MAOS of quinoxalines, conjugated pyrazolylquinoxalines and fused pyrazoloquinoxalines from L-ascorbic and D-isoascorbic acid

Article abstract of DOI:10.1080/07328300701252359

Microwave-assisted organic synthesis (MAOS) has been used to accelerate the conversion of L-ascorbic acid (1) and D-isoascorbic acid (2) to the title heterocycles by conversion to 3-(L-threo- or D-erythro-glycerol-1-yl) quinoxaline-2-carboxylic acid o-ami

Full text of DOI:10.1080/07328300701252359

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MAOS of Quinoxalines, Conjugated
Pyrazolylquinoxalines and Fused
Pyrazoloquinoxalines from l‐Ascorbic and
d‐Isoascorbic Acid
El Sayed H. El Ashry a , Kamal F. Atta a , Salah Aboul‐Ela a & Razika Beldi a
a Chemistry Department, Faculty of Science, Alexandria University,
Alexandria, Egypt
Version of record first published: 07 May 2007
To cite this article: El Sayed H. El Ashry, Kamal F. Atta, Salah Aboul‐Ela & Razika Beldi (2007): MAOS
of Quinoxalines, Conjugated Pyrazolylquinoxalines and Fused Pyrazoloquinoxalines from l‐Ascorbic and
d‐Isoascorbic Acid , Journal of Carbohydrate Chemistry, 26:1, 1-16
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Journal of Carbohydrate Chemistry, 26:1–16, 2007
Copyright # Taylor & Francis Group, LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300701252359
MAOS of Quinoxalines,
Conjugated
Pyrazolylquinoxalines and
Fused Pyrazoloquinoxalines
from L-Ascorbic and
D-Isoascorbic Acid
El Sayed H. El Ashry, Kamal F. Atta, Salah Aboul-Ela, and
Razika Beldi
Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
Microwave-assisted organic synthesis (MAOS) has been used to accelerate the conversion
of L-ascorbic acid (1) and D-isoascorbic acid (2) to the title heterocycles by conversion to
3-(L-threo- or D-erythro-glycerol-1-yl)quinoxaline-2-carboxylic acid o-aminoanilides (7
and 8), which were transformed to lactones 9 and 10, respectively, under acidic condition.
The acetylation of compounds 9 and 10 afforded 3-(L-threo- or D-erythro-2,3-di-O-acetyl-
glycerol-1-yl)quinoxaline-2-carboxylic-g-lactones (11 and 12). Treatment of 10 with phe-
nylhydrazine gave the hydrazides 13. 3-[1-Phenylhydrazono-L-threo-2,3,4-trihydroxybu-
tyl]-1H-quinoxalin-2-one (14) and its D-erythro-analog 15 were prepared from 1 and 2.
Subsequent cyclizations gave the respective pyrazolylquinoxalines 16 and 17 and
pyrazolo[3,4-b]quinoxalines 26 and 27. The regioselectivities of allylation and epoxypro-
pylation of 16 and 17 were investigated and could be interpreted by the semiempirical
AM1 method. Degradation of 26 or 27 gave 1-phenylpyrazolo[3,4-b]quinoxaline-3-carbox-
aldehyde (28). Degradation of 14 or 15 gave aldehyde 29. The combination of using micro-
wave (MW) and bentonite, as a support, has improved the yields in less reaction times in
addition to performing the reactions under environmentally clean conditions.
Keywords Microwave, Bentonite, Quinoxalines, Quinoxalinones, Pyrazolylquinoxa-
lines, Pyrazoloquinoxalines, AM1 method, Alkylation, Ascorbic acid
Received June 22, 2006; accepted January 3, 2007.
Presented at the II Mediterranean Organic Chemistry Meeting, Almeria, Spain, 2004,
38. A part of the PhD thesis of Razika Beldi, who is on leave from the Ministry of
Higher Education and Scientific Research, Algeria.
Address correspondence to E. S.H. El Ashry, Chemistry Department, Faculty of Science,
Alexandria University, Alexandria, Egypt. E-mail: eelashry60@hotmail.com
1

