The reaction of ethyl 2-oxo-2H-chromene-3-carboxylate with hydrazine hydrate

Article abstract of DOI:10.3390/molecules18022084

Although salicylaldehyde azine (3) was reported in 1985 as the single product of the reaction of ethyl 2-oxo-2H-chromene-3-carboxylate (1) with hydrazine hydrate, we identified another main reaction product, besides 3, which was identified as malono-hydrazide (4). In the last two decades, however, some articles have claimed that this reaction afforded exclusively hydrazide 2 and they have reported the use of this hydrazide 2 as a precursor in the syntheses of several heterocyclic compounds and hydrazones 6. We reported herein a study of the formation of 2 and a facile route for the synthesis of the target compounds N'-arylidene-2-oxo-2H-chromene-3-carbohydrazides 6a-f.

Full text of DOI:10.3390/molecules18022084

Molecules 2013, 18, 2084-2095; doi:10.3390/molecules18022084
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
The Reaction of Ethyl 2-oxo-2H-chromene-3-carboxylate with
Hydrazine Hydrate
Hatem A. Abdel-Aziz 1,2,*, Tilal Elsaman 1, Mohamed I. Attia 1,3 and Amer M. Alanazi 1
1
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University,
P.O. Box 2457, Riyadh 11451, Saudi Arabia
2
Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo 12622, Egypt
3
Department of Medicinal and Pharmaceutical Chemistry, National Research Center, Dokki,
Cairo 12622, Egypt
* Author to whom correspondence should be addressed; E-Mail: hatem_741@yahoo.com;
Tel.: +966-1467-3764; Fax: +966-1467-6220.
Received: 12 January 2013; in revised form: 29 January 2013 / Accepted: 30 January 2013 /
Published: 6 February 2013
Abstract: Although salicylaldehyde azine (3) was reported in 1985 as the single product of
the reaction of ethyl 2-oxo-2H-chromene-3-carboxylate (1) with hydrazine hydrate, we
identified another main reaction product, besides 3, which was identified as
malono-hydrazide (4). In the last two decades, however, some articles have claimed that
this reaction afforded exclusively hydrazide 2 and they have reported the use of this
hydrazide 2 as a precursor in the syntheses of several heterocyclic compounds and
hydrazones 6. We reported herein a study of the formation of 2 and a facile route for the
synthesis of the target compounds N'-arylidene-2-oxo-2H-chromene-3-carbohydrazides 6a–f.
Keywords: salicylaldehyde azine; malonohydrazide; coumarins; hydrazides/hydrazones;
ring-opening
1. Introduction
The hydrazides are very useful starting materials for the construction of several functionalized
heterocycles with a broad spectrum of biological activities, and consequently they have been studied in
considerable detail over the decades [1,2]. For instance, hydrazides are versatile raw materials to
synthesize pyrroles [3], pyrazoles [4], 1,3-thiazoles [5], 1,3,4-oxadiazoles [6], 1,2,4-triazoles [7], 1,3,4-

Molecules 2013, 18
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thiadiazoles [8], 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles [9] and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines [10].
The common practical route for hydrazide synthesis is the treatment of esters with hydrazine hydrate.
The use of microwave irradiation is a recent contribution to this field for the facile preparation of
hydrazides by solvent-free reactions of acid derivatives with hydrazine hydrate [11,12]. On the other
hand, there is a great deal of interest in chromene-2-ones, especially 3-substituted derivatives, due to
their important pharmacological effects, including analgesic, anti-arthritis, anti-inflammatory,
anti-pyretic, anti-viral, anti-cancer and anticoagulant properties [13–15]. In the light of previous data
and in continuation of our interest in the chemistry of hydrazides [16–24], our efforts targeted the
synthesis of hydrazide 2 through the title reaction according to the literature methods [25–36], with the
intention of subsequently treating hydrazide 2 with different aldehydes to obtain hydrazones 6a–f for
our biological screening program. We report herein the results achieved to this end.
