.0
1.1
1.1
1.1
2.0
3.0
4.0
4.0
4.0
25–30
25–30
25–30
25–30
25–30
25–30
30–35
35–40
16.2
49.8
52.6
53.1
63.9
69.7
78.5
85.7
Reaction conditions: 4-chlorobenzaldehyde (1.0 mmol), K2CO3 (3.0 mmol) in t-BuOH (20 mL), Fre-
quency: 40 kHz
123

N. Xiao et al.
The reaction flask was located in the water bath of the ultrasonic cleaner, where the
surface of reactants was slightly lower than the level of the water and irradiated at
35–40 °C for the period as indicated in Tables 1, 2, 3, 4, and 5 (the reaction was
monitored by TLC). Water temperature of the ultrasonic cleaner bath was controlled
by addition or removal of water from the ultrasonic bath. After completion of the
reaction, the solvent was evaporated under reduced pressure. The residue was
quenched with sat. aq Na2S2O3 until the iodine color almost disappeared, and then
extracted with CH2Cl2 (4 9 10 mL). The combined organic layer was dried over
Na2SO4 and filtered. CH2Cl2 was concentrated and the residue was purified on
silica-gel column chromatography (200–300 mesh) using ethyl acetate:petroleum
(6:1 v/v) as eluent. The authenticity of the known compounds 3a–3d, 3f and 3i were
established by comparing their melting points with data reported in the literature,
their 1H NMR, 13C NMR, and mass spectra. The remaining products were unknown
1
compounds and established by their H NMR, 13C NMR and mass spectrometry.
Compound 3a
2-(4-Chlorophenyl)-4,5-dihydrooxazole, white crystal. 1H NMR (600 MHz,
CDCl3): dH 7.88 (d, J = 8.5 Hz, 2H, ArH), 7.38 (d, J = 8.5 Hz, 2H, ArH), 4.43
(t, J = 9.5 Hz, 2H, CH2), 4.05 (t, J = 9.5 Hz, 2H, CH2); 13C NMR (150 MHz,
CDCl3): dC 163.8, 137.4, 129.5, 128.6, 126.3, 67.8, 55.0; m/z(ESI): 182.1
[M ? H]?.
Table 2 The effect of solvent on the synthesis of 3a
Entry
Solvent
T (°C)
Time (h)
Frequency (kHz)
Isolated yield (%)
1
C2H5OH
CH3OH
DMF
35–40
35–40
35–40
35–40
35–40
35–40
35–40
35–40
35–40
35–40
35–40
82
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
40
40
40
40
40
40
40
40
25
40
8.3
6.6
2
3
8.7
4
CH3CN
CHCl3
27.8
28.5
29.8
45.8
85.7
69.8
67.1
NR
5
6
THF
7
CH3COOC2H5
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
8
9a
10b
11c
12d
NR
Reaction conditions: 4-chlorobenzaldehyde (1.0 mmol), 2-aminoethanol (4.0 mmol), I2 (3.0 mmol),
K2CO3 (3.0 mmol) in t-BuOH (20 mL)
a
Frequency: 25 kHz
b
Operated in nitrogen atmosphere
c
Without ultrasonication with molecular iodine and potassium carbonate at 35–40 °C
Without ultrasonication with molecular iodine and potassium carbonate at reflux temp
d
123

An efficient one-pot synthesis of 2-oxazolines
Table 3 The effect of the K2CO3 on the yield of 3a under ultrasound
Entry
K2CO3 (equiv.)
T (°C)
Time (h)
Isolated yield (%)
1
2
3
4
0
35–40
35–40
35–40
35–40
4.0
4.0
4.0
4.0
61.7
73.1
77.4
85.7
1.0
2.0
3.0
Reaction conditions: 4-chlorobenzaldehyde (1.0 mmol), 2-aminoethanol (4.0 mmol), I2 (3.0 mmol) in t-
BuOH (20 mL)
Table 4 The synthesis of 2-oxazoline derivatives
Entry
R
Product Method Aa
Method Ba
MP °C [Ref.]
