Green and efficient protocol for the synthesis of N-(2-hydroxyethyl)anilines by the alkylation reaction in ionic liquid

Article abstract of DOI:10.1080/00397911.2014.941877

A green and efficient protocol for the synthesis of N-(2-hydroxyethyl)anilines by the selective alkylation reaction in ionic liquid [BMIM]BF₄ (1-butyl-3-methylimidazolium tetrafluoroborate) has been developed, eliminating the need for toxic and expensive catalysts and volatile organic solvents. The effects of the amount of ionic liquid, temperature, time, and substrate structure on the reaction were investigated. The conversion and selectivity of N-(2-hydroxyethyl)anilines obtained in ionic liquid [BMIM]BF₄ are significantly increased in comparison to those traditional methods. Furthermore, the ionic liquid could be easily separated and reused at least five times. It provided a simple and efficient alternative way for the industrial synthesis of N-(2-hydroxyethyl)anilines.

Full text of DOI:10.1080/00397911.2014.941877

1
Synthetic Communications , 44: 3368–3374, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.941877
GREEN AND EFFICIENT PROTOCOL FOR THE
SYNTHESIS OF N-(2-HYDROXYETHYL)ANILINES BY
THE ALKYLATION REACTION IN IONIC LIQUID
Hui Guo, Yuwei Zhuang, Jian Cao, and Guobao Zhang
High and New Technology Research Center of Henan Academy of Sciences,
Zhengzhou, China
GRAPHICAL ABSTRACT
Abstract A green and efficient protocol for the synthesis of N-(2-hydroxyethyl)anilines
4
by the selective alkylation reaction in ionic liquid [BMIM]BF (1-butyl-3-methylimida-
zolium tetrafluoroborate) has been developed, eliminating the need for toxic and expens-
ive catalysts and volatile organic solvents. The effects of the amount of ionic liquid,
temperature, time, and substrate structure on the reaction were investigated. The conver-
sion and selectivity of N-(2-hydroxyethyl)anilines obtained in ionic liquid [BMIM]BF
4
are significantly increased in comparison to those traditional methods. Furthermore, the
ionic liquid could be easily separated and reused at least five times. It provided a simple
and efficient alternative way for the industrial synthesis of N-(2-hydroxyethyl)anilines.
Keywords Alkylation reaction; ionic liquid; N-(2-hydroxyethyl)anilines; selectivity
INTRODUCTION
N-(2-Hydroxyethyl)anilines are important substances and intermediates of
polymeric dye, organic pigments, hair dye, and other fine chemicals. The straight-
forward method for the synthesis of N-(2-hydroxyethyl)aniline is the reaction of
0
aniline with 2-chloroethanol or ethylene oxide. However, two products, 2,2 -
0
(
(
phenylazanediyl)diethanol and N-(2-hydroxyethyl)aniline, are obtained and 2,2 -
[
1–3]
phenylazanediyl)diethanol is the main product.
Trifluoromethyl-substituted
N-(2-hydroxyethyl)aniline can be synthesized by a two-step method, but the draw-
backs of this method are that the reaction is carried out in dioxan and the total yield
is poor; furthermore, hydrochloric acid has to be used to regulate pH after the end of
[
4]
reaction. A lot of efforts have been made to overcome these drawbacks. Maurizio
Received March 27, 2014.
Address correspondence to Guobao Zhang, High and New Technology Research Center of Henan
Academy of Sciences, Zhengzhou 450002, China. E-mail: gh3324@163.com
3
368