El Ashry et al.
2
INTRODUCTION
Acceleration of organic, organometallic, and solid state reactions by microwave
(MW) irradiation have paved the way for applying this technique in organic
synthesis[1–3] to enhance reaction rates and improve environmental as well
as economical aspects. Moreover, MW may also play a role in the stereo- or
regioselectivities of the reactions.[4] Recently, we have successfully used MW
in our laboratory for accelerating organic reactions.[3] The availability of carbo-
hydrates as renewable biomasses has attracted attention to make their use as
precursors for materials of various applications[5,6] based on innovative tech-
nologies and biological activities. Much work from our laboratory has
utilized carbohydrates as raw materials for the synthesis of various types of
heterocycles.[6,7] L-Ascorbic acid and D-isoascorbic acid were used as precur-
sors for variant heterocycles, such as the quinoxaline ring. The attraction
toward this ring system was motivated by its incorporation in natural
products and its potent biological activities.[8] Accordingly, the microwave-
assisted organic synthesis (MAOS) of quinoxalines, conjugated pyrazolylqui-
noxalines, and fused pyrazoloquinoxalines from L-ascorbic acid (1) and its
D-erythro analog 2 has been investigated and compared with conventional
procedures.[9–17]
RESULTS AND DISCUSSION
3-(L-Threo-Glycerol-1-yl)quinoxaline-2-carboxylic acid o-aminoanilide (7) was
obtained in 87% yield by MW irradiation, for 1 min, of L-ascorbic acid (1)
with two equivalents of o-phenylenediamine in the presence of benzoquinone,
while the conventional procedure[10] required much more time to obtain a
comparable yield. The reaction is assumed to proceed via the oxidation of 1
to the respective dehydroascorbic acid, which, upon reaction with two equiva-
lents of o-phenylenediamine, gave 7 via 5.[18] Acid hydrolysis of 7 required
7 min of irradiation to afford 53% of 3-(L-threo-glycerol-1-yl)quinoxaline-2-
carboxylic-g-lactone (9). Similarly, 2 was oxidized to 4 and converted to
3-(D-erythro-glycerol-1-yl)quinoxaline-2-carboxylic acid o-aminoanilide (8) via
6, which upon hydrolysis gave 10. Acetylation of 9 and 10 was performed in
the MW oven for 2 min to give 93% and 86% yields, respectively, of 11 and
12. Hydrazinolysis of 10 gave 3-(D-erythro-glycerol-1-yl)quinoxaline-2-car-
boxylic acid phenylhydrazide (13) (Sch. 1).
Synthesis of 3-(1-phenylhydrazono-L-threo–2,3,4-trihydroxybutyl)-1H-
quinoxalin-2-one (14) was achieved in 86% yield by MW irradiation for
2.5 min of L-ascorbic acid (1) with o-phenylenediamine and phenylhydrazine
in the presence of acetic acid; the conventional method[9] required a much
longer time (1 h) of heating to give 73% yield. The reaction required one equiv-
alent only of o-phenylenediamine, which presumably proceeded via the

Microwave-Assisted Organic Synthesis
3
Scheme 1: Reaction of ascorbic acids with o-phenylene diamine.
formation of 5, whose reaction with phenylhydrazine gave 14. Similarly,
D-isoascorbic acid gave 15.
Dehydrative cyclization of 14 or 15 could take place by incorporating the
hydrazone residue with either the glycerolyl side chain or the quinoxaline
ring. When their dehydrations have been carried out by the action of hydroxy-
lamine hydrochloride under MW irradiation for 4 min, the yield of 3-[5-(hydro-
xymethyl)-1-phenylpyrazol-3-yl]-1H-quinoxalin-2-one (16) was 65%, while the
presence of bentonite as a support gave a comparable yield (71%). Using acetic
anhydride as a dehydrating agent gave 17 in 84% yield. Addition of drops of
triethylamine did not improve the yield, but a better yield (95%) was
obtained upon supporting the reactants on bentonite. Getting the same
product from 14 or 15 was due to the loss of their chirality as a result of dehy-
drative elimination. Deacetylation of 17 with aqueous sodium hydroxide
under MW irradiation for 2.5 min gave low yield (40%) of 16, but again a
much better yield (92%) was obtained from the same reactants when sup-
ported on bentonite. On the other hand, the reaction did not proceed success-
fully when 17 was supported on bentonite without the presence of sodium
hydroxide (Sch. 2).

