Synthesis of 4-(1H-Azol-1-ylmethyl)benzohydrazides and their acyclic and heterocyclic derivatives

Article abstract of DOI:10.1007/s11176-005-0180-7

4-(1H-Azol-1-ylmethyl)benzohydrazides were prepared from methyl 4-(bromomethyl)benzoate, azoles, and hydrazine hydrate. Reactions of 4-(1H-imidazol-1-ylmethyl)benzohydrazide with carbonyl compounds gave hydrazones whose tautomerism was studied. From the h

Full text of DOI:10.1007/s11176-005-0180-7

Russian Journal of General Chemistry, Vol. 75, No. 1, 2005, pp. 111 117. Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 1, 2005,
pp. 123 129.
Original Russian Text Copyright
2005 by Osyanin, Purygin, Belousova.
Synthesis of 4-(1H-Azol-1-ylmethyl)benzohydrazides
and Their Acyclic and Heterocyclic Derivatives
V. A. Osyanin, P. P. Purygin, and Z. P. Belousova
Samara State University, Samara, Russia
Received April 18, 2003
Abstract 4-(1H-Azol-1-ylmethyl)benzohydrazides were prepared from methyl 4-(bromomethyl)benzoate,
azoles, and hydrazine hydrate. Reactions of 4-(1H-imidazol-1-ylmethyl)benzohydrazide with carbonyl com-
pounds gave hydrazones whose tautomerism was studied. From the hydrazides, 1,3,4-oxadiazoles, 1,2,4-tri-
azole-5-thione, and N-benzoyl-N -alkyl(aryl)sulfonylhydrazines were synthesized.
Hydrazides and their functional derivatives were
used to prepare a series of antitubercular and anti-
bacterial preparations [1, 2]. Many heterocyclic com-
pounds directly prepared from hydrazides, too,
possess valuable biological and physicochemical
properties. Azole substitution in such compounds
strongly affects their properties [3]. Aimed at the
synthesis of azole-substituted hydrazides, we develo-
ped a method for preparing 4-(1H-azol-1-ylmethyl)-
benzohydrazides and a series of their acyclic and
heterocyclic derivatives.
Methyl 4-(1H-azol-1-ylmethyl)benzoates Ia Id
were synthesized from methyl (4-bromomethyl)benz-
oate and azoles AzH in the presence of sodium
hydride in anhydrous DMF. Subsequent boiling of
methyl benzoates Ia Id with hydrazine hydrate for 3
4 h gave hydrazides IIa IId.
O
N2H4 H2O
AzH, NaH
BrCH2
COOCH3
AzCH2
COOCH3
AzCH2
C
NHNH2
Ia Id
IIa IId
Az = imidazol-1-yl (Ia, IIa), benzimidazol-1-yl (Ib, IIb), 1,2,4-triazol-1-yl (Ic, IIc), benzotriazol-1-yl (Id, IId).
After purification, the yields of the hydrazides were
79 86%. The IR spectra contain C=O and NH absorp-
tion bands at 1672 1622 and 3339 3165 cm , res-
pectively. In the spectra measured in D2O, the NH
proton signals disappear because of fast exchange.
formation of benzoylhydrazones can be catalyzed by
acids. However, we failed to prepare ketone acylhyd-
razones in the presence of sulfuric or p-toluenesul-
fonic acid, probably because the preferred protonation
center was the nitrogen atom of the heterocyclic
fragments, and the use of much catalysts shifted the
equilibrium to the starting compounds.
1
The hydrazides were reacted with various carbonyl
compounds to obtain 4-(1H-azol-1-ylmethyl)benzoyl-
hydrazones IIIa IIIh. The reactions with aromatic
aldehydes proceed rather fast without catalysts at 1:1
reagent molar ratios in 95% ethanol.
The IR spectra of acylhydrazones III contain a
1
broad band at 3200 3100 cm , belonging to a hydro-
gen-bonded NH group. In the spectra of compounds
IIIf and IIIh, an additional band is present near
1
With isatin, too, compound IIIi was obtained by
simply boiling equimolar reagent amounts for 4 h in
ethanol.
3340 cm , assignable to free NH group. The carbonyl
1
group appears at 1680 1637 cm .
