2H-pyran-2-one-3-carbothioamide derivatives: Synthesis and reaction with hydrazine hydrate

Article abstract of DOI:10.1002/jhet.2

N-Aryl-4-hydroxy-6-methyl-2H-pyran-2-one-3-carbothiamides and N-aryl-4-hydroxycoumarin-3-carbothiamides were synthesized by the reaction of arylisothiocyanates with 4-hydroxy-6-methylpyran-2-one and 4-hydroxycoumarin, respectively. Novel products 3-[bis(a

Full text of DOI:10.1002/jhet.2

18
2H-Pyran-2-one-3-carbothioamide Derivatives: Synthesis and
Reaction with Hydrazine Hydrate
Vol 46
Malika Makhloufi-Chebli,a Maamar Hamdi,a* Artur M. S. Silva,b
Olivier Duval,c and Jean-Jacques Helesbeuxc
a
´
´ ´
´
Laboratoire de Chimie Organique Appliquee (Groupe Heterocycles associe CRAPC),
´ `
Faculte de Chimie, Universite des Sciences et de la Technologie Houari Boumediene, BP32,
´
El-Alia 16111 Bab-Ezzouar, Alger, Algerie
bDepartment of Chemistry and QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
c
´
´
´
UFR Universite des Sciences Pharmaceutiques et Ingenierie de la Sante, Laboratoire SONAS 16
bd Daviers, 49045 ANGERS, Cedex 1, France
*E-mail: prhamdi@gmail.com
Received April 28, 2008
DOI 10.1002/jhet.2
Published online 4 February 2009 in Wiley InterScience (www.interscience.wiley.com).
N-Aryl-4-hydroxy-6-methyl-2H-pyran-2-one-3-carbothiamides and N-aryl-4-hydroxycoumarin-3-car-
bothiamides were synthesized by the reaction of arylisothiocyanates with 4-hydroxy-6-methylpyran-2-
one and 4-hydroxycoumarin, respectively. Novel products 3-[bis(arylamino)methylene]-6-methyl-2H,4H-
pyran-2,4-diones and N,N0-diaryl-4-hydroxycoumarin-3-carboximidamides have also been obtained in
the same reactions. Novel 4-acetoacetyl-3-phenylamino-4,5-dihydro-5H-pyrazol-5-ones were synthesized
from the reaction of N-aryl-4-hydroxy-6-methyl-2H-pyran-2-one-3-carbothiamides with an excess of hy-
drazine. The structure of all compounds was established by NMR and mass spectra.
J. Heterocyclic Chem., 46, 18 (2009).
INTRODUCTION
RESULTS AND DISCUSSION
2-Pyrones and coumarins are an important class of het-
erocyclic compounds presenting important pharmaceuti-
cal properties. They have been found in a large number of
natural products displaying significant biological activ-
ities, and certain synthetic derivatives are biologically
active compounds (e.g., potent HIV-1 protease and photo-
synthetic electron transport inhibitors; presenting seda-
tive, anticonvulsive, anesthetic, and antifungal properties)
[1–8]. These important potential applications led to the
development of a plethora of synthetic procedures to syn-
thesize pyrone derivatives either by traditional approaches
or by transition metal-catalyzed procedures [9–21].
Taking into consideration the referred important biologi-
cal activities of the 2-pyrones and coumarins and following
our studies on the transformations of 4-hydroxy-6-methyl-
pyran-2-one (triacetic acid lactone, TAL) 1 [22] and 4-
hydroxycoumarin 4 [23–25], we developed a new synthetic
method for N-aryl-4-hydroxy-6-methyl-2H-pyran-2-one-3-
carbothioamides 2 and N-aryl-4-hydroxycoumarin-3-carbo-
thioamides 5. In these transformations, novel products 3-
[bis(arylamino)methylene]-6-methyl-2H,4H-pyran-2,4-dio-
nes 3 and N,N0-diaryl-4-hydroxycoumarin-3-carboximida-
mides 6 have also been obtained. In this communication,
the synthesis of novel 4-acetoacetyl-3-arylamino-4,5-dihy-
dro-5H-pyrazol-5-ones 10 were also established, by the
reaction of N-aryl-4-hydroxy-6-methyl-2H-pyran-2-one-3-
carbothioamides 2 with hydrazine hydrate.