Time Isolated Time Isolated
(h)
yield
(%)
(h)
yield
(%)
1
4-ClC6H4
3a
3b
3c
3d
3e
3f
4
85.7
4
63.9
76–78 (77–79) [40]
41–42 (40–42) [40]
71–73 (71–72) [35]
59–61 (61.5–62) [35]
119–120
2
3-ClC6H4
4
70.4
78.8
67.2
75.1
81.6
65.9
54.2
76.5
64.5
33.7
4
47.6
41.2
53.5
58.7
40.7
45.9
44.9
67.9
44.3
22.9
3
4-CH3C6H4
4-CH3OC6H4
3-NO2C6H4
4-NO2C6H4
3,4-Cl2C6H3
4.5
5
4.5
5
4
5
5
5
6
4.5
4
4.5
4
175 (174) [35]
91–92
7
3g
8
3,4-(OCH2O)C6H3 3h
3.5
2
3.5
2
123–125
9
4-Pyridyl
3i
3j
113–114 (111–112) [46]
oil
10
11
12
13
14
a
2-Pyridyl
3
3
4-(CH3)2NC6H4
C6H5CH=CH
CH3(CH2)5
CH3(CH2)2
3k
3
3
162–165
5
NRb
NRb
NRb
5
NRb
NRb
NRb
5
5
5
5
Method A: ultrasound irradiation. Method B: stirred at 35–40 °C under silent condition
No reaction
b
Compound 3b
1
2-(3-Chlorophenyl)-4,5-dihydrooxazole, light yellow crystal. H NMR (600 MHz,
CDCl3): dH 7.94 (t, J = 1.7 Hz, 1H, ArH), 7.82–7.83 (m, 1H, ArH), 7.43–7.45 (m,
1H, ArH), 7.34(t, J = 7.9 Hz, 1H, ArH), 4.44 (t, J = 9.5 Hz, 2H, CH2), 4.06 (t,
J = 9.5 Hz, 2H, CH2); 13C NMR (150 MHz, CDCl3): dC 163.5, 134.4, 131.3, 129.6,
129.5, 128.3, 126.3, 67.8, 55.0; m/z(ESI): 182.0 [M ? H]?.
123

N. Xiao et al.
Table 5 Synthesis of chiral 2-oxazolines from 4-chlorobenzaldehyde with chiral amino-alcohols under
ultrasound
Entry Amino alcohols
Product
Time (h) Isolated
yield (%)
MP (°C)
1
3
71.0
Oil
2
3
4
4
65.3
59.9
Oil
42–44
Reaction conditions: 4-chlorobenzaldehyde (1.0 mmol), chiral amino-alcohols (4.0 mmol), I2 (3.0 m-
mol), K2CO3 (3.0 mmol) in t-BuOH (20 mL)
Compound 3c
2-(4-Methylphenyl)-4,5-dihydrooxazole, white crystal. 1H NMR (600 MHz,
CDCl3): dH 7.83 (d, J = 8.2 Hz, 2H, ArH), 7.21 (d, J = 8.0 Hz, 2H, ArH), 4.40
(t, J = 9.5 Hz, 2H, CH2), 4.04 (t, J = 9.5 Hz, 2H, CH2), 2.38 (s, 3H, CH3); 13C
NMR(150 MHz, CDCl3): dC 164.7, 141.6, 129.0, 128.1, 125.0, 67.5, 54.9, 21.5; m/
z(ESI): 162.1 [M ? H]?.
Compound 3d
2-(4-Methoxyphenyl)-4,5-dihydrooxazole, white crystal. 1H NMR (600 MHz,
CDCl3): dH 7.87–7.90 (m, 2H, ArH), 6.90–6.92 (m, 2H, ArH), 4.40 (t,
J = 9.5 Hz, 2H, CH2), 4.03 (t, J = 9.4 Hz, 2H, CH2), 3.84 (s, 3H, CH3); 13C
NMR(150 MHz, CDCl3): dC 164.4, 162.0, 129.9, 120.3, 113.7, 67.5, 55.3, 54.9;
HRMS m/z (ESI): calcd for [C10H12NO2 ? H]?178.0863, found 178.0860.