It is known that acylhydrazones III can exist as
1
By TCL it was established that in the presence of
tautomers A C [4 6]. Analysis of the H NMR and
traces of water cyclohexanone acylhydrazone is hydro- IR spectra show that the acylhydrazones in crystal and
lyzed to the starting compounds. It is known that in DMSO solutions are present in form A. The absorp-
1070-3632/05/7501-0111 2005 Pleiades Publishing, Inc.

112
OSYANIN et al.
N
N
O
O
R1
R1
C
R1
C
NHNHSO2R2
Xa Xc
NHN=CR2R3
IIIa IIIh
O
IV
R2R3C=O
HC(OC2H5)2
R2SO2Cl
O
N
N
O
PhCOCl
BrCN
R1
C
R1
C
R1
NH2 HBr
NHNH2
NHNHCOPh
O
II
V
NaHCO3
POCl3
N
N
CH2=CHCH2NCS
R1
NH2
N
N
O
R1
Ph
VIIa, VIIb
O
VI
S
O
R1
C
C CH2CH=CH2
NHNH
VIII
NaOH
NH
N
N
N
H+
R1
S
R1
SNa+
N
N
CH2CH=CH2
IX
CH2CH=CH2
R1 = p-C6H4CH2Az; R2 = H, R3 = C6H5 (IIIa); R2 = H, R3 = 2-HOC6H4 (IIIb); R2 = H, R3 = 4-HOC6H4 (IIIc), R2 = H,
R3 = 4-HO-3-CH3OC6H3 (IIId); R2 = H, R3 = (CH3)2NC6H4 (IIIe); R2R3 = (CH2)4 (IIIf); R2 = CH3, R3 = 4-HOC6H4
(IIIg), R2R3 = (CH2)5 (IIIh); R2 = CH3 (Xa); R2 = C6H5 (Xb); R2 = 4-CH3C6H4 (Xc); Az = imidazol-1-yl (IIIa IIIg, IV,
V, VI, VIIa, VIII, IX, Xa Xc), 1,2,4-triazol-1-yl (IIIh), benzimidazol-1-yl (VIIb).
O
NH N
O
O
O
IIa
N
H
H2O
N
H
N
N
IIIi
1
of the NH protons in the H NMR spectra of com-
pounds IIIf and IIIh whose IR spectra contain a
broad absorption band of free NH group are the
lowest, implying that here the hydrogen bonds involv-
ing the NH protons are the weakest. The signals of
phenolic hydroxyls in the spectra of compounds IIIc,
IIId, and IIIg are at 9.51 9.89 ppm, whereas the
respective signal in the spectrum of compound IIIb is
at 12.05 ppm. This result provides evidence in favor
of intramolecular hydrogen bonding (form D). The
1
tion bands at 1530 cm , that would appear if struc-
ture B [ (N=CO)] or quinoid structure C had been
formed in the presence in the benzene ring of ortho-
or para-hydroxy group [ (NHCH=CC=O)] [4, 5] are
lacking.
1
In the H NMR spectra, the NH proton appears at
9.31 11.80 ppm. The strong deshielding can be ex-
plained by hydrogen bonding [7]. The chemical shifts
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 1 2005

SYNTHESIS OF 4-(1H-AZOL-1-YLMETHYL)BENZOHYDRAZIDES
113
O
H
O
R C NH N=CH
R C=N N=CH
OH
OH
A
B
O
R C NH NH CH
O
C
H.
H
.
+
N
.
NHCOR
.
.
NHCOR
.
.
O
N
O
D
E
1
lack in the H NMR spectrum of splitting from the
methine proton points to lack of intramolecular proton
transfer and formation of structure E. The lack of the
HOC=N proton signal rules out presence of
structure B in DMSO.
hydro-1H-1,2,4-triazole-5-thione (IX). Its IR spectrum
contains absorption bands at 2600 2500 and 900
850 cm [ (SH)] and a strong band at 1507 cm
1
1
assignable to the thioamide group, which provides
evidence for the thione structure. The absorption
1
maximum near 1345 cm due to C=S vibrations in
Hydrazides are used in organic synthesis for pre-
paring a great variety of heterocyclic systems. Of
particular interest is synthesis of 1,3,4-oxadiazoles
and triazole-1,2,4-triones [8 10]. To prepare a 5-un-
substituted 1,3,4-oxadiazole, we made use of the reac-
tion of orthoformic ester with 4-(1H-imidazol-1-yl-
triazole-1,2,4-thiones, too, is supportive of the pro-
posed structure.
