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. 2024 Feb 21;9(9):10146–10159. doi: 10.1021/acsomega.3c06653

Utility of 2-Chloro-N-arylacetamide and 1,1′-(Piperazine-1,4-diyl)bis(2-chloroethanone) as Versatile Precursors for Novel Mono- and Bis[thienopyridines]

Mostafa E Salem †,‡, Abbas H Abdullah ‡, Magdi E A Zaki †, Ismail A Abdelhamid ‡,*, Ahmed H M Elwahy ‡,*
PMCID: PMC10918660  PMID: 38463260

Abstract

graphic file with name ao3c06653_0012.jpg

A series of novel thieno[2,3-b]pyridines linked to N-aryl carboxamides or (carbonylphenoxy)-N-(aryl)acetamides, as well as bis(thieno[2,3-b]pyridines) linked to piperazine core via methanone or carbonylphenoxyethanone units, were synthesized by treating the appropriate chloroacetyl- or bis-bromoacetyl derivatives with 2-mercaptonicotinonitrile derivatives in ethanolic sodium ethoxide at reflux. The spectral data were used to determine the compositions of novel compounds.

Introduction

Thieno[2,3-b]pyridine derivatives occupy a unique position and have received considerable attention due to their diverse pharmacological activities, which include anticancer,1,2 antiviral,2,3 anti-inflammatory,4,5 antimicrobial,5,6 antidiabetic,7,8 and osteogenic9 antiproliferative activity. Furthermore, they can be used as adenosine A1 receptor ligands for the potential treatment of epilepsy10 and as antiplatelet drugs.11 Several research publications on this motif as a core in prospective small-molecule medicines have been published (Figure 1).12,13 Furthermore, several drugs on the market contain thienopyridine nuclei. Prasugrel, and clopidogrel, for example, have all been reported as antiplatelet drugs (Figure 1).14 The amide group can be found in a wide range of drugs, and many industrial materials, such as polymers, detergents, and lubricants.15,16 Their biological activities include antitumor, anthelmintic, antispasmodic, antifungal, antibacterial, insecticidal, and herbicidal properties.17 In terms of medicine, roughly one-quarter of all marketed drugs (and two-thirds of all drug candidates) contain at least one amide bond.18 Furthermore, molecules with an acetamide linkage or its derivatives as core structures have received significant attention due to their potential therapeutic applications as anti-inflammatory,19 anticancer,20 analgesic,21 antimicrobial,21−23 anticonvulsant,24 antituberculosis agents,25 and anti-COVID-19 agents.26 Some acetamide derivatives, such as paracetamol V27 (Figure 1), have been shown to have analgesic or sedative properties. Furthermore, AdipoRon VI28 (Figure 1), a phenoxyacetamide drug, has received considerable attention as a potential treatment for cardiovascular disease, obesity, diabetes, and nonalcoholic fatty liver disease. Moreover, compounds with a 2-phenoxy-N-phenylacetamide core structure have garnered a lot of attention due to their antibacterial, antiparasitic, anticancer, and antiviral properties.23,29 The piperazine scaffold has also been reported to exhibit antibacterial, antituberculosis, anticancer, antiviral, anti-inflammatory, antipsychotic, anti-Alzheimer’s, antifungal, antidiabetic, as well as analgesic, anticonvulsant, and antimalarial properties.30−39Figure 1 depicts many medications that have a piperazine core as a fundamental structural feature. Furthermore, over the last few decades, the concept of molecular hybridization has received a lot of attention in the field of drug design. This tool combines two pharmacophoric moieties from different classes of bioactive molecules to create new hybrid molecules with improved biological efficacy and resistance.40,41

Figure 1.

Figure 1

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Some medications that have thieno[2,3-b]pyridine, acetamide, phenoxyacetamide, and piperazine as fundamental structural features.

Considering these findings and our continuous interest in developing heterocycles with improved pharmacophoric characteristics,42−80 we report the design and synthesis of new hybrid compounds that comprise thieno[2,3-b]pyridines linked to piperazine or amide-containing moieties.