Compound 3e
1
2-(3-Nitrophenyl)-4,5-dihydrooxazole, white crystal. H NMR (600 MHz, CDCl3):
dH 8.78 (t, J = 1.8 Hz, 1H, ArH), 8.32–8.34(m, 1H, ArH), 8.28 (dt, J1 = 7.7 Hz,
J2 = 1.3 Hz, 1H, ArH), 7.61 (t, J = 8.0 Hz, 1H, ArH), 4.51 (t, J = 9.6 Hz, 2H,
CH2), 4.12 (t, J = 9.6 Hz, 2H, CH2); 13C NMR (150 MHz, CDCl3): dC 162.7,
148.3, 133.9, 129.6, 129.5, 125.8, 123.3, 68.2, 55.2; m/z(ESI): 193.0 [M ? H]?.
123

An efficient one-pot synthesis of 2-oxazolines
Compound 3f
2-(4-Nitrophenyl)-4,5-dihydrooxazole, light yellow crystal. 1H NMR (600 MHz,
CDCl3): dH 8.25–8.27 (m, 2H, ArH), 8.10–8.12 (m, 2H, ArH), 4.50 (t, J = 9.7 Hz,
2H, CH2), 4.13 (t, J = 9.6 Hz, 2H, CH2); 13C NMR (150 MHz, CDCl3): dC 162.9,
149.5, 133.5, 129.2, 123.5, 68.1, 55.2; m/z(ESI): 193.1 [M ? H]?.
Compound 3g
2-(3,4-Dichlorophenyl)-4,5-dihydrooxazole, white crystal. 1H NMR (600 MHz,
CDCl3): dH 8.03 (d, J = 1.9 Hz, 1H, ArH), 7.77 (dd, J1 = 8.4 Hz, J2 = 1.9 Hz, 1H,
ArH), 7.48 (d, J = 8.4 Hz, 1H, ArH), 4.45 (t, J = 9.5 Hz, 2H, CH2), 4.06 (t,
J = 9.5 Hz, 2H, CH2); 13C NMR(150 MHz, CDCl3): dC 162.8, 135.6, 132.7, 130.4,
130.1, 127.7, 127.3, 68.0, 55.0; m/z(ESI): 216.1 [M ? H]?.
Compound 3h
2-(3,4-Piperonyl)-4,5-dihydrooxazole, light yellow crystal. 1H NMR (600 MHz,
CDCl3): dH 7.49 (dd, J1 = 8.2 Hz, J2 = 1.6 Hz, 1H, ArH), 7.41 (d, J = 1.5 Hz, 1H,
ArH), 6.82 (d, J = 8.2 Hz, 1H, ArH), 6.01 (s, 2H, CH2), 4.40 (t, J = 9.5 Hz, 2H,
CH2), 4.02 (t, J = 9.4 Hz, 2H, CH2); 13C NMR (150 MHz, CDCl3): dC 164.2,
150.2, 147.6, 123.1, 121.8, 108.4, 108.0, 101.5, 67.6, 54.8; m/z(ESI): 192.1
[M ? H]?.
Compound 3i
2-(4-Pyridyl)-4,5-dihydrooxazole, light yellow crystal. 1H NMR (600 MHz,
CDCl3): dH 8.71 (d, J = 5.9 Hz, 2H, ArH), 7.78 (d, J = 6.0 Hz, 2H, ArH), 4.48
(t, J = 9.7 Hz, 2H, CH2), 4.10 (t, J = 9.7 Hz, 2H, CH2); 13C NMR (150 MHz,
CDCl3): dC 163.0, 150.2, 135.1, 121.9, 67.9, 55.1; m/z(ESI): 149.1 [M ? H]?.