El Ashry et al.
4
Scheme 2: Alkylation of quinoxalinone.
Allylation of 16 by allyl bromide in the presence of potassium carbonate
under MW irradiation gave the N- and O-allyl derivatives 18 and 20 in 57%
and 30% yield, respectively. Similarly, 17 gave 19 and 21, where the
N-isomeric product was also the major one. On the other hand, reaction of 16
or 17 with epichlorohydrin in the presence of bentonite under MW irradiation
afforded the N-(epoxy)-propylated derivatives 22 and 23 in 60% and 63% yields,
respectively, whereas the corresponding O-(epoxy)-propylated derivatives 23a

Microwave-Assisted Organic Synthesis
5
and 23b could not be detected. Surprisingly, reaction of 17 with epichlorohy-
drin in the presence of potassium carbonate in DMF gave the dihydroxypropyl
derivative 24 under MW conditions and the conventional method, the structure
of which was confirmed by its identity with the product resulting from the
ring opening of the oxirane ring in 23, by aqueous acid, to give the respective
diol in 24. Moreover, its acetylation gave the corresponding di-O-acetyl deriva-
tive 25.
The above results of alkylation of the quinoxaline ring attracted our atten-
tion to investigate the regioselectivity that has taken place via a theoretical
approach by using the AM1 semiempirical method as a part of the MOPAC
computational package. The AM1 semiempirical method offers more accurate
parameterization than other methods.[19]
In order to determine the factors affecting the regioselectivity of the
alkylation of the quinoxalinone ring, its tautomerism was considered. There
are two tautomeric forms for that ring, the lactam 16 and 17 and the
lactim forms 16a and 17a, which upon abstraction of a proton, would form
the respective intermediates b and c, presumably in an equilibrated state,
whose ratio could be a determinant factor for the ratio of the obtained N-
and O-alkylated products (Sch. 3). The aqueous phase semiempirical calcu-
lated heats of formation and relative stabilities (RS) of quinoxaline deriva-
tives 16 and 17 as well as their intermediates and alkylated products are
listed in Table 1. The heats of formation values suggest that the tautomeric
lactam form and its deprotonated form in b are favored over the lactim
form and its deprotonated form c. Thus, the relative stabilities of 16 and
16b are higher than the respective forms of a and c by 29.75 kcal mol21
and 23.31 kcal mol21. The heat of formation of the lactam form of
compound 17 is smaller than that of form a (RS ¼ 210.53 kcal mol21) and
the deprotonated b is also smaller than c (RS ¼ 210.47 Kcal mol21). Such
results could explain the favored attack of the alkylating agent on the N-
position more than that on the O-position. Moreover, the heats of formation
(DH) of the N-alkylated derivatives indicate their stability over the O-alkyl-
ated one. The energy occupied orbital values of the form b of both compounds
16 and 17 is preferred because their values of energy (HOMO) are smaller
than that in the c form, which was required for giving the best orbital
overlap between the occupied orbital of 16 or 17 and the unoccupied orbital
of the alkylating reagents, where the frontier orbitals of the two reactants
should be on the same energy gap or possess approximate minimal energy
values.[19]
The second type of dehydrative cyclization in 14 or 15 by elimination of
one molecule of water between the hydrazone residue and the quinoxali-
none ring took place to form a pyrazole fused to the quinoxaline ring; in
this case no loss of chirality can take place whereby 26 and 27, respectively,
were obtained (Sch. 4). This cyclization had taken place under MW

El Ashry et al.
6
Scheme 3: Tautomerism in quinoxalinone.
irradiation, in the presence of aqueous sodium hydroxide solution to give 26
in 60% yield and 27 in 89% yield, but when bentonite was used as support,
the yield was 89% and 95%, respectively, without any experimental
problems.
Table 1: AM1 calculationsa of the studied molecules.
DH kcal
RSb kcal
mol21
E LUMO
eV
E HOMO
eV
Comp. No
mol21
16
80.61
90.36
50.83
29.75
23.308
210.53
210.47
210.34
27.36
20.836
20.718
2.079
28.690
29.078
23.976
23.984
28.752
29.014
23.818
24.216
28.614
28.634
28.741
28.615
16a
16b
16c
17
17a
17b
17c
18
54.14
2.100
215.98
226.51
190.09
200.56
108.01
118.34
247.07
254.43
20.470
20.905
2.382
2.539
20.773
20.736
20.439
20.880
20
23
23b
aCalculations in the aqueous phase.
bRS: relative stability in kcal mol21. RS ¼ DHone 2 DHol, minus sign indicates
the predominance of the form “one.”