Treatment of 4-hydroxy-6-methylpyran-2-one 1 with
arylisothiocyanates in the presence of sodium hydride in
DMF for 15 h led to the formation of a solid after the
addition of water to the reaction mixture. The aqueous
layer was acidified with hydrochloric acid (pH ¼ 4–5),
and after vigorous stirring at room temperature for 1.5
h, it led to the formation of a new solid. The elemental
analysis and the mass spectra of the first solid indicated
the absence of sulfur in the structure and that two mole-
cules of arylisothiocyanates reacted with 1. In the case
of compound 3a, apart from the molecular ion at m/z
320 (C19H16N2O3), its mass spectrum presents peaks
corresponding to the loss of PhANH2 and PhANH and
intense peaks at m/z 85 and 65 corresponding to the
characteristic fragments from cleavage of the 2-pyrone
ring. These data suggest the formation of 3-(bis-phenyl-
aminomethylene)-6-methyl-2H,4H-pyran-2,4-dione 3a.
1
This structure was also supported by its H NMR spec-
trum, which presents four signals as singlets at d 2.23,
5.73, 12.00, and 14.18 ppm because of the 6-Me, H-5,
and two NH proton resonances, respectively. The 13C
NMR spectrum of 3a presents two signals for the reso-
nance of each carbon of the pyrandione moiety: C-3 (d
85.2 and 104.4 ppm), C-5 (d 105.8 and 108.4 ppm), C-6
(d 140.3 and 163.4 ppm), C-4 (d 178.8 ppm assigned to
CAOH; d 186.2 ppm assigned to C¼¼O), and C-10 [d
168.9 ppm assigned to ¼¼C(NHAr)2; d 182.5 ppm
C
V
2009 HeteroCorporation

January 2009
2H-Pyran-2-one-3-Carbothioamide Derivatives
19
Scheme 1
Scheme 2
major product (75%), while using two molar equivalent
led to the formation of 3-[bis(phenylamino)methylene]-
6-methyl-2H,4H-pyran-2,4-dione 3a as the major prod-
uct (90%). This condensation was attempted in DMSO
as solvent and in the presence of triethylamine giving
rise to the expected products 2a and 3a in 45 and 55%
yield, respectively.
assigned to AC(NHAr)¼¼NAr and the signals of the aro-
matic carbon. The appearance of this type of double
13C NMR spectra is due to the presence of two tauto-
meric forms of compound 3a (Scheme 1). All the spec-
troscopic features of 3b and 3c are similar to those
described for 3a, except for the resonances of the aro-
matic moieties and for the corresponding m/z values;
confirming the generality of the reaction for other sub-
stituted arylisothiocyanates (Scheme 1).
To confirm the formation mechanism of 3a–c, we
have reacted 2a with one equivalent of aniline in DMF
for 2 h at room temperature and 3a was obtained in
good yield (90%).
The elemental analysis and the mass spectrum of the
second solid are consistent with the structure of N-aryl-4-
hydroxy-6-methyl-2H-pyran-2-one-3-carbothiamides 2a–c,
The condensation of 4-hydroxycoumarin 4 with aryli-
sothiocyanates, using DMSO as solvent, gave the corre-
sponding N-aryl-4-hydroxycoumarin-3-carbothioamides
5a,b and also N,N0-diaryl-4-hydroxycoumarin-3-carboxi-
midamides 6a,b (Scheme 3). The 1H NMR spectra of
5a,b show two singlets at d 13.34–13.35 and 17.45–
17.60 ppm because of the resonance of NH and OH
groups, whereas the 13C NMR spectra show a character-
istic carbothiamoyl signal at d 188.4–189.1 ppm.
The IR spectrum of 6a presented strong peaks at 1636–
1617 and 3479–3407 cmꢀ1, which were attributed to the
carbonyl (C¼¼O) and AOH groups on the coumarin ring,
respectively. The mass spectra of compounds 6a,b indi-
cated that the coumarin ring was conserved, with peaks
being observed corresponding to the fragmentation of the
coumarin ring at m/z 134, 143, and 117 [28,29]. From
1
bearing sulfur and nitrogen atoms in the structure. The H
NMR spectra of 2a–c present four singlets at d 2.29–2.30,
6.36–6.38, 12.70–12.92, and 14.90–15.89 ppm because of
the resonance of 6-Me, H-5, NH, and OH, respectively.
The 13C NMR spectra of 2a–c present signals characteris-
tics of the carbothiamoyl group at d 187.5–189.6 ppm.
The mass spectra of 2a–c present peaks corresponding to
the molecular ion followed by the peaks corresponding to
the loss of ArANH2 and ArANH and intense peaks at m/
z 85 and 65 corresponding to the characteristic fragments
from cleavage of the 2-pyrone ring.
