Bis(2-cyanoacetamide) in Heterocyclic Synthesis: Synthesis of Some Bis[2-oxopyridine, 2-iminochromene, Chromeno[3,4-c]pyridine, Benzochromeno[3,4-c]pyridine] Derivatives

Introduction

We have worked on a project for the past years that aims to provide new, straightforward methods for synthesizing several new heterocycles of biological importance using inexpensive, readily available starting intermediates in laboratories^1-12. The synthesis of novel mono- and bis-heterocyclic derivatives, which are predicted to display a variety of biological activities, has drawn more interest in recent years^13-20. The pyridine unit was found in structurally simple pharmaceutical agents like 2-pyridone ligand, isoniazid, milrinone, bupicomide, and SD-560^21-27 (Figure 1). Functionalized chromenes are widely used to synthesize promising compounds in medicinal chemistry^28-35. Wide-ranging pharmacological activity, such as antibacterial³⁶, anti-inflammatory³⁷, antimicrobial³⁸, anti-proliferative³⁹, hypotensive⁴⁰, and antirheumatic⁴¹ properties, have been reported for derivatives of chromenopyridine. Many natural and pharmaceutical compounds contain fused chromenes like chromenopyridines. For example, chromeno[3,4-c]pyridine (C) may be an antipsychotic since it blocks D4 receptors³⁶; schumaniophytine (A) and isoschumaniophytine (B) may be antiviral, central and autonomic system depressing⁴² (Figure 1). Furthermore, anti-inflammatory, antibacterial, antifungal, and antitubercular^43-45 properties are demonstrated by chromeno[3,4–c]pyridines. In light of the aforementioned findings, we present here the synthesis of bis(benzylidene, pyridines, chromenes, and chromeno(3,4-pyridine) derivatives comprising a new diphenyl-methylene spacer using N,N’-(methylenebis(1,4-phenylene))bis(2-cyanoacetamide) as a suitable precursor.

Figure 1: Biologically active pyridine, chromene, and chromenopyridine units privileged pharmacophore prevalent in pharmaceutical agents. Click here to View Figure

Materials and Methods

General methods

Melting points were determined on the Cole-Parmer Digital Melting Point Apparatus instrument and are uncorrected. IR spectra (KBr) were measured on a Nicolet Summit FTIR iS50 spectrometer. NMR spectra (¹H & ¹³C) were recorded in (DMSO–d₆) on a Varian Gemini 500 (500 MHz for ¹H and 125 MHz for ¹³C) spectrometer using TMS as a standard reference; chemical shifts are conveyed as δ units. The elemental analyses were performed on a Perkin-Elmer 240 microanalyzer, PE 2400 Series II CHNS/O Analyzer at the Microanalytical Center, Al-Azhar University, Cairo, Egypt. 

N,N’-(Methylenebis(4,1-phenylene))bis(2-cyanoacetamide) (3).

A solution of 4,4′-methylenedianiline 1 (10 mmol, 1.98g), compound 2 (20 mmol, 3.26g) in benzene (40 ml) underwent reflxux for 2 hrs, then filtered while hot, and then recrystallized (Table 1).

Synthesis of benzylidene derivatives 5a-c:

The appropriate aromatic aldehyde (namely; 4-Cl, 4-F-, 4-OMe-benzaldehyde, 20 mmol, 2.82g, 2.48g, 2.72g, respectively) in EtOH (30 ml) containing pip. (0.5 mL), compound 3 (10 mmol, 3.32g) was added. The solution underwent refluxing for 6 hrs. The obtained product by refluxing was collected, filtered, and recrystallized to give 5a-c (Table 1).

Synthesis of 1,1′-(Methylenebis(4,1-phenylene))bis(4,6-dimethyl-2-oxo-1,2-dihydro-pyridine-3-carbonitrile) (7).

Compound 3 (10 mmol, 3.32g) and acetylacetone 6 (20 mmol, 2g) with piperidine (0.5 ml) was refluxed in an oil-bath for 2 hours and then cooled. The product that obtained, collected, and recrystallized (Table 1).

Synthesis of 1,1′-(Methylenebis(4,1-phenylene))bis(6-amino-4-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile) (8):

A solution of the 3 (10 mmol, 3.32g), acetaldehyde (20 mmol, 0.88g), malononitrile (20 mmol, 1.32g), and piperidine (0.5 ml) in EtOH (50 ml) was refluxed for 3 hrs. The product was recrystallized (Table 1).

Synthesis of bis(2-oxopyridone) derivatives 10a,b & 12a-c:

General procedure

Compound 3 (10 mmol, 3.32g), suitable cinnamonitrile 9a/9b (20 mmol, 3.36g, 3.78g, respectively) orethyl cinnamates 11a-c (20 mmol, 4.72g, 4.30g, 4.32g, respectively), and pip. (0.5 ml) in absolute ethanol (30 ml) was refluxed for 6 hours. The basic solid was collected and recrystallized to give  10a,b, 12a-c (Table 1).

