Green synthesis of N-(2-hydroxyethyl)anilines by the selective alkylation reaction in H2O

Article abstract of DOI:10.1080/00397911.2020.1793205

Based on our previous work, a safer and more sustainable protocol for the synthesis of N-(2-Hydroxyethyl)anilines has been developed. The synthesis included the selective alkylation reaction of aniline with 2-chloroethanol in H₂O, eliminating the need for any catalysts and solvents during synthesis. Comparing with our previous work, the salient features of this methodology are eco-friendliness, economic benefit, and the ease of obtaining target compounds. The selective alkylation reaction in H₂O is amenable to scale-up for the synthesis of N-(2-Hydroxyethyl)anilines.

Full text of DOI:10.1080/00397911.2020.1793205

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Green synthesis of N-(2-hydroxyethyl)anilines by
the selective alkylation reaction in H2O
Hui Guo , Jia Hao , Tingting Sun , Zuoyao Wang , Jian Cao & Guobao Zhang
To cite this article: Hui Guo , Jia Hao , Tingting Sun , Zuoyao Wang , Jian Cao & Guobao Zhang
(2020): Green synthesis of N-(2-hydroxyethyl)anilines by the selective alkylation reaction in H2O,
Synthetic Communications
To link to this article: https://doi.org/10.1080/00397911.2020.1793205
View supplementary material
Published online: 16 Jul 2020.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=lsyc20

R
SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2020.1793205
Green synthesis of N-(2-hydroxyethyl)anilines by the
selective alkylation reaction in H2O
Hui Guoa, Jia Haoa, Tingting Sunb, Zuoyao Wanga, Jian Caoa, and Guobao Zhanga
aHigh & New Technology Research Center of Henan Academy of Sciences, Zhengzhou, P. R. China;
bInstitue of Geographical Sciences, Henan Academy of Sciences, Zhengzhou, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 30 December 2019
Based on our previous work, a safer and more sustainable protocol
for the synthesis of N-(2-Hydroxyethyl)anilines has been developed.
The synthesis included the selective alkylation reaction of aniline
with 2-chloroethanol in H2O, eliminating the need for any catalysts
and solvents during synthesis. Comparing with our previous work,
the salient features of this methodology are eco-friendliness, eco-
nomic benefit, and the ease of obtaining target compounds. The
selective alkylation reaction in H2O is amenable to scale-up for the
synthesis of N-(2-Hydroxyethyl)anilines.
KEYWORDS
Alkylation reaction; H2O;
N-(2-Hydroxyethyl)anilines;
selectivity
GRAPHICAL ABSTRACT
NH2
OH
H2O
Cl
N
OH
OH
OH
N
H
2,2'-(phenylazanediyl)diethanol
N-(2-Hydroxyethyl)aniline
A green and efficient alternative way for the industrial synthesis of
N-hydroxyethyl anilines was developed, eliminating the need for
toxic and expensive catalysts and volatile organic solvents. The
selectivity of N-hydroxyethyl anilines obtained in H2O are signifi-
cantly increased in comparison to those traditional methods.
Introduction
Replacement or elimination of toxic reagents or volatile organic solvents in chemical
processes is one of the main goals of green chemistry. In order to achieve the goals, it
is necessary to develop greener and more sustainable synthetic strategies.[1,2] Nitrogen-
containing compounds are widely applied in organic synthesis and pharmaceutical
chemistry.[3–5] N-(2-Hydroxyethyl)anilines, which are one kind of important nitrogen-
containing compounds, continue to attract interest due to their importance as substan-
ces and intermediates of polymeric dye, organic pigments, hair dye, and other fine
chemicals. The alkylation reaction of aniline has been shown to be a very common
method for synthesis of the N-(2-Hydroxyethyl)anilines, however, the yield of objective
compound was low because of the exist of the byproduct.[6,7] Numerous attempts to
CONTACT Hui Guo
gh3324@163.com
High & New Technology Research Center of Henan Academy of Sciences,
Zhengzhou, P. R. China.
Supplemental data for this article can be accessed on the publisher's website.
ß 2020 Taylor & Francis Group, LLC