Surprisingly, to the best of our knowledge, 3-[bis
(arylamino)methylene]-6-methyl-2H,4H-pyran-2,4-diones
3a–c or related compounds have never been described
in the literature; however, Bruno et al. have studied an
analogous reaction of 5,6-dihydro-4-hydroxy-6-methyl-
2H-pyran-2-one with arylisothiocyanates under the same
experimental conditions and have isolated only 5,6-dihy-
dro derivatives of compounds 2a–c [26]. The formation
of compounds 3a–c would be explained through the for-
mation of unstable intermediates thiocarbamic acid
derivatives from arylisothiocyanates, which yields ani-
line derivatives after a decarboxylation-type reaction
[27] that react with the already formed N-aryl-4-
hydroxy-6-methyl-2H-pyran-2-one-3-carbothioamides 2a–c
affording 3a–c (Scheme 2). The yield of 3a was consid-
erably dependent on the amount of phenylisothiocya-
nate; using one molar equivalent 4-hydroxy-6-methyl-N-
phenyl-2H-pyran-2-one-3-carbothioamide 2a was the
1
their H NMR spectra, it is possible to observe the pres-
ence of signals corresponding to the resonances of two
Scheme 3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

20
M. Makhloufi-Chebli, M. Hamdi, A. M. S. Silva, O. Duval, and J.-J. Helesbeux
Vol 46
Scheme 4
EXPERIMENTAL
Melting points were determined on a Stuart scientific SPM3
1
apparatus fitted with a microscope and are uncorrected. H and
13C NMR spectra were recorded in CDCl3 or DMSO-d6 solu-
tions on Bruker Avance 300 (300.13 MHz for 1H and 75.47
1
MHz for 13C) and Nujeol GSX 270 WB (270.00 MHz for H
and 67.5 MHz for 13C) spectrometers. Chemical shifts are
reported in ppm (d) using TMS as internal reference and cou-
pling constants (J) are given in Hz. 13C assignments were
made using DEPT-135, HSQC, and HMBC (delays for one
bond and long-range J C/H couplings were optimized for 145
and 7 Hz, respectively) experiments. Mass spectra are obtained
with ESI(þ) and GC-MS. Positive-ion ESI mass spectra were
acquired using a Q-TOF 2 instrument [diluting 1 lL of the
sample chloroform solution (ꢁ10ꢀ5 M) in 200 lL of 0.1% tri-
fluoroacetic acid/methanol solution. Nitrogen was used as neb-
ulizer gas and argon as collision gas. The needle voltage was
set at 3000 V, with the ion source at 80ꢂC and desolvation
temperature at 150ꢂC. Cone voltage was 35 V].
General procedure for the synthesis of N-aryl-4-hydroxy-
6-methyl-2H-pyran-2-one-3-carbothioamides (2a–c) and 3-
[bis(arylamino)methylene]-6-methyl-2H,4H-pyran-2,4-diones
(3a–c). A solution of arylisothiocyanates (21 mmol) dissolved in
5 mL of DMF was added to a stirred solution of 2.52 g (20
mmol) of 4-hydroxy-6-methylpyran-2-one 1 and 0.576 g (24
mmol) of NaH 20% in mineral oil in 10 mL of DMF, under a
nitrogen atmosphere. The reaction mixture was stirred at room
temperature for 15 h. After this period, 50 mL of cold water
was added to the reaction mixture, and the precipitate thus
formed was collected by filtration and washed several times with
a (1:1) mixture of diethyl ether:light petroleum. The solid was in
each case recrystallized from isopropyl alcohol giving 3-[bis-
(arylamino)methylene]-6-methyl-2H,4H-pyran-2,4-diones 3a–c:
3a, 1.92 g (30%); 3b, 1.92 g (20%); 3c, 3.08 (35%).
exchangeable protons at d 13.30–13.35 and 17.46–17.54
ppm, then assigned to the NH and OH groups, respec-
tively. The 13C NMR spectra showed that compound 6a,b
exist as a mixture of two tautomers (Scheme 3).