Microwave-Assisted Organic Synthesis
7
Scheme 4: Synthesis of fused quinoxalines.
3-Carboxaldehyde-1-phenyl-pyrazolo[3,4-b]quinoxaline (28) has been
formed by irradiation of a suspension of 26 or 27 in an aqueous solution of
sodium metaperiodate in MW for 6 min. The cleavage of 14 or 15 under MW
irradiation for 2 min gave 3-[1-(phenylhydrazono)glyoxal-1-yl]-2-quinoxalin-
one (29), which was acetylated under MW irradiation for 1 min to obtain
compound 30 (Table 2).
In conclusion, conversion of L-ascorbic and D-isoascorbic acids to quinox-
alines, quinoxalinones, conjugated pyrazolylquinoxalinones, and fused
pyrazoloquinoxalines was successfully carried out by applying MW irradia-
tion. The procedures avoided the use of many amounts of solvents and were
completed in much shorter times under better environmental conditions.
The use of bentonite as a support has improved the yields in most
cases. The mode of alkylation could be explained by the computational
methods.

El Ashry et al.
8
Table 2: Comparison of Results from microwave (MW) and conventional method
(CM).
Time
Yield (%)
Comp.
No
Mp (8C)
Found/literature
Reagentc MW (min) CM (h) MW CM
7
8
9
10
11
12
13
14
15a
a
a
b
b
c
c
d
e
e
f
2
2
2
91 87[10]
94 67[11]
178/180–181[10]
2
219–220/218–219[11]
187/187[9]
7
24
24
76
60[9]
7
69 72[11]
183–185/184–186[11]
2
93
94–95
2
0.5
86 77[11]
80
180/178–179,[11]184[13]
163–165/165–167[11]
219/216[9]
4
2
2.5
2.5
4
1.5
1.5
8
86
86 93[12]
80[9]
200–202/203[13]/205[12]
65
70[9] 255–257/255[9]/250–252[14]
16b
16
g
f
g
h
i
2
6
4
2.5
2
71
76
95
40
92
17a
17b
c
7
0.25
84 90[14]
250/249–250[14]
j
k
c
j
k
l
8
7
6
8
7
7
75
95
75
70
88
18
19
20
21
22
23
24
25
26
2
4
2
4
57 41[15]
171–172/176[15]
182/195–196[15]
104–106/105–108[15]
98–100
l
l
5
7
5
53
47
30 20[15]
l
27
64
60
86
90
60
20
—
m
m
n
o
p
18
—
194–196
20
8
—
6
—
182
74
208
3
24
1
85
95[9]
158–160
196–198/194[9]
4
q
p
2
2
89
89
27
82
75
86
212–214/212–213[16]
q
r
r
2
6
4
95
67
60
28a
28b
29a
29b
30
24
24
146–148/144[16]
250/242[12]/244[17]
r
2
84
s
r
s
2
4
2
92
84
90
203–204/200–202[7g]
o
1
2
90 90[7g]
aFrom L-ascorbic acid.
bFrom D-isoascorbic acid.
cReagents shown in the schemes.

