Synthesis of novel bis(chromenes) and bis(chromeno[3,4-C]pyridine) incorporating piperazine moiety

Article abstract of DOI:10.1080/00397911.2019.1595658

Novel bis(2-oxo-2H-chromene) as well as bis(2-imino-2H-chromene) derivatives incorporating piperazine moiety were prepared by the cyclocondensation reaction of bis(2-hydroxybenzaldehyde) with two equivalents of each of the appropriate β-ketoesters or acetonitrile derivatives. The bis(2-imino-2H-chromene-3-carbothioamide) derivative was used as a key synthon for construction of novel bis(3-(4-substituted thiazol-2-yl)-2H-chromen-2-one) derivatives via its cyclocondensation with a series of the appropriate α-halocarbonyl derivatives. Moreover, the bis(2-hydroxybenzaldehyde) reacted with four equivalents of the appropriate acetonitrile derivatives to afford the corresponding bis(3H-chromeno[3,4-c]pyridine) derivatives. Elucidation of the structure of the novel bis(chromenes) bearing piperazine nucleus was established by the spectral data and elemental analyses.

Full text of DOI:10.1080/00397911.2019.1595658

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis of novel bis(chromenes) and
bis(chromeno[3,4-C]pyridine) incorporating
piperazine moiety
Ahmed E. M. Mekky & Sherif M. H. Sanad
To cite this article: Ahmed E. M. Mekky & Sherif M. H. Sanad (2019): Synthesis of novel
bis(chromenes) and bis(chromeno[3,4-C]pyridine) incorporating piperazine moiety, Synthetic
Communications, DOI: 10.1080/00397911.2019.1595658
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https://doi.org/10.1080/00397911.2019.1595658
Synthesis of novel bis(chromenes) and
bis(chromeno[3,4-C]pyridine) incorporating
piperazine moiety
Ahmed E. M. Mekky
and Sherif M. H. Sanad
Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
ABSTRACT
ARTICLE HISTORY
Received 7 February 2019
Novel bis(2-oxo-2H-chromene) as well as bis(2-imino-2H-chromene)
derivatives incorporating piperazine moiety were prepared by the
cyclocondensation reaction of bis(2-hydroxybenzaldehyde) with
two equivalents of each of the appropriate b-ketoesters or aceto-
nitrile derivatives. The bis(2-imino-2H-chromene-3-carbothioamide)
derivative was used as a key synthon for construction of novel bis(3-
(4-substituted thiazol-2-yl)-2H-chromen-2-one) derivatives via its
cyclocondensation with a series of the appropriate a-halocarbonyl
derivatives. Moreover, the bis(2-hydroxybenzaldehyde) reacted with
four equivalents of the appropriate acetonitrile derivatives to afford
the corresponding bis(3H-chromeno[3,4-c]pyridine) derivatives.
Elucidation of the structure of the novel bis(chromenes) bearing
piperazine nucleus was established by the spectral data and elemen-
tal analyses.
KEYWORDS
Piperazine; bis(chromenes);
bis(chromeno[3,4-c]pyri-
dines); bis((thiazolyl)
chromenes)
GRAPHICAL ABSTRACT
Introduction
Chromenes represent a noteworthy class of both naturally occurring and synthetic het-
erocyclic derivatives incorporating oxygen with typical benzopyrone skeleton. In recent
years, using of chromenes in medicinal chemistry attracts more interest.[1] Chromenes
CONTACT Sherif M. H. Sanad
sherif_hamed1980@yahoo.com
Chemistry Department, Faculty of Science, Cairo
University, Giza 12613, Egypt.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

