Synthesis and NMR spectroscopic characteristics of a series of hydrazide-hydrazones containing furoxan ring derived from isoeugenoxyacetic acid

Article abstract of DOI:10.1002/jhet.868

A novel hydrazide, 2-methoxy-4-(3-methyfuroxan-4-yl)-5- nitrophenoxyacetylhydrazine, was prepared from isoeugenoxyacetic acid. The hydrazide was condensed with aromatic aldehydes to give a series of 20 hydrazide-hydrazones incorporating the furoxan ring. The structure of obtained compounds was determined by analytical and spectral data. It was demonstrated that the two sets of resonance signals in the ¹H-NMR and ¹³C-NMR spectra of the examined hydrazide-hydrazones are caused by E_N-C(O) and Z_N-C(O) conformers. The energy barriers for the conformation exchange were determined by ¹H-NMR-measurement at various temperatures. Among seven tested hydrazide-hydrazones, four compounds exhibit inhibition activities in vitro on human epidermis carcinoma (KB-cell) with IC₅₀ = 47, 68, 79, and 103 μg/mL.

Full text of DOI:10.1002/jhet.868

814
Synthesis and NMR Spectroscopic Characteristics of a Series of
Hydrazide-Hydrazones Containing Furoxan Ring Derived from
Isoeugenoxyacetic Acid
Vol 49
a
b
a
*
Nguyen Huu Dinh, Hoang Thi Tuyet Lan, Tran Thi Thu Trang,
and Pham Van Hoana
aDepartment of Chemistry, Hanoi National University of Education, Hanoi, Vietnam
bDepartment of Chemistry, University of Transportation, Hanoi, Vietnam
*
E-mail: nguyenhuudinh1954@yahoo.com
Received October 15, 2010
DOI 10.1002/jhet.868
View this article online at wileyonlinelibrary.com.
A novel hydrazide, 2-methoxy-4-(3-methyfuroxan-4-yl)-5-nitrophenoxyacetylhydrazine, was prepared
from isoeugenoxyacetic acid. The hydrazide was condensed with aromatic aldehydes to give a series of
20 hydrazide-hydrazones incorporating the furoxan ring. The structure of obtained compounds was
determined by analytical and spectral data. It was demonstrated that the two sets of resonance signals in
1
the H-NMR and 13C-NMR spectra of the examined hydrazide-hydrazones are caused by EN–C(O) and
1
ZN–C(O) conformers. The energy barriers for the conformation exchange were determined by H-NMR-
measurement at various temperatures. Among seven tested hydrazide-hydrazones, four compounds
exhibit inhibition activities in vitro on human epidermis carcinoma (KB-cell) with IC50 = 47, 68, 79,
and 103 mg/mL.
J. Heterocyclic Chem., 49, 814 (2012).
INTRODUCTION
RESULTS AND DISCUSSION
Hydrazide-hydrazones have long attracted attention
owing to their remarkable biological and pharmacologi-
cal properties such as antituberculosis [1–4], anti-
bacterial, antifungal [5–11], anticonvulsant [12,13],
anti-inflammatory [14], antimalarial [15], and anti-HIV [16]
activities.
A key intermediate for the title compounds, 2-methoxy-
4-(3-methyfuroxan-4-yl)-5-nitro-phenoxyacetylhydrazine (N),
was prepared from isoeugenoxyacetic acid as described in
Scheme 1. The numeration on these structures is used specif-
ically for NMR analysis only.
Compound K was prepared by reaction of isoeugen-
oxyacetic acid with nitrous acid; the nitro compound
L was obtained by nitration of K (see “Experimental”
Many compounds containing furoxan ring, a nitric
oxide (NO) releasing moiety, display a variety of biolog-
ical activities. The anti-inflammatory activity, the vasodi-
lator activity, and the inhibition of platelet aggregation are
well known [17–20]. Also, antiparasitic properties,
mutagenic and anticancer effects, and antimicrobial and
fungicidal activities are reported [18,21]. In recent years,
several classes of hybrid compounds, which obtained by
combining appropriate pharmacophoric groups with
NO-releasing functions, have been described [22], such
as NO-aspirin [23], NO-steroids [24], and NO-guanidines
[25]. Some compounds described in these works are
now under clinical investigations. This has prompted
us to synthesize a series of hydrazide-hydrazones con-
taining furoxan ring derived from isoeugenoxyacetic
acid (2-methoxy-4-(prop-1-enyl)phenoxyacetic acid) and
to find out if the resulting compounds have any biological
action.
1
section). In the H-NMR spectrum of K, there are three
4
signals of three aromatic protons: 7.32 (d, J = 2 Hz);
3
4
3
7.28 (dd, J = 8, J = 2 Hz); and 7.05 (d, J = 8 Hz).