Hydrazides fairly readily react with sulfonyl chlo-
rides in pyridine. In the IR spectra of the reaction
products, there are absorption bands due to asym-
metric and symmetric vibrations of the SO2 group
methyl)benzohydrazide.
2-[4-(1H-Imidazol-1-yl-
1
(1340 and 1180 cm , respectively) [12].
methyl)phenyl]-5-phenyl-1,3,4-oxadiazole (VI) was
synthesized by cyclization of diacylhydrazine V under
the action of POCl3. 5-Amino-substituted 1,3,4-oxa-
diazoles VIIa and VIIb were obtained by the reac-
tions of cyanogen bromide with hydrazides in ab-
solute ethanol under stirring for 10 h at room tempera-
ture. Attempted synthesis of 2-[4-(1H-imidazol-1-yl-
methyl)phenyl]-5-methyl-1,3,4-oxadiazole from the
corresponding hydrazide and ethyl acetimidate hydro-
chloride failed.
1
The yields, melting points, and IR and H NMR
spectra of the synthesized compounds are listed in
the table.
EXPERIMENTAL
The IR spectra were obtained on an IKS-29 instru-
1
ment in mineral oil. The H NMR spectra were ob-
tained on a Bruker instrument at 400 MHz, solvents
(CD3)2SO, CD3CN, or D2O, internal reference HMDS.
The IR spectra of 1,3,4-oxadiazoles IV, VI, VIIa,
and VIIb display very strong absorption maxima at
1622 1600 and 1502 1460 cm , characteristic of
stretching vibrations of the oxadiazole ring. The
presence of this ring is confirmed by the observation
of absorption bands at 1245 1227 and 1028
Methyl 4-(1H-azol-1-ylmethyl)benzoates Ia Id.
Azole, 0.04 mol, was added in portions to a suspen-
sion of 0.04 mol of NaH (89% suspension in Paraffin)
in 30 ml of anhydrous DMF. The mixture was stirred
until hydrogen no longer evolved, after which a solu-
tion of 0.04 mol of (4-bromomethyl)benzoate in 20 ml
of DMF was added over the course of 15 min at 5
10 C, and the mixture was stirred for 4 h. The solvent
was removed in a vacuum, the residue was dissolved
in benzene with heating, undissolved residue was
filtered off, the filtrate was evaporated in a vacuum,
and the residue was recrystallized from a benzene
cyclohexane mixture.
1
1
1022 cm , assignable to stretching vibrations of the
=COC= fragment [11].
N -(Allylthiocarbonyl)-4-(1H-imidazol-1-ylmethyl)-
benzohydrazide (VIII) was synthesized from allyl iso-
thiocyanate and hydrazide IIa. When heated with al-
kali for 1 h, the product undergoes cyclization into
4-allyl-3-[4-(1H-imidazol-1-ylmethyl)phenyl]-4,5-di-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 1 2005

114
OSYANIN et al.
Yields, melting points, and IR and 1H NMR spectra of the synthesized compounds
1
mp,
C
IR spectrum, cm
1H NMR spectrum, , ppm (solvent)
Ia
Ib
74
72
76 77 1709, 1612, 1500, 1456, 1436, 3.85 s (3H, CH3), 5.35 s (2H, CH2), 7.06 s (1H, azole
1302, 1278, 1231, 1190, 1081, 731 H4), 7.29 s (1H, azole H5), 7.37 d (2H, arom. H3), 7.69 d
(2H, arom. H2), 7.77 s (azole H2)
102 103 1721, 1710, 1612, 1495, 1443, [CD3CN] 3.85 s (3H, CH3), 5.51 s (2H, CH2), 7.24 m (2H,
1426, 1365, 1282, 1261, 741, 732 azole H), 7.32 d (2H, arom. H3), 7.35 m (1H, azole H),
7.71 m (1H, azole H), 7.95 d (2H, arom. H2, J2,3 8.1 Hz),
8.11 s (1H, azole H2) [CD3CN]
Ic
77
68
84
79
111 112 2967, 1713, 1611, 1576, 1506, 3.87 s (3H, CH3), 5.44 s (2H, CH2), 7.37 d (2H, arom.
1451, 1341, 1312, 1287, 1110
H3), 7.90 s (1H, azole H3), 7.99 d (2H, arom. H2, J2,3
8.4 Hz), 8.32 s (1H, azole H5 ) [CD3CN]
Id
130 131 1728, 1613, 1454, 1436, 1283, 3.85 s (3H, CH3), 5.82 s (2H, CH2), 7.37 d (2H, arom.
