Syntheses and characterizations of imidazole-4,5-diacylhydrazones

Article abstract of DOI:10.1081/SCC-120021831

Tartaric acid was transformed into imidazole-4,5-dicarboxylic acids 2, then via esterification, hydrazinolysis, condensation with aromatic aldehyde in glacial acetic acid to furnish seven title compounds in about 24% overall yield.

Full text of DOI:10.1081/SCC-120021831

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Syntheses and Characterizations of Imidazole-4,5-
diacylhydrazones
Guifa Su a , Jiangke Qin a , Qingling Ni a & Hongtao Mu a
a Department of Chemistry and Chemical Engineering, Guangxi Normal University, Guilin,
P.R. China
Version of record first published: 20 Aug 2006
To cite this article: Guifa Su, Jiangke Qin, Qingling Ni & Hongtao Mu (2003): Syntheses and Characterizations of
Imidazole-4,5-diacylhydrazones, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 33:14, 2429-2435
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 14, pp. 2429–2435, 2003
Syntheses and Characterizations of
Imidazole-4,5-diacylhydrazones
*
Guifa Su, Jiangke Qin, Qingling Ni, and Hongtao Mu
Department of Chemistry and Chemical Engineering,
Guangxi Normal University, Guilin, P.R. China
ABSTRACT
Tartaric acid was transformed into imidazole-4,5-dicarboxylic acids
2, then via esterification, hydrazinolysis, condensation with aromatic
aldehyde in glacial acetic acid to furnish seven title compounds in
about24% overall yield.
Key Words: Tartaric acid; Imidazole-4,5-dicarboxylic acid;
Imidazole-4,5-diacylhydrazone.
*Correspondence: Guifa Su, Research Associate, Department of Chemistry,
Louisiana State University, 232 Choppin Hall, Baton Rouge 70803, Louisiana,
USA; Fax: +1-225-578-3458; E-mail: su_gf@sina.com.
2429
DOI: 10.1081/SCC-120021831
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2430
Su et al.
Imidazoles are widely distributed in nature, and known as ‘‘biocata-
lyst’’ and ‘‘biological ligand.’’ They play a vital role in life activities.[1]
Schiff bases containing polyfunctional groups have not only produced
stable metal complexes, but these ligands and their metal complexes
also have a significant role in the domains of stereochemistry, model
systems of biochemical interest, drugs, herbicides and fungicides, cataly-
sis, stabilizers, polymers, pigments and dyes, etc.[2] One type of Schiff
base, acylhydrazones and their metal complexes possess excellent insecti-
cidal,[3] antimicrobial[3–7] and genotoxic activities.[7] Mostacylhydrazones
were synthesized by extensive reflux of a solution of acylhydrazine and an
aromatic aldehyde. Recently we reported a practical and convenient
synthesis of thiophene-2,5-diacylhydrazones. The key step is the reaction
of thiophene-2,5-dicarboxylic acid dihydrazide with an aromatic alde-
hyde in glacial acetic acid for several minutes.[8] Here we wish to
reporta fastand efficientsynhtesis of imidazole-4,5-diacylhydrazones
5 (Sch. 1).
The molar ratio between ester and hydrazine reagents affected
the formation of imidazole-4,5-dicarboxylic acid dihydrazide (4). At a
molar ratio of 1:4, the reaction was incomplete even after 6 h. In our
experiments, we used a 1:8 (ester:hydrazine ratio).
Scheme 1.

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Imidazole-4,5-diacylhydrazones
2431
The condensation of imidazole-4,5-dicarboxylic acid dihydrazide (4)
with aromatic aldehyde in glacial acetic acid was completed in several
minutes. This fast reaction is supposed due to the differences in solubility
between acylhydrazine 4 and the reaction intermediates (amino alcohols),
and between the intermediates and diacylhydrazones 5.[8] Acetic acid is a
poor solventfor 4 and mostdiacylhydrazones 5 (besides 5a which
is partially soluble in hot acetic acid). With the addition of aldehyde,
dihydrazide 4 reacted with it and formed the soluble intermediate.
By quickly eliminating two molecules of water from amino alcohols,
diacylhydrazone 5 were precipitated.
In summary, we have described a fastand efficientsynhtesis for
imidazole-4,5-diacylhydrazones 5: condensation of imidazole-4,5-dicar-
boxylic acid dihydrazide with aromatic aldehydes in glacial acetic acid
for several minutes. This method offers high yield with mild reaction
conditions, short reaction time, and simple work-up.
EXPERIMENTAL
General Considerations
All reagents were obtained from commercial suppliers. Liquid
reagents and solvents were purified by standard procedures shortly
before use. Melting points were obtained by using a WRS-IA melting
pointapparaut s and uncorrecetd.
All elemental analyses were performed by Carlo Erba model 1106
1
analyzer. H NMR spectra were recorded on a Varian INOVA 500 MHz
spectrometer in DMSO-d6. Infrared spectra were recorded on a Nicolet
ESP 360 FT-IR spectrometer as KBr pellets.
1H-Imidazole-4,5-dicarboxylic acid (2) was synthesized according to
the literature,[9] white solid, m.p. 278–280ꢀC (decomposition), yield 40%
(lit. 43–48%, m.p. 280ꢀC).
Dimethyl 1H-imidazole-4,5-dicarboxylate (3) was synthesized with
modified procedures of literature.[10] After neutralizing with calcium
carbonate, the mixture was filtered, the filtrate was put into the
refrigerator and allowed to stand overnight. The mixture was
filtered, the solid was dried and recrystallized from methanol to
furnish a white solid, m.p. 200–202ꢀC, yield 70%. (lit. 200–203ꢀC,
yield 72%[10]).
1H-Imidazole-4,5-dicarboxylic acid dihydrazide (4). To a flask con-
taining 1.5 g (8.2 mmol) of dimethyl 1H-imidazole-4,5-dicarboxylate

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Su et al.
28 mL of methanol was added. The mixture was refluxed until all imida-
zole-4,5-dicarboxylate had dissolved. 2.96 mL of 80% hydrazine hydrate
(76.6 mmol) was added, the mixture was heated to reflux for 3 h, cooled to
r.t. and filtered. The crude product was recrystallized from water to give
1.75 g (95%) of 4 as a white solid, m.p.>300ꢀC.
Imidazole-4,5-diacylhydrazone (5). To a flask were added 0.184 g
(1 mmol) of imidazole-4,5-dicarboxylic acid dihydrazide and 10 mL of
glacial acetic acid. The stirred mixture was heated in a water bath.
Then, 2 mmol of aromatic aldehyde was added at 60ꢀC. With the addi-
tion of aldehyde, dihydrazide 4 dissolved and a clear solution was
obtained before a solid precipitated very quickly. When the reaction
was complete (several minutes, monitored by TLC), the mixture was
cooled and filtered. The solid was washed with ethanol, then with water
until the washings were neutral (for 5a and 5d, firstwashed with hexane
and acetic acid, then washed with ethanol and water). The crude pro-
duct was purified by recrystallization from DMF-water (5a also can be
recrystallized from glacial acetic acid), then dried (5c and 5d are easily
oxidized, therefore must be dried and kept under vacuum and room
temperature).
DMF and DMSO are good solvents for compound 5.
There are three characteristic absorption bands in IR of acylhydra-
zone 5. The bands at1656–1667 cm ꢁ1, 1554–1561 cmꢁ1 and 1255–
1302 cmꢁ1 are assigned as ꢀC¼O (amide I), ꢀC¼N (amide II) and ꢀC-N
(amide III) modes respectively. The imidazole ring-skeletal vibration
(ꢂ1550 cmꢁ1) overlaps with amide II. Two protons at ꢂ14.2 and
ꢂ12.0 ppm were assigned as –CONH–; two protons at ꢂ8.50 ppm were
assigned as –N¼CH–, because there are cis and trans isomers in acyl-
hydrazones and ꢁcis>ꢁtrans. The proton at 8.0 ppm was assigned as
2-imidazole-H, a characteristic peak of imidazole nucleus.
5a. White solid, yield 86%, m.p.>300ꢀC, Rf (AcOEt/EtOH ¼
1:1) ¼ 0.86. Anal. calcd. for C19H16O2N6 C, 63.33; H, 4.44; N, 23.33.
Found: C, 63.27; H, 4.35; N, 23.23. IR (ꢀ): 3130 (s, N-H), 1661 (s,
C¼O), 1556 (s, mixed C¼N and imidazole ring-skeletal vibration),
1291 (m, C-N). 1H NMR: ꢁ 14.29 (1H, s, –CO-NH–), 13.67 (1H, s, 1-imi-
dazole-H), 12.07 (1H, s, –CO-NH–), 8.67 (1H, s, –N¼CH–), 8.45 (1H, s,
–N¼CH–), 8.03 (1H, s, 2-imidazole-H), 7.4–7.8 (10H, m, Ph).
5b. Pale yellow crystal, yield >99%, m.p.>300ꢀC, Rf (HOAc/
AcOEt ¼ 1:20) ¼ 0.70. Anal. calcd. for C19H16O4N6 C, 58.16; H, 4.08;
N, 21.43. Found: C, 57.93; H, 3.92; N, 21.28. IR (ꢀ): 3150 (s, N-H),
1657 (s, C¼O), 1558 (s, mixed C¼N and imidazole ring-skeletal
1
vibration), 1276 (m, C-N). H NMR ꢁ 14.27 (1H, s, –CO-NH–), 13.71
(1H, s, 1-imidazole-H), 12.40 (1H, s, –CO-NH–), 11.11, 11.05 (2H,

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Imidazole-4,5-diacylhydrazones
2433
s, –OH), 8.89 (1H, s, –N¼CH–), 8.61 (1H, s, –N¼CH–), 8.06 (1H, s,
2-imidazole-H), 6.9–7.7 (8H, m, Ph).
5c. Pale yellow crystal, yield 83%, m.p. 277–279ꢀC (decomposition),
Rf (HOAc/AcOEt ¼ 1:20) ¼ 0.65. Anal. calcd. for C15H12O4N6 C, 52.94;
H, 3.53; N, 24.71. Found: C, 52.76; H, 3.43; N, 24.63. IR (ꢀ) 3131 (s,
N-H), 1661 (s, C¼O), 1558 (s, mixed C¼N and imidazole ring-skeletal
vibration), 1282 (m, C-N). 1H NMR ꢁ 14.29 (1H, s, –CO-NH–),
13.66 (1H, s, 1-imidazole-H), 12.12 (1H, s, –CO-NH–), 8.56 (1H, s,
–N¼CH–), 8.28 (1H, s, –N¼CH–), 8.6-7.9 (6H, m, furan), 8.01 (1H, s,
2-imidazole-H).
5d. White crystal, yield 90%, m.p.>300ꢀC, Rf (HOAc/
AcOEt ¼ 1:20) ¼ 0.66. Anal. calcd. for C19H14O6N8 C, 50.67; H, 3.11;
N, 24.89. Found: C, 50.52; H, 3.09; N, 24.73. IR (ꢀ) 3251 (m, N-H),
1667 (s, C¼O), 1559 (s, mixed C¼N and imidazole ring-skeletal
vibration), 1299 (m, C-N). 1H NMR ꢁ 14.25 (1H, s, –CO-NH–),
13.74 (1H, s, 1-imidazole-H), 12.40 (1H, s, –CO-NH–), 8.72 (1H, s,
–N¼CH–), 8.60 (1H, s, –N¼CH–), 8.06 (1H, s, 2-imidazole-H), 7.7–8.3
(8H, m, Ph).
5e. Yellow crystal, yield 96%, m.p. 274–275ꢀC (decomposition). Rf
(HOAc/EtOAc ¼ 1:20) ¼ 0.72. Anal. calcd. for C23H20O2N6 C, 66.99; H,
4.85; N, 20.39. Found: 66.72; H, 4.61; N, 20.17. IR (ꢀ) 3269 (m, N-H),
1659 (s, C¼O), 1554 (s, mixed C¼N and imidazole ring-skeletal
1
vibration), 1302 (m, C-N). H NMR ꢁ 14.24 (1H, s, –CO-NH–), 13.65
(1H, s, 1-imidazole-H), 12.00 (1H, s, –CO-NH–), 8.46 (1H, d, J ¼ 8 Hz,
–N¼CH–), 8.15 (1H, d, J ¼ 9 Hz, –N¼CH–), 8.01 (1H, s, 2-imidazole-H),
7.0–7.7 (14H, m, PhCH¼CH–).
5f. Yellow crystal, yield 91%, m.p. 263ꢀC. Rf (HOAc/EtOAc ¼
1:20) ¼ 0.64. Anal. calcd. for C21H20O4N6 C, 60.00; H, 4.76; N, 20.00.
Found: C, 59.84; H, 4.63; N, 19.72. IR (ꢀ) 3123 (m, N-H), 1657 (s, C¼O),
1561 (s, mixed C¼N and imidazole ring-skeletal vibration), 1255 (s,
1
C-N). H NMR ꢁ 14.24 (1H, s, –CO-NH–), 13.60 (1H, s, 1-imidazole-
H), 11.91 (1H, s, CO-NH-), 8.61 (1H, s, –N¼CH–), 8.35 (1H,
s, –N¼CH–), 8.06 (1H, s, 2-imidazole-H), 7.0–8.0 (8H, m, Ph), 3.83
(6H, s, –OCH3).
5g. Yellow crystal, yield 92%, m.p.>300ꢀC. Rf (HOAc/EtOAc) ¼
0.78. Anal. calcd. for C21H20O6N6 C, 55.75; H, 4.42; N, 18.58. Found:
C, 55.66; H, 4.37; N, 18.47. IR (ꢀ) 3173 (s, N-H), 1656 (s, C¼O), 1559 (s,
mixed C¼N and imidazole ring-skeletal vibration), 1283 (s, C-N).
1H NMR ꢁ 14.20 (1H, s, –CO-NH–), 13.56 (1H, s, 1-imidazole-H),
11.83 (1H, s, –CO-NH–), 9.50, 9.46 (2H, s, –OH), 8.54 (1H, s,
–N¼CH–), 8.28 (1H, s, –N¼CH–), 8.07 (1H, s, 2-imidazole-H), 6.9–7.4
(6H, m, Ar), 3.84 (6H, s, –OCH3).

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Su et al.
ACKNOWLEDGMENT
Financial supportfrom Young Nautral Science Foundaiton from
Guangxi Normal University, P.R. China is gratefully acknowledged.
We thank Dr. Rongjuan Cong in Louisiana State University for a critical
reading of the manuscript.
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Received in the USA November 19, 2002

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