Saccharin as an organocatalyst for quinoxalines and pyrido[2,3-b[pyrazines Syntheses

Article abstract of DOI:10.1080/00397911.2013.795596

A room-temperature procedure using saccharin as catalyst has been described for the cyclocondensation of different 1,2-arylenediamines with various 1,2-dicarbonyl compounds, yielding either quinoxalines or pyrido[2,3-b] pyrazines. The reactions proceed in very short reaction times in methanol, and the target heterocycles are isolated in quantitative yields after addition of water, filtration, and drying. Substituted pyrido[2,3-b]pyrazines can also be reached regioselectively by reacting α-ketoaldehydes with 2,3-diaminopyridine. Taylor and Francis Group, LLC.

Full text of DOI:10.1080/00397911.2013.795596

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Saccharin as an Organocatalyst for Quinoxalines and
Pyrido[2,3-b]Pyrazines Synthesis
Frédéric Lassagne a , Floris Chevallier a & Florence Mongin a
a Institut des Sciences Chimiques de Rennes, Equipe Chimie et Photonique Moléculaires, UMR
6226 CNRS-Université de Rennes 1 , 35042 Rennes , France
Accepted author version posted online: 15 Aug 2013.
To cite this article: Synthetic Communications (2013): Saccharin as an Organocatalyst for Quinoxalines and Pyrido[2,3-
b]Pyrazines Synthesis, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, DOI: 10.1080/00397911.2013.795596
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Saccharin as an Organocatalyst for Quinoxalines and Pyrido[2,3-b]Pyrazines
Synthesis
Frédéric Lassagne1,, Floris Chevallier1, Florence Mongin1
1Institut des Sciences Chimiques de Rennes, Equipe Chimie et Photonique Moléculaires,
UMR 6226 CNRS-Université de Rennes 1, 35042 Rennes, France
Address correspondence to Frédéric Lassagne, Chimie et Photonique Moléculaires, UMR
6226 CNRS-Université de Rennes 1, Bâtiment 10A, Case 1003, Campus Scientifique de
Beaulieu, 35042 Rennes, France E-mail: frederic.lassagne@univ-rennes1.fr
Abstract
A room temperature procedure using saccharin as catalyst has been described for the
cyclocondensation of different 1,2-arylenediamines with various 1,2-dicarbonyl
compounds, yielding either quinoxalines or pyrido[2,3-b]pyrazines. The reactions
proceed in very short reaction times in methanol, and the target heterocycles are isolated
in quantitative yields after addition of water, filtration and drying. Substituted pyrido[2,3-
b]pyrazines can also be reached regioselectively by reacting α-ketoaldehydes with 2,3-
diaminopyridine.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications® for the following free supplemental resource(s):
Full experimental and spectral details.]
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KEYWORDS: Saccharin, Quinoxaline, Pyrido[2,3-b]pyrazine, Room temperature
reaction
INTRODUCTION
Quinoxalines and pyrido[2,3-b]pyrazines are polynitrogen heterocyclic compounds
possessing interesting biological activities and used as therapeutics, for example acting as
antimicrobial,[1a] antiinflammatory,[2] antimalarial,[3] anticancer,[1b] and antidepressant.[4]
Their skeleton is also present in various organic dyes,[5] efficient electroluminescent
materials,[6] and organic semiconductors.[7]
The most common synthetic route to reach these scaffolds is the condensation of 1,2-
diketones with 1,2-arylenediamines in refluxing ethanol or acetic acid (Scheme 1).[8]
In the last decade many methods were investigated for the preparation of quinoxalines,
and different catalysts and solvents were evaluated in order to improve the yield of this
cyclocondensation. Among the different systems used for this purpose, we can cite
sulfamic acid in methanol,[9] molecular iodine,[10] 2-iodoxybenzoic acid,[11]
Montmorillonite K-10,[12] polyaniline sulfate,[13] heteropolyacids,[14] and citric acid,[15] as
well as metal precursors such as cerium(IV) ammonium nitrate,[16] Zn/L-proline,[17]
nickel nanoparticles,[18] zirconium tetrakis(dodecyl sulfate),[19] gallium(III) triflate,[20] and
carbon-doped MoO3–TiO2.[21]
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Most of the traditional processes suffer from several disadvantages such as pollution,
waste treatment, high cost, poor chemical yields, long reaction times, and tedious workup
procedures, which limit their use. Despite remarkable efforts, the development of
environmentally benign processes and effective method for the synthesis of quinoxalines
is still an important challenge. Keeping these aspects in mind, efforts were focused to
develop green chemistry for quinoxaline synthesis in both solvent and catalyst respects.
To the best of our knowledge, the acidic form of saccharin (1,1-dioxo-1,2-benzothiazol-
3-one, Figure 1), cheaply available benign (edible) chemical, with mild acidity (pKa 1.9),
hydrolytic stability, and absence of volatibility or corrosivity has never been used as a
Brønsted acid to catalyse the synthesis of quinoxaline derivatives.
Herein, we wish to report an efficient and facile methodology for high purity quinazoline
synthesis using saccharin as a white crystalline solid catalyst at room temperature in
different solvents.
RESULTS AND DISCUSSION
In order to determine the optimum conditions, we screened the impact of both solvent
and catalyst to substrate ratio on the course of the reaction using as model condensation
the reaction between 1,2-phenylenediamine (1a) and benzil (2a).
Initially, the reaction in the presence of saccharin (10 mol%) was carried out using five
polar solvents: methanol, ethanol, isopropanol, water and acetonitrile (Table 1). This
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evaluation showed reactions in quantitative yields within 5 min using polar organic
solvents methanol and acetonitrile (Table 1, entries 1 and 5) while ethanol and
isopropanol gave lower yields under the same reaction conditions (Table 1, entries 2 and
3). In pure water, and even after 1 h reaction time, the compound 3a was obtained in only
60 % yield (Table 1, entry 4).
Ethyl acetate, dichloromethane, diethyl ether and toluene were also screened and afforded
the product in excellent yields. Using dichloromethane, the reaction was finished after 5
min (Table 1, entry 7) whereas 10 min were necessary using ethyl acetate and diethyl
ether (Table 1, entries 6 and 8), and 15 min using toluene (Table 1, entry 9).
This study shows that methanol, acetonitrile and dichloromethane are better solvents as
regards short reaction times than ethanol, which leads to a lower 90% yield after 5 min
reaction time. Compared with acetonitrile and dichloromethane, methanol is a solvent
more in accordance with sustainable chemistry, and it was thus considered as the best
solvent for further studies.
Different catalyst loadings (1 mol%, 5 mol% and 10 mol% of saccharin) were next tested
using methanol as solvent. All these reactions afforded 3a in a quantitative yield after 5
min reaction time (Table 2, entries 2-4) whereas the reaction proved much slower without
catalyst (Table 2, entry 1).
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Using 5 mol% of saccharin, the scope of the present method was then further determined
by condensation of different 1,2-arylenediamines with various 1,2-dicarbonyl compounds
(Table 3).
As regards the 1,2-arylenediamine, extended reaction times for the reaction with benzil
(2a) were logically noted in the case of π-deficient 2,3-diaminopyridine (1c, entry 3, 3 h
reaction time) and, above all, using 4-nitro-1,2-phenylenediamine (1d, entry 4, 4 h
reaction time) against 5 min for 1,2-phenylenediamine (1a, entry 1) and its 4-methyl
derivative (1b, entry 2). Nevertheless, all the products were still obtained in excellent
yields.
Concerning the 1,2-dicarbonyl compounds, 1,2-diketones such as pyruvophenone (2b,
entry 5), 1,2-indanedione (2c, entry 6) and 2,3-butanedione (2d, entry 7), as well as aryl
glyoxal hydrates such as both phenyl and 2-thienyl derivatives (2e and 2f, entries 8 and 9)
also reacted with 1,2-phenylenediamine (1a) with success in short reaction times.
The reaction between 2, 3-diaminopyridine (1c) and 2-thienyl glyoxal hydrate (2f) can
theoretically lead to two regioisomeric thienyl-substituted pyrido[2,3-b]pyrazines.
Besides a total conversion under the same reaction conditions, the predominant formation
of the regioisomer 3j (isolated by chromatography over silica gel in 95% yield) was
surprisingly noticed (entry 10). The structures of 3j and 3j’ were unequivocally identified
on the basis of NMR experiments. The crude reaction mixture containing 3j and the other
regioisomer 3j' showed two singlet peaks at 9.26 and 9.45 ppm, respectively
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corresponding to their H2 and H3 protons. In addition, there is possible correlation
between H2 and Ca in 3j, and between H3 and Cb (which is more deshielded than Ca) in
3j' (see Figure 2). The HMBC NMR experiment performed on each compound 3j and 3j’
showed that the proton at 9.26 ppm correlates with the less deshielded Ca (136.5 ppm,
withdrawing effect of only one nitrogen) of 3j (main product) and that the proton at 9.45
ppm correlates with the more deshielded Cb (150.2 ppm, withdrawing effect of two
nitrogens) of 3j' (minor product). Such a regioselectivity could result from a favoured
reaction between the stronger nucleophile site of 2,3-diaminopyridine (1c) at its 3
position and the stronger electrophilic site of 2-thienyl glyoxal hydrate (2f) which is the
aldehyde function. Finally, using aryl glyoxal hydrates as 1,2-dicarbonyl compound led
to shorter reaction times than using 1,2-diketones, as evidenced for example by the
reaction of 2,3-diaminopyridine (1c) with 2-thienyl glyoxal hydrate (2f) and benzyl (2a)
in respectively 15 min (entry 10) and 3 h (entry 3).
In order to strengthen the novelty of present method, we have compared our results with
some reported procedures using conventional methods to prepare the compound 3a. The
results are summarized in Table 4.
As we can see, saccharin gave quantitative yields after short reaction times. Furthermore,
according to the optimized procedure, we evaluated the reusability of saccharin as
follows. To 1,2-phenylenediamine (10 mmol) in methanol (10 mL) were added saccharin
(0.5 mmol) and benzil (10 mmol). After 5 min reaction time, the mixture was cooled
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using an ice bath, the solid was filtered, and the filtrate was used for the next run with
fresh reactants within five cycles without noticeably decreasing catalytic activity.
CONCLUSION
In summary, we have developed a safe and economical process for the catalytic synthesis
of quinoxaline and pyrido[2,3-b]pyrazine derivatives from 1,2-arylenediamines and 1,2-
dicarbonyl compounds at room temperature. The reusability of saccharin, a catalyst easy
to handle, its availability and commercial low cost, its environmental acceptability and
absence of toxicity, the mild reaction conditions, the simple work-up procedure, and the
short reaction times are the strong practical points of the presented method.
EXPERIMENTAL
Column chromatography was performed using silica gel 60 (230–400 mesh). Melting
points were measured on a Kofler apparatus and are uncorrected. 1H and 13C nuclear
magnetic resonance (NMR) spectra were recorded on a Bruker Avance III spectrometer
at 300 and 75 MHz, respectively. 1H chemical shifts (δ) are given in ppm relative to the
solvent residual peak, and 13C chemical shifts relative to the central peak of the solvent
signal.[30] High- resolution mass spectra (HRMS) were recorded on a Bruker micrOTOF
Q II instrument. 1,2-Diketones, 1,2-arylenediamines, acetophenone, 2-acetylthiophene,
phenyl glyoxal hydrate (2e), 1,2-indanedione (2c) were purchased from Aldrich and 2-
thienyl glyoxal hydrate (2f) from Alfa Aesar.
General Procedure For The Quinoxalines And Pyrido[2,3-B]Pyrazines Synthesis
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To the required 1,2-dicarbonyl compound 2 (10 mmol) in methanol (10 mL) were
successively added saccharin (92 mg, 0.5 mmol) and the required 1,2-arylenediamine 1
(10 mmol). The mixture was stirred for the appropriate time at room temperature
(reaction monitored by TLC), and poured into water (10 mL). The solid was collected by
filtration and dried to afford the product 3. The isomers 3j and 3j’ were separated by
chromatography over silica gel (CH2Cl2-AcOEt 8:2). All products were characterized by
1H NMR, and 13C NMR and were identified by comparison of the spectral data and
melting points with those reported in literature (supporting information).
Spectral (1H NMR, and 13C NMR) and HRMS data of new compounds are given.
11H-Indeno[1,2-B]Quinoxaline (3f)
White solid, mp 160 °C. 1H NMR (300 MHz, CDCl3), δ (ppm): 4.06 (s, 2H), 7.47-7.70
(m, 5H), 8.02-8.20 (m, 3H). 13C NMR (75 MHz, CDCl3), δ (ppm): 36.0, 122.7, 125.8,
128.0, 128.8, 129.0, 129.1, 129.2, 131.1, 138.0, 141.2, 142.0, 143.5, 154.6, 159.4. HRMS
(ESI) m/z calcd for C15H12N2: 219.0922 [M+H]+; found: 219.0926.
3-(2-Thiophenyl)Pyrido[2,3-B]Pyrazine (3j)
Yellow crystals, mp 160 °C. 1H NMR (300 MHz, CDCl3), δ (ppm): 7.16 (dd, 1H, J = 3.8
and 5.0), 7.56 (dd, 1H, J = 1.1 and 5.0), 7.59 (dd, 1H, J = 4.2 and 8.3), 7.93 (dd, 1H, J =
1.1 and 3.8), 8.35 (dd, 1H, J = 1.9 and 8.3), 9.07 (dd, 1H, J = 1.9 and 4.2), 9.26 (s, 1H).
13C NMR (75 MHz, CDCl3), δ (ppm): 124.4, 128.6, 128.7, 131.6, 136.5, 138.1, 141.4,
143.3, 150.3, 150.7, 154.4. HRMS (ESI) m/z calcd for C11H9N3S: 214.0439 [M+H]+;
found 214.0440.
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2-(2-Thiophenyl)Pyrido[2,3-B]Pyrazine (3j’)
Pale yellow solid, mp 172 °C. 1H NMR (300 MHz, CDCl3), δ (ppm): 7.23 (dd, 1H, J =
3.8 and 5.0), 7.59 (dd, 1H, J = 1.0 and 5.0), 7.71 (dd, 1H, J = 4.2 and 8.4), 7.91 (dd, 1H, J
= 1.0 and 3.8), 8.43 (dd, 1H, J = 1.9 and 8.4), 9.08 (dd, 1H, J = 1.9 and 4.2), 9.45 (s, 1H).
13C NMR (75 MHz, CDCl3), δ (ppm): 125.9, 128.2, 128.9, 131.1, 137.7, 138.4, 141.3,
145.3, 148.7, 150.0, 152.7. HRMS (ESI) m/z calcd for C11H9N3S: 214.0439 [M+H]+;
found: 214.0436.
SUPPLEMENTARY MATERIAL
Supporting information: general procedures, characterization data, and 1H and 13C NMR
spectra. This material can be found via the “Supplementary Content” section of this
article’s webpage.
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Table 1. Synthesis of the quinoxaline 3a at r.t. using saccharin (10 mol%) in solvents of
O
NH2
N
Ph
saccharin (10 mol%)
Ph
+
Ph
solvent, r.t.
NH2
N
Ph
O
1a
2a
3a
different polarities.
Entry
Solvent
Reaction time (min)
Yielda (%)
>99
90
1
2
3
4
5
6
7
8
9
Methanol
Ethanol
5
5
Isopropanol
Water
Acetonitrile
Ethyl acetate
Dichloromethane
Diethyl ether
Toluene
5
85
60
5
60
>99
97
10
5
>99
95
10
15
80
aIsolated yield.
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Table 2. Synthesis of the quinoxaline 3a at r.t. in methanol using different saccharin
O
NH2
N
Ph
saccharin (x mol%)
Ph
+
Ph
MeOH, r.t.
NH2
N
Ph
O
1a
2a
3a
loadings.
Entry
x (mol%)
Reaction time (min)
Yielda (%)
50
1
2
3
4
0
1
60
5
>99
5
10
5
5
>99
>99
aIsolated yield.
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Table 3. Extension to the synthesis of various quinoxaline and pyrido[2,3-b]pyrazine
O
R
X
NH2
R
X
N
R2
R1
saccharin (5 mol%)
R1
+
R2
MeOH, r.t.
NH2
N
O
1
2
3
derivatives.
Entry 1,2-Arylenediamine 1,2-Dicarbonyl compound
Product 3
Reaction time (min) Yield (%)a
O
NH2
N
Ph
1
2
3
5
>99
>99
95
Ph
Ph
Ph
Ph
Ph
Ph
NH2
N
3a
Ph
O
O
O
2a
O
1a
N
Ph
Ph
NH2
5
N
NH2
NH2
1b
2a
O
3b
N
N
N
Ph
180
NH2
N
3c
Ph
N
2a
O
1c
O2N
NH2
NH2
O2N
Ph
Ph
4
5
6
240
10
5
96
97
92
Ph
Ph
N
O
O
2a
O
1d
NH2
3d
N
Ph
Ph
NH2
NH2
N
3e
2b
O
1a
1a
N
NH2
NH2
O
N
N
2c
3f
O
7
8
9
10
15
15
92
NH2
NH2
N
O
2d
1a
1a
1a
3g
O
N
Ph
>99
94
Ph
CHO, H2O
O
NH2
NH2
N
3h
2e
N
N
S
CHO, H2O
2f
NH2
S
3i
10
15
15
95b
5b
O
N
NH2
NH2
N
N
N
N
S
CHO, H2O
2f
S
1c
3j
N
S
N
3j'
aIsolated yield.
b Regioisomers isolated by chromatography over silica gel (eluent: 80/20 CH2Cl2-
AcOEt).
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Table 4. Conventional quinoxaline (3a) preparations using different catalysts/solvents at
r.t.
Entry Catalyst
Mol% Solvent
Time
(min)
10
Yield Ref.
1
Cerium(IV) ammonium
5
H2O
98
[16]
nitrate
2
3
Iodine
10
1
MeCN
AcOH
H2O
5
15
150
5
95
98
[10]
[11]
[12]
[17]
[13]
[9]
[22]
[14]
[20]
[31]
[15]
This
study
2-Iodoxybenzoic acid
Montmorillonite K-10
Zn[(L)-proline]
Poly-aniline sulfate salt
Sulfamic acid
CuSO4, 5H2O
H4SiW12O40
4
10
10
5
>99
96
5
AcOH
Cl(CH2)2Cl
MeOH
MeOH/H2O
H2O
6
15
5
92
7
5
>99
97
8
10
5
5
9
60
5
96
10
11
12
13
Gallium(III) triflate
APTS/NaPTS
Citric acid
5
EtOH
>99
96
5
H2O
7
3
EtOH
<1
5
94
Saccharin
1 or 5 MeOH
>99
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Scheme 1. Most common synthetic route to reach quinoxalines.
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Figure 1. Saccharin as its acidic form.
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Figure 2. Identification of regioisomers 3j and 3j’ by NMR HMBC experiment.
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