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A. E. M. MEKKY AND S. M. H. SANAD
Figure 1. Some bioactive drugs bearing chromene or piperazine core.
exhibit excellent contributions in both the inhibition and healing of various diseases.[2–4]
Thus, chromenes show a wide spectrum of bioactivities such as antioxidant,[5–7] anti-
microbial[8–10] and anti-inflammatory, analgesic,[11–13] and anticancer agents.[14–16]
Moreover, chromenes such as warfarin and dicoumarol have been used as essential oral
anticoagulant drugs (Figure 1).[17,18] Also, chromenes exhibit a wide range of anti neu-
rodegenerative activities such as anti-Alzheimer’s disease[19–22] and anti-Parkinson’s
disease.[23–25]
On the other hand, piperazine core is included in various synthetic drugs as antiangi-
nals, antidepressants, antihistamines, antiserotonergics, and antipsychotics. Befuraline
and ziprasidone are examples of therapeutic drugs, incorporating piperazine moiety,
approved by the FDA (Figure 1).[26–30] Molecules bearing both bis- and hybrid-hetero-
cycles were found to show wide bioactivities, especially as fungicidal, antimicrobial, and
anthelmintic.[31–34] Various publications reported the synthesis of chromene and pipera-
zine derivatives in addition to bis-heterocyclic compounds due to their important bio-
logical activity.[35–45]
Inspired by the above-mentioned findings, and in continuation of our attention in
the preparation of bis(heterocycles),[46–55] our research group report herein, the syn-
thetic potential of the bis(2-hydroxybenzaldehyde) as key intermediate for the synthesis
of novel hybrid bis(chromenes) bearing piperazine moiety.
Results and discussion
Initially, our goal was to design facile synthetic route for the preparation of piperazine-
chromene hybrids. 1,4-Bis[(3-formyl-4-hydroxyphenyl)methyl]piperazine 3[56] was
chosen as the key synthon for this purpose. Compound 3 was simply prepared from the
reaction of 5-(chloromethyl)-2-hydroxybenzaldehyde 2 with piperazine in dichlorome-
thane in the presence of triethylamine (TEA). Compound 2 was prepared by the reac-
tion of salicylaldehyde with formaldehyde in hydrochloric acid (Scheme 1).[57]
The bis(2-hydroxybenzaldehyde) 3 has encouraged us to study its reactivity as a syn-
thon for construction of a novel bis(2-oxo-2H-chromene) derivatives by its treatment

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3
Scheme 1. Synthesis of bis(2-hydroxybenzaldehyde) 3.
Scheme 2. Synthesis of bis(2-oxo-2H-chromenes) 5, 7, and 9.
with b-ketoesters and diethyl malonate, respectively. Generally, such synthetic approach
involves a Knoevenagel condensation followed by an intramolecular cyclization. Thus,
the treatment of bis(2-hydroxybenzaldehyde) 3 with two equivalents of ethyl acetoace-
tate 4 in refluxing dioxane in the presence of a catalytic amount of diethyl amine
(DEA) within three hours produces one product that has been identified as bis(2-oxo-
2H-chromene) derivative 5 (Scheme 2). The mass spectrum of the formed product gave
1
a molecular ion peak at m/z ¼ 486. Its H NMR spectrum revealed three singlet signals
at d 2.40, 2.57 and 3.53 due to piperazine, acetyl and methylene protons, two doublets,
and one singlet signals in the region d 7.40–7.83 due to aromatic protons, accompanied
by chromene H-4 as singlet signal at d 8.62 (see Experimental section).
Similarly, ethyl benzoylacetate 6 and diethyl malonate 8 were reacted with bis(2-
hydroxybenzaldehyde) 3, under the same reaction condition, affording bis(2-oxo-2H-
chromene) 7 and 9, respectively (Scheme 2).
Also, bis(2-hydroxybenzaldehyde) 3 was reacted with active methylene compounds
containing nitrile function to obtain a series of bis(2-imino-2H-chromenes). For
example, the cyclocondensation of two equivalents of ethyl cyanoacetate 10 with bis(2-
hydroxybenzaldehyde) 3 in refluxing dioxane in the presence of catalytic amount of
DEA afforded bis(2-imino-2H-chromene-3-carboxylate) derivative 11 (Scheme 3). The
elemental analysis and spectral data were fully well-matched with the given structure
11. For example, its IR spectrum showed the absence of nitrile group absorption band
and presence of NH absorption band at 3315 cmꢀ1. Its mass spectrum gave a molecular
1
ion peak at m/z ¼ 544. The H NMR spectrum of 11 offered triplet and quartet signals
at d 1.05 and d 4.31 due to ethyl group protons, two singlet signals at d 2.41 and 3.52