Results and Discussion

As precursors for our targeted synthesis, we chose 2-chloro-N-arylylacetamides 1a,b which were prepared by stirring the appropriate arylamine with 2-chloroacetyl chloride under basic conditions. The synthesis of novel thieno[2,3-b]pyridine-2-carboxamide derivatives 4a–d was performed by the reaction of 6-phenyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile 2a,b with 1a,b in ethanol containing sodium ethoxide (Scheme 1). The reaction proceeded via the initial formation of 2-((3-cyano-6-phenylpyridin-2-yl)thio)-N-phenylacetamide intermediates 3a–d. The latter compound could be isolated upon treatment of 2a,b with the appropriate 2-chloro-N-arylylacetamides derivatives 1a,b in ethanol containing piperidine at reflux. Heating of 3a–d with sodium ethoxide in ethanol at reflux afforded 4a–d in good yields.

Scheme 1. Synthesis of Thienopyridine Linked to N-Aryl Carboxamides 4a–d.

Scheme 1

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The structures of compounds 4a–d were established based on their spectral data and elemental analyses. Thus, the mass spectrum of 3c as a representative example reveals a molecular ion peak at m/z 393 that corresponds to its molecular mass. Compound 4c’s IR spectra revealed the existence of absorption bands at 3427, 3278, and 1640 cm–1, which correspond to the amino group and carbonyl band, respectively. The effective ring closure of compound 3c into 4c is confirmed by the absence of absorption bands typical of the cyano group in compound 4c and the presence of this band in compound 3c. Furthermore, the ring closure of 3c to 4c is further supported by the 1H NMR spectra. Therefore, compound 3c showed a singlet signal integrating two protons at δ 4.26 ppm, indicating the existence of SCH2 protons, but compound 4c lacks this signal. The remaining protons were seen at the anticipated integral values and chemical shifts (see the Experimental Section). The scope of our research was expanded to encompass the synthesis of novel thieno[2,3-b]pyridines coupled to N-arylacetamide units via carbonylphenoxy groups. Bromoacetyl derivatives 7a,b(81) were employed as flexible precursors for this purpose. They were successfully obtained from the corresponding 2-(acetylylphenoxy)-N-arylacetamides 6a,b upon treatment with N-bromosuccinimide (NBS) in the presence of p-TsOH. Compounds 6a,b(81) were produced via the reaction of the potassium salt of para-hydroxyacetophenone 5 with the corresponding 2-chloro-N-arylacetamide derivatives 1a,b in boiling DMF (Scheme 2).

Scheme 2. Synthesis of α-Bromoketones Linked to N-Arylacetamide 7a,b.

Scheme 2

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Thus, the reaction of 6-phenyl-2-thioxo-1,2-dihydropyridine-3-carbonitriles 2a,b with 2-(4-(2-bromoacetyl)phenoxy)-N-arylacetamides 7a,b in ethanol containing piperidine at reflux afforded 2-(4-(2-((3-cyano-6-phenylpyridin-2-yl)thio)acetyl)phenoxy)-N-arylacetamide intermediates 8a–d in 81–88% yields. Cyclization of the latter compounds in an ethanolic solution containing sodium ethoxide at reflux afforded the corresponding thienopyridine derivatives 9a–d as sodium salts in 81–84% yields (Scheme 3).

Scheme 3. Synthesis of Thienopyridines (Sod. Salts) Linked to N-Arylacetamide 9a–d.

Scheme 3

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It is worth mentioning that cyclization of 6-phenyl-2-thioxo-1,2-dihydropyridine-3-carbonitriles 2a,b with 2-(4-(2-bromoacetyl)phenoxy)-N-arylacetamides 7a,b in an ethanolic solution containing K2CO3 at reflux afforded the corresponding thienopyridine derivatives 9′b–d in 76–77% yields (Figure 2).

Figure 2.

Figure 2

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Structures of thienopyridines linked to N-arylacetamide.

The 1H NMR spectrum of 9′b displayed a singlet signal at 4.81 ppm for the −OCH2 in addition to a signal at 10.19 ppm for the NH group. The other signals appeared at their expected positions. On the other hand, the disappearance of the −OCH2 signal from the spectra of compounds 9a–d can be observed.