Compound 3j
2-(2-Pyridyl)-4,5-dihydrooxazole, light yellow oil. 1H NMR (600 MHz, CDCl3): dH
8.71 (d, J = 4.6 Hz, 1H, ArH), 8.05 (d, J = 7.9 Hz, 1H, ArH), 7.77–7.80 (m, 1H,
ArH), 7.39–7.41 (m, 1H, ArH), 4.53 (t, J = 9.7 Hz, 2H, CH2), 4.13 (t, J = 9.7 Hz,
2H, CH2); 13C NMR (150 MHz, CDCl3): dC 163.9, 149.7, 146.7, 136.6, 125.5,
123.8, 68.2, 55.1; HRMS m/z (ESI): calcd for [C8H9N2O ? H]?149.0709, found
149.0712.
Compound 3k
2-(4-N,N-Dimethylaminophenyl)-4,5-dihydrooxazole, orange crystal. 1H NMR
(600 MHz, CDCl3): dH 7.79–7.81 (m, 2H, ArH), 6.66 (d, J = 9.0 Hz, 2H, ArH),
4.36 (t, J = 9.4 Hz, 2H, CH2), 4.00 (t, J = 9.4 Hz, 2H, CH2), 3.00 (s, 6H, CH3);
123

N. Xiao et al.
13C NMR (150 MHz, CDCl3): dC 165.0, 152.3, 129.5, 115.1, 111.1, 67.2, 54.8,
40.1; m/z(ESI): 191.1 [M ? H]?.
Compound 3l
2-(4-chlorophenyl)-5-methyl-4,5-dihydrooxazole, light yellow oil. [a]20 D = -
1
56.4o (c = 1.0, CH2Cl2). H NMR (600 MHz, CDCl3): dH 7.87 (d, 2H, J = 8.5,
ArH), 7.38 (d, 2H, J = 8.5, ArH), 4.83–4.88 (m, 1H, CH), 4.14 (dd, J1 = 14.5 Hz,
J2 = 9.4 Hz, 1H, CH2), 3.60 (dd, J1 = 14.5 Hz, J2 = 7.4 Hz, 1H, CH2), 1.43 (d,
3H, J = 6.2, CH3); dC 163.0, 137.4, 129.5, 128.6, 126.6, 76.5, 61.6, 21.1; HRMS
m/z (ESI): calcd for C10H11ClNO [M ? H]?196.0523, found 196.0526.
Compound 3m
2-(4-chlorophenyl)-4-ethyl-4,5-dihydrooxazole, light yellow oil. [a]20 D = 0
1
(racemate, c = 1.0, CH2Cl2). H NMR (600 MHz, CDCl3): dH 7.87–7.89 (m, 2H,
ArH), 7.37–7.39 (m, 2H, ArH), 4.46–4.49 (m, 1H, CH2), 4.21–4.26 (m, 1H, CH),
4.05 (t, 1H, J = 8.0, CH2), 1.73–1.80 (m, 1H, CH2), 1.57–1.62 (m, 1H, CH2), 1.00
(t, 3H, J = 7.4, CH3); 13CNMR (150 MHz, CDCl3): dC 162.6, 137.4, 129.6, 128.6,
126.4, 72.3, 68.1, 28.6, 10.0; HRMS m/z (ESI): calcd for C11H13ClNO
[M ? H]?210.0680, found 210.0683.
Compound 3n
2-(4-chlorophenyl)-4-isopropyl-4,5-dihydrooxazole, light green crystal. [a]20
1
D = 0 (racemate, c = 1.0, CH2Cl2). H NMR (600 MHz, CDCl3): dH 7.87–7.90
(m, 2H, ArH), 7.36–7.39 (m, 2H, ArH), 4.40–4.42 (m, 1H, CH2), 4.12–4.15 (m, 1H,
CH2), 4.07–4.11 (m, 1H, CH), 1.82–1.88 (m, 1H, CH), 1.03 (d, 3H, J = 6.7, CH3),
0.92 (d, 3H, J = 6.8, CH3); 13C NMR (150 MHz, CDCl3): dC 162.5, 137.3, 129.6,
128.6, 126.5, 72.7, 70.3, 32.8, 18.9, 18.1; HRMS m/z (ESI): calcd for C12H15ClNO
[M ? H]?224.0836, found 224.0836.