2. Results and Discussion
The contradictory data reported in last two decades [25–36], alerted us to be careful in our
preparation of hydrazide 2, for instance the hours of reflux used in the title reaction were 2 h [28,33],
3 h [29], 4 h [30], 6 h [27,36] and 10 h [26,34], and afforded different yields of the claimed hydrazide 2:
99% [25], 90% [26], 80% [27–30], 72% [32], 65% [31] and 62% [34]. Moreover, different melting points
have been reported for the claimed hydrazide 2 (m.p. 136–138 °C [26], 145 °C [32], 206–209 °C [30]).
When we reacted an equimolar ratio of ester 1 with hydrazine hydrate at reflux and followed the
reaction progress by TLC, the spot of ester 1 still remained, even after refluxing for 20 h. However, the
ester 1 was completely consumed after refluxing 2 h when we used excess hydrazine hydrate (2.5 equiv.).
In this case, after cooling, we isolated yellow crystals with melting point 205–206 °C.
The IR, mass and NMR spectral data did not coincide however with those of the expected hydrazide
1
2. For example, the H-NMR of our yellow crystals revealed one D2O-exchangeable signal, whereas
there were no carbonyl resonances in the 13C-NMR data. In addition, its IR spectrum showed no
evidence of the characteristic lactone carbonyl absorption band, while the mass spectrum of these
crystals showed a peak at m/z 240.5 and not the expected one at m/z 204 corresponding to the
molecular ion of claimed hydrazide 2.
In an exhaustive literature survey of the reaction product(s) of ester 1 and hydrazine hydrate,
bearing in consideration the possible ring-openings of chromene-2-ones [37], Soliman et al. [38]
described, in 1985, the reaction of ethyl 2-oxo-2H-chromene-3-carboxylate (1) with hydrazine hydrate
in refluxing ethanol, in which they obtained salicylaldehyde azine (3) in 31.5% and 42.4% yields for
one and two equivalent of hydrazine hydrate, respectively, instead of the claimed hydrazide 2. The
structure of the well-known and commercially available salicylaldehyde azine (3), was rigorously
proven by independent synthesis using the reaction of salicylaldehyde with hydrazine hydrate [39].
Comparison of the melting point and spectral data for an authentic sample of compound 3 and the
yellow crystals produced in our trials, gave us absolute confidence to assign the structure of these
crystals to be salicylaldehyde azine (3), in complete agreement with the results of Soliman and his co-
workers (Scheme 1).

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Scheme 1. The reaction of ester 1 with hydrazine hydrate.
O
O
O
O
1
NH2NH2
X
O
O
NH2
O
O
N
N
N
H2N
NH2
H
N
N
OH
HO
O
H
H
3
4
2
Ar-CHO
5a-f
O
N
Ar
N
H
O
O
6a-f
Although the azine 3, produced by Soliman et al. through the reaction of ester 1 with hydrazine
hydrate, proved to be identical with the substance we have produced by the same reaction, in the
current work, when the filtrate was evaporated under vacuum, after separation of salicylaldehyde azine
(3), a white powder was produced, which was recrystallized from ethanol to give colorless flakes with
1
mp. 153–154 °C. H-NMR of the latter showed a singlet at δ 3.41 integrating for 2Hs, in addition to
two D2O-exchangeable signals at δ 4.38 and δ 9.07 integrating for 2H and 1H, respectively, whereas
13
its C-NMR spectrum showed only two peaks, the first of a sp3 carbon at δ 46.5 and the second for
1
two sp2 carbons at δ 170.7. The H- or 13C-NMR spectra did not show any aromatic protons or
carbons, respectively. The mass spectrum of the latter compound exhibited a peak at m/z 132.3.
Furthermore, on the basis of formation of salicylaldehyde azine (3) and according to the reported
ring-opening behavior of the 2H-chromene moiety, we can propose a mechanism for the formation of
compound 3 and we can predict the structure of the obtained unknown compound in the title reaction.
