Green and efficient synthesis of quinoxaline derivatives via ceric ammonium nitrate promoted and in situ aerobic oxidation of α-hydroxy ketones and α-keto oximes in aqueous media

Article abstract of DOI:10.1248/cpb.56.79

The direct conversion of α-hydroxy ketones and α-keto oximes into quinoxaline derivatives in the presence of a catalytic amount of ceric ammonium nitrate via metal-catalyzed aerobic oxidation followed by in situ trapping with aromatic 1,2-diamines in water as a green and efficient reaction media, is reported.

Full text of DOI:10.1248/cpb.56.79

January 2008
Notes
Chem. Pharm. Bull. 56(1) 79—81 (2008)
79
Green and Efficient Synthesis of Quinoxaline Derivatives via Ceric
Ammonium Nitrate Promoted and in Situ Aerobic Oxidation of
a
a
-Hydroxy Ketones and -Keto Oximes in Aqueous Media
Ahmad SHAABANI* and Ali MALEKI
Department of Chemistry, Shahid Beheshti University; P. O. Box 19396–4716, Tehran, Iran.
Received June 7, 2007; accepted October 2, 2007
The direct conversion of a-hydroxy ketones and a-keto oximes into quinoxaline derivatives in the presence
of a catalytic amount of ceric ammonium nitrate via metal-catalyzed aerobic oxidation followed by in situ trap-
ping with aromatic 1,2-diamines in water as a green and efficient reaction media, is reported.
Key words quinoxaline; aerobic oxidation; a-hydroxy ketone; ceric ammonium nitrate; diamine
The methodology for heterocyclic synthesis represents a fully carried out in aqueous medium.21—24) The solvophobic
powerful approach for the rapid build-up of molecular com- properties of water are able to generate an internal pressure
plexity from potentially simple starting materials.1) Nitrogen- and promote the association of the reactants in a solvent cav-
containing heterocycles are abundant in nature and exhibit ity during the activation process and accelerate a reaction.
diverse and important biological properties.2) Quinoxaline These properties of water are very efficient for condensation
derivatives as an important class of nitrogen-containing hete- reactions in which the entropy of reaction decreases in the
rocycles are known to exhibit a wide range of biological ac- transition state.
tivities such as antiviral, antibacterial, antiinflammatory and
During the course of our studies towards the development
kinase inhibitor properties.3—10) The echinomycin11) and the of new routes to the synthesis of heterocyclic compounds
triostins12) are well known as antibiotic families of quinoxa- using green reaction mediums25—27) and new catalysts,28,29)
line derivatives.
we wish to report the direct conversion of a-hydroxy ketones
A number of synthetic strategies have been reported for 1 and a-keto oximes 2 into quinoxaline derivatives 4a—g in
the synthesis of quinoxaline derivatives.2,13) The most com- water as an environmentally benign solvent in the presence
mon method is the condensation of an aryl 1,2-diamine with of a catalytic amount of ceric ammonium nitrate (CAN) via
a 1,2-dicarbonyl compound in refluxing acetic acid for 2— metal-catalyzed aerobic oxidation followed by in situ trap-
12 h giving 34—85% yields14) or in high boiling point sol- ping with aromatic 1,2-diamines 3 (Chart 1).
vent such as dimethylsulfoxide (DMSO)15) in the presence of
Experimental
catalytic amounts of molecular iodine.