In the spectrum of L, there are two singlets at 7.43 and
7.85 ppm, corresponding to two aromatic protons at para-
positions relative to one another. This indicates that the nitro
group is introduced into para-position relative to methoxy
group. Acid L was esterified to form M, and then M reacted
1
with hydrazine hydrate to give hydrazide N. The H-NMR
signals of K, L, M, and N are listed in Table 1.
Gasco et al. [26] showed that the chemical shift of a ring
methyl group adjacent to the N-oxide oxygen of furoxans
occurs at 2.30–2.33 ppm, while a ring methyl group remote
from it or a ring methyl group of furazan appears at 2.50–
2.53 ppm. The signal of the ring methyl group (10-H) of
K–N appears as a singlet at 2.01–2.35 ppm (Table 1)
© 2012 HeteroCorporation

July 2012
Synthesis and NMR Spectroscopic Characteristics of a Series of Hydrazide-Hydrazones
Containing Furoxan Ring Derived from Isoeugenoxyacetic Acid
815
Scheme 1. Synthesis of hydrazides N from isoeugenoxyacetic acid.
Table 1
1H-NMR signals of K–N, d (ppm), J (Hz).
Compd.
3-H
5-H
6-H
7a-H
7b-H
10-H
11-H
12-H
K
L
M
N
7.32, d, J 2
7.43, s
7.44, s
7.28, dd, J 8, 2
7.05, d, J 8
7.85, s
7.88, s
4.78, s
4.97, s
5.06, s
4.74, s
3.85, s
3.96, s
3.96, s
3.96, s
2.31, s
2.02, s
2.02, s
2.01, s
–
–
–
–
–
–
–
4.21, q, J 7
9.35, s
1.23, t, J 7
4.37, s
7.42, s
7.90, s
indicating that the methyl group is at position 3 of the
furoxan ring and the furoxan ring was not reduced by hy-
drazine hydrate to furazan ring. The absence of signals at
4.21 ppm (2H) and 1.23 ppm (3H) and the presence of
two singlets at 9.35 ppm (1H) and 4.37 ppm (2H) in the
spectrum of N (Table 1) demonstrate that ―OCH2CH3
group on M was replaced by ―NHNH2 group and the ni-
tro group was not reduced during the refluxing M with hy-
drazine hydrate (see “Experimental” section).
accurately assigned based on analyzing the spin–spin split-
ting patterns, for some compounds, 2D NMR was also
used. For example, in the case of N20 (Ar = 3-indolyl,
Table 4), the cross peaks a, b, a0, b0, and c in HMBC spec-
trum (Fig. 1) allow to assign signals of 13-C, 19-C, and 12-
C; the cross peak t of 8-C indicates that the singlet at 7.43
ppm belongs to 3-H but not to 6-H; the cross peaks v of
14-C and x of 18-C show that the triplet at 7.21 ppm belongs
to 16-H while the cross peaks y of 17-C and z of 19-C show
that the triplet at 7.15 ppm belongs to 15-H. The NMR data
of the hydrazide-hydrazones are listed in Tables 3, 4, 5, and
6 (see “Experimental” section).
It can be supposed that the two sets of resonance signals
in the NMR spectra of the examined hydrazide-hydrazones
are associated with two isomers (major and minor com-
pounds). Thus, the question arises “What is the cause of
these two structures?”
The investigated hydrazide-hydrazones were obtained
by condensation of hydrazide N with aromatic aldehydes
as shown in Scheme 2 with moderate yield expectedly.
The numeration on the structures in Scheme 2 is used spe-
cifically for NMR analysis only.
It was observed that the 1H-NMR and 13C-NMR spectra
of the hydrazide-hydrazones consist of two sets of reso-
nance signals associated with two structures (major and
minor compounds; see, e.g., Fig. 1). All resonance signals
in the NMR spectra of examined compounds were
To answer the above question, firstly, it must be
assessed whether the furoxan ring in the compounds
Scheme 2. Synthesized hydrazide-hydrazones.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

816
N. H. Dinh, H. T. Tuyet Lan, T. T. Thu Trang, and P. Van Hoan
Vol 49
Figure 1. Partial HMBC spectrum of N20.
underwent isomerization in the condensation reaction (the
position of N-oxide group is changed). The chemical shifts
of H10 and C10 of the methyl group attached with the fur-
oxan ring are in the range 2.02–2.35 ppm (Table 3) and
7.6–11.55 ppm (Table 5), respectively. These data indicate
that the methyl group is adjacent to the N-oxide oxygen of
the furoxan ring [26], as shown in Scheme 2, that is, the
isomerization has not taken place.
