Efficient synthesis and characterization of novel bis(chromenes) and bis(benzo[f]chromenes) linked to thiazole units

Article abstract of DOI:10.1080/00397911.2020.1846748

New carbothioamides, linked to chromene or benzo[f]chromene units, were taken as key synthons for the present study. These carbothioamides were prepared, in good yields, by the cyclocondensation of the appropriate 2-hydroxybenzaldehydes or 2-hydroxy-1-naphthaldehyde with 2-cyanoethanethioamide. Next, the precursors carbothioamides were reacted with different α-halocarbonyl compounds and bis(α-bromoketones). These reactions afforded the corresponding 4-(substituted)thiazoles and thiazol-4(5H)-ones, in addition to bis(thiazoles), linked to different cores. Additionally, thiazol-4(5H)-ones were condensed with the appropriate bis(aldehydes) to yield the corresponding bis(thiazol-4(5H)-ones), linked to chromene or benzo[f]chromene units via different cores.

Full text of DOI:10.1080/00397911.2020.1846748

Synthetic Communications
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Chemistry
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Efficient synthesis and characterization of novel
bis(chromenes) and bis(benzo[f]chromenes) linked
to thiazole units
Sherif M. H. Sanad & Ahmed E. M. Mekky
To cite this article: Sherif M. H. Sanad & Ahmed E. M. Mekky (2020): Efficient synthesis and
characterization of novel bis(chromenes) and bis(benzo[f]chromenes) linked to thiazole units,
Synthetic Communications, DOI: 10.1080/00397911.2020.1846748
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https://doi.org/10.1080/00397911.2020.1846748
Efficient synthesis and characterization of novel
bis(chromenes) and bis(benzo[f]chromenes) linked to
thiazole units
Sherif M. H. Sanad
and Ahmed E. M. Mekky
Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
ABSTRACT
ARTICLE HISTORY
Received 20 September 2020
New carbothioamides, linked to chromene or benzo[f]chromene
units, were taken as key synthons for the present study. These carbo-
thioamides were prepared, in good yields, by the cyclocondensation
of the appropriate 2-hydroxybenzaldehydes or 2-hydroxy-1-naphthal-
dehyde with 2-cyanoethanethioamide. Next, the precursors carbo-
thioamides were reacted with different a-halocarbonyl compounds
and bis(a-bromoketones). These reactions afforded the correspond-
ing 4-(substituted)thiazoles and thiazol-4(5H)-ones, in addition to
bis(thiazoles), linked to different cores. Additionally, thiazol-4(5H)-
ones were condensed with the appropriate bis(aldehydes) to yield
the corresponding bis(thiazol-4(5H)-ones), linked to chromene or
benzo[f]chromene units via different cores.
KEYWORDS
3H-Benzo[f]chromen-3-one;
2H-Chromen-2-one;
hantzsch thiazole synthesis;
thiazol-4(5H)-one
GRAPHICAL ABSTRACT
Introduction
Chromenes are a category of naturally occurring as well as synthetic heterocyclic deriva-
tives. They belong to the family of benzopyrones and have a wide range of cytoprotec-
tive and modulatory roles which can be translated into multiple disease therapeutic
potentials. The level of biological activity seems to be determined by their
CONTACT Sherif M. H. Sanad
sherif_hamed1980@yahoo.com
Chemistry Department, Faculty of Science, Cairo
University, Giza, Egypt.
Supplemental data for this article can be accessed on the publisher’s website
ß 2020 Taylor & Francis Group, LLC