GREEN SYNTHESIS OF N-(2-HYDROXYETHYL)ANILINES
3369
4
Scheme 1. Alkylation reaction of aniline in ionic liquid [BMIM]BF .
et al. reported that the N-(2-hydroxyethyl)aniline could be obtained by the reaction
[
of primary aromatic amines with alkylene carbonates, and Yin et al. reported that
5]
N-(2-hydroxyethyl)aniline could be produced by the reaction of amino alcohols with
[6]
aryl halides using copper as catalyst. However, no benign methods with the advan-
tages of easy operation, convenient recycling, and no organic solvents have so far
appeared for the synthesis of N-(2-hydroxyethyl)aniline by the reaction of aniline
with 2-chloroethanol.
Ionic liquids have attracted increasing attention because of their special
properties, such as good solvating ability, negligible vapor pressure, nonexplosive
[
7–9]
properties, and polymeric molecules.
number of reactions, such as the synthesis of quinazolinone derivatives, synthesis
They have been successfully applied in a
[
10]
[11]
[12]
of aromatic hydrazone,
[
Knoevenagel reaction,
reaction, and so on. We have successfully produced raspberry ketone and phenyl
acetate with ionic liquids as solvents and catalysts.
internal redox esterification
13]
[
14,15]
As part of our systematic
research into ionic liquids and continuing our investigations into industrial applica-
tions, herein we report a benign approach for the synthesis of N-(2-hydroxyethyl)-
aniline catalyzed in ionic liquids. High conversion and good selectivity could be
obtained in ionic liquid [BMIM]BF , eliminating the need for a volatile organic sol-
4
vent and additional catalyst. In particular, the ionic liquid was very easy to separate
and reuse.
For the beginning of this study, the reaction of aniline with 2-chloroethanol
was employed as the model (Scheme 1). Table 1 lists the effects of the amount of
the ionic liquid on the reaction. As can be seen in Table 1, the conversion of the
reaction would increase from 80% to 85% when the amount of ionic liquid decreased
from 1.5 to 1 mmol (Table 1, entries 1 and 2). At the same time, the selectivity of N-
(2-hydroxyethyl)aniline would increase from 90% to 92%. However, the conversion
and selectivity of the reaction would decrease when the amount of ionic liquid
decreased from 1 to 0.5 mmol (Table 1, entries 2 and 3). After the screening, the
optimal amount of ionic liquid was about 1 mmol.
a
Table 1. Effect of amount of ionic liquid on the reactions
b
b
Entry
Amount of ionic liquid (mmol)
Conversion (%)
Monoalkylation product selectivity (%)
1
2
3
1.5
1
80
85
78
90
92
89
0.5
a
ꢀ
Reaction conditions: 1 mmol aniline, 1 mmol 2-chloroethanol, 100 C, 6 h.
Conversion and selectivity determined by HPLC.
b

3370
H. GUO ET AL.
a
Table 2. Effect of ratio on the reactions
b
b
Entry
Ratio (2-chloroethanol=aniline)
Conversion (%)
Monoalkylation product selectivity (%)
1
2
3
3:1
1.5:1
1:1
100
90
65
90
92
85
a
ꢀ
Reaction conditions: 1 mmol aniline, 1 mmol [BMIM]BF
Conversion and selectivity determined by HPLC.
4
, 100 C, 6 h.
b
Then different reactant ratios were tested and the results are represented in
Table 2. The conversion of the reaction would increase when the quantity of 2-chlor-
oethanol increased from 1.5 to 3 mmol, whereas the selectivity of N-(2-hydroxyethy-
l)aniline was only 65% (Table 2, entries 1 and 2). The conversion of the reaction
would reduce when the quantity of 2-chloroethanol decreased from 1.5 to 1 mmol.
At the same time, the selectivity of N-(2-hydroxyethyl)aniline would increase slightly
(
Table 2, entry 3). Therefore, the optimal ratio was 1.5:1.
The effect of reaction temperature is shown in Table 3. The best conversion
ꢀ
and selectivity were obtained when the reaction temperature was 100 C. The conver-
ꢀ
ꢀ
sion would reduce when reaction temperature decreased from 90 C to 100 C,
whereas the selectivity would reduce when reaction temperature increased from
ꢀ
ꢀ
1
00 C to 120 C.
The effect of reaction time is shown in Table 4. The conversion increased as
time was prolonged, but selectivity decreased. The best result was obtained when
the reaction was carried out for 6 h. Continuing to prolong the reaction time could
not increase the conversion.
With the optimal reaction conditions in hands, we then examined the scope and
limitations of this strategy for other structurally diverse substrates, and the results
are listed in Table 5. The reactions of 3-methylaniline and 4-methylaniline with
2
-chloroethanol in [BMIM]BF produced the corresponding N-(2-hydroxyethyl)ani-
4
lines with good conversion and high selectivity (Table 5, entries 2 and 3), but the
reaction conversion of 2-methylaniline with 2-chloroethanol was lower under the
same reaction conditions because of the steric effect of substituent (Table 5, entry 1).
A control experiment was designed to demonstrate that the reaction was an
ionic liquid–catalyzed process. In the absence of ionic liquid, the reaction could
0
produce two products, 2,2 -(phenylazanediyl)diethanol and N-(2-hydroxyethyl)ani-
0
line, and 2,2 -(phenylazanediyl)diethanol is the main product.
a
Table 3. Effect of temperature on the reactions
ꢀ
b
b
Entry
Temperature ( C)
Conversion (%)
Monoalkylation product selectivity (%)
1
2
3
80
100
120
82
90
92
93
90
85
a
ꢀ
Reaction conditions: 1 mmol aniline, 1.5 mmol 2-chloroethanol, 1 mmol [BMIM]BF
Conversion and selectivity determined by HPLC.
4
, 100 C, 6 h.
b