Synthesis of 2-Iminochromene derivatives (14 and 15): General procedure

A solution of bis(cyanoacetamide) 3 (10 mmol, 3.32g) and the requested salicylaldehyde derivative (20 mmol, 2.44g, 3.44g, respectively), NH₄OA_c (3 g) in EtOH (40 ml) was refluxed for 3hrs. The product that obtained was filtered off while solution hot and recrystallized to give 14 and/or 15 (Table 1).

Synthesis of (benzo)chromeno[3,4-c]pyridines 16 and 18

General procedure: bis(chromene) derivative 14 (10 mmol, 5.41g), and malononitrile or ethyl cyanoacetate (20 mmol, 1.32g, 2.26g, respectively) and pip. (0.5 ml) in dioxan (40 mL) was refluxed for 3 hrs., The obtained solid was filtered off and recrystallized to give 16 and/or 18 respectively (Table 1).

Table 1: Physical data of the compounds

Compd. No.	M.P. (oC)	Yield (%) Cryst. Solvent	Formula (Mol. Wt.)	Elemental Analyses Calcd. /Found %
				C	H	N
3	233-35	93 (A)	C19H16N4O2 (332.36)	68.66 68.50	4.85 4.78	16.86 16.71
5a	271-73	86 (C)	C33H22Cl2N4O2 (577.47)	68.64 68.49	3.84 3.72	9.70 9.56
5b	267-69	81 (B)	C33H22F2N4O2 (544.56)	72.79 72.63	4.07 3.92	10.29 10.18
5c	260-62	88 (C)	C35H28N4O4 (568.63)	73.93 73.80	4.96 4.80	9.85 9.72
7	278-280	79 (C)	C29H24N4O2 (460.54)	75.63 75.51	5.25 5.11	12.17 12.04
8	>300°C	70 (B)	C29H20N8O2  (512.53)	67.96 67.82	3.93 3.72	21.86 21.69
10a	292-94	73 (B)	C41H28N8O2  (664.73)	74.08 73.91	4.25 4.08	16.86 16.70
10b	>300°C	81 (B)	C39H22Cl2N8O2 (705.56)	66.39 66.22	3.14 3.05	15.88 15.61
12a	>300°C	71 (B)	C43H32Cl2N6O6 (799.67)	64.59 64.42	4.03 4.10	10.51 10.32
12b	296-98	76 (B)	C45H38N6O6 (758.84)	71.23 71.08	5.05 4.92	11.08 10.96
12c	263-65	68 (B)	C45H38N6O8 (790.83)	68.35 68.20	4.84 4.63	10.63 10.46
14	254-56	79 (B)	C33H24N4O4 (540.58)	73.32 73.19	4.48 4.31	10.36 10.24
15	277-79	81 (B)	C41H28N4O4 (640.70)	76.86 76.72	4.41 4.25	8.74 8.60
16	>300	62 (B/D)	C39H24N8O4 (668.67)	70.05 69.86	3.62 3.47	16.76 16.62
18	>300	67 (B/D)	C43H34N6O8 (762.78)	67.71 67.57	4.49 4.36	11.02 10.84

