Synthesis and reactivity of 6-methyl-4H-furo[3,2c]pyran-3,4-dione

Article abstract of DOI:10.1002/jhet.490

An efficient synthesis of 3-bromoacetyl-4-hydroxy-6-methyl-2H-pyran-2-one by bromination of dehydroacetic acid in glacial acetic acid is described. Novel 4-hydroxy-6-methyl-3-(2-substituted-thiazol-4-yl)-2H-pyran-2-ones have been prepared from the reactio

Full text of DOI:10.1002/jhet.490

January 2011
Synthesis and Reactivity of 6-Methyl-4H-furo[3,2c]pyran-3,4-
dione
31
a
Djamila Hikem-Oukacha, Yahıa Rachedi, Maamar Hamdi, *
a
a
¨
and Artur M. S. Silvab*
a
´
´
Laboratoire de Chimie Organique Appliquee Faculte de Chimie, USTHB, BP 32 El-Alia,
´
Bab-Ezzouar 16111 Alger, Algerie
bDepartment of Chemistry & QOPNA, University of Aveiro, 3810-193, Aveiro, Portugal
*E-mail: prhamdi@gmail.com or artur.silva@ua.pt
Received January 14, 2010
DOI 10.1002/jhet.490
Published online 31 August 2010 in Wiley Online Library (wileyonlinelibrary.com).
An efficient synthesis of 3-bromoacetyl-4-hydroxy-6-methyl-2H-pyran-2-one by bromination of
dehydroacetic acid in glacial acetic acid is described. Novel 4-hydroxy-6-methyl-3-(2-substituted-thia-
zol-4-yl)-2H-pyran-2-ones have been prepared from the reaction of 3-bromoacetyl-4-hydroxy-6-methyl-
2H-pyran-2-one with thioamides, thiourea, and diphenylthiocarbazone. The condensation reaction of
6-methyl-4H-furo[3,2c]pyran-3,4-dione, obtained from the reaction of 3-bromoacetyl-4-hydroxy-6-
methyl-2H-pyran-2-one with aliphatic amines, with benzaldehydes and acetophenones led to novel 2-ary-
lidene-6-methyl-2H-furo[3,2-c]pyran-3,4-diones and 6-(2-arylprop-1-enyl)-2H-furo[3,2-c]pyran-3,4-dio-
nes. The structure of all compounds was established by elemental analysis, IR, NMR, and mass spectra.
J. Heterocyclic Chem., 48, 31 (2011).
INTRODUCTION
natural occurring 2-pyrones have been extensively stud-
ied as building blocks for a wide range of important bio-
logically active heterocyclic compounds, such as phero-
mones, pyridones, styrylpyrones, pyrazoles, benzodiaze-
pines, and coumarins [13–23]. Therefore, these studies,
an efficient synthetic methodology allowing a simple
introduction of a plethora of substituents into the struc-
tures of these 2-pyrones still constitutes a challenge for
the scientific community. Following our interest in the
use of DHA as a building block for the synthesis of
other heterocyclic compounds, we focused our attention
on the selective a-monobromination of DHA, trying to
prepare 3-bromoacetyl-4-hydroxy-6-methyl-2H-pyran-2-
one 4. Indeed, a-haloketones are versatile building
blocks for the preparation of several classes of com-
pounds due to their high reactivity and selective trans-
formation [24]. It is already known that the reaction of
DHA with a stoichiometric amount of bromine in
2-Pyrone, a six-membered cyclic unsaturated ester,
and its derivatives constitutes a large family of biologi-
cally active natural products, abundantly found in ani-
mals, insects, plants, bacteria, and microbial systems [1–
7]. Small changes in the substitution pattern on the 2-
pyrone ring often lead to diverse biological properties.
For instance, 4-hydroxy-2-pyrones are considered as one
important classes of anti-HIV agents and exhibit a wide
range of antifungal, phytotoxic, antimicrobial, cytotoxic,
and neurotoxic activities [8–10]. Other 2-pyrone deriva-
tives have shown a huge potential in the treatment of
Alzheimer’s and other dementia diseases [11,12].
The 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2-one
1
[dehydroacetic acid (DHA)] is converted into 4-
hydroxy-6-methyl-2H-pyran-2-one 2 (triacetic lactone)
by the action sulfuric acid (Scheme 1) [8]. These two
C
V
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32
D. Hikem-Oukacha, Y. Rachedi, M. Hamdi, and A. M. S. Silva
Vol 48
Scheme 1
ment of all protonated carbon resonances while the con-
nectivities found in the HMBC spectrum (e.g., OH !
C-3, C-4, and C-5; 6-CH3 ! C-5 and C-6) supports the
structure of 4.
Besides the work of Rao and coworkers [28] on the
transformation of 4 into the corresponding mercapto de-
rivative, and of Briel et al. [29] on their transformation
into furanones and other DHA derivatives, the possible
reactive sites of compound 4 [26] (Scheme 2) led us to
start a program to study their reactivity toward aliphatic
amines, thioamides, thiourea, and diphenylthiocarba-
zone, which will allow the synthesis of a wide range of
new heterocyclic compounds. The initial experiments
considered the reaction with aliphatic primary amines
(methylamine, ethylamine, butylamine, and hexylamine).
Heating 4 with an equimolar amount of a primary amine
in ethanol for 1 h led to the formation of a single prod-
uct. The mass spectra of the obtained compound 8
revealed the presence of the peaks at m/z 167 [(M þ
H)þ] and 189 [(M þ Na)þ], suggesting the elimination
of one HBr molecule relatively to the starting material
4. On the other hand, the OH resonance was not
chloroform yielded the corresponding 5-bromo-DHA 3,
while when the reaction media was saturated with
hydrogen bromide prior to the addition of bromine 3-
bromoacetyl-4-hydroxy-6-methyl-2H-pyran-2-one
4
(50% yield) was obtained (Scheme 1). The reaction
of DHA with two molar equivalent of bromine gave
the 5-bromo-3-bromoacetyl-4-hydroxy-6-methyl-2H-py-
ran-2-one 5, while the reaction with N-bromosuccinimide
yielded a mixture of compounds (e.g., 3-bromo-DHA 4
and 6) [25]. Recently, Prakash and coworkers found 5-
bromo-3-(dibromoacetyl)-4-hydroxy-6-methyl-2H-pyran-
2-one 7 as the result of the bromination of DHA with
an excess of bromine in chloroform and in the presence
of a catalytic amount of iodine (Scheme 1) [26,27].
In the present manuscript, we describe a selective
monobromination of DHA and the reactivity of the
obtained 3-bromoacetyl-4-hydroxy-6-methyl-2H-pyran-
2-one 4 with aliphatic amines, thioamides, thiourea, and
diphenylthiocarbazone. We will also report the study on
the condensation reaction of 6-methyl-4H-furo[3,2-
1
observed in the H NMR spectrum and the two signals
at dH 2.39 and 4.75 ppm in a 3:2 proportion, assigned to
the proton resonances of the methyl and methylene
groups, supports the structure of 6-methyl-2H-furo[3,2-
c]pyran-3,4-dione (8, Scheme 2). The formation of 8
can be envisaged by an intramolecular cyclocondensa-
tion assisted by aliphatic amines. The formation of this
type of compound has been already reported by heating
DHA in the presence of several aliphatic and aromatic
amines [30].
c]pyran-3,4-dione
acetophenones.
8
with
benzaldehydes
and
In the second part of our study, we investigated the
reactivity of 3-bromoacetyl-4-hydroxy-6-methyl-2H-py-
ran-2-one 4 toward various substituted thioamides, thio-
urea, and diphenylthiocarbazone (Scheme 3). This trans-
formation gives rise to thiazoles, a class of heterocyclic
compounds possessing important biological activities
[2,3,6,7,9,10,16–22]. Three different procedures (A–C)
have been applied in the Hantzsch reaction. The first
one (A) consider the conventional Hantzsch reaction
[1,4,5,31–45], by refluxing an ethanol solution of 4 with
thioamides, thiourea, and diphenylthiocarbazone for 4–6
h, being the reaction products obtained in good yields
RESULTS AND DISCUSSION
3-Bromoacetyl-4-hydroxy-6-methyl-2H-pyran-2-one 4
was firstly synthesized by Harris et al. [25], but our
studies on this hard procedure proved that it did not
give reproducible results. Therefore, the knowledge that
acidic medium favour a-bromination at the acetyl group
led us to consider the treatment of a DHA solution in
glacial acetic acid with a stepwise addition of bromine
in glacial acetic acid. This new synthetic method
afforded pyranone 4 in a simple and reproducible way
(Scheme 2). The structure of compound 4 was con-
Scheme 2
1
firmed by elemental analysis, mass spectra, and H and
13C NMR data. Compound 4 was clearly distinguishable
from other monobromo derivatives on the basis of its
NMR spectra, namely by the resonances of the acetyl
methylene group [dH 4.71 (s, 2H, CH2Br), dC 35.2
(CH2Br)] suggesting an a-bromination on the methyl
group of DHA. The HSQC spectrum allowed the assign-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2011
Synthesis and Reactivity of 6-Methyl-4H-furo[3,2c]pyran-3,4-dione
33
Scheme 3
Scheme 4
ber of nitrogen atoms; being the peaks at m/z 314 and
336 corresponding to the ions (M þ H)þ and (M þ
Na)þ of a molecule with the formula C15H11N3O3S. We
have tried to isolate some reaction intermediates, but
none of our attempts to isolate a six-membered hetero-
cyclic compounds 13 with three heteroatoms was suc-
cessful (Scheme 4) [46,47]. The formation of a similar
six-membered heterocyclic rings can be envisaged in the
reaction leading to thiazoles 11b and 11c but none of
them was observed and the expected compounds were
obtained in good yields.
and without need of purification. Microwave irradiation
was used as an alternative source of heating in the other
methods, using ethanol as solvent (B) or in the solvent-
free reaction conditions (C). In the latter case, the solid
support of neutral aluminium oxide was impregnated
with the appropriate thioamides, thiourea, and diphe-
nylthiocarbazone and of 4. The three methods yielded
the same solid compounds 11a–e (Scheme 3). The main
advantage of microwave irradiation was the shortening
of the reaction time, from 5 h in the case of procedure
A for 5–10 min in procedures B and C, since compara-
ble yields were obtained in all of them (Table 1).
6-Methyl-2H-furo[3,2-c]pyran-3,4-dione
8 has two
susceptible sites to react with aldehydes and ketones.
Following our previous work on this type of reactions
[16], we decided to study the reactivity of 8 with ben-
zaldehydes and acetophenones in acid conditions (in a
1:1 mixture of HCl:acetic acid) (Scheme 5). The mass
spectra of the reaction products of 6-methyl-2H-
furo[3,2-c]pyran-3,4-dione 8 with benzaldehydes prove
there was the condensation with only one molecule of
aldehyde, while the NMR data reveal the absence of the
methylene group of the dihydrofuran ring and the pres-
ence of the methyl group (dH ꢀ 2.4 ppm; dC 21 ppm)
of the pyranone ring. All these data supports the struc-
ture of 2-arylidene-6-methyl-2H-furo[3,2-c]pyran-3,4-
diones 14a–f. Therefore, the NMR data of compounds
obtained in the reaction of 5 with acetophenones, result-
ing from the condensation reaction of only one ketone
molecule, present the methylene group (dH ꢀ 5 ppm; dC
77 ppm) of the dihydrofuran ring and does not have the
methyl group of the pyranone ring. The new vinylic
Structure of 11e was unequivocally determined and
suggests the loss of an aniline molecule during its for-
1
mation. In fact the H and 13C NMR spectra support the
presence of only one phenyl ring from the starting
diphenylthiocarbazone. From the HSQC spectrum, one
can conclude that H-50 (dH 8.48 ppm) is bonded to the
carbon appearing at dC 117.9 ppm, typical of a 2,4-dis-
ubstituted thiazole ring. Elemental analysis and mass
spectrometry also confirms the presence of an odd num-
Table 1
Reaction conditions and yields obtained in the reactions of 4 with
thioamides, thiourea, and diphenylthiocarbazone.
Obtained
compounds
Power
(W)
Reaction
time (min)
Yield
(%)
Procedure
Scheme 5
11a
11b
11c
11d
11e
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
–
300
5
8
70
82
72
79
93
84
80
92
89
75
88
82
77
89
85
200
300
–
200
300
–
200
300
–
240
7
10
300
10
8
300
10
10
360
5
200
300
–
200
300
10
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

34
D. Hikem-Oukacha, Y. Rachedi, M. Hamdi, and A. M. S. Silva
Vol 48
145 and 7 Hz, respectively) experiments. Positive-ion ESI
mass spectra were acquired using a Q-TOF 2 instrument [dilut-
ing 1 lL of the sample chloroform solution (ꢀ10ꢁ5M) in 200
lL of 0.1% trifluoroacetic acid/methanol solution. Nitrogen
was used as nebulizer gas and argon as collision gas. The nee-
dle voltage was set at 3000 V, with the ion source at 80ꢂC and
desolvation temperature at 150ꢂC. Cone voltage was 35 V].
Infrared spectra (KBr) were determined as KBr pellets of the
solids on a Magna-IR 550 series II Nicolet apparatus. UV
spectra were recorded on Cary 50 Scan UV–vis spectrometer
in acetonitrile solutions.
bond was identified by their proton (dH ꢀ 7.5 ppm;) and
carbon [dC ꢀ 128 (¼¼CH) and 136–137 (¼¼C) ppm]
resonances. All these data and the connectivities found
in the HMBC (¼¼CH ! ¼¼C, CH3, C-10, C-6, and C-7;
CH3 ! vinylic carbons and C-10) are only compatible
with the structure of 6-(2-arylprop-1-enyl)-2H-furo[3,2-
c]pyran-3,4-dione 15a,b.
The reaction of 6-methyl-2H-furo[3,2-c]pyran-3,4-
dione 8 with benzaldehydes gives rise to 14a–f resulting
from the condensation with the active methylene group
of the furanone ring, while the reaction with acetophe-
nones yielded 15a,b as a result of the condensation with
the active methyl group of the pyran ring (Scheme 5).
This site selectivity is probably due to the steric hin-
drance from the acetophenone. These reactions were
also carried out under microwave irradiation being
obtained the same products in a slight high yield and a
shorter reaction time (2–3 min). All the attempts to
obtain a double condensation (at methylene and methyl
groups) by using a bigger excess of the carbonyl com-
pounds and longer reaction time in classic heating con-
ditions and under microwave irradiation were
unsuccessful.
3-Bromoacetyl-4-hydroxy-6-methyl-2H-pyran-2-one (4). A
solution of bromine (0.27 mL, 5 mmol) in glacial acetic acid
(10 mL) was added stepwise to a solution DHA 1 (0.84 g, 5
mmol) in glacial acetic acid (20 mL). After a reflux of 2 h, the
reaction mixture was poured into H2O (100 mL) and ice (50
g). The obtained solid was filtered off and recrystallized from
a 1:1 mixture of hexane–chloroform, being 3-bromoacetyl-4-
hydroxy-6-methyl-2H-pyran-2-one 3 obtained as yellow crys-
tals (0.75 g, 61%): mp 118–119ꢂC (lit. 111–114ꢂC [25]); IR
(m, cmꢁ1): 3160–3530, 1690–1735, 1717, 1641, 1350, 1260,
1240, 1180, 1150, 1070, 1020, 990; UV (kmax, nm): 236 (e,
3.289), 328 (e, 3.223); NMR (CDCl3): d 2.31 (d, 3H, J ¼ 0.6
Hz, 6-CH3), 4.71 (s, 2H, CH2Br), 6.03 (s, 1H, H-5), 15.51 (s,
1H, OH); 13C NMR: d 20.8 (6-CH3), 35.2 (CH2Br), 99.4 (C-
3), 101.3 (C-5), 160.6 (C-6), 170.1 (C-2), 180.9 (C-4), 197.2
(C¼¼O, ketone); ESI(þ)-MS: m/z 271 [(M þ Na)þ, 81Br, 18],
269 [(M þ Na)þ, 79Br, 20], 249 [(M þ H)þ, 81Br, 90], 247
[(M þ H)þ, 79Br, 95], 167 [(M ꢁ Br)þ, 100]. Anal. Calcd. for
C8H7BrO4: C, 38.89; H, 2.86. Found: C, 39.10; H, 2.80.
6-Methyl-2H-furo[3,2-c]pyran-3,4-dione (8). A solution of
3-bromoacetyl-4-hydroxy-6-methyl-2H-pyran-2-one 4 (1.24 g,
5 mmol) and primary aliphatic amines (5 mmol) in ethanol (20
mL) was refluxed, with stirring, for 1 h. After cooling the
reaction mixture, the formed solid was filtered off and recrys-
tallized from cold ethanol leading to 6-methyl-2H-furo[3,2-
c]pyran-3,4-dione 8 (0.54 g, 65%): mp 199–200ꢂC; IR (m,
According to the literature data, it is difficult to estab-
lish the stereochemistry of compounds similar to 15a–f
[48], but the Z isomer is generally the more stable (Aus-
tin Model) and more frequent found one [49,50]. Taken
into consideration these data, we postulate that we have
obtained (Z)-2-arylidene-6-methyl-2H-furo[3,2-c]pyran-
3,4-diones 14a–f. In the case of compounds 15a,b, we
postulate a (E)-stereochemistry based on the steric hin-
drance between the phenyl and the pyranone rings.
cmꢁ1): 1767, 1694, 1565, 1482, 1450, 1220, 1145; UV (kmax
,
1
nm): 267 (e, 1.228); H NMR (CDCl3): d 2.39 (s, 3H, 6-CH3),
4.75 (s, 2H, H-2), 6.22 (s, 1H, H-7); 13C NMR (CDCl3): d
21.4 (6-CH3), 76.5 (C-2), 96.6 (C-7), 101.3 (C-9), 155.6 (C-6),
173.8 (C-4), 188.8 (C-8), 192.1 (C-3); ESI(þ)-MS: m/z 189
[(M þ Na)þ, 64], 167 [(M þ H)þ, 19]. Anal. Calcd. for
C8H6O4: C, 57.84; H, 3.64. Found: C, 57.90; H, 3.76.
General procedure for the synthesis of 4-hydroxy-6-methyl-
3-(2-substituted-thiazol-4-yl)-2H-pyran-2-ones (11a–e). Pro-
cedure A. A solution of 3-bromoacetyl-4-hydroxy-6-methyl-
2H-pyran-2-one 4 (0.24 g, 1 mmol) and the appropriate thioa-
mide, thiourea, and diphenylthiocarbazone (1 mmol) in ethanol
(20 mL) was reflux until total consumption of the starting ma-
terial (see Table 1).
CONCLUSION
In summary, we report herein an efficient methodol-
ogy for the synthesis of thiazoles 11a–e, 2-arylidene-6-
methyl-2H-furo[3,2-c]pyran-3,4-diones 14a–f, and 6-(2-
arylprop-1-enyl)-2H-furo[3,2-c]pyran-3,4-diones 15a,b.
The synthesis under microwave irradiation of these teth-
ered compounds is straightforward with moderate yields
and high purity of the final compounds.
EXPERIMENTAL
Procedure B. Conditions similar to procedure A save the
use of microwave irradiation as source of energy (power and
reaction conditions in Table 1).
Procedure C. The mixture of ethyl ether (10 mL), neutral
alumina (1 g), the appropriate thioamide, thiourea, or diphe-
nylthiocarbazone (1 mmol) and 3-bromoacetyl-4-hydroxy-6-
methyl-2H-pyran-2-one 4 (0.24 mmol), in a mortar, is ground
vigorously until total solvent evaporation. This solid mixture
was submitted to microwave irradiation under conditions indi-
cated in Table 1.
General remarks. Melting points were determined on a
Stuart scientific SPM3 apparatus fitted with a microscope and
are uncorrected. 1H and 13C NMR spectra were recorded in
CDCl3 or DMSO-d6 solutions on a Bruker Avance 300
(300.13 MHz for 1H and 75.47 MHz for 13C) spectrometer.
Chemical shifts are reported in ppm (d) using TMS as internal
reference and coupling constants (J) are given in Hz. 13C
assignments were made using gHSQC and gHMBC (delays for
one bond and long-range J C/H couplings were optimized for
Journal of Heterocyclic Chemistry
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January 2011
Synthesis and Reactivity of 6-Methyl-4H-furo[3,2c]pyran-3,4-dione
35
4-Hydroxy-6-methyl-3-(2-methylthiazol-4-yl)-2H-pyran-2-
one (11a). This compound was obtained as a white solid with
mp 140–141ꢂC; IR (m, cmꢁ1): 3100–3500, 2980, 1754, 1660,
1448, 1490, 1379, 990, 820, 735; UV (kmax, nm): 344 (e,
0.227); 1H NMR (DMSO-d6): d 2.22 (s, 3H, 6-CH3), 2.23(s,
3H, 60-CH3), 6.17 (s, 1H, H-5), 7.13 (s, 1H, H-50), 14.13 (s,
General procedure for the synthesis of 2-arylidene-6-
methyl-2H-furo[3,2-c]pyran-3,4-dione (14a–f).
Classical
heating conditions. A solution of 6-methyl-2H-furo[3,2-c]py-
ran-3,4-dione 8 (0.38 g, 2.3 mmol) and the appropriate benzal-
dehyde (5 mmol) in a mixture of glacial acetic acid (12 mL)
and hydrochloric acid (12 mL) was refluxed, with stirring, for
1 h. After cooling the reaction mixture to room temperature,
the obtained solid was collected by filtration and purified by
recrystallization from boiling chloroform, yielding 2-arylidene-
6-methyl-2H-furo[3,2-c]pyran-3,4-diones (14a–f): 14a (0.28 g,
49%); 14b (0.37 g, 57%), 14c (0.34 g, 52%); 14d (0.44 g,
58%), 14e (0.35 g, 52%); 14f (0.31 g, 46%).
13
1H, OH); C NMR (DMSO-d6): d 20.5 (6-CH3), 35.2 (20-
CH3), 98.4 (C-3), 102.6 (C-5), 101.6 (C-50), 140.2 (C-40),
160.8 (C-6), 162.7 (C-20), 168.7 (C-2), 181.0 (C-4); ESI(þ)
-
MS: m/z 224 [(M þ H)þ, 100], 246 [(M þ Na)þ, 10]. Anal.
Calcd. for C10H9NO3S: C, 53.90; H, 4.06; N, 6.27. Found: C,
53.82; H, 4.02; N, 6.15.
3-(2-Aminothiazol-4-yl)-4-hydroxy-6-methyl-2H-pyran-2-
one (11b). This compound was obtained as a yellow solid
with mp 290–292ꢂC; IR (m, cmꢁ1): 3100–3500, 2980, 1754,
1660, 1448, 1490, 1379, 990, 820, 735; UV (kmax, nm): 344
Microwave conditions. A solution of 6-methyl-2H-furo[3,2-
c]pyran-3,4-dione 8 (0.19 g, 1.15 mmol) and the appropriate
benzaldehyde (2.3 mmol) in a mixture of glacial acetic acid
(10 mL) and hydrochloric acid (10 mL) was irradiated with
microwave radiation (600 W) for a 2–3 min. After cooling the
reaction mixture to room temperature, the resulting solid is fil-
tered and recrystallized from chloroform, yielding 2-arylidene-
6-methyl-2H-furo[3,2-c]pyran-3,4-diones (14a–f): 14a (0.16 g,
55%); 14b (0.20 g, 62%), 14c (0.19 g, 60%); 14d (0.24 g,
65%), 14e (0.20 g, 59%); 14f (0.18 g, 55%).
2-Benzylidene-6-methyl-2H-furo[3,2-c]pyran-3,4-dione
(14a). This compound was obtained as a yellow solid with
mp 219–220ꢂC. IR (m, cmꢁ1): 1767, 1660, 1590, 1480, 1247,
1040, 895, 760, 700; 1H NMR (DMSO-d6): d 2.46 (s, 1H, 6-
CH3), 6.84 (s, 1H, H-7), 7.13 (s, 1H, ¼¼CH), 7.50–7.53 (m,
1H, H-40), 7.70–7.73 (m, 2H, H-30,50), 7.81–7.84 (m, 2H, H-
20,60); 13C NMR (DMSO-d6): d 21.2 (6-CH3), 96.8 (C-7),
101.0 (C-9), 126.2 (C-30,50), 128.0 (C-40), 128.9 (C-20,60),
130.2 (¼¼CH), 132.5 (C-10), 155.5 (C-6), 169.3 (C-2), 173.9
(C-4), 188.6 (C-8), 193.0 (C-3); ESI(þ)-MS: m/z 255 [(M þ
H)þ, 100], 277 [(M þ Na)þ, 60]. Anal. Calcd. for C15H10O4:
C, 70.86; H, 3.96. Found: C, 70.93; H, 3.99.
1
(e, 0.227); H NMR (DMSO-d6): d 2.23 (s, 3H, 6-CH3), 6.18
(s, 1H, H-5), 7.15 (s, 1H, H-50), 8.40 (s, 2H, NH2), 14.27 (s,
1H, OH); 13C NMR (DMSO-d6): d 19.4 (6-CH3), 92.7 (C-3),
101.3 (C-5), 101.9 (C-50), 139.2 (C-40), 162.0 (C-6), 168.0 (C-
20), 169.3 (C-2), 178.5 (C-4); ESI(þ)-MS: m/z ESI(þ)-MS: m/z
225 [(M þ H)þ, 100], 247 [(M þ Na)þ, 45]. Anal. Calcd. for
C9H8N2O3S: C, 48.21; H, 3.60; N, 12.49. Found: C, 48.18; H,
4.00; N, 12.38.
3-(2-Hydrazinylthiazol-4-yl)-4-hydroxy-6-methyl-2H-pyran-
2-one (11c). This compound was obtained as a yellow solid
with mp 240–242ꢂC; IR (m, cmꢁ1) 3100–3500, 2980, 1754,
1660, 1448, 1490, 1379, 990, 820, 735; UV (kmax, nm) 344 (e,
0.227); 1H NMR (DMSO-d6): d 2.23 (s, 3H, 6-CH3), 6.20 (s,
1H, H-5), 7.43 (s, 1H, H-50), 9.94 (s, 1H, NH), 14.02 (s, 1H,
OH); 13C NMR (DMSO-d6): d 19.4 (6-CH3), 94.0 (C-3), 101.2
(C-5), 104.5 (C-50), 141.6 (C-40), 161.5 (C-6), 168.4 (C-20),
169.9 (C-2), 179.6 (C-4); ESI(þ)-MS: m/z 240 [(M þ H)þ,
100], 262 [(M þ Na)þ, 60]. Anal. Calcd. for C9H9N3O3S: C,
45.18; H, 3.79; N, 17.56. Found: C, 45.01; H, 3.83; N, 17.46.
4-(4-Hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)thiazole-2-
carbothioamide (11d). This compound was obtained as a
yellow solid with mp 268–269ꢂC; IR (m, cmꢁ1): 3100–3500,
2-(4-Methoxybenzylidene)-6-methyl-2H-furo[3,2-c]pyran-3,4-
dione (14b). This compound was obtained as a yellow solid
with mp 171–172ꢂC. IR (m, cmꢁ1): 1767, 1662, 1590, 1480,
1
1247, 1005, 730, 700; H NMR (DMSO-d6): d 2.39 (s, 1H, 6-
2980, 1754, 1660, 1448, 1490, 1379, 990, 820, 735; UV (kmax
,
CH3), 3.84 (s, 3H, OCH3), 6.74 (s, 1H, H-7), 7.15 (s, 1H,
¼¼CH), 7.50–7.53 (m, 2H, H-30,50), 7.70–7.73 (m, 2H, H-20,60);
13C NMR (DMSO-d6): d 21.2 (6-CH3), 56.1 (OCH3), 96.8 (C-
7), 101.0 (C-9), 114.2 (C-30,50), 130.2 (¼¼CH), 131.0 (C-10, C-
20,60), 154.5 (C-40), 155.5 (C-6), 169.3 (C-2), 174.0 (C-4),
188.6 (C-8), 193.0 (C-3); ESI(þ)-MS: m/z 285 [(M þ H)þ,
100], 307 [(M þ Na)þ, 48)]. Anal. Calcd. for C16H12O5: C,
67.60; H, 4.25. Found: C, 67.67; H, 4.30.
nm): 344 (e, 0.227); 1H NMR (DMSO-d6): d 2.26 (d, 3H,
J ¼ 0.6 Hz, 6-CH3), 6.31(s, 1H, H-5), 8.52 (s, 1H, H-50),
10.32 (s, 2H, NH2), 12.42 (s, 1H, OH); 13C NMR (DMSO-d6):
d 19.4 (6-CH3), 94.3 (C-3), 100.9 (C-5), 124.9 (C-50), 149.3
(C-40), 161.7 (C-6), 167.6 (C-20), 169.9 (C-2), 179.3 (C-4),
185.50 (C¼¼S); ESI(þ)-MS: m/z ESI(þ)-MS: m/z 269 [(M þ
H)þ, 100], 291 [(M
þ
Na)þ, 55]. Anal. Calcd. for
C10H8N2O3S2: C, 44.76; H, 3.01; N, 10.44. Found: C, 44.70;
H, 2.95; N, 10.32.
2-(4-Chlorobenzylidene)-6-methyl-2H-furo[3,2-c]pyran-3,4-
dione (14c). This compound was obtained as a yellow solid
with mp 268–269ꢂC. IR (m, cmꢁ1): 1766, 1660, 1593, 1482,
4-Hydroxy-6-methyl-3-(2-(phenyldiazenyl)thiazol-4-yl)-2H-
pyran-2-one (11e). This compound was obtained as a red
solid with mp 275–277ꢂC; IR (m, cmꢁ1) 3100–3500, 2980,
1754, 1660, 1448, 1490, 1379, 990, 820, 735; UV (kmax, nm)
344 (e, 0.227); 1H NMR (DMSO-d6): d 2.31(s, 3H, 6-CH3),
6.09 (s, 1H, H-5), 8.48 (s, 1H, H-50), 7.58–7.62 (m, 3H, Ph-
Hortho þ para), 8.01–8.05 (m, Ph-Hmeta), 13.84 (s, 1H, OH); 13C
NMR (DMSO-d6): d 20.1 (6-CH3), 94.3 (C-3), 101.5 (C-5),
117.9 (C-50), 124.1 (Ph-Cortho þ para), 129.5 (Ph-Cmeta), 133.5
(Ph-Cipso), 142.2 (C-40), 162.2 (C-6), 162.3 (C-20), 169.0 (C-2),
177.4 (C-4); ESI(þ)-MS: m/z 314 [(M þ H)þ, 100], 336 [(M þ
Na)þ, 40]. Anal. calcd. for C15H11N3O3S: C, 57.50; H, 3.54;
N, 13.41. Found: C, 57.45; H, 3.43; N, 16.08.
1
1247, 1040; H NMR (DMSO-d6): d 2.43 (d, 3H, J ¼ 0.6 Hz,
6-CH3), 6.97 (d, 1H, J ¼ 0.6 Hz, H-7), 7.05 (s, 1H, ¼¼CH),
7.59 (d, 2H, J ¼ 8.6 Hz, H-30,50), 7.94 (d, 2H, J ¼ 8.6 Hz, H-
20,60); 13C NMR (DMSO-d6): d 21.2 (6-CH3), 96.8 (C-7),
101.0 (C-9), 127.2 (C-20,60), 128.9 (C-30,50), 130.2 (¼¼CH),
133.0 (C-10, C-40), 155.5 (C-6), 169.3 (C-2), 174.0 (C-4),
188.6 (C-8), 192.9 (C-3); ESI(þ)-MS: m/z 289 [(M þ H)þ,
35Cl, 48], 291 [(M þ H)þ, 37Cl, 14], 311 [(M þ Na)þ, 35Cl,
100], 313 [(M þ Na)þ, 37Cl, 30]. Anal. Calcd. for C15H9ClO4:
C, 62.41; H, 3.14. Found: C, 62.38; H, 3.10.
2-(4-Bromobenzylidene)-6-methyl-2H-furo[3,2-c]pyran-3,4-
dione (14d). This compound was obtained as a yellow solid
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

36
D. Hikem-Oukacha, Y. Rachedi, M. Hamdi, and A. M. S. Silva
Vol 48
with mp 240–241ꢂC. IR (m, cmꢁ1): 1767, 1661, 1592, 1481,
1247, 1040, 990, 820, 735; 1H NMR (DMSO-d6): d 2.43 (d,
3H, J ¼ 0.6 Hz, 6-CH3), 6.97 (d, 1H, J ¼ 0.6 Hz, H-7), 7.02
(s, 1H, ¼¼CH), 7.86 (d, 2H, J ¼ 8.6 Hz, H-30,50), 7.72 (d, 2H,
J ¼ 8.6 Hz, H-20,60); 13C NMR (DMSO-d6): d 21.3 (6-CH3),
96.7 (C-7), 101.0 (C-9), 127.1 (C-20,60), 128.9 (C-30,50), 130.2
(¼¼CH), 133.0 (C-10, C-40), 155.6 (C-6), 169.2 (C-2), 173.9 (C-
4), 188.5 (C-8), 192.9 (C-3); ESI(þ)-MS: m/z 333 [(M þ H)þ,
79Br, 100], 335 [(M þ H)þ, 81Br, 98], 355 [(M þ Na)þ, 79Br,
40], 357 [(M þ Na)þ, 81Br, 38]. Anal. Calcd. for C15H9BrO4:
C, 54.08; H, 2.72. Found: C, 54.00; H, 2.82.
6-Methyl-2-(4-nitrobenzylidene)-2H-furo[3,2-c]pyran-3,4-
dione (14e). This compound was obtained as a yellow solid
with mp 220–222ꢂC. IR (m, cmꢁ1) 1766, 1660, 1592, 1480,
1247, 1040, 1000, 950, 885, 840, 780, 750, 705; 1H NMR
(DMSO-d6): d 2.43 (d, 3H, J ¼ 0.6 Hz, 6-CH3), 6.97 (d, 1H, J
¼ 0.6 Hz, H-7), 7.05 (s, 1H, ¼¼CH), 7.59 (d, 2H, J ¼ 8.6 Hz,
H-20,60), 7.94 (d, 2H, J ¼ 8.6 Hz, H-30,50); 13C NMR (DMSO-
d6): d 21.3 (6-CH3), 96.8 (C-7), 101.0 (C-9), 123.9 (C-30,50),
127.1 (C-20,60), 130.2 (¼¼CH), 139.5 (C-10), 142.9 (C-40),
155.6 (C-6), 169.3 (C-2), 173.9 (C-4), 188.6 (C-8), 192.9 (C-
3); ESI(þ)-MS: m/z 300 [(M þ H)þ, 45], (MþþH, 45), 322
[(M þ Na)þ, 100]. Anal. Calcd. for C15H9NO6: C, 60.21; H,
3.03; N, 4.68. Found: C, 60.17; H, 3.00; N, 4.60.
3H, CH3), 4.92 (s, 2H, H-2), 6.70 (s, 1H, H-7), 7.41–7.49 (m,
4H, ¼¼CH, H-30,40,50), 7.62–7.65 (m, 2H, H-20,60); 13C NMR
(DMSO-d6): d 20.9 (CH3), 77.1 (C-2), 96.8 (C-7), 99.4 (C-9),
127.9 (¼¼CH), 128.5 (C-20,60), 128.8 (C-40), 129.5 (C-30,50),
132.5 (C-10), 137.0 (¼¼C), 155.5 (C-6), 173.9 (C-4), 188.6 (C-
8), 192.9 (C-3); ESI(þ)-MS: m/z 269 [(M þ H)þ, 100], 291
[(M þ Na)þ, 65]. Anal. Calcd. for C16H12O4: C, 71.64; H,
4.51. Found: C, 71.70; H, 4.56.
6-(2-Bromophenylprop-1-enyl)-2H-furo[3,2-c]pyran-3,4-
dione (15b). This compound was obtained as a yellow solid
with mp 188–190ꢂC. IR (m, cmꢁ1): 1740, 1640, 1566, 1441,
1
1449, 1219, 1132, 990, 820, 735; H NMR (DMSO-d6): d 2.39
(s, 3H, CH3), 5.39 (s, 2H, H-2), 6.84 (s, 1H, H-7), 7.51-7.55
(m, 3H, ¼¼CH, H-20,60), 7.70–7.72 (m, 2H, H-30,50);13C NMR
(DMSO-d6): d 20.7 (CH3), 77.1 (C-2), 96.8 (C-7), 100.9 (C-9),
128.0 (¼¼CH), 128.3 (C-40), 128.8 (C-20,60), 129.33 (C-30,50),
133.1 (C-10), 135.9 (¼¼C), 155.1 (C-6), 173.1 (C-4), 188.6 (C-
8), 193.0 (C-3); ESI(þ)-MS: m/z 347 [(M þ H)þ, 79Br, 100],
349 [(M þ H)þ, 79Br, 98], 371 [(M þ Na)þ, 79Br, 58], 369
[(M þ H)þ, 81Br, 60]. Anal. Calcd. for C16H11BrO4: C, 55.36;
H, 3.19. Found: C, 56.28; H, 3.12.
Acknowledgments. The authors thank the University of Aveiro,
FCT, and FEDER for funding the Organic Chemistry Research
Unit.
6-Methyl-2-(2-nitrobenzylidene)-2H-furo[3,2-c]pyran-3,4-
dione (14f). This compound was obtained as a yellow solid
with mp 280–281ꢂC. IR (m, cmꢁ1): 1766, 1660, 1591, 1480,
1
1248, 1040, 950, 885, 780, 750; H NMR (DMSO-d6): d 2.43
REFERENCES AND NOTES
(s, 3H, 6-CH3), 6.92 (s, 1H, H-7), 7.27 (s, 1H, ¼¼CH), 7.73–
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1H, H-60), 8.17–8.20 (m, 1H, H-30); 13C NMR (DMSO-d6): d
21.2 (6-CH3), 96.8 (C-7), 100.9 (C-9), 127.3 (C-30), 127.4 (C-
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[(M þ H)þ, 48]. Anal. Calcd. for C15H9NO6: C, 60.21; H,
3.03; N, 4.68. Found: C, 60.19; H, 3.01; N, 4.62.
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Synthesis and Reactivity of 6-Methyl-4H-furo[3,2c]pyran-3,4-dione
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