Secondly, it is possible that the considered hydrazide-
hydrazones may exist as geometrical isomers in respect to
the N¼C double bonds and as conformers about N―C(O)
bond as shown in Figure 2.
the single bond of N–C(O) (68–71 kJ/mol) of similar com-
pounds [28,29], and therefore, the two observed structures
are two conformers due to the hindered rotation around the
hydrazide N―C(O) single bond, but they are not two geo-
metrical isomers at the hydrazone N¼CH double bond. It
has been pointed out that hydrazones derived from alde-
hydes and substituted hydrazides are present in the solution
in the E-configuration at N¼CH bond [30]; in DMSO-d6,
the major compound is EN―C(O)EN¼C isomer and the minor
compound is ZN―C(O)EN¼C isomer [28,29]. Thus, it is
clearly demonstrated that the two sets of resonance signals
in the NMR spectra of the examined hydrazide-hydrazones
are caused by the EN―C(O)EN¼C and ZN―C(O)EN¼C isomers.
It was seen that, for some series of hydrazide-hydra-
zones such as the considering hydrazide-hydrazones, the
hydrazide-hydrazones derived from eugenoxyacetic acid,
1,3-benzothiazol-2-ylthioacetic acid [31], 4-terbuthylphe-
noxyacetic acid [32], and 2-pyridinecarboxylic acid [33],
two sets of NMR signals were observed. However, for
many other series, such as hydrazide-hydrazones derived
from substituted benzoic acid [1,34,35], nicotinic acid, iso-
nicotinic acid [36,37], thiophene carboxylic acid [38], and
others, only one set of NMR signals was observed. Consid-
ering the structure of these series of hydrazide-hydrazones,
it was reasoned that the intramolecular hydrogen bond of
hydrazide NH may be the cause of this difference as shown
in Scheme 3.
1H-NMR spectra of N3 were recorded at various tempera-
tures. It is observed that when the temperature is increased
in the range of 333–363 K, the 1H signals broaden and sub-
sequently coalesce, and the two sets of resonance signals be-
come one set, that is, the two above-mentioned isomers
associate with a chemical equilibrium. It is well known that
the energy barrier for dynamic exchange processes (ΔG{)
can be evaluated using the following equation [27]:
ΔG{ = RTc[22.96 + ln(Tc/dn)] (J/mol)
where Tc is the temperature at which two signals of a pro-
ton coalesce and dn is the difference between the resonance
frequencies of the proton in the two structures. For calcu-
1
lating ΔG{, the singlets of 7a-H and i-H in the H-NMR
spectra of N3 are chosen and the data are listed as below:
For the hydrazide-hydrazones where the hydrazide NH
cannot form intramolecular hydrogen bond (e.g., hydra-
zide-hydrazones derived from substituted benzoic acid) in
solution, the hydrazide NH forms intermolecular hydrogen
bond only; thus these hydrazide-hydrazones exist only in
EN―C(O)EN¼C conformer.
Proton
Tc (K)
dn (Hz)
ΔG{ (kJ/mol)
7a-H
i-H
363
353
243
150
70.5
69.9
It can be seen that the obtained ΔG{ values are compara-
ble to the ΔG{ values of the conformation exchange at
Some reported compounds were tested for cell cytotoxicity
on cancer cell KB; the results are listed as given below.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2012
Synthesis and NMR Spectroscopic Characteristics of a Series of Hydrazide-Hydrazones
Containing Furoxan Ring Derived from Isoeugenoxyacetic Acid
817
Table 2
Synthetical, analytical, and IR spectral data of the hydrazide‐hydrazones N1–N20.