Microwave-Assisted Organic Synthesis
9
EXPERIMENTAL
General Methods
Melting points were determined on a Melt-temp apparatus and are uncor-
rected. TLC was performed on Baker–Flex silica gel 1B-F plates using
n-hexane ethyl acetate (H/E) as developing solvents, and the spots were
detected by their characteristic colors and by UV light absorption. Irradiation
was done in a domestic microwave oven E.M. 230 M (800-watt output power).
Table 2 shows the data of melting points and references for the compounds
known in the literature. The known compounds prepared under MWI were ident-
ified mainly by melting points and IR spectra. The reactions were performed in
closed Teflon vessels. 1H NMR and 13C NMR spectra were recorded on a Jeol spec-
trometer (500 MHz). The chemical shifts are expressed on d-scale using Me4Si as
a standard, and coupling constant values are given in Hz. Microanalyses were
performed in the Microanalysis Unit at the Faculty of Science, Cairo University.
The theoretical calculations of the corresponding products were done by using
AM1 semiempirical method as a part of the MOPAC 7.0 program.
3-(L-Threo- or D-erythro-glycerol-1-yl)quinoxaline-2-
carboxylic Acid o-Aminoanilide (7 or 8)
A mixture of ascorbic acid 1 or 2 (0.2 g, 1.14 mmol) and benzoquinone
(0.13 g) in methanol-water (1:1, 3 mL) was stirred for 2 h at rt, treated with a
suspension of O-phenylenediamine (0.25 g, 2.27 mmol) in methanol (1 mL),
and then irradiated for 2 min. The solid that separated out after cooling was
filtered off and successively washed with water and ethanol to obtain 7 Rf
0.23 and 8 Rf 0.28 (H/E 1/2).
3-(L-Threo- or D-erythro-glycerol-1-yl)quinoxaline-2-
carboxylic-g-lactone (9 or 10)
A suspension of 7 or 8 (0.1 g, 0.28 mmol) in water (2 mL) was treated with
HCl (0.1 mL) and subjected to MW irradiation for 7 min, then kept at 08C over-
night. The products 9 and 10 were filtered off and washed with ethanol; Rf 0.43;
Rf 0.53 (H/E 1/2), respectively.
3-(L-Threo- or D-erythro-2,3-Di-O-acetyl-glycerol-1-
yl)quinoxaline-2-carboxylic-g-lactone (11 or 12)
A suspension of 9 or 10 (0.1 g, 0.41 mmol) in acetic anhydride (2 mL) was irra-
diated for 2 min. The mixture was poured onto crushed ice and the product was
filtered and successively washed with water and ethanol; Rf 0.60 (H/E 2/1).

El Ashry et al.
10
3-(D-Erythro-Glycerol-1-yl)quinoxaline-2-carboxylic acid
phenyl hydrazides
A mixture of 10 (0.1 g, 0.41 mmol) in ethanol (2 mL) and hydrazine hydrate
(0.5 mL) was irradiated for 4 min, then concentrated. The product was filtered
off; Rf 0.18 (H/E 1/3).
3-(1-Phenylhydrazono-2,3,4-trihydroxybut-1-yl)quinoxalin-
2-ones (14 or 15)
A suspension of 1 or 2 (1 mmol) in water (4 mL) and ethanol (3 mL) was
treated with O-phenylenediamine (1 mmol), phenyl hydrazine (1 mmol), and
acetic acid (0.15 mL). The reaction mixtures were irradiated for 4 min to give
red crystals of 14 Rf 0.17 (H/E 1/3) or 15 Rf 0.2 (H/E 1/3).
3-[5-Hydroxymethyl-1-phenylpyrazol-3-yl]quinoxalin-2-one
(17)
A mixture of 14 or 15 (0.56 mmol), hydroxylamine hydrochloride (0.04 g),
bentonite (0.20 g), and ethanol (4 mL) was subjected to MW irradiation, and
then ice water was added to give colorless crystals of 16, Rf 0.18 (H/E 1/1).
Alternatively, a mixture of 17 (0.28 mmol), bentonite (0.10 g), and sodium
hydroxide (0.10 g) in ethanol-water (1:1, 6 mL) was subjected to MW
irradiation for 2 min. Acetic acid was added to give 16.
3-[5-(Acetoxymethyl)-1-phenylpyrazol-3-yl]-quinoxalin-2-
one (17)
Bentonite (0.5 g) was added to a suspension of 14 or 15 (1.40 mmol) in
acetic anhydride (4 mL). The mixture was irradiated by MW for 7 min and
then cooled. Crushed ice was added and the precipitate was filtered. The
product 17 was extracted with ethanol and crystallized in colorless needles,
Rf 0.37 (H/E 1/1). Alternatively, a suspension of 14 or 15 (1.40 mmol) in
acetic anhydride (4 mL) and drops of triethylamine was irradiated for 8 min,
then processed as above to give 18.
Allylation of 3-[5-(hydroxymethyl- or 3-[5-(acetoxymethyl)
1-phenyl-pyrazol-3-yl]quinoxalin-2-one (16 or 17)
A mixture of 16 or 17 (0.47 mmol) and potassium carbonate (0.07 g) in DMF
(5 mL) was treated with allyl bromide (0.04 mL), then subjected to irradiation
with MW for 5–7 min. The crude product was recrystallized from ethanol to
give two products from each compound: 18 and 20 from 16, and 19 and 21
from 17.