Recently, the synthesis of quinoxaline derivatives with
Apparatus Melting points were measured on an Electrothermal 9100
apparatus and are uncorrected. The elemental analyses were performed with
condensation of o-phenylenediamine and a 1,2-dicarbonyl
compound in MeOH/AcOH16) under microwave irradiation at
100 °C has been reported, but requires special instrumenta-
tion. In addition, improved methods have been developed for
the synthesis of quinoxaline derivatives including the Bi-cat-
alyzed oxidative coupling of epoxides and ene-1,2-di-
amines,17) and the cyclization of a-arylimino oximes of a-di-
carbonyl compounds under reflux conditions in acetic anhy-
dride.18) Moreover, Taylor and his co-worker19,20) have shown
that quinoxalines can be produced in one-pot process com-
mencing from a-hydroxy ketones using a manganese diox-
ide-mediated or aerobic oxidation palladium acetate-cat-
alyzed tandem oxidation process with in situ trapping of a-
dicarbonyls with aromatic 1,2-diamines. These oxidation and
condensation reactions into a single operation provide a sig-
an Elementar Analysensysteme GmbH VarioEL. Mass spectra were recorded
on a Finnigan-MAT 8430 mass spectrometer operating at an ionization po-
tential of 70 eV. IR spectra were recorded on a Shimadzu IR-470 spectrome-
1
ter. H- and 13C-NMR spectra were recorded on a Bruker DRX-300 Avance
spectrometer at 300.13 and 75.47 MHz, respectively.
All of the chemicals were purchased from Fluka, Merck and Aldrich and
1
used without purification. All the products were identified by IR, H-NMR,
13C-NMR and mass spectral data.
General Procedure for the Preparation of Quinoxalines (4a—g) a-
Hydroxy ketone 1 or a-keto oxime 2 (1 mmol), 1,2-diamine 3 (1 mmol),
CAN (0.05 mmol) and water (5 ml) were taken in 50 ml two-necked round
bottomed flask equipped with a gas passing tube. Air was bubbled at a rate
of 5 ml/min into the reaction mixture while stirring for appropriate time at
room temperature. After completion of the reaction as indicated by TLC
(ethyl acetate/n-hexane, 1 : 1), the reaction mixture was washed with water
(3ꢀ10 ml) and the solid residue was crystallized from ethanol to give pure
product 4.
General Procedure for the Preparation of Pyrazine-2,3-dicarboni-
nificant improvement to existing procedure. However, in the triles (6a, b) a-Hydroxy ketone 1 (1 mmol), 2,3-diaminomaleonitrile 5
(1 mmol), CAN (0.05 mmol) and water (5 ml) were taken in 50 ml two-
necked round bottomed flask equipped with a gas passing tube. Air was bub-
case of manganese dioxide, the requirement for an excess of
it (usually 10 equiv) detracts from commercial attractiveness
and green credentials of this process and with palladium ac-
etate-catalyzed aerobic oxidation the reaction requires long
times (24 h) for completion at ambient temperature in toluene
as a toxic solvent. It is important to note that the yield of re-
action with palladium acetate is only trace after 1 h.
In recent years, water as an environmentally benign sol-
vent has attracted interests because of its favorable properties
and a variety of catalytic reactions which have been success-
Chart 1. Synthesis of Quinoxaline Derivatives
∗ To whom correspondence should be addressed. e-mail: a-shaabani@cc.sbu.ac.ir © 2008 Pharmaceutical Society of Japan

80
Vol. 56, No. 1
1131, 1100, 902, 874, 763, 656. MS m/z: 254 (Mꢂ), 226, 144, 109, 74, 43.
5,6-Dimethylpyrazine-2,3-dicarbonitrile (6a, C8H6N4): Yellow solid; mp
110—112 °C. 1H-NMR (CDCl3) d: 2.72 (6H, s). 13C-NMR (CDCl3) d:
158.0, 130.3, 113.2, 22.7. IR (KBr) cmꢁ1: 3030, 2955, 2150, 1577, 1469,
1345. MS m/z: 158 (Mꢂ), 117, 76, 41.
bled at a rate of 5 ml/min into the reaction mixture while stirring for appro-
priate time at room temperature. After completion of the reaction as indi-
cated by TLC (ethyl acetate/n-hexane, 2 : 1), the reaction mixture was
washed with water (2ꢀ10 ml) and the solid residue was crystallized from
ethanol to give pure product 6.