IR, cm−1
Molecular
Yield
Compd. (%)
Mp (°C)/
cryst. from
formula/
M; +MS (m/z)
Analysis
Calcd./found (%)
nNH/nOH
nCH
nC ¼ O
nC ¼ N, nC ¼ C
N1
58
69
70
72
75
57
54
70
65
66
74
69
53
60
78
71
78
77
75
62
214–215
DMF–H2O 2:1
197
DMF–H2O 2:1
206
Dioxan–EtOH 1:1
209–210
DMF–EtOH 1:1
207–208
EtOH–H2O 2:1
199
Dioxan–H2O 2:1
215–216
Dioxan–H2O 2:1
226–227
DMSO–H2O 3:1
175–176
EtOH–H2O 2:1
209
Dioxan–H2O 2:1
198–199
DMF–H2O 2:1
227–228
Dioxan–H2O 3:1
230–231
DMF–H2O 2:1
240–241
DMF–H2O 1:1
213
Dioxan–H2O 3:1
202–203
3198
3211
3091, 2970
1689
1611, 1577
C19H17N5O7
427.36; 428
C20H19N5O7
441.39; −
C20H19N5O7
441.39; −
C19H16N5O7Cl
461.86; 462
C19H16N5O7Cl
461.86; −
C20H19N5O8
457.39; −
C20H19N5O8
457.39; −
C20H17N5O9
471.39; −
C20H19N5O9
473.39; −
C21H22N6O7
470.42; −
C19H17N5O8
443.36; −
C19H17N5O8
443.36; 444
C19H17N5O8
443.36; −
C19H17N5O9
459.36; −
C19H16N6O9
472.36; −
C19H16N6O9
472.36; 473
C19H16N6O9
472.36; −
C18H16N6O7
428.35; −
C17H15N5O8
417.32; −
C21H18N6O7
466.39; −
53.34
4.01
3.72
4.34
4.02
4.34
3.99
3.49
3.15
3.49
3.21
4.19
4.32
4.19
4.29
3.63
3.45
4.05
3.87
4.71
4.47
3.86
3.58
3.86
3.52
3.86
3.59
3.73
3.56
3.41
3.68
3.41
3.66
3.41
3.65
3.76
3.90
3.62
3.24
3.89
3.69
16.39
16.63
53.01
54.42
54.18
54.42
54.04
49.41
49.67
49.41
49.70
52.52
52.17
52.52
52.49
50.96
51.24
50.74
51.05
53.62
53.91
51.47
51.77
51.47
51.81
51.47
51.69
49.68
49.97
48.31
48.02
48.31
48.62
48.31
48.59
50.47
50.14
48.93
50.24
54.08
53.77
N2
3070, 2935
3098, 2977
3069, 2936
3095, 2968
3093, 2930
3088, 2933
3086, 2923
3060, 2926
30812934
1693
1691
1707
1691
1684
1691
1687
1681
1690
1686
1702
1676
1670
1712
1691
1691
1690
1688
1694
1615, 1587
15.87
16.13
15.87
16.11
15.16
14.86
15.16
14.82
15.31
15.59
15.31
14.98
14.86
14.59
14.79
15.12
17.86
17.98
15.79
15.55
15.79
15.42
15.79
15.63
15.25
15.46
17.79
18.03
17.79
17.47
17.79
17.56
19.62
19.88
16.78
16.46
18.02
18.37
N3
3199
1616, 1582, 1525
1623, 1582, 1525
1611, 1529
N4
3344
N5
3187
N6
3199
1611, 1583, 1523
1610, 1576, 1522
1615, 1578, 1529
1616, 1521
N7
3336
N8
3199
N9
3562/3206
3200
N10
N11
N12
N13
N14
N15
N16
N17
N18
N19
N20
1612 1529
3192/3100
3290/3200
3573/3212
3525/3454
3210
2930, 2852
3070, 2935
3096, 2939
3065, 2923
3081, 2925
3093, 2924
3095, 2975
3095, 2982
3065, 2936
3058, 2923
1618, 1580, 1532
1612, 1531
1606, 1537, 1509
1611, 1587, 1515
1617, 1580, 1527
1614, 1584, 1533
1611, 1582, 1530
1617, 1576, 1519
1614, 1577, 1523
1614, 1588, 1523
3191
DMF–H2O 2:1
228
Dioxan–H2O 3:1
229–230
DMF–H2O 1:1
223–224
DMF–EtOH 1:1
242–243
3194
3180
3193
3341, 3250
EtOH– H2O 3:1
epidermis carcinoma (KB) was tested at the Experimental
Biological Lab—Institute of Chemistry (Hanoi), according to
the method described in ref. 39.
Compounds
N4
N5
N10 N15 N17 N18 N20
IC50 ( mg/mL) 103 >128 >128 47 >128 68
79
2-Methoxy-4-(3-methyfuroxan-4-yl)phenoxyacetic acid
(K). Isoeugenoxyacetic acid (22.2 g, 0.1 mol) was dissolved in
50 mL of acetic acid. To this solution, NaNO2 (15.1 g, 0.12 mol)
was added in portions over 4 h and stirred at 25–30ꢁC for an
additional hour. The reaction mixture was poured into 100 mL
of water. The resulting yellow precipitate was collected,
washed by water, and recrystallized from ethanol–water 1:1 by
volume to give light yellow leaf crystals. The yield 17.4 g
(62%), mp 145–146ꢁC. IR (KBr): 2500–3100, broad (OH);
3068; 3003; 2946 (C―H), 1727 (C¼O); 1605, 1526 (ring).
