Efficient synthesis of novel bis(dihydropyrano[2,3-c ]pyrazoles), bis(4 H - chromenes) and bis(dihydropyrano[3,2-c ]chromenes) with amide functionality

A synthesis of novel bis(1,4-dihydropyrano[2,3-c ]pyrazole-5-carbonitriles), bis(4 H -chromene-3-carbonitriles) and bis(dihydropyrano[3,2-c ]chromenes), which are linked to aliphatic spacers via amide linkages was achieved via multicomponent reactions (MCR) of the appropriate bis-aldehyde with two equivalents of both of malononitrile and 3-methylpyrazol-5-one, dimedone or 4-hydroxycoumarin in a basic solution


Introduction
The amide group is one of the most popular and reliable functionalities in organic chemistry.Amides are a core structural unit in the skeleton of proteins and frequently occur in a wide variety of molecules, such as natural products and biologically active compounds including pharmaceuticals (e.g., the marketed drugs Atorvastatin 1, Lisinopril 2 and Valsartan 3 (Figure 1).2][3][4][5][6][7] The Michael addition reaction represents a powerful synthetic approach in the area of synthetic heterocyclic chemistry.][10][11] On the other hand, MCRs are efficient synthetic tools for one-pot syntheses of complex organic molecules.6][17][18] Pyrans constitute an important class of biologically active natural and synthetic products.0][21][22] Furthermore, the presence of more than one active moiety in the molecule is believed to alter positively the activity for the intended application.7][28][29][30][31][32][33] In continuation of the aforementioned effort, we report herein, the synthesis of new bis(1,4dihydropyrano[2,3-c]pyrazole-5-carbonitrile), bis(4H-chromene-3-carbonitrile) and bis(dihydropyrano[3,2c]chromene) containing molecules which are linked to aliphatic spacers by amide linkages via a MCR procedure aiming at increased biocompatibility for the application as bioactive agents.

AUTHOR(S)
alkylation reaction with bis(2-chloroacetamide) 4a in basic medium to give the target molecules 8-10.The TLC of the reaction mixtures indicates the presence of a mixture of products which could unfortunately not be separated or identified (Scheme 1).In the second approach, the bis-aldehyde 12a containing an amide linkage was prepared following the reported methods described by our group 8,[38][39][40][41] via the reaction of the potassium salt of the salicylaldehyde 11 with the corresponding bis(2-chloroacetamide) 4a in boiling DMF (Scheme 2).
The IR spectra of compound 9a revealed the presence of primary amino groups by absorptions at ν 3487 and 3410 cm -1 in addition to the cyano and the carbonyl groups at ν 2175 and 1674 cm -1 , respectively.The 1 H NMR spectrum of compound 9a showed the presence of two singlets integrated by 12 protons at δH 0.97 and 1.01 assigned to four CH3 groups.In addition, it showed a singlet signal at 4.76 ppm assigned to the pyran-H4.
The IR spectrum of compound 10a showed the presence of primary amino groups by absorptions at ν 3325 and 3279 cm -1 .In addition, it revealed the cyano band at ν 2184 cm -1 .The carbonyl groups showed a broad band at 1671 cm -1 .The 1 H NMR spectrum of 10a showed the presence of the pyran-H4 as a singlet signal at δH 5.02.It is worthy to note that compounds 9a and 10a featured the methylene ether linkage OCH2 as a multiplet signal at δH 4.44-4.59,although their precursor 12a exhibits a singlet for these protons at δH 4.63.This may be attributed to the generation of stereogenic centers (in the dihydropyran rings) in the products, which are close enough to the diastereotopic CH2 protons.All other protons were seen at the expected chemical shifts and integral values (see Experimental Section and Supporting Information).
To extend the scope of these MCRs, a series of bis-aldehydes 12a-h containing amide linkages have been prepared by the reaction of the potassium salt of appropriate hydroxybenzaldehydes 11a-c with the corresponding bis(2-chloroacetamides) 4a-d in boiling DMF (Table 1).

HMBC characterization
The chemical structures of compounds 8a, 9b and 10f as representative examples were supported by their HMBC spectra.The HMBC spectra revealed correlation peaks in accordance with their proposed structures and thus the possibility of the other regioisomers [8a (II), 9b (II) and 10f (II)] (Figure 2) were excluded.

Conclusions
We developed an efficient approach for the synthesis of new bis(1,4-dihydropyrano[2,3-c]pyrazole-5carbonitrile), bis(4H-chromene-3-carbonitrile) and bis(dihydropyrano[3,2-c]chromene) compounds which are linked to aliphatic spacers via amide linkages.Structural assignments for these products were supported by the spectral data and elemental analyses.The mild reaction conditions, good yields and easily accessible starting material are the advantages of this reaction which can then be considered a useful methodology to new bis-heterocycles.

Experimental Section
General.Melting points were measured with a Stuart melting point apparatus and are 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 solvent on Varian Gemini NMR spectrometer at 300 and 75 MHz, respectively, using TMS as an internal standard.Chemical shifts were reported as δ values (ppm) while couplings constants (J) are measured in hertz (Hz).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 Micro analytical center, Cairo University.General method for synthesis of compounds 10a-g, 18a and 18b A mixture of the appropriate bis-aldehydes (12a-g, 17a or 17b) (1 mmol), malononitrile 13 (2 mmol), and 4hydroxy-2H-chromen-2-one 16 (2 mmol) in pyridine (10 mL) was heated at reflux for 2 h.The crude solid was collected by filtration and recrystallized from the appropriate solvent.General procedure for the synthesis of compounds 12a-h, 17a and 17b.A solution of the potassium salt of salicylaldehyde, m-hydroxybenzaldehyde or p-formylbenzoic acid (10 mmol) (prepared by dissolving aldehydes 11a-c or p-formylbenzoic acid 21 (10 mmol) in absolute EtOH (5 mL) containing KOH (0.56 g, 10 mmol) and evaporating the ethanol under reduced pressure) and the appropriate dichloro compounds 4a-d (5 mmol) in DMF (10 mL) was heated at reflux for 5 min.The potassium chloride was separated by filtration, the solvent was then removed in vacuo and the remaining residue was washed with water and purified by recrystallization from the appropriate solvent to give the corresponding compounds 12a-h, 17a and 17b.