Our investigation was expanded to encompass the preparation of bis(thieno[2,3-b]pyridines) 12a,b connected to the piperazine ring via carbonyl groups. In the first step, 1,1′-(piperazine-1,4-diyl)bis(2-chloroethan-1-one) (10) was prepared via the reaction of piperazine with two mole equivalents of chloroacetyl chloride in the presence of anhydrous K2CO3. Subsequent reaction of compound 10 with the appropriate 6-phenyl-2-thioxo-1,2-dihydropyridine-3-carbonitriles 2a,b in ethanol containing piperidine at reflux afforded bis(sulfanediyl)bis(6-phenylnicotinonitriles) 11a and 11b in 74 and 79% yields, respectively. The latter compounds underwent cyclization to give the corresponding piperazine-1,4-diylbis((3-amino-6-phenylthieno[2,3-b]pyridin-2-yl)methanones) 12a,b in 70–72% yields, respectively, upon heating in ethanolic solution containing sodium ethoxide (Scheme 4).

Scheme 4. Synthesis of Bis(thienopyridines) Linked to Piperazine Core 12a,b.

Scheme 4

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The structures of compounds 12a and 12b were established based on their spectral data and elemental analyses. Thus, compound 12a showed in its IR spectra the presence of absorption bands at 3415, 34260, and 1633 cm–1 characteristic for the amino group and the carbonyl band, respectively. The piperazine and NH2 appeared as two broad signals at 3.75 and 6.03 ppm. All other protons were seen at the expected chemical shifts and integral values (see the Experimental Section). The structures of compounds 12a and 12b were determined using their elemental analyses and spectrum data. As a result, compound 12a displayed absorption peaks in its infrared spectra at 3415, 34260, and 1633 cm–1, which are indicative of the amino group and the carbonyl band, respectively. 1H NMR revealed the piperazine and NH2 protons as two broad signals at 3.75 and 6.03 ppm. Other protons were seen at the anticipated integral values and chemical shifts (see the Experimental Section). Thieno[2,3-b]pyridines 16a,b linked to piprazine core via carbonylphenoxyacetyl linker could also be prepared in good yields starting from 1,1′-(piperazine-1,4-diyl)bis(2-(4-(2-bromoacetyl)phenoxy)ethanones) 14a,b. The latter compounds were prepared in 69–71% yields by reacting 1,1′-(piperazine-1,4-diyl)bis(2-(4-acetylphenoxy)ethanone) 13a,b with N-bromosuccinimide in the presence of p-toluenesulfonic acid (PTSA) in acetonitrile. Compounds 13a and b were successfully obtained in 77 and 79% yields, respectively, by the reaction of 1,1′-(piperazine-1,4-diyl)bis(2-chloroethanone) with the potassium salts of ortho- and para-hydroxyacetophenone 5a,b in DMF at reflux (Scheme 5). The 1H NMR spectra of 14b indicated the presence of CH2–Br protons, resonated at δ 4.82 as singlet signals integrating four protons.

Scheme 5. Synthesis of Bis(α-bromoketones) Linked to Piperazine Core 14a,b.

Scheme 5

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The interaction of the 6-phenyl-2-thioxo-1,2-dihydropyridine-3-carbonitriles 2a,b with the relevant bromoacetyl derivatives 14a,b in ethanol containing piperidine at reflux yielded bis(sulfanediyl)bis(6-phenylnicotinonitriles) 15a–d in 76–78% yields (Scheme 6).

Scheme 6. Synthesis of Bis(sulfanediyl)bis(6-phenylnicotinonitriles) 15a–d.

Scheme 6

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Subsequent cyclization of 15c and 15d in ethanol containing sodium ethoxide at reflux afforded the corresponding bis(thieno[2,3-b]pyridines) 16a and 16b in 68 and 69% yields, respectively (Scheme 7). Analytical and spectral evidence confirmed the structure of 16a and 16b. Compound 16a had IR bands at 3420, 3315, 1695, and 1650 cm–1 that were representative of the NH2 and the ketonic and amide C=O groups, respectively. The 1H NMR spectra of compound 16a exhibited a singlet signal at δ 5.02, indicating the presence of OCH2 protons. Furthermore, the mass spectra of 16a revealed the appropriate molecular ion peaks at m/z = 886.

