Studies on dehydro-L-ascorbic acid and dehydro-D-isoascorbic acid hydrazones

Article abstract of DOI:10.1039/a807584k

2-Arylhydrazones of dehydro-L-ascorbic acid and its analogues are established as precursors for the synthesis of various heterocyclic compounds including triazoles, pyrazoles, imidazoles and isoxazoles; many of these compounds show great chemotherapeutic effects.

Full text of DOI:10.1039/a807584k

View Article Online / Journal Homepage / Table of Contents for this issue
296 J. CHEM. RESEARCH (S), 1999
J. Chem. Research (S),
1999, 296^297y
Studies On Dehydro-L-ascorbic Acid and
Dehydro-D-isoascorbic Acid Hydrazonesy
Mohamed A. El-Sekily,a Mohamed E. Elba*b and Farid S. Fouadb
a Department of Chemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
b Department of Chemistry, Faculty of Education, Damanhour, Alexandria University, Alexandria, Egypt
2-Arylhydrazones of dehydro-L-ascorbic acid and its analogues are established as precursors for the synthesis of
various heterocyclic compounds including triazoles, pyrazoles, imidazoles and isoxazoles;1^6 many of these com-
pounds show great chemotherapeutic effects.
Treatment of L-threo-2,3-hexodiulosono-1,4-lactone-2-(p-
tolylhydrazone) (1) with methylhydrazine a¡orded the bis-
hydrazone 2 (Scheme 1). The IR spectrum showed the
lactone band at 1740 cm 1. Acetylation of 2 did not give
the expected di-O-acetyl derivative but instead elimination
of acetic acid and hydrolysis of the methylhydrazone moiety
took place to give 3 as con¢rmed by its microanalytical, IR
and 1H NMR data. Compound 3 was also obtained by
treatment of 1 with Ac2O and pyridine. Similarly benzo-
ylation of 1 a¡orded 4. Treatment of 2 with hydrazine
hydrate followed by acidi¢cation gave the pyrazolinedione
5 through opening of the lactone ring followed by internal
nucleophilic attack on the carbonyl group. The IR spectrum
of 5 showed the amide band at 1655 cm 1. Compound 5
was also obtained from
1 by heating with excess
methylhydrazine. Acetylation of 5 a¡orded the tri-O-acetyl
derivative 6. Periodate oxidation of 5 resulted in the con-
sumption of 2 moles of the oxidant and formation of
the aldehyde 7 whose IR spectrum showed the aldehyde car-
bonyl at 1700 cm 1. Sodium tetrahydroborate reduction of
7 gave the corresponding 3-hydroxymethyl derivative 8.
Treatment of 1 with HBr/AcOH gave the dibromo deriva-
tive 9. Similar treatment of the mono-arylhydrazones 10
and 11 with HBr/AcOH a¡orded the corresponding
dibromo derivatives 12 and 13. Their IR spectra showed
the lactone and C2-carbonyl groups and the disappearance
of the hydroxy groups (Scheme 2).
The mass spectrum of 12 showed the molecular ion peak
(also the base peak) at m/z 392, 390 and 388 (1 : 2 : 1). Con-
densation of 12 with p-nitrophenyl-hydrazine semicarbazide
and thiosemicarbazide a¡orded compounds 14, 15 and 16,
respectively. Condensation of 11 with hydroxylamine
a¡orded the corresponding oxime 17. Careful treatment
of 17 with NaOH followed by acidi¢cation resulted in
the formation of the isoxazoline-dione 18 whose IR
spectrum revealed a carbonyl band at 1731 cm 1. The
reaction of L-threo-2,3-hexodiulosono-1,4-lactone (19) and
Scheme 1
Experimental
Melting points were recorded on a Total (Buchi) apparatus and are
uncorrected. IR (KBr) spectra were recorded on a 580 B Perkin Elmer
IR spectrometer. The 1H NMR spectra were recorded on a Varian
EM-390, 90 MHz NMR spectrometer using TMS as the standard.