2H-1-Benzopyran-2-one (coumarin) derivatives are highly reactive because the pyran-2-one ring is an
aliphatic moiety that is likely to undergo ring-opening under nucleophilic attack at the lactone acyl
centre or nucleophilic conjugate addition at the carbon-carbon double bond [37]. Therefore, in ester 1
we have two nucleophilic centers in addition to the carbonyl function in the ester side chain (Scheme 2).
The previous facts led our proposed mechanism to suppose malonohydrazide (4) to be the structure
of the compound isolated from the filtrate of the title reaction. In addition, comparing analytical data of
the isolated malonohydrazide (4) with that of authentic sample of malonohydrazide (m.p. 151–153 °C) [40]
revealed them to be identical in all aspects. Moreover, the proposed mechanism proved the needed
molar ratio of hydrazine hydrate (2.5 mol equiv.) to achieve full consumption of ester 1. However,
compounds 3 and 4 were also isolated when the reaction proceeded at 0–5 °C.

Molecules 2013, 18
Scheme 2. The proposed mechanism for the reaction of ester 1 with hydrazine hydrate and
2087
its molar ratio equation.
O
O
O
O
H2N
NH2
2NH2NH2
-EtOH
N
N
H
H
O
O
OH
1
9
NH2NH2
9
O
O
O
O
O
O
O
O
H2N
NH2 H2N
NH2
H2N
NH
2 H2N
NH2
N
H
N
H
N
H
N
H
N
H
N
H
N
N
H
H
H
N
H
N
H
H
N
N
OH
HO
OH
HO
9
H
H
9
10
O
O
H2N
NH2
2
+
N
(2.5) NH2NH2
N
N
N
1
(0.5) 3
+
4
H
H
4
OH
HO
Our attention was next shifted to the synthesis of our targeted hydrazones 6a–f (Scheme 1). Scheme
3 shows a representative retrosynthetic approach for this class of compounds. The ethyl
3-(2-arylidenehydrazinyl)-3-oxopropanoates 8a–f were condensed with salicylaldehyde (5f) to
generate the targeted hydrazones 6a–f. Compounds 8a–f were synthesized from the reaction of ethyl
3-hydrazinyl-3-oxopropanoate (7) with the appropriate aldehydes 5a–e.
Scheme 3. Retrosynthetic analysis of the targeted derivatives 6a–f.
O
O
O
O
NH2
N
Ar
O
O
O
N
O
N
H
H
N
Ar
7
N
8a-f
H
+
+
O
Ar-CHO
CHO
OH
5a-e
6a-f
5f
Thus, treatment of ethyl 3-hydrazinyl-3-oxopropanoate (7) [38] with the appropriate aldehydes 5a–f
in refluxing ethanol yielded the corresponding ethyl 3-(2-arylidenehydrazinyl)-3-oxopropanoates 8a–f
(Scheme 4).

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Scheme 4. Synthetic route for synthesis of hydrazones 6a–f.
Ar-CHO
O
O
O
O
5a-f
N
Ar
NH2
O
N
H
O
N
EtOH
H
8a-f
7
CHO
OH
5f (2 mole equ.)
Piperidine/EtOH
Piperidine/EtOH
5f
6a-f
6f
5, 6, 8
Ar
a
b
c
d
e
f
Ph
4-CH3O-C6H4
4-Cl-C6H4
3,4,-O-CH2-O-C6H4
thiophen-2-yl
2-OHC6H4
Next, the condensation reaction of hydrazones 8a–f with salicyaldehyde (5f) in the presence of
piperidine afforded exclusively compounds 6a–f. IR spectra of the latter products revealed two
carbonyl absorption bands in the 1704–1699 and 1666–1610 cm−1 regions, in addition to the
1
absorption band of NH function in the 3291–3195 cm−1 region. Their H-NMR spectra exhibited NH
group D2O-exchangeable signals in the δ 11.65–11.95 region, in addition to two singlet signals in the δ
8.38–8.71 and δ 8.90–8.94 regions corresponding to the –CH=C– group of the hydrazone function and
pyran ring, respectively. In our hands, the melting points of 8a, 8b and 8c were recorded as 258–260 °C,
265–267 °C and 288–290 °C, respectively, while the reported melting points of the latter claimed
compounds 205–207 °C, 194–196 °C and 216–218 °C, respectively [30]. Finally, compound 6f was
synthesized directly by the reaction of ethyl 3-hydrazinyl-3-oxopropanoate (7) with two mol equiv. of
salicylaldehyde (5f) in the presence of piperidine.