Scheme 7. Synthesis of Bis(thieno[2,3-b]pyridines) 16a and 16b.

Scheme 7

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On the other hand, an attempt to synthesize bis(thieno[2,3-b]pyridine) 17 through cyclization of 15b in ethanol containing sodium ethoxide at reflux was unsuccessful. Instead, the reactions gave 2-((benzofuran-3-ylmethyl)thio)-4,6-diphenylnicotinonitrile 19 in 82% yield (Scheme 8). It is suggested that compound 17 was formed initially and then intramolecular cyclocondensation of the methylene group with the ketonic groups at the 2-position of thienopyridine leading to the formation of the corresponding 2-bezofuranyl derivative 18 followed by hydrolysis and subsequent decarboxylation under the reaction conditions to give 19. Similar behavior of some related systems has been previously reported.82

Scheme 8. Synthesis of 2-((Benzofuran-3-ylmethyl)thio)-4,6-diphenylnicotinonitrile 19.

Scheme 8

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It is worth mentioning that treatment of 15a under similar conditions gave a mixture of nonisolable products.

A plausible mechanism of the formation of thieno[2,3-b]pyridines is outlined in Scheme 9. The reaction of the appropriate α-haloketone with the corresponding pyridinethione results in the formation of thienopyridines via an initial nucleophilic substitution reaction of the appropriate α-haloketone with the corresponding thienopyridines to give the intermediate S-alkylated product. Base-catalyzed intramolecular cyclization was used on the latter compounds to efficiently prepare the target thieno[2,3-b]pyridines via intermediates I and II. After treating pyridinethione with the appropriate α-halokeone in an ethanolic solution containing TEA in a catalytic amount, the intermediate S-alkylated product was successfully isolated.

Scheme 9. Plausible Mechanism for the Formation of Thieno[2,3-b]pyridines.

Scheme 9

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Conclusions

We established an effective synthesis of hitherto unknown thienopyridines and bis(thienopyridines) connected to arene or heteroarene via phenoxymethyl groups. The newly synthesized compounds fulfilled the “hybrid molecules” idea, which seeks to combine two potential pharmacophores in a single molecule. We think that the inclusion of two pharmacophoric units in the newly synthesized compounds will increase their biological activity. Our present study attempts to widen the use of the stated technique by synthesizing more hybrid compounds with useful biological potency.

Experimental Section

Melting points were determined in open glass capillaries with a Gallenkamp apparatus. Elemental analyses were carried out at the Microanalytical Center of Cairo University, Giza, Egypt. Infrared spectra were recorded as potassium bromide disks on a Pye Unicam SP 3-300 and Shimadzu FTIR 8101 PC infrared spectrophotometer. NMR spectra were recorded on a JEOL JNM-LA500 spectrometer, operating at 500 MHz for 1H NMR, and 125.65 MHz for 13C NMR. Chemical shifts were reported downfield from TMS (= 0) for 1H NMR. For 13C NMR, chemical shifts were reported in the scale relative to the solvent used as an internal reference. Mass spectra (EI) were obtained at 70 eV with a type Shimadzu GCMQP 1000 EX spectrometer. Analytical thin-layer chromatography was performed using precoated silica gel 60,778 plates (Fluka), and the spots were visualized with UV light at 254 nm.

General Procedure for the Synthesis of 2-((3-Cyano-4-alkyl-6-phenylpyridin-2-yl)thio)-N-(aryl)acetamide 3a–d

The proper 2-mercapto-4,6-disubstituted nicotinonitrile 2a or 2b (10 mmol) was added to a solution of 2-chloro-N-arylacetamides 1a,b (10 mmol) in ethanol (25 mL) containing 0.2 mL of TEA. The reaction mixture was heated at reflux for 3 h. The title compounds 3a–d were produced by filtering out and recrystallizing the solid that was formed after cooling from ethanol/DMF”.