1223, 1088, 744, 737
H3), 7.41 7.57 m (2H, azole H5,6), 7.83 d (2H, arom.
H2), 7.86 d, 8.12 d (2H, azole H4,7) [CD3CN]
IIa
IIb
154 155 3317, 3285, 3180, 1622, 1569, 5.25 s (2H, CH2), 7.09 s (1H, azole H4), 7.14 s (1H, azole
1570, 1541, 1504, 1387, 1337, H5), 7.33 d (2H, arom. H3), 7.70 d (2H, arom. H2, J2,3
1275, 1229
8.1 Hz), 7.79 s (1H, azole H2) [D2O]
164 165 3334, 3277, 3188, 3164, 3087, 4.50 br.s (2H, NH2), 5.55 s (2H, CH2), 7.20 m (2H, azole
1626, 1573, 1626, 1495, 1433, H), 7.35 d (2H, arom. H3), 7.49 m (1H, azole H), 7.66 m
1366, 1349, 1319, 1282, 1265
(1H, azole H), 7.77 d (2H, arom. H2, J2,3 8.1 Hz), 8.41 s
(1H, azole H2), 9.69 s (1H, NH) [(CD3)2SO]
IIc
86
81
87
170 171 3332, 3283, 3189, 1625, 1573, 5.53 s (2H, CH2), 7.41 d (2H, arom. H3), 7.75 d (arom.
1539, 1507, 1457, 1374, 1349, H2, J2,3 8.1 Hz), 8.13 s (1H, azole H3), 8.62 s (1H, azole
1321, 1273, 1137, 1014, 958
H5) [D2O]
IId
IIIa
161 162 3336, 3256, 1661, 1631, 1613, 1573, 5.85 s (2H, CH2), 6.75 t, 6.86 d, 7.04 d, 7.14 t, 7.37 t,
1548, 1504, 1495, 1454, 1442, 1340, 7.50 t, 7.76 d, 8.02 (8H, arom. H, azole H), 9.87 s (1H,
1304, 1278, 1221
NH) [(CD3)2SO]
189 190 3165, 3117, 1665, 1618, 1563, 1510, 5.29 s (2H, CH2), 6.94 s (2H, azole H4), 7.21 s (2H, azole
1437,
1352,
1277,
1231
H5), 7.38 d (2H, arom. H, J 7.8 Hz), 7.45 m (3H, arom.
H), 7.72 m (2H, arom. H), 7.89 d (2H, arom. H, J 7.2 Hz),
7.79 s (1H, azole H2), 8.45 s (1H, CH=N), 11.80 s (1H,
NH) [(CD3)2SO]
IIIb
IIIc
IIId
79
74
68
225 227 3149, 3098, 1662, 1651, 1610, 1347, 5.30 s (2H, CH2), 6.93 m (3H, ald. H3,5, azole H4), 7.21 s
1285, 1261
(1H, azole H5), 7.30 t (1H, ald. H4), 7.39 d (2H, arom.
H3), 7.54 d (1H, ald. H6), 7.79 s (1H, azole H2), 7.92 d
(2H, arom. H2), 8.63 s (1H, CH=N), 11.25 s (1H, NH),
12.05 s (1H, OH) [(CD3)2SO]
260 261 3225, 3117, 1651, 1613, 1598, 1550, 5.28 s (2H, CH2), 6.84 d (2H, ald. H3), 6.94 s (1H, azole
1508, 1455, 1284, 1272, 1163
H4), 7.20 s (1H, azole H5), 7.36 d (2H, arom. H3), 7.55 d
(2H, ald. H2, J2,3 7.5 Hz), 7.79 s (1H, azole H2), 7.87 d
(2H, arom. H2, J2,3 7.8 Hz), 8.33 s (1H, CH=N), 9.89 s
(1H, OH), 11.57 s (1H, NH) [(CD3)2SO]
240 241 3246, 3173, 3112, 1657, 1627, 1585, 3.83 s (3H, CH3), 5.29 s (2H, CH2), 6.84 d (1H, ald. H5),
1558, 1502, 1426, 1292, 1269
6.94 s (1H, azole H4), 7.09 d (1H, ald. H6), 7.21 s (1H,
azole H5), 7.31 s (1H, ald. H2), 7.37 d (2H, arom. H3),
7.79 s (1H, azole H2), 7.87 d (2H, arom. H2, J2,3 7.8 Hz),
8.33 s (1H, CH=N), 9.51 s (1H, OH), 11.60 s (1H, NH)
[(CD3)2SO]
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 1 2005

SYNTHESIS OF 4-(1H-AZOL-1-YLMETHYL)BENZOHYDRAZIDES
115
Table (Contd.)