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A. E. M. MEKKY AND S. M. H. SANAD
Scheme 3. Synthesis of bis(2-imino-2H-chromenes) 11, 13, 15, 17, and bis(2-oxo-2H-chromene) 18.
due to piperazine and methylene protons, doublet and multiplet signals in the region d
7.44–7.72 for aromatic protons, a singlet signal at d 8.90 attributable to chromene H-4,
in addition D2O-exchangeable singlet signal at d 9.31 due to NH protons (see
Experimental section).
Analogously, bis(2-hydroxybenzaldehyde) 3 was cyclocondensed with two equivalents
of 2-cyanoacetamide 12 and two equivalents 2-cyanoethanethioamide 14 under the
same previous reaction conditions obtaining bis(2-imino-2H-chromene-3-carboxamide)
13 and bis(2-imino-2H-chromene-3-carbothioamide) 15, respectively (Scheme 3). The
structures of the formed bis(2-imino-2H-chromene) derivatives 13 and 15 were eluci-
dated by elemental analyses, spectral data (see Experimental section).
The treatment of bis(2-hydroxybenzaldehyde) 3 with two equivalents of malononitrile
16 in refluxing dioxane in the presence of DEA afforded the corresponding bis(2-
imino-2H-chromene-3-carbonitrile) derivative 17 (Scheme 3). The IR spectrum of 17
revealed absorption bands at 3301 and 2187 cmꢀ1 due to (NH) and (CN), respectively.
1
Its H NMR showed the presence of a singlet signal at d 8.35 due to chromene H-4 and
a typical D2O-exchangeable singlet signal at d 8.78 attributed to imino proton (NH).
All other protons were seen at the expected chemical shifts and integral values (see
Experimental section). On the other hand, two equivalents of malononitrile 16 were
reacted with bis(2-hydroxybenzaldehyde) 3 in acetic acid and sodium acetate mixture
yielding bis(2-oxo-2H-chromene-3-carbonitrile) derivative 18 (Scheme 3). The structure

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SYNTHETIC COMMUNICATIONSV
5
Scheme 4. Synthesis of bis(3-(thiazol-2-yl)-2H-chromen-2-ones) 21, 23a-c, 25, and 27.
of the latter compound 18 was confirmed by elemental analysis, spectral data (see
Experimental section).
Bis(2-imino-2H-chromene-3-carbothioamide) derivative 15 has encouraged us to
hybrid the chromene ring with thiazole moiety via its cyclocondensation with a-halocar-
bonyl compounds and chloroacetonitrile, respectively. Thus, the reaction of bis(2-
imino-2H-chromene-3-carbothioamide) derivative 15 with chloroacetone 19 in refluxing
dimethylformamide (DMF) in the presence of TEA as a catalyst yielded bis(3-(4-methyl-
thiazol-2-yl)-2H-chromen-2-one) derivative 21 (Scheme 4). The IR spectrum of 21
revealed the absence of (NH) and (NH2) absorption bands and presence of (C ¼ O)
absorption band at 1719 cmꢀ1. Its mass spectrum gave a molecular ion peak at m/
1
z ¼ 596. Its H NMR showed the presence of a characteristic two singlet signals at d
2.60 and 8.38 due to thiazole CH3 group and chromene H-4, respectively (see
Experimental section). It is worth mentioning that bis(2-imino-2H-chromene-3-carbo-
thioamide) derivative 15 easily cyclocondensed with chloroacetone 19 to form the corre-
sponding bis(3-(4-methylthiazol-2-yl)-2H-chromen-2-imine) (20). We failed to obtain