2-((3-Cyano-4-methyl-6-phenylpyridin-2-yl)thio)-N-(p-tolyl)acetamide (3a)

Off-white powder (89% Yield), mp 197–199 °C; IR (cm–1): 3387 (NH), 2214 (CN), 1674 (CO); 1H NMR (DMSO): δ 2.31 (s, 3H, CH3), 2.48 (s, 3H, CH3), 4.23 (s, 2H, SCH2), 7.09 (d, J = 10 Hz, 2H, ArH), 7.28–7.48 (m, 5H, ArH), 7.80 (s, 1H, pyridine-5-H), 8.09 (d, J = 10 Hz, 2H, ArH), 10.33 (s, 1H, NH); 13C NMR: δ 20.0, 22.6, 43.5, 105.4, 122.3, 127.0, 127.7, 128.4, 129.1, 132.4, 135.8, 137.5, 146.5, 149.6, 150.0, 153.4, 170.4; MS: m/z (%) 373 (M+). Anal. Calcd For C22H19N3OS: C, 70.75; H, 5.13; N, 11.25; S, 8.58. Found: C, 70.71; H, 5.14; N, 11.23; S, 8.57%.

2-((3-Cyano-4,6-diphenylpyridin-2-yl)thio)-N-(p-tolyl)acetamide (3b)

Creamy powder (83% Yield), mp 266–268 °C; IR (cm–1): 3325 (NH), 2224 (CN), 1671 (CO); 1H NMR (DMSO): δ 2.25 (s, 3H, CH3), 4.31 (s, 2H, SCH2), 7.11 (d, J = 8.1 Hz, 2H, ArH), 7.31–7.76 (m, 10H, ArH), 7.89 (s, 1H, pyridine-5-H), 8.22 (d, J = 8.1 Hz, 2H, ArH), 10.35 (s, 1H, NH); MS: m/z (%) 435 (M+). Anal. Calcd For C27H21N3OS: C, 74.46; H, 4.86; N, 9.65; S, 7.36. Found: C, 74.48; H, 4.83; N, 9.64; S, 7.37%.

N-(4-Chlorophenyl)-2-((3-cyano-4-methyl-6-phenylpyridin-2-yl)thio)acetamide (3C)

Off-white powder (85% Yield), mp 200–202 °C; IR (cm–1): 3364 (NH), 2214 (CN), 1658 (CO); 1H NMR (DMSO): δ 2.52 (s, 3H, CH3), 4.26 (s, 2H, SCH2), 7.33 (d, J = 6.9 Hz, 2H, ArH), 7.35–7.65 (m, 5H, ArH), 7.84 (s, 1H, pyridine-5-H), 8.10 (d, J = 7.2 Hz, 2H, ArH), 10.55 (s, 1H, NH); 13C NMR: δ 20.0, 35.0, 104.6, 115.1, 117.2, 120.5, 126.8, 127.3, 128.4, 128.9, 130.5, 136.5, 138.0, 153.5, 157.7, 160.9, 166.0; MS: m/z (%) 393 (M+). Anal. Calcd For C21H16ClN3OS: C, 64.04; H, 4.09; N, 10.67; S, 8.14. Found: C, 64.02; H, 4.06; N, 10.69; S, 8.13%.

N-(4-Chlorophenyl)-2-((3-cyano-4,6-diphenylpyridin-2-yl)thio)acetamide (3d)

Creamy powder (81% Yield), mp 250–252 °C; IR (cm–1): 3331 (NH), 2221 (CN), 1667 (CO); 1H NMR (DMSO): δ 4.32 (s, 2H, SCH2), 7.33 (d, J = 8.1 Hz, 2H, ArH), 7.36–7.76 (m, 10H, ArH), 7.90 (s, 1H, pyridine-5-H), 8.20 (d, J = 8.4 Hz, 2H, ArH), 10.60 (s, 1H, NH); MS: m/z (%) 455 (M+). Anal. Calcd For C26H18ClN3OS: C, 68.49; H, 3.98; N, 9.22; S, 7.03. Found: C, 68.49; H, 3.97; N, 9.22; S, 7.01. %.

General Procedure for the Synthesis of N-Arylthieno[2,3-b]pyridine-2-carboxamide Derivatives 4a–d

A solution of 2-(3-cyanopyridin-2-ylthio)-N-arylacetamides 3a–d (10 mmol) in ethanol (25 mL) containing sodium ethoxide (10 mmol) was heated at reflux for 2 h. After cooling the reaction mixture, the solvent was vacuum-evaporated. The solid residue was collected and recrystallized from DMF to afford 4a–d”.