General Procedure for the Preparation of 2,3-Dihydro-1H-perimidins
5,6-Bis(4-methoxyphenyl)pyrazine-2,3-dicarbonitrile (6b, C20H14N4O2):
Pale yellow solid; mp 190—192 °C. 1H-NMR (CDCl3) d: 7.63 (4H, d,
Jꢃ6.8 Hz), 6.95 (4H, d, Jꢃ6.8 Hz), 3.87 (6H, s). 13C-NMR (CDCl3) d:
164.9, 155.2, 132.4, 129.2, 126.7, 117.4, 114.3, 55.7. IR (KBr) cmꢁ1: 3038,
2964, 2840, 2146, 1607, 1482, 1380, 1261, 1173. MS m/z (%): 342 (Mꢂ),
234, 131, 117, 108, 76, 41.
1-(2,3-Dihydro-2-methyl-1H-perimidin-2-yl)ethanone (8a, C14H14N2O):
Brown solid; mp 184—187 °C (dec.). 1H-NMR (CDCl3) d: 7.12 (2H, t,
Jꢃ7.64 Hz), 6.91 (2H, d, Jꢃ8.1 Hz), 6.46 (2H, d, Jꢃ7.2 Hz), 3.32 (2H, br s),
2.07 (3H, s), 1.45 (3H, s). 13C-NMR (CDCl3) d: 212.0, 141.7, 134.6, 127.5,
115.6, 112.0, 104.5, 71.9, 24.8, 23.8. IR (KBr) cmꢁ1: 3280, 3242, 3050,
2950, 1710, 1589, 1469. MS m/z: 226 (Mꢂ), 157, 126, 72, 43. Anal. Calcd:
C, 74.31; H, 6.24; N, 12.38; Found: C, 74.35; H, 6.22; N, 12.43.
(8a, b) a-Hydroxy ketone
1
(1 mmol), naphthalene-1,8-diamine
7
(1 mmol), CAN (0.05 mmol) and water (5 ml) were taken in 50 ml two-
necked round bottomed flask equipped with a gas passing tube. Air was bub-
bled at a rate of 5 ml/min into the reaction mixture while stirring for appro-
priate time at room temperature. After completion of the reaction as indi-
cated by TLC (ethyl acetate/n-hexane, 3 : 1), the reaction mixture was
washed with water (2ꢀ10 ml) and the solid residue was crystallized with
ethanol to give pure product 8.
Compounds Characterization Data 2,3-Diphenylquinoxaline (4a,
1
C20H14N2): White solid; mp 124—126 °C. H-NMR (CDCl3) d: 8.16—8.24
(2H, m), 7.74—7.80 (2H, m), 7.50—7.58 (4H, m), 7.30—7.38 (6H, m). 13C-
NMR (CDCl3) d: 153.5, 141.3, 139.1, 130, 129.9, 129.2, 128.8, 128.3. IR
(KBr) cmꢁ1: 3055, 1550, 1488, 1436, 1342, 1071, 974, 768, 696. MS m/z:
282 (Mꢂ), 205, 128, 77.
(2,3-Dihydro-2-phenyl-1H-perimidin-2-yl)(phenyl)methanone (8b,
1
C24H18N2O): Dark brown solid; mp 195—197 °C (dec.). H-NMR (CDCl3)
6,7-Dichloro-2,3-diphenylquinoxaline (4b, C20H12Cl2N2): Purple solid;
mp 146—147 °C. 1H-NMR (CDCl3) d: 8.32 (2H, s), 7.50—7.54 (4H, m),
7.33—7.40 (6H, m). 13C-NMR (CDCl3) d: 154.6, 140.5, 137.3, 132.8,
130.2, 129.9, 129.2, 128.9. IR (KBr) cmꢁ1: 3055, 1534, 1437, 1334, 1184,
1105, 1018, 960, 881, 765, 693. MS m/z: 350 (Mꢂ), 204, 146, 77.