Microwave-Assisted Organic Synthesis
11
1-N-Allyl-3-[5-(hydroxymethyl)-1-phenylpyrazol-3-yl]
quinoxalin-2-one (18)
Rf 0.45 (H/E 1/1)
1-N-Allyl-3-[5-(acetoxymethyl)-1-phenyl-pyrazol-3-yl]
quinoxalin-2-one (19)
1
Rf 0.48 (H/E 1/1). H NMR (500 MHz, CDCl3): d ¼ 2.06 (s, 3H, CH3CO),
5.01 (d, 2H, J ¼ 4.6 Hz, H-30, H-300), 5.13 (d, 2H, J ¼ 6.85 Hz, CH2-O), 5.20
(d, 1H, J ¼ 16.8 Hz, H-10), 5.30 (d, 1H, J ¼ 10.7 Hz, H-100), 5.95–6.03 (m, 1H,
H-20), 7.30–7.87 (10H, Ar-H). 13C NMR (CDCl3): dc ¼ 20.9 (CH3CO), 44.7 (C-
20), 56.6 (C-30), 76.9 (C-10), 113.0, 114.1, 118.2, 123.9, 125.7, 128.9, 129.3,
130.5, 131.2, 132.5, 133.3, 138.4, 139.1 (C-aromatic), 147.7 (CH2O), 153.9
(C55N), 170.3 (CO). Anal. Calcd for C23H20N4O3 (400.15): C, 68.99; H, 5.03;
N, 13.99. Found: C, 68.85; H, 5.28; N, 13.86.
1-O-Allyl-3-[5-(hydroxymethyl)-1-phenyl-pyrazol-3-yl]
quinoxalin-2-one (20)
Rf 0.50 (H/E 1/1).
1-O-Allyl-3-[5-(acetoxymethyl)-1-phenyl-pyrazol-3-yl]
quinoxalin-2-one (21)
1
Rf 0.56 (H/E 1/1). H NMR (500 MHz, CDCl3): d ¼ 2.09 (s, 3H, CH3), 5.16
(d, 2H, J ¼ 1.5 Hz, H-30, H-300), 5.17 (d, 2H, J ¼ 2.3 Hz, CH2-OAc), 5.37 (dd,
1H, J1 ,1 ¼ 10.7 Hz, J1 ,2 ¼ 1.5 Hz, H-100), 5.59 (dd, 1H, Hz, J1 ,1 ¼ 1.5 Hz,
H-10), 6.22–6.28 (m, 1H, H-20), 7.40–8.17 (10H, Ar-H). 13C NMR (CDCl3):
dc ¼ 23.1 (CH3CO), 38.9 (C-20), 56.4 (C-30), 67.6 (C-10), 112.2, 118.5, 125.6,
126.7, 126.9, 128.9, 129.4, 129.6, 129.9, 130.9, 132.7, 138.4, 138.9, 139.1
(C-aromatic), 139.9 (CH2O), 140.9 (C-N), 147.7 (C55N), 170.5 (CO).
00
0
00
0
0
00
1-(2,3-Epoxyprop-1-yl)-3-[5-(hydroxymethyl or 3-[5-
(acetoxymethyl)-1-phenyl-pyrazol-3-yl]-quinoxalin-2-
one (22 or 23)
A mixture of 17 or 18 (0.14 mmol), bentonite, and epichlorohydrin
(0.02 mL) in DMF (4 mL) was irradiated in MW oven for 18–20 minutes. The
product was extracted from ethanol to give 23 and 24, respectively. Data of
23: 1H NMR (500 MHz, DMSO-d6): d ¼ 3.72 (ddd, 1H, J3 ,2 ¼ 5.3 Hz,
0
J3 ,3 ¼ 6.1 Hz, H-300), 3.81 (ddd, 1H, J3 ,2 ¼ 4.6 Hz, J3 ,3 ¼ 6.1 Hz, H-30),
4.13–4.19 (m, 1H, H-20), 4.37–4.40 (m, 2H, CH2-N), 4.54 (d, 2H, J ¼ 6.1 Hz,
CH2-O), 5.62 (dd, 1H, J ¼ 5.3 Hz, J ¼ 6.1 Hz, OH, D2O exchangeable),
00
0
0
0
0
00

