Synthesis of dihydropyridine, fused dihydropyridines and benzo[4,5]imidazo[2,1-b]quinazolines linked to ester and amide moieties via a benzene ring as new hybrid molecules

Abstract A series of novel 2-oxo-2-(arylamino)ethyl 4-formylbenzoates were prepared via the reaction of the potassium salt of p-formylbenzoic acid with 2-chloro-N-aryl-acetamide in DMF at reflux. A new series of 1,4-dihydropyridin-3,5-dicarbonitriles, hexahydroacridine-1,8-diones, decahydropyrimido[4,5-b]quinolines, and hexahydrobenzo[4,5]imidazo[2,1-b]quinazolines which are linked to N-aryl-benzoyloxyacetamide were obtained through the Hantzsch reaction of various 2-oxo-2-(arylamino)ethyl 4-formylbenzoate with the respective 3-aminocrotononitrile or a mixture of 1,3-dicarbonyl compounds and amine source. The structures of the novel compounds were confirmed using a variety of spectra. Graphical abstract


Introduction
The ester moiety is a versatile structural motif found in pharmaceuticals and natural products.In this regard, numerous notable natural compounds containing ester groups, including the anticancer medication quiderone [1] and the chemotherapeutic medicine taxol [2][3][4] for the treatment of breast and ovarian cancer have been reported.Also, the amide motif is the backbone of peptides and is a significant structural component of many natural commodities and useful materials.A 2006 survey revealed amides in 25% of all already marketed medications and two-thirds of therapeutic prospects.10][11][12][13][14] The 1.4-DHPs are a well-known class of biologically active heterocyclic compounds.It has been demonstrated that the therapeutic efficacy of some of them (including Nicardipine I, Amlodipine II, Nitrendipine III, and Nifedipine IV) is related to their ability to bind to calcium channels, reducing transmembrane calcium movement.[23] In light of these findings and our ongoing interest in the synthesis of bis-heterocycles [24][25][26][27][28][29][30][31] C-C bond formation [32][33][34][35][36][37][38][39][40][41][42][43][44] that includes Hantzsch reaction, [45][46][47][48] as effective ways to synthesize a variety of heterocycles, we present here the design and synthesis of novel scaffolds based on 1,4-dihydropyridine or fused dihydropyridines linked to benzoyloxyacetamide as new hybrid molecules.

Results and discussions
For the synthesis of the target compounds, the precursors 2-oxo-2-(arylamino)ethyl 4-formylbenzoate 4a-d were chosen.They were created by reacting the potassium salt of p-formylbenzoic acid 2 in DMF at reflux with 2-chloro-N-aryl-acetamide 3a-d (Scheme 1).
The research also included the synthesis of hexahydroacridine-1,8-diones 8a,b in conjunction with 2-oxo-2-(arylamino)ethyl benzoate.As a result of the reaction of aldehydes 4a,b in ethanol with two equivalents of dimedone 7 and an excess of ammonium acetate, compounds 8a,b were formed (Scheme 3).The structures of the formed products were determined using various spectral tools.The presence of two singlets integrated by 12 protons at 0.86 and 1.02 ppm assigned to two CH 3 groups was detected in the 1 H NMR spectrum of 8a.The four methylene groups (H2, H4, H5, and H7) combined by eight protons appeared as multiplets in the 1.96-2.45ppm range.Furthermore, the singlet signals at 4.86 and 4.89 ppm correspond to -OCH 2 -and acridine-H9, respectively.At 9.36 and 10.14 ppm, the NH groups appeared as broad singlets.
Due to the biological significance of acridines, we expanded our scope to include the synthesis of various forms of 9-aryl-hexahydroacridine-1,8-dione.In acetic acid, aldehydes 4a,b react with one equivalent of both dimedone The methyl groups were assigned as three singlets at 0.88, 1.02, and 2.24 ppm in the 1 H NMR spectrum of 13a.Furthermore, it revealed a multiplet for H7 and H9 of the dimedone moiety at 2.00-2.18ppm.At 4.84 and 4.85 ppm, quinolin H5 and -OCH 2appeared as two singlets.Furthermore, it revealed four exchangeable broad NH protons at 7.94, 8.87, 10.03, and 12.15 ppm.At 7.10, 7.38, 7.45, and 7.87 ppm, the aromatic protons appeared as four doublets.

Conclusions
We developed a simple and efficient method for synthesizing a variety of novel aldehydes with ester and amide linkages.Furthermore, we used these new aldehydes as versatile precursors in the three-component Hantzsch and Michael reactions to create a series of fused-pyran and fused dihydropyridines.The current protocol is characterized by mild conditions, a quick reaction time, high efficiency, and exceptional functional group tolerance.We believe that incorporating ester and amide linkages, the most versatile structural motifs commonly used in pharmaceuticals would improve the biological activities of the resulting fused heterocyclic systems.

General procedure for the synthesis of compounds 11a-e
A mixture of aldehyde 4a or 4b (1 mmol), dimedone 7 (1 mmol), and the appropriate cyclic enaminones 9a-d (1 mmol) in acetic acid (10 mL) was heated at reflux for 5 h.The crude solid was isolated and recrystallized from ethanol/acetic acid (3:1) to give compounds 11a-e.
two singlet signals integrated by 6 protons at 0.92 and 1.06 ppm assigned to two CH 3 .Furthermore, the two singlets at 4.83 and 6.52 ppm are attributed to -OCH 2 -and quinazolin-H12, respectively.At 10.02 and 11.24 ppm, the two NH groups appeared as two broad singlets.All of the other protons are in their expected positions.Scheme 7 depicts a possible mechanism for the creation of the target products.The reaction most likely consists of two steps.As the first step in this mechanism, one equivalent of dimedone 7 and aldehydes 4 are thought to undergo a Knoevenagel condensation reaction, producing the intermediate arylidene 17.The second step is thought to involve the Michael addition reaction of 17 (Michael acceptor) with one equivalent of the 1H-benzo[d]imidazol-2-amine 14 (Michael donor).As a 1,3-binucleophile (NH 2 and NH) of 1H-benzo[d]imidazol-2-amine reacts with 14 via two distinct routes to produce one of two regioisomers.The carbonyl group of 17 and the exocyclic NH 2 group of 14 were combined, and the NH group of 14 is then nucleophilically added to the b-carbon of the electrophilic center of 17.The desired products 15 are produced after the water molecules are removed (Scheme 7, pathway A).According to the second pathway, the NH group of 1H-benzo[d]imidazol-2-amine 14 is combined with the carbonyl group of 17, followed by the nucleophilic addition of the NH 2 group of 14 with the b-carbon of the electrophilic center of 17.The following water removal results in the formation of 16 (Scheme 7, pathway B).

Scheme 7 .
Scheme 7. A plausible mechanism for the formation of compounds 15 and 16.