1
mp,
C
IR spectrum, cm
1H NMR spectrum, , ppm (solvent)
IIIe
53
232 233 3175, 1655, 1609, 1592, 1502, 1290, 3.32 s (6H, CH3), 5.28 s (2H, CH2), 6.76 d (2H, ald. H3),
1275
6.93 s (1H, azole H4), 7.20 s (1H, azole H5), 7.36 d (2H,
arom. H3), 7.54 d (2H, ald. H2, J2,3 8.4 Hz), 7.78 s (1H,
azole H2), 7.87 d (2H, arom. H2, J2,3 7.8 Hz), 8.30 s (1H,
CH=N), 11.48 s (1H, NH) [(CD3)2SO]
IIIf
62
67
141 142 3335, 3015, 1680, 1537, 1471, 1310, 1.71 m (4H, CH2CH2CH2), 2.37 m (4H, =CCH2), 5.29 s
1269, 1221, 1105, 1076
(2H, CH2), 6.94 s (1H, azole H4), 7.21 s (1H, azole H5),
7.36 d (2H, arom. H3), 7.76 s (1H, azole H2), 7.86 d (2H,
arom. H2, J2,3 7.8 Hz), 9.38 s (1H, NH) [CD CN]
3
IIIg
249 251 3395, 3190, 1673, 1628, 1532, 1277, 2.27 s (3H, CH3), 5.28 s (2H, CH2), 6.80 d (2H, ald. H3),
1245, 1167, 1087, 1012
6.93 s (1H, azole H4), 7.21 s (1H, azole H5), 7.36 d (2H,
arom. H3, J 7.2 Hz), 7.70 br.s (2H, ald. H2), 7.79 s (1H,
azole H2), 7.84 br.s (2H, arom. H2), 9.75 s (1H, OH),
10.59 s (1H, NH) [(CD3)2SO]
IIIh
IIIi
70
64
150 151 3342, 3285, 3122, 1637, 1618, 1504, 1.69 m (6H, CH2CH2CH2), 2.36 m (4H, =CCH2), 5.42 s
1476, 1403, 1242
(2H, CH2), 7.35 d (2H, arom. H3), 7.80 d (2H, arom. H2),
7.89 s (1H, azole H3), 8.32 s (1H, azole H5), 9.31 br.s
(1H, NH) [CD3CN]
295 296 3124, 1694, 1673, 1621, 1556, 1347, 5.33 s (2H, CH2), 6.95 s (1H, azole H4), 6.97 d (1H, isatin
(decomp.) 1301, 1262, 1212, 1191, 1152, 1120, H7), 7.12 t (1H, isatin H5), 7.23 s (1H, azole H5), 7.40 t
1105, 1078
(1H, isatin H6), 7.44 d (2H, arom. H3), 7.60 d (1H, isatin
H4), 7.81 s (1H, azole H2), 7.88 d (2H, arom. H2, J2,3
8.1 Hz), 11.34 s (1H, NH), 13.88 s (1H, isatin NH)
[(CD3)2SO]
IV
V
79
75
139 140 1659, 1614, 1585, 1555, 1502, 1438, 5.32 s (1H, CH2), 6.94 s (1H, azole H4), 7.22 s (1H, azole
1229, 1116, 1026
H5), 7.44 d (2H, arom. H3), 7.79 s (1H, azole H2), 8.02 d
(2H, arom. H2, J2,3 8.1 Hz), 9.32 s (1H, oxadiazole H)
[(CD3)2SO]
238 239 3258, 3125, 1679, 1650, 1512, 1279, 5.30 s (2H, CH2), 6.94 s (1H, azole H4), 7.22 s (1H, azole
1229
H5), 7.37 d (2H, arom. H3, J 8.1 Hz), 7.55 m (3H, arom.