1H-NMR see Table 1. 13C-NMR: 149.49 (1-C), 149.17 (2-C),
EXPERIMENTAL
IR spectra were recorded on a IMPACK-410 NICOLET
spectrometer in KBr disks at 400–4000 cmꢀ1. The ESI mass spec-
tra (+MS) of N1, N4, N12, N16, and N18 were recorded using
Agilent LC-MSD-Trap-SL series 1100. NMR spectra were
recorded on Bruker AVANCE 500 MHz spectrometer, in
DMSO-d6 with TMS as the internal standard, all at 298–300 K,
for N3 also at 303–373 K. The cytotoxicity toward Human
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

818
N. H. Dinh, H. T. Tuyet Lan, T. T. Thu Trang, and P. Van Hoan
Vol 49
Table 3
1H‐NMR signals of hydrazide‐moiety of examined compounds, δ (ppm).
Compd.
N1
N2
N3
N4
N5
N6
N7
3‐H
6‐H
7a‐H
7b‐H
10‐H
NH
11.71; s
11.62; 11.69; s
11.64; 11.65; s
11.86; 11.96 s
11.75; 11.76; s
11.70; s
11.55; s
11.56; s
11.53; s
11.41; 11.40; s
10.95; 11.65; s
11.65; 11.66; s
11.49; s
11.11; 11.43; s
11.98; s
7.44; 7.50; sa
7.42; 7.45; s
7.43; 7.45; s
7.42; 7.47; s
7.42; 7.45; s
7.43; 7.45; s
7.42; 7.45; s
7.40; 7.43; s
7.43; 7.45; s
7.43; 7.45; s
7.42; 7.45; s
7.43; 7.46; s
7.41; 7.43; s
7.41; 7.45; s
7.43; 7.45; s
7.43; 7.45; s
7.43; s
7.86; 7.95; s
7.84; 7.95; s
7.84; 7.93; s
7.86; 7.94; s
7.85; 7.93; s
7.85; 7.94; s
7.84; 7.94; s
7.91; 7.93; s
7.93; s
7.82; 7.84; s
7.85; 7.95; s
7.85; 7.93; s
7.92; 7.94; s
7.83; 7.94; s
7.87; 7.94; s
7.87; 7.94; s
7.87; 7.93; s
7.86; 7.93; s
7.82; 7.92; s
7.87; 7.97; d
5.47; 4.96; s
5.44; 4.94; s
5.44; 4.93; s
5.47; 4.57; s
5.46; 4.95; s
5.46; 4.95; s
5.42; 4.92; s
5.14; 4.90; s
5.43; 4.92; s
5.40; 4.90; s
5.43; 4.96; s
5.44; 4.94; s
5.40; 4.91; s
5.38; 4.93; s
5.45; 4.97; s
5.52; 4.99; s
5.51; 4.99; s
5.48; 4.96; s
5.36; 4.93; s
5.47; 4.92; s
3.98; 3.99; s
3.97; 3.98; s
3.97; 3.98; s
3.97; 3.98; s
3.97; 3.98; s
3.98; 3.99; s
3.97; s 3.98; s
3.95; s
3.93; 3.98; s
3.98; 3.99; s
3.98; 3.97; s
3.97; 3.98; s
3.97; 3.98; s
3.96; 3.98; s
3.97; s
2.03; 2.35; s
2.02; 2.34; s
2.03; 2.13; s
2.02; s
2.02; 2.35; s
2.03; s
2.03; s
2.01; s
2.02; s
2.03; s
2.02; s
2.02; 2.35; s
2.02; s
2.02; s
2.02; s
2.03; s
2.02; s
2.02; s
2.03; s
N8
N9
N10
N11
N12
N13
N14
N15
N16
N17
N18
N19
N20
3.98; s
3.97; s
3.97; 3.98; s
3.97; 3.98; s
3.98; s
11.93; s
11.99; s
11.86; s
11.63; s
7.42; 7.45; s
7.42; 7.45; s
7.43; 7.45; s
2.02; s
11.38; 11.36; s
aProton signals of the major compound were written before proton signals of the minor one, multiplicity is common for both.
Figure 2. Four possible isomers of the considered hydrazide-hydrazones.
110.97 (3-C), 119.18 (4-C), 120.52 (5-C), 113.17 (6-C), 64.82
(7a-C), 55.78 (7b-C), 156.98 (8-C), 112.91 (9-C), 8.98 (10-C),
169.78 (C¼O). Anal. Calcd. for C12H12N2O6, M 280.23 au: C,
51.43; H, 4.31; N, 10.00. Found: C, 51.68; H, 4.08; N, 10.25.
ms: m/z 280 (M+·), 264 (M+·ꢀO); 220 (M+·ꢀ2NO).
