Convenient synthesis and anti-proliferative activity of some benzochromenes and chromenotriazolopyrimidines under classical methods and phase transfer catalysis

Article abstract of DOI:10.1080/00397911.2019.1675173

A new series of benzochromene, benzochromenopyrimidine, and benzotriazolopyrimdine derivatives 3-10 were prepared via reaction of ethyl formimidate 2 with primary amines such as sulfanilamide, cyclohexylamine, 3-aminopyridine, 4-aminoantipyrine in addition to its reactions with different acid hydrazides. Compound 5 was further allowed to react with different C-electrophiles by classical and phase transfer catalysis conditions to get novel chromenotriazolopyrimidine derivatives. Screening of the antitumor activity in some of the newly synthesized compounds was tested in vitro against a panel of two human tumor cell lines namely HepG2 and HCT-116 cell lines. Compounds 4, 7, 8, 10, and 20 showed remarkable broad-spectrum antitumor activity.

Full text of DOI:10.1080/00397911.2019.1675173

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
Convenient synthesis and anti-proliferative
activity of some benzochromenes and
chromenotriazolopyrimidines under classical
methods and phase transfer catalysis
Amira T. Ali & Mohamed H. Hekal
To cite this article: Amira T. Ali & Mohamed H. Hekal (2019): Convenient synthesis and
anti-proliferative activity of some benzochromenes and chromenotriazolopyrimidines
under classical methods and phase transfer catalysis, Synthetic Communications, DOI:
10.1080/00397911.2019.1675173
To link to this article: https://doi.org/10.1080/00397911.2019.1675173
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https://doi.org/10.1080/00397911.2019.1675173
Convenient synthesis and anti-proliferative activity of some
benzochromenes and chromenotriazolopyrimidines under
classical methods and phase transfer catalysis
Amira T. Ali and Mohamed H. Hekal
Faculty of Science, Chemistry Department, Ain Shams University, Cairo, Egypt
ABSTRACT
ARTICLE HISTORY
Received 22 August 2019
A new series of benzochromene, benzochromenopyrimidine, and
benzotriazolopyrimdine derivatives 3-10 were prepared via reaction
of ethyl formimidate 2 with primary amines such as sulfanilamide,
cyclohexylamine, 3-aminopyridine, 4-aminoantipyrine in addition to
its reactions with different acid hydrazides. Compound 5 was further
allowed to react with different C-electrophiles by classical and phase
transfer catalysis conditions to get novel chromenotriazolopyrimidine
derivatives. Screening of the antitumor activity in some of the newly
synthesized compounds was tested in vitro against a panel of two
human tumor cell lines namely HepG2 and HCT-116 cell lines.
Compounds 4, 7, 8, 10, and 20 showed remarkable broad-spectrum
antitumor activity.
KEYWORDS
Benzochromenes; chrome-
notriazolopyrimidines; ethyl
formimidate; phase transfer
catalysis; antitumor activity
GRAPHICAL ABSTRACT
Introduction
Heterocycles containing the chromene moiety exhibit important features that make
them an engaging target for synthesis. Chromenes represent a category of naturally
occurring compounds.[1,2] The literature discloses that chromenes have a broad range of
pharmacological activities such as antimicrobial,[3–7] antitumor.[8–11] For example,
CONTACT Mohamed H. Hekal
mohahekal2007@yahoo.com
Faculty of Science, Chemistry Department, Ain Shams
University, Abbassia sq., Cairo 11566, 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