2,3-Bis(4-methoxyphenyl)quinoxaline (4c, C22H18N2O2): Yellow solid; mp
150—151 °C. 1H-NMR (CDCl3) d: 8.10—8.17 (2H, m), 7.72—7.76 (2H,
m), 7.52 (4H, d, Jꢃ8.7 Hz), 6.90 (4H, d, Jꢃ8.7 Hz), 3.85 (6H, s). 13C-NMR
(CDCl3) d: 160.2, 153.0, 141.1, 131.8, 131.3, 129.5, 129.0, 13.8, 55.3. IR
(KBr) cmꢁ1: 3045, 2925, 1601, 1508, 1460, 1387, 1339, 1294, 1242, 1165,
1023, 971, 829, 764, 548. MS m/z: 342 (Mꢂ), 313, 166, 76.
d: 7.66—7.83 (2H, m), 7.36—7.53 (3H, m), 6.86—7.23 (9H, m), 6.42 (2H,
d, Jꢃ7.9 Hz), 3.75 (2H, br s). 13C-NMR (CDCl3) d: 203.1, 143.1, 141.2,
138.0, 135.9, 134.2, 134.11, 133.6, 132.6, 131.9, 130.3, 128.3, 128.2, 126.7,
126.2, 124.2, 123.1, 122.7, 121.5, 119.2, 117.2, 114.1, 109.4, 98.8. IR (KBr)
cmꢁ1: 3325, 3263, 3056, 2954, 1707, 1582, 1473. MS m/z: 350 (Mꢂ), 246,
170, 157, 126, 77. Anal. Calcd: C, 82.26; H, 5.18; N, 7.99; Found: C, 82.20;
H, 5.22; N, 7.96.
Results and Discussion
Although CAN is far superior to many other one-electron
oxidants, the vast majority of CAN-mediated oxidations re-
quire more than two equivalents of the oxidant for comple-
tion of the reaction. This precludes its use in large-scale
transformations. Development of reactions requiring only
catalytic amounts of CAN is therefore very important.30—32)
To illustrate the need of catalyst, the reaction between o-
phenylenediamine and benzoin has been studied in various
molar ratios of CAN under air blowing in water. In the ab-
sence of CAN, the reaction yield was trace. The best results
have been obtained with 5 mol% of CAN after 45 min at
room temperature. The yield of reaction with increasing the
quantity of CAN is not considerably increased.
2,3-Dimethylquinoxaline (4d, C10H10N2): Yellow solid; mp 105—106 °C.
1H-NMR (CDCl3) d: 7.93—7.99 (2H, m), 7.62—7.68 (2H, m), 2.71 (6H, s).
13C-NMR (CDCl3) d: 153.4, 141.1, 128.8, 128.3, 23.2. IR (KBr) cmꢁ1
:
3100, 2990, 1563, 1483, 1431, 1392, 1315, 1158, 984, 760, 669, 611. MS
m/z: 158 (Mꢂ), 117, 76, 50.
6,7-Dichloro-2,3-dimethylquinoxaline (4e, C10H8Cl2N2): Yellow solid; mp
198—200 °C. 1H-NMR (CDCl3) d: 8.08 (2H, s), 2.72 (6H, s). 13C-NMR
(CDCl3) d: 154.9, 139.8, 133.1, 129.1, 23.2. IR (KBr) cmꢁ1: 3135, 3000,
1591, 1455, 1391, 1317, 1170, 1098, 888, 847, 755. MS m/z: 226 (Mꢂ), 185,
145, 118, 74.
2-Methyl-3-propylquinoxaline (4f, C12H14N2): Yellow solid; mp 63—
1
64 °C. H-NMR (CDCl3) d: 7.90—7.98 (2H, m), 7.61—7.67 (2H, m), 2.97
(2H, t, Jꢃ7.8 Hz), 2.76 (3H, s), 1.87—1.93 (2H, m), 1.09 (3H, t, Jꢃ7.2 Hz).