Results and discussion
To optimize the reaction conditions, synthesis of 2-(4-chlorophenyl)-4,5-dihy-
drooxazole (3a) through the condensation of 4-chlorobenzaldehyde (1a) and
2-aminoethanol (2) using molecular iodine and potassium carbonate in t-BuOH was
selected as the test cases under ultrasound irradiation. The results are summarized in
Tables 1, 2, and 3. As shown in Table 1, the molar ratio of molecular iodine had a
great influence on the reaction yield. When the equiv. of I2 was 1.0, 2.0 and 3.0 in
the presence of 1.1 molar equivalents of 2-aminoethanol, the yields of 3a were 16.2,
49.8 and 52.6 % (Table 1, entries 1–3) respectively. The dosage of 2-aminoethanol
also affected the reaction yield. When the amount of 2-aminoethanol was 2.0, 3.0,
and 4.0 mmol and other conditions were identical, the yields of 3a were 53.1, 63.9
and 69.7 %, respectively (Table 1, entries 4–6). Finally, different reaction
123

An efficient one-pot synthesis of 2-oxazolines
temperatures were assayed (Table 1, entries 6–8), setting the optimal reaction
temperature to 35–40 °C.
In addition, a series of polar solvents (C2H5OH, CH3OH, DMF, CH3CN, CHCl3,
THF and CH3COOC2H5) were also screened, giving rise to product 3a in poor yield
(Table 2, entries 1–7). All the results showed that t-BuOH was more effective for
the conversion of aldehydes to 2-oxazolines than other solvents. The same reaction
was also carried out with 25 kHz ultrasound irradiation and 3a was obtained in
69.8 % yield (Table 2, entry 9) indicating that the frequency of ultrasound
irradiation can have a big impact on the reaction. To exclude the possible affection
of atmospheric oxygen, the reaction of 1a and 2 was carried out under nitrogen
atmosphere at the same condition. A moderate decrease in yield of 3a was
demonstrated (Table 2, entry 10), showing that atmospheric oxygen may play a
certain role in this reaction. No product was obtained when the comparison of the
reaction without ultrasonication with molecular iodine and potassium carbonate at
R.T./elevated temperature (Table 2, entry 11–12).
The amount of K2CO3 was also tested and the results are summarized in Table 3
with respect to the formation of 3a. In the absence of K2CO3, only molecular iodine
with moderate oxidizing capacity was insufficient to produce 3a (Table 3, entry 1).
When three-fold K2CO3 was employed, an 85.7 % yield of 3a was observed
(Table 3, entry 4).
Based on the results above, the optimized reaction conditions were chosen for the
synthesis of 2-oxazolines as follows: aromatic aldehyde (1, 1.0 mmol), 2-ami-
noethanol (2, 4.0 mmol), I2 (3.0 mmol), K2CO3 (3.0 mmol) in t-BuOH (20 mL),
bath temperature 35–40 °C, and ultrasonic frequency 40 kHz.
Under this condition, a series of 2-oxazoline derivatives were synthesized by one-
pot reaction of aldehyde and 2-aminoethanol in the presence of molecular iodine and
potassium carbonate in t-BuOH at 35–40 °C under ultrasound irradiation. The results
are summarized in Table 4 (Method A). The yields of the 2-oxazolines were
dependent on the substituting groups present on the substrates. For aromatic
aldehydes bearing electron-withdrawing groups such as chloro- and nitro-, it
proceeded at faster rates than those containing electron-donating groups such as
methyl and methoxy: 4-chlorobenzaldehyde (1a) was converted to the desired
products in 85.7 % yield during 4 h (Table 4, entry 1), while the treatment of
4-methoxybezaldehyde (1d) with 2-aminoethanol provided the corresponding 2-(4-
methoxyphenyl)-4,5-dihydrooxazole (3d) in 67.2 % yield (Table 4, entry 4). This
was attributed to that electron-withdrawing groups on the aromatic ring can increase
the reactivity of the aldehyde to form imine which is critical in the formation of
2-oxazolines. Otherwise, these groups conjugated with the carbonyl, makes it more
electrophile, thus promoting cyclization of the intermediate. So, para-substituted
aldehydes gave products in higher yields than meta-substituted examples.