El Ashry et al.
12
7.34–7.85 (10H, Ar-H). 13C NMR (CDCl3): dc ¼ 48.2 (C-3), 54.6 (C-1), 68.2 (C-2),
111.6, 115.8, 124.2, 124.7, 128.7, 129.8, 130.2, 130.9, 132.9, 133.6, 139.6
(C-aromatic), 147.3 (CH2O), (C-N), 154.2 (C55N). Anal. Calcd for C21H18N4O3
(374.39): C, 67.37; H, 4.85; N, 14.86. Found: C, 67.05; H, 4.60; N, 14.59. Data of 24
1H NMR (500 MHz, DMSO-d6): d ¼ 1.98 (s, 3H, CH3CO), 3.71 (dd, 1H,
J3 ,2 ¼ 5.3 Hz, J3 ,3 ¼ 10.7 Hz, H-300), 3.81 (dd, 1H,, J3,2 ¼ 4.6 Hz, J3 ,3 ¼ 10.7 Hz,
0
00
0
0
00
H-30), 4.12–4.18 (m, 1H, H-20), 4.39 (ddd, 2H, J1 ,1 ¼ 9.2 Hz, J1 ,2 ¼ 4.6 Hz,
0
00
0
0
J1 ,2 ¼ 4.9 Hz, H-10, H-100), 5.15 (s, 2H, CH2-O), 7.35–7.85 (m, d, 10H, Ar-H). 13C
NMR (CDCl3): dc ¼ 20.9 (CH3CO), 48.2 (C-30), 54.6 (C-10), 68.2 (C-20), 111.9, 115.8,
124.2, 125.4, 129.4, 130.0, 130.2, 131.0, 132.9, 133.7, 138.8, 139.2 (C-aromatic),
147.4 (CH2O), 154.2 (C55N), 170.7 (C55O). Anal. Calcd for C23H20N4O4 (416.42):
C, 66.34; H, 4.84; N, 13.45. Found: C, 66.07; H, 4.65; N, 13.19.
00
0
3-[5-(Acetoxymethyl)-1-phenyl-pyrazol-3-yl]-1-(2,3-
dihydroxypropyl)-quinoxalin-2-one (24)
Method A. A mixture of 17 (0.2 g, 0.6 mmol) and potassium carbonate
(0.1 g, 0.7 mmol) in DMF was heated for 1 h, the epichlorohydrin (0.08 mL,
0.8 mmol) was added, and the reaction mixture was stirred at rt for 3 h, and
then the mixture was poured onto ice water. After successive washing with
water, the precipitate was recrystallized from ethanol to give 24 in 60%
yield, which could be also given under the same conditions by using microwave
irradiation for 6 min.
Method B. A suspension of 23 (0.14 mmol) in distilled water (3 mL) and a
drop of HCl was refluxed for 4 h, and then the solvent was evaporated under
reduced pressure. The residue was extracted with chloroform and crystallized
1
from ethanol to give compound 24 as colorless crystals. Rf 0.27 (H/E 1/2). H
NMR (500 MHz, DMSO-d6): d ¼ 1.98 (s, 3H, CH3CO), 3.48 (q, 2H,
J3,2 ¼ 5.3 Hz, J3,3 ¼ 10.7 Hz, J3 ,2 ¼ 5.3 Hz, J3 ,3 ¼ 10.7 Hz, H-30, H-300),
3.93–3.94 (m, 1H, H-20), 4.35 (dd, 2H, Jcis ¼ 4.6 Hz, J gem ¼ 8.4 Hz, H-10,
H-100), 4.81 (dd, 1H, J ¼ 5.3 Hz, J ¼ 6.1 Hz, OH, D2O exchangeable), 4.96
(d, 1H, J ¼ 5.3 Hz, OH, D2O exchangeable), 5.15 ( s, 2H, CH2-O), 7.34–7.98
0
00
0
00
0
13
(m, d, 10H, Ar-H). C NMR (CDCl3): dc ¼ 21.0 (CH3CO), 56.7 (C-10), 64.6
(C-30), 69.4 (C-20), 113.0, 116.0, 124.0, 125.4, 129.3, 130.0, 130.2, 130.8, 133.0,
138.7, 139.3 (C-aromatic), 147.6 (CH2O), 147.7 (C-N), 154.2 (C55N), 170.4
(CO). Anal. Calcd for C23H22N4O5 (434.44): C, 63.59; H, 5.10; N, 12.90.
Found: C, 63.61; H, 4.82; N, 13.05.
3-[5-(Acetoxymethyl)-1-phenyl-pyrazol-3-yl]-1-(2,3-di-O-
acetoxy-propyl)-quinoxalin-2-one (25)
A solution of 24 (0.2 g, 0.46 mmol) in pyridine (2 mL) and acetic anhydride
(2 mL) was irradiated for 3 min, then poured onto ice water. The product that

Microwave-Assisted Organic Synthesis
13
separated off was recrystallized from ethanol. Rf 0.37 (H/E 1/1). 1H NMR
(500 MHz, CDCl3): d ¼ 1.93, 2.07, 2.09 (3 s, 9H, 3 ꢀ CH3CO), 4.30 (dd, 1H,
J1 ,1 ¼ 12.2 Hz, J1 ,2 ¼ 5.3 Hz, H-10), 4.37–4.41 (m, 1H, H-100), 4.45 (t, 1H,
0
00
0
0
J3 ,2 ¼ 6.9 Hz, J3 ,3 ¼ 13.7 Hz, H-30), 4.78 (dd, 1H, J3 ,2 ¼ 5.3 Hz,
0
0
0
00
00
0
J3 ,3 ¼ 14.5 Hz, H-300), 5.13 (s, 2H, CH2O), 5.51–5.55 (m, 1H, H-20), 7.35–
8.07 (10H, Ar-H). 13C NMR (CDCl3): dc ¼ 20.9 (2 ꢀ CH3CO), 29.8 (CH3CO),
56.5 (C-10), 64.6 (C-30), 69.4 (C-20), 112.9, 113.8, 124.2, 125.7, 129.0, 129.3,
130.6, 131.4, 132.7, 138.5, 139.0 (C-aromatic), 147.5 (CH2O), 147.8 (C-N),
154.3 (C55N), 170.2, 170.4, 170.6 (3 ꢀ CO). Anal. Calcd for C27H26N4O7
(518.51): C, 62.54; H, 5.05; N, 10.81. Found: C, 62.37; H, 4.98; N, 10.59.
00
0
3-(L-Threo- or D-erythro-glycerol-1-yl)-1-phenyl-pyrazolo
[3,4-b]quinoxalines (26 or 27)
A suspension of 14 or 15 (1.40 mmol) in 0.01 N sodium hydroxide (25 mL),
bentonite (0.50 g), and 1-butanol (1.5 mL) was irradiated in a MW oven for
2 min to give yellow crystals of 21 or 22; Rf 0.2 (H/E 1/3).
1-Phenyl-pyrazolo[3,4-b]quinoxaline-3-carboxaldehyde
(28)
A mixture of 26 or 27 (0.22 mmol) in a solution of sodium metaperiodate
(0.4 mmol) in water (2 mL) was subjected to irradiation in a MW oven to give
orange crystals of 24; Rf 0.7 (H/E 2/1).
3-Cyano-1-phenyl-pyrazolo[3,4-b]quinoxaline (31) 3-[1-
(Phenylhydrazono)glyoxal-1-yl]-quinoxaline-2 (29)
A mixture of 14 or 15 (0.42 mmol) and bentonite (0.15 g) in a solution of
sodium metaperiodate was subjected to irradiation in MW oven for 2 min.
The product was extracted with ethanol, then recrystallized from ethanol; Rf
0.48 (H/E 1/1).
2-Acetoxy-3-(2-acetyl-2-phenylhydrazono)-2,3-
dihydrofuro[2,3-b]quinoxaline (30)
The compound 32 (0.05 g, 0.067 mmol) was dissolved in pyridine (1.5 mL)
and acetic anhydride (3 mL), then irradiated for 1 min, allowed to cool, and
left over night at rt. The reaction mixture was poured onto crushed ice, and
the product that separated out was filtered off, washed repeatedly with
water, and recrystallized from ethanol in pale yellow; Rf 0.67 (H/E 1/1).

El Ashry et al.
14
ACKNOWLEDGMENTS
The authors thank Dr. A. El Nemr for the AM1 calculations. The continued
support from the AvH Foundation is highly appreciated.
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