3-Amino-4-methyl-6-phenyl-N-(p-tolyl)thieno[2,3-b]pyridine-2-carboxamide (4a)

Yellow powder (83% Yield), mp 249–251 °C; IR (cm–1): 3441, 3289 (NH2), 1635 (CO); 1H NMR (DMSO): δ 2.25 (s, 3H, CH3), 2.84 (s, 3H, CH3), 6.95 (s, 2H, NH2), 7.11 (d, J = 10 Hz, 2H, ArH), 7.44–7.54 (m, 5H, ArH), 7.97 (s, 1H, pyridine-5-H), 8.12 (d, J = 10 Hz, 2H, ArH), 9.43 (s, 1H, NH); 13C NMR: δ 17.0, 20.9, 120.0, 121.6, 122.5, 124.1, 128.0, 128.8, 129.7, 133.1, 136.4, 142.7, 146.8, 151.5, 155.6, 166.6, 167.3; MS: m/z (%) 373 (M+). Anal. Calcd For C22H19N3OS: C, 70.75; H, 5.13; N, 11.25; S, 8.58. Found: C, 70.71; H, 5.12; N, 11.23; S, 8.55%.

3-Amino-4,6-diphenyl-N-(p-tolyl)thieno[2,3-b]pyridine-2-carboxamide (4b)

Orange powder (80% Yield), mp > 300 °C; IR (cm–1): 3448, 3291 (NH2), 1629 (CO); 1H NMR (DMSO): δ 2.38 (s, 3H, CH3), 7.34 (d, J = 8.4 Hz, 2H, ArH), 7.40–7.73 (m, 10H, ArH), 7.78 (s, 2H, NH2), 8.03 (s, 1H, pyridine-5-H), 8.22 (d, J = 8.4 Hz, 2H, ArH), 9.58 (s, 1H, NH); MS: m/z (%) 435 (M+). Anal. Calcd For C27H21N3OS: C, 74.46; H, 4.86; N, 9.65; S, 7.36. Found: C, 74.46; H, 4.85; N, 9.63; S, 7.34%.

3-Amino-N-(4-chlorophenyl)-4-methyl-6-phenylthieno[2,3-b]pyridine-2-carboxamide (4c)

Yellow powder (79% Yield), mp 240–242 °C; IR (cm–1): 3427, 3278 (NH2), 1640 (CO); 1H NMR (DMSO): δ 2.86 (s, 3H, CH3), 7.01 (s, 2H, NH2), 7.33 (d, J = 8.4 Hz, 2H, ArH), 7.47–7.72 (m, 5H, ArH), 7.97 (s, 1H, pyridine-5-H), 8.16 (d, J = 8.4 Hz, 2H, ArH), 9.60 (s, 1H, NH); 13C NMR: δ 20.2, 118.7, 122.8, 124.0, 127.0, 127.1, 128.3, 128.9, 129.8, 137.6, 138.0, 145.8, 149.2, 156.2, 159.6, 164.2; MS: m/z (%) 393 (M+). Anal. Calcd For C21H16ClN3OS: C, 64.04; H, 4.09; N, 10.67; S, 8.14. Found: C, 64.03; H, 4.09; N, 10.66; S, 8.10%.

3-Amino-N-(4-chlorophenyl)-4,6-diphenylthieno[2,3-b]pyridine-2-carboxamide (4d)

Orange powder (76% Yield), mp 267–269 °C; IR (cm–1): 3421, 3277 (NH2), 1631 (CO); 1H NMR (DMSO): δ 7.34 (d, J = 8.7 Hz, 2H, ArH), 7.49–7.72 (m, 12H, ArH, NH2), 7.78 (s, 1H, pyridine-5-H), 8.23 (d, J = 8.1 Hz, 2H, ArH), 9.21 (s, 1H, NH); MS: m/z (%) 455 (M+). Anal. Calcd For C26H18ClN3OS: C, 68.49; H, 3.98; N, 9.22; S, 7.03. Found: C, 68.49; H, 3.96; N, 9.22; S, 7.02%.