2-Methoxy-4-(3-methyfuroxan-4-yl)-5-nitrophenoxyacetic
acid (L). To a stirred solution of HNO3 (22 mL, D = 1.41 g/
mL) and H2SO4 (32 mL, D = 1.84 g/mL), 14.01 g (0.05 mol) of
K was slowly added over an hour at 0ꢁC. The reaction mixture
was stirred at 50–60ꢁC for 4 h and then was allowed to cool to
room temperature. The cooled mixture was poured into 50 mL
of water. The solid was collected, washed by water, and
recrystallized from ethanol–water 1:1 by volume to give white
needle crystals. The yield 9.75 g (60%), mp 180ꢁC. IR (KBr):
2700–3100, broad (OH); 3089, 2960, 2917 (C–H), 1738
(C¼O); 1614, 1577, 1516 (ring). 1H-NMR see Table 1. 13C-
NMR: 148.74 (1-C), 153.43 (2-C), 114.59 (3-C), 114.87 (4-
C), 139.95 (5-C), 109.71 (6-C), 65.35 (7a-C), 56.85 (7b-C),
156.34 (8-C), 113.71 (9-C), 7.61 (10-C), 169.37 (C¼O). Anal.
Calcd. for C12H11N3O8, M 325.23 au: C, 44.32; H, 3.41; N,
12.92. Found: C, 44.65; H, 3.08; N, 12.65. ms: m/z 325(M+·),
279 (M+·ꢀNO2), 265 (M+·ꢀ2NO).
Ethyl 2-methoxy-4-(3-methyfuroxan-4-yl)-5-nitrophenoxyacetate
(M). A mixture of 3.25 g (0.01 mol) of L, 35 mL of ethanol, and
1.5 mL of H2SO4 was refluxed for 24 h. The reaction mixture was
allowed to cool to room temperature and then was neutralized by
Scheme 3. Two conformers of the examined hydrazide-hydrazones.
Ar
C
H
H
H
CH3
N
CH3
CH3
CH3
O
O
H
N
C
Ar
Sol.
N
O
N
O
O
O
N
N
N
O
Sol.
+
N
H2C
C
H2C
C
O2N
O2N
O
EN-C(O)EN=C
ZN-C(O)EN=C
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2012
Synthesis and NMR Spectroscopic Characteristics of a Series of Hydrazide-Hydrazones
Containing Furoxan Ring Derived from Isoeugenoxyacetic Acid
819
Table 4
1H NMR signals of aldehyde-moiety of examined compounds, d (ppm), J (Hz).
Comp.
Ar
i-H
12-H
13-H
14-H
15-H
16-H
Others
N1
8.06; s
8.30; s
7.73; m
7.74; m
7.46; m
7.45; m
7.46; m
7.73; m
7.74; m
–
N2
N3
8.31; s
8.55; s
–
7.25; m
7.32; t
J: 7.5
7.27; m
7.77; m
J: 7.5
17-H: 2.45; 2,50; s
17-H: 2.33; 2,34; s
8.01; s
8.24; s
7.59; 7.62;
d; J: 8
7.23; 7.26;
d; J: 8
–
7,23; 7,26; 7.9; 7.62;
a
d; J: 8
d; J: 8
N4
N5
8.42; s
8.68; s
–
7.53; d
J: 7.5
7.45; t
J: 7.5
7.42; d
J: 7.5
7.97; 8.03;
s; J: 7.5
–
–
8.04; s
8.28; s
7.50; d
J: 8.5
7.73; 7.75
d; J: 8.5
–
7.75; 7.73
d; J: 8.5 J: 8.5
7.50; d
7.28; m
N6
N7
8.02; s
8.26; s
7.30; s
–
7.01; d
7.36; t
J: 7.5
17-H: 3.80; s
17-H: 3.81; s
–
J: 7
7.99; s
8.23; s
7.66; d
J: 9
7.00; d
J: 9
–
–
–
7.00; d
7.66; d
J: 9
J: 9
N8
N9
7.82; s
8.17; s
7.25; s
7.35; s
–
–
6.95; d
J: 7.5
7.13; 7.15
d; J: 8
17-H: 6.06; s
7.83; s
8.16; s
7.29; s
7.32; s
6.83; d
7.09; 7.11
d; J: 8
OH: 9.50; s
17-H: 3.83; s
J: 8
N10
N11
N12
7.93; s
8.13; s
7.53; d
J: 9
6.74; d
J: 8.5
–
6.74; d
J: 8.5
7.53; d
J: 9
17-H: 2.97; s
8.34; s
8.51; s
–
6.92; d
J: 7.5
7.25; 7.30
t; J: 7.5
6.86; 6.91 7.55; 7.72
t; J: 7.5
OH: 10.05; s
10.95; s
d; J: 7.5
7.96; s
8.18; s
7.13; s
7.17; s
–
6.83; dd
J: 7; 1.5
7.24; t
J: 8
7.09; 7.12;
d; J: 8
OH: 9.61; s
N13
N14
7.92; s
8.16; s
7.55; d
J: 8.5
6.82; d
J: 8.5
–
–
6.82; d
J: 8.5
7.55; d
J: 8.5
OH: 9.92; s
9.95; s
8.21; s
8.36; s
–
–
6.30; s
6.35; m
7.32; 7.50
d; J: 8.5
OH: 9.94; s
11.75; s
N15
N16
8.42; s
8.69; s
8.07; 8.13
d; J: 8
7.81; t
J: 7.5
7.68; t
J: 7.5
8.06; d
J: 8.5
–
–
8.17; s
8.41; s
8.53; s
–
–
8.25; m
8.26; m
7.75; t
J: 8
8,16; d
8,18;d
(Continues)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

820
N. H. Dinh, H. T. Tuyet Lan, T. T. Thu Trang, and P. Van Hoan
Vol 49
Table 4
(Continued)
Comp.