Compared with the condensation catalyzed by (diacetoxyiodo)benzene in
acetonitrile at room temperature reported in the literature [36], the present
procedure offers several advantages including faster reaction rates and higher yields.
The reaction of 4-chlorobenzaldehyde (1a) and 4-nitrobenzaldehyde (1f) with
2-aminoethanol in presence of (diacetoxyiodo)benzene in acetonitrile gave corre-
sponding products in 65 and 52 % yields in 8 and 9 h, respectively. Whereas, in the
123

N. Xiao et al.
presence of molecular iodine and potassium carbonate in t-BuOH at 35–40 °C under
ultrasound irradiation, the same experiment can be finished within 4 and 4.5 h with
85.7 and 81.6 % yields (Table 4, entries 1 and 6), respectively.
Unfortunately, when cinnamaldehyde, or aliphatic aldehyde (Table 4, entries
12–14) were used, no desired products were obtained under standard conditions. It
is considered that the aliphatic chain enlarged the required activation energy gap in
the formation of imine intermediates and prevented forming a conjugated plane that
destabilized the product.
To verify the effect of ultrasound irradiation on this reaction, the contrast test was
performed with stirring alone under silent condition at 35–40 °C (Table 4, Method
B). From the results, we can see that the reactions under silent condition gave lower
yields of the corresponding products than that under ultrasound. For example, the
synthesis of 3a and 3f were carried out under silent condition for 4 and 4.5 h with
yields of 63.9 and 40.7 %, respectively, while the same reaction under ultrasound
irradiation within the same time gave 85.7 and 81.6 % yields, respectively (Table 4,
entries 1 and 6). It is clear that ultrasound irradiation can improve the results. When
the present procedure was applied to chiral amino-alcohols, the corresponding
optically active 2-oxazolines (3l–3n) were also obtained in moderate yields
(Table 5, entries 1–3).
The reason may be the cavitation effect caused by ultrasonication. When the
reaction system was irradiated under ultrasonic waves, cavitation occurs with
microenvironment of local transient high pressure, temperature and microfluidiza-
tion, which can provide special physical and chemical conditions for the reaction
system [54–56]. These can cause the reaction to take place rapidly.
A plausible reaction mechanism for 2-oxazolines is shown in Scheme 3. Firstly,
molecular iodine bonds with the carbonyl oxygen increasing the reactivities of the
aldehydes and the aminoethanol react with the aldehyde to form Shiff bases as the
intermediate (I). Then, intramolecular nucleophilic attack of OH on the iodine-
activated group C=N to form the intermediate (II). The oxazolidine reacted with I2
H
Cl
I2/K2CO3, air
O
O
H2N
OH
t-BuOH, 35-40 oC, u.s.
+
N
I2
Cl
2
1
3
-HI
(Removed by K2CO3)
-I2
(-H2O)
I
N
H
H
I2
Cl
I2
-HI
N
N
H
O
Cl
OH
O
(Removed by K2CO3)
Cl
I
II
III
Scheme 3 Plausible reaction mechanisms for 2-oxazolines
123

An efficient one-pot synthesis of 2-oxazolines
to afford the intermediate (III). Finally, the HI was removed by K2CO3 to afford
2-oxazolines.
Conclusion
In summary, we have found an efficient method for the synthesis of 2-oxazolines by
condensation of aldehydes with 2-aminoethanol using molecular iodine in the
presence of potassium carbonate in t-BuOH at 35–40 °C under ultrasound
irradiation. The advantages of this procedure are short reaction times, and simple
experimental and work-up procedures.
Acknowledgments The project was supported by Natural Science Foundation of Hebei Province
(B2011201072).
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