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A. E. M. MEKKY AND S. M. H. SANAD
Scheme 5. Synthesis of bis(4-oxo-3H-chromeno[3,4-c]pyridine) 28 and bis(4-thioxo-3H-chromeno[3,4-
c]pyridine) 29.
the latter due to its rapid hydrolysis under the reaction conditions to give bis(3-(4-
methylthiazol-2-yl)-2H-chromen-2-one) derivative 21 (Scheme 4).
In the same manner, 2-bromo-1-phenylethanone 22a, 2-bromo-1-(4-chlorophenyl)e-
than-1-one 22b, 2-bromo-1-(4-bromophenyl)ethan-1-one 22c, 2-chloroacetonitrile 24,
and ethyl chloroacetate 26 were reacted with bis(2-imino-2H-chromene-3-carbothioa-
mide) derivative 15 in DMF, in the presence of a catalytic amount of TEA to afford the
corresponding bis(3-(4-arylthiazol-2-yl)-2H-chromen-2-one) 23a–c, bis(3-(4-aminothia-
zol-2-yl)-2H-chromen-2-one) 25, and bis(3-(4-oxothiazol-2-yl)-2H-chromen-2-one) 27,
respectively (Scheme 4).
In continuation of our work, we take a peek into the reaction of bis(2-hydroxybenzal-
dehyde) 3 with four equivalents of active methylene compounds containing nitrile func-
tion. For example, four equivalents of 2-cyanoacetamide 12 was reacted with compound
3 in refluxing dioxane and few drops of DEA as a basic catalyst, affording bis(4-oxo-
1
3H-chromeno[3,4-c]pyridine) derivative 28 (Scheme 5). The H NMR of 28 showed
three D2O-exchangeable singlet signals d at 7.59, 8.91, and 11.60 due to NH2, imino
proton, and pyridine NH, respectively. All other protons revealed at the expected chem-
ical shifts and integral values (see Experimental section). Similarly, bis(2-hydroxybenzal-
dehyde) 3 was reacted with four equivalents of 2-cyanoethanethioamide 14 under the
same conditions to afford bis(4-thioxo-3H-chromeno[3,4-c]pyridine) 29 (Scheme 5).
Conclusion
We describe a facile synthetic route for a series of novel bis(2-oxo-2H-chromenes),
bis(2-imino-2H-chromenes) and bis(3H-chromeno[3,4-c]pyridines) incorporating
piperazine moiety via the cyclocondensation of bis(2-hydroxybenzaldehyde) with the
appropriate b-ketoesters or acetonitriles. Also, bis(3-(4-substituted thiazol-2-yl)-2H-
chromen-2-ones) are prepared by the cyclocondensation of bis(2-imino-2H-chromene-
3-carbothioamide) with a series of the appropriate a-halocarbonyl derivatives. The struc-
ture of the target chromene-piperazine hybrids was elucidated by both spectral data and
elemental analyses.

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7
Experimental
All organic solvents used in this study were commercial. All other chemicals were
acquired from Merck (Merck KGaA, Darmstadt, Germany) or Aldrich (Sigma-Aldrich
Corporation as a subsidiary of Merck KGaA, St. Louis, Missouri, USA) and not sub-
jected for further purification. The melting points are uncorrected and measured on a
Stuart melting point device. IR spectra were recorded on a Smart iTR, which is an
ultra-high-performance, versatile Attenuated Total Reflectance (ATR) sampling acces-
sory on the Nicolet iS10 FT-IR spectrometer. NMR spectra were recorded on Varian
1
Mercury spectrophotometer (300 MHz for H and 75 MHz for 13C) using TMS as an
internal standard and DMSO-d6 as solvent and chemical shifts were expressed as d ppm
units. units. Mass spectra were recorded on a GC-MS-QP1000EX spectrometer using
inlet type at 70 eV. Elemental analyses were performed using a EuroVector instrument
C, H, N, S analyzer EA3000 Series. Compounds 2[57] and 3[56] were prepared according
to the literature procedure.
Synthesis of bis(2-oxo-2H-chromene) derivatives 5, 7, and 9
A mixture of bis(2-hydroxybenzaldehyde) 3 (5 mmol) and each of ethyl acetoacetate 4,
ethyl benzoylacetate 6 or diethyl malonate 8 (10 mmol) in dioxane (20 mL) in the pres-
ence of five drops of DEA was heated at reflux for 3 h. The reaction was cooled, fil-
trated, washed with cold ethanol and the reaction products were recrystallized from the
proper solvent.
1,4-Bis[(3-acetyl-2-oxo-2H-chromen-6-yl)methyl]piperazine (5)
Yellow crystals (glacial acetic acid, 91%); m.p. 239–241 ꢁC; IR (t cmꢀ1): 1725, 1678
1
(CO); H NMR (DMSO-d6): d 2.40 (s, 8H, 4 piprazine CH2), 2.57 (s, 6H, 2 CH3), 3.53
(s, 4H, 2 CH2), 7.40 (d, J ¼ 8.5 Hz, 2H, ArH), 7.65 (d, J ¼ 8.5 Hz, 2H, ArH), 7.83 (s, 2H,
ArH), 8.62 (s, 2H, 2 chromene H-4); 13C NMR (DMSO-d6): d 30.5, 52.3, 60.6, 117.2,
122.0, 124.5, 129.1, 131.3, 137.0, 147.4, 153.8, 159.2, 195.4; MS m/z (%): 486 (Mþ, 65.2);
Anal. for C28H26N2O6: C, 69.12; H, 5.39; N, 5.76. Found: C, 69.38; H, 5.60; N, 5.59%.
ORCID
Ahmed E. M. Mekky
Sherif M. H. Sanad
http://orcid.org/0000-0002-8226-010X
http://orcid.org/0000-0002-0186-6418
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