Nitrilotris(Methylenephosphonic Acid) as a New Highly Efficient and Recyclable Br?Nested Acid Catalyst for the Synthesis of Quinoxaline Derivatives under Mild and Green Conditions

Article abstract of DOI:10.1080/10426507.2014.990017

Nitrilotris(methylenephosphonic acid) has been introduced as a novel organocatalyst for the preparation of quinoxalines. It can efficiently catalyze the synthesis of quinoxaline derivatives from 1,2-diamines and 1,2-diketones under mild, efficient, and eco-friendly conditions. Excellent yields, very short reaction times, safety, and recyclability of the catalyst system are other features of the proposed method.

Full text of DOI:10.1080/10426507.2014.990017

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Nitrilotris(methylenephosphonic acid) as a new highly
efficient and recyclable brønested acid catalyst for the
synthesis of quinoxaline derivatives under mild and
green conditions
Safoura Fathia & Ali Reza Sardariana
a Department of Chemistry, College of Sciences, Shiraz University, Shiraz 75454, Iran, E-mail:
Accepted author version posted online: 06 Apr 2015.
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To cite this article: Safoura Fathi & Ali Reza Sardarian (2015): Nitrilotris(methylenephosphonic acid) as a new highly
efficient and recyclable brønested acid catalyst for the synthesis of quinoxaline derivatives under mild and green conditions,
Phosphorus, Sulfur, and Silicon and the Related Elements, DOI: 10.1080/10426507.2014.990017
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Nitrilotris(methylenephosphonic acid) as a new highly efficient and recyclable brønested
acid catalyst for the synthesis of quinoxaline derivatives under mild and green conditions
Safoura Fathia and Ali Reza Sardariana,*
Department of Chemistry, College of Sciences, Shiraz University, Shiraz 75454, Iran
*E-mail: sardarian@susc.ac.ir; s.fathi2007@gmail.com;
Tel.: +98-711-2284822; fax: +98-711-2286008
Abstract
Nitrilotris(methylenephosphonic acid) has been introduced as a novel organocatalyst for the
preparation of quinoxalines. It can efficiently catalyze the synthesis of quinoxaline derivatives
from 1,2-diamines and 1,2-diketones under mild, efficient, and eco-friendly conditions. Excellent
yields, very short reaction times, safety and recyclability of the catalyst system are other features
of the proposed method.
Keywords: Nitrilotris(methylenephosphonic acid); 1,2-Diamines; 1,2-Diketones ; Quinoxalines;
Organocatalyst; Recyclable catalyst
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Introduction
Developing operationally simple and environmentally benign routes for organic compounds
having high synthetic as well as biological potential is one of the fundamental objectives in
synthetic organic chemistry [1]. Quinoxaline derivatives are an important class of nitrogen-
containing heterocycles with a diverse range of biological activity and are useful intermediates in
organic synthesis [2]. Therefore, synthesizing quinoxaline derivatives has been the subject of
many researches and a variety of strategies has been reported in the literature including the
coupling of α-diazoketones with aryl 1,2-diamines[3], reductive cyclization of 1,2-dicarbonyl
compounds with 2-nitroanilines[4], oxidative cyclization of α-hydroxyketones with o-
phenylenediamine[5], the reaction of α-ketoximes and 1,2-diamines[6], oxidative coupling of
epoxides and ene-1,2-diamines[7], reaction of o-phenylenediamine with α-bromoketone[8].
Moreover, direct condensation of 1,2-diamines and 1,2-diketones has been applied for
preparation of quinoxaline derivatives as the most simple, straightforward and popular method.
A variety of reagents has been used to promote this transformation such as AcOH[9],
[12]
montmorillonite K-10 [10], Polyaniline sulfate salt [11], cerium(IV) ammonium nitrate
,
sulfamic acid [13], Wells-Dawson heteropolyacid [14], ionic liquid 1-n-butylimidazolium
tetrafluoroborate [15], zirconium tetrakis(dodecylsulfate) [16], iodine [17], gallium(III) triflate [18], β-
cyclodextrin[19], nanomagnetic Fe3O4[20] , NbCl5[21],Cu/SBA-15[22],and Pd/SBA-15[23]
.