Ar
i-H
12-H
13-H
14-H
15-H
16-H
Others
N17
8,14; s
8,38; s
7,99; d
8,28; d
J: 7
–
8,28; d
7,99; d
J: 7
–
J: 7
J: 7
N18
8.11; s
8.34; s
8,90; s
8,85; s
–
8,14; d
J: 8
7,47; dd
J: 8; 5
8,61; m
–
–
–
N19
N20
7,93; s
8,18; s
–
6,93; d
J: 3
6,63; m
7.84; s
–
–
–
8,23; s
8,44; s
7,81; s
7,82; s
–
8.21; 8.15;
d; J: 7,5
7.14; 7.15 7.19; 7,21
t; J: 7.5 t; J: 7,5
17-H: 7,45; d
11-H: 11,56; s
aProton signals of the major compound were written before proton signals of the minor one, multiplicity and coupling constant are common for both.
Na2CO3. The resulting precipitate was collected, washed by water,
and recrystallized from ethanol–water 3:1 by volume to give light
yellow needle crystals. The yield 2.2 g (62%), mp 131–132ꢁC. IR
(KBr): 3110, 2981, 2924 (C―H), 1747 (C¼O); 1616, 1573, 1480
(ring). 1H-NMR see Table 1. 13C-NMR: 148.50 (1-C), 153.44 (2-
C), 114.66 (3-C), 115.06 (4-C), 139.93 (5-C), 110.12 (6-C), 65.56
(7a-C), 56.85 (7b-C), 156.22 (8-C), 113.62 (9-C), 7.56 (10-C),
167.91 (C¼O), 60.89 (11-C), 13.97 (12-C). Anal. Calcd. for
C14H15N3O8, M 353.29 au: C, 47.59; H, 4.28; N, 11.89. Found:
C, 47.23; H, 4.52; N, 12.05.
Table 5
13C NMR signals of hydrazide-moiety of examined compounds, d (ppm).
Comp.
1-C
2-C
3-C
4-C
5-C
6-C
7a-C
7b-C
8-C
9-C
10-C
C = O
N1
149.81a
149.48
149.32
148.95
149.27
148.90
149.28
148.94
149.33
149.00
149.20
148.99
149.36
149.16
151.47
151.49
149.30
148.92
149.37
149.04
149.24
148.90
149.29
149.00
149.28
149.00
149.24
149.07
149.48
149.19
153.87
154.10
153.39
153.50
153.35
153.60
153.36
153.59
153.36
153.59
153.37
153.60
153.37
153.50
153.36
153.40
153.36
153.62
153.40
153.63
153.36
153.70
153.40
153.60
153.37
153.60
153.38
152.90
153.48
153.71
114.99
114.97
114.46
115.09
115.19
114.52
115.24
114.50
114.80
114.51
114.67
114.66
115.16
114.60
115.10
114.67
115.15
114.70
115.20
114.69
115.24
114.67
115.18
114.55
114.70
114.70
115.30
114.69
115.30
114.70
115.22
114.67
115.19
140.39
140.49
139.98
139.90
140.01
139.90
139.98
110.36
110.74
109.87
66.30
67.66
65.91
66.33
65.83
67.05
65.78
67.12
65.78
67.18
65.84
67.20
65.88
67.23
65.80
67.27
65.78
67.08
65.81
67.23
65.79
68.00
65.87
67.10
65.82
67.13
65.67
67.22
66.14
67.41
57.30
57.39
56.80
56.89
56.80
56.89
56.78
56.87
56.78
56.86
56.79
56.84
56.80
56.88
56.78
56.87
56.78
56.88
56.81
56.90
56.81
156.85
155.72
156.34
155.20
156.34
155.40
156.34
155.30
156.36
114.17
8.11
11.55
7.59
11.03
7.61
168.64
163.84
168.04
163.26
168.35
163.70
168.23
163.46
167.85
163.04
167.98
163.00
167.79
163.00
167.45
162.80
167.80
163.27
167.77
162.96
168.48
164.80
168.48
163.77
168.36
163.50
167.86
163.28
167.23
162.50
N2
113.66
113.68
113.67
113.67
113.66
113.66
113.66
113.69
113.72
113.69
113.67
113.66
113.65
113.79
N4
114.46
114.44
109.88
110.40
109.84
110.30
109.81
110.26
109.84
110.20
109.80
110.33
109.82
110.20
109.87
110.41
109.84
110.30
109.86
10.08
7.59
N5
N7
114.43
114.46
114.47
139.88
139.96
139.99
7.59
7.60
7.59
7.59
7.59
7.62
7.61
7.59
7.59
7.59
7.65
N8
156.35
156.35
156.35
N9
114.47
114.44
139.95
