Green synthesis of some tetrahydroquinoline derivatives and evaluation as anticancer agents

Nuha M.M. Alanazi; Ibrahim O. Althobaiti; Yasser A. El-Ossaily; Wael A.A. Arafa; Mohamed Y. El-Sayed; Hamud A. Altaleb; Hanaa Y. Ahmed; Mahmoud S. Tolba

doi:10.1016/j.arabjc.2023.104543

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Original article

03 2023

:16;

104543

doi:

10.1016/j.arabjc.2023.104543

Green synthesis of some tetrahydroquinoline derivatives and evaluation as anticancer agents

Nuha M.M. Alanazi^{^a,^b}, Ibrahim O. Althobaiti^{^c}, Yasser A. El-Ossaily^{^a,^d,⁎}, Wael A.A. Arafa^{^a,^e}, Mohamed Y. El-Sayed^{^a}, Hamud A. Altaleb^{^f}, Hanaa Y. Ahmed^{^g}, Mahmoud S. Tolba^{^h,⁎}

a Department of Chemistry, College of Science, Jouf University, P.O.Box 2014, Sakaka, Saudi Arabia

b Department of Nursing, Northern College of Nursing, Arar, 73311, Saudi Arabia

c Department of Chemistry, College of Science and Arts, Jouf University, P.O.Box 756, Al-Qurayat Branch, Sakaka, Saudi Arabia

d Department of Chemistry, Faculty of Science, Assiut University, Assiut, Egypt

e Department of Chemistry, Faculty of Science, Fayoum University, P.O. Box 63514, Fayoum City, Egypt

f Department of Chemistry, Faculty of Science, Islamic University of Madinah, Madinah 42351, Saudi Arabia

g The Regional Center for Mycology and Biotechnology, Al-Azhar University, Cairo, 11371, Egypt

h Chemistry Department, Faculty of Science, New Valley University, El-Kharja 72511, Egypt

⁎Corresponding authors at: Department of Chemistry, College of Science, Jouf University, P.O.Box 2014, Sakaka, Saudi Arabia (Y.A. El-Ossaily). yaboubakr@ju.edu.sa (Yasser A. El-Ossaily), Mahmoud.tolba@sci.nvu.edu.eg (Mahmoud S. Tolba)

Received: 2022-11-5, Accepted: 2023-1-1,

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

Abstract

This study demonstrates the design and synthesis of heterocyclic compounds with diverse biological effects. Using an ionic liquid catalyst, a sonosynthetic approach for the assembly of bis-arylidene cycloalkanone derivatives (bis-chalcones) has been reported. Three cancer cell lines Hepatocellular carcinoma cells (HepG-2), Breast carcinoma cells (MCF-7), and Lung carcinoma cells (A-549) were utilized to investigate the antiproliferative effects of some selected samples. Many evaluated drugs exhibited good to moderate cytotoxicity against the examined cell lines. Notably, the IC₅₀ values for the S-alkyl derivatives ranged from 2.86 to 13.14 µg/mL.

Keywords

Green

Antiproliferative

Thienoquinolines

Pyrimidothienoquinoline

sonosynthesis

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1 Introduction

The building of diverse organic molecule structures from easily available reactants while taking economic and environmental factors into account is crucial from either an industrial or scholarly viewpoint (Wagner et al., 1993). The development of chemical methods that employ more eco-sustainable materials, atom-efficient operations, and energy-saving approaches to decrease waste creation is a crucial requirement considering rising environmental pollution and its substantial impact on biological processes (Patil et al., 2020). Environmental solvents, such as water, are preferred for chemical reactions because they are widely available, non-toxic, and non-combustible (Simbera et al., 2014). In addition, the Claisen–Schmidt reaction is a well-established method for forming carbon–carbon bonds and synthesizing α, and β-unsaturated carbonyl compounds (Gawande et al., 2013). It is also a suitable approach for the assembly of, α,α‘-bis(arylidene)cycloalkanones, which have a variety of applications in biotechnology and pharmaceuticals (Song et al., 2009), quinine reductase enzymes (Eiden et al., 1984), anti-parasitic (Dinkova-Kostova et al., 1998), cholesterol regulators (Piantadosi et al., 1973); pyrrolidines (Braga et al., 2014), cytotoxicity (Raj et al., 2003), and acetyltransferase enzymes (Dimmock et al., 1976). Utilizing a multicomponent reaction technique, Also the benefit the advantage of green chemistry, we will keep on developing eco-friendly synthetic facility methods (Tolba et al., 2022; Tolba et al., 2021; Tolba et al., 2021 ). So, herein a simple multicomponent reaction approach was given for producing tetrahydroquinoline derivatives with promising biological activities.

2 Results and discussion

Due to the diverse applications of bis-benzylidene cycloalkanones, much effort has been devoted to creating safe, effective, and environmentally friendly techniques for synthesizing these compounds utilizing one-pot, three-component procedures. Several procedures (Costi et al., 2007; Wang et al., 2002; Li et al., 2003; Hosoya et al., 2012; Javanshir et al., 2014; Vashishtha et al., 2015; Ghasemzadeh and Akhlaghinia, 2019; Abaee et al., 2006 ) for the assembly of bis-arylidene cycloalkanones have been published. Even though several of these methods appear to have distinct advantages, some of them have downsides, such as the use of dangerous solvents, poisonous chemicals, time-consuming procedures, and frequently non-recyclable catalysts. Ionic liquids (ILs) have been identified as eco-friendly dual reagents (solvent and catalyst) due to their excellent properties, such as low cost, accessibility, reusability, and high solubility, as well as their capacity for gram-scale production (An et al., 2008; Egorova and Ananikov, 2018). Recently, various new ILs based on DABCO have been effectively utilized as catalysts in the Claisen–Schmidt reaction (Shirini et al., 2017) and the synthesis of imidazoles. We show the creation of a variety of α,α′-bis[(aryl or allyl)idene]cycloalkanone derivatives employing DABCO-based IL through ultrasound-assisted Claisen–Schmidt reaction as part of our effort to investigate novel approaches for heterocyclic design (Shirini et al., 2017; Arafa, 2018; Arafa, 2018; Arafa and Ibrahim, 2018 ). Our first objective was to investigate the IL's catalytic performance in the assembly of, α,α′-bis(substituted benzylidene)cycloalkanones under the following conditions: environmentally friendly solvents, decreased catalyst quantity, low reaction temperature, and rapid pioneer reaction yield. Using modeled reagents, the reaction parameters were optimized with these aims in mind: 4-chlorobenzaldehyde (2a) (2.0 mmol) with cyclohexanone (1) (1.0 mmol) (Scheme 1), the obtained results were reported in Table 1. Subsequently, several variables, including the energy source, reaction rate, IL dose, and solvent type, were exhaustively examined to determine the optimal reaction conditions.

The synthetic route for bis-chalcone (3a).

Table 1 Optimization of the model reaction (Scheme 1).

Entry	Catalyst	Conditions	Solvent	Temp (^oC)	Time (min)	Yield (%)
1.	NaOH (10 %)	Stirring	EtOH	rt	180	65
2.	NaOH (10 %)	Stirring	EtOH	90	180	82
3.	None	Stirring	EtOH	90	180	0
4.	NaOH (10 %)	)))) ^a	EtOH	rt	180	85
5.	NaOH (10 %)	))))	H₂O	rt	180	87
6.	KOH (10 %)	))))	H₂O	rt	180	85
7.	LiOH (10 %)	))))	H₂O	rt	180	87
8.	DABCO (3.0 mol%)	))))	H₂O	rt	180	92
9.	IL (1.0 mol%)	))))	H₂O	rt	10	95
10.	IL (2.0 mol%)	))))	H₂O	rt	5	97
11.	IL (3.0 mol%)	))))	H₂O	rt	8	95

a )))): ultrasonic irradiation (intensity of 80%).

The 2,6-bis((E)-4-chlorobenzylidene)cyclohexane-1-one (3a) was produced in 65 % yield under conventional conditions by stirring the reactants in a NaOH/EtOH solution at ambient temperature. A few unreacted starting materials were also observed, despite the reaction being performed for an extended period (Table 1, entry 1). The reaction yield was increased by increasing the reaction temperature (Table 1, entry 2). However, the use of such strong bases resulted from side reactions (such as the self-condensation of aldehydes and ketones), which decreased the yields of the desired products (Egorova and Ananikov, 2018). Even after 3 h of refluxing the reactants under catalyst-free conditions, the needed product, (3a) was not observed (TLC) in the reaction profile (Table 1, entry 3). In addition, by executing the reaction under ultrasonic irradiation for 3 h, 85 % of the desired product was produced (Table 1, entry 4). In addition, sonicating the model reactants in aqueous NaOH resulted in a little increase in reaction yield (Table 1, entry 5). Next, a variety of bases, including KOH, LiOH, and 1,4-diazobicyclo [2.2.2] octane (DABCO), were screened to produce a distinct reaction profile and a sped-up reaction rate (Table 1, entries 6–8). None of the previously suggested bases performed better than DABCO, which had the greatest yield (92 %, Table 1, entry 8). Such observations prompted us to examine the reaction in the context of several catalytic strategies. Considering the utilization of ILs enhanced the efficiencies of reactions and considering the acceptable yield achieved employing DABCO in the aforesaid template reaction, we decided to extend our research to the utilization of IL comprised DABCO. [DABCO-EtOH] [AcO], a DABCO-based IL, was designed using the widely obtainable DABCO (A) and 2-chloroethan-1-ol (B), then refluxed with NaOAc as an ion exchange salt (Scheme 2) (Abaee et al., 2006). Interestingly, the reaction progressed effectively with 1.0 mol% [DABCO-EtOH] [AcO] (D) and yielded the desired product in superior yield (95 %) in approximately 10 min (Table 1, entry 9). Several concentrations of catalyst have been utilized on the template reaction to explore the influence of catalyst dosage on this condensation process. The maximum yield (97 %) of the intended product was obtained with 2.0 mol% of the IL catalyst in 5 min (this is might because as the active sites accessible for the reaction increased, both reaction yield and rate were improved as well, (Table 1, entry 10).

Synthesis of ionic liquid, [DABCO-EtOH] [AcO] (D).