3 ,4 ), 7.79 s (1H, azole H2), 7.92 m (4H, arom. H2,2 ),
H
10.47 s (2H, NH) [(CD3)2SO]
VI
74
69
65
173 174 1622, 1585, 1460, 1245, 1025 5.34 s (2H, CH2), 6.97 s (1H, azole H4), 7.25 s (1H, azole
H5), 7.48 d (2H, arom. H3), 7.65 m (3H, arom. H), 7.84 s
(1H, azole H2), 8.13 d (4H, arom. H) [(CD3)2SO]
VIIa
VIIb
224 225 3328, 3118, 1642, 1584, 1545, 1411, 5.27 s (2H, CH2), 6.93 s (1H, azole H4), 7.21 m (3H,
1280, 1227, 1074, 1028
azole H5, NH2), 7.37 d (2H, arom. H3, 7.77 d (2H, arom.
H2), 7.78 s (1H, azole H2) [(CD3)2SO]
225 227 3350 2900, 1664, 1600, 1579, 1495, 5.50 s (4H, CH2, NH2), 7.25 m (2H, azole H), 7.35 d (2H,
(decomp.) 1289, 1275
arom. H3), 7.39 m (1H, azole H), 7.71 m (1H, azole H),
7.83 d (2H, arom. H2, J2,3 8.4 Hz), 8.12 s (1H, azole H2)
[CD3CN]
VIII
82
164 165 3274, 3174, 1672, 1612, 1567, 1534, 4.10 s (2H, CH2CH=CH2), 5.03 d (1H, trans-CH=CH2),
1504, 1290, 1229
5.12 d (1H, cis-CH=CH2), 5.27 s (2H, CH2), 5.82 m (1H,
CH=), 6.92 s (1H, azole H4), 7.18 s (1H, azole H5), 7.35 d
(2H, arom. H3), 7.77 s (1H, azole H2), 7.90 d (2H, arom.
H2, J2,3 8.1 Hz), 8.22 br.s (1H, NHCH2), 9.33 s (1H, NH),
10.32 br.s (1H, CONH) [(CD3)2SO]
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116
OSYANIN et al.
Table (Contd.)
1
mp,
C
IR spectrum, cm
1H NMR spectrum, , ppm (solvent)
IX
70
217 218 3135, 3117, 1535, 1510, 1492, 1438, 4.67 d.t (2H, CH2CH=CH2, J 4.8 Hz), 4.95 d.d (1H,
1415, 1405, 1363, 1348, 1300, 1272 trans-CH=CH2, J 17.1 Hz), 5.17 d.d (1H, cis-CH=CH2, J
10.6, Jcis, trans 0.9 Hz), 5.25 s (2H, CH2), 5.88 m (1H,
CH=), 6.99 s (1H, azole H4), 7.06 s (1H, azole H5), 7.35 d
(2H, arom. H3), 7.62 s (1H, azole H2), 7.64 d (2H, arom.
H2, J2,3 8.4 Hz) [CD CN]
3
Xa
Xb
72
75
154 155 3182, 1660, 1505, 1362, 1285 3.12 s (3H, CH3), 5.25 s (2H, CH2), 6.92 s (1H, azole
H4), 7.20 s (1H, azole H5), 7.31 d (2H, arom. H3), 7.65 d
(2H, arom. H2, J2,3 7.5 Hz), 7.79 s (1H, azole H2), 9.74 s
(1H, SO2NH), 10.58 s (1H, CONH) [(CD3)2SO]
178 179 3204, 1663, 1616, 1574, 1506, 1451, 5.24 s (2H, CH2), 6.93 s (1H, azole H4), 7.19 s (1H, azole
(decomp.) 1422, 1337, 1290, 1185
H5), 7.28 d (2H, arom. H3), 7.52 m, 7.61 m (3H, arom.
H
3 ,4 ), 7.66 d (2H, arom. H2, J2,3 7.5 Hz), 7.78 s (1H,
azole H2), 7.82 d (2H, arom. H2 , J2 ,3 .8 Hz), 9.95 s (1H,
SO2NH), 10.65 s (1H, CONH) [(CD3)2SO]
Xc
68
203 205 3144, 1664, 1566, 1506, 1347, 1294, 2.42 s (3H, CH3), 5.25 s (2H, CH2), 6.94 s (1H, azole H4),
(decomp.) 1229
7.19 s (1H, azole H5), 7.27 d (2H, arom. H3), 7.60 d (2H,
arom. H3 ), 7.68 d (2H, arom. H2, J2,3 7.5 Hz), 7.79 s (1H,
azole H2), 7.82 d (2H, arom. H2, J2 ,3 6.8 Hz), 9.96 s (1H,
SO2NH), 10.63 s (1H, CONH) [(CD3)2SO]
4-(1H-Azol-1-ylmethyl)benzohydrazides IIa IId.
mixture was refluxed for 8 h with a Dean Stark trap.