A = EtOH, B = dioxane, C = AcOH, D = DMF

Table 2: The characteristic spectroscopic data of the prepared compounds

Compd. No.	IR	1H-NMR	13C-NMR
3	3304 (NHstr), 3089 (=CHstr), 2956, 2923 (CH2str), 2259 (C≡Nstr), 1664 (C=Ostr), 1612 (C=Cstr)	3.85 (2H, s, CH2), 3.87 (4H, s, 2CH2), 7.16 (4H, dd, ArH), 7.42 (4H, dd, ArH), 10.23 (2H, s, 2NH)	27.1 (CH2), 62.4 (CH2), 116.5 (C≡N), 119.9, 129.5, 136.8, 137.4 (Ar-C), 161.3 (C=O)
5a	3327 (NHstr), 2922, 2851 (=CHstr), 2215 (C≡N), 1675 (C=O)	3.92 (s, 2H, CH2), 7.22 (dd, 4H, ArH), 7.59 (dd, 4H, ArH), 7.66 (dd, 4H, ArH), 7.98 (dd, 4H, ArH), 8.25 (s, 2H, 2 benzylidene-H), 10.28 (s, 2H, 2NH)	27.3, 108.6, 116.4, 121.3, 129.4, 129.9, 131.3, 132.1, 136.7, 137.5, 137.9, 149.8, 160.6
5b	3320 (NHstr), 3034 (=CHstr), 2925 (CHstr) 2221 (C≡N), 1672 (C=O)	3.87 (2H, s, CH2), 7.19 (4H, dd, ArH), 7.42 (4H, dd, ArH), 7.55 (4H, dd, ArH), 8.02 (4H, dd, ArH), 8.22 (2H, s, 2 benzylidene-H), 10.32 (2H, s, 2NH)	27.3, 107.4, 117.0, 117.2, 121.2, 129.12, 129.15, 129.4, 133.31, 133.38, 136.7, 137.9, 150.0, 163.6, 165.6
5c	3332 (NHstr), 3032 (=CHstr), 2933, 2840 (CHstr) 2216 (C≡N), 1676 (C=O)	3.86 (6H, s, 2OCH3), 3.90 (2H, s, CH2), 7.17 (4H, dd, ArH), 7.21 (4H, dd, ArH), 7.57 (4H, dd, ArH), 8.00 (4H, dd, ArH), 8.19 (2H, s, 2 benzylidene-H), 10.23 (2H, s, 2NH)	26.4, 56.1, 104.1, 115.4, 117.4, 121.2, 124.9, 129.4, 133.1, 136.9, 137.8, 150.8, 161.3, 163.2
7	3063 (=CHstr), 2955 (CHstr), 2222 (C≡Nstr), 1652 (C=Ostr)	1.94 (6H, s, 2CH3), 2.37 (6H, s, 2CH3), 3.83 (2H, s, CH2), 6.42 (2H, s, pyridine-H5), 7.24 (4H, dd, ArH), 7.46 (4H, dd, ArH)	20.6, 21.5, 26.6, 108.8, 115.9, 127.8, 129.7, 135.2, 136.2, 142.4, 152.3, 160.8
8	3422, 3394 (NH2), 2937, 2862 (CH aliph.), 2196 (2 C≡N), 1687 (C=O)	2.38 (6H, s, 2CH3), 3.85 (2H, s, CH2), 7.27 (4H, dd, ArH), 7.55 (4H, dd, ArH), 7.95 (4H, s, 2NH2)	22.0, 26.3, 76.2, 88.3, 116.2, 116.8, 126.6, 129.9, 129.4, 131.7, 132.0, 135.3, 145.1, 157.7, 159.1, 160.1
10a	3282, 3199 (NH2str), 3090 (=CHstr), 2220 (C≡N), 1679 (C=O)	2.39 (6H, s, 2CH3), 3.86 (2H, s, CH2), 7.33 (4H, dd, ArH), 7.37 (4H, dd, ArH), 7.43 (4H, dd, ArH), 7.52 (4H, dd, ArH), 7.83 (4H, hump, 2NH2)	19.0, 26.9, 75.3, 88.2, 116.1, 116.8, 126.1, 126.6, 129.0, 129.4, 130.2, 131.7, 134.3, 134.5, 143.5, 157.5, 159.4, 161.0
10b	3324, 3204 (NH2str), 3055 (=CHstr), 2970 (CHstr) 2229 (C≡N), 1677 (C=O)	3.87 (2H, s, CH2), 7.32 (4H, dd, ArH), 7.54 (4H, dd, ArH), 7.58 (4H, dd, ArH), 7.67 (4H, dd, ArH), 7.93 (4H, hump, 2NH2)	27.4, 75.8, 88.5, 116.1, 116.8, 129.0, 129.4, 130.4, 131.4, 132.3, 134.0, 135.7, 142.8, 157.7, 160.0, 160.6
12a	3378, 3292 (NH2str), 2970, 2881 (CHstr) 2214 (C≡N), 1742, 1673 (C=O)	1.29 (6H, t, 2CH3), 3.90 (2H, s, CH2), 4.33 (4H, q, 2CH2), 7.22 (4H, d, ArH), 7.43 (4H, d, ArH), 7.55 (4H, d, ArH), 7.68 (4H, d, ArH), 8.26 (4H, s, 2NH2)	16.4, 26.3, 56.4, 75.9, 88.2, 116.9, 126.1, 126.6, 128.9, 129.4, 130.2, 130.9, 131.1, 131.7, 134.4, 135.2, 143.4, 145.1, 157.7, 159.1, 160.9, 176.7
12b	3362, 3268 (NH2str), 2210 (C≡N), 1730, 1669 (C=O)	1.46 (6H, t, 2CH3), 2.14 (s, 6H, 2CH3), 3.88 (2H, s, CH2), 4.38 (4H, q, 2CH2), 7.32 (4H, dd, ArH), 7.58 (4H, dd, ArH), 8.05 (4H, dd, ArH), 8.18 (4H, dd, ArH), 8.52 (4H, s, 2NH2)	18.7, 22.4, 29.2, 56.1, 75.1, 87.9, 115.8, 125.8, 126.3, 128.7, 129.2, 129.9, 131.5, 132.0, 134.3, 144.8, 157.2, 159.1, 160.7, 173.8
12c	3410, 3357 (NH2str), 2211 (C≡N), 1725, 1676 (C=O)	1.25 (6H,t, 2CH3), 3.83 (6H, s, 2OCH3), 3.87 (2H, 2, CH2), 4.45 (4H, q, 2CH2), 7.15 (4H, d, ArH), 7.41 (4H, d, ArH), 7.52 (4H, d, ArH), 7.64 (4H, d, ArH), 7.98 (4H, s, 2NH2)	21.3, 27.1, 58.7, 66.8, 75.7, 88.4, 116.9, 126.1, 126.6, 128.7, 128.9, 129.4, 130.2, 131.4, 131.7, 134.5, 143.4, 145.1, 157.7, 159.1, 160.0, 175.4
14	3297 (NH), 1678 (C=O)	3.88 (2H, s, CH2), 7.15 (4H, d, ArH), 7.19 (2H, d, ArH), 7.25 (2H, t, ArH), 7.55 (2H, t, ArH), 7.66 (4H, dd, ArH), 7.78 (2H, d, ArH), 8.52 (2H, s, 2 chromene-H4), 9.22 (2H, s, 2C=NH), 12.78 (2H, s, 2 CONH)	27.8, 115.7, 118.4, 120.0, 121.4, 124.2, 130.1, 133.3, 134.6, 141.6, 149.8, 155.7, 157.4, 163.5
15	3230 (NH), 1671 (C=O)	3.87 (2H, s, CH2), 6.97 (2H, d, ArH), 7.20 (4H, dd, ArH), 7.45 (4H, dd, ArH), 7.61 (2H, t, ArH), 7.76 (2H, t, ArH), 7.91 (2H, d, ArH), 8.05 (2H, d, ArH), 8.19 (2H, d, ArH), 8.47 (2H, t, ArH), 9.20 (2H, s, 2 benzochromene-H4), 9.62 (2H, s, 2C=NH), 12.80 (2H, s, 2 CONH)	26.7, 116.2, 119.6, 122.14, 122.17, 124.9, 125.6, 127.3, 128.9, 129.2, 129.8, 130.3, 134.1, 134.5, 137.1, 138.8, 153.8, 156.3, 163.7
16	3421, 3351, 3192 (NH2/ NH), 2226 (C≡N), 1680 (C=O)	3.86 (2H, s, CH2), 6.98 (2H, s, NH2), 7.20 (4H, d, ArH), 7.45 (4H, d, ArH), 7.52 (2H, t, ArH), 7.61 (2H, d, ArH), 7.76 (2H, t, ArH), 7.89 (2H, d, ArH), 9.79 (2H, s, 2NH)	26.6, 75.2, 110.4, 116.4, 126.6, 127.6, 128.5, 130.8, 135.7, 153.2, 157.9, 162.3, 162.4
18	3435, 3329, 3241 (NH2/ NH), 2218 (C≡N), 1679, 1734 (C=O)	1.33 (3H, t, CH3), 3.88 (2H, s, CH2), 4.25 (2H, d, CH2), 6.92 (4H, s, 2NH2), 7.25 (4H, d, ArH), 7.47 (4H, d, ArH), 7.59 (2H, t, ArH), 7.72 (2H, d, ArH), 7.77 (2H, t, ArH), 7.92 (2H, d, ArH), 9.38 (2H, s, 2NH)	27.3, 79.6, 112.3, 116.2, 125.4, 127.8, 129.9, 131.9, 137.8, 150.2, 154.4, 159.2, 163.4, 164.2, 167.6