GREEN SYNTHESIS OF N-(2-HYDROXYETHYL)ANILINES
3371
a
Table 4. Effect of time on the reactions
b
b
Entry
Time (h)
Conversion (%)
Monoalkylation product selectivity (%)
1
2
3
4
5
1
2
3
6
8
30
50
75
90
90
98
96
92
90
88
a
ꢀ
Reaction conditions: 1 mol aniline, 1.5 mol 2-chloroethanol, 1 mol [BMIM]BF
Conversion and selectivity determined by HPLC.
4
, 100 C.
b
a
Table 5. Alkylation reaction in ionic liquid
Monoalkylation
product selectivity (%)
b
b
Entry
1
Substrate 1
Substrate 2
Product
Conversion (%)
68
90
2
80
88
3
4
5
76
46
55
90
100
95
6
7
50
95
95
52
82
c
90
8
a
ꢀ
Reaction conditions: substrate 1=substrate 2 ¼ 1 mmol=1.5 mmol, 1 mmol [BMIM]BF
4
, 100 C, 6 h.
b
Conversion and selectivity determined by HPLC.
c
ꢀ
Reaction conditions: substrate 1=substrate 2 ¼ 1 mol=1.5 mol, 10 mmol [BMIM]BF
4
, 100 C, 6 h.

3372
H. GUO ET AL.
a
Table 6. Recycling of ionic liquid [BMIM]BF
4
b
b
Run
Conversion (%)
Monoalkylation product selectivity (%)
1
2
3
4
5
90
90
90
89
88
90
90
90
89
89
a
b
ꢀ
Reaction conditions: 1 mol aniline, 1.5 mol 2-chloroethanol, 1 mol ionic liquid, 100 C, 6 h.
Conversion and selectivity determined by HPLC.
In addition to the substrates with electron-donating groups, substrates
with electron-withdrawing groups were also investigated. The reactions of
-chloroaniline, 3-chloroaniline, and 4-chloroaniline with 2-chloroethanol in
BMIM]BF4 produced the corresponding N-(2-hydroxyethyl)anilines with poor
2
[
conversion; this was due to the electrophilic effect of substituent. The selectivity
was good for the reactions (Table 5, entries 4–6).
A more complicated compound such as a -naphthyl amine could also be used
as substrate to obtain the corresponding monoalkylation product with good selec-
tivity (Table 5, entry 7).
A large-scale reaction was attempted with 1 mol of aniline and 1.5 mol of
-chloroethanol under the same reaction conditions. As shown in Table 5, good con-
2
version and selectivity were obtained, which revealed this catalyst was practical even
for large-scale reaction (Table 5, entry 8).
The remaining ionic liquid could be reused without any additional operation.
The reaction of aniline with 2-chloroethanol was repeated five times and the results
are shown in Table 6. It could be seen that the ionic liquid remained consistent
activity and good yields were obtained.
CONCLUSION
In summary, a green and efficient method for the synthesis of N-(2-hydro-
xyethyl)anilines by the alkylation reaction in ionic liquid was reported for the first
time. High selectivity and good conversion could be obtained in [BMIM]BF . Fur-
4
thermore, the separation and recycling of the ionic liquid were easy with only a slight
loss of their activity. Considering the high conversion and good selectivity, con-
venient preparation, and easy recycling of ionic liquid, this method can provide a
good alternative for the industrial synthesis of N-(2-hydroxyethyl)anilines.
EXPERIMENTAL
1
H spectra were recorded in CDCl with a Bruker Avance DMX 500 spec-
3
trometer at 400 and 100 MHz. Chemical shifts are reported in ppm (d), relative to
tetramethylsilane (TMS) as the internal standard. Infrared (IR) spectra were
measured with a Nicolet Nexus FTIR 670 spectrophotometer. All reactions were
carried out with efficient stirring in a round-bottomed flask at room temperature,