Chemical shifts (d) are given in ppm. Elemental analyses agreed with
the assigned structures.
m-bromophenylhydrazine
gave
the
m-bromophenyl-
hydrazone 20 (Scheme 2). Its IR spectrum showed the
1
lactone band at 1750 cm besides the C3-carbonyl band
L-threo-2,3-Hexodiulosono-1,4-lactone-2-p-tolylhydrazone-3-methyl-
hydrazone (2).öA solution of 1 (1 g, 3.59 mmol) in ethanol
(30 ml) was re£uxed for 2 h with methylhydrazine (1 ml) and AcOH
(3 ml). The mixture was then concentrated and cooled. The separated
product (0.95 g, 86%) was recrystallized from ethanol to give red
1
at 1675 cm
.
On treatment with hydroxylamine
hydrochloride, 20 gave the 2-hydrazono-3-hydroxyimino
derivative 21. Dehydrative cyclization of 21 with Ac2O
a¡orded the furano-triazole derivative 22 whose 1H
NMR spectrum showed the two OAc groups at d 2.0
and 2.1. Upon treatment of 22 with concentrated ammonia
in methanol, deacetylation occurred concurrently with open-
ing of the lactone ring to a¡ord the triazole-4-carboxamide
derivative 23 whose IR spectrum showed the amide band
1
needles, mp 188^190 ꢀC; nmax/cm 3400 (OH) and 1740 (lactone
CˆO).
5-(2-Acetoxyethylidene)tetrahydrofurantrione 3-p-Tolylhydrazone
(3).öA solution of 1 or 2 (0.1 g) in dry pyridine (10 ml) was treated
with Ac2O (5 ml), kept overnight at room temp. and then poured onto
crushed ice. The separated solid (92 and 81%, respectively) was
recrystallized from ethanol to give yellow needles; mp 173^174 ꢀC;
1
1
at 1666 cm in addition to the hydroxy band at 3412 cm
.
1
nmax/cm 1780 (lactone CˆO) and 1730 ester (CˆO); dH (CDCl3)
2.1 (s, 3 H, OAc), 2.33 (s, 3 H, CH3-p), 4.77 (d, 2 H, H-2), 5.82
(m, 1 H, H-1), 7.0^7.5 (m, 4 H, Ar-H) and 12.7 (s, 1 H, NH).
5-(2-Benzoyloxyethylidene)tetrahydrofurantrione 3-p-Tolylhydrazone
(4).öA solution of 1 (0.1 g, 0.36 mmol) in dry pyridine (10 ml) was
treated with BzCl (0.2 ml) as mentioned above (0.1 g, 76%). It
was recrystallized from ethanol to give yellow needles; mp
* To receive any correspondence.
y This is a Short Paper as de¢ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1999, Issue 1]; there is
therefore no corresponding material in J. Chem. Research (M).

View Article Online
J. CHEM. RESEARCH (S), 1999 297
Dibromo Derivatives 9, 12 and 13.öA suspension of the mono-
hydrazones 1, 108 or 119 (1 g) in 30% HBr in AcOH (30 ml) was stirred
for 24 h at room temp. and then poured on to water (100 ml). Com-
pounds 9, 12 and 13 (71^81%) were recrystallized from
chloroform^ethanol (1:1 v/v) to give yellow prisms, mp 168^169,
160^161 and 159^160 ꢀC respectively. The IR spectra revealed the
lactone CˆO at 1772^1740 and the C3^O at 1696^1680 cm 1; dH
for 12 (CDCl3) 4.1 (m, 2 H, H-6), 4.86 (m, 1 H, H-5), 5.72 (d, 1
H, H-4), 7.1^7.72 (m, 5 H, Ph) and 9.32 (s, 1 H, NH).
R2
O
R2
R1
R1
R3
O
O
HO
O
O
R4
X
O
N
NH
10 R1 = H, R2 = OH, X = NNHPh
11 R1 = OH, R2 = H, X = NNHC6H4-Br-p
19 R1 = OH, R2 = H, X = O
R5
12 R1 = R4 = R5 = H, R2 = R3 = Br
13 R2 = R5 = H, R1 = R3 = R4 = Br
20 R2 = R4 = H, R1 = R3 = OH, R5 = Br
Condensation Products of 5,6-Dibromo-5,6-dideoxy-D-erythro-2,3-
hexodiulosono-1,4-lactone-2-phenylhydrazone (14^16).öA solution
of 12 (0.1 g, 0.25 mmol) in ethanol (20 ml) was re£uxed for 6 h with
p-nitrophenylhydrazine, semicarbazide hydrochloride and sodium
acetate or thiosemicarbazide in the presence of a catalytic amount
of AcOH (yield 62^87%). Compounds 14, 15 and 16 were recrystal-
OH
O
HO
O
Br
O
R1
Br
O
HO
N
N NH
R2
lized from ethanol; mp 159^160, 172^174 and 159^160 ꢀC, respect-
17 R1 = Br, R2 = H
21 R1 = H, R2 = Br
RHNN
N NHPh
1
ively. The IR spectra revealed the lactone CˆO at 1738^1730 cm
.
14 R = p-NO2–C6H4
15 R = CONH2
16 R = CSNH2
L-threo-2,3-Hexodiulosono-1,4-lactone-2-p-bromophenylhydrazone-
3-oxime (17).öA solution of 11 (1 g, 2 mmol) in ethanol (30 ml)
was re£uxed for 3 h with hydroxylamine hydrochloride (1 g,
14.4 mmol), sodium acetate (1.2 g; 14.6 mmol) and acetic acid (5 ml);
water (50 ml) was added and the mixture left to cool. The separated
solid (0.85 g, 81.7%) was recrystallized from ethanol to give yellow
OAc
O
N
AcO
O
OH
needles; mp 209^210 ꢀC; nmax/cm 3400 (OH) and 1730 (lactone
1
N
N
N
O
HO
CˆO).
HO
3-(L-threo-Glycerol-1-yl)-4,5-isoxazoinedione-4-p-bromophenylhydra-
zone (18).öA suspension of 17 (0.5 g, 1.4 mmol) in water (10 ml)
was heated with 10% NaOH (20 ml) to 80 ꢀC, cooled, made neutral
with AcOH and kept overnight at room temp. The product AcOH
(0.3 g, 60%) was recrystallized from ethanol^water (1:1 v/v) to give
N
O
NH
Br
22
1
OH
pale yellow needles; mp 128^130 ꢀC; nmax/cm 3368 (OH) and 1731
Br
18
CONH2
(lactone CˆO).
HO
L-threo-2,3-Hexodiulosono-1,4-lactone-2-m-bromophenylhydrazone
(20).öA solution of 19 in 50 ml of a water^ethanol mixture (1 : 1
v/v), obtained by oxidation of L-ascorbic acid (7.2 g, 28.4 mmol) with
iodine (7.2 g, 28.4 mmol) in ethanol (20 ml), was treated with
m-bromophenylhydrazine hydrochloride (1 g, 4.47 mmol) and sodium
acetate (1 g, 12.1 mmol) at room temp. The separated solid (2 g, 20%)
was recrystallized from ethanol, giving orange needles; mp
N
N
HO
N
Br
23
1
156^157 ꢀC; nmax/cm 3450 (OH), 3118 (NH), 1750 (lactone CˆO)
Scheme 2
and 1675 (C3ˆO).
L-threo-2,3-Hexodiulosono-1,4-lactone-2-m-bromophenylhydrazone-
3-oxime (21).öObtained from 20 as mentioned in the synthesis of
1
17; (0.8 g, 77%); mp 209^210 ꢀC; nmax/cm 3362 (OH), 3134 (NH),
1735 (lactone CˆO).
158^159 ꢀC; nmax/cm 1 1760 (lactone CˆO) and 1719 (ester CˆO); dH
([2H6]DMSO) 2.3 (s, 3 H, CH3-p), 5.03 (d, 2 H, H-2), 6.06 (m, 1 H,
H-1), 7.1^8.0 (m, 9 H, Ar-H) and 12.73 (s, 1 H, NH).
2-Acetyloxy-1-[5-(3-bromophenyl)-3-oxohydrofurano[3,4-d]1,2,3-tri-
triazolyl]ethyl Acetate (22).öObtained by acetylation of 21 as
mentioned in the synthesis of 3; (0.1 g, 85%); mp 99^100 ꢀC;
3-(L-threo-Glycerol-1-yl)-1-methyl-4,5-pyrazolindione 4-p-Tolylhy-
drazone (5).ö(A) A solution of 2 (0.5 g, 63 mmol) in ethanol
(20 ml) was re£uxed for 1 h with hydrazine hydrate (1 ml). The
mixture was concentrated and then allowed to cool. The product
(0.2 g, 40%) was recrystallized from ethanol to give yellow needles;
1
nmax/cm 1780 (lactone CˆO) and 1745 (ester CˆO); dH (CDCl3):
2.04 and 2.1 (2 s, 6 H, 2 OAc), 4.45 (m, 2 H, CH2), 5, 52 (q, 1
H, H-1), 5.86 (d, 1 H, H-6) and 7.5^7.87 (m, 4 H, Ar-H).
2-m-Bromophenyl-5-carboxamide-4-(L-threo-glycerol-1-yl)-1,2,3-tri-
azole (23).öA solution of 22 (0.1 g, 0.24 mmol) in methanol (10
ml) was treated with conc. NH3 (5 ml), left overnight at room temp.,
concentrated under reduced pressure and the separated solid
(30 mg, 84%) recrystallized from ethanol as colourless needles, mp
mp 163^165 ꢀC; nmax/cm 3300 (OH) and 1655 (OCN); (B) A sol-
1
ution of 1 (1 g, 3.5 mmol) in ethanol (50 ml) was re£uxed for 10
h with methylhydrazine (10 ml). The product (0.5 g, 45%) was ident-
ical with that obtained by method A.
1
165^166 ꢀC; nmax/cm 3412 (OH), 3126 (NH) and 1666 (OCN).
1-Methyl-3-(1,2,3-tri-O-acetyl-L-threo-glycerol-1-yl)-4,5-pyrazolin-
dione 4-p-Tolylhydrazone (6).öAcetylation of 5, as mentioned in
the synthesis of 3, gave 6 as a syrup which was puri¢ed by column
chromatography (silica gel) eluted with ethyl acetate^methanol (9:1
Received, 29th September 1998; Accepted, 3rd November 1998
Paper E/8/07584K
1
v/v) (0.13 g, 70%); nmax/cm 1745 (ester CˆO) and 1653 (OCN);
dH (CDCl3) 2.00 (s, 6 H, 2OAc) 2.1 (s, 3 H, OAc), 2.33 (s, 3 H, CH3-p),
3.33 (s, 3 H, N-CH3), 4.18 (m, 2 H, H-3), 5.66 (m, 1 H, H-2), 6.1 (d,
1 H, H-1), 7.0^8.0 (m, 4 H, Ar-H) and 13.55 (s, 1 H, NH).
References
1
2
3
M. A. El Sekily, Pharmazie, 1979, 34, 531.
S. H. Mancy, Alex. J. Pharm. Sci., 1993, 7, 119.
M. A. El Sekily and S. Mancy, Arabian J. Sci. Eng., 1993, 18,
405.
3-Carboxaldehyde-1-methyl-4,5-pyrazolindione 4-p-Tolylhydrazone
(7).öA suspension of 5 (0.1 g, 0.33 mmol) in water (10 ml) was stirred
for 6 h at room temperature with sodium metaperiodate (0.2 g, 0.93
mmol) in water (5 ml). The resulting solid (65 mg; 82%) was
4
5
S. H. Mancy, Alex. J. Pharm. Sci., 1993, 7, 139.
M. A. El Sekily, S. Mancy, I. E. El Kohly, E. S. H. El Ashry,
H. S. El Khadem and D. L. Swartz, Carbohydr. Res., 1977,
59, 141.
M. A. El Sekily, S. Mancy and K. Atta, Arabian J. Sci. Eng.,
1991, 16(2A), 201.
recrystallized from ethanol as red needles; mp 135^136 ꢀC; nmax/cm
1
1700 (CHO), 1650 (OCN) and 1600 (CˆN).
1-Methyl-3-hydroxymethyl-4,5-pyrazolinedione 4-p-Tolylhydrazone
(8).öA solution of 7 (0.1 g; 0.41 mmol) in methanol (10 ml) was
stirred with a solution of sodium tetrahydroborate (0.1 g, 2.6 mmol)
in water (10 ml) that was added in small portions. The solution
was acidi¢ed with AcOH (1 ml) and the separated solid (60 mg,
59.5%) was recrystallized from ethanol as yellow crystals; mp
6
7
8
9
M. A. El Sekily and S. Mancy, Carbohydr. Res., 1982, 110, 229.
M. A. El Sekily and S. Mancy, Carbohydr. Res., 1983, 124, 97.
E. S. H. El Ashry, Y. El Kilany and H. Abdel Hamid,
Carbohydr. Res., 1988, 172, 308.
117^118 ꢀC; nmax/cm 3450 (OH) and 1650 (OCN).
1