2
A. T. ALI AND M. H. HEKAL
Scheme 1. Reaction of ethyl formimidate 2 with primary amines under conventional ther-
mal conditions.
crolibulin is currently in phase II of clinical trials for the treatment of advanced solid
tumors.[12] Also chromenes and benzochromenes exhibit other pharmacological activ-
ities such as antioxidant,[13,14] vasculardisurpting,[15] antileishmanial,[16] and anal-
gesic.[17] On the other hand, triazolopyrimidines are a class of hybrid heterocycles of
pyrimidine ring fused with triazole which having improved activity. 1,2,4-
Triazolopyrimidine is one of important ring systems that has drawn the attention for its
different biological activities as antiviral,[18] antimicrobial,[19,20] antitumor agents.[21–26]
Phase transfer catalysis (PTC) has been used for the synthesis of organic compounds in
both liquid-liquid and solid-liquid reaction mixtures to accelerate reaction rates by sup-
porting formation of interphase transfer of molecules and making reactions between
two phases possible. Applications of (PTC) in industrial processes supply great benefits
for the environments.[27–32]
As a continuation our previous work on synthesis of heterocyclic compounds and
using (PTC) in construction of new systems,[33–36] we report the synthesis of fused sys-
tems as benzo[f]chromenes, benzo[5,6]chromeno[2,3-d]pyrimidines, and benzo[5,6]-
chromeno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines.
Result and discussion
The starting material 3-amino-1-(p-tolyl)1-H-benzo[f]chromene-2-carbonitrile 1 was
prepared according to the literature[37] through the treatment of malononitrile, p-methyl
benzaldehyde and b-naphthol in the presence of catalytic amount of piperidine.

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Scheme 2. Reaction of ethyl formimidate 2 with different acid hydrazides.
Refluxing of enaminonitrile 1 with triethyl orthoformate in the presence of freshly dis-
tilled acetic anhydride gave ethyl formimidate 2 which we then exploited for the synthe-
ses of novel chromenopyrimidines and chromenotriazolopyrimidines was displayed to
heating under reflux with different primary amines in either dioxane and/or dry pyri-
dine (Scheme 1). Thus, Reaction of compound 2 with sulfanilamide in dry pyridine
afforded the uncyclized formamidine derivative 3. The supportive clue for the structure
3 deduced from the IR spectrum which showed absorption bands at 3194 (br.), 2185,
and 1652 cmꢀ1 corresponding to (NH, NH2), (CꢁN) and (C¼N), respectively. During
treatment of compound 2 with cyclohexylamine in either dioxane and/or dry pyridine a
nonisolable addition product was formed first, followed by elimination of nonisolable
ethyl-N-cyclohexylformimidate to return to the enaminonitrile 1 as a sole product. The
spectroscopic data are in good agreement with the proposed structure (cf.
experimental).
Aminolysis of compound 2 using 3-aminopyridine in boiling dioxane, formimidamide
derivative 5 was formed. The structure of 5 was elucidated by elemental analysis and
1
spectroscopic data. H NMR of compound 5 revealed its existence as (Z, E)-isomers in
the ratio 55:45 through the appearance of two singlet signals at d 5.48, 5.51 ppm for
pyran protons and two signals at 10.58, 11.03 ppm attributed for (NH) protons.
Whereas the benzochromeno[2,3-d]pyrmidine derivative 6 was obtained by reaction of
2 with 3-aminopyridine in dry pyridine (Scheme 1). Adequate evidence for the cyclized
structure 6 was substantiated from the correct elemental analysis and the spectral data.
Thus, IR spectrum of 6 showed the appearance of absorption band for the NH group at

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A. T. ALI AND M. H. HEKAL
Scheme 3. Synthesis of triazolopyrimidine derivatives 11, 13, and 14.
3274 cmꢀ1 and along with the absence of any absorption band for the nitrile function is
1
in agreement with the structure 6 as well as H NMR spectrum is in favor with the sug-
gested structure (cf. experimental).
Also refluxing compound 2 with 4-aminoantipyrine in either dioxane or dry pyri-
dine gave formimidamide derivative 7. The structure of new prepared compound 7
was established from its analytical and spectral data (cf. experimental).
Meanwhile, the reactivity of compound 2 with acid hydrazides namely, thiosemicar-
bazide, hydrazide derivative (A) and/or cyanoacetohydrazide has been reported (Scheme
2). Thus, triazolo[1,5-c]pyrimidine derivative 8 was obtained in fairly good yield upon
refluxing the formimidate derivative 2 with thiosemicarbazide in dry pyridine. The
structure of compound 8 was deduced by studying its spectroscopic data. Thus, the IR
spectrum showed absence of the absorption band of the CꢁN group in addition to
the presence of NH2 group at 3336 and 3169 cmꢀ1. While refluxing compound 2
with hydrazide derivative (A) in dry pyridine afforded the uncyclized derivative 9.
The structure of compound 9 was established from its analytical and spectral data
(cf. experimental). On the other hand, treatment of ethyl formimidate 2 with cyanoace-
tohydrazide in dry pyridine gave chromenotriazolopyrimdine derivative 10 as the sole
1
product in fairly good yield (Scheme 2). In the H-NMR spectrum of compound 10, the