GREEN SYNTHESIS OF N-(2-HYDROXYETHYL)ANILINES
3373
unless otherwise stated, and monitored by thin-layer chromatography (TLC). All
chemicals were obtained from commercial suppliers and were used without further
purification.
Preparation of Acidic Ionic Liquid [BMIM]BF4
[
16]
Ionic liquid [BMIM]BF was synthesized by the literature method.
The
preparation was very convenient and the structure of the ionic liquid was character-
4
1
1
ized by H NMR spectroscopy. H NMR (CDCl , 400 MHz): d ¼ 0.90 (t, 3H), 1.26
3
(
(
m, 2H), 1.77 (m, 2H), 3.85 (s, 3H), 4.16 (t, 2H), 7.67 (s, 1H), 7.74 (s, 1H), 9.05
s, 1H).
Typical Procedure for Alkylation of Hydroxybenzenes
2-Chloroethanol (1.5 mmol, 120 mg) was added to a mixture of aniline
1 mmol, 93 mg) in [BMIM]BF (1 mmol). After addition, the reaction was stirred
(
4
ꢀ
for 6 h at 100 C. The reaction was monitored by TLC. After the completion of reac-
tion, reaction mixture was extracted with ethyl acetate. The ionic liquid could be
further washed with ethyl acetate and reused several times without further purifi-
cation. The solvent was evaporated and the product was isolated by column chroma-
tography. Pale yellow oil; IR (neat) n: 3395, 3051, 3022, 2942, 2878, 1603, 1506, 1460,
ꢁ
1 1
1
432, 1322, 1263, 1180, 1122, 1057, 992, 913, 898, 871, 751, 694, 508 cm ; H NMR
(
1
400 MHz, CDCl ): d ¼ 2.12 (br. s, 1H), 3.27 (t, 2H), 3.79 (t, 2H), 3.96–3.98 (br. t,
3
H), 6.63–6.76 (m, 3H), 7.16–7.20 (m, 2H).
SUPPORTING INFORMATION
Full experimental detail, IR, and H spectra can be accessed on the publisher’s
website.
1
REFERENCES
1
2
3
4
5
. Yao, H. B.; Wang, M. L.; Zhang, Y. C.; et al. Chin. J. Org. Chem. 2003, 11, 156.
. Shi, M.; Chen, Y. J. Fluor. Chem. 2003, 2, 219.
. Shen, K. H.; Zhang, R.; Liu, J. M. Chin. J. Aanal. Chem. 2001, 1, 32.
. Li, X. F.; Li, Y. L.; Tang, S. W.; et al. J. Zhejiang Univ. Technol. 2011, 6, 596.
. Maurizio, S.; Massimo, F.; Vittorio, L.; Alvise, P.; Marco, N. Org. Biomol. Chem. 2010, 8,
5187.
6. Yin, H. Q.; Jin, M.; Chen, W.; Chen, C.; Zheng, L. K.; Wei, P.; Han, S. Q. Tetrahedron
Lett. 2012, 53, 10.
7
8
. Saha, D.; Saha, A.; Ranu, B. C. Green Chem. 2009, 11, 733.
. Bortolinia, O.; Ninoa, A. D.; Garofaloa, A.; Maiuoloa, L.; Russo, B. Synth Commun.
2010, 16, 2483.
9. Saravanamurugana, S.; Fehrmanna, R.; Riisager, A. Synth Commun. 2012, 22, 3383.
10. Wang, S. L.; Yang, K.; Yao, C. S.; Wang, X. S. Synth Commun. 2012, 3, 341.
11. Wang, H. B.; Sun, L.; Li, X. N.; Duan, J. L.; Pei, W. Synth Commun. 2011, 21, 3223.
12. Tahmassebi, D.; Wilsona, L. J. A.; Kieser, J. M. Synth Commun. 2009, 14, 2605.

3374
H. GUO ET AL.
13. Yu, Y. Y.; Hua, L.; Zhu, W. W.; Shi, Y.; Cao, T.; Qiao, Y. X.; Hou, Z. S. Synth Commun.
2013, 9, 1287.
1
1
4. Guo, H.; Zhang, G. B.; Zhuang, Y. W.; Cao, J.; Zhao, G. S. CN Patent 102584554 A, 2011.
5. Guo, H.; Zhang, G. B.; Zhuang, Y. W.; Wang, Y.; Cao, J.; Guo, X. Z. CN Patent
102942478 A, 2012.
16. Ma, C. A.; Chen, S.; Chu, Y. Q.; Mao, X. B. Acta Phys.-Chim. Sinica 2007, 4, 575.