2
S. M. H. SANAD AND A. E. M. MEKKY
Figure 1. Structure of some chromene-based anticoagulant drugs.
physicochemical properties.[1] In recent years, design of new drugs incorporating chro-
mene moiety is an interesting field in medicinal and pharmaceutical chemistry.[2]
Heterocyclic derivatives bearing chromene moiety exhibit excellent activity in the
treatment of neurodegenerative diseases including anti-Alzheimer’s and anti-Parkinson’s
diseases.[3,4] This is due their exceptional selective inhibitory activities of acetylcholin-
esterase,[5–8] and monoamine oxidase B enzymes.[8–11] Additionally, chromenes play a
major role in coagulation inhibition. Figure 1 shows some approved anticoagulant-based
chromenes.[12,13]
Chromene derivatives display a wide range of bioactivities including antimicro-
bial,[14–18], anti-inflammatory, analgesic,[19–22] antioxidant,[6,23,24] and antifungal.[25]
Furthermore, they demonstrate a significant wide range of bioactivities including antitu-
mor activities,[26–30] antiproliferative,[16,31] anti-Hepatitis C virus,[32,33] and anthelmin-
tic agents.[22]
Chromene hybrids linked to thiazole units possess tremendous bioactivities. These
hybrids can act as antimicrobial,[34–36] anticancer,[34,37–41] antioxidant,[40,42] antifun-
gal.[43] They are also selective inhibitors for acetylcholinesterase,[44] and alkaline phos-
phatase.[45] In addition, these hybrids act as potential adenosine receptor ligands,[46]
promising inhibitors of a-glucosidase,[47] and aldose reductase.[48]
Numerous publications reported the synthesis of chromenes and their hybrids with
thiazole units based on their remarkable pharmaceutical and medicinal uses.[49–54] In
connection with our efforts to design facile synthetic routes for the preparation of bis-
heterocyclic derivatives,[55–61] we report herein efficient strategies for the synthesis of
bis(chromenes) and benzo[f]chromene hybrids, linked to thiazole units via differ-
ent cores.
Results and discussion
2-Hydroxy-5-((p-tolylthio)methyl)benzaldehyde 3a was simply prepared from the reac-
tion of 5-(chloromethyl)-2-hydroxybenzaldehyde 1[62] with 4-methylbenzenethiol 2 in
ethanol containing an equivalent amount of potassium hydroxide.[63,64] On the other
hand, the reaction of 1 with diethylamine in acetonitrile at reflux gave 5-((diethylami-
no)methyl)-2-hydroxybenzaldehyde 3b (Scheme 1).[65] Cyclocondensation of 2-hydroxy-
benzaldehydes 3a,b with 2-cyanoethanethioamide 5, in the presence of diethylamine
(DEA) in dioxane at reflux, obtaining the corresponding 2-imino-2H-chromene-3-car-
bothioamides 6a and 6b, respectively (see Scheme 1 and Experimental section).[49]
The carbothioamide functional group in 2-imino-2H-chromene-3-carbothioamides
6a,b allowed us to hybridize the chromene ring with thiazole moiety via its

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3
Scheme 1. Synthesis of 2-imino-2H-chromene-3-carbothioamides 6a and 6b.
Scheme 2. Cyclocondensation of 2-imino-2H-chromene-3-carbothioamides 6a,b with a-halocarbonyl
compounds 7, 9, 11, and 13.
cyclocondensation with a-halocarbonyl compounds. Thus, the reaction of 2-imino-2H-
chromene-3-carbothioamide derivative 6a with chloroacetone 7, in DMF at reflux in the
presence of triethylamine (TEA) as a basic catalyst. yielded 3-(4-methylthiazol-2-yl)-6-
1
((p-tolylthio)methyl)-2H-chromen-2-one 8a (Scheme 2).[66] The H-NMR spectrum of
8a showed six singlet signals at d 2.21, 2.60, 4.10, 7.47, 7.67 and 8.39 ppm assigned to p-
CH3, thiazole-CH3, SCH2, thiazole-H, chromene-H5 and chromene-H4 protons, respect-
ively. It revealed also two doublet signals at d 7.10 and 7.21 ppm corresponding to four
aromatic protons, in addition to two doublet signals at d 7.26 and 7.39 ppm

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S. M. H. SANAD AND A. E. M. MEKKY
Scheme 3. Synthesis of bis[3-(thiazol-2-yl)-2H-chromen-2-ones] 16a and 16b.
corresponding to chromene-H7 and H8 protons, respectively. Its 13C-NMR spectrum
revealed three signals at d 14.2, 20.3, 20.4, 35.9 and 165.2 ppm attributed to thiazole-
CH3, p-CH3, SCH2 and CO carbons, in addition to 15 signals corresponding to aro-
matic, thiazole and chromene carbons (see Experimental section). Also, chloroacetone 7
cyclocondensed with 6b in the same reaction conditions to afford 6-((diethylamino)-
methyl)-3-(4-methylthiazol-2-yl)-2H-chromen-2-one 8b.
In the same manner, ethyl chloroacetate 9, a-bromoketones 11 and 13 were reacted
with the appropriate carbothioamides 6a,b in DMF in the presence of TEA to afford
the corresponding 2-(2-oxo-2H-chromen-3-yl)thiazol-4(5H)-ones 10a,b and 3-(thiazol-
2-yl)-2H-chromen-2-ones 12a,b and 14a,b, respectively (see Scheme
2
and
Experimental section).[49]
Inspired by 2-imino-2H-chromene-3-carbothioamides 6a,b cyclocondensation with
a-halocarbonyl compounds, we examined the reaction of 6a,b with bis(a-bromoketone)
15.[67] These reactions were carried out using TEA as a basic catalyst in DMF at reflux
and resulted in the formation of the corresponding bis(3-(thiazol-2-yl)-2H-chromen-2-
1
ones) 16a,b, respectively (Scheme 3).[68] The H-NMR spectrum of 16a, as a representa-
tive example, showed a quintet and triplet signals at d 2.18 and 4.17 ppm corresponding
to propane spacer. In addition, it revealed five singlet signals at d 2.25, 4.12, 7.71, 8.03
and 8.51 ppm assigned to p-CH3, SCH2, chromene-H5, thiazole-H and chromene-H4
protons, respectively. Furthermore, it showed a multiplet signal at d 7.06–7.89 ppm cor-
responding to 16 aromatic protons, in addition to protons of chromene-H7 and H8. Its
13C-NMR spectrum revealed five signals at d 20.2, 28.3, 35.8, 66.4 and 164.7 ppm attrib-
uted to p-CH3, OCH2CH2, SCH2, OCH2 and CO carbons, in addition to 19 signals cor-
responding to aromatic, thiazole and chromene carbons (see Experimental section).
Stimulated by the results achieved with a-halocarbonyl compounds (7, 9, 11, and 13)
and bis(a-bromoketone) 15, we extended our investigation by the reaction of 6a,b
with bis(a-bromoketone) 17, linked to thieno[2,3-b]thiophenecore.[69] Using the
same reaction conditions that yielded the products 16, compound 17 was reacted
with the appropriate 2-imino-2H-chromene-3-carbothioamides 6a,b to afford the
corresponding bis[3-(thiazol-2-yl)-2H-chromen-2-ones] 18a,b, respectively, linked to

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Scheme 4. Synthesis of thieno[2,3-b]thiophene-linked bis[3-(thiazol-2-yl)-2H-chromen-2-ones] 18a
and 18b.
Scheme 5. Synthesis of bis(2-(2-oxo-2H-chromen-3-yl)thiazol-4(5H)-one) derivatives 20a and 20b.
thieno[2,3-b]thiophene-2,5-dicarboxylate core by phenoxymethyl linkage (see Scheme 4
and Experimental section).[69]
The structure of 2-(2-oxo-2H-chromen-3-yl)thiazol-4(5H)-one 10,b derivatives
encouraged us to explore their reaction with the appropriate bis(aldehyde).[70] Thus,
4,40-(propane-1,3-diylbis(oxy))dibenzaldehyde 19 reacted with two equivalents of the
appropriate 10,b. The reaction was carried out in DMF at reflux containing a few drops
of piperidine as a catalyst, to afford the corresponding bis(2-(2-oxo-2H-chromen-3-
yl)thiazol-4(5H)-one) derivatives 20a and 20b, respectively (Scheme 5).[71] The 1H-
NMR spectrum of 20b, as a representative example, revealed a triplet and quartet

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S. M. H. SANAD AND A. E. M. MEKKY
Scheme 6. Synthesis of thieno[2,3-b]thiophene-linked bis(2-(2-oxo-2H-chromen-3-yl)thiazol-4(5H)-one)
derivatives 22a and 22b.
signals at d 1.00 and 2.44 ppm corresponding to ethyl protons. Additionally, it showed a
quintet and triplet signals at d 2.22 and 4.19 ppm corresponding to propane spacer.
Also, it revealed four singlet signals at d 3.48, 7.58, 8.03 and 8.26 ppm assigned to
NCH2, chromene-H5, methine-H and chromene-H4 protons, respectively. Furthermore,
it showed a multiplet signal at d 7.07–7.70 ppm corresponding to 16 aromatic protons,
in addition to protons of chromene-H7 and H8. Its 13C-NMR spectrum revealed six sig-
nals at d 11.4, 28.5, 46.6, 56.3, 66.6 and 168.3 ppm attributed to CH2CH3, OCH2CH2,
CH2CH3, NCH2, OCH2 and thiazole-CO carbons, in addition to 16 signals correspond-
ing to aromatic, methine, thiazole and chromene carbons (see Experimental section).
These findings are consistent with studies previously published by Thanh and Toan
et.al. on similar coumarin hybrids.[72–74]
Also, 2-(2-oxo-2H-chromen-3-yl)thiazol-4(5H)-one derivatives 10,b were condensed,
under the latter reaction conditions, with diethyl 3,4-bis((4-formylphenoxy)methyl)th-
ieno[2,3-b]thiophene-2,5-dicarboxylate 21 affording the thieno[2,3-b]thiophene-linked
bis(2-(2-oxo-2H-chromen-3-yl)thiazol-4(5H)-one) derivatives 22a and 22b, respectively
(see Scheme 6 and Experimental section).[71]
From all above-mentioned results, we had intended to prepare bis[2-(thiazol-2-yl)-
3H- benzo[f]chromen-3-one] and bis[2-(3-oxo-3H-benzo[f]chromen-2-yl)thiazol-4(5H)-
one]. To this end, 3-imino-3H-benzo[f]chromene-2-carbothioamide 24 was prepared
through the cyclocondensation of 2-hydroxy-1-naphthaldehyde 23 with 2-cyanoethane-
thioamide 5. This reaction was carried out using the catalyst DEA in dioxane at reflux.
Additionally, 2-(3-oxo-3H-benzo[f]chromen-2-yl)thiazol-4(5H)-one 25 was prepared via
the reaction of ethyl chloroacetate 9 with 24, in DMF containing DEA at reflux
(Scheme 7).[66]

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7
Scheme 7. Synthesis of bis[2-(thiazol-2-yl)-3H- benzo[f]chromen-3-ones] 26 and 27.
Scheme 8. Synthesis of bis[2-(3-oxo-3H-benzo[f]chromen-2-yl)thiazol-4(5H)-one] 28 and 29.
Then, 3-imino-3H-benzo[f]chromene-2-carbothioamide 24 allowed to react with the
appropriate bis(a-bromoketones) 15 and 17, in the presence of TEA as a catalyst in
DMF at reflux, to yield the corresponding bis[2-(thiazol-2-yl)-3H-benzo[f]chromen-3-
1
ones] 26 and 27, respectively (Scheme 7).[68,69] The H-NMR spectrum of 27, as a
representative example, revealed a triplet and quartet signals at d 1.31 and 4.33 ppm cor-
responding to ethoxy protons. Additionally, it revealed two singlet signals at d 5.61 and

8
S. M. H. SANAD AND A. E. M. MEKKY
7.99 ppm assigned to OCH2 and thiazole-H protons, respectively. Furthermore, it
showed a multiplet signal at d 7.06–8.08 corresponding to 8 aromatic protons, in add-
ition to 14 protons of benzo[f]chromene. Its 13C-NMR spectrum revealed five signals at
d 14.3, 61.4, 62.3, 162.2 and 166.4 ppm attributed to OCH2CH3, OCH2CH3, OCH2,
chromene-CO and ester-CO carbons, in addition to 23 signals corresponding to aro-
matic,
thiazole,
thienothiophene
and
benzochromene
carbons
(see
Experimental section).
Two equivalents of 2-(3-oxo-3H-benzo[f]chromen-2-yl)thiazol-4(5H)-one 25 condensed
with the appropriate bis(aldehydes) 19 and 21, in DMF containing piperidine. The
mixture was heated at reflux for 5 h to afford the corresponding bis[2-(3-oxo-3H-benzo[f]-
chromen-2-yl)thiazol-4(5H)-ones] 28 and 29, respectively (see Scheme
8
and
Experimental section).[71]
Conclusion
The precursors carbothioamides, linked to 2-imino-2H-chromene or 3-imino-3H-ben-
zo[f]chromene units, were prepared and then reacted with different a-halocarbonyl
compounds as well as bis(a-bromoketones). These reactions afforded the corresponding
4-(substituted)thiazoles and thiazol-4(5H)-ones as well as bis(thiazoles), linked to differ-
ent cores. Additionally, thiazol-4(5H)-ones were condensed with the appropriate bis(al-
dehydes). These reactions afforded the corresponding bis(thiazol-4(5H)-ones), linked to
chromene or benzo[f]chromene units via different cores.
Experimental
Materials
All solvents were acquired from commercial sources and used as received unless other-
wise stated. All other chemicals were acquired from Merck or Aldrich and used without
further purification. The melting points were measured on a Stuart melting point appar-
atus and are uncorrected. IR spectra were recorded on a Smart iTR, which is an ultra-
high-performance, versatile Attenuated Total Reflectance (ATR) sampling accessory on
the Nicolet iS10 FT-IR spectrometer. NMR spectra were recorded on Bruker Avance III
400 MHz spectrometer (400 MHz for 1H and 100 MHz for 13C) using TMS as an
internal standard and DMSO-d6 as solvent and chemical shifts were expressed as d
ppm. Elemental analyses were carried out on a EuroVector instrument C, H, N, S ana-
lyzer EA3000 Series (Milano, Italy) and their results were found to be in good agree-
ment ( 0.4%) with the calculated values.
The procedures and spectral data
Synthesis of bis[3-(thiazol-2-yl)-2H-chromen-2-ones] 16 and 18
A mixture of each of 2-imino-2H-chromene-3-carbothioamides 6a,b (10 mmol) and
each of bis(a-bromoketones) 15 and 17 (5 mmol) in DMF (20 mL) in the presence of
TEA (1 mL) was heated at reflux for 5 h. The reaction was cooled, filtrated, washed with
cold ethanol and the reaction product was recrystallized from the proper solvent.

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3,30-(((Propane-1,3-diylbis(oxy))bis(4,1-phenylene))bis(thiazole-4,2-diyl))bis(6-((p-tol-
ylthio)methyl)-2H-chromen-2-one) (16a)
Pale yellow soild (dioxane, 80%); m.p. 290 ꢀC; IR (t cmꢁ1): 1712 (CO); 1H-NMR
(DMSO-d6): d 2.18 (quint, J ¼ 6.4 Hz, 2H, OCH2CH2), 2.25 (s, 6H, 2 x p-CH3), 4.12 (s,
4H, 2 x SCH2), 4.17 (t, J ¼ 6.4 Hz, 4H, 2 x OCH2), 7.06 (d, J ¼ 8 Hz, 4H, Ar-H’s), 7.12
(d, J ¼ 8 Hz, 4H, Ar-H’s), 7.19 (d, J ¼ 8 Hz, 4H, Ar-H’s), 7.32–7.35 (m, 4H, 2 x H7 and
2 x H8), 7.71 (s, 2H, 2 x H5), 7.89 (d, J ¼ 8 Hz, 4H, Ar-H’s), 8.03 (s, 2H, 2 x thiazole-
H), 8.51 (s, 2H, 2 x H4); 13C-NMR (DMSO-d6): d 20.2 (p-CH3), 28.3 (OCH2CH2), 35.8
(SCH2), 66.4 (OCH2), 112.7, 115.0, 117.9, 118.4, 122.4, 124.2, 126.5, 129.3, 129.8, 130.0,
131.5, 131.7, 132.4, 135.6, 144.7, 148.8, 151.8, 159.6, 160.6, 164.7; Anal. for
C55H42N2O6S4 (955.1): C, 69.16; H, 4.43; N, 2.93; found: C, 69.03; H, 4.52; N, 3.05%.
Diethyl 3,4-bis((4-(2-(2-oxo-6-((p-tolylthio)methyl)-2H-chromen-3-yl)thiazol-4-yl)phe-
noxy)methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate (18a)
1
Pale yellow soild (DMF, 65%); m.p. above 300 ꢀC; IR (t cmꢁ1): 1719, 1700 (CO); H-
NMR (DMSO-d6): d 1.28 (t, J ¼ 6.8 Hz, 6H, 2 x OCH2CH3), 2.22 (s, 6H, 2 x p-CH3),
4.15 (s, 4H, 2 x SCH2), 4.31 (q, J ¼ 6.8 Hz, 4H, 2 x OCH2CH3), 5.64 (s, 4H, 2 x OCH2),
7.06 (d, J ¼ 8.8 Hz, 4H, Ar-H’s), 7.11 (d, J ¼ 8 Hz, 4H, Ar-H’s), 7.20 (d, J ¼ 8 Hz, 4H,
Ar-H’s), 7.34–7.37 (m, 4H, 2 x H7 and 2 x H8), 7.64 (s, 2H, 2 x H5), 7.70 (d,
J ¼ 8.8 Hz, 4H, Ar-H’s), 7.98 (s, 2H, 2 x thiazole-H), 8.36 (s, 2H, 2 x H4); 13C-NMR
(DMSO-d6): d 14.5 (OCH2CH3), 20.3 (p-CH3), 35.9 (SCH2), 61.2 (OCH2CH3), 62.2
(OCH2), 112.9, 115.2, 117.6, 118.2, 122.8, 124.4, 127.7, 129.1, 129.2, 129.7, 130.2, 131.2,
131.5, 132.6, 135.2, 137.0, 143.2, 145.8, 146.2, 147.4, 150.3, 158.9, 160.2, 164.4, 166.2;
Anal. for C66H50N2O10S6 (1223.4): C, 64.79; H, 4.12; N, 2.29; found: C, 64.86; H, 4.03;
N, 2.45%.
Full experimental details, 1H- and 13C-NMR spectra for all new compounds. This
material can be found via the “Supplementary Content” section of this
article’s webpage.
Disclosure statement
No potential conflict of interest was reported by the author(s).
ORCID
Sherif M. H. Sanad
Ahmed E. M. Mekky
http://orcid.org/0000-0002-0186-6418
https://orcid.org/0000-0002-8226-010X
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