 

Results and Discussion

Cyanoacetamide derivatives are versatile synthetic intermediates in organic synthesis due to their accessibility and their tendency to undergo nucleophilic additions. Also, cyanoacetamide derivatives are the key precursor for many drugs having a broad spectrum in various branches of medicine chemistry, because of their multiplicity uses in the drug industry^46-49.

The crucial intermediate, bis(cyanoacetamide) 3 containing methylene bridge was obtained in quantitative yield (93%) by the reaction of 4,4′-methylenedianiline 1 with two-equivalents of cyanoacetylating agent 2 in refluxing benzene (Scheme 1). IR spectrum of key intermediate 3 displayed bands at 3304 cm^-1 due to NH group, 2259 cm^-1 due to C≡N group, 1664 cm^-1 for the C=O group. Moreover, the ¹HNMR spectrum exposed a singlet at 3.85 ppm for two CH₂ protons, a singlet at 3.87 for methylene bridge protons, two doublets at 7.16, 7.42 for Ar-protons, and a singlet at 10.23 ppm assigned to amino protons; ¹³C NMR exhibited signals at δ_C: 27.1 ppm assigned to CH₂-bridge, 62.4 ppm assigned to (CH₂C≡N), 116.5 ppm (C≡N), 161.3 ppm assigned to (C=O), and aromatic-c’s appeared at 119.9-137.4 ppm. The reaction of 3 with some electrophiles was investigated. Thus, bis(benzylidene) derivatives 5a-c were gained in great yield via condensation of 3 with aromatic aldehydes 4a-c (namely, 4-Cl, 4-F, 4-OMe-benzaldehye) in 1:2 molar ratio in alcoholic-piperidine at reflux conditions (Scheme 1). Assignment of 5a-c was long-established based on their spectral records. IR spectrum of compounds 5a-c demonstrated the characteristic bands for the imino group at 3327 cm^-1, for the C≡N group at 2215 cm^-1, and C=O at 1675 cm^-1. ¹HNMR spectrum (DMSO-d₆) of 5a exposed three singlets at 3.92, 8.25 and 10.28 ppm for CH2, two benzylidene-H and CONH, respectively, and the ArH in the spectrum appeared at 7.22-7.98 ppm. ¹³C NMR of compound 5a exhibited signals at δ_C: 27.38 ppm assigned to CH₂-bridge, 108.62 =C-C≡N, 116.45 ppm for carbonitrile groups, 149.81 ppm (benzylidene-C), 160.63 ppm for carbonyl groups, and the aromatic C’s was found in the spectrum at 121.38-137.99 ppm, for more details of characterization of compounds 5a-c; see experimental section.

Scheme 1 Click here to View Scheme

Cyclocondensation of compound 3 with pentane-2,4-dione 6 afforded bis(4,6-dimethyl-2-pyridone) derivative 7, via heterocyclization of the intermediate A by elimination of two H₂O molecules. Refluxing of bis(cyano-acetamide) derivative 3 with acetaldehyde, and malononitrile gave pyridine derivative 8, Scheme 2. IR spectrum of 7 presented the characteristic bands at 2222 and 1652 cm^-1 for C≡N & C=O groups, respectively. Furthermore, the ¹HNMR of compound 7 naked two singlets at 1.94 and 2.37 ppm attributed to four methyl protons, 3.83 ppm for methylene-bridge protons, singlet at 6.42 ppm for two pyridine-H5, and aromatic protons appeared as two doublets at 7.24 and 7.46 ppm. ¹³CNMR spectrum this compound exhibited signals at 20.6, 21.5 ppm for two methyl-c’s, signal at 26.6 ppm for methylene-C, signal at 115.9 for two C≡N, the signal at 152.3 ppm for C-4, the signal at 160.8 ppm for C-2, and signals from 108.8-142.4 ppm for aromatic-c’s. IR spectrum of pyridine derivative 8 revealed characteristic bands at 3422, 3394 cm^-1 for amino group, at 2937, 2862 cm^-1 for aliphatic-CH, at 2196 cm^-1 for C≡N group, and 1687 cm^-1 for C=O group. ¹HNMR spectrum of 8 exposed a singlet at 2.38 ppm for two CH₃ protons, 3.85 ppm for methylene bridge protons, two doublets at 7.27 and 7.55 ppm for Ar-H, singlet at 7.95 ppm attributed to two amino protons. ¹³CNMR spectrum of 8 demonstrated signals at 22.0 ppm for two methyl-c’s, a signal at 26.3 ppm for methylene-C, two signals at 76.2, and 88.3 ppm assigned to C-5, and C-3, respectively, signals at 116.2, 116.8 ppm attributed to two C≡N, signals at 157.7, 159.1, 160.1 ppm attributed to C-2, C-6, and C-4, respectively, besides aromatic signals were found in the spectrum at 126.6-145.1 ppm.

Scheme 2 Click here to View Scheme

Compound 3 underwent the reaction with arylidenemalononitriles 9a,b (in 1: 2 molar ratio) in refluxing ethanolic-piperidine and gave bis(3,5-dicyano-2-pyridone) derivatives 10a,b, while its reaction with ethyl cinnamates 11a,b afforded bis(pyridine) derivatives 12a-c and the other possible structure 13a-c was excluded upon the spectral data, Scheme 3. IR of 10a exhibited a strong band at 3282 and 3199 cm⁻¹, attributed to the amino groups, besides the existence of a strong bands at 2220 and 1679 cm⁻¹ attributed to carbonitrile & carbonyl functional groups, respectively. The ¹H NMR spectrum displayed two singlets at 2.39, 3.86 ppm for two methyl and methylene protons, four doublets at 7.33, 7.37, 7.43, 7.52 ppm for aromatic protons, hump at 7.83 ppm corresponding to two NH₂ protons. ¹³CNMR spectrum of 10a displayed signals at 19.0 ppm for two methyl-c’s, a signal at 26.9 ppm for CH₂, two signals at 75.3, 88.2 ppm assigned to C-5, C-3, respectively, two signals at 116.1, 116.8 ppm attributed to two C≡N, three signals at 157.5, 159.4, 161.0 ppm attributed to C-2, C-6, C-4, correspondingly, beside and aromatic signals at 126.1-143.5 ppm. The structure of 10b was entirely consistent with the elemental analysis and spectroscopic information. (see. Experimental section). IR spectrum of 12a showed intense stretching band at 3378, 3292 cm^-1 for NH₂ groups, 2214 cm^-1 for C≡N groups, and 1673, 1742 cm^-1 for each pyridine-2-one and ester functional groups, respectively. Its ¹HNMR spectrum revealed signals at 1.29 ppm for two ester-CH₃ protons (triplet), 3.90 ppm for methylene protons (singlet), 4.33 ppm for two ester-CH₂ protons (quartet), 8.26 corresponding to two amino protons (singlet), and the Ar-H appeared at 7.22-7.68 ppm. The ¹³CNMR spectrum of compound 12a showed peaks at 16.4 ppm for CH₃-ester residue, 26.36 ppm for CH₂, 56.4 ppm for CH₂-ester residue, two peaks at 75.9, 88.2 ppm assigned to C-5, C-3, respectively, peak at 116.9 ppm for C≡N, three signals at 157.7, 159.1, 160.9 ppm assigned to C-2, C-6, C-4, respectively, a signal at 176.7 assigned to ester-carbonyl group, and the aromatic signals were found in the spectrum at 126.1-145.1 ppm. The IR, ¹HNMR, and ¹³CNMR spectra of derivatives 12b,c were per their structure.

Scheme 3 Click here to View Scheme

The formation of compounds 10a,b, and 12a-c was supposed to progress most likely via the initial addition of activated CH₂ in compound 3 to arylidene-malononitriles 9a,b and/or ethyl cinnamates 11a-c forming the adduct B. The proton transfer results in the transformation of B into C. Isomerization of C to D and subsequent oxidation via loss of two hydrogen molecules resulted in the creation of the final products 10a,b, and 12a-c, Scheme 4.

Scheme 4 Click here to View Scheme

Refluxing of compound 3 with 2-hydroxybenzaldehyde in ethanolic-NH₄OAc medium gave bis(2-iminochromene) derivative 14. Analogy, bis(benzo[f]chromeno) derivative 15 was obtainedbyheating compound 3 with 2-hydroxynaphthalene-1-carbaldehyde, scheme 5. The lack of frequency of the C≡N in the IR of each compounds 14,15, indicates the formation of the products. Also, the structure of 14 was reinforced by the ¹HNMR spectrum which presented singlet at 8.52 ppm for two chromene-H4, two singlets at 9.22, 12.78 ppm for C=NH and CONH groups, respectively, and the aromatic protons emerged as multiplets at 7.15-7.78 ppm. ¹HNMR spectrum of 15 which showed three singlets at 9.20, 9.62 and 12.80 ppm for benzo chromene-H4, C=NH and CONH protons, respectively, beside aromatic protons at 6.97-8.47 ppm.

Scheme 5 Click here to View scheme

The corresponding bis(2-amino-4H-chromeno[3,4-c]pyridine) derivative 16 was gainedviarefluxing of bis(iminochromene) derivative 14 with malononitrile in dioxan containing piperidine as a catalyst,  Scheme 5. Analogy, reaction of 14 with ethyl cyano-acetate gave chromenopyridine derivative 18 not 17 grounded on the spectral data. The presence of strong absorption bands for (C≡N) indicates the formation of compounds 16&18. Further support for the compounds is the lack of chromene-H4 in their ¹H NMR spectra and the existence of peaks for C≡N and ester functional groups in their ¹³C NMR spectra. 

The reaction pathway for the creation of compound 16&18 was assumed to continue via Michael addition of the activated CH₂ in dicyanomethane or ethylcyanoacetate to deficient double bond of 14 to provide adducts A and A’ followed by addition of NH₂ group to carbonitrile group, tautomerization then oxidation by loss of two hydrogen molecules, Scheme 6.

Scheme 6 Click here to View Figure

Conclusion

A facile and suitable preparations of some distinctive bis (benzylidenes, pyridines, chromene, benzochromene, chromeno[3,4-c]-pyridines) containing diphenyl-methylene spacer hve been illustrated. Utilizing elemental analysis and ¹H&¹³C-NMR, the specified compounds’ chemical structures were determined.

Acknowledgement

 The authors would like to express their deep gratitude’s to the Northern Border University, Kingdom of Saudi Arabia for providing financial support of this research (project 2022-11-1922).

Conflicts of interest

There are no conflicts of interest.

Funding Sources

There are no funding sources

References

1. Hessein, S.A.; El-Sharief, M.A.M.Sh.; Abbas, S.Y.; Thabet, H.Kh.; Ammar, Y. A. Croat. Chem. Acta, 2016, 89, 91–100.
   CrossRef
2. Ammar, Y.A.; Al-Sehemi, A.G.; Ali, M.M.; Mohamed, Y.A.; Thabet, H.Kh.; El-Gaby, M.S.A. Heteroletters, 2015, 5, 157-167.
3.  Ammar, Y.A.;  El-Gaby, Salem, M. A. Arabian Journal of Chemistry, 2014, 179, 615-622.
   CrossRef
4. Ragab, A.; Fouad, S. A.; Abu Ali, O. A.; Ahmed, E. M.; Ali, A. M.; Askar, A. A.; Ammar, Y. A. Antibiotics (Basel), 2021, 10(2), 162-193.
   CrossRef
5. Salem, M. A., Abbas, S. Y.; El-Sharief, M. A.M. Sh.; Alzahrani, A. Y.; Helal, M. H.; H. Kh. Thabet, Synthetic Communications, 2021, 51, 3325-3331.
   CrossRef
6. Thabet, H.Kh. Oriental Journal of Chemistry, 2020,36, 320-326.
7. Ubeid, M.T.; Thabet, H.Kh.; El-Feky, S.A. Heterocyclic Communications, 2016,22, 43-47.
   CrossRef
8. Thabet, H. Kh.; Al-Hossainy, A.F.; Imran M.Optical Materials, 2020, 105, 109915.
9. Alam, Md J.; Alam, O.; Naim, M.J.; Nawaz, F.; Manaithiya, A.; Imran, M.; Thabet, H.Kh.; Alshehri, S.; Ghoneim, M. M.; Alam, P.; Shakeel, F. Molecules, 2022, 27, 8708-8781.
   CrossRef
10. Khan, A.; Diwan, A.; Thabet, H.Kh.; Imran, M. Drug Development Research, 2020,81, 573-584.
    CrossRef
11. Khan, A.; Diwan, A.; Thabet, H.Kh.; Imran, M.; Bakht, Md. A. Molecules, 2020, 25, 2002-2021.
    CrossRef
12. El-Feky, S.A.; Thabet, H.Kh.; Ubeid, M.T. Journal of Fluorine Chemistry, 2014, 161, 87-94.
    CrossRef
13. Zimmermann, L.A.; de Moraes, M.H.; da Rosa, R.; de Melo, E.B.; Paula, F.R.; Schenkel, E.P.; Steindel, M.; Bernardes, L.S.C. Bioorganic & Medicinal Chemistry, 2018, 26, 4850–4862.
    CrossRef
14. Larghi, E.L.; Bruneau, A.; Sauvage,F.; Alami, M.; Gauduchon, J.V.; Messaoudi, S. Molecules, 2022, 27, 412-425.
    CrossRef
15. Vasilenko, D.A.; Sadovnikov, K.S.; Sedenkova, K.N.; Karlov, D.S.; Radchenko, E.V.; Grishin, Y.K.; Rybakov, V. B.; Kuznetsova, T.S.; Zamoyski, V.L.; Grigoriev, V. V.; Palyulin, V.A.; Averina, E.B. Molecules, 2021, 26, 6411-6426.
    CrossRef
16. Popov, A. B.; Vianelo, R.; Grbčić, P.; Sedić,M.; Pavelić, S. K.; Pavelić,K.; Malić, S. R. Molecules, 2021, 26, 3334-3360.
    CrossRef
17. Stack, D.L.; Masuda, J.D. Molbank, 2017, 2017, M962.
    CrossRef
18. Kour, J.; Khajuria, P.; Verma, P.K.; Kapoor, N.; Kumar, A.; Sawant, S.D. ACS Omega, 2022, 7, 15, 13000–13009.
    CrossRef
19. E. M.; Eid, H.M.E.; Hassaneen, I.A.; Abdelhamid, Elwahy, A.H.M. Journal of Heterocyclic Chemistry, 2020, 57, 2243-2255.
    CrossRef
20. Al-Jumaili, M.H.A.; Hamad, A.A.; Hashem, H.E.; Hussein, A.D.; Muhaidi, M.J.; Ahmed, M.A.; Albanaa, A.H.A.; Siddique, F.; Bakr, E.A. Journal of Molecular Structure, 2023, 1271, 133970.
    CrossRef
21. Hwang, J.; Strange, N.; Phillips, M.J.A.; Krause, A.L.; Heywood, A.; Gamble, A.B.; Huston, W.M.; Tyndall, J.D.A. Eur. J. Med. Chem., 2021, 224, 113692.
    CrossRef
22. Parraguez, M.F.; Miranda, C.A.; Cho, Y.H.; Mahana, H. P.; Garrido, C.G.; Chung, H.; Faúnde, M.; Mahana, D.P. Int. J. Mmol. Sci. 2021, 22, 11212.
    CrossRef
23. Boraei, A.T.A.; Eltamany, E.H.; Ali, I.A.I.; Gebriel, S. M.; Nafie, M.S. Bioorg. Chem. 2021, 111, 104877.
    CrossRef