The next step of our work considered the reaction of
compounds 2a–c with hydrazine hydrate. These com-
pounds 2a–c have four (A, B, C, D) susceptible centers of
nucleophilic attack, three of them into the pyrone ring,
and a single molecule of hydrazine would therefore be
liable to give a wide range of products (Scheme 4). Com-
pounds 2a–c reacted with hydrazine hydrate under reflux
in a (1:1) mixture of ethanol/acetic acid and yielded only
a single isolated solid as the reaction product. Elemental
analysis and mass spectra showed that only one molecule
of hydrazine had reacted, and the mass spectra also indi-
cated the presence of fragments corresponding to an ace-
toacetyl group, with peaks at m/z 85, 56, and 43. This
The aqueous layer was acidified with HCl 1N (pH ¼ 4–5).
After vigorous stirring at room temperature for 1.5 h, the pre-
cipitate thus formed was collected by filtration and washed
several times with diethyl ether. The solid was in each case
recrystallized from methanol giving N-aryl-4-hydroxy-6-
methyl-2H-pyran-2-one-3-carbothioamides 2a–c: 2a, 3.13 g
(60%); 2b, 5.10 g (75%); 2c, 2.57 g (40%).
1
structure was also supported by the H NMR spectra of
10a–c, which present five singlets characteristics of a tau-
tomeric equilibrium of acetoacetyl groups at d 2.06–2.07,
2.32–2.33, 4.30–4.40, 6.11–6.13, and 16.30–16.70 ppm.
These signals are assigned to the proton resonances of
CH3 (keto-enol form), CH3 (b-diketone), CH2 (b-dike-
tone), CH, and OH (keto-enol form), respectively. We
also observed two other singlets at d 7.90–8.62 and
13.00–13.15 ppm, which were assigned to the NH-pyrazo-
lone and NHAAr groups, respectively. This condensation
reaction allowed us to synthesize novel aminopyrazole
derivatives in good yields (95–98%).
An explanation for the formation of pyrazole deriva-
tives 10a–c considered the hydrazine attack to the thioa-
mide group (center A) of compounds 2a–c leading to
the carboximidamides 7a–c. An intramolecular nucleo-
philic attack of the amine group from the amide moiety
to the lactone carbonyl carbon (center D) gave rise to
intermediates 8a–c, which can follow two possible path-
ways (a and b). However, the isolation of pyrazole-type
compounds 10a–c led us to conclude that 8a–c under-
went the opening of the pyran ring by pathway b.
4-Hydroxy-6-methyl-N-phenyl-2H-pyran-2-one-3-carbothio-
amide (2a). This compound was obtained as yellow powder,
1
mp 189–190ꢂC; H NMR (CDCl3): d 2.30 (s, 3H, CH3), 6.37
(s, 1H, H-5), 7.31 (t, 1H, J ¼ 7.5 Hz, ArH), 7.43 (t, 2H, J ¼
7.50 Hz, ArH), 7.53 (d, 2H, J ¼ 7.5 Hz, ArH), 12.92 (s, 1H,
NH), 15.89 (s, 1H, OH); 13C NMR (CDCl3): d 19.1, 97.6,
102.6, 124.8, 127.0, 128.6, 137.1, 162.8, 165.3, 175.7, 187.5;
ms (EI): m/z 263 (6, 34S), 262 [28, (MþH)þ], 261 (Mþꢃ, 100,
32S), 260 (77), 228 (87), 93 (42), 77 (40), 85 (32), 69 (12).
Anal. Calcd. for C13H11NO3S (261.30): C, 59.76; H, 4.24; N,
5.36. Found: C, 60.07; H, 4.60; N, 5.59.
N-(4-Bromophenyl)-4-hydroxy-6-methyl-2H-pyran-2-one-3-
carbothioamide (2b). This compound was obtained as yellow
1
powder, mp 190–191ꢂC; H NMR (DMSO-d6): d 2.29 (s, 3H,
CH3), 6.38 (s, 1H, H-5), 7.58 (d, 2H, J ¼ 8.0 Hz, ArH), 7.63
(d, 2H, J ¼ 8.0 Hz, ArH), 12.70 (s, 1H, NH), 15.30 (s, 1H,
OH); 13C NMR (DMSO-d6): d 20.0, 99.7, 102.9, 120.0, 128.0,
132.7, 137.4, 163.2, 166.0, 174.8, 188.7; ms (ESIþ): m/z 364
[7, (MþNa)þ, 81Br, 32S), 362 [9, (MþNa)þ, 79Br, 32S], 342
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2009
2H-Pyran-2-one-3-Carbothioamide Derivatives
21
[80, (MþH)þ, 81Br, 32S], 340 [100, (MþH)þ, 79Br, 32S]. Anal.
Calcd. for C13H10BrNO3S (340.19): C, 45.90; H, 2.96; N,
4.11. Found: C, 45.95; H, 3.01; N, 4.16.
triethylamine dissolved in 10 mL of DMSO. The reaction mix-
ture was stirred at room temperature for 15 h. After the addi-
tion of 50 mL of cold water, the precipitate thus formed was
filtered and washed several times with a (1:1) mixture of
diethyl ether:light petroleum. The solid was in each case
recrystallized from isopropyl alcohol giving N,N0-diaryl-4-
hydroxycoumarin-3-carboximidamides 6a,b: 6a, 979.0 mg
(55%); 6b, 1.15 g (45%).
The aqueous layer was acidified with HCl 1N (pH ¼ 4–5).
After vigorous stirring at room temperature for 1.5 h, the pre-
cipitate thus formed was collected by filtration and washed
several times with diethyl ether. The solid was in each case
recrystallized from isopropyl alcohol giving N-aryl-4-hydroxy-
coumarin-3-carbothioamides 5a,b: 5a, 445.5 mg (30%); 5b,
659.8 mg (35%).
N-(2,5-Dimethoxyphenyl)-4-hydroxy-6-methyl-2H-pyran-2-
one-3-carbothioamide (2c). This compound was obtained as
1
yellow powder, mp 169–170ꢂC; H NMR (DMSO-d6): d 2.28
(s, 3H CH3), 3.80 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 6.36 (s,
1H, H-5), 7.60 (d, 1H, J ¼ 7.3 Hz, ArH), 7.70 (d, 1H, J ¼ 7.3
Hz, ArH), 8.10 (s, 1H, ArH), 12.70 (s, 1H, NH), 14.90 (s, 1H,
OH); 13C NMR (DMSO-d6): d 20.3, 58.0, 60.0, 100.9, 102.7,
125.8, 127.0, 129.6, 131.2, 131.5, 131.8, 162.9, 165.9, 174.0,
189.6; ms (EI): m/z 321 (Mþꢀ, 45), 233 (100), 221 (5), 189
(8), 125 (8), 116 (10), 85 (20), 69 (55). Anal. Calcd. for
C15H15NO5S (321.40): C, 56.06; H, 4.70; N, 4.36. Found: C,
55.95; H, 4.57; N, 4.36.
3-[Bis(phenylamino)methylene]-6-methyl-2H,4H-pyran-2,4-
dione (3a). This compound was obtained as yellow powder,
4-Hydroxy-N-phenylcoumarin-3-carbothioamide (5a). This
1
compound was obtained as yellow powder, mp 145–146ꢂC; H
1
mp 147–148ꢂC; H NMR (CDCl3): d 2.23 (s, 3H, CH3), 5.73
NMR (CDCl3): d 6.88–7.54 (m, 5H, ArH), 7.68–8.17 (m, 4H,
ArH), 13.35 (s, 1H, NH), 17.60 (s, 1H, OH); 13C NMR
(CDCl3): d 98.2, 117.0, 124.1, 125.4, 126.2, 128.1, 128.9,
129.5, 135.7, 137.7, 152.5, 163.6, 175.1 (CAOH), 189.1
(C¼¼S), ms (ESIþ): m/z 320 [100, (MþNa)þ], 298 [45,
(MþH)þ]. Anal. Calcd. for C16H11NO3S (297.33): C, 64.63;
H, 3.73; N, 4.71. Found: C, 64.68; H, 3.71; N, 4.71.
(s, 1H, H-5), 6.70–6.86 (m, 5H, ArH), 7.14–7.28 (m, 5H,
ArH), 12.00 (s, 1H, NH) 14.18 (s, 1H, OH); 13C NMR
(CDCl3): d 19.1, 19.5, 85.2, 104.4, 105.8, 108.4, 117.4, 119.8,
123.4, 126.8, 128.2, 129.3, 140.3, 142.1, 144.8, 161.0, 163.4,
168.9, 178.8, 182.5, 186.2; IR: m (cmꢀ1) 3478, 3209, 3031,
1636, 1550, 1448, 1342, 927, 759, 696; ms (EI): m/z 320
(Mþꢀ, 18), 227 (14), 194 (38), 93 (100), 85 (4), 69 (17). Anal.
Calcd. for C19H16N2O3 (320.34): C, 71.24; H, 5.03; N, 8.74.
Found: C, 71.79; H, 5.13; N, 8.72.
N-(4-Bromophenyl)-4-hydroxycoumarin-3-carbothioamide
(5b). This compound was obtained as yellow powder, mp
270–271ꢂC; 1H NMR (CDCl3): d 6.75 (d, 2H, J ¼ 9.8 Hz,
ArH), 7.17 (d, 2H, J ¼ 9.8 Hz, ArH), 7.31 (t, 1H, J ¼ 9.0 Hz,
ArH), 7.37 (d, 1H, J ¼ 9.0 Hz, ArH), 7.69 (t, 1H, J ¼ 9.0 Hz,
ArH), 8.12 (d, 1H, J ¼ 9.0 Hz, ArH), 13.34 (s, 1H, NH),
17.45 (s, 1H, OH); 13C NMR (CDCl3): d 97.3, 116.0, 123.7,
125.3, 126.8, 131.2, 131.7, 134.7, 135.7, 136.0, 151.5, 162.7,
179.4 (CAOH), 188.4 (C¼¼S); ms (ESIþ): m/z 400 [26,
(MþNa)þ, 81Br], 398 [29, (MþNa)þ, 79Br], 378 [96, (MþH)þ,
81Br], 376 [100, (MþH)þ, 79Br]. Anal. Calcd. for C16H10
BrNO3S (376.23): C, 51.08; H, 2.68; N, 3.72. Found: C,
51.39; H, 3.04; N, 3.95.
3-[Bis(4-bromophenylamino)methylene]-6-methyl-2H,4H-
pyran-2,4-dione (3b). This compound was obtained as yellow
1
powder, mp 159–160ꢂC; H NMR (DMSO-d6): d 2.27 (s, 3H,
CH3), 5.93 (s, 1H, H-5), 7.43 (d, J ¼ 8.0 Hz, 2H, ArH), 7.49
(d, J ¼ 8.1 Hz, 2H, ArH), 7.55 (d, J ¼ 8.1 Hz, 2H, ArH),
7.62 (d, J ¼ 8.0 Hz, 2H, ArH), 13.20 (s, 1H, NH), 14.3 (s, 1H,
OH); 13C NMR (DMSO-d6): d 19.6, 20.0, 88.9, 103.3, 108.0,
117.1, 119.9, 126.1, 131.8, 132.3, 135.6, 137.6, 158.7, 162.3,
165.7, 166.3, 174.9, 182.9, 188.8; ms (ESIþ): m/z 503 [5,
(MþNa)þ, 2 ꢄ 81Br], 501 [9, (MþNa)þ, 81Br, 79Br), 499 [4,
(MþNa)þ, 2 ꢄ 79Br], 481 [50, (MþH)þ, 2 ꢄ 81Br], 479 [100,
(MþH)þ, 81Br, 79Br], 477 [52, (MþH)þ, 2 ꢄ 79Br]. Anal.
Calcd. for C19H14Br2N2O3 (478.13): C, 47.73; H, 2.95; N,
5.86. Found: C, 47.78; H, 2.96; N, 5.88.
3-[Bis(2,5-dimethoxyphenylamino)methylene]-6-methyl-2H,
4H-pyran-2,4-dione (3c). This compound was obtained as
white powder, mp 186–187ꢂC; 1H NMR (DMSO-d6): d 2.24
(s, 3H, CH3), 3.80 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 6.25
(s, 1H, H-5), 7.40 (d, J ¼ 7.2 Hz, 1H, ArH), 7.58 (d, J ¼ 7.2
Hz, 1H, ArH), 7.60 (s, 1H, ArH), 7.67 (d, J ¼ 8.2 Hz, 1H,
ArH), 7.70 (d, J ¼ 8.2 Hz, 1H, ArH), 8.12 (s, 1H, ArH),
13.20 (s, 1H, NH), 14.20 (s, 1H, OH); 13C NMR (DMSO-
d6): d 19.6, 19.9, 56.6, 88.9, 100.8, 103.3, 124.3, 125.5,
125.6, 126.5, 126.9, 130.8, 131.1, 131.3, 138.8, 139.8, 140.0,
147.0, 149.0, 162.9, 164.0, 165.0, 174.9, 180.0, 189.9; ms
(EI): m/z 440 (20), 368 (14), 358 (29), 253 (9), 233 (69),
207 (100), 85 (12), 69 (20). Anal. Calcd. for C23H24N2O7
(440.45): C, 60.52; H, H 5.30; N, 6.14. Found: C, 61.07; H,
5.61; N, 6.39.