After cooling, crystals formed and were filtered off
and recrystallized from an ethanol ethyl acetate
mixture.
A mixture of 0.07 mol of methyl 4-(1H-azol-1-yl-
methyl)benzoate and 30 ml of 99% hydrazine hydrate
was refluxed for 4 h. After cooling, a precipitate
formed and was filtered off and recrystallized from a
benzene ethanol mixture.
N -(2-Oxo-2,3-dihydro-1H-3-indolylidene)-4-
(1H-imidazol-1-ylmethyl)benzohydrazide (IIIi).
Isatin, 3.4 mmol, and 3.4 mmol of hydrazide IIa in
20 ml of absolute ethanol was refluxed for 4 h. An
orange precipitate formed and was filtered off and
recrystallized from an ethanol DMF mixture.
N -(Phenylmethylidene)-, N -[(2-hydroxypheny)-
methylidene]-, N -[(4-hydroxypheny)methylidene]-,
N -[(4-hydroxy-3-methoxypheny)methylidene]-, and
N -[(4-dimethylaminopheny)methylidene]-4-(1H-
imidazol-1-ylmethyl)benzohydrazides (IIIa IIIe).
A mixture of 1.5 mmol of 4-(1H-imidazol-1-ylmethyl)-
benzohydrazide (IIa) and 1.5 mmol of aromatic al-
dehyde in 7 ml of 95% ethanol was heated under re-
flux for 3 h. After cooling, a precipitate formed and
was filtered off and recrystallized from an ethanol
DMF mixture.
2-[4-(1H-Imidazol-1-ylmethyl)phenyl]-1,3,4-oxa-
diazole (IV). Hydrazide IIa, 2.3 mmol, was refluxed
with 20 ml of orthoformic ester for 8 h. The ester was
removed in a vacuum, and the residue was recrystal-
lized from ethanol.
N-Benzoyl-N -[4-(1H-imidazol-1-ylmethyl)]benz-
oylhydrazine (V). A solution of 2.3 mmol of benzoyl
chloride in 3 ml of dioxane was added over the course
of 20 min to a stirred solution of hydrazide IIa and
2.3 mmol of NaHCO3 in a mixture of 4 ml of dioxane
and 2 ml of water. The mixture was stirred at room
temperature for 15 h. The solvent was removed in a
vacuum, and the residue was washed with water and
recrystallized from an ethanol dioxane mixture.
N -(Cyclopentylidene)-4-(1H-imidazol-1-yl-
methyl)benzohydrazide (IIIf), N -[1-(4-hydroxy-
phenyl)ethylidene]-4-(1H-imidazol-1-ylmethyl)-
benzohydrazide (IIIg), and N -(cyclohexylidene)-4-
(1H-1,2,4-triazol-1-ylmethyl)benzohydrazide (IIIh).
Two drops of triethylamine was added to 1.5 mmol
of hydrazide IIa and 1.5 mmol of ketone in 50 ml of a
mixture of benzene and absolute ethanol, and the
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SYNTHESIS OF 4-(1H-AZOL-1-YLMETHYL)BENZOHYDRAZIDES
117
2-[4-(1H-Imidazol-1-ylmethyl)phenyl]-5-phenyl-
1,3,4-oxadiazole (VI). A mixture of 0.63 mmol of
hydrazine V and 2.5 ml of POCl3 was heated for 2 h.
After cooling, the solution was poured into ice water,
neutralized to pH 7 with NaOH. The precipitate that
formed was thoroughly stirred with water, dissolved
in ethanol with heating, the hot solution was filtered,
the filtrate was evaporated, and the residue was re-
crystallized from a dioxane ethyl acetate mixture.
N-[4-(1H-Imidazol-1-ylmethyl)benzoyl]-N -(4-
phenylsulfonyl)hydrazine (Xb) and N-[4-(1H-
imidazol-1-ylmethyl)benzoyl]-N -(4-tosyl)hydrazine
(Xc) were prepared like compound Œa by treatment
of compound IIa with benzenesulfonyl chloride and
tosyl chloride, respectively.
REFERENCES
1. Carcelli, M., Mazza, P., Pelizzi, C., Pelizzi, G., and
Zani, F., J. Inorg. Biochem., 1995, vol. 57, no. 1,
p. 43.
5-Amino-2-[4-(1H-imidazol-1-ylmethyl)phenyl]-
1,3,4-oxadiazole (VIIa). A solution of 1.64 of cyano-
gen bromide in 3 ml of absolute ethanol was added to
a solution of 1.64 mmol of hydrazide IIa in 10 ml of
absolute ethanol, and the nixture was stirred at room
temperature for 10 h. To the colorless precipitate,
1.64 mmol of NaHCO3 in 4 mlof water was added.
The resulting solution was stirred for 2 h, the solvent
was removed in a vacuum, and the residue was
washed with water and recrystallized from ethanol.
2. Figueiredo, J.M., Camara, C. de A., Amarante, E.G.,
Miranda, A.L. P., Santos, F.M., Rodrigues, C.R.,
Fraga, C.A.M., and Barreiro, E.J., Bioorg. Med.
Chemistry, 2000, vol. 8, no. 9, p. 2243.
3. Borgne, M., Marchand, P., Delevoye-Seiller, B., Ro-
bert, J.-M., Baut, G., Hartmann, R.W., and Palzer, M.,
Bioorg. Med. Chem. Lett., 1999, no. 9, p. 333.
4. Agarwala, B.V., Hingorani, S., and Nagana Gow-
da, G.A., Inorg. Chim. Acta, 1990, vol. 176, no. 1,
p. 149.
5-Amino-2-[4-(1H-benzimidazol-1-ylmethyl)-
phenyl]-1,3,4-oxadiazole (VIIb) was synthesized like
compound VIIa from compound IIb and cyanogen
bromide.
5. Uehara, N., Kanbayashi, M., Hoshino, H., and Yot-
suyanagi, T., Talanta, 1989, vol. 36, no. 10, p. 1031.
N -(Allylthiocarbonyl)-4-(1H-imidazol-1-yl-
methyl)benzohydrazide (VIII). A mixture 4.6 mmol
of hydrazide IIa and 0.46 ml of allyl isothiocyanate
in 5 ml of ethanol was refluxed for 2 h. After cooling,
colorless crystals formed and were filtered off and re-
crystallized from ethanol.
6. Narang, K.K. and Aggarwal, A., Indian J. Chem.,
1975, vol. 13, no. 3, p. 1072.
7. Galic, N., Peric, B., Kojic-Prodic, B., and Cimer-
man, Z., J. Mol. Struct., 2001, vol. 559, no. 1, p. 187.
8. Monamed, N.A. and Al-Afaleq, E.I., Polymer, 1999,
vol. 40, no. 3, p. 617.
4-Allyl-3-[4-(1H-imidazol-1-ylmethyl)phenyl]-
4,5-dihydro-1H-1,2,4-triazole-5-thione (IX). A solu-
tion of 1.43 mmol of NaOH in 10 ml of water was
added to 0.95 mmol of compound VIII, and the mix-
ture was refluxed for 1 h. The solution was cooled and
acidified with acetic acid to pH 4. The precipitate that
formed was filtered off and recrystallized from ethanol.
9. Hetzeim, A. and Mockel, K., Adv. Heterocycl. Chem.,
1966, vol. 7, p. 183.
10. Kucukguzel, I., Kucukguze, S G., Rollas, S., and
Kiraz, M., Bioorg. Med. Chem. Lett., 2001, vol. 11,
no. 13, p. 1703.
11. Kelarev, V.I., Karahanov, R.A., Morozova, G.V.,
Kapo-Schi-schi, K., Kuatbekov, A.M., and Poli-
vin, Yu.N., Khim. Geterotsikl. Soedin., 1994, no. 1,
p. 115.
N-[4-(1H-Imidazol-1-ylmethyl)benzoyl]-N -(4-
methylsulfonyl)hydrazine (Xa).
A
solution of
1.85 mmol of hydrazide IIa in 6 ml of pyridine was
added to a solution of 1.85 mmol of mesyl chloride in
5 ml of absolute pyridine. The mixture was stirred for
4 h, pyridine was removed in a vacuum, and the
residue was washed with water and recrystallized from
ethanol.
12. Kazitsyna, L.A. and Kupletskaya, N.B., Primenenie
UF-, IK- i YaMR-spektroskopii v organicheskoi khimii
(Application of UV, IR, and NMR Spectroscopy in
Organic Chemistry), Moscow: Vysshaya Shkola, 1971,
p. 255.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 1 2005