24. Shang, Y.; Wu, C.; Gao, Q.; Liu, C.; Li, L. Zhang, X.; Cheng, H.G.; Liu, S.; Zhou,Q. Nat. Commun. 2021, 12, 2988.
    CrossRef
25. Fioravanti, R.; Stazi, G.; Zwergel, C.; Valente, S.; Mai, Chem. Rec., 2018, 12, 1818–1832.
    CrossRef
26. Bera, M. K.; Domínguez, M. ; Hommes, P. ; Reissig, H. U. Beilstein J. Org. Chem. 2014, 10, 394–404.
    CrossRef
27. Elinson, M. N.; Vereshchagin, A. N.; Bobrovsky, S. I.; Nasybullin, R. F.; Ilovaisky, A. I.; Merkulova V. M. Comptes Rendus Chimie, 2016, 19, 293-298.
    CrossRef
28. Maleki, A.; Azizi, M.; Emdadi, Z. Green Chemistry Letters and Reviews, 2018,11, 573-582.
    CrossRef
29. Song, X.; Gao, C.; Zhang, X.; Fan, X. J. Org. Chem. 2018, 83, 24, 15256–15267.
    CrossRef
30. Koz, G.; Koz,Ö. Z. Naturforsch., 2017, 72, 647–653.
    CrossRef
31. Neo, A.G.; Castellano, T.G.; Marcos, C.F. Arkivoc 2017, part iii, 21-31.
    CrossRef
32. Raj, V.; Lee, J. Frontiers in Chemistry, 2020, 8, Article 623.  
    CrossRef
33. Ballarotto,M.; Solinasa, M.; Temperini, A. Org. Biommol. Chem., 2021, 19, 10359-10375.
    CrossRef
34. Song, Z.; Jia, Y.; Zhang, D.; Wang, D. European Journal of Oragnic Chemistry, 2021, 2021, 1942-1948.
    CrossRef
35. Rajput, D.; Jan, G.; Karuppasamy, M.; Bhuvanesh, N.; Nagarajan, S.; Maheswari, C. U.; Menéndez, J. C.; Sridharan, V. J. Org. Chem., 2023, 88, 11778–11792.
    CrossRef
36. Douka, M.D.; Litinas, K.E. Molecules 2022, 27, 7256-7347.
    CrossRef
37. Alizadeh, A.; Bayat, F.; Zhu, Z. Research on Chemical Intermediates, 2016, 42,  5927–5936.
    CrossRef
38. Mohamed, Kh.S.;   Elbialy, E.E. Heterocycles, 2020, 100, 1035-1047.
    CrossRef
39. Banerjee, S.; Wang, J.; Pfeffer, S.; Ma, D.; Pfeffer, L.M.; Patil, SA.; Li, W.; Miller, D.D. Design, Molecules, 2015, 20, 17152–17165.
    CrossRef
40. Kibou, Z.; Villemin, D.; Lohier, J. F.; Cheikh, N.; Bar, N.; Braham, N. C. Tetrahedron, 2016, 72, 1653-1661.
    CrossRef
41. Gajurel, S.; Sarkar, R.; Sarkar, F. K.; Kyndiah, L.; Pal, K. ACS Omega. 2022, 7, 48087–48099.
    CrossRef
42. Mekky, A.E.M.; Sanad, S.M.H. Synthetic Communications, 2019, 49, 1385–1395.
    CrossRef
43. Adolfsson, D.E.; Tyagi, M.; Singh, P.; Deuschmann, A.; Ådén, J.; Gharibyan, A.L.; Jayaweera, S.W.; Lindgren, A.E.G.; Olofsson, A.; Almqvist, F. J. Org. Chem. 2020, 85, 14174–14189.
    CrossRef
44. Hu, Z.; Wang, C.; Sitkoff, D.; Cheadle, N. L.; Xu, S.; Muckelbauer, J. K.; Adam, L. P.; Wexler, R. R.; Quan, M. L. Bioorg. & Med. Chem. Lett., 2020, 30, 127474
    CrossRef
45. Behbehani, H.; Dawood, K.M.; Aryan, F.A.; Ibrahim, H.M. ACS Omega, 2021, 6(49), 34065–34074.
    CrossRef
46. Ghozlan, S. A. S.; Abdelmoniem, A. M.; Ramadan, M. A.; Abdelwahab, H. M.; Abdelrahman, M. G. M.; Abdelhamid, I. A. Arkivoc, 2020, part i, 297-399.
    CrossRef
47. Emam, D. R.; Soliman, N. N.; Fadda, A. A.; Bayoumy, N. M.; Journal of Molecular Structure, 2024, 1297 (Part 2), 137009.
    CrossRef
48. Hamed, E. O.; Assy, M. G.; Shalaby, A. M.; Sayed, R. E. Russian Journal of Organic Chemistry, 2020, 56, 2005–2013.
    CrossRef
49. Fadda, A. A.; Ghanem, R. A.; Gaffer, H. E.; Waly, M. M.; Tawfik, E. H. Polycyclic Aromatic Compounds, 2023, 43 (4), 3429-3449.
    CrossRef

---

This work is licensed under a Creative Commons Attribution 4.0 International License.