2
H. GUO ET AL.
overcome these drawbacks, Cu0 powder,[8] Fe3O4 magnetic nanoparticles-supported
EDTA–copper(II) complex (Fe3O4-EDTA–Cu(II)),[9] a heterogeneous catalyst system
composed of CuI and polystyrene-supportedN(-(4-(aminomethyl)naphthalen-1-yl)-N(-
phenyl-1H-pyrrole-2-carbohydrazide(PSAP),[10] and ruthenium pincer complex(Ru-
MACHO-BH)[11]have been used as catalysts, but these synthetic methods are limited
due to their drawbacks, such as violent reaction conditions, toxic and expensive catalysts
and hazardous results to environment. Therefore, green and controlled synthesis
method for the preparation of the N-(2-Hydroxyethyl)anilines are still highly desirable.
Although we recently reported a synthesis of such compounds through the reaction of
aniline with 2-chloroethanol in ionic liquid [BMIM]BF4 (1-butyl-3-methylimida zolium
tetrafluoroborate),[12] the concept of green chemistry encouraged us to develop a safer
and more sustainable synthetic method, meanwhile, achieve the goal of control of the
reaction depth at the one-time alkylation, and avoidance of the generation of the two-
time alkylation by-product.
H2O is not only environmentally friendly but also has many economic advan-
tages.[13–16] In addition to being an environmentally benign reaction medium,[17–20]
H2O has unique chemical and physical properties that allow it to promote many organic
reactions, such as synthesis of navenone B,[21] synthesis of quinazoline-2,4(1H,3H)-dio-
nes,[22] synthesis of sulfonylated N-Heteroaromatics,[23] aerobic oxidation of sulfides to
sulfoxides.[24] Inspired by these important breakthrough and following our continued
pursuit of developing effective and environmentally benign synthetic strategies, herein
we reported a safer and more sustainable method for the synthesis of N-(2-
Hydroxyethyl)aniline by the controllable selective alkylation reaction in H2O. Good con-
version and high selectivity could be obtained, eliminating the need for any additional
catalyst and volatile organic solvent.
Results and discussion
To establish the feasibility of this strategy as well as to optimize the reaction conditions,
the reaction of aniline with 2-chloroethanol was employed as the model (Scheme 1).
Initially, the effects of the amount of H2O on the reaction were tested. Among the dif-
ferent amount of the H2O surveyed, 1 ml was found to be the most suitable amount for
the model reaction (Table 1, Entries 1–4).
In order to maximize the product conversion and selectivity, we then tested the dif-
ferent reactant ratios (Table 1, Entries 2 and 5–8). Conversions would increase when
the ratio (2-chloroethanol/aniline) increased from 0.5:1 to 3:1, while the selectivity of N-
(2-Hydroxyethyl)aniline would decrease. The ideal ratio for the synthesis of N-(2-
Hydroxyethyl)aniline was 1:1. Other reaction temperatures including 60 and 100 ꢀC
were screened (Table 1, Entries 9 and 10), but no better result was got. It seemed that
NH2
OH
H2O
Cl
N
OH
OH
OH
N
H
2,2'-(phenylazanediyl)diethanol
N-(2-Hydroxyethyl)aniline
Scheme 1. The alkylation reaction of aniline with 2-chloroethanol in H2O.

R
SYNTHETIC COMMUNICATIONSV
3
Table 1. Optimization of the reaction conditions for the model reactiona.
Amount of
H2O (ml)
Ratio (2-chloroethanol/
aniline)
Temperature
(ꢀC)
Conversion
(%)
Selectivity
(%)
Entry
Time (h)
1
2
3
4
5
6
7
8
2
1
0.5
0.1
1
1
1
1
1
1
1
1:1
1:1
1:1
1:1
3:1
2:1
1.5:1
0.5:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
80
80
80
80
80
80
80
80
60
100
80
80
80
80
80
80
6
6
6
6
6
6
6
6
6
6
1
2
3
8
10
12
70
80
65
50
95
91
87
72
30
92
15
25
40
85
81
77
90
95
90
90
55
75
85
95
95
76
100
100
97
95
87
82
9
10
11
12
13
14
15
16
1
1
1
1
1
aConversion and selectivity determined by HPLC.
high temperature would lead the selectivity of N-(2-Hydroxyethyl)aniline decrease, while
low temperature would lead the conversion of N-(2-Hydroxyethyl)aniline decrease. It
should be noted that time has an important impact on the reaction. The conversion
increased as time prolonged. The best result was obtained when the reaction was carried
out for 8 h. Continuing to prolong the reaction time could not increase the conversion
(Table 1, Entries 2 and 11–16). Overall, the best reaction conditions for synthesizing N-
(2-Hydroxyethyl)aniline are achieved by employing the reaction of aniline with 2-chlor-
oethanol in H2O (1 ml) at 80 ꢀC for 8 h.
To explore the scope of the model reaction, we firstly substituted 2-methylaniline, 3-
methylaniline, 4-methylaniline, and 4-methoxybenzenamine under optimal reaction con-
ditions. The reactions of 3-methylaniline, 4-methylaniline and 4-methoxybenzenamine
with 2-chloroethanol in H2O proceeded smoothly and the desired N-(2-
Hydroxyethyl)anilines were obtained with good conversion and high selectivity (Table
2, Entries 2–4). But the reactions conversion of 2-methylaniline with 2-chloroethanol
was lower under the same reaction conditions because of the steric effect of substituent
(Table 2, Entry 1).
To further explore the scope of the procedure reported in Table 1, the method-
ology was evaluated by using 2-chloroaniline, 3-chloroaniline, 4-chloroaniline, and 2-
nitrobenzenamine under the same conditions. Although these reactions could proceed
smoothly, the conversions were lower due to the electrophilic effect of substituent
(Table 2, Entries 5–8). More complicated substrates, such as N-ethylbenzenamine
and a-naphthyl amine also could undergo the selective alkylation reaction and give
the desired N-(2-Hydroxyethyl)anilines (Table 2, Entries 9 and10).
A large scale reaction was attempted with 1 mol of aniline and 1 mol of 2-chloroetha-
nol in H2O. As shown in Table 2, high conversion and selectivity were obtained; this
result revealed this protocol was practical even for large scale reaction (Table 2,
Entry 11).

4
H. GUO ET AL.
Table 2. The alkylation reaction in ionic liquida.
Entry
Substrate1
Product
Conversion(%)b Selectivity(%)b
Substrate2
NH2
Cl
1
62
95
OH
OH
HN
Cl
H2N
2
75
95
OH
OH
HN
Cl
3
4
5
6
78
70
50
58
95
95
95
95
OH
OH
H2
N
HN
H
OH
Cl
O
NH2
O
N
OH
NH2
Cl
Cl
OH
OH
Cl
HN
Cl
Cl
Cl
OH
OH
H2N
HN
Cl
Cl
Cl
H2N
7
8
55
52
95
95
OH
OH
HN
Cl
OH
OH
O2N
NH2
NH2
O2N HN
HO
NH
Cl
9
60
95
OH
OH
Cl
NH
10
11
50
80
95
OH
N
NH2
OH
Cl
95c
OH
N
H
aReaction conditions: 1 mmol substrate 1, 1 mmol substrate 2, 1 ml H2O, 80 ꢀC, 8 h; bConversion and selectivity deter-
c
mined by HPLC; Reaction conditions: 1 mol substrate 1, 1 mol substrate 2, 3 ml H2O, 80 ꢀC, 8 h.
Conclusion
In this study, we developed an efficient, green, and sustainable approach for the synthe-
sis of N-(2-Hydroxyethyl)anilines. This synthetic method involves a selective alkylation
reaction of aniline with 2-chloroethanol under a catalyst-free condition in H2O.
Comparing with our previous work, advantages of this method include a significant
reduction in the amount of toxic 2-chloroethanol needed, increase of selectivity of
objective product, eliminating the need for any additional catalysts and the ease of
obtaining target compounds, thus it can provide a better alternative way for the indus-
try synthesis of N-(2-Hydroxyethyl)anilines.