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Scheme 4. Synthesis of chromenotriazolopyrimidine derivatives 15–19.
appearance of a singlet signal attributable to the –CH2CN protons at d 4.51 ppm con-
firmed the outcome of the cyclization reaction.
A number of chromenotriazolo[1,5-c]pyrimdines were synthesized using aceto-
nitrile derivative 10 upon treatment with different C-electrophiles. Thus, condensa-
tion of compound 10 with cinnamaldehyde in refluxing dioxane and in the presence
of catalytic amount of piperidine gave the corresponding arylidine derivative 11
(Scheme 3). The chemical structure of 11 was supported on the basis of elemental
analysis and spectral data. Its IR spectrum showed absorption band at 2220 cmꢀ1 for
conjugated CꢁN group.
Furthermore, the reactivity of triazolopyrimidine derivative 10 towards activated
nitrile has been investigated as shown in Scheme 3. Thus, the reaction of compound 10
with 2-(4-chlorobenzylidine)malononitrile in refluxing dioxane in the presence of a
catalytic amount of piperidine furnished the condensed product 13 instead enaminoni-
trile derivative 12. This structure was confirmed by elemental analysis and spectral data.
In addition, the strong evidence for the structure 13 is forthcoming from an authentic
sample prepared from condensation of compound 10 with p-chlorobenzaldehyde in

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A. T. ALI AND M. H. HEKAL
Scheme 5. Synthesis of chromenotriazolopyrimidine derivatives 20–22.
refluxing dioxane in the presence of catalytic amount of piperidine (TLC, mp and IR
1
comparison) (Scheme 3). Also, the absence of a broad singlet in the H-NMR spectrum
corresponding to NH2 argued against the formation of the putative enaminonitrile
derivative 12.
Moreover, The Gewald reaction[38] of compound 10 with elemental sulfur and phenyl
isothiocyanate in absolute ethanol containing triethylamine as a basic catalyst led to
functionalized thiazoline 14. (Scheme 3). The structure of the prepared compound was
elucidated on the basis of elemental analysis and spectral data. The IR spectrum of thia-
zoline 14 revealed the absence of CꢁN absorption band and the presence of new
absorption bands at 3442, 3318 cmꢀ1 assignable to the amino group and a band at
1
1228 cmꢀ1 due to C¼S group. Furthermore, H NMR spectrum was characterized by
the existence of thiazolopyrimidine H-5 at d 9.79 ppm as well as a singlet signal at d
6.98 ppm for NH2 protons exchangeable by D2O.
In this study, acetonitrile derivative 10 was utilized as a precursor for synthesis of
biologically active triazolopyrimdine derivatives under phase transfer catalysis conditions
using solid-liquid phase system (dioxane/K2CO3/tetrabutyl ammonium bromide
(TBAB)), where the reactants in dioxane existed in organic phase in which K2CO3 was
suspended. The reaction mechanism includes two consecutive catalytic cycles, the first
one proton abstraction from nucleophile occurs on solid carbonate surface then the
formed anion immigrates as ion-pair into the organic phase in which the second step
concerned with substitution occurred.[39] The one-pot reaction of compound 10 with
dihalo-compounds namely chloroacetyl chloride, 1,2-dibromoethane, 1,3-dibromopro-
pane and/or monohalo-compounds such as methyl iodide, benzyl chloride in dioxane in
the presence of carbondisulphide as a reactant under PTC conditions (Scheme 4)
afforded triazolopyrimdine derivatives 15–19. The structures of these compounds were

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Table 1. Cytotoxicity (IC50) of the tested compounds on different cell lines.
In vitro cytotoxicity IC50 (mM)a
Compounds no.
HePG2
HCT-116
1
3
5
6
7
8
9
10
11
13
14
16
17
18
19
20
22
DOX
14.81 1.3
36.49 2.7
31.50 2.4
49.23 2.9
6.18 0.5
8.49 0.7
43.56 2.6
10.05 1.0
17.32 1.6
93.32 5.2
58.17 3.5
24.84 2.1
72.98 4.6
67.90 3.6
54.06 3.2
4.26 0.3
18.62 1.9
4.50 0.2
9.37 0.8
11.21 1.1
38.67 2.5
53.03 3.2
4.98 0.4
7.61 0.6
48.28 2.9
8.12 0.7
19.74 1.5
86.14 4.9
16.35 1.4
30.42 2.3
79.60 4.3
74.16 3.8
61.59 3.6
3.19 0.2
23.61 1.8
5.23 0.3
aIC (lM): 1–10 (very strong), 11–20 (strong), 21–50 (moderate), 51–100 (weak), above 100 (non-cytotoxic). DOX: Doxorubicin.
50
evidenced by studying their elemental analyses and spectroscopic data. Thus, the
appearance of conjugated nitrile at lower frequency in the IR spectra of compounds 15,
16, 18, and 19 than that observed with the title compound 10 were in agreement with
the suggested structures.
The formation of 1,3-dithiolanone derivative 15 has been deduced from appearance
of the absorption band at 1731 cmꢀ1 for C¼O group in IR spectrum as well as the pres-
1
ence of a singlet signal in H-NMR spectrum at 4.51 ppm for (S–CH2–CO). The appear-
ance of two triplet signals at d 3.79 and 3.87 ppm for (–CH2–CH2–) of compound 16 is
1
completely in agreement with the proposed structure whereas H-NMR spectrum of 17
showed triplet signal at 2.28 for central (–CH2–), triplet at 3.21 for (S–CH2–), triplet at
3.24 for (–CH2–Br) and singlet signal at 4.51 ppm for (–CHCN–) which confirmed the
uncyclized structure. In addition, the structures of triazolo[1,5-c]pyrimdines 18 and 19
were established from their analytical and spectral data (cf. experimental).
To show the synthetic potentiality of compound 10, the reactivity of 10 with isothiocya-
nates was investigated. Thus, one pot reaction of benzochromeno[1,2,4]triazolo[1,5-c]pyr-
imdine derivative 10 with phenyl isothiocyanate in dioxane and tetrabutylammonium
bromide (TBAB) under PTC conditions afforded the non-isolable intermediate (C),
which was converted in situ to the newly synthesized compounds 20–22 (Scheme 5)
upon treatment with hydrochloric acid, chloroacetylchloride and methyl iodide,
respectively. The structures of the latter products were established on the basis of
elemental analysis, spectral data. The appearance of a cyano absorption band around
2175 cmꢀ1 in their IR spectra in addition of a band at 1728 cmꢀ1 for C¼O in case of
1
thiazolidinone derivative 21. H-NMR spectra of these compounds are in agreement
with the assigned structures (cf. experimental).
We evaluated the cytotoxicity of the synthesized compounds against two human
tumor cell lines (Table 1, Figure 1). The cell lines were hepatocellular carcinoma
(HePG-2) and colon cancer (HCT-116). In general, the cytotoxic activity of the

8
A. T. ALI AND M. H. HEKAL
180
160
140
120
100
80
60
40
20
0
HePG2
HCT-116
Figure 1. Cytotoxic activity of the tested compounds on different cell lines.
examined compounds ranged from very strong to weak activity. The optimal results
were observed for compounds 7, 8, and 20 which showed IC50 6.18 0.5, 8.49 0.7, and
4.26 0.3 lM for the HePG-2 cell line, respectively. While compounds 1, 7, 8, 10, and
20 showed very strong activities with IC50 9.37 0.8, 4.98 0.4, 7.61 0.6, 8.12 0.7, and
3.19 0.2 lM for the HCT-116 cell line, respectively.
Structure-activity relationship (SAR)
By comparing the experimental cytotoxicity of the compounds reported in this study to
their structures, the following SAR was postulated.
ꢂ
ꢂ
Compound 7 showed very strong cytotoxic activity, this is maybe due to the
presence of antipyrine ring.
Compound 8 showed very strong cytotoxic activity, this is due to the presence of
NH2 group which is available to form a hydrogen bond with either one of the
nucleobases of the DNA and causes its damage.
ꢂ
Compound 20 showed very strong activity, this is due to the presence of NH
and SH groups which may add to any unsaturated moiety in DNA or forming a
hydrogen bond with either one of the nucleobases of the DNA and causes
it damage.
Materials and methods
Chemistry
All melting points were taken on a Griffin and George melting-point apparatus (Griffin
& George Ltd., Wembley, and Middlesex, UK) and are uncorrected. IR spectra were
recorded on Pye Unicam SP1200 spectrophotometer (Pye Unicam Ltd., Cambridge,
1
UK) by using the KBr wafer technique. H-NMR spectra were determined on a Varian
Gemini 400 MHz by using tetramethylsilane as internal standard (chemical shifts in d
scale). Elemental analyses were carried out at the Microanalytical Unit, Faculty of

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Science, Ain Shams University, using a Perkin-Elmer 2400 CHN elemental analyzer
(Waltham, MA), and satisfactory analytical data ( 0.4) were obtained for all com-
pounds. The homogeneity of the synthesized compounds was controlled by thin-layer
chromatography (TLC), using aluminum sheet silica gel F254 (Merck). The antitumor
activities were performed at Microanalytical Center of Mansoura University, Egypt.
3-amino-1-(p-tolyl)-1H-benzo[f]chromene-2-carbonitrile 1
A solution of malononitrile (0.66 g, 10 mmol), p-methylbenzaldehyde (1.2 ml, 10 mmol),
and b-naphthol (1.44 g, 10 mmol) in absolute ethanol (30 ml) containing piperidine
(0.5 ml) was heated under reflux for 2 h. The deposited solid was filtered off, dried and
then crystallized from ethanol to give 1 as white crystals, 90% yield, mp 272–273 ꢃC
[Lit. mp: 268–269 ꢃC].
Ethyl (E)-N-(2-cyano-1-(p-tolyl)-1H-benzo[f]chromen-3-yl)formimidate 2
A solution of enaminonitrile 1 (3.12 g, 10 mmol) and triethylorthoformate (6 mL,
30 mmol) and acetic anhydride (15 mL) was heated at reflux for 6 h. The formed solid
was filtered off, dried, and then crystallized from ethanol to give 2 as pale yellow crys-
tals, 88% yield, mp 160–162 ꢃC. IR (KBr, ꢀ, cmꢀ1): 3019 (CH aromatic), 2208 (CꢁN),
1653 (C¼N). Anal. Calcd. for C24H20N2O2 (368.44): C, 78.24; H, 5.47; N, 7.60. Found:
C, 78.32; H, 5.53; N, 7.57.
Cytotoxicity assay
The cytotoxic activity of eleven compounds was tested against two human tumor cell
lines namely: hepatocellular carcinoma (liver) HePG-2 and colon cancer (HCT-116).
The cell lines were obtained from the ATCC via the Holding Company for Biological
Products and Vaccines (VACSERA, Cairo, Egypt). Doxorubicin was used as a standard
anticancer drug for comparison. The reagents used were RPMI-1640 medium, MTT,
DMSO and 5-fluorouracil (Sigma Co., St. Louis, MO, USA), and Fetal Bovine Serum
(GIBCO, Paisley, UK).
The different cell lines[40,41] mentioned above were used to determine the inhibitory
effects of compounds on cell growth using the MTT assay. This colorimetric assay is
based on the conversion of the yellow tetrazolium bromide (MTT) to a purple formazan
derivative by mitochondrial succinate dehydrogenase in viable cells. The cells were cul-
tured in RPMI-1640 medium with 10% fetal bovine serum. Antibiotics added were 100
units/mL penicillin and 100 mg/mL streptomycin at 37 ꢃC in a 5% CO2 incubator. The
cell lines were seeded[42] in a 96-well plate at a density of 1.0 ꢄ 104 cells/well at 37 ꢃC
for 48 h under 5% CO2 incubator. After incubation the cells were treated with different
concentration of compounds and incubated for 24 h. After 24 h of drug treatment,
20 mL of MTT solution at 5 mg/mL was added and incubated for 4 h. Dimethyl sulfoxide
(DMSO) in volume of 100 mL was added into each well to dissolve the purple formazan
formed. The colorimetric assay is measured and recorded at absorbance of 570 nm using
a plate reader (EXL 800, BioTech, Winoosky, VT, USA).

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A. T. ALI AND M. H. HEKAL
The relative cell viability in percentage was calculated as (A570 of treated samples/
A570 of untreated sample) ꢄ 100.
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