Nonetheless, catalyst loadings greater than 2.0 mol% resulted in a reduction in reaction effectiveness (Table 1, entry 11). This might be due to the catalyst dosage increased, similarly does the reaction viscosity, lowering the ultrasonic strength in certain parts of the reaction solution (Arafa et al., 2018). Consistently, the bubbles in particular reactor locations may not be properly created (Nakano et al., 1987). Thence, 2.0 mol% was recommended as the best catalyst molar ratio (Table 1, Entry 10).

The scope of the current protocol has been also evaluated for assembling bis-chalcones starting with various aldehydes (Scheme 2). In general, the electronic properties of motifs attached to aldehydes have a minimal influence on reaction efficacy. The reaction was exceptionally adaptable to both electron-releasing motifs, including p-methyl (3c, 96 %) and p-methoxy (3d, 97 %), as well as electron-accepting motifs, including p-nitro (3e, 98 %), o-nitro (3f, 95 %), p-chloro (3a, 99 %), o-cyano (3 g, 97 %), and p-flouro (3b, 96 %). Gratifyingly, heterocyclic aldehydes namely thiophene carboxaldehyde and furfural, similarly had a successful and smooth reaction with cyclohexanone, yielding the condensed products 3 h and 3i in 96 % and 93 % yields, respectively (Scheme 2). The melting point and spectral data of all the assembled compounds are matched to those mentioned in the research (Wagner et al., 1993; Costi et al., 2007; Wang et al., 2002; Li et al., 2003; Hosoya et al., 2012; Javanshir et al., 2014 ). For example, ¹H NMR of derivative 3 h exhibited a singlet at δ = 7.97 ppm assigned for the vinylic proton. The aromatic protons appeared as multiples in the range of 7.51–7.09 ppm. In addition, the two multiples at δ = 2.91–2.89 and 1.95–1.703 ppm are assigned to the aliphatic protons. Additionally, the ¹³C NMR of derivative 3 h demonstrated distinguished signals at δ = 189.1, 28.2, and 21.7 ppm attributed for the C⚌O, and CH₂ motifs, respectively (see Scheme 3).

[DABCO-EtOH] [AcO]-catalyzed preparation of bis chalcones (3a–i) a (Costi et al., 2007; Wang et al., 2002; Li et al., 2003; Hosoya et al., 2012; Javanshir et al., 2014; Vashishtha et al., 2015; Ghasemzadeh and Akhlaghinia, 2019; Abaee et al., 2006) aReaction conditions: cyclohexanone and aryl aldehyde, IL (2.0 mol%), water (5.0 mL) at rt.

To assess the practicality of scaling up the current approach, the model reaction was carried out on a gram scale using optimum conditions, yielding the anticipated compound 3a in superior yield (97 %; Scheme 4). Diverse sustainable measurements such as process mass intensity (PMI), E-factor (EF), reaction mass efficiency (RME), and atom economy (AE) also have been addressed (Scheme 4).³¹ The greater environmental adaptability criteria, such as lower PMI (1.12) and EF (0.017), as well as high values of YE (12.2 %), CE (100 %), AE (90.5 %), and RME (88.8 %), verified the established protocol's eco-sustainable approach.

Whereas we could not examine the mechanism of the current reaction, Scheme 5 depicts a probable approach enabling the synthesis of bis-chalcones (3a-i). Firstly, the IL active centers (OH & nitrogen lone pair of electrons) could be efficiently activated the reactant molecules to undergo the condensation reaction in an appropriate manner (Scheme 4). Thereby, both aldehyde and ketone are stimulated by such active sites, thus facilitating the removal of a water molecule, yielding the non-isolable intermediate (I). This intermediate underwent another condensation reaction with the second molecule of aldehyde and afforded the required products (3a-i) in excellent yields. It may be inferred that the ionic liquid enhanced both the yield and the rate of the reaction.

A tentative mechanism for the assembly of derivatives 3a-i.

The compounds comprising the quinoline motif have been used in several biological applications in the last decade. For example, employed as an immune regulator, anti-inflammatory, analgesic, anti-allergic, and memory enhancer (Show et al., 2007; Gogate et al. 2003). Thus, our next endeavor turned out to be the design and synthesis of a library of hitherto unreported heterocyclic compounds containing such a significant nucleus; quinoline. The target tetrahydroquinoline-2-thione derivatives (5a, b) were smoothly obtained via the reaction of 2,6-bis-4-chlorobenzylidenecyclohexanones (3a, b) with cyanothioacetamide (4) utilizing EtONa as a catalyst (Scheme 6).

Synthetic pathway for the preparation of the target tetrahydroquinoline derivatives (5a-10). (Madkour et al., 2018).

FT-IR, NMR spectroscopy, and MS were used to deduce the chemical structure of the newly synthesized compound 5a. For example, the FT-IR spectrum of derivative 5a demonstrated absorption bands at 2214 cm⁻¹ attributed to the stretching frequencies of the C≡N group. Further, the mass spectrum of the isolated compound 5a revealed the required molecular ion peak, as well as its elemental analyses, were compatible with the calculated values. Compound 5a displayed a molecular ion peak at m/z 422 corresponding to C₂₃H₁₆Cl₂N₂S, with a base peak at m/z 388 corresponding to the spelling of the H₂S molecule.

Alkylated heterocyclic compounds are essential precursors that may be employed to synthesize polysubstituted fused heterocyclic derivatives (Jiménez-González et al., 2012). Such alkylated derivatives have prospective applications as recyclable agrochemicals (El-Taweel, 2010), medicines, and dye precursors (Jubeen et al., 2018; Kumar and Narasimhan, 2018). Consequently, our next target is to evaluate the possibility of one of the designed thiol derivatives for the S-alkylation reaction. To achieve this target, quinoline-2-thione.

5a was permitted to react with a diversified of halo-derivatives including chloroaceonitrile, ethyl bromoacetate, chloroacetic acid, 4-chlorobenzyl chloride, and ethyl iodide 6a-e using sodium ethoxide and/or K₂CO₃ as a base to afford the expected 2-alkylated compounds 7a-e. The molecular structure of the S-alkylated derivatives 7a-e was interpreted from their mass spectrometric analyses, FT-IR, and NMR. For example, the FT-IR spectrum of derivative 7b demonstrated a distinguished stretching band at 2214 cm⁻¹ assigned to the absorption frequencies of the C≡N group. Besides, the absorption band at 1743 cm⁻¹ is assigned to the C⚌O motif. Additionally, the ¹H NMR spectrum of 7d exhibited two singlet signals that related to the S-CH₂ group at δ = 4.54 ppm and vinyl proton at δ = 7.96 ppm. Besides, the aromatic protons appeared as a multiplet at δ = 7.45–7.27 ppm, and three multiplets at δ = 2.80–1.70 ppm for the methylene protons (CH₂). The existence of distinguished signals in the ¹³C NMR spectrum of derivative 7d is compatible with the suggested structure. The resonances owing to the carbons of the four CH₂, which emerge at δ = 33.9, 27.6, 27.4, and 22.3 ppm, are the most essential part of the spectrum. In addition, the mass spectra of the isolated compounds 7a-d revealed the required molecular ion peak, and their elemental analyses were compatible with the calculated values. For example, derivative 7b presented a molecular ion peak at m/z 508 equivalent to C₂₇H₂₂Cl₂N₂O₂S; in agreement with the molar mass of the proposed structure. The synthesized S-alkylated derivatives 7a-c possessed two distinctive function groups, active methylene, and cyano motifs, that could be used for the design of various fused heterocycles under cyclization conditions. Interestingly, when the S-alkylated derivatives 7a-c boiled in ethanol containing a catalytic amount of NaOEt, underwent a cyclization reaction and afforded the thieno[2,3-b]quinolines 8a-c in excellent outcomes. Surprisingly, the thieno[2,3-b]quinolines 8a-c could be also obtained in quantitative yields directly by refluxing the thiol derivative 5a with appropriate halo-derivatives 6a-c using two equivalents of NaOEt (Scheme 6). The reaction starts with a sulfur-nucleophilic attack to the halo-derivatives 6a-c to afford the S-alkyl derivatives 7a-c which in turn undergoes another carbon-nucleophilic attack to the cyano group followed by aromatization to finally afford the thieno[2,3-b] quinolines 8a-c (Scheme 7).

A tentative mechanism for the assembly of derivatives 8a-c.

FT-IR, NMR, and mass spectra were utilized to demonstrate the molecular structure of derivatives 8a-c. For example, the FT-IR spectrum of derivative 8b exhibits bands in the frequency of 3487, 3340, and 1666 cm⁻¹ corresponding to NH₂ and C⚌O, respectively. The absence of the stretching frequency belongs to the cyano motif and the decrease in the absorption value of the carbonyl group indicates the cyclization of S-alkyl derivatives. The ¹H NMR spectral analysis of the obtained compounds (for example, 8b), showed two distinctive singlets at δ = 5.35 and 8.09 ppm attributed to the amino (NH₂; this is strong evidence to prove the cyclization) and vinyl (C = CH) protons, respectively. Additionally, the quartet-triplet pattern appeared at δ = 4.29–4.25 and 1.34–1.32 ppm, respectively. The other protons appeared in their respective regions. Besides, in the ¹³C NMR, the ring closure may be observed by the disappearance of the signals at 112 and 30 ppm corresponding to the C≡N and CH₂-S groups, respectively. In addition, the MS of the isolated derivatives 8a-c revealed the required molecular ion peaks, and their elemental analyses were compatible with the calculated values. For example, derivatives 8b, c displayed molecular ion peaks at m/z 508 equivalent to C₂₇H₂₂Cl₂N₂O₂S 8b, and at m/z 480 equivalent to C₂₅H₁₈C_l2N₂O₂S 8c: in agreement with the molar mass of the proposed structure. On refluxing the amino-cyano derivative 8a in dry pyridine containing an equimolar amount of acetic anhydride, (E)-N-(8-(4-chlorobenzylidene)-4-(4-chlorophenyl)-2-cyano-5,6,7,8-tetrahydrothieno[2,3-b]quinolin-3-yl)acetamide 9 was obtained in quantitative yield (Scheme 6). Further, the amino ester derivative 8b could be reacted with the 1-chloro-4-isothiocyanatobenzene in DMF under refluxing conditions to provide the unreported pyrimidine-2-thione derivative 10 in an acceptable yield (Scheme 6). The chemical structure of derivative 10 was elucidated via FT-IR, and MS. The MS of the isolated derivative 10 presented the required molecular ion peak (m/z 632) with a base peak at m/z 125 corresponding to 4-chlorocyclohepta-2,4,6-trien-1-ylium. Besides, the elemental analysis was compatible with the calculated value. Furthermore, when derivative 5a was reacted with dialkylacetylenedicarboxylates (DMAD and DEAD, (11a, b) in dichloromethane (DCM) afforded after purification, yellow and orange crystalline products 14a, b respectively (Scheme 8). From the obtained results of the elemental analyses and mass spectrum (m/z 594) of the reaction product 14b, the molecular formula could be estimated to be: C₃₁H₂₆Cl₂N₂O₄S 14b which is compatible with the suggested compound 12 (supposing that the NH added to the CBC in DEAD). Besides, the IR spectrum of the obtained product 14b demonstrated two absorption bands at ʋ_max 1720 and 1714 assigned to the C⚌O motifs (ester), a distinguished band at 2222 cm⁻¹ attributed to the cyano group, and no absorption bands corresponding to the amide C⚌O (for derivative 12). Thus, the proposed structure 12 was excluded. The ¹H and ¹³C NMR demonstrated a pattern, which cannot be justified for either of the derivatives 12 or 13. The existence of signals for the two ester carbonyl groups in the ¹³C NMR, and two ethyl signals (quartet/triplet pattern) in the ¹H NMR spectrum of derivative 14b, as well as the complete lack of the amide carbonyl absorption band in the FT-IR spectrum, gave us the assumption that a Michael addition occurred from the SH nucleophile in the tautomer mercaptopyridine to the activated CBC of DEAD. Moreover, the ¹³C NMR showed no signals attributed to the C⚌S motifs. As a result, the molecular structures of 14a, b have been proposed for these compounds.

3 Biological evaluation

3.1

3.1 Cytotoxicity activities

The in vitro cytotoxicity activities applications of some of these selected compounds (5a, 5b, 7d, 7e, 8b, and 10) were investigated against HepG-2, MCF-7, and A-549 cell lines employing MTT (3-(4,5)- dimethylthiahiazo(-zy1)-3,5-di-phenytetrazoliumromide) assay and utilizing Doxorubicin as a reference compound (Table 2). Interestingly, the antitumor activity of these selected compounds (Table 2) showed significant differences depending on the molecular structures. In general, derivatives 5a and 5b exhibited superior activities against both HepG-2 and MCF-7 with IC₅₀ ranged 2.86–13.14 µg/mL. However, these derivatives displayed moderate activities towards A-549 (25.54 and 28.45 µg/mL, respectively). Besides, derivatives 7d, 7e, and 8b showed moderate activities in comparison with the reference material (Doxorubicin, Table 2).

Table 2 IC₅₀ values for compounds 5a, 5b, 7d, 7e, 8b, 10, and Doxorubicin.

Compound	IC₅₀ values (µg/mL)
Compound	HepG-2	MCF-7	A-549
5a	2.86 ± 0.22	3.17 ± 0.39	25.54 ± 1.15
5b	11.23 ± 0.55	13.14 ± 0.86	28.45 ± 1.03
7d	29.40 ± 1.28	59.35 ± 2.41	42.81 ± 1.37
7e	56.52 ± 2.04	60.21 ± 1.97	116.02 ± 2.94
8b	51.42 ± 1.96	79.81 ± 2.05	55.78 ± 2.34
10	108.97 ± 3.81	157.82 ± 3.96	121.96 ± 3.12
Doxorubicin	0.75 ± 0.11	1.02 ± 0.14	1.27 ± 0.35

4 Experimental section

4.1

4.1 Materials

Electrothermal IA9100 melting point apparatus (UK) was used to monitor the melting points that were reported incorrectly. On a Shimadzu DR-8001 spectrometer, IR spectra were measured. As an inner standard, TMS was employed using either CDCl₃ or DMSO‑d₆ as a solvent to obtain the NMR data, which were done using a Jeol 600 MHz NMR scanner. A Hewlett Packard MS-5988-USA spectrometer has been employed to record mass spectra at 70 eV. Organic solvents and fine chemicals were received and utilized without purification from Aldrich, Fluka, or Across chemicals manufacturers.

4.2

4.2 Synthesis of the catalyst [DABCO-EtOH][AcO].

A mixture of 2-chloro-1-ethanol (0.067 mL, 1.0 mmol) and 1,4-diazobicyclo[2.2.2]octane (DABCO) (0.112 g, 1.0 mmol) in EtOH (20.0 mL) was sonicated for 1 h. After the completion of the reaction (confirmed by TLC), the solvent was evaporated under reduced pressure, and the intermediate A was obtained and used in the next step without any purification. Then, sodium acetate (0.0820 g, 1.0 mmol) was added to a solution of A (0.192 g, 1.0 mmol) in EtOH (20 mL). The mixture was sonicated for another 1 h, and the solvent was removed under reduced pressure to give the corresponding IL catalyst (B).

4.3

4.3 General methods for synthesis of bis-chalcone derivatives (3a-i)

4.3.1

4.3.1 Conventional method:

A mixture of cyclohexanone (1) (1.0 mmol), aromatic aldehydes (2a-i) (2.0 mmol), and five drops of NaOH (10 %) were dissolved in ethanol (20.0 mL) at room temperature with continuous stirring for three hours to get the target products α, α'-bis chalcone derivatives(3a-i), which was recrystallized from ethanol. 4.3.2. Ultrasonic protocol using [DABCO-EtOH] [AcO] as a catalyst.

A 25.0 mL round flask had been charged with cyclohexanone (1) (1.0 mmol), aldehydes (2a-i) (2.0 mmol), [DABCO-EtOH] [AcO] (2.0 mol%), and 10.0 mL water. The reaction vessel had been immersed in the ultrasonic bath and sonicated at room temperature for an adequate period. After completion of the reaction (established by TLC, eluent: MeOH/DCM = 1:9 vol), the solid component that isolated out had been filtered out and washed with H₂O, dried, and crystallized from ethanol to afford the pure compounds. The catalyst had been recovered from the aqueous layer under vacuum, washed with n-hexane, and reused for the next reactions. The authenticity samples of the products (3a–i) was elucidated by comparing their melting points with literature and their data on FT-IR.^15–22 4.3.3. 2,6-Bis((E)-4-chlorobenzylidene) cyclohexan-1-one (3a).

Yellow plates; yield: 99 %; m.p. 195–198 °C; FT-IR (KBr, cm⁻¹): ν_max 1666 (C⚌O), 1604 and 1573 (C⚌C). ¹H NMR (CDCl₃), δ_H (ppm): 7.78–6.96 (m, 10H; 2 = CH and 8 Ar-H), 2.75 (br, 4H, 2CH₂), 1.83 (br, 2H, CH₂); ¹³C NMR, δ_C (ppm): 187.8 (C⚌O), 159.4, 137.2, 133.9, 131.9, 128.7, 113.0 (2 = CH and Ar-C), 28.5, 23.1(3CH₂). Analysis calculated for C₂₀H₁₆Cl₂O (343.25); C, 69.98; H, 4.70; Cl, 20.66 %, Found; C, 69.94; H, 4.73; Cl, 20.62 %.

4.3.2

4.3.2 2,6-Bis((E)-4-fluorobenzylidene) cyclohexan-1-one (3b).

Yellow needles; yield: 96 %; m.p. greater than 400 °C; FT-IR (KBr, cm⁻¹): ν_max 1666 (C⚌O), 1604 and 1566 (C⚌C). ¹H NMR (CDCl₃), δ_H (ppm): 7.76–6.93 (m, 10H; 2 = CH and 8 Ar-H), 2.72 (br, 4H, 2CH₂), 1.82 (br, 2H, CH₂); ¹³C NMR, δ_C (ppm): 184.4 (C⚌O), 158.3, 138.4, 132.2, 132.7, 129.1, 113.1 (2 = CH and Ar-C), 27.4, 22.8 (3CH₂). Analysis calculated for C₂₀H₁₆F₂O (310.34); C, 77.40; H, 5.20; F, 12.24 %, Found; C, 77.43; H, 5.24; F, 12.27.

4.3.3

4.3.3 2,6-Bis((E)-4-methylbenzylidene) cyclohexan-1-one (3c).

Yellow plats; yield 96 %; m.p. 174 °C; FT-IR (KBr, cm⁻¹): ν_max 1658 (C⚌O), 1566 and 1597 (C⚌C). ¹H NMR (CDCl₃), δ_H (ppm): 7.74–6.97 (m, 10H; 2 = CH and 8 Ar-H), 2.76 (br, 4H, 2CH₂), 2.01 (br, 2H, CH₂), 1.87 (s, 6H, 2CH₃); ¹³C NMR, δ_C (ppm): 187.0 (C⚌O), 159.2, 137.8, 133.2, 131.7, 128.8, 113.6 (2 = CH and Ar-C), 28.3, 23.4 (3CH₂), 14.3 (2 CH₃). Analysis calculated for C₂₂H₂₂O (302.42): C, 87.38; H, 7.33 %, Found: C, 87.35; H, 7.36 %.

4.3.4

4.3.4 2,6-Bis((E)-4-methoxybenzylidene) cyclohexan-1-one (3d).

Yellow flaxes; yield: 97 %; m.p. 165–167 °C; FT-IR (KBr, cm⁻¹): ν_max 1658 (C⚌O), 1589 and 1543 (C⚌C). ¹H NMR (CDCl₃), δ_H (ppm): 7.74–6.90 (m, 10H; 2 = CH and 8 Ar-H), 3.82 (s, 6H, 2OCH₃), 2.89 (br, 4H, 2CH₂), 1.78 (br, 2H, CH₂); ¹³C NMR, δ_C (ppm): 190.6 (C⚌O), 159.5, 136.5, 133.9, 131.9, 128.7, 113.0 (2 = CH and Ar-C), 54.3 (2 OCH₃), 28.3, 22.2 (3CH₂). Analysis calculated for C₂₂H₂₂O₃ (334.42): C, 79.02; H, 6.63 %, Found: C, 79.06; H, 6.60 %.

4.3.5

4.3.5 2,6-Bis((E)-4-nitrobenzylidene) cyclohexan-1-one (3e).

Brown; yield: 98 %; m.p. 213 °C; FT-IR (KBr, cm⁻¹): ν_max 1666 (C⚌O), 1512 and 1589 (C⚌C). ¹H NMR (CDCl₃), δ_H (ppm): 7.76–6.92 (m, 10H; 2 = CH and 8 Ar-H), 2.71 (br, 4H, 2CH₂), 1.98 (br, 2H, CH₂); ¹³C NMR, δ_C (ppm): 186.3 (C⚌O), 158.3, 136.9, 134.2, 132.3, 129.4, 113.5 (2 = CH and Ar-C), 28.8, 24.5 (3CH₂). Analysis calculated for C₂₀H₁₆N₂O₅ (364.36): C, 65.93; H, 4.43; N, 7.69 %, Found: C, 65.97; H, 4.48; N, 7.65 %.

4.3.6

4.3.6 2,6-Bis((E)-2-nitrobenzylidene) cyclohexan-1-one (3f).

Coffee; yield: 95 %; m.p. 96 °C; FT-IR (KBr, cm⁻¹): ν_max 1697 (C⚌O), 1519 and 1566 (C⚌C). ¹H NMR (CDCl₃), δ_H (ppm): 7.69–6.92 (m, 10H; 2 = CH and 8 Ar-H), 2.74 (br, 4H, 2CH₂), 2.21 (br, 2H, CH₂); ¹³C NMR, δ_C (ppm): 186.5 (C⚌O), 159.7, 137.4, 133.6, 131.3, 128.4, 113.1 (2 = CH and Ar-C), 28.5, 23.1 (3CH₂). Analysis calculated for C₂₀H₁₆N₂O₅ (364.36): C, 65.93; H, 4.43; N, 7.69 %, Found: C, 65.96; H, 4.47; N, 7.65 %.

4.3.7

4.3.7 2,6-Bis(E)-4-cyanobenzylidenecyclohexan-1-one (3 g).

Yellow plates; yield: 97 %; m.p. 232 °C; FT-IR (KBr, cm⁻¹): ν_max 2222 (C≡N), 1666 (C⚌O), 1597 and 1581 (C⚌C). ¹H NMR (CDCl₃), δ_H (ppm): 7.73–7.01 (m, 10H; 2 = CH and 8 Ar-H), 2.73 (br, 4H, 2CH₂), 2.15 (br, 2H, CH₂); ¹³C NMR, δ_C (ppm): 187.0 (C⚌O), 159.2, 137.8, 133.2, 131.7, 128.8, 113.6 (2 = CH and Ar-C), 105 (2C≡N), 28.3, 23.4 (3CH₂). Analysis calculated for C₂₂H₁₆N₂O (324.38): C, 81.46; H, 4.97; N, 8.64 %, Found: C, 81.49; H, 4.94; N, 8.68 %.

4.3.8

4.3.8 (2E,6E)-2,6-Bis(thiophen-2-ylmethylene)cyclohexan-1-one (3 h).

Yellow flaxes; yield: 96 %; m.p. 164 °C. FT-IR (KBr, cm⁻¹): ν_max 1643 (C⚌O) and 1589 (C⚌C); ¹H NMR (CDCl₃), δ_H (ppm): 7.97 (s, 2H, =CH), 7.51–7.09 (m, 6H, thiophene-H), 2.91–2.89 (br, 4H, 2CH₂), 1.95–1.703 (br, 2H, CH₂); ¹³C NMR δ_C (ppm): 189.1 (C⚌O), 139.6, 133.1, 132.9, 130.0, 129.8, 127.7 (Ar-C and CH = C), 28.2, 21.7 (3CH₂). Analysis calculated for C₁₆H₁₄OS₂ (286.41): C, 67.10; H, 4.93; S, 22.39 %, Found: C, 67.07; H, 4.90; S, 22.43 %.

4.3.9

4.3.9 ((2E,6E)-2,6-Bis(furan-2-ylmethylene)cyclohexan-1-one (3i).

Brown flakes; yield: 95 %; m.p. 223 °C; FT-IR (KBr, cm⁻¹): ν_max 1643 (C⚌O), 1543 and 1589 (C⚌C); ¹H NMR (CDCl₃), δ_H (ppm): 7.53–6.49 (m, 8H, 2 = CH and 6 furan-H), 2.99 (br, 4H, 2CH₂) and 1.88 (br, 2H, CH₂). ¹³C NMR δ_C (ppm): 188.8 (C⚌O), 152.6, 152.2, 144.6, 133.0, 132.7, 116.1, 112.4 (CH = C and, Ar-C), 27.8, 21.2 (3CH₂). Analysis calculated for C₁₆H₁₄O₃ (254.29): C, 75.58; H, 5.55 %, Found: C C, 75.54; H, 5.52 %.

4.4

4.4 Synthesis of derivatives 5a, b

A solution of bis-chalcone derivatives (3a, and/or 3b, 1.0 mmol), cyanothioacetamide (1.0 mmol), and sodium ethoxide (2.0 mmol, prepared by mixing 0.32 g Na in 30.0 mL absolute EtOH) was boiled for 7 h. To the resulting solution, a few drops of HCl (36.0 %) was added, and the obtained solid was separated, and crystallized from a proper solvent.

4.4.1

4.4.1 (E)-8-(4-chlorobenzylidene)-4-(4-chlorophenyl)-2-thioxo-2,3,5,6,7,8-hexahydroquinoline-3-carbonitrile (5a)

Orange crystals; yield: 67 %; m.p. 288–289 °C; IR (V_max, cm⁻¹): 2214 (C≡N); ¹H NMR (DMSO‑d₆), δ_H (ppm): 8.13–7.45 (m, 9H, ArH& =CH), 2.82–1.72 (m, 7H, CH& 3CH₂); ¹³C NMR δ_C (ppm): 105 (C≡N), 117 (CH = ) and 158.6(C⚌S). Analysis calculated for C₂₃H₁₆Cl₂N₂S (423.4); C, 65.25; H, 3.81; N, 6.62 %, Found; C, 65.28; H, 3.80; N, 6.64 %; EI-MS (m/z): 422.1 [M⁺−1].

4.4.2

4.4.2 (E)-8-(4-fluorobenzylidene)-4-(4-fluorophenyl)-2-thioxo-2,3,5,6,7,8-hexahydroquinoline-3-carbonitrile (5b)

Yellow crystals; yield: 77 %; m.p. 201–203 °C; IR (V_max, cm⁻¹): 2191 (C≡N); ¹H NMR (DMSO‑d₆), δ_H (ppm): 8.21–7.51 (m, 9H, ArH& =CH), 2.84–1.76 (m, 7H, CH& 3CH₂); ¹³C NMR δ_C (ppm): 105 (C≡N), 115 (CH = ) and 159.7 (C⚌S). Analysis calculated for C₂₃H₁₆F₂N₂S (390.5); C, 70.75; H, 4.13; N, 7.17 %; Found; C, 70.76; H, 4.16; N, 7.19 %.

4.5

4.5 Synthesis of S-alkylated derivatives (7a-d).

Method A:

A mixture of 5a (1.0 mmol) and various alkyl halides (6a-e) (1.0 mmol) namely chloroacetonitrile, ethyl bromoacetate, chloroacetic acid, 4-chlorobenzyl chloride, and ethyl iodide, in 20.0 mL ethanol containing 1.0 mmol Na metal were stirred at ambient temperature for 20 min then boiled for 7 h. And then to the resulting solution, few droplets of dilute hydrochloric acid were added, and the obtained precipitate were crystallized from EtOH/dioxane (9:1) and identified as S-alkylated derivatives (7a-e).

Method B:

A mixture of 5a (1.0 mmol), various alkyl halides (6a-e) (1.0 mmol) namely chloroacetonitrile, ethyl bromoacetate, chloroacetic acid, 4-chlorobenzyl chloride, and ethyl iodide, in 20.0 mL dimethylformamide and 0.5 g K₂CO₃ were stirred at ambient temperature for 4 h. And then the reaction mixture was filtered off, and poured into ice-cold water to furnish precipitate which was separated and recrystallized from the ethanol/dioxane (9:1) and identified as S-alkylated derivatives (7a-e).

4.5.1

4.5.1 (E)-8-(4-chlorobenzylidene)-4-(4-chlorophenyl)-2-((cyanomethyl)thio)-5,6,7,8-tetrahydroquinoline-3-carbonitrile (7a)

Coffee crystals; yield 54 %; m.p. decompose at 332 °C; IR (V_max, cm⁻¹): 2214, 2207 (2C≡N); ¹H NMR (CDCl₃), δ_H (ppm): 7.93 (s, 1H, =CH), 7.43–7.15 (m, 8H, Ar-H), 4.38 (s, 2H, S-CH₂), 2.83–1.87 (m, 6H, 3CH₂). ¹³C NMR δ_C (ppm): 158.3, 155.0, 130.1, 129.7, 128.8, 128.6 (Ar-C), 115.5(2C≡N), 105.6 (=CH), 32.8 (CH₂), 28.2, 27.7, 23.5(3CH₂) Analysis calculated C₂₅H₁₇Cl₂N₃S (462.4) Calcd C, 64.94; H, 3.71; N, 9.09; S, 6.93 %; Found; C, 64.95; H, 3.74; N, 9.10 %. EI-MS (m/z): 460.2 [M⁺−2].

4.5.2

4.5.2 Ethyl(E)-2-((8-(4-chlorobenzylidene)-4-(4-chlorophenyl)-3-cyano-5,6,7,8-tetrahydro-quinolin-2-yl) thio) acetate (7b)

Brown crystals; yield 83 %; m.p. 230–227 °C; IR (V_max, cm⁻¹): 2214 (C≡N); 1743 (C⚌O); ¹H NMR (DMSO‑d₆), δ_H (ppm): 7.97 (s, 1H, =CH), 7.44–7.25 (m, 8H, Ar-H), 4.42 (s, 2H, S-CH₂), 3.87 (q, J = 7.2 Hz, 2H, CH₂), 2.81–1.81 (m, 6H, 3CH₂),1.36(t, J = 8.1 Hz, 3H, CH₃). ¹³C NMR δ_C (ppm): 166.76 (C⚌O), 157.4, 156.2, 132.4, 130.7, 129.4, 128.8 (Ar-C), 115.4 (C≡N), 105.8 (=CH),61.4 (CH₂), 33.2 (CH₂), 29.3, 28.6, 24.5(3CH₂), 14.6(CH₃). Analysis calculated C₂₇H₂₂C_l2N₂O₂S (509.4) Calcd. C, 63.66; H, 4.35; N, 5.50 %; Found: C, 63.67; H, 4.38; N, 5.45 %. EI-MS (m/z): 508.4 [M⁺−1].

4.5.3

4.5.3 (E)-2-((8- (4-Chlorobenzylidene)-4-(4-chlorophenyl)-3-cyano-5,6,7,8-tetrahydroquinolin-2- yl)thio)acetic acid (7c)

Yellow crystals; yield 70 %; m.p. 198–200 °C; IR (V_max, cm⁻¹): 2206 (C≡N); 1712 (C⚌O); 2931 (CH₂). ¹H NMR (DMSO‑d₆), δ_H (ppm): 9.65 (s, 1H, OH), 7.95 (s, 1H, =CH), 7.51–7.21 (m, 8H, Ar-H), 4.43 (s, 2H, S-CH₂), 2.86–1.76 (m, 6H, 3CH₂). ¹³C NMR δ_C (ppm): 164.3 (C⚌O), 158.3, 154.1, 131.7, 130.9, 129.5, 128.4 (Ar-C), 115.7 (C≡N), 105.6 (=CH), 32.6 (CH₂), 28.3, 27.6, 23.5(3CH₂). Analysis calculated C₂₅H₁₈Cl₂N₂O₂S (481.4) Calcd: C, 62.38; H, 3.77; N, 5.82 %; Found: C, 62.40; H, 3.80; N, 5.84 %; EI-MS (m/z): 480 [M⁺−1].

4.5.4

4.5.4 (E)-2-((4-Chlorobenzyl) thio)-8-(4-Chlorobenzylidene)-4-(4-Chlorophenyl)-5,6,7,8-tetr hydroquinoline-3-Carbonitrile (7d)

Yellow crystals; yield 95 %; m.p. 212–214 °C; IR (V_max, cm⁻¹): 2214 (C≡N); 2954 (CH₂); ¹H NMR (CDCl₃), δ_H (ppm): 7.96 (s, 1H, =CH), 7.45–7.27 (m, 12H, Ar-H), 4.54 (s, 2H, S-CH₂), 2.80–1.70 (m, 6H, 3CH₂). ¹³C NMR δ_C (ppm): 158.3, 155.1, 155.0, 153.2, 131.0, 130.1, 129.7, 129.3, 128.8, 128.6 (Ar-C), 115.4 (C≡N), 105.3 (=CH), 33.9 (CH₂), 27.6, 27.4, 22.3 (3CH₂). Analysis calculated C₃₀H₂₁C_l3N₂S (547.9) Calcd: C, 65.76; H, 3.86; N, 5.11 %; Found: C, 65.77; H, 3.89; N, 5.12 %. EI-MS (m/z): 547.4 [M].

4.5.5

4.5.5 (E)-8-(4-Chlorobenzylidene)-4-(4-chlorophenyl)-2-(ethylthio)-5,6,7,8-tetrahydro-quinoline-3- carbonitrile (7e)

Yellow crystals; yield 79 %; m.p. 252–254 °C; IR (V_max, cm⁻¹): 2214 (C≡N); 2924 (CH₂). ¹H NMR (DMSO‑d₆), δ_H (ppm): 7.94 (s, 1H, =CH), 7.55–7.34(m, 8H, Ar-H), 4.47 (q, J = 7.4 Hz, 2H, S-CH₂), 2.85–1.87 (m, 6H, 3CH₂), 1.43(t, J = 7.9 Hz, 3H, CH₃). ¹³C NMR δ_C (ppm): 158.6, 153.5, 132.6, 130.2, 129.3, 128.8 (Ar-C), 115.4 (C≡N), 105.1 (=CH), 33.1 (CH₂), 29.6, 28.2, 24.7(3CH₂). Analysis calculated C₂₅H₂₀Cl₂N₂S (451.4) Calcd: C, 66.52; H, 4.47; N, 6.21 %; Found: C, 66.53; H, 4.50; N, 6.22 %; EI-MS (m/z): 449.3 [M⁺−2].

4.6

4.6 Synthesis of derivatives (8a-c).

Method A:

Derivatives (7a-c) (1.0 mmol) in 30.0 mL ethanol containing 1.0 mmol metallic sodium were refluxed for 5 h, and then the resulting solution was neutralized by using dilute hydrochloric acid to give derivatives 8a-c with good yield. The resulting products (8a-c) were crystallized from the proper solvent.

Method B:

Derivatives 8a-c were obtained directly on refluxing of the thiol derivative (5a) with halo-derivatives (6a-c) in ethanol containing 2.0 mmol of sodium metal for 6 h and then the solution was neutralized by using dilute hydrochloric acid to give derivatives 8a-c with good yield. The obtained products 8a-c were crystallized from the proper solvent.

4.6.1

4.6.1 (E)-3-Amino-8-(4-chlorobenzylidene)-4-(4-chlorophenyl)-5,6,7,8-tetrahydro-3H-1 l4-thieno[2,3-b] quinoline-2-carbonitrile (8a)

Yellow crystals; yield 55 %; m.p. 313–314 °C; IR (V_max, cm⁻¹): 2198 (C≡N); 3479, 3325 (NH₂), ¹H NMR (CDCl₃), δ_H (ppm): 8.12 (br, 1H, =CH), 7.64–7.2 (m, 8H, Ar-H), 4.3 (s, 2H, NH₂), 2.82–1.55 (m, 6H, 3CH₂). Analysis calculated C₂₅H₁₇Cl₂N₃S (462.4) Calcd C, 64.94; H, 3.71; N, 9.09 %; Found; C, 64.96; H, 3.74; N, 9.11 %. EI-MS (m/z): 460.2[M⁺-2].

4.6.2

4.6.2 Ethyl(E)-3-amino-8-(4-chlorobenzylidene)-4-(4-chlorophenyl)-5,6,7,8-tetrahydro-thieno [2,3- b] quinoline-2-carboxylate (8b)

Yellow; yield 83 %; m.p. 270–271 °C; IR (V_max, cm⁻¹): 3487, 3340 (NH₂); 1666 (C⚌O). ¹H NMR (CDCl₃), δ_H (ppm): 8.09 (s, H, C = CH), 7.62–6.609 (m, 8H, Ar-H), 5.35 (s, 2H, NH₂), 4.29–4.25 (q, 2H, CH₂), 1.346–1.32 (t, 3H, CH₃), 2.84–1.55 (m, 6H, 3CH₂).¹³C NMR δ_C (ppm): 178 (C⚌O), 136.0, 135.2, 131.1, 130.8, 129.9, 129.8, 129.6, 128.4, 127.7 (Ar-C), 60.6 (CH₂), 27.2, 23.5, 22.7 (3CH₂), 14.59 (CH₃). Analysis calculated C₂₇H₂₂Cl₂N₂O₂S (509.4) Calcd: C, 63.66; H, 4.38; N, 5.51 %; Found, C, 63.67; H, 4.41; N, 5.52 %. EI-MS (m/z): 508.5 [ M⁺−1].

4.6.3

4.6.3 (E)-3-Amino-8-(4-chlorobenzylidene)-4-(4-chlorophenyl)-5,6,7,8-tetrahydrothieno[2,3-b] quinoline-2-carboxylic acid (8c)

Dark yellow crystals; yield 70 %; m.p. 178–179 °C; IR (V_max, cm⁻¹): 3495–3400 (NH₂); 2500–3200 (OH), 2939 (CH₂); 1635 (C⚌O). ¹H NMR (DMSO‑d₆), δ_H (ppm): 7.97 (s, 1H, =CH), 7.62–7.21 (m, 8H, Ar-H), 6.63 (s, 1H, OH), 5.44 (br, 2H, NH₂), 2.46–1.64 (m, 6H, 3CH₂). Analysis calculated C₂₅H₁₈Cl₂N₂O₂S (481.4) Calcd: C, 62.38; H, 3.77; N, 5.82 %; Found: C, 62.40; H, 3.80; N, 5.84 %. EI-MS (m/z): 480.3 [M⁺−1].

4.7

4.7 (E)-N-(8-(4-chlorobenzylidene)-4-(4-chlorophenyl)-2-cyano-5,6,7,8- tetrahydrothieno[2,3-b]quinolin-3-yl)acetamide (9)

To a hot solution of compound 8a (1.0 mmol) in 20 mL dry pyridine, acetic anhydride (1.0 mmol) was added. After that the reaction was refluxed further to 3 h. After cooling the reaction mixture was poured into crushed ice / water with vigorous stirring to get yellow precipitate which filtered off, dried and recrystallized from ethanol/benzene (9:1) as flaxes crystals; Yield: 68 %; m.p. 236–237 °C; IR (V_max, cm⁻¹): 2222 (C≡N); 3325 (N—H); 1535 (C⚌C); 1720 (C⚌O), ¹H NMR (CDCl₃), δ_H (ppm): 8.15 (s, 1H, =CH), 7.55–7.03 (m, 9H, Ar-H, NH), 2.87–1.76 (m, 9H, 3CH₂, CH₃). Analysis calculated C₂₇H₁₉Cl₂N₃OS (504.4) Calcd: C, 64.29; H, 3.80; N, 8.33 %; Found C, 64.32; H, 3.76; N, 8.30 %.

4.8

4.8 (E)-7-(4-Chlorobenzylidene)-3,11-bis(4-chlorophenyl)-2-thioxo-2,3,7,8,9,10-hexahydro pyrimido[4′,5′:4,5]thieno[2,3-b]quinolin-4(1H)-one (10)

A mixture of 8a (1.0 mmol) and 4-chlorophenylisothiocyanate (1.0 mmol) in DMF (20.0 mL) were refluxed for 4 h. After cooling, the obtained solution poured into crushed ice/water with vigorous stirring to get precipitate, which filtered off, dried, and recrystallized from dioxane as orange plates; Yield: 80 %; m.p. 257–260 °C; IR (V_max, cm⁻¹): 3379 (N—H), 1666 (C⚌O), 1566 (C⚌C). Analysis calculated C₃₂H20Cl₃N3OS₂ (633.0) Calcd: C, 60.72; H, 3.18; N, 6.64 %; Found C, 60.73; H, 3.121; N, 6.65 %. %. EI-MS (m/z): 632.4 [M⁺−1].

4.9

4.9 Synthesis of dialkyl 2-((8-((E)-4-chlorobenzylidene)-4-(4-chlorophenyl)-3-cyano-5,6,7,8-tetrahydroquinolin-2-yl) thio) maleate (14a, b).

General method: A solution of dialkylacetylenedicarboxylate (11a, b) (1.0 mmol) and 5a (1.0 mmol) in DCM (20.0 mL) containing a catalytic amount of triethylamine were stirring at ambient temperature for three hours. The formed rigid substance was separated from the mother liquor by a vacuum pump and the obtained product is crystallized from ethanol to afford derivatives 14a, b.

4.9.1

4.9.1 Dimethyl 2-((8-((E)-4-chlorobenzylidene)-4-(4-chlorophenyl)-3-cyano-5,6,7,8-tetrahydro quinolin-2-yl)thio)maleate (14a).

Yellow flakes; yield: 68 %; m.p. 220–221 °C; IR (V_max, cm⁻¹): 2222 (C≡N); 1527 (C⚌C); 1712,1710 (C⚌O). ¹H NMR (CDCl₃), δ_H (ppm): 8.05 (s, 1H, =CH), 7.48 (s, 1H, =CH), 7.46–7.03 (m, 8H, Ar-H), 2.82–2.78 (t, J = 7.2 Hz, 2H, CH₂), 2.53–2.50 (t, J = 7.2 Hz, 2H, CH₂), 2.22–2.18 (m, 2H, CH₂), 1.97(s, 3H, CH₃) and 1.94 (s, 3H, CH₃), ¹³C NMR δ_C (ppm): 164.7, 164.5 (2C = O), 157.3, 155.6, 153.4, 135.4, 131.7, 129.8,129.45,129.41, 128.5, 106.4 (Ar-C), 117.0 (C≡N), 28.7, 24.3 (3CH₂), 14.56, 13.74 (2CH₃). Analysis calculated C₂₉H₂₂Cl₂N₂O₄S (565.5) Calcd: C, 61.60; H, 3.92; N, 4.95 %; Found C, 61.65; H, 3.94; N, 4.97 %.

4.9.2

4.9.2 Diethyl2-((8-((E)-4-chlorobenzylidene)-4-(4-chlorophenyl)-3-cyano-5,6,7,8-tetrahydro-quinolin-2- yl)thio)maleate (14b).

Orange flakes, 0.07 g (57 %) yield; m.p. 297–299 °C; IR (V_max, cm⁻¹): 2222 (C≡N); 1720, 1714 (C⚌O); 3055 (CH₂). ¹H NMR (CDCl₃), δ_H (ppm): 8.06 (s, 1H, =CH), 7.49 (s, 1H, =CH), 7.47–7.05 (m, 8H, Ar-H), 4.302–4.267 (q, J = 7.1 Hz, 2H, CH₂), 4.068–4.033 (q, J = 7.1 Hz, 2H,CH₂), 2.81–2.79 (t, J = 7.0 Hz, 2H, CH₂), 2.51–2.49 (t, J = 7.1 Hz, 2H, CH₂), 1.71–1.68 (m, 2H, CH2), 1.34–1.294 (t, 3H, CH₃) and 0.983–0.960 (t, 3H, CH₃), ¹³C NMR δ_C (ppm): 164.6, 164.4 (2C = O), 157.3, 155.6, 153.4, 135.4, 131.7, 129.8,129.45,129.41, 128.6, 105.7 (Ar-C), 115.0 (C≡N), 62.4, 61.6 (2CH₂), 27.6, 22.1 (3CH₂), 14.29, 13.84 (2CH₃). Analysis calculated C₃₁H₂₆Cl₂N₂O₄S (593.5) Calcd: C, 61.60; H, 3.92; N, 4.95 %; Found C, 61.63; H, 3.95; N, 4.92 %. EI-MS (m/z): 594.4 [M⁺+1].

4.10

4.10 Cytotoxicity activities against three tumor cell lines for compounds 5a, 5b, 7d, 7e, 8b, and 10.

The in vitro cytotoxicity activities of some selected compounds (5a, 5b, 7d, 7e, 8b, and 10) against HepG-2, MCF-7, and A-549 cell lines were tested by MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay utilizing Doxorubicin as a reference compound (Abo-Ashour et al., 2019).

5 Conclusions

We have reported the design and green synthesis of some heterocyclic molecules with diverse biological properties. A methodology for the construction of bis-arylidene cycloalkanone derivatives (bis-chalcones) using an ionic liquid substance as a catalyst has been provided. Simple multicomponent procedures are outlined for the environmentally friendly production of tetrahydroquinoline(1H)thions. Good yields of novel thienoquinolino compounds were also produced. Three cancer cell lines Hepatocellular carcinoma cells (HepG-2), Breast carcinoma cells (MCF-7), and Lung carcinoma cells (A-549) were used to examine the antiproliferative effects of some selected derivatives. The majority of evaluated drugs exhibited moderate to excellent cytotoxicity against the examined cell lines. Notably, the IC₅₀ values for the S-alkyl derivatives ranged from 2.86 to 13.14 µg/mL.

Acknowledgement

The authors would like to thank the Deanship of Graduate Studies at Jouf University for funding and supporting this research through the initiative of DGS, Graduate Students Research Support (GSR) at Jouf University, Saudi Arabia.

Conflicts of interest

There are no conflicts of interest to be declared.

References

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[CrossRef] [Google Scholar]
Arafa W.A.A., . Sustainable Catalytic Process with a High Eco-Scale Score for the Synthesis of Novel Series of Bischalcones through Claisen-Schmidt Condensation. J. Heterocycl. Chem.. 2018;55(2):456-464.
[CrossRef] [Google Scholar]
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[CrossRef] [Google Scholar]
Costi R., Di Santo R., Artico M., Miele G., Valentini P., Novellino E., Cereseto A., . Cinnamoyl Compounds as Simple Molecules That Inhibit P300 Histone Acetyltransferase. J. Med. Chem.. 2007;50(8):1973-1977.
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[CrossRef] [Google Scholar]
Eiden F., Rademacher G., Schünemann J., . Xanthone Aus Chromon-Derivaten. Arch. Pharm. (Weinheim). 1984;317(6):539-547.
[CrossRef] [Google Scholar]
El-Taweel F.M.A., . Synthesis of Some New Pyrazolo[4,3-B]Pyridine, Pyridine, Pyrazolo[1,5-A]Pyrimidine and Thiazole Derivatives. Bull. des Sociétés Chim. Belges. 2010;104(9):567-572.
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Gogate P.R., Wilhelm A.M., Pandit A.B., . Some Aspects of the Design of Sonochemical Reactors. Ultrason. Sonochem.. 2003;10(6):325-330.
[CrossRef] [Google Scholar]
Hosoya T., Nakata A., Yamasaki F., Abas F., Shaari K., Lajis N.H., Morita H., . Curcumin-like Diarylpentanoid Analogues as Melanogenesis Inhibitors. J. Nat. Med.. 2012;66(1):166-176.
[CrossRef] [Google Scholar]
Javanshir S., Mojtahedi M.M., Eslami J., . A Highly Efficient Method for Synthesis of Bisarylmethylidenes of Cyclic Ketones in [BMIm]Cl/NaOH System as New and Recyclable Catalyst. Curr. Chem. Lett.. 2014;3(2):63-70.
[CrossRef] [Google Scholar]
Jiménez-González C., Constable D.J.C., Ponder C.S., . Evaluating the “Greenness” of Chemical Processes and Products in the Pharmaceutical Industry—a Green Metrics Primer. Chem. Soc. Rev.. 2012;41(4):1485-1498.
[CrossRef] [Google Scholar]
Jubeen F., Iqbal S.Z., Shafiq N., Khan M., Parveen S., Iqbal M., Nazir A., . Eco-Friendly Synthesis of Pyrimidines and Its Derivatives: A Review on Broad Spectrum Bioactive Moiety with Huge Therapeutic Profile. Synth. Commun.. 2018;48(6):601-625.
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Li J.-T., Yang W.-Z., Chen G.-F., Li T.-S., . A Facile Synthesis of α, Α′- Bis (Substituted Benzylidene) Cycloalkanones Catalyzed by KF/Al 2 O 3 Under Ultrasound Irradiation. Synth. Commun.. 2003;33(15):2619-2625.
[CrossRef] [Google Scholar]
Madkour H.M.F., El-Hashash M.A.M., Salem M.S., Mahmoud A.l., Ali O., . Synthesis, antileishmanial and cytotoxicity activities of fused and nonfused tetrahydroquinoline derivatives. Res. Chem. Intermed.. 2018;44:3349.
[CrossRef] [Google Scholar]
Nakano T., Irifune S., Umano S., Inada A., Ishii Y., Ogawa M., . Cross-Condensation Reactions of Cycloalkanones with Aldehydes and Primary Alcohols under the Influence of Zirconocene Complexes. J. Org. Chem.. 1987;52(11):2239-2244.
[CrossRef] [Google Scholar]
Patil R.C., Patil U.P., Jagdale A.A., Shinde S.K., Patil S.S., . Ash of Pomegranate Peels (APP): A Bio-Waste Heterogeneous Catalyst for Sustainable Synthesis of α, Α′-Bis(Substituted Benzylidine)Cycloalkanones and 2-Arylidene-1-Tetralones. Res. Chem. Intermed.. 2020;46(7):3527-3543.
[CrossRef] [Google Scholar]
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Shirini F., Langarudi M.S.N., Daneshvar N., . Preparation of a New DABCO-Based Ionic Liquid [H 2 -DABCO][H 2 PO 4 ] 2 } and Its Application in the Synthesis of Tetrahydrobenzo[b ]Pyran and Pyrano[2,3- d ]Pyrimidinone Derivatives. J. Mol. Liq.. 2017;234:268-278.
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Song D., Chen Y., Wang R., Liu C., Jiang H., Luo G., . Crossed-Aldol Condensation of Cycloalkanones with Aromatic Aldehydes Catalyzed by Copper(II) Trifluoroacetate. Prep. Biochem. Biotechnol.. 2009;39(2):201-207.
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Tolba M.S., Ul-Malik M.A.A., El-Dean A.M.K., Geies A.A., Radwan S.M., Zaki R.M., Sayed M., Mohamed S.K., Abdel-Raheem S.A.A., . An Overview on Synthesis and Reactions of Coumarin Based Compounds. Curr. Chem. Lett.. 2022;11(1):29-42.
[CrossRef] [Google Scholar]
Vashishtha M., Mishra M., Undre S., Singh M., Shah D.O., . Molecular Mechanism of Micellar Catalysis of Cross Aldol Reaction: Effect of Surfactant Chain Length and Surfactant Concentration. J. Mol. Catal. A Chem.. 2015;396:143-154.
[CrossRef] [Google Scholar]
Wagner G., Vieweg H., Leistner S., . Synthesis of 11-Aryl-7,8,9,10-Tetrahydro-1,2,3-Triazino-(4’,5’:4,5)-Thienol- -(2,3-b)-Quinolines with Antianaphylactic Action. Pharmazie. 1993;48(8):576-578.
[Google Scholar]
Wang J.-X., Kang L., Hu Y., guo Wei B., . Synthesis of Bis (Substituted Benzylidene)Cycloalkanone using Supported Reagents And Microwave Irradiation. Synth. Commun.. 2002;32(11):1691-1696.
[CrossRef] [Google Scholar]

Appendix A

Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.arabjc.2023.104543.

Appendix A

Supplementary data

The following are the Supplementary data to this article:

Supplementary data 1

Download

Introduction

Results and discussion

Biological evaluation

Cytotoxicity activities

Experimental section

Materials
Synthesis of the catalyst [DABCO-EtOH][AcO].
General methods for synthesis of bis-chalcone derivatives (3a-i)
Synthesis of derivatives 5a, b
Synthesis of S-alkylated derivatives (7a-d).
Synthesis of derivatives (8a-c).
(E)-N-(8-(4-chlorobenzylidene)-4-(4-chlorophenyl)-2-cyano-5,6,7,8- tetrahydrothieno[2,3-b]quinolin-3-yl)acetamide (9)
(E)-7-(4-Chlorobenzylidene)-3,11-bis(4-chlorophenyl)-2-thioxo-2,3,7,8,9,10-hexahydro pyrimido[4′,5′:4,5]thieno[2,3-b]quinolin-4(1H)-one (10)
Synthesis of dialkyl 2-((8-((E)-4-chlorobenzylidene)-4-(4-chlorophenyl)-3-cyano-5,6,7,8-tetrahydroquinolin-2-yl) thio) maleate (14a, b).
Cytotoxicity activities against three tumor cell lines for compounds 5a, 5b, 7d, 7e, 8b, and 10.

Conclusions

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[1] Abaee M.S., Mojtahedi M.M., Sharifi R., Zahedi M.M., Abbasi H., Tabar-Heidar K., . Facile Synthesis of Bis(Arylmethylidene)Cycloalkanones Mediated by Lithium Perchlorate under Solvent-Free Conditions. J. Iran. Chem. Soc.. 2006;3(3):293-296.
[CrossRef] [Google Scholar]

[2] Abo-Ashour M.F., Eldehna W.M., Nocentini A., Bonardi A., Bua S., Ibrahim H.S., Elaasser M.M., Kryštof V., Jorda R., Gratteri P., Abou-Seri S.M., Supuran C.T., . 3-Hydrazinoisatin-Based Benzenesulfonamides as Novel Carbonic Anhydrase Inhibitors Endowed with Anticancer Activity: Synthesis, in Vitro Biological Evaluation and in Silico Insights. Eur. J. Med. Chem.. 2019;184:111768
[CrossRef] [Google Scholar]

[3] An L.-T., Zou J.-P., Zhang L.-L., . Polymer-Supported Sulphonic Acid Catalyzed Cross-Aldol Condensation: An Expeditious Synthesis of α, Α′-Bis(Substituted Benzylidene) Cycloalkanones. Catal. Commun.. 2008;9(3):349-354.
[CrossRef] [Google Scholar]

[4] Arafa W.A.A., . Sustainable Catalytic Process with a High Eco-Scale Score for the Synthesis of Novel Series of Bischalcones through Claisen-Schmidt Condensation. J. Heterocycl. Chem.. 2018;55(2):456-464.
[CrossRef] [Google Scholar]

[5] Arafa W.A.A., . An Eco-Compatible Pathway to the Synthesis of Mono and Bis-Multisubstituted Imidazoles over Novel Reusable Ionic Liquids: An Efficient and Green Sonochemical Process. RSC Adv.. 2018;8(29):16392-16399.
[CrossRef] [Google Scholar]

[6] Arafa W.A.A., Ibrahim H.M., . A Sustainable Strategy for the Synthesis of Bis-2-Iminothiazolidin-4-Ones Utilizing Novel Series of Asymmetrically Substituted Bis-Thioureas as Viable Precursors. RSC Adv.. 2018;8(19):10516-10521.
[CrossRef] [Google Scholar]

[7] Arafa W.A.A., Faty R.A.M., Mourad A.K., . A New Sustainable Strategy for Synthesis of Novel Series of Bis-Imidazole and Bis-1,3-Thiazine Derivatives. J. Heterocycl. Chem.. 2018;55(8):1886-1894.
[CrossRef] [Google Scholar]

[8] Braga S.F.P., Alves É.V.P., Ferreira R.S., Fradico J.R.B., Lage P.S., Duarte M.C., Ribeiro T.G., Júnior P.A.S., Romanha A.J., Tonini M.L., Steindel M., Coelho E.F., de Oliveira R.B., . Synthesis and Evaluation of the Antiparasitic Activity of Bis-(Arylmethylidene) Cycloalkanones. Eur. J. Med. Chem.. 2014;71:282-289.
[CrossRef] [Google Scholar]

[9] Costi R., Di Santo R., Artico M., Miele G., Valentini P., Novellino E., Cereseto A., . Cinnamoyl Compounds as Simple Molecules That Inhibit P300 Histone Acetyltransferase. J. Med. Chem.. 2007;50(8):1973-1977.
[CrossRef] [Google Scholar]

[10] Dimmock J.R., Hamon N.W., Hindmarsh K.W., Sellar A.P., Turner W.A., Rank G.H., Robertson A.J., . Evaluation of 2-benzylidenecyclohexanones and 2,6-bis(Benzylidene)Cyclohexanones for Antitumor and Cytotoxic Activity and as Inhibitors of Mitochondrial Function in Yeast: Metabolism Studies of (E)-2-benzylidenecyclohexanone. J. Pharm. Sci.. 1976;65(4):538-543.
[CrossRef] [Google Scholar]

[11] Dinkova-Kostova A.T., Abeygunawardana C., Talalay P., . Chemoprotective Properties of Phenylpropenoids, Bis(Benzylidene)Cycloalkanones, and Related Michael Reaction Acceptors: Correlation of Potencies as Phase 2 Enzyme Inducers and Radical Scavengers. J. Med. Chem.. 1998;41(26):5287-5296.
[CrossRef] [Google Scholar]

[12] Egorova K.S., Ananikov V.P., . Fundamental Importance of Ionic Interactions in the Liquid Phase: A Review of Recent Studies of Ionic Liquids in Biomedical and Pharmaceutical Applications. J. Mol. Liq.. 2018;272:271-300.
[CrossRef] [Google Scholar]

[13] Eiden F., Rademacher G., Schünemann J., . Xanthone Aus Chromon-Derivaten. Arch. Pharm. (Weinheim). 1984;317(6):539-547.
[CrossRef] [Google Scholar]

[14] El-Taweel F.M.A., . Synthesis of Some New Pyrazolo[4,3-B]Pyridine, Pyridine, Pyrazolo[1,5-A]Pyrimidine and Thiazole Derivatives. Bull. des Sociétés Chim. Belges. 2010;104(9):567-572.
[CrossRef] [Google Scholar]

[15] Gawande M.B., Bonifácio V.D.B., Luque R., Branco P.S., Varma R.S., . Benign by Design: Catalyst-Free in-Water, on-Water Green Chemical Methodologies in Organic Synthesis. Chem. Soc. Rev.. 2013;42(12):5522.
[CrossRef] [Google Scholar]

[16] Ghasemzadeh M.S., Akhlaghinia B., . PdII Immobilized on Ferromagnetic Multi-Walled Carbon Nanotubes Functionalized by Aminated 2-Chloroethylphosphonic Acid with S-Methylisothiourea (FMMWCNTs@CPA@SMTU@PdII NPs) Applied as a Highly Efficient and Recyclable Nanostructured Catalyst for Suzuki–M. Aust. J. Chem.. 2019;72(9):674.
[CrossRef] [Google Scholar]

[17] Gogate P.R., Wilhelm A.M., Pandit A.B., . Some Aspects of the Design of Sonochemical Reactors. Ultrason. Sonochem.. 2003;10(6):325-330.
[CrossRef] [Google Scholar]

[18] Hosoya T., Nakata A., Yamasaki F., Abas F., Shaari K., Lajis N.H., Morita H., . Curcumin-like Diarylpentanoid Analogues as Melanogenesis Inhibitors. J. Nat. Med.. 2012;66(1):166-176.
[CrossRef] [Google Scholar]

[19] Javanshir S., Mojtahedi M.M., Eslami J., . A Highly Efficient Method for Synthesis of Bisarylmethylidenes of Cyclic Ketones in [BMIm]Cl/NaOH System as New and Recyclable Catalyst. Curr. Chem. Lett.. 2014;3(2):63-70.
[CrossRef] [Google Scholar]

[20] Jiménez-González C., Constable D.J.C., Ponder C.S., . Evaluating the “Greenness” of Chemical Processes and Products in the Pharmaceutical Industry—a Green Metrics Primer. Chem. Soc. Rev.. 2012;41(4):1485-1498.
[CrossRef] [Google Scholar]

[21] Jubeen F., Iqbal S.Z., Shafiq N., Khan M., Parveen S., Iqbal M., Nazir A., . Eco-Friendly Synthesis of Pyrimidines and Its Derivatives: A Review on Broad Spectrum Bioactive Moiety with Huge Therapeutic Profile. Synth. Commun.. 2018;48(6):601-625.
[CrossRef] [Google Scholar]

[22] Kumar S., Narasimhan B., . Therapeutic Potential of Heterocyclic Pyrimidine Scaffolds. Chem. Cent. J.. 2018;12(1):38.
[CrossRef] [Google Scholar]

[23] Li J.-T., Yang W.-Z., Chen G.-F., Li T.-S., . A Facile Synthesis of α, Α′- Bis (Substituted Benzylidene) Cycloalkanones Catalyzed by KF/Al 2 O 3 Under Ultrasound Irradiation. Synth. Commun.. 2003;33(15):2619-2625.
[CrossRef] [Google Scholar]

[24] Madkour H.M.F., El-Hashash M.A.M., Salem M.S., Mahmoud A.l., Ali O., . Synthesis, antileishmanial and cytotoxicity activities of fused and nonfused tetrahydroquinoline derivatives. Res. Chem. Intermed.. 2018;44:3349.
[CrossRef] [Google Scholar]

[25] Nakano T., Irifune S., Umano S., Inada A., Ishii Y., Ogawa M., . Cross-Condensation Reactions of Cycloalkanones with Aldehydes and Primary Alcohols under the Influence of Zirconocene Complexes. J. Org. Chem.. 1987;52(11):2239-2244.
[CrossRef] [Google Scholar]

[26] Patil R.C., Patil U.P., Jagdale A.A., Shinde S.K., Patil S.S., . Ash of Pomegranate Peels (APP): A Bio-Waste Heterogeneous Catalyst for Sustainable Synthesis of α, Α′-Bis(Substituted Benzylidine)Cycloalkanones and 2-Arylidene-1-Tetralones. Res. Chem. Intermed.. 2020;46(7):3527-3543.
[CrossRef] [Google Scholar]

[27] Piantadosi C., Hall I.H., Irvine J.L., Cycloalkanones C.G.L., . 2. Synthesis and Biological Activity of. Alpha., Alpha’.-Dibenzylcycloalkanones. J. Med. Chem.. 1973;16(7):770-775.
[CrossRef] [Google Scholar]

[28] Raj A.A., Raghunathan R., SrideviKumari M., Raman N., . Synthesis, Antimicrobial and Antifungal Activity of a New Class of Spiro Pyrrolidines. Bioorg. Med. Chem.. 2003;11(3):407-419.
[CrossRef] [Google Scholar]

[29] Shirini F., Langarudi M.S.N., Daneshvar N., . Preparation of a New DABCO-Based Ionic Liquid [H 2 -DABCO][H 2 PO 4 ] 2 } and Its Application in the Synthesis of Tetrahydrobenzo[b ]Pyran and Pyrano[2,3- d ]Pyrimidinone Derivatives. J. Mol. Liq.. 2017;234:268-278.
[CrossRef] [Google Scholar]

[30] Show K.-Y., Mao T., Lee D.-J., . Optimisation of Sludge Disruption by Sonication. Water Res.. 2007;41(20):4741-4747.
[CrossRef] [Google Scholar]

[31] Simbera J., Sevcik R., Pazdera P., . New One-Pot Methods for Preparation of Cyclohexanecarbonitrile—Green Chemistry Metrics Evaluation for One-Pot and Similar Multi-Step Syntheses. Green Sustain. Chem.. 2014;04(02):70-79.
[CrossRef] [Google Scholar]

[32] Song D., Chen Y., Wang R., Liu C., Jiang H., Luo G., . Crossed-Aldol Condensation of Cycloalkanones with Aromatic Aldehydes Catalyzed by Copper(II) Trifluoroacetate. Prep. Biochem. Biotechnol.. 2009;39(2):201-207.
[CrossRef] [Google Scholar]

[33] Tolba M.S., Sayed M., Kamal El-dean A.M., Hassanien R., Ahmed M., Abdel-Raheem S.A.A., . Design, Synthesis and Antimicrobial Screening of Some New Thienopyrimidines. Org. Commun.. 2021;4:365-376.
[CrossRef] [Google Scholar]

[34] Tolba M.S., Sayed A.M., Sayed M., Ahmed M., . Design, Synthesis, Biological Evaluation, and Molecular Docking of Some New Thieno[2,3-d] Pyrimidine Derivatives. J. Mol. Struct.. 2021;1246:131179
[CrossRef] [Google Scholar]

[35] Tolba M.S., Ul-Malik M.A.A., El-Dean A.M.K., Geies A.A., Radwan S.M., Zaki R.M., Sayed M., Mohamed S.K., Abdel-Raheem S.A.A., . An Overview on Synthesis and Reactions of Coumarin Based Compounds. Curr. Chem. Lett.. 2022;11(1):29-42.
[CrossRef] [Google Scholar]

[36] Vashishtha M., Mishra M., Undre S., Singh M., Shah D.O., . Molecular Mechanism of Micellar Catalysis of Cross Aldol Reaction: Effect of Surfactant Chain Length and Surfactant Concentration. J. Mol. Catal. A Chem.. 2015;396:143-154.
[CrossRef] [Google Scholar]

[37] Wagner G., Vieweg H., Leistner S., . Synthesis of 11-Aryl-7,8,9,10-Tetrahydro-1,2,3-Triazino-(4’,5’:4,5)-Thienol- -(2,3-b)-Quinolines with Antianaphylactic Action. Pharmazie. 1993;48(8):576-578.
[Google Scholar]

[38] Wang J.-X., Kang L., Hu Y., guo Wei B., . Synthesis of Bis (Substituted Benzylidene)Cycloalkanone using Supported Reagents And Microwave Irradiation. Synth. Commun.. 2002;32(11):1691-1696.
[CrossRef] [Google Scholar]

Green synthesis of some tetrahydroquinoline derivatives and evaluation as anticancer agents

Abstract

Abstract

Keywords

Green

Antiproliferative

Thienoquinolines

Pyrimidothienoquinoline

sonosynthesis

1 Introduction

2 Results and discussion

3 Biological evaluation

3.1 Cytotoxicity activities

4 Experimental section

4.1 Materials

4.2 Synthesis of the catalyst [DABCO-EtOH][AcO].

4.3 General methods for synthesis of bis-chalcone derivatives (3a-i)

4.3.1 Conventional method:

4.3.2 2,6-Bis((E)-4-fluorobenzylidene) cyclohexan-1-one (3b).

4.3.3 2,6-Bis((E)-4-methylbenzylidene) cyclohexan-1-one (3c).

4.3.4 2,6-Bis((E)-4-methoxybenzylidene) cyclohexan-1-one (3d).

4.3.5 2,6-Bis((E)-4-nitrobenzylidene) cyclohexan-1-one (3e).

4.3.6 2,6-Bis((E)-2-nitrobenzylidene) cyclohexan-1-one (3f).

4.3.7 2,6-Bis(E)-4-cyanobenzylidenecyclohexan-1-one (3 g).

4.3.8 (2E,6E)-2,6-Bis(thiophen-2-ylmethylene)cyclohexan-1-one (3 h).

4.3.9 ((2E,6E)-2,6-Bis(furan-2-ylmethylene)cyclohexan-1-one (3i).

4.4 Synthesis of derivatives 5a, b

4.4.1 (E)-8-(4-chlorobenzylidene)-4-(4-chlorophenyl)-2-thioxo-2,3,5,6,7,8-hexahydroquinoline-3-carbonitrile (5a)

4.4.2 (E)-8-(4-fluorobenzylidene)-4-(4-fluorophenyl)-2-thioxo-2,3,5,6,7,8-hexahydroquinoline-3-carbonitrile (5b)

4.5 Synthesis of S-alkylated derivatives (7a-d).

4.5.1 (E)-8-(4-chlorobenzylidene)-4-(4-chlorophenyl)-2-((cyanomethyl)thio)-5,6,7,8-tetrahydroquinoline-3-carbonitrile (7a)

4.5.2 Ethyl(E)-2-((8-(4-chlorobenzylidene)-4-(4-chlorophenyl)-3-cyano-5,6,7,8-tetrahydro-quinolin-2-yl) thio) acetate (7b)

4.5.3 (E)-2-((8- (4-Chlorobenzylidene)-4-(4-chlorophenyl)-3-cyano-5,6,7,8-tetrahydroquinolin-2- yl)thio)acetic acid (7c)

4.5.4 (E)-2-((4-Chlorobenzyl) thio)-8-(4-Chlorobenzylidene)-4-(4-Chlorophenyl)-5,6,7,8-tetr hydroquinoline-3-Carbonitrile (7d)

4.5.5 (E)-8-(4-Chlorobenzylidene)-4-(4-chlorophenyl)-2-(ethylthio)-5,6,7,8-tetrahydro-quinoline-3- carbonitrile (7e)

4.6 Synthesis of derivatives (8a-c).

4.6.1 (E)-3-Amino-8-(4-chlorobenzylidene)-4-(4-chlorophenyl)-5,6,7,8-tetrahydro-3H-1 l4-thieno[2,3-b] quinoline-2-carbonitrile (8a)

4.6.2 Ethyl(E)-3-amino-8-(4-chlorobenzylidene)-4-(4-chlorophenyl)-5,6,7,8-tetrahydro-thieno [2,3- b] quinoline-2-carboxylate (8b)

4.6.3 (E)-3-Amino-8-(4-chlorobenzylidene)-4-(4-chlorophenyl)-5,6,7,8-tetrahydrothieno[2,3-b] quinoline-2-carboxylic acid (8c)

4.7 (E)-N-(8-(4-chlorobenzylidene)-4-(4-chlorophenyl)-2-cyano-5,6,7,8- tetrahydrothieno[2,3-b]quinolin-3-yl)acetamide (9)

4.8 (E)-7-(4-Chlorobenzylidene)-3,11-bis(4-chlorophenyl)-2-thioxo-2,3,7,8,9,10-hexahydro pyrimido[4′,5′:4,5]thieno[2,3-b]quinolin-4(1H)-one (10)

4.9 Synthesis of dialkyl 2-((8-((E)-4-chlorobenzylidene)-4-(4-chlorophenyl)-3-cyano-5,6,7,8-tetrahydroquinolin-2-yl) thio) maleate (14a, b).

4.9.1 Dimethyl 2-((8-((E)-4-chlorobenzylidene)-4-(4-chlorophenyl)-3-cyano-5,6,7,8-tetrahydro quinolin-2-yl)thio)maleate (14a).

4.9.2 Diethyl2-((8-((E)-4-chlorobenzylidene)-4-(4-chlorophenyl)-3-cyano-5,6,7,8-tetrahydro-quinolin-2- yl)thio)maleate (14b).

4.10 Cytotoxicity activities against three tumor cell lines for compounds 5a, 5b, 7d, 7e, 8b, and 10.

5 Conclusions

Acknowledgement

Conflicts of interest

References

Appendix A

Supplementary data

Appendix A

Supplementary data

Supplementary data 1

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