A green and practical reduction of N-(4-chlorophenyl)-2-nitroaniline and its derivatives to corresponding N-substituted-benzene-1,2-diamines using thiourea dioxide

Article abstract of DOI:10.1016/j.tetlet.2020.151599

A new effective approach for synthesizing diverse N-substituted-benzene-1,2-diamines is reported. The treatment of N-substituted-2-nitroanilines with thiourea dioxide in the presence of sodium hydroxide efficiently formed the corresponding N-substituted-benzene-1,2-diamines, including N-(4-chlorophenyl)benzene-1,2-diamine with a good yield of 94%. The by-product is environmentally-friendly urea and is easy to separate from the product by filtration procedure that enhances the convenience of the approach.

Full text of DOI:10.1016/j.tetlet.2020.151599

Journal Pre-proofs
A green and practical reduction of N-(4-chlorophenyl)-2-nitroaniline and its
derivatives to corresponding N-substituted-benzene-1,2-diamines using thiour-
ea dioxide
Cong-Shan Zhong, Jian-Lan Cui, Si-Yuan Yu, Xiao Wang, Ning Wang
PII:
S0040-4039(20)30008-3
DOI:
https://doi.org/10.1016/j.tetlet.2020.151599
TETL 151599
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 November 2019
18 December 2019
7 January 2020
Please cite this article as: Zhong, C-S., Cui, J-L., Yu, S-Y., Wang, X., Wang, N., A green and practical reduction
of N-(4-chlorophenyl)-2-nitroaniline and its derivatives to corresponding N-substituted-benzene-1,2-diamines using
thiourea dioxide, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.151599
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Graphical Abstract
A green and practical reduction of N-(4-
chlorophenyl)-2-nitroaniline and its
derivatives to corresponding N-substituted-
benzene-1,2-diamines using thiourea dioxide
Cong-Shan Zhong, Jian-Lan Cui , Si-Yuan Yu, Xiao Wang, Ning Wang
NH2
NO2
TDO, NaOH
R
R
N
H
N
50℃,EtOH-H2O
H

1
Tetrahedron Letters
journal homepage: www.elsevier.com
A green and practical reduction of N-(4-chlorophenyl)-2-nitroaniline and its
derivatives to corresponding N-substituted-benzene-1,2-diamines using thiourea
dioxide
Cong-Shan Zhong, Jian-Lan Cui , Si-Yuan Yu, Xiao Wang, Ning Wang
School of Chemical Engineering and Technology, North University of China, Taiyuan 030051, China
ARTICLE INFO
ABSTRACT
 Corresponding author. Tel.: +86-155-132-94306; fax: +86-155-132-94306; e-mail:414559203@qq.com
Article history:
Received
A new effective approach for synthesizing diverse N-substituted-benzene-1,2-diamines is
reported. The treatment of N-substituted-2-nitroanilines with thiourea dioxide in the presence of
Received in revised form
Accepted
Available online
sodium hydroxide efficiently formed the corresponding N-substituted-benzene-1,2-diamines,
including N-(4-chlorophenyl)benzene-1,2-diamine with a good yield of 94%. The by-product is
environmentally-friendly urea and is easy to separate from the product by filtration procedure
that enhances the convenience of the approach.
2009 Elsevier Ltd. All rights reserved.
Keywords:
Thiourea dioxide
N-(4-chlorophenyl)benzene-1,2-diamine
N-substituted-benzene-1,2-diamine
N-substituted-2-nitroanilines
1. Introduction
There is considerable interest in N-substituted-benzene-1,2-diamine derivatives due to their effective bioactivities. The
diphenylamine group is an important group of organic chemistry and can be found in pharmaceutical synthesis intermediate. For
example, as one of the most important categories of N-substituted-benzene-1,2-diamine derivatives, N-(4-chlorophenyl)benzene-1,2-
diamine has been intensively employed as intermediate in clofazimine (CFZ) synthesis worldwide (the synthetic route of CFZ is shown
in Scheme 1). CFZ is an important antimycobacterial agent recommended by the World Health Organization (WHO) as a first-line drug
to treat leprosy and second-line drug to treat Multidrug-Resistant tuberculosis (MDR-TB).1 At present, millions of people still suffer
from refractory TB every year, which threaten the global progress towards the the targets of The WHO’s End TB Strategy.2 Therefore,
both the clinical use and the synthesis of CFZ are extensively attracting more and more attention.3
In particular, the early studies on the synthesis of N-(4-chlorophenyl)benzene-1,2-diamine (4a), an important intermediate of CFZ,
mainly focused on the traditional reducing agents, such as iron powder,4 zinc powder,5 and stannous chloride.6 Although these methods
are effective, a large amount of metal residues will be produced, which poses a serious threat to the environment. Additionally, the
crude product is easy to be oxidized into brown solid during the complicated post-treatment process. It is necessary to design a green
and effective reaction route for reducing N-substituted-2-nitroanilines into the corresponding diamines. It is the first proposed green
approach to synthesize 4a and N-substituted-benzene-1,2-diamine derivatives using thiourea dioxide (TDO) as a reducing agent, which
will significantly improve the synthesis efficiency of CFZ.

2
Tetrahedron Letters
NO2
NH2
Cl
Cl
F
Cl
NH2
2a
(ⅱ)
N
H
N
H
NO2
(ⅰ)
1
3a
4a
(ⅲ)
Cl
Cl
N
N
N
N
N
NHHCl
NH2
(ⅳ)
NH
NH
Cl
Cl
clofazimine
5
Scheme 1. Synthesis of CFZ. Reagents and conditions: (i) Et3N, solvent free, 140 ℃, 9 h; (ii) Fe/ NH4Cl or Zn/CH3COOH; (iii) FeCl3·6H2O,
HCl; rt, 10h; (iv) dioxane, reflux, 6 h.
As a powerful reducing agent, TDO can reduce a variety of compounds such as metal ions,7 ketones8 and aldehydes,9 and it is
currently used in the bleaching process of wool in the textile industry. The stability of TDO [(NH2)2CSO2] in alkaline solution is
significantly lower than that in neutral or acid conditions. Because a large amount of OH- in alkaline solution acts as a good
nucleophilic agent to attack the carbon center, resulting in the breaking of C-S bond and the formation of urea residue and sulfoxylate.
As a strong reducing agent, sulfoxylate can reduce the aromatic nitro groups into the corresponding amino groups.10 Scheme 2 shows
the proposed reduction mechanism. TDO is much cleaner and safer than traditional reducing agents and the
2
3(NH2)2CSO2 + 6OH
NO2
3(NH ) CO + 3H O +
(1)
(2)
3SO2
2 2
2
NH2
2
+
2
R
R
+ H2O
+
3SO2
3SO3
N
H
N
H
Scheme 2. Proposed
reduction mechanism between TDO and N-substituted-2-nitroanilines in alkaline solutions.
reduction reaction produces non-toxic wastes, such as sodium sulfite and urea.11 More importantly, the approach also has the
advantages of convenient operation and simple post-processing mode, and is very suitable for industrial production.
2. Results and discussion
Initially, the reaction conditions were optimized by using N-(4-chlorophenyl)-2-nitroaniline (3a) as a model compound and TDO as
a reducing agent. The effects of molar ratio, alkali and solvent were investigated and the results are summarized in Table 1. In theory,
the molar ratio of 3a, TDO and NaOH was 1: 3: 6 according to the proposed reduction mechanism mentioned above. But the actual
dosage of the reagents was greater than the theoretical value in the experiment.
Relying on obtained results, the influence of different ratios of 3a, TDO and NaOH were explored in EtOH-H2O (v/v, 1/3) (Table 1,
Entries 1–9). In the presence of 1 equiv. of 3a, the synthesis of compound 3a to 4a was investigated with the number of equivalents of
TDO and NaOH changing, and the yield of 4a increased as the amount of TDO increased from 3 to 5 equiv. No substantial
improvement in the yield was observed with a further increase in TDO. In these reactions, TDO was added in batches to the mixture
within 15 minutes. Meanwhile, a good yield of 92% could be obtained too when thiourea dioxide was added to the mixture slowly over
2 h (Table 1, entry 7). As a result, the optimal ratio of TDO to 3a was 5: 1 and the yields from 87 to 94% can be afforded. The effect of
the amount of NaOH on the reaction was also studied. An increase in yield was observed when the amount of NaOH increased from 5
to 10 equiv.. The molar ratio was 1: 5: 10 and a satisfactory yield of 94% was obtained by using the mixed solvent of EtOH and H2O
(v/v, 1/3) (Table 1, entry 6).
Additionally, the effects of alkali other than NaOH in the reaction mixture had not been investigated. It was speculated that the
decomposition of thiourea dioxide is related to the strength of alkalinity. The stronger the alkalinity, the stronger the promoting effect
on the decomposition of thiourea dioxide. Interested in this idea, the effect of TDO on the reduction of aromatic nitro compounds in the
presence of different alkalis was studied. Therefore, KOH, Na2CO3, K2CO3, NaHCO3 and NaAc were used in the reaction with a mixed
solvent of EtOH and H2O (Entries 10-14). Among them, in the presence of weak alkali NaHCO3, a yield of 57% was obtained.
Moreover, when NaAc was used in the reaction, no product was obtained. Na2CO3 and K2CO3 could help increase the yields to 86%
and 87%. As expected, strong base NaOH and KOH had the more positive effect on this reduction reaction after comparison in yield.
As a result, NaOH, which was cheaper and more commonly used, was more suitable in this reaction than KOH.
Owing to the poor solubility of 3a in water and the solubility of TDO in organic solvents, the reduction reaction would not actually
take place in pure water or in pure organic solvents. For this reason the reduction reactions were carried out in a mixture of water and
organic solvents. Next, Entries 15–18 showed that the reduction reaction of 3a with TDO did not occur in the presence of NaOH and
mixed solvents such as THF-H2O and CH3CN-H2O. However, using EtOH, MeOH and DMF with H2O
Table
Cl
Cl 1. Optimization of reaction condition in the reduction of 4aa
NO2
NH2
TDO, 50 ℃
N
H
N
H
3a
4a

3
Reaction
components
Molar
ratio
Solventc
(1/3)
Time
(h)
Yield（
%）d
Entry
1
3a/TDO/NaOH
3a/TDO/NaOH
1：3：6
EtOH-H2O
EtOH-H2O
2.4
2.4
68
73
2
3
1: 3.5: 7
3a/TDO/NaOH
3a/TDO/NaOH
3a/TDO/NaOH
3a/TDO/NaOH
3a/TDO/NaOH
3a/TDO/NaOH
3a/TDO/NaOH
3a/TDO/Na2CO3
3a/TDO/K2CO3
3a/TDO/KOH
1：4：8
1：5：5
1: 5: 9
EtOH-H2O
EtOH-H2O
EtOH-H2O
EtOH-H2O
EtOH-H2O
EtOH-H2O
EtOH-H2O
EtOH-H2O
EtOH-H2O
EtOH-H2O
EtOH-H2O
EtOH-H2O
DMF-H2O
2.4
2.3
1.8
1.5
2.5
1.4
1.4
2.5
2.5
2.3
2.6
-
76
87
91
94
92b
93
92
86
87
90
57
0
4
5
6
1: 5: 10
1: 5: 10
1: 6: 12
1: 7: 14
1: 5: 5
7
8
9
10
11
12
13
14
15
16
17
18
1: 5: 5
1: 5: 10
3a/TDO/NaHCO3 1: 5: 10
3a/TDO/NaAc
3a/TDO/NaOH
3a/TDO/NaOH
3a/TDO/NaOH
3a/TDO/NaOH
1: 5: 10
1: 5: 10
1: 5: 10
1: 5: 10
1: 5: 10
1.6
2.3
-
85
92
0
MeOH-
H2O
CH3CN-
H2O
THF-H2O
-
0
a Reaction conditions: compound 3a (10 mmol), alkali, solvent (20 mL). 5 equiv. TDO was added in batches within 15 minutes, stirred at 50 °C.
b Compound 3a (10 mmol), NaOH (10 equiv.), EtOH-H2O (20 mL), 5 equiv. TDO was added in batches over 2h, stirred at 50 °C.
c Volume ratio 1:3.
d Isolated yield.
as solvents could significantly promote the reduction reaction. The yield of the reaction in DMF-H2O was medium, and the reaction
time in MeOH-H2O was longer. It could be concluded that EtOH-H2O (v/v, 1/3) is the best solvent choice. Product 4a was insoluble in
water and slightly soluble in ethanol, while inorganic salts such as the by-product urea was soluble in water but not in ethanol, so when
the ratio of water to ethanol was 3: 1, the product could be successfully obtained by reaction and suspended in mixed solvents, which
could be filtered easily and enhance the convenience of the treatment. As stated before, when the molar equivalent of 3a, TDO and
NaOH was 1: 5: 10 respectively, the effective reduction of 3a was the best. Subsequently, 4a was obtained at 50 ℃ within 1.5 h and
the yield was 94% (Table 1, Entry 6).
Table 2. Traditional reaction condition in the synthesis of 4a
NO2
NH2
Cl
Cl
N
H
3a
N
H
4a

4
Tetrahedron Letters
Temperature
Reaction
Time
Yield
(%)a
Entry
Molar ratio
(℃)
components
(h)
1b
2c
3c
4c
3a/ Fe/NH4Cl
3a/ Zn/HAc
1:4.5:0.2
1:3.8:0.005
1:5:2
80
rt
2.5
3.5
1.5
3.5
81
64
76
68
3a/ NaBH4/CuS4
3a/ SnCl2
rt
1：5
70
a Isolated yield.
b
The reaction was conducted in mixed solvent EtOH-H2O (v/v, 10/1).
The reaction was conducted in EtOH.
c
For the purpose of exploring an optimum approach of the synthesis of 4a, some reactions employing traditional reducing agents to
form products were also planned. And the results are listed in Table 2. Fe/NH4Cl system could be used as a reducing agent to smoothly
reduce 3a to 4a in yield of 81%. However, the reaction generated a large amount of iron mud, which contained organic impurities
and had the difficulty in handling. When SnCl2 were selected as reductant, the reduction reaction was conducted at the reflux
temperature with a slightly longer time to yield 4a in 68%. When the reduction system of Zn/HAc or NaBH4/CuSO4 were selected, the
reaction could be carried out at room temperature, but both of them had medium yield in 64% and 76% respectively. The common
characteristic of these approaches was the difficulty of product separation from the excess metal residue. It was worth mentioning that,
the product could be obtained in good yields by simple filtration by using a new reducing agent thiourea dioxide in the reduction
reaction. And this approach was more environmentally friendly and more effective than the above experimental method.
Under the optimal conditions, a series of N-substituted-benzene-1,2-diamine derivatives were synthesized. As shown in Table 3, 1-
fluoro-2-nitro-benzene was employed as raw material to react with different aromatic anilines, aliphatic amines and imidazole in the
presence of triethylamine at 140℃. And the desired products 3a-j were obtained. Unfortunately, the meta-substitud nitroaniline were
failded to obtained owing to the low activity of 1-Fluoro-3-nitrobenzene during nucleophilic substitution reaction. N-(4-chlorophenyl)-
4-nitroaniline (3k) also had a poor yield under the same condition.12 Next, the desired N-substituted-2-nitroaniline derivatives were
treated with TDO in the presence of NaOH at 50 ℃ in EtOH-H2O (v/v, 1/3). Notably, when the substituted groups were aromatic
anilines, the yields of products were good (4a-4f, 86%-94%). Aliphatic amines as substituted groups could give moderate yields (4g-4i,
55%-74%). However, when 1-(2-nitrophenyl)imidazole (3j) and N-(4-chlorophenyl)-4-nitroaniline (3k) were used as raw material
under the same reduction reaction conditions, only trace amount of product 4j and 4k were detected. It was likely that the different
solubility of 4j and 4k in the reaction system affected the reduction process, and side reactions might occur.
To sum up, this reaction method was more suitable for the synthesis of aromatic anilines substituted derivatives with good yield.
Table
3.
Synthesis
of
N-substituted-benzene-1,2-diamine
derivatives.a
TDO(5 equiv)
NaOH(10 equiv)
NO2
NH2
F
Et3N (0.5 equiv)
NH2
R
R
+
R
140℃
N
H
N
H
NO2
50℃,EtOH-H2O
1
3a-k
4a-k
2

5
NH2
NH2
NH2
Cl
N
H
N
H
N
H
4a
4b
, 91%
4c
, 90%
, 94%
NH2
NH2
Cl
Cl
NH2
OCH3
Br
N
H
N
N
H
H
4d
, 86%
4f
, 87%
4e
, 91%
NH2
N
NH2
NH2
OH
N
H
N
H
4g
4h
4k
4i
, 74%
, 55%
NH2
, 56%
H
N
N
N
H2N
Cl
4j
, Trace
, Trace
a Reaction conditions: 1 (11 mmol), 2 (16 mmol), Et3N (5.5 mmol), solvent-free, 140 ℃, 9 h; 3a-k (10 mmol), TDO (50 mmol), NaOH (100 mmol), EtOH-H2O (20
mL,v/v, 1/3), 50 ℃. Yields refer to isolated pure products.
Conclusion
An effective system for the preparation of N-substituted-benzene-1,2-diamine derivatives with green reduction agent TDO in the
presence of NaOH was established. In particular, A new effective and useful synthetic reaction of N-(4-chlorophenyl)-2-nitroaniline
with TDO was carried out to give N-(4-chlorophenyl) benzene-1,2-diamine in yield of 94% in this study. Compared with earlier
methods, this procedure has several advantages including simplicity in experiments and work-up and no generated toxic commercial
wastes. Furthermore, This approach only needed simple filtration to give the corresponding diamines due to the poor solubility of the
products. There was no doubt that all these advantages were effective improvements to the existing methods for the synthesis of N-
substituted-benzene-1,2-diamine derivatives. And further research is also needed for the reduction reactions of various types of
nitrobenzene.
The reagent TDO was used as reducing agent for the first time in the synthesis of N-(4-chlorophenyl)benzene-1,2-diamine.
Compared with the reducing agents reported in the literature, TDO had the advantages of good stability, low environmental pollution
and inexpensive. It would provide a new approach of CFZ’s production in laboratory and industry.
Acknowledgement
We are grateful to the North University of China Analyticaland Testing Center for the NMR characterisation.
References and notes
1. World Health Organization. WHO model list of essential medicines: 20th list, March 2017, 2017.
2. World Health Organization. Global tuberculosis report 2018. Geneva, Switzerland, 2018.
3. Bannigan, P.; Durack, E.; Madden, C.; Lusi, M.; Hudson, S. P. Acs Omega. 2017, 2, 8969–8981.
4. (a) Taylor, A. M.; Vaswani, R. G.; Gehling, V. S.; Hewitt, M. C.; Leblanc, Y.; Audia, J. E.; Bellon, S.; Cummings, R. T.; Côté, A.; Harmange, J. C.
ACS. Med. Chem Lett. 2015, 7, 145–150; (b) Wang, H.; Gao, X.; Zhang, X.; Jin, H.; Tao, K.; Hou, T. Bioorg. Med. Chem. Lett. 2017, 27, 90–93.
5. (a) Liu, B.; Liu, K.; Lu, Y.; Zhang, D.; Yang, T.; Li, X.; Ma, C.; Zheng, M.; Wang, B.; Zhang, G. Molecules. 2012, 17, 4545–4559; (b) Zhang, D.; Lu,
Y.; Liu, K.; Liu, B.; Wang, J.; Zhang, G.; Zhang, H.; Liu, Y.; Wang, B.; Zheng, M. J. Med. Chem. 2012, 55, 8409–8417.
6. Kamal, A.; Babu, A. H.; Ramana, A. V.; Sinha, R.; Yadav, J. S.; Arora, S. K. Bioorg. Med. Chem. Lett. 2005, 15, 1923–1926.
7. (a) Mcgill, J. E.; Lindstrom, F. Anal. Chem. 1977, 49, 26–29; (b) Mot, A.; Zoltan, K.; Svistunenko, D. A.; Damian, G.; Silaghi-Dumitrescu, R.;
Makarov, S. V. Dalton. Trans. 2010, 39, 1464–1466; (c) Salnikov, D. S.; Dereven’kov, I. A.; Makarov, S. V.; Ageeva, E. S.; Lupan, A,; Surducan,
M.; Silaghi-Dumitrescu, R. Rev. Roum. Chim. 2012, 57, 353–359.
8. Nakagawa, K.; Minami, K. Tetrahedron Lett. 1972, 13, 343–346.
9. Dhillon, R. S. Asian. J. Res. Chem. 2013, 6, VIII.
10. (a) Radu, S. Sodium dithionite, rongalite and thiourea oxides: chemistry and application, World Scientific, 2016; (b) Koniecki, W. B; Linch, A. L.
Anal. Chem. 1958, 30, 1134–1137; (c) Huang, S. L.; Chen, T. Y. J. Chin. Chem. Soc. 1975. 22. 91–94; (d) Nakagawa, K.; Mineo, S.; Kawamura, S.;
Minami, K. Yakugaku Zasshi. 1977, 97, 1253–1256.
11. Chua, C. K.; Ambrosi, A.; Pumera, M. J. Mater. Chem. 2012, 22, 11054–11061.
12. Poor yields were observed for the reaction of 4-fluoro-1-nitrobenzene, 1-Fluoro-3-nitrobenzene with 4-chloroaniline, aniline to form N-(4-
chlorophenyl)-3-nitroaniline, 3-nitro-N-phenylaniline and N-(4-chlorophenyl)-4-nitroaniline (3k).

6
Tetrahedron
H
N
H
N
H
O2N
O2N
N
O2N
Cl
Cl
Not Detected
Not Detected
3k, 35%
Supplementary Material
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Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that
could have appeared to influence the work reported in this paper.
Graphical Abstract
A green and practical reduction of N-(4-
chlorophenyl)-2-nitroaniline and its
derivatives to corresponding N-substituted-
benzene-1,2-diamines using thiourea dioxide
Cong-Shan Zhong, Jian-Lan Cui , Si-Yuan Yu, Xiao Wang, Ning Wang
NH2
NO2
TDO, NaOH
R
R
N
H
N
H
50℃,EtOH-H2O
 Thiourea dioxide is first used in the reduction of N-substituted-2-nitroanilines
 Thiourea dioxide has the advantages of good stability and inexpensive
 This procedure do not generated toxic commercial wastes
 Simple filtration is needed to give N-(4-chlorophenyl)benzene-1,2-diamine