Although these methods are useful and suitable for specific synthetic situation, these methods
suffer from one or more disadvantages such as long reaction times[10,13,20], high temperatures[19]
,
using expensive catalysts[18], using toxic solvents[11,13] as well as toxic metal-based catalysts
[12,18,21],
, tedious work up[17], the requirement of microwave[24] or ultrasound irradiation[25],
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cumbersome experiment and multistep procedures for the catalyst preparation[22,23]. Therefore,
design and introduction of a simple, safe, cost effective, efficient, and benign method is still
needed for the synthesis of quinoxaline derivatives.
Compared with the traditional metal-based catalysts, organocatalysts have drawn much attention,
owing to their low toxicity, operational simplicity and high efficiency[26] . One of the attractive
phosphonic acid derivatives is nitrilotris(methylenephosphonic acid) (NTMPA), whose formula
can be also represented as the zwitterion form due to a different way of proton binding (Scheme
1).
The solid state of NTMPA is a white crystalline powder and it is soluble in water [27]. Although
there are many papers which have reported the application of NTMPA as a chelating agent with
different metal atoms [28], there is no report on its application in organic synthesis.
These suitable and interesting features of NTMPA encourage us to study its efficiency in a
simple, practical and environmentally benign synthesis of quinoxaline derivatives from α-
diketones and o-phenylenediamines.
Results and Discussion
For optimization of the reaction parameters, the preparation of 2,3-diphenylquinoxaline from
benzil and o-phenylenediamine was chosen as the model reaction (Scheme 2).
A blank reaction was carried out using benzil and o-phenylenediamine in ethanol (2 mL) at room
temperature in the absence of NTMPA, which resulted in low yield, 40 %, even after a period of
12 h. The model reaction using NTMPA (10 mol%), in ethanol (2 mL) afforded a low yield of
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desired product (Table 1, entry 2) although no product was achieved in water as solvent (Table 1,
entry 3). The application of a water/ethanol mixture (50:50) was able to complete the reaction
quickly and give a quantitative yield (Table 1, entry 7). Encouraged by this promising result,
water/ethanol mixture (50:50) was chosen as a green medium to perform the rest of study (Table
1). The effect of other organic solvents such as acetonitrile, ethyl acetate and dichloromethane
was also checked on the model reaction. The model reaction did not proceed as well as in the
mixture of water/ethanol (Table 1, entries 4-6).
In the next step, the effect of catalyst amount on the model reaction was studied at room
temperature. When 10 mol% of the catalyst was used, a complete conversion of the starting
material to the corresponding quinoxaline was observed (Table 1, entry 7). Using lower amount
of the catalyst, 7.5 and 5mol%, gave the same results (Table 1, entries 8 and 9) but further
decreasing in the catalyst loading, 2.5mol%, resulted in lower conversion (Table 1, entry 10).
Thus 5 mol% of NTMPA was chosen as the appropriate amount of the catalyst in the synthesis
of quinoxaline derivatives.
With the optimized reaction parameters in hand, the efficiency of NTMPA on the preparation of
quinoxalines using variety of 1,2-diamines and 1,2-diketones was explored at room temperature
in water/ethanol mixture (50:50), which the corresponding results have been summarized in
Table 2.
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The reaction of o-phenylenediamine with various aromatic 1,2-diketones (Table 2, entries 1, 2)
resulted in high yield of the substituted quinoxalines. Anisil, as a 1,2-diketone, with two
electron-donating methoxy substitutions reacted with several of o-phenylenediamines in longer
times and with slightly lower yields compared with benzil (Table 2, entries 2, 6, 9 and 14). Also
the generality of this catalytic reaction was confirmed by examination of the reaction of variety
of o-phenylenediamines with 2,3-butanedione, as an aliphatic 1,2-diketone, and 1-
phenylpropane-1,2-dione. In all of these reactions, the related products were obtained in high
yields and short reaction times (Table 2, entries 3, 4,7,10 and 13).
On the other hand, by in the presence of electron-donating substituents in 1,2-diamine moiety,
excellent yields of products and short time of reactions were observed. For example 4-methyl-
1,2-phenylenediamine (Table 2, entries 5-7) and 4,5-dimethyl-1,2-phenylenediamine (Table 2,
entry 16) were active and afforded their corresponding quinoxalines very quickly. Whereas a
reverse effect was observed with electron withdrawing substituent in 1,2-diamine part, such as 4-
chloro-1,2- phenylenediamine (Table 2, entries 8-10).
Although nitrilotris(methylenephosphonic acid) worked under homogenous conditions, it could
conveniently be handled and removed from the reaction mixture. Hence, for investigation of its
recyclability power, condensation of benzil and o-phenylenediamine was selected as model
reaction. This organocatalyst was simply separated from the reaction mixture by evaporation of
water and ethanol, and was reused for 5 cycles with small changes in yields (Table 3).
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In order to show the effectiveness of our proposed method to prepare quinoxalines, we compared
the obtained results from our protocol in the presence of 5 mol% of NTMPA in H2O/EtOH
(50:50) at room temperature with the some reported catalysts in literatures (Table 4).
According to the results exhibited in Table 4, it was apparent that NTMPA, as an organocatalyst,
not only catalyzes the synthesis of 2, 3-diphenylquinoxaline in eco-friendly and metal free
condition but also produces the desired product at higher yield and in shorter reaction time
compared with other studied catalyst.
Experimental
General experimental procedure for the synthesis of quinoxaline derivatives
A mixture of 1,2-diamines (1 mmol) and 1,2-dicarbonyls (1 mmol) in ethanol (3 mL) was
poured to the solution of NTMPA (5 mol%, 15 mg) in distilled water (3 mL) at room
temperature. The reaction was monitored by thin-layer chromatography (TLC). After completion
of the reaction, water (10 mL) was added, and the mixture was extracted with dichloromethane
(3×10 mL). The organic layer was dried over anhydrous Na2SO4, and concentrated to give the
crude product. The crude product was purified by recrystallization from ethanol. All the products
1
were characterized by comparison of their melting points with known compounds and H NMR
spectra.
Conclusions
In summary, we have introduced a new organocatalyst in organic synthesis with exceptional
catalytic activity in acid-catalyzed quinoxaline preparation. This offered protocol works under
eco-friendly, metal free, aqueous media and mild reaction conditions. These advantages along
with its simple work-up procedure and reusability of the catalyst make NTMPA a highly
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valuable catalyst in organic chemistry and our method more compatible with green chemistry
rules. Further studies on other applications of the mentioned catalyst are currently in progress in
our laboratory.
Acknowledgments
We are grateful to research council of Shiraz University for the partial support of this work.
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Table 1. Optimization of solvents and NTMPA amount on the model reaction
Entry
Catalyst (mol%)
Solvent
Ethanol
Ethanol
Water
EtOAc
Time (min) Conversion (%)
1
2
3
4
5
6
7
8
9
0
20
30
90
60
120
45
5
5
5
5
20
45
0
57
10
10
10
10
10
10
10
7.5
5
CH2Cl2
acetonitrile
H2O/Ethanol
H2O/Ethanol
H2O/Ethanol
H2O/Ethanol
H2O/Ethanol
67
100
100
100
95
10
11
2.5
1.0
30
92
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Table 2. Catalyzed synthesis of quinoxalines by nitrilotris(methylenephosphonic acid) at room
temperature
O
O
R1
R2
NH2
N
N
R1
R2
+
NH2
1
2
3a-q
Time Yield
M.p.
(Lit.)
Entry
1
1,2-Diamine
1,2-Diketone Product
Ref.
[29]
(min)
(%)
O
Ph
NH2
125-127
3a
3b
3c
3d
5
97
NH2
NH2
NH2
NH2
NH2
NH2
NH2
O
(128-129)
Ph
O
O
PhOCH3-4
149-151
2
3
4
16
5
91
96
94
[29]
[30]
[24]
(151-152)
PhOCH3-4
CH3
O
103-105
O
O
(105-106)
CH3
Ph
54-56
(55)
10
O
CH3
Ph
H3C
H3C
NH2
O
133-135
5
6
3e
3f
8
91
94
[30]
[31]
(135-137)
NH2
NH2
NH2
O
Ph
O
O
PhOCH3-4
124-126
25
(125-127)
PhOCH3-4
CH3
H3C
NH2
NH2
O
88-90
(91)
7
3g
10
96
[32]
O
CH3
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Cl
Cl
NH2
NH2
O
O
Ph
117-119
8
9
3h
3i
3j
10
25
86
83
[33]
[34]
(115-116 )
Ph
NH2
NH2
O
O
PhOCH3-4
PhOCH3-4
PhCH3-4
148-150
(151-152 )
Cl
NH2
NH2
O
O
88-90
10
11
10
17
89
90
[35]
[36]
(89-91)
PhCH3-4
O
PhC
NH2
O
O
Ph
Ph
140-142
3k
NH2
(139-140)
O2N
O2N
NH2
NH2
O
O
Ph
191-193
3l
12
13
30
35
86
82
[31]
[37]
(193-194)
Ph
NH2
NH2
O
CH3
135-137
3m
(134-135)
O
CH3
O2N
NH2
NH2
O
O
PhCH3-4
191-193
3n
3o
14
15
60
15
85
90
[31]
[38]
(192-194)
PhCH3-4
Ph
O
NH2
NH2
158-160
(158)
O
Ph
Ph
Ph
H3C
H3C
NH2
NH2
O
O
176–177
3p
16
35
80
[20]
(176–178)
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O
O
Ph
NH2
NH2
144-146
3q
17
24
92
[39]
(144-145)
N
Ph
a 1,2-diamine (1 mmol), benzil (1 mmol) and 0.015 g catalyst were stirred in EtOH/H2O [1/1
(v/v)] at room temperature
b Isolated yields
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Table 3. Recycling survey of nitrilotris(methylenephosphonic acid)
Run Number
Yield
1
100
5
2
100
5
3
4
5
6
98
10
98
25
96
25
92
50
Time
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Table 4. Comparison of the efficiency of some reported catalysts used in the synthesis of 2, 3-
diphenylquinoxaline with NTMPA
Entry
Catalyst
Iodine
Conditions
CH3CN/RT
Time (min)
Yield (%)
98
Ref.
[40]
1
2
3
4
5
6
7
3
20
33
150
5
Polyaniline-sulfate salt
Nano-TiO2
Mont-K-10a
Ga(OTf)3
CH2Cl2/RT
95
[11]
Solvent free/RT
H2O/RT
88
[41]
100
99
[10]
Ethanol/H2O/RT
Ethanol/H2O/RT
H2O/EtOH/RT
[18]
CSAb
60
5
95
[42]
NTMPA
100
This work
a Mont-K-10:Montmorilonite-K-10
b CSA: cellulose sulfuric acid
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O
O
P
OH
P
HO
HO
OH
N
HO
HO
NH2
NH2
O
O
R1
R2
P O
N
N
R1
R2
+
H2O/EtOH, r.t.
R
R
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O
P
O
O
P
O
P
O
OH
OH
HO
HO
HO
HO
P
OH
NH
N
HO
HO
P O
P O
HO
HO
Scheme 1. Zwitterion forms of nitrotris(methylenephosphonic acid)
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NH2
NH2
N
N
O
O
NTMPA / Solvent
Room Temperature
+
Scheme 2. Synthesis of 2, 3-diphenylquinoxaline by nitrilotris(methylenephosphonic acid)
20
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