R
SYNTHETIC COMMUNICATIONSV
5
Experimental
Materials and general methods
1H spectra and 13C NMR were recorded in CDCl3 with a Bruker AVANCE DMX 500
spectrometer at 400 and 100 MHz, respectively. Chemical shifts are reported in ppm
(d), relative to tetramethylsilane (TMS) as the internal standard. IR spectra were meas-
ured with a Nicolet Nexus FTIR 6700 spectrophotometer. All reactions were carried out
with efficient stirring in a round bottom flask, unless otherwise stated, and monitored
by TLC. All chemicals were obtained from commercial suppliers and were used without
further purification.
Typical procedure for alkylation of hydroxybenzenes
To a mixture of aniline (1 mmol, 93 mg) in H2O (1 ml), 2-chloroethanol (1 mmol,
80 mg) was added. After addition, the reaction was stirred for 8 h at 80 ꢀC. The reaction
was monitored by TLC. After the completion of reaction, reaction mixture was
extracted with ethyl acetate. The solvent was evaporated and the product was isolated
by column chromatography. Pale yellow oil; IR (neat) ꢀ: 3397, 3052, 3025, 2944, 2879,
1605, 1507, 1461, 1434, 1325, 1261, 1182, 1124, 1058, 995, 914, 898, 873, 754, 692,
1
504 cmꢁ1; H NMR (400 MHz, CDCl3): d ¼ 2.12(br. s, 1H), 3.27(t, J ¼ 4Hz, 2H), 3.79 (t,
J ¼ 4Hz, 2H), 3.96–3.98 (br, 1H), 6.63–6.66 (m, 2H), 6.72–6.76 (m, 1H), 7.16–7.20 (m,
2H). 13C NMR (100 MHz,CDCl3): d ¼ 46.1, 61.2, 113.2, 117.9, 129.3, 148.1. HRMS: calcd
for C8H11NO (Mþ) 137.084, found 137.084.
1
Full experimental detail, IR, H spectra, 13C NMR, HRMS. This material can be
found via the “Supplementary Content” section of this article’s webpage.
Funding
This work was financially supported by the Excellent Youth Training Program Foundation of
Henan Academy of Sciences [200402002].
References
[1] Chen, C.; Cao, Y. T.; Wu, X. X.; Cai, Y. L.; Liu, J.; Xu, L.; Ding, K. H.; Yu, L. Chin.
Chem. Lett. 2020, 31, 1078–1082. DOI: 10.1016/j.cclet.2019.12.019.
[2] Cao, H. G.; Qian, R. R.; Yu, L. Catal. Sci. Technol. 2020, 10, 3113–3121. DOI: 10.1039/
d0cy00400f.
[3] Chu, S. N.; Cao, H. G.; Chen, T.; Shi, Y. C.; Yu, L. Catal. Commun. 2019, 129, 105730.
DOI: 10.1016/j.catcom.2019.105730.
[4] Zheng, Y. H.; Wu, A. Q.; Ke, Y. Y.; Cao, H. G.; Yu, L. Chin. Chem. Lett. 2019, 30,
937–941. DOI: 10.1016/j.cclet.2019.01.012.
[5] Yu, L.; Qian, R. R.; Deng, X.; Wang, F.; Xu, Q. Sci. Bull 2018, 63, 1010–1016. DOI: 10.
1016/j.scib.2018.06.002.
[6] Alshammari, A. S.; Natte, K.; Kalevaru, N. V.; Bagabas, A.; Jagadeesh, R. V. J. Catal. 2020,
382, 141–149. DOI: 10.1016/j.jcat.2019.12.012.
[7] Llabres-Campaner, P. J.; Ballesteros-Garrido, R.; Ballesteros, R.; Abarca, B. Tetrahedron.
2017, 73, 5552–5561. DOI: 10.1016/j.tet.2017.08.006.

6
H. GUO ET AL.
[8] Martina, K.; Rinaldi, L.; Baricco, F.; Boffa, L.; Cravotto, G. Synlett. 2015, 26, 2789–2794.
DOI: 10.1055/s-0035-1560173.
[9] Mostafalu, R.; Kaboudin, B.; Kazemi, F.; Yokomatsu, T. RSC. Adv. 2014, 4, 49273–49279.
DOI: 10.1039/C4RA08137D.
[10] Yi, Z.; Huang, M. N.; Wan, Y. Q.; Zhu, X. H. Synthesis. 2018, 50, 3911–3920. DOI: 10.
1055/s-0037-1609578.
[11] Chen, J. B.; Wang, J. Q.; Tu, T. Chem. Asian J. 2018, 13, 2559–2565. DOI: 10.1002/asia.
201800759.
[12] Guo, H.; Zhuang, Y. W.; Cao, J.; Zhang, G. B. Synth. Commun. 2014, 44, 3368–3374.
DOI: 10.1080/00397911.2014.941877.
[13] Li, X. J.; Lv, C. N.; Jia, X. B.; Cheng, M. Q.; Wang, K.; Hu, Z. G. ACS Appl. Mater.
Interfaces 2017, 9, 827–835. DOI: 10.1021/acsami.6b12334.
[14] Guo, W. G.; Li, X. H.; Liu, Y.; Li, C. ACS Catal. 2018, 8, 328–341. DOI: 10.1021/acscatal.
7b02118.
[15] Park, K.; Lee, S. Org. Lett. 2015, 17, 1300–1303. DOI: 10.1021/acs.orglett.5b00303.
[16] Xie, L. Y.; Peng, S.; Liu, F.; Liu, Y. F.; Sun, M.; Tang, Z. L.; Jiang, S.; Cao, Z.; He, W. M.
ACS Sustain. Chem. Eng. 2019, 7, 7193–7199. DOI: 10.1021/acssuschemeng.9b00200.
[17] Paladhi, S.; Bhati, M.; Panda, D.; Dash, J. J. Org. Chem. 2014, 79, 1473–1480. DOI: 10.
1021/jo402515d.
[18] Yu, L.; Ren, L. F.; Xu, B.; Guo, R. Synth. Commun. 2011, 41, 3237–3245. DOI: 10.1080/
00397911.2010.517614.
[19] Butler, R. N.; Coyne, A. G. J. Org. Chem. 2015, 80, 1809–1817. DOI: 10.1021/jo502732y.
[20] Butler, R. N.; Coyne, A. G.; Cunningham, W. J.; Moloney, E. M. J. Org. Chem. 2013, 78,
3276–3291. DOI: 10.1021/jo400055g.
[21] Li, P. F.; Wang, H. L.; Qu, J. J. Org. Chem. 2014, 79, 3955–3962. DOI: 10.1021/jo5004086.
[22] Ma, J.; Han, B. X.; Song, J. L.; Hu, J. Y.; Lu, W. J.; Yang, D. Z.; Zhang, Z. F.; Jiang, T.;
Hou, M. Q. Green Chem. 2013, 15, 1485–1489. DOI: 10.1039/C3GC00091E.
[23] Xie, L. Y.; Peng, S.; Tan, J. X.; Sun, R. X.; Yu, X. Y.; Dai, N. N.; Tang, Z. L.; Xu, X. H.;
He, W. M. ACS Sustain. Chem. Eng. 2018, 6, 16976–16981. DOI: 10.1021/acssuschemeng.
8b04339.
[24] Zhang, H.; Chen, C. Y.; Liu, R. H. Synth. Commun. 2012, 42, 811–819. DOI: 10.1080/
00397911.2010.531439.