3. Experimental
3.1. General
Infrared (IR) Spectra were recorded as KBr disks using the Perkin Elmer FT-IR Spectrum BX
apparatus. Melting points were determined on a Gallenkamp melting point apparatus and are
uncorrected. NMR Spectra were scanned in DMSO-d6 on a Jeol NMR spectrophotometer operating at
1
13
400 MHz for H and 100 MHz for C. Chemical shifts are expressed in -values (ppm) relative to
TMS as an internal standard. Coupling constants (J) are expressed in Hz. D2O was added to confirm
the exchangeable protons. Mass spectra were measured on an Agilent Triple Quadrupole 6410 QQQ
LC/MS equipped with an ESI (electrospray ionization) source. The elemental analyses were performed
at the Microanalytical Center of Cairo University. Ethyl 3-hydrazinyl-3-oxopropanoate (7) was
prepared according to the reported method (m.p. 68–69 °C) [40].

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3.2. The Reaction of Ethyl 2-oxo-2H-Chromene-3-carboxylate (1) with Hydrazine Hydrate
A mixture of ethyl 2-oxo-2H-chromene-3-carboxylate (1, 2.18 g, 10 mmol) and hydrazine hydrate,
(99%, 1.3 g, 25 mmol) in absolute ethanol (50 mL) was heated under reflux for 2 h. The precipitate
formed was filtered off, washed with ethanol and dried. Recrystallization from ethanol gave yellow
crystals of salicyaldehyde azine (3) [38,39] (1.15 g, 48%); m.p. 205–206 °C (204.3 °C) [39]; IR ν
1
3350–2830 (OH), 1633 (C=N) cm−1; H-NMR δ 6.84–7.72 (m, 8H, ArH), 8.86 (s, 2H, –CH=), 10.90
13
(s, D2O exch., 2H, OH); C-NMR δ 117.9, 118.7, 121.4, 132.0, 132.5, 159.2, 162.0; MS m/z: 240.5
(M+). Anal. calcd. for C14H12N2O2 (240.26): C, 69.99; H, 5.03; N, 11.66%. Found: C, 70.23; H, 5.17;
N, 11.48%. Evaporation of the filtrate of the latter reaction gave a residue, which was washed with
70% ethanol, dried and recrystallized from ethanol to yield colorless flakes of malonohydrazide (4)
[40] (1.14 g, 86%); m.p. 153–154 °C (151–153 °C); IR ν 3323–3246 (NH2, NH), 1635 (C=O), cm−1;
1H-NMR δ 3.41 (s, 2H, CH2), 4.38 (s, D2O exch., 4H, 2NH2), 9.07 (s, D2O exch., 2H, NH); 13C-NMR
δ 46.5 (CH2), 170.7 (2C=O); MS m/z: 132.3 (M+). Anal. calcd. for C3H8N4O2 (132.12): C, 27.27; H,
6.10; N, 42.41%. Found: C, 27.04; H, 6.38; N, 42.16%.
3.3. General Procedure for the Synthesis of Ethyl 3-(2-arylidenehydrazinyl)-3-oxopropanoates 8a–f
A solution of hydrazide 7 (1.46 g, 10 mmol) and the appropriate aldehyde 5a–f (10 mmol) in
absolute ethanol (30 mL) was refluxed for 1h and then cooled to 5–10 °C. The solid formed was
collected by filtration, washed with ethanol and crystallized from ethanol to afford hydrazones 8a–f.
Ethyl 3-(2-benzylidenehydrazinyl)-3-oxopropanoate (8a).Yield (2.0 g, 85%); m.p. 115–17 °C (m.p.
1
111–113 °C [41]); IR ν 3292 (NH), 1735 (C=O, ester), 1682 (C=O, amide) cm−1; H-NMR δ 1.17 (t,
J = 6.6 Hz, 3H, CH3), 3.65 (s, 2H, CH2), 4.09 (q, J = 6.6 Hz, 2H, CH2), 7.41–7.71 (m, 5H, ArH), 7.96 (s,
13
1H, –CH=), 11.58 (s, D2O exch., 1H, NH); C-NMR δ 14.6 (CH3), 41.8 (CH2), 61.0 (CH2), 127,3,
129.2, 129,3, 129.8, 134.6 (ArC), 143.7 (–CH=), 168.3 (C=O), 168.5 (C=O); MS m/z: 257.1 (M++23).
Anal. calcd. for C12H14N2O3 (234.25): C, 61.53; H, 6.02; N, 11.96%. Found: C, 61.27; H, 5.85; N,
12.19%.
Ethyl 3-(2-(4-methoxybenzylidene)hydrazinyl)-3-oxopropanoate (8b). Yield (2.46 g, 93%); m.p.
116–118 °C (m.p. 110–111 °C [41]); IR ν 3293 (NH), 1728 (C=O, ester), 1681 (C=O, amide) cm−1;
1H-NMR δ 1.16 (t, J = 6.6 Hz, 3H, CH3), 3.62 (s, 2H, CH2), 3.80 (s, 3H, OCH3), 4.08 (s, 2H, CH2),
4.07 (q, J = 6.6, Hz, 2H, CH2), 6.98 (d, J = 8.8, Hz, 2H, ArH), 7.57 (d, J = 8.8 Hz, 2H, ArH), 7.90 (s,
13
1H, –CH=), 11.44 (s, D2O exch., 1H, NH); C-NMR δ 14.6 (CH3), 41.7 (CH2), 55.9 (OCH3), 60.9
(CH2), 114.8, 127.2, 128.9, (ArC), 143.5 (–CH=), 161.2 (ArC), 168.2 (C=O), 168.3 (C=O); MS m/z:
265.2 (M++1), 287.2 (M++23). Anal. calcd. for C13H16N2O4 (264.28): C, 59.08; H, 6.10; N, 10.60%.
Found: C, 60.24; H, 6.36; N, 10.57%.
Ethyl 3-(2-(4-chlorobenzylidene)hydrazinyl)-3-oxopropanoate (8c). Yield (2.23 g, 83%); m.p. 168–170 °C
1
(m.p. 160–163 °C [41]); IR ν 3292 (NH), 1733 (C=O, ester), 1675 (C=O, amide) cm−1; H-NMR δ
1.16 (t, J = 6.6 Hz, 3H, CH3), 3.65 (s, 2H, CH2), 4.08 (q, J = 6.6 Hz, 2H, CH2), 7.49 (d,
J = 8.8 Hz, 2H, ArH), 7.65 (d, J = 8.1, Hz, 2H, ArH), 7.96 (s, 1H, –CH=), 11.64 (s, D2O exch., 1H,

Molecules 2013, 18
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NH); 13C-NMR δ 14.6 (CH3), 41.5 (CH2), 61.1 (CH2), 128.9, 129.4, 133.6, 134.9 (ArC), 142.4
(–CH=), 168.2 (C=O), 168.5 (C=O); MS m/z: 291.1 (M++23). Anal. calcd. for C12H13ClN2O3 (268.70):
C, 53.64; H, 4.88; N, 10.43%. Found: C, 53.75; H, 5.04; N, 10.25%.
Ethyl 3-(2-(benzo[d][1,3]dioxol-5-ylmethylene)hydrazinyl)-3-oxopropanoate (8d). Yield (2.37 g, 85%);
1
m.p. 158–160 °C; IR ν 3187 (NH), 1736 (C=O, ester), 1676 (C=O, amide) cm−1; H-NMR δ 1.17 (t,
J = 7.36 Hz, 3H, CH3), 3.61 (s, 2H, CH2), 4.07 (q, J = 7.36 Hz, 2H, CH2), 6.07 (s, 2H, CH2), 6.95 (d,
J = 8.1 Hz, 1H, ArH), 7.06 (d, J = 8.8 Hz, 1H, ArH), 7.22 (s, 1H, ArH), 7.86 (s, 1H, –CH=), 11.46
13
(s, D2O exch., 1H, NH); C-NMR δ 14.6 (CH3), 41.8 (CH2), 60.9 (CH2), 102.1 (CH2), 105.2, 108.9,
123.7, 129.1 (ArC), 143.3 (–CH=), 148.5, 149.5 (ArC), 168.30 (C=O), 168.33 (C=O); MS m/z: 279.1
(M++1), 301.1 (M++23). Anal. calcd. for C13H14N2O5 (278.26): C, 56.11; H, 5.07; N, 10.07%. Found:
C, 56.19; H, 4.93; N, 9.86%.
Ethyl 3-oxo-3-(2-(thiophen-2-ylmethylene)hydrazinyl)propanoate (8e). Yield (1.87 g, 78%); m.p.
118–120 °C; IR ν 3292 (NH), 1732 (C=O, ester), 1677 (C=O, amide) cm−1; 1H-NMR δ 1.19 (t, J = 7.32 Hz,
3H, CH3), 3.57 (s, 2H, CH2), 4.09 (q, J = 7.32 Hz, 2H, CH2), 8.14 (s, 1H, –CH=), 7.10 (t, J = 4.4 Hz,
1H, thiophene H), 7.40 (d, J = 2.92 Hz, 1H, thiophene H), 7.62 (d, J = 4.4 Hz, 1H, thiophene H); 11.56
(s, D2O exch., 1H, NH); MS m/z: 241.1 (M++1), 263.1 (M++23). Anal. calcd. for C10H12N2O3S
(240.28): C, 49.99; H, 5.03; N, 11.66; S, 13.34%. Found: C, 49.79; H, 5.07; N, 11.86; S, 13.53%.
Ethyl 3-(2-(2-hydroxybenzylidene)hydrazinyl)-3-oxopropanoate (8f). Yield (2.15 g, 86%); m.p.
148–150 °C; IR ν 3191–3090 (NH, OH), 1734 (C=O, ester), 1667 (C=O, amide) cm−1; 1H-NMR δ 1.17
(t, J = 7.32 Hz, 3H, CH3), 3.62 (s, 2H, CH2), 4.09 (q, J = 7.32 Hz, 2H, CH2), 6.82–6.93 (m, 2H, ArH),
7.21–7.31 (m, 1H, ArH), 7.54–7.62 (m, 1H, ArH), 8.27 (s, 1H, –CH=), 9.99 (s, D2O exch., 1H, OH),
13
11.49 (s, D2O exch., 1H, NH); C-NMR δ 14.6 (CH3), 41.7 (CH2), 61.0 (CH2), 116.7, 119.9, 120.7,
126.5, 131.7 (ArC), 141.1 (–CH=), 162.1, (ArC), 168.1 (C=O), 168.2 (C=O); MS m/z: 251.2 (M++1),
273.1 (M++23). Anal. calcd. for C12H14N2O4 (250.25): C, 57.59; H, 5.64; N, 11.19%. Found: C, 57.46;
H, 5.67; N, 11.03%.
3.4. General Procedure for the Synthesis of N'-Arylidene-2-oxo-2H-chromene-3-carbohydrazides 6a–f
To a solution of the appropriate hydrazone 8a–f (1 mmol) and salicaldehyde (5f) (0.122 g, 1 mmol)
in absolute ethanol (25 mL), a catalytic amount of piperidine (0.3 mL) was added. The reaction
mixture was refluxed for 1 h. The formed precipitate was filtered off, washed with ethanol, dried and
recrystallized from EtOH/DMF to give hydrazides 6a–f.
N'-Benzylidene-2-oxo-2H-chromene-3-carbohydrazide (6a). Yield (254 mg, 87%); m.p. 258–260 °C;
IR ν 3249 (NH), 1700 (C=O, lactone), 1665 (C=O, amide) cm−1; 1H-NMR δ 7.46–7.51 (m, 4H, ArH),
7.55 (d, J = 8.1 Hz, 1H, ArH), 7.76–7.77 (m, 3H, ArH), 8.03 (d, J = 8.1 Hz, 1H, ArH), 8.48 (s, 1H,
13
–CH=), 8.93 (s, 1H, –CH=), 11.78 (s, D2O exch., 1H, NH); C-NMR δ 116.8, 116.9, 118.9, 119.9,
125.8, 127.2, 127.9, 129.4, 130.9, 131.0, 134.5, 134.9, 145.2 (ArC), 148.2 (–CH=), 149.9 (–CH=), 154.5
(C=O); MS m/z: 293.1 (M++1), 315.1 (M++23). Anal. calcd. for C17H12N2O3 (292.29): C, 69.86; H,
4.14; N, 9.58%. Found: C, 69.58; H, 4.03; N, 9.36%.

Molecules 2013, 18
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N'-(4-Methoxybenzylidene)-2-oxo-2H-chromene-3-carbohydrazide (6b). Yield (290 mg, 90%); m.p.
265–267 °C; IR ν 3257 (NH), 1704 (C=O, lactone), 1666 (C=O, amide) cm−1; 1H-NMR δ 3.82 (s, 3H,
OCH3), 7.04 (d, J = 8.8 Hz, 2H, ArH), 7.48 (t, J = 7.4 Hz, 1H, ArH), 7.55 (d, J = 8.8 Hz, 1H, ArH), 7.71
(d, J = 8.1 Hz, 2H, ArH), 7.79 (t, J = 8.1 Hz, 1H, ArH), 7.02 (d, J = 7.3 Hz, 1H, ArH), 8.40 (s, 1H,
–CH=), 8.90 (s, 1H, –CH=), 11.65 (s, D2O exch., 1H, NH); MS m/z: 323.2 (M++1). Anal. calcd. for
C18H14N2O4 (322.31): C, 67.07; H, 4.38; N, 8.69%. Found: C, 66.79; H, 4.44; N, 8.75%.
N'-(4-Chlorobenzylidene)-2-oxo-2H-chromene-3-carbohydrazide (6c). Yield (265 mg, 81%); m.p.
288–290 °C; IR ν 3250 (NH), 1704 (C=O, lactone), 1665 (C=O, amide) cm−1; 6.95 (d, J = 7.4 Hz, 1H,
ArH), 7.48 (t, J = 7.3 Hz, 2H, ArH), 7.55 (d, J = 8.1 Hz, 2H, ArH), 7.78 (d, J = 8.1 Hz, 2H, ArH), 8.02
(d, J = 6.6 Hz, 1H, ArH), 8.49 (s, 1H, –CH=), 8.94 (s, 1H, –CH=), 11.95 (s, D2O exch., 1H, NH); MS
m/z: 327.1 (M++1). Anal. calcd. for C17H11ClN2O3 (326.73): C, 62.49; H, 3.39; N, 8.57%. Found: C,
62.31; H, 3.39; N, 8.48%.
N'-(Benzo[d][1,3]dioxol-5-ylmethylene)-2-oxo-2H-chromene-3-carbohydrazide (6d). Yield (259 mg,
77%); m.p. 286–288 °C; IR ν 3256 (NH), 1704 (C=O, lactone), 1665 (C=O, amide) cm−1;
1H-NMR δ 6.11 (s, 2H, CH2), 6.94–7.79 (m, 6H, ArH), 8.02 (d, J = 6.6 Hz, 1H, ArH), 8.38 (s, 1H,
–CH=), 8.92 (s, 1H, –CH=), 11.69 (s, D2O exch., 1H, NH); MS m/z: 337.1 (M++1). Anal. calcd. for
C18H12N2O5 (336.30): C, 64.29; H, 3.60; N, 8.33%. Found: C, 64.02; H, 3.54; N, 8.52%.
2-Oxo-N'-(thiophen-2-ylmethylene)-2H-chromene-3-carbohydrazide (6e). Yield (239 mg, 80%); m.p.
1
282–284 °C; IR ν 3291 (NH), 1700 (C=O, lactone), 1664 (C=O, amide) cm−1; H-NMR δ 7.45–7.78
(m, 6H, thiophene H, ArH), 8.02 (d, J = 8.1 Hz, 1H, ArH), 8.69 (s, 1H, –CH=), 8.91 (s, 1H, –CH=),
13
11.85 (s, D2O exch., 1H, NH); C-NMR δ 116.8 (–CH=), 118.9, 119.9, 125.8, 128.6, 130,1, 130.8,
132.3, 134.9, 139.1 (ArC, thiophene C), 145.1 (–CH=), 148.3, 154.4 (ArC), 158.5 (C=O), 160.4
(C=O); MS m/z: 299.1 (M++1). Anal. calcd. for C15H10N2O3S (298.32): C, 60.39; H, 3.38; N, 9.39; S,
10.75%. Found: C, 60.36; H, 3.15; N, 9.31; S, 10.59%.
N'-(2-Hydroxybenzylidene)-2-oxo-2H-chromene-3-carbohydrazide (6f). Yield (271 mg, 88%); m.p.
1
298–300 °C; IR ν 3195–3049 (NH, OH), 1699 (C=O, lactone), 1610 (C=O, amide) cm−1; H-NMR δ
6.96 (d, J = 6.6 Hz, 2H, ArH), 7.33 (t, J = 8.1 Hz, 1H, ArH), 7.48 (t, J = 8.1 Hz, 1H, ArH), 7.55–7.57
(m, 3H, ArH, OH), 7.79 (t, J = 8.1 Hz, 1H, ArH), 8.02 (d, J = 7.3 Hz, 1H, ArH), 0.00 (s, 1H, –CH=),
8.71 (s, 1H, –CH=), 8.92 (s, 1H, –CH=); MS m/z: 309.2 (M++1), 331.1 (M++23). Anal. calcd. for
C17H12N2O4 (308.29): C, 66.23; H, 3.92; N, 9.09%. Found: C, 66.02; H, 4.11; N, 8.92%.
3.5. Direct Synthesis of 6f
To a solution of hydrazide 7 (0.146 g, 1 mmol) and salicaldehyde (5f) (0.244 g, 2 mmol) in absolute
ethanol (25 mL), a catalytic amount of piperidine (0.3 mL) was added. The reaction mixture was
refluxed for 1 h. The formed precipitate was filtered off, washed with ethanol, dried and recrystallized
from EtOH/DMF to give 240 mg of 6f in 78% yield.

Molecules 2013, 18
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4. Conclusions
We have identified another main product, confirmed as malohydrazide (4), besides salicylaldehyde
azine (3) which was reported by Soliman et al. in 1985 [38] as the sole product of the title reaction.
Whereas the observations of this investigation have confirmed the identity of salicylaldehyde azine (3)
and malonohydrazide (4), as the compounds produced through the reaction of ester 1 with hydrazine
hydrate, the structures of products claimed to be formed from hydrazide 2 in investigations reported
over the last two decades [25–36] need to be reassigned. Moreover, we described an efficient synthetic
route for our targeted hydrazones 6a–f. Generalization of the latter established method can be widely
used in synthesis of library of coumarin-based hydrazones.
Acknowledgments
The authors extend their appreciation to the Deanship of Scientific Research at King Saud
University for funding this work through research group No. RGP-VPP-196.
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Sample Availability: Samples of the compounds are available from Dr. Hatem A. Abdel-Aziz,
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457,
Riyadh 11451, Saudi Arabia.
© 2013 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).