4-Hydroxy-N,N0-diphenylcoumarin-3-carboximidamide
(6a). This compound was obtained as white powder, mp 179–
1
180ꢂC; H NMR (CDCl3): d 6.82–7.68 (m, 10 H, ArH), 8.05–
8.10 (m, 4H, ArH), 13.30 (s, 1H, NH), 17.54 (s, 1H, OH); 13C
NMR (CDCl3): d 89.3, 97.7, 116.2, 116.5, 120.7, 123.6, 124.0,
124.9, 125.7, 125.8, 127.6, 128.4, 129.0, 135.2, 136.0, 137.2,
152.0, 152.6, 158.7, 163.0, 165.9, 174.6, 179.6, 188.6; IR: m
(cmꢀ1) 3479, 3407, 3235, 1617, 1381, 1048, 754; ms (ESIþ):
m/z 379 [80, (MþNa)þ], 357 [100, (MþH)þ]. Anal. Calcd. for
C22H16N2O3 (356.34): C, 74.15; H, 4.53; N, 7.86. Found: C,
73.60; H, 4.52; N, 7.88.
N,N0-Di(4-bromophenyl)-4-hydroxycoumarin-3-carboxim-
idamide (6b). This compound was obtained as white powder,
1
mp 235–236ꢂC; H NMR (CDCl3): d 6.74 (d, 2H, J ¼ 9.6 Hz,
ArH), 7.17 (d, 2H, J ¼ 8.7 Hz, ArH), 7.28 (d, 1H, J ¼ 9.3
Hz, ArH), 7.31 (d, 2H, J ¼ 8.7 Hz, ArH), 7.37 (t, 1H, J ¼ 9.3
Hz, ArH), 7.55 (d, 2H, J ¼ 9.6 Hz, ArH), 7.69 (t, 1H, J ¼ 9.3
Hz, ArH), 8.12 (d, 1H, J ¼ 9.3 Hz, ArH), 13.35 (s, 1H, NH),
17.46 (s, 1H, OH); 13C NMR (CDCl3): d 89.4, 97.4, 116.1,
122.2, 123.8, 124.5, 124.7, 126.9, 131.3, 135.7, 149.2, 151.6,
158.7, 162.7, 166.0, 174.3, 180.2, 189.5; ms (EI): m/z 512
(40), 449 (9), 447 (10), 359 (18), 357 (20), 216 (15), 215
(100), 214 (15), 213 (99), 183 (3.9), 181 (4), 158 (2.5), 156
(3), 155 (25), 143 (2), 134 (50), 117 (2), 107 (9), 76 (8). Anal.
General procedure for the synthesis of N-aryl-4-hydroxy-
coumarin-3-carbothioamides (5a,b) and N,N0-diaryl-4-
hydroxycoumarin-3-carboximidamides (6a,b). Aryliso-thio-
cyanates (15 mmol) was added to a stirred solution of 0.81 g
(5 mmol) of 4-hydroxycoumarin 4 and 0.8 mL (5 mmol) of
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

22
M. Makhloufi-Chebli, M. Hamdi, A. M. S. Silva, O. Duval, and J.-J. Helesbeux
Vol 46
P. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R.; Rees,
C. W., Eds.; Pergamon Press: Oxford, 1984; Chapter 2.23, pp 647–
736; [c] Hepworth, J. D. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R.; Rees, C. W., Eds.; Pergamon Press: Oxford, 1984;
Chapter 2.24, pp 737–884.
Calcd. for C22H14Br2N2O3 (514.17): C, 51.39; H, 2.74; N,
5.45. Found: C, 51.64; H, 2.80; N, 5.51.
General procedure for the synthesis of 4-acetoacetyl-3-
arylamino-4,5-dihydro-5H-pyrazol-5-ones (10a–c). Acetic
acid (10 mL) and 5 mL ethanol were added to a mixture of
N-aryl-4-hydroxy-6-methyl-2H-pyran-2-one-3-carbothioamides
2a–c (10 mmol) and 5 mL (0.1 mol) of hydrazine hydrate.
The reaction mixture was refluxed for 5 h and poured into
crushed ice, and then the solid was collected by filtration,
washed with water, and with a (1:1) mixture of water:ethanol.
The solid was in each case recrystallized from A (1:1) mixture
of ethanol:acetone giving 4-acetoacetyl-3-arylamino-4,5-dihy-
dro-5H-pyrazol-5-ones 10a–c (which are in equilibrium with
the corresponding enolic form): 10a, 2.47 g (95%); 10b, 3.21
g (95%); 10c, 3.13 g (98%).
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4-Acetoacetyl-3-phenylamino-4,5-dihydro-5H-pyrazol-5-one
(10a). This compound was obtained as green powder, mp
179–180ꢂC; 1H NMR (CDCl3): d 2.06 (s, CH3-enol), 2.32 (s,
CH3-dione), 3.90 (s, 1H, H-4), 4.40 (s, CH2-dione), 6.11 (s,
CH-enol), 7.31–7.53 (m, 5H, ArH), 8.60 (s, 1H, NH), 13.15 (s,
1H, NH), 16.70 (s, 1H, OH); 13C NMR (CDCl3): d 20.7, 64.0,
97.2, 104.0, 126.0, 127.6, 129.6, 137.3, 164.2, 164.5, 177.9,
188.3; ms (EI): m/z 260 [100, (MþH)þ], 228 (80), 217 (9),
203 (7), 175 (20), 93 (67), 77 (47), 85 (50), 56 (14), 43 (20).
Anal. Calcd. for C13H13N3O3 (259.26): C, 60.23; H, 5.02; N,
16.22. Found: C, 60.73; H, 5.38; N, 16.45.
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A.; Motta, A. J. Agric. Food Chem., 2003, 51, 6957–6960.
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2004, 45, 6299–6301.
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8996–9002.
4-Acetoacetyl-3-(4-bromophenylamino)-4,5-dihydro-5H-pyr-
azol-5-one (10b). This compound was obtained as green pow-
der, mp 200–202ꢂC; 1H NMR (CDCl3): d 2.07 (s, CH3-enol),
2.32 (s, CH3-dione), 3.91 (s, 1H, H-4), 4.40 (s, CH2-dione),
6.11 (s, CH-enol), 7.40 (d, 2H, J ¼ 9.1 Hz, ArH), 7.56 (d, 2H,
J ¼ 9.1 Hz, ArH), 8.62 (s, 1H, NH), 13.15 (s, 1H, NH), 16.50
(s, 1H, OH); 13C NMR (CDCl3): d 20.1, 65.0, 97.3, 104.0,
121.0, 127.3, 132.2, 136.3, 164.1, 164.7, 178.0, 188.6; ms
(ESIþ): m/z 362 [96, (MþNa)þ, 81Br], 360 [100, (MþNa)þ,
79Br], 340 [45, (MþH)þ, 81Br], 338 [50, (MþH)þ, 79Br].
Anal. Calcd. for C13H12BrN3O3 (338.16): C, 46.29; H, 3.56;
N, 12.46. Found: C, 45.74; H, 3.20; N, 12.23.
4-Acetoacetyl-3-(2,5-dimethoxyphenylamino)-4,5-dihydro-5H-
pyrazol-5-one (10c). This compound was obtained as green
powder, mp 186–187ꢂC; 1H NMR (CDCl3): d 2.07 (s, CH3-
enol), 2.33 (s, CH3-dione), 3.86 (s, 1H, H-4), 3.93 (s, 3H,
OCH3), 3.95 (s, 3H, OCH3), 4.30 (s, CH2-dione), 6.13 (s, CH-
enol), 7.37 (d, 1H, J ¼ 8.9 Hz, ArH), 7.49 (d, 1H, J ¼ 8.9 Hz,
ArH), 7.70 (s, 1H, ArH), 7.90 (s, 1H, NH), 13.00 (s, 1H, NH),
16.40 (s, 1H, OH); 13C NMR (CDCl3): d 20.1, 54.0, 58.0,
65.0, 104.0, 122.7, 125.2, 127.5, 131.3, 132.9, 136.6, 164.1,
164.9, 178.0, 188.0; ms (ESIþ): m/z 342 [100, (MþNa)þ], 320
[33, (MþH)þ]. Anal. Calcd. for C15H17N3O5 (319.31): C,
56.43; H, 5.33; N, 13.16. Found: C, 56.98; H, 5.34; N, 13.70.
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Acknowledgment. The authors thank the University of Aveiro,
FCT, and FEDER for funding the Organic Chemistry Research
Unit.
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[1] For comprehensive reviews on 2-pyrones, see: [a] Brogden,
P. J.; Gabbutt, C. D.; Hepworth, J. D. In Comprehensive Heterocyclic
Chemistry; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon Press:
Oxford, 1984; Vol. 3, Part 2B, Chapter 2.22, pp 573–646; [b] Ellis, G.
[29] Porter, R. N.; Baldas, J. Mass Spectrometry of Heterocyclic
Compounds; Wiley-Interscience: New York, 1985; p 214.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet