Facile one-pot, three-component synthesis of novel fused 4 H -pyrans incorporating 2-phenoxy-N -phenylacetamide core as novel hybrid molecules via Michael addition reaction

Multitarget-directed medicines (hybrid drugs) are an effective therapeutic option for multifactorial illnesses. In this study, novel 2-phenoxy-N -phenylacetamide hybrids with various heterocyclic scaffolds such as 2-amino-3-cyano-4 H -chromene, 2-amino-3-cyanopyrano[3,2-c ]chromene, and 6-amino-5-cyano-1,4-dihydropyrano[2,3-c ]pyrazole were efficiently synthesized. A three-component reaction of the relevant 2-(4-formylphenoxy)- N - (aryl)acetamide with one equivalent of malononitrile and the appropriate active methylene reagent, such as dimedone, 4-hydroxycoumarine or 3 H -pyrazol-3-one, is used as the synthesis approach. The structures of the novel compounds were confirmed using a variety of spectra.


Introduction
Multicomponent reactions, which are described as synthetic procedures that combine three or more substrates in a highly regio-and stereoselective way to generate structurally-complex organic compounds, have witnessed a remarkable increase in applications across all disciplines of organic synthesis. It is an extremely effective technique in drug discovery, heterocyclic, and combinational chemistry. [1][2][3][4][5][6][7] Molecular hybridization is a good drug-design and development technique that focuses on combining various pharmacophores to create novel, pharmacologically-active molecules. The primary objective is to boost therapeutic efficacy while reducing side effects and preventing medication resistance. [8][9][10][11][12][13] Michael addition is a well-known reaction in organic synthesis, established by Arthur Michael as one of the most advantageous techniques for the creation of mild C-C bonds. The reaction consists of the nucleophilic addition of a nucleophile to an α,β-unsaturated carbonyl molecule under basic conditions or with acidic catalysts. The Michael addition reaction has been widely explored in the synthesis of natural products and heterocyclic compounds. [14][15][16] In the realm of medicinal chemistry, compounds having a 2-phenoxy-N-phenylacetamide core structure 1 (Figure 1) have sparked a lot of attention. [17][18][19] These compounds have been shown to exhibit antibacterial, antiparasitic, anticancer, and antiviral properties. [20][21][22][23][24][25][26]  A range of natural and synthetic compounds having fused pyran systems was reported to have antibacterial, antiviral, anticoagulant, anti-anaphylactic, anticancer, antifungal, anticancer, antimalarial, antihyperglycemic, antidyslipidemic, diuretic, and neurodegenerative properties. 26  In light of these findings, this work aimed to synthesize novel 2-phenoxy-N-phenylacetamide hybrids with heterocyclic scaffolds such as 2-amino-3-cyano-4H-chromene, 2-amino-3-cyanopyrano[3,2-c]chromene, and 6-Scheme 1. Synthesis of 2-(4-formylphenoxy)-N-(aryl)acetamides 7a-d.
The structures of 7a-d were validated by analytical and spectroscopic methods. Compound 7a exhibited IR bands at 1680 and 1658 cm -1 , indicating the amide and aldehydic CO groups, respectively. In the 1 H NMR spectra of compound 7 derivatives, singlet signals corresponding to -OCH2-and formyl protons were found at 4.85 and 10.17 ppm, respectively. Furthermore, the mass spectra of 7a derivatives indicated the correct molecular ion peaks at m/z = 255.
The reactivity of 7a with several active methylene compounds was then studied. A three-component reaction of aldehyde 7a with one equivalent of both malononitrile 8 and dimedone 9, in the presence of piperidine as a basic catalyst and ethanol at reflux, resulted in a good yield of 2-(4-(2-amino-3-cyano-4Hchromen-4-yl)phenoxy)-N-phenylacetamide 10a (Scheme 2). ppm, for the methylene ether bond OCH2. All other protons' chemical shifts and integrated values were as predicted.
All of the above-mentioned processes for the synthesis of compounds 10, 12, and 14 may follow the same path mechanistically, which includes condensation of aldehydes 7 with one equivalent of malononitrile to create arylidene-malononitrile derivatives 15. The intermediate Michael adducts 16 were created by reacting the latter compounds with one equivalent of one of the appropriate active methylene compounds. Tautomerization of 16 to 17, and subsequent intramolecular cyclization, yields the cyclic intermediates 18, which then tautomerize to yield target molecules 10, 12 or 14, respectively (Scheme 5).

Scheme 5.
A plausible mechanism for the formation of target molecules 10, 12 or 14.
The 1 H NMR spectrum of compound 15a exhibited a singlet signal of olefinic CH protons at 8.40 ppm. Additionally, mass spectrometry validated the molecular formula of C18H13N3O2 by displaying the proper molecular ion peak at m/z 303. Attempts were made under various basic conditions to produce compounds 10, 12, and 14 by alkylation of the suitable phenols 19 45,46 , 20 47 , and 21 48 with 2-chloro-N-phenylacetamide 6 (Scheme 7). Unfortunately, we were unable to separate pure samples of the target products from the reaction products due to some technical difficulties which may include competition for N-alkylating products. Scheme 7. Attempted synthesis of 10, 12, and 14 by alkylation pathway.
It is thought that the formation of 23 begins with the formation of the adduct 25 following treatment of 15 with 22. After removing one mole of malononitrile, the adduct 25 decomposes to generate 23 rather than undergoing a cyclization to 24 (as depicted in Scheme 9). The compositions of 23 were determined via spectroscopic analyses. For example, the 1 H-NMR spectra of 23b exhibited a singlet signal at 4.84 ppm attributed to the two -OCH2 groups. The ylidene H-atoms were revealed as a singlet signal at 7.82 ppm. Aromatic protons were also represented by multiplets in their expected locations.

Conclusions
We have developed a simple and fast synthesis of chromenes, pyrano[3,2-c]pyrazoles, and pyrano[3,2c]chromenes, each linked to a 2-phenoxy-N-phenylacetamide core, using a three-component method consisting of aldehydes, malononitrile, and the appropriate cyclic-1,3-dione. The reactions go smoothly, resulting in high yields of the required products. Attempts to synthesize these compounds via alkylation of the relevant phenols with 2-chloro-N-arylacetamide were unsuccessful.

Experimental Section
General. Melting points were measured with a Stuart melting point apparatus and were uncorrected. The IR spectra were recorded using a FTIR Bruker-vector 22 spectrophotometer as KBr pellets. The 1 H and 13 C NMR spectra were recorded in DMSO-d6 as a solvent with Varian Mercury VXR-300 NMR spectrometer operating at 300 MHz and 75 MHz and Bruker AVS NMR spectrometer at 400 MHz and 100 MHz, respectively, using TMS as an internal standard. Chemical shifts were reported as δ values in ppm. Mass spectra were recorded with a Shimadzu GCMS-QP-1000 EX mass spectrometer in EI (70 eV) model. The elemental analyses were performed at the Microanalytical Center, Cairo University.