139.96
N10
N11
N13
N15
N16
N18
N19
N20
114.43
114.48
114.46
114.50
114.48
139.90
139.98
139.91
139.99
139.77
156.36
156.43
156.40
156.34
156.33
114.49
114.56
114.46
114.51
114.47
114.54
114.48
114.58
139.99
140.00
109.91
110.37
109.87
110.34
109.92
110.38
109.89
110.36
56.81
56.90
56.80
56.88
56.78
56.87
56.86
56.93
156.32
156.60
156.34
153.62
156.49
139.89
139.98
139.99
a13 C signals of the major compound were written before 13 C signals of the minor compound.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2012
Synthesis and NMR Spectroscopic Characteristics of a Series of Hydrazide-Hydrazones
Containing Furoxan Ring Derived from Isoeugenoxyacetic Acid
821
Table 6
13C‐NMR signals of aldehyde‐moiety of examined compounds, δ (ppm).
Compd.
Ar
i‐C
11‐C
12‐C
13‐C
14‐C
15‐C
16‐C
17‐C
N1
144.79a
148.42
134.36
134.46
127.48
127.66
129.26
129.29
130.53
130.73
129.26
129.29
127.48
127.66
–
N2
N4
143.62
146.67
136.73
136.97
131.81
132.00
126.79
129.87
128.62
129.65
129.95
126.10
130.85
130.94
19.48
19.98
140.29
143.84
131.47
131.80
133.00
133.20
131.15
127.11
127.00
127.53
–
N5
N7
N8
N9
143.03
146.64
132.80
132.89
128.83
128.89
134.50
134.72
128.62
128.83
128.89
–
144.18
147.80
126.45
126.48
128.57
128.78
114.24
114.30
160.78
160.97
114.24
114.30
128.57
128.78
55.26
101.50
55.57
143.96
147.80
128.35
125.34
105.20
147.94
148.10
149.34
108.33
108.40
123.24
123.44
144.64
148.47
109.24
109.71
147.94
148.15
148.89
149.02
115.49
111.71
121.45
122.19
N10
N11
145.18
148.50
121.16
128.26
128.52
111.71
149.37
149.39
128.26
128.52
39.83
141.89
148.09
131.30
131.59
157.30
157.70
116.13
116.35
129.14
118.57
115.68
119.91
119.35
–
N13
N15
144.67
148.29
124.91
128.75
129.00
115.68
159.39
159.59
128.75
129.00
–
–
140.01
143.50
128.06
128.10
149.24
121.16
124.50
124.70
130.66
130.80
133.51
133.70
128.56
N16
N18
142.05
145.57
135.74
135.90
148.23
129.81
124.21
124.50
130.32
130.50
133.04
133.25
–
–
141.49
145.28
–
148.50
148.78
133.62
133.50
123.81
150.56
150.80
N19
134.44
137.74
–
–
148.87
148.94
113.89
113.99
112.12
121.84
145.09
145.32
–
–
N20b
141.83
145.26
130.70
111.32
120.52
120.67
122.72
111.94
a13C signals of the major compound were written before 13C signals of the minor compound.
b18‐C: 137.16; 19‐C: 124.12; 124.33.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

822
N. H. Dinh, H. T. Tuyet Lan, T. T. Thu Trang, and P. Van Hoan
Vol 49
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2-Methoxy-4-(3-methyfuroxan-4-yl)-5-nitrophenoxyacetylhydrazine
(N). A solution of 3.53 g (0.01 mol) of M, 1.0 mL of N2H4·H2O
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General procedure for the preparation of hydrazide-
hydrazones N1–N20.
A solution of 1 mmol of N and 1
mmol of an aromatic aldehyde dissolved in 15–25 mL of
ethanol was refluxed over 5–10 h. Upon cooling the mixture to
room temperature, the resulting precipitate was collected and
recrystallized. The synthetical, analytical, and spectral data of
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet