4,6-diacetylresorcinol in heterocyclic synthesis, part i: Synthesis and biological evaluation of some new linearly and angularly substituted pyrano[3,2-g] chromenes via vilsmeier-haack formylation of 4,6- diacetylresorcinol, its schiff bases, and hydrazones

Article abstract of DOI:10.1080/00397911.2013.783074

Application of Vilsmeier-Haack reaction on 4,6-diacetylresorcinol (1) led to the formation of 4,6-dioxo-4H,6H-pyrano[3,2-g]chromene-3,7-dicarboxaldehyde (2) in good yield. The dicarboxaldehyde 2 was condensed with some carbon and nitrogen nucleophiles. Some aliphatic and aromatic Schiff bases of 4,6-diacetylresorcinol (1) were subjected to Vilsmeier-Haack formylation reaction to afford 4,6-bis(alkyl/arylimino)-4H,6H-pyrano[3,2-g]chromene-3,7- dicarbaldehydes 10, 14, and 15. Also, treatment of some bis-hydrazones of 4,6-diacetylresorcinol 16-19 with Vilsmeier-Haack reagent afforded the corresponding 4,6-bis(4-formylpyrazol-3-yl)resorcinols 20 and 21, which underwent oxidation with iodine to yield the pyrano[3,2-g]chromeno[4,3-c:7,6-c] dipyrazole-4,8-diones 22 and 23, respectively. Most of the synthesized compounds revealed weak antimicrobial activities. It was noticed that the dicarboxaldehydes 2, 10, 14, and 15 exhibited moderate antibacterial activity against Gram-positive bacteria, yeast, and fungus. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.783074

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4,6-Diacetylresorcinol in Heterocyclic
Synthesis, Part I: Synthesis and Biological
Evaluation of Some New Linearly and
Angularly Substituted Pyrano[3,2-
g] Chromenes via Vilsmeier–Haack
Formylation of 4,6-Diacetylresorcinol, Its
Schiff Bases, and Hydrazones
Tarik E. Ali a , Magdy A. Ibrahim a , Zeinab M. El-Gendy a & Eman M.
El-Amin a
a Department of Chemistry , Faculty of Education, Ain Shams
University , Roxy , Cairo , Egypt
Published online: 05 Sep 2013.
To cite this article: Tarik E. Ali , Magdy A. Ibrahim , Zeinab M. El-Gendy & Eman M. El-Amin (2013)
4,6-Diacetylresorcinol in Heterocyclic Synthesis, Part I: Synthesis and Biological Evaluation of Some
New Linearly and Angularly Substituted Pyrano[3,2-g] Chromenes via Vilsmeier–Haack Formylation of
4,6-Diacetylresorcinol, Its Schiff Bases, and Hydrazones, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 43:24, 3329-3341
To link to this article: http://dx.doi.org/10.1080/00397911.2013.783074
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Synthetic Communications1, 43: 3329–3341, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.783074
4,6-DIACETYLRESORCINOL IN HETEROCYCLIC
SYNTHESIS, PART I: SYNTHESIS AND BIOLOGICAL
EVALUATION OF SOME NEW LINEARLY AND
ANGULARLY SUBSTITUTED PYRANO[3,2-g]
CHROMENES VIA VILSMEIER–HAACK FORMYLATION
OF 4,6-DIACETYLRESORCINOL, ITS SCHIFF BASES,
AND HYDRAZONES
Tarik E. Ali, Magdy A. Ibrahim, Zeinab M. El-Gendy, and
Eman M. El-Amin
Department of Chemistry, Faculty of Education, Ain Shams University,
Roxy, Cairo, Egypt
GRAPHICAL ABSTRACT
Abstract Application of Vilsmeier–Haack reaction on 4,6-diacetylresorcinol (1) led to the
formation of 4,6-dioxo-4H,6H-pyrano[3,2-g]chromene-3,7-dicarboxaldehyde (2) in good
yield. The dicarboxaldehyde 2 was condensed with some carbon and nitrogen nucleophiles.
Some aliphatic and aromatic Schiff bases of 4,6-diacetylresorcinol (1) were subjected
to Vilsmeier–Haack formylation reaction to afford 4,6-bis(alkyl=arylimino)-4H,6H-
pyrano[3,2-g]chromene-3,7-dicarbaldehydes 10, 14, and 15. Also, treatment of some
bis-hydrazones of 4,6-diacetylresorcinol 16–19 with Vilsmeier–Haack reagent afforded
the corresponding 4,6-bis(4-formylpyrazol-3-yl)resorcinols 20 and 21, which underwent
oxidation with iodine to yield the pyrano[3,2-g]chromeno[4,3-c:7,6-c]dipyrazole-4,8-
diones 22 and 23, respectively. Most of the synthesized compounds revealed weak anti-
microbial activities. It was noticed that the dicarboxaldehydes 2, 10, 14, and 15 exhibited
moderate antibacterial activity against Gram-positive bacteria, yeast, and fungus.
Received January 17, 2013.
Address correspondence to Tarik E. Ali, Department of Chemistry, Faculty of Education, Ain
Shams University, Roxy, Cairo, Egypt. E-mail: tarik_elsayed1975@yahoo.com
3329

3330
T. E. ALI ET AL.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Antimicrobial activities; 4,6-diacetylresorcinol; pyrano[3,2-g]chromenes;
Vilsmeier–Haack formylation
INTRODUCTION
The Vilsmeier–Haack reaction is a widely used method for the formylation of
activated aromatic and heteroaromatic compounds.[1,2] The reactions of aliphatic
substrates, particularly carbonyl compounds[3,4] with chloromethyleneiminium salts,
led to multiple iminoalkylations in the presence of excess reagent and the resulting
intermediates underwent cyclization to afford aromatic or heterocyclic compounds.[5]
Multifunctional intermediates derived from these reactions (e.g., b-chloroenalde-
hydes) are subsequently exploited for the synthesis of functionalized heterocycles
or other valuable target molecules.[6] Dibenzyl ketone on treatment with
chloromethyleneiminium salt underwent multiple iminoalkylations followed by
cyclization to afford 3,5-diphenyl-4H-pyran-4-one.[7] Furthermore, the reactions of
2-hydroxyacetophenones with Vilsmeier–Haack reagent also involve an iminoalkyl-
ation cyclization sequence, leading to the formation of 3-formylchromones.[8–10]
The chromone and coumarin derivatives are found in the molecular structure
of many important natural secondary metabolites[11,12] and compounds with high
pharmacological activity.[13,14] The incorporation of a fused heterocyclic moiety in
the parent chromone and coumarin alters their properties and converts them into
more important derivatives.[15,16] Large numbers of heterocycles fused with chro-
mone and coumarin are used as drugs and dyes.[17,18]
In our recent work, we have demonstrated the utility of the Vilsmeier–Haack
reagent in the synthesis of functionalized heterocyclic systems such as pyrazoles,
chromeno[4,3-c]pyrazoles, and chromeno[2,3-g]indazoles.[19] Thus, as a continuation
of our research interest in the synthesis of highly valuable heterocycles,[20,21] we
prepared 4,6-diacetylresorcinol, its Schiff bases and hydrazones followed by examin-
ation of their reactivities toward Vilsmeier–Haack reagent. Also, the preliminary
antimicrobial activities of the synthesized compounds were screened.
RESULTS AND DISCUSSION
4,6-Diacetylresorcinol (1) was prepared in excellent yield via acetylation of res-
orcinol with acetic anhydride in the presence of freshly fused zinc chloride according
to the previously reported procedure (Scheme 1).[22] Application of Vilsmeier–Haack
reaction on the substrate 1 afforded 4,6-dioxo-4H,6H-pyrano[3,2-g] chromene-3,7-
dicarboxaldehyde (2) in good yield (Scheme 1). It may be mentioned here that com-
pound 2 was obtained by Mallaiah and Srimannarayana [23] in poor yield. However,
no full spectral characterization of this product was made. The proposed mechanism
for the formation of 2 involved double formylation at each methyl group of 1, fol-
lowed by self-cyclization and then hydrolysis in basic medium (Scheme 2).[24] The
infrared (IR) spectrum of compound 2 showed three characteristic absorption bands

SUBSTITUTED PYRANO[3,2-g] CHROMENES
3331
Scheme 1. Formation of 4,6-dioxo-4H,6H-pyrano[3,2-g]chromene-3,7-dicarboxaldehyde (2) via Vilsmeier–
Haack reaction of the substrate 1.
at 1707, 1655, and 1625 cmꢀ1 assignable to CHO, C Opyrone, and C C functions,
respectively. The 1H NMR spectrum of compound 2 exhibited a singlet at d
10.10 ppm for the formyl protons and the protons of the pyrone rings in position
2 resonated at d 8.76 ppm. In addition, two singlets were present at d 7.94 and
9.02 ppm corresponding to the protons H-10 and H-5, respectively.[25]
Furthermore, its mass spectrum revealed the molecular ion peak at m=z 270 (Mþ),
which agreed with the suggested molecular formula.
=
=
The chemical reactivity of 4,6-dioxo-4H,6H-pyrano[3,2-g]chromene-3,7-
dicarboxaldehyde (2) was studied via its simple condensation reactions with some
carbon and nitrogen nucleophiles. Thus, compound 2 was condensed with aniline
and hydroxylamine hydrochloride in dry dimethylformamide (DMF) to give moder-
ate yields of the corresponding bis-azomethine 3 and bis-oxime 4, respectively
Scheme 2. Proposed mechanism of the formation of compound 2.

3332
T. E. ALI ET AL.
Scheme 3. Condensation reactions of dicarboxaldehyde 2 with some nitrogen and carbon nucleophiles.
(Scheme 3). The IR spectra of compounds 3 and 4 clearly showed disappearance of
the aldehyde absorption band, and new bands at d 1594 and 1629 cmꢀ1 appeared for
imino groups for them, respectively. The H NMR spectrum of 4 showed the OH
1
=
signal at d 12.74 ppm in addition to the protons H-5, CH N, and H-10 appeared
at d 8.89, 7.95, and 7.48 ppm, respectively.
The Knoevenagel condensation reaction of compound 2 with acyclic and cyclic
active methylene groups was studied. Thus, the reaction of 2 with malononitrile and
ethyl cyanoacetate in dry DMF containing a few drops of triethylamine afforded
2,20-[(4,6-dioxo-4H,6H-pyrano[3,2-g]chromene-3,7-diyl)dimethylidene]dipropanedi-
nitrile (5) and diethyl 3,30-[(4,6-dioxo-4H,6H-pyrano[3,2-g]chromene-3,7-diyl)]-
bis(2-cyanoprop-2-enoate) (6), respectively (Scheme 3). Similarly, condensation of
2 with barbaturic acid as cyclic active methylene compound in glacial acetic acid
and freshly fused sodium acetate yielded 5,50-[(4,6-dioxo-4H,6H-pyrano[3,2-
g]chromene-3,7-diyl)dimethylidene]dipyrimidine-2,4,6-(1H,3H,5H)-trione
(7)
(Scheme 3). The assigned structures of 5–7 were confirmed by the correct elemental
analysis in addition to the spectral data. Their IR spectra revealed characteristic
absorption bands at region 2220 ꢀ 2192 cmꢀ1 for nitrile groups in compounds 5
and 6, in addition to the characteristic absorption bands for the carbonyl groups
of 6 and 7 appeared at 1733 (C Oester) and 1707 (C Oamide) cmꢀ1, respectively.
The 1H NMR spectrum of 6 showed the ethoxy protons at d 1.22 (CH3) and
4.19 ppm (CH2), whereas compound 7 revealed the NH protons as broad signal at
=
=
=
d 11.50 ppm and the exocyclic CH C protons as singlet at d 6.94 ppm.
We selected some aliphatic and aromatic Schiff bases of 4,6-diacetylresorcinol
as model compounds to examine their chemical behavior under Vilsmeier–Haack
formylation conditions. Thus, treatment of 4,6-bis[1-(ethylimino)ethyl]resorcinol
(8) and 4,6-bis[1-(benzylimino)ethyl]resorcinol (9) with Vilsmeier–Haack reagent
afforded 4,6-bis(ethylimino)-4H,6H-pyrano[3,2-g]chromene-3,7-dicarbaldehyde (10)
and 2,10-diphenylpyrano[3,2-g]chromeno[4,3-b:7,6-b]dipyrrole (11), respectively

SUBSTITUTED PYRANO[3,2-g] CHROMENES
3333
Scheme 4. Vilsmeier–Haack formylation of aliphatic Schiff bases of 4,6-diacetylresorcinol 8 and 9.
(Scheme 4). The proposed mechanism for the formation of 10 involved double for-
mylation at each methyl group of acetyl groups in compound 8, followed by
self-cyclization and then hydrolysis in basic medium as occurred in the formation
of 2. Also, the proposed mechanism for the formation of 11 involved monoformyla-
tion at each methyl and methylene groups of 9, followed by self-cyclization and then
hydrolysis in basic medium (Scheme 4). The analytical and spectroscopic data
proved the proposed structures of 10 and 11. Their IR spectra revealed the formyl
groups at 1704 cmꢀ1 in compound 10 while it was absent in compound 11. The
1H NMR spectrum of 10 showed the aldehydic protons at d 10.08 ppm and the ethyl
1
groups at d 1.20 (CH3) and 4.25 (CH2). Furthermore, the H-NMR spectrum of 11
did not show any aldehydic proton but showed the Hꢀ3 proton of pyrrole rings at d
7.90 ppm, which supports the cyclization process. The mass spectra of compounds 10
and 11 showed the parent ion peaks at m=z 266 (Mꢀ2Et) and 412 (Mþ), respectively.
On the other hand, the novel 4,6-bis(phenylimino)-4H,6H-pyrano[3,2-
g]chromene-3,7-dicarbaldehyde (14) and 4,6-bis(4-methylphenylimino)-4H,6H-
pyrano[3,2-g]chromene-3,7-dicarbaldehyde (15) were obtained from treatment of
4,6-bis[1-(phenylimino)ethyl]resorcinol (12) and 4,6-bis[1-(4-methylphenylimino)-
ethyl]resorcinol (13), respectively, with Vilsmeier–Haack reagent (Scheme 5). The

3334
T. E. ALI ET AL.
Scheme 5. Vilsmeier–Haack formylation of aromatic Schiff bases of 4,6-diacetylresorcinol 12 and 13.
proposed mechanism for the formation of compounds 14 and 15 involved double
formylation at each methyl group of acetyl groups 8, followed by self-cyclization
and then hydrolysis in basic medium as occurred in formation of 2 and 10. The
IR spectra of 14 and 15 showed strong absorption bands at 1690 and 1698 cmꢀ1
1
assignable to CHO groups, respectively. Their H NMR spectra exhibited singlets
at d 10.20 and 10.11 ppm for the formyl protons, respectively. The protons of the
pyrone rings in position 2 resonated at d 8.51 and 9.07 ppm, respectively. Moreover,
their mass spectral data revealed their molecular ion peaks at m=z 420 and 448,
respectively.
The present work was also extended to apply the Vilsmeier–Haack formylation
reaction on some hydrazones of 4,6-diacetylresorcinol that led to new 4,6-bis(4-
formylpyrazol-3-yl)resorcinol systems. Thus, the bis-hydrazone 16, bis-semicarba-
zone 17, and bis-thiosemicarbazone 18 were treated with Vilsmeier–Haack reagent
under the previous conditions to afford only one, a pale brown crystalline product
named, 4,6-bis(4-formyl-1H-pyrazol-3-yl)resorcinol (20) (Scheme 6).[26] Formation
of compound 20 involved double formylation at the methyl groups of compounds
þ
=
16–18 followed by nucleophilic attack of NH groups at –CH N (CH3)2 moieties
to eliminate two molecules of dimethylamine. The basic hydrolysis removes the
amide and thioamide moieties to give the final product 20 (Scheme 7). The spectral
1
data of 20 supported the proposed structure because its H NMR spectrum dis-
played a broad singlet (D2O exchangeable) at d 12.50 ppm due to NH and OH pro-
tons and a singlet at d 9.80 ppm due to the aldehydic protons. The H-5 protons of the
formed pyrazole rings were also observed at d 8.41 ppm. Also, its IR spectrum
showed very a broad absorption band at 3119 cmꢀ1 due to NH and OH groups
and a strong band for the aldehyde groups at 1692 cmꢀ1. Similarly, when the bis-
phenylhydrazone 19 was subjected to Vilsmeier–Haack reagent, it gave 4,6-
bis(4-formyl-1-phenylpyrazol-3-yl)resorcinol (21) (Scheme 6). The structure of 21
was proved by the analytical and spectroscopic data. Its 1H NMR spectrum

SUBSTITUTED PYRANO[3,2-g] CHROMENES
3335
Scheme 6. Formation of compounds 20–23 from their hydrazones 16–19.
Scheme 7. Proposed mechanism for formation of compounds 20 and 21 from their hydrazones 16–19.

3336
T. E. ALI ET AL.
displayed the aldehydic protons at d 9.85 ppm and H-5 of pyrazole rings at d
9.21 ppm, respectively. The mass spectrum of 21 recorded the molecular ion peak at
m=z 450 (66%), which agreed with the molecular formula of the proposed structure.
The oxidation reaction of compounds 20 and 21 with iodine in dimethylsul-
foxide (DMSO) containing a few drops of concentrated sulfuric acid[27] afforded
the new fused angularly polyheterocyclic systems, namely, pyrano[3,2-g]chromeno
[4,3-c:7,6-c]dipyrazole-4,8-(4H) dione (22) and 2,10-diphenylpyrano[3,2-g]chromeno
[4,3-c:7,6-c]dipyrazole-4,8-(4H)dione (23), respectively (Scheme 6). The absorption
bands of the carbonyl groups appeared at 1716 and 1752 cmꢀ1 in the IR spectra
of 22 and 23, respectively. Also, their structures were confirmed from 1H-NMR spec-
tra by disappearance of OH and CHO protons in compounds 20 and 21 (see the
experimental section). Finally, the molecular ion peaks of 22 and 23 were recorded
in accordance with their molecular formulas.
ANTIMICROBIAL EVALUATION
The newly synthesized target compounds were evaluated for their in vitro anti-
bacterial activity against Staphylococcus aureus (ATCC 25923) and Bacillus subtilis
(ATCC 6635) as example of Gram-positive bacteria and Escherichia coli (ATCC
25922) and Salmonella typhimurium (ATCC 14028) as examples of Gram-negative
bacteria. They were also evaluated against Candida albicans (ATCC 10231) as yeast
and the fungus Aspergillus fumigatus. Agar diffusion technique was used for the
determination of the preliminary antibacterial and antifungal activities.[28] The test
was performed on medium potato dextrose agar (PDA), which contained infusion
of 200 g potatoes, 6 g dextrose, and 15 g agar. Uniform-size filter paper disks (three
disks per compound) were impregnated by equal volume (10 ml) from the concentra-
tions of 500 and 1000 mg=mL dissolved compounds in dimethylformamide (DMF)
and carefully placed on inoculated agar surface after incubation for 36 h at 27 ꢁC
in the case of bacteria and for 48 h at 24 ꢁC in the case of fungi. Cephalothin, chlor-
amphenicol and cycloheximide were used as reference drugs for Gram-positive bac-
teria, Gram-negative bacteria, and yeast and the fungus, respectively. The obtained
results were recorded for each tested compound as average diameter of inhibition
zones of the bacteria, yeast, and fungus around the disks in mm at the concentrations
500 and 1000 mg=mL. The antimicrobial activities were determined by measuring the
inhibition zones (Table 1).
1. The results depicted in Table 1 revealed that the most of tested compounds
displayed variable inhibitory effects on the growth of the tested Gram-positive
and Gram-negative bacterial strains, and also against yeast and fungus.
2. In general, most of the tested compounds revealed weak activities against the
microorganism strains.
3. It was noticed that pyrano[3,2-g]chromene-3,7-dicarboxaldehydes 2, 10, 14, and
15 exhibited moderate antibacterial activity against Gram-positive bacteria, yeast,
and fungus.
4. Regarding the structure–activity relationship of the formed bis-aldehydes 2, 10,
14, and 15, the results revealed that compound 2 exhibited a good activity profile,
=
which indicated that C Opyrone is more effective than C Nazomethine groups.
=

SUBSTITUTED PYRANO[3,2-g] CHROMENES
3337
Table 1. In vitro antimicrobial activities of the synthesized compounds 2–23 at 500 and 1000 mg=mL by
disc diffusion assay
Zone of inhibition (mm)a
Bacteria Gram
(þ) ve
Bacteria Gram
(–) ve
Yeast
Fungi
Concentration
(mg=ml)
S.
aureus
B.
subtilis
E.
coli
S.
typhimurium
C.
albicans
A.
fumigatus
Compound
2
500
1000
500
18
21
8
13
19
—
—
—
—
—
—
—
—
—
—
10
13
—
—
9
—
—
7
—
—
7
19
25
—
—
—
—
—
—
—
—
—
—
19
25
—
—
8
20
23
—
—
—
—
—
—
—
—
—
—
16
19
—
—
16
19
18
22
—
—
—
—
14
16
16
19
26
37
3
1000
500
10
—
—
—
—
—
—
—
—
12
15
—
—
12
14
12
18
8
9
10
—
—
8
4
7
1000
500
9
5
—
—
—
—
7
1000
500
10
—
—
8
6
1000
500
7
1000
500
9
9
10
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
28
36
—
—
—
—
—
—
—
—
8
1000
500
11
1000
500
14
1000
500
13
10
14
—
—
—
—
13
16
12
16
25
35
13
16
20
—
—
16
20
12
17
13
15
28
35
15
1000
500
20
1000
500
8
10
—
—
—
—
—
—
27
38
21
—
—
14
17
11
15
26
35
1000
500
22
1000
500
23
1000
500
Standard drug
1000
aLow activivity, 6–12 mm; moderate activity, 13–19 mm; high activity, 20–30 mm. —, no inhibition or
inhibition less than 5 mm.
5. Conversion of pyrano[3,2-g]chromene-3,7-dicarboxaldehydes 2 to other deriva-
tives 3–7 unfortunately produced very weak antimicrobial activities, which indi-
=
=
=
cated that C Oformyl is more effective than the exocyclic C N and C C groups.
6. On the other hand, pyrano[3,2-g]chromeno[4,3-c:7,6-c]dipyrazole-4,8-(4H)diones
22 and 23 recorded moderate activities against the tested microorganisms except
Gram-negative bacteria.
7. In conclusion, the objective of the present study was to synthesize and investigate
the antimicrobial activities of some new functionalized 4,6-dixo- and 4,8-dioxo-
pyrano[3,2-g]chromenes with the hope of discovering new structure leads for

3338
T. E. ALI ET AL.
antimicrobial agents. Generally, the prepared compounds showed lower to mod-
erate activities. However, none of the tested compounds was as or more active
than the reference drugs.
EXPERIMENTAL
The melting point was determined in an open capillary tube on a digital Stuart
SMP-3 apparatus. Infrared spectra were measured on a Fourier transform infrared
1
(FTIR) Nicolet IS10 spectrophotometer (cmꢀ1), using KBr disks. The H NMR
spectra were measured on Mercury-300BB (300 MHz), using DMSO-d6 as a solvent
and the chemical shifts d downfield from tetramethylsilane (TMS) as an internal
standard. The 13C NMR spectra could not be measured for all these compounds
because of their poor solubility in greater concentrations in most common solvents.
Mass spectra were recorded on a gas chromatographic DI analysis Shimadzu instru-
ment Q-2010 Plus at 70 eV. Elemental analyses were performed on Perkin-Elmer
2400II at the Chemical War Department, Ministry of Defense, Cairo, Egypt. All
the bis-Schiff bases 8,[29] 9,[30] 12,[31] 13,[31] bis-hydrazones 16,[32] and 19,[32] and
bis-(thio)semicarbazones 17,[33] and 18[33] were prepared according to the reported
procedures in the literature.
Synthesis of Compounds 2, 10, 11, 14, 15, 20, and 21: General
Procedure for Vilsmeier–Haack Formylation of 4,6-Diacetylresorcinol
(1), bis-Schiff Bases 8, 9, 12, 13, and bis-Hydrazones 16–19
The Vilsmeier–Haack reagent was prepared by adding POCl3 (60 mmol, 6 mL)
dropwise to ice-cold dry DMF (30 mL) while stirring. The mixture was then stirred
for 10–15 min at 0 ꢁC. Each one of the compounds 1, 8, 9, 12, 13, and 16–19
(10 mmol) was added as a solution in DMF (10 mL) to the Vilsmeier–Haack reagent.
Then the mixture was stirred for 6 h at 60–70 ꢁC. The reaction mixture was cooled
and poured into crushed ice, and 3 g of sodium acetate was added under constant
manual stirring. The reaction mixture was kept aside overnight. The resulting
precipitate was filtered off and crystallized from DMF to give the corresponding pro-
ducts 2, 10, 11, 14, 15, 20, and 21, respectively.
Synthesis of Compounds 3 and 4: General Procedure for
Condensation of 2 with Nitrogen Nucleophiles
A mixture of compound 2 (2.5 mmol, 0.67 g) and freshly distillated aniline and
hydroxylamine hydrochloride (5 mmol) in dry dimethylformamide (25 ml) was
heated under reflux for 6 h. After cooling, the formed precipitates were filtered off
and crystallized from dimethylformamide to give the products 3 and 4, respectively.
Synthesis of Compounds 5 and 6: General Procedure for
Condensation of 2 with Acyclic Carbon Nucleophiles
A mixture of compound 2 (2.5 mmol, 0.67 g), malononitrile, and ethyl cyano-
acetate (5 mmol) in dry dimethylformamide (25 ml) containing a few drops of

SUBSTITUTED PYRANO[3,2-g] CHROMENES
3339
triethylamine was heated under reflux for 6 h. After cooling, the formed precipitates
were filtered off and crystallized from dimethylformamide to give the products 5 and
6, respectively.
Synthesis of 5,5’-[(4,6-Dioxo-4H,6H-pyrano[3,2-g]chromene-3,7
-diyl)dimethylidene] Dipyrimidine-2,4,6(1H,3H,5H)-trione (7)
A mixture of compound 2 (2.5 mmol, 0.67 g) and barbaturic acid (5 mmol,
0.32 g) in glacial acetic acid (25 ml) and freshly fused sodium acetate (2 g) was heated
under reflux for 6 h. The reaction mixture was cooled, poured into crushed ice, and
kept under constant manual stirring for 1 h. The resulting precipitate was filtered off,
washed with water several times, and crystallized from dimethylformamide to give
the product 7.
Synthesis of Compounds 22 and 23: General Procedure for
Oxidation of 20 and 21 with Iodine
Iodine (10 mol%) and four to five drops of concentrated sulfuric acid were
added to a solution of each compound 20 and 21 (2.5 mmol) in dimethylsulfoxide
(15 ml). The reaction mixture was heated under reflux at 120 ꢁC for 10 h. The con-
tents were cooled to room temperature and poured into ice-cooled water. The sepa-
rated solids were filtered off and washed with diluted sodium thiosulfate solution.
The obtained products were crystallized from dimethylformamide to give the pro-
ducts 22 and 23, respectively.
SUPPORTING INFORMATION
Full characterization of the synthesized compounds and spectral data can be
found via Supplementary Content section of this article’s Web page.
CONCLUSION
An efficient one-pot synthesis of 4,6-dioxo-4H,6H-pyrano[3,2-g]chromene-3,7-
dicarboxaldehyde (2) was achieved from application of Vilsmeier–Haack formyla-
tion on 4,6-diacetylresorcinol. This general protocol provides a novel and facile
access to other substituted linearly and angularly pyrano[3,2-g]chromenes by sequen-
tial Vilsmeier–Haack formylation, intramolecular cyclization, and aromatization
reactions of Schiff bases and hydrazones of 4,6-diacetylresorcinol.
ACKNOWLEDGMENT
The authors are very grateful to the Department of Microbiology, Faculty of
Agriculture, Al-Azhar University, Nasr-City, Cairo, Egypt, for performing the anti-
microbial evaluation.

3340
T. E. ALI ET AL.
REFERENCES
1. Meng, G.; Sha, Y. W.; Zhang, R.; Bai, N. Mild synthesis of N0-aryl-N,N-dimethylforma-
midinium chloride by Vilsmeier–Haack reagent. Chin. Chem. Lett. 2011, 22, 1043–1046.
2. Chang, C. H.; Tsai, H. J.; Huang, Y. Y.; Lin, H. Y.; Wang, L. Y.; Wu, T. S.; Wong, F. F.
Selective synthesis of pyrazolo[3,4-d]pyrimidine, N-(1H-pyrazol-5-yl)formamide, or N-
(1H-pyrazol-5-yl)formamidine derivatives from N-1-substituted-5-aminopyrazoles with
new Vilsmeier-type reagents. Tetrahedron 2013, 69, 1378–1386.
3. Mehranpour, A. M.; Hashemnia, S.; Azamifar, F. Synthesis of new malonaldehyde
derivatives using 2-heteroaryl-substituted trimethinium salts. Tetrahedron Lett. 2013, 54,
321–323.
4. Marson, C. M. Reactions of carbonyl compounds with (monohalo) methyleniminium
salts (Vilsmeier reagents). Tetrahedron 1992, 48, 3659–3726.
5. Meth-Cohn, O. The synthesis of pyridines, quinolines, and other related systems by the
Vilsmeier and the reverse Vilsmeier method. Heterocycles 1993, 35, 539–557.
6. Smeets, S.; Asokan, C. V.; Motmans, F.; Dehaen, W. Synthesis and functionalization of
double-picket-fence porphyrins starting from 4,6-disubstituted pyrimidine-5-carbalde-
hydes. J. Org. Chem. 2000, 65, 5882–5885.
7. Fischer, G. W.; Schroth, W. Pyryliumverbindungen, IX: Pyryliumsalze aus ketovinyl-
enaminen. Chem. Ber. 1969, 102, 590–602.
8. Sabitha, G. 3-Formylchromone as a versatile synthon in heterocyclic chemistry. Aldrich.
Acta 1996, 29, 13–25.
9. Nohara, A.; Umetani, T.; Sanno, Y. A facile synthesis of chromone-3-carboxaldehyde,
chromone-3-carboxylic acid, and 3-hydroxymethylchromone. Tetrahedron Lett. 1973,
14, 1995–1998.
10. Nohara, A.; Umetani, T.; Sanno, Y. Studies on antianaphylactic agents, I: A facile syn-
thesis of 4-oxo-4H-1-benzopyran-3-carboxaldehydes by Vilsmeier reagents. Tetrahedron
1974, 30, 3553–3561.
11. Rowely, D. C.; Hansen, M. S. T.; Rhodes, D.; Sotrier, C. A.; Ni, H.; McCammon, J. A.;
Bushmanb, F. D.; Fenicala, W. Thalassiolins A–C: New marine-derived inhibitors of HIV
cDNA integrase. Bioorg. Med. Chem. 2002, 10, 3619–3625.
12. Murray, R. D. H. Progress in the Chemistry of Organic Natural Products: The Naturally
Occurring Coumarins; Springer: Vienna, 2002.
13. Romanelli, G. P.; Virla, E. G.; Duchowicz, P. R.; Gaddi, A. L.; Ruiz, D. M.; Bennardi,
D. O.; Ortiz, E. D. V.; Autino, J. C. Sustainable synthesis of flavonoid derivatives, qsar
study and insecticidal activity against the fall armyworm, Spodoptera frugiperda (Lep.:
Noctuidae). Agric. Food Chem. 2010, 58, 6290–6295.
14. Burlison, J. A.; Neckers, L.; Smith, A. B.; Maxwell, A.; Blagg, B. S. Novobiocin:
Redesigning a DNA gyrase inhibitor for selective inhibition of hsp90. J. Am. Chem.
Soc. 2006, 128, 15529–15536.
15. Sahidhara, K. V.; Kumar, A.; Kumar, M.; Sarker, J.; Sinha, S. Synthesis and in vitro
evaluation of novel coumarin–chalcone hybrids as potential anticancer agents. Bioorg.
Med. Chem. Lett. 2010, 20, 7205–7211.
16. Panteleon, V.; Kostakis, I. K.; Markos, P.; Pouli, N.; Andreadou, I. Synthesis and free
radical scavenging activity of some new spiropyranocoumarins. Bioorg. Med. Chem.
2008, 18, 5781–5784.
17. Dawane, B. S.; Konda, S. G.; Badade, R. G.; Bhosale, R. B. An efficient one-pot synthe-
sis of some new 2,4-diarylpyrido[3,2-c]coumarins as potent antimicrobial agents.
J. Heterocycl. Chem. 2010, 47, 237–241.
18. Rajagopal, R.; Sheno, U. V.; Padmanabhan, S.; Sequeira, S.; Seshardi, S. Synthesis of
fluorescent 2,3-fused coumarin derivatives. Dyes Pigments 1990, 13, 167–175.

SUBSTITUTED PYRANO[3,2-g] CHROMENES
3341
19. Abdel-Aziz, S. A.; Ali, T. E.; El-Mahdy, K. M.; Abdel-Karim, S. M. Synthesis and anti-
microbial activities of some novel bis-pyrazole derivatives containing a hydrophosphoryl
unit. Eur. J. Chem. 2011, 2, 25–35.
20. Hassanin, H. M.; Ibrahim, M. A.; Alnamer, Y. A. Synthesis and antimicrobial activity of
some novel 4-hydroxyquinolin-2(1H)-ones and pyrano[3,2-c] quinolinones from 3-(1-
ethy1–4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)-3-oxopropanoic acid. Turk. J. Chem.
2012, 36, 682–699.
21. Ali, T. E.; Ibrahim, M. A. Synthesis and antimicrobial activity of chromone-linked
2-pyridone fused with 1,2,4-triazoles, 1,2,4-triazines, and 1,2,4-triazepines ring systems.
J. Braz. Chem. Soc. 2010, 21, 1007–1016.
22. Reddy, M. V. B.; Shen, Y.-C.; Ohkoshi, E.; Bastow, K. F.; Qian, K.; Lee, K.-H.; Wu,
T.-S. Bis-chalcone analogues as potent NO production inhibitors and as cytotoxic agents.
Eur. J. Med. Chem. 2012, 47, 97–103.
23. Mallaiah, B. V.; Srimannarayana, G. Synthesis and antiallergic activity of some linearly
fused benzo[1,2-b:5,4-b0]dipyrones. Indian J. Chem. 1982, 21B, 975–976.
24. Lebedev, A. V.; Lebedeva, A. B.; Sheludyakov, V. D.; Kovaleva, E. A.; Ustinova, O. L.;
Kozhevnikov, I. B. Synthesis of 3-substituted arylpyrazole-4-carboxylic acids. Russ. J.
Gener. Chem. 2005, 75, 782–789.
25. Eiden, F.; Schaumburg, E. A. Pyrazolo-chromone, benzo-di- und tripyrazole aus
benzo-di- und tripyronen. Tetrahedron Lett. 1972, 13, 1593–1596.
26. Sharma, P. K.; Chandak, N.; Kumar, P.; Sharma, C.; Aneja, K. R. Synthesis and biologi-
cal evaluation of some 4-functionalized-pyrazoles as antimicrobial agents. Eur. J. Med.
Chem. 2011, 46, 1425–1432.
27. Lokhande, P.; Hassanzadeh, K.; Konda, S. G. A novel and efficient approach for the
synthesis of new halo substituted 2-arylpyrazolo[4,3-c]coumarin derivatives. Eur. J. Chem.
2011, 2, 223–228.
28. Rahman, A. U.; Choudhary, M. I.; Thomsen, W. J. Bioassay Techniques for Drug
Development; Harwood Academic: Amsterdam, the Netherlands, 2001.
29. Abu-Hussen, A. A. A. Synthesis and spectroscopic studies on ternary bis-Schiff-base
complexes having oxygen and=or nitrogen donors. J. Coord. Chem. 2006, 59, 157–176.
30. Shebl, M. Synthesis and spectroscopic studies of binuclear metal complexes of a tetra-
dentate N2O2 Schiff base ligand derived from 4,6-diacetylresorcinol and benzylamine.
Spectrochim. Acta Part A 2008, 70, 850–859.
31. Pandya, J. H.; Ganatra, K. J. Synthesis, characterization, and biological evaluation of
bis-bidentate Schiff base metal complexes. Inorg. Chem.: Indian J. 2008, 3, 182–187.
32. Shyamala, B. S.; Jayatyagaraju, V. bis-Bidenticity of 2,4-dihydroxy-5-acetylacetophenone
and its derivatives with divalent nickel and copper. Synth. React. Inorg. Met.-Org. Chem.
2003, 33, 63–75.
33. Seleem, H. S.; El-Shetary, B. A.; Khalil, S. M.; Mostafa, M.; Shebl, M. Structural
diversity in copper(II) complexes of bis(thiosemicarbazone) and bis(semicarbazone)
ligands. J. Coord. Chem. 2005, 58, 479–493.