13C-NMR (CDCl3) d: 156.3, 141.5, 130.2, 129.8, 128.6, 127.8, 126.6, 125.9,
35.6, 23.5, 19.3, 13.9. IR (KBr) cmꢁ1: 3100, 2995, 1556, 1481, 1457, 1320,
1148, 1126, 997, 768, 746, 609. MS m/z: 186 (Mꢂ), 171, 158, 76, 45.
6,7-Dichloro-2-methyl-3-propylquinoxaline (4g, C12H12Cl2N2): Purple
It is important to note, this reaction didn’t proceed effi-
ciently without air blowing and the reaction yield was only
about 30% after stirring 5 h at room temperature.
1
solid; mp 90—91 °C. H-NMR (CDCl3) d: 8.12 (1H, s), 8.09 (1H, s), 2.95
(2H, t, Jꢃ7.8 Hz), 2.75 (3H, s), 1.83—1.89 (2H, m), 1.08 (3H, t, Jꢃ7.3 Hz).
13C-NMR (CDCl3) d: 158.0, 154.6, 139.9, 139.6, 132.9, 132.9, 129.3, 129.0,
The results of in situ aerobic oxidation and CAN catalyzed
37.7, 22.8, 20.9, 14.0. IR (KBr) cmꢁ1: 3040, 2950, 1589, 1369, 1310, 1169, condensation reaction of a-hydroxy ketone 1 or a-keto
Table 1. Synthesis of Quinoxalines in the Presence of CAN via Aerobic Oxidation in Water at Room Temperature
Yielda) (%)
(Time, min)
Entry
R1
R2
R3
X
Product
1
2
3
4
5
6
7
8
9
H
Cl
H
H
Cl
H
Cl
H
Cl
H
Ph
Ph
Ph
CHOH
CHOH
CHOH
CHOH
4a
4b
4c
4d
4e
4f
4g
4a
4b
4c
97 (45)
92 (50)
93 (45)
86 (55)
80 (50)
65 (60)
67 (60)
72 (55)
63 (45)
70 (50)
Ph
p-MeOC6H4
Me
p-MeOC6H4
Me
Me
Me
Me
Ph
Me
n-Pr
n-Pr
Ph
CHOH
CꢃNOH
CꢃNOH
CꢃNOH
CꢃNOH
CꢃNOH
Ph
Ph
10
p-MeOC6H4
p-MeOC6H4
a) Isolated yields.

January 2008
81
CAN as a promoter was developed in aqueous medium in
high yields at room temperature. To the best of our knowl-
edge this is the first report of the synthesis of quinoxalines
using CAN in conjunction with aerobic oxidation in water
and this new reaction conditions open an important alterna-
tive to the use of toxic solvents. Also this protocol gives ex-
cellent results for the synthesis of pyrazine and perimidine
annulated heterocyclic systems from the reaction of a-hy-
droxy ketones with 2,3-diaminomaleonitrile and naphtha-
lene-1,8-diamine, respectively.
Chart 2. Synthesis of Pyrazine-2,3-dicarbonitriles
Acknowledgements This work was supported by the Catalysis Center
of Excellence (CCE) at Shahid Beheshti University.
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oxime 2 with 1,2-diamine 3 are given in Table 1. The proce-
dure gives the products in excellent yields.
In order to explore the scope and limitations of this reac-
tion, we extended the procedure to various 1,2-dialkyl and
1,2-diaryl a-hydroxy ketones and a-keto oximes. We found
that the reaction proceeds very efficiently in all cases and the
reaction time decreased for 1,2-diaryl ones.
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and naphthalene-1,8-diamine 7. In the case of DAMN, the re-
action gave the pyrazine-2,3-dicarbonitriles 6a, b in excellent
yields within very short reaction times (Chart 2) and with
naphthalene-1,8-diamine 7 the 2,3-dihydro-1H-perimidines
8a, b were obtained (Chart 3).
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Conclusions
In summary, a new, green and efficient approach for the
synthesis of quinoxaline derivatives by the in situ oxidation
and condensation of aliphatic and aromatic a-hydroxy ke-
tones or a-keto oximes with various 1,2-diamines using