General Procedure for the Synthesis of 8a–d

The 2-mercapto-4,6-disubstituted nicotinonitrile 2a or 2b (10 mmol) was added to a solution of the appropriate 2-(2-bromoacetyl)phenoxy-N-arylcetamide 7a,b (10 mmol) in ethanol (25 mL) containing a few drops TEA. For 3 h, the reaction mixture was heated at reflux. The solid obtained upon cooling was filtered off and recrystallized from ethanol/DMF to afford the title compounds 8a–d.

2-(4-(2-((3-Cyano-4-methyl-6-phenylpyridin-2-yl)thio)acetyl)phenoxy)-N-(p-tolyl)acetamide (8a)

Colorless powder (88% Yield), mp 210–212 °C; IR (cm–1): 3460 (NH), 2214 (CN), 1674 (CO), 1643 (CO); 1H NMR (DMSO): δ 2.26 (s, 3H, CH3), 2.51 (s, 3H, CH3), 4.85 (s, 2H, SCH2), 4.94 (s, 2H, OCH2), 7.12–7.54 (m, 9H, ArH), 7.79–7.81 (m, 3H, pyridine-5-H, ArH), 8.11 (d, J = 8.1 Hz, 2H, ArH), 10.07 (s, 1H, NH); MS: m/z (%) 507 (M+). Anal. Calcd For C30H25N3O3S: C, 70.99; H, 4.96; N, 8.28; S, 6.32. Found: C, 70.97; H, 4.95; N, 8.25; S, 6.33%.

2-(4-(2-((3-Cyano-4,6-diphenylpyridin-2-yl)thio)acetyl)phenoxy)-N-(p-tolyl)acetamide (8b)

Creamy powder (85% Yield), mp 184–186 °C; IR (cm–1): 3425 (NH), 2219 (CN), 1671 (CO), 1650 (CO); 1H NMR (DMSO): δ 2.26(s, 3H, CH3), 4.87 (s, 2H, SCH2), 5.00 (s, 2H, OCH2), 7.12–7.74 (m, 14H, ArH), 7.85 (s, 1H, pyridine-5-H), 7.91 (d, J = 7.8 Hz, 2H, ArH), 8.15 (d, J = 8.7 Hz, 2H, ArH), 10.11 (s, 1H, NH); MS: m/z (%) 569 (M+). Anal. Calcd For C35H27N3O3S: C, 73.79; H, 4.78; N, 7.38; S, 5.63. Found: C, 73.77; H, 4.78; N, 7.35; S, 5.60%.

N-(4-Chlorophenyl)-2-(4-(2-((3-cyano-4-methyl-6-phenylpyridin-2-yl)thio)acetyl)phenoxy)acetamide (8C)

Colorless powder (83% Yield), mp 214–216 °C; IR (cm–1): 3464 (NH), 2215 (CN), 1670 (CO), 1658 (CO); 1H NMR (DMSO): δ 2.51 (s, 3H, CH3), 4.85 (s, 2H, SCH2), 4.94 (s, 2H, OCH2), 7.15–7.41 (m, 8H, ArH), 7.69 (d, J = 8.7 Hz, 2H, ArH), 7.79–7.81 (m, 2H, pyridine-5-H, ArH), 8.11 (d, J = 8.7 Hz, 2H, ArH), 10.30 (s, 1H, NH); MS: m/z (%) 527 (M+). Anal. Calcd For C29H22ClN3O3S: C, 65.97; H, 4.20; N, 7.96; S, 6.07. Found: C, 65.97; H, 4.21; N, 7.93; S, 6.05%.

N-(4-Chlorophenyl)-2-(4-(2-((3-cyano-4,6-diphenylpyridin-2-yl)thio)acetyl)phenoxy)acetamide (8d)

Creamy powder (81% Yield), mp 198–200 °C; IR (cm–1): 3431 (NH), 2221 (CN), 1667 (CO), 1647 (CO); 1H NMR (DMSO): δ 4.90 (s, 2H, SCH2), 5.00 (s, 2H, OCH2), 7.16–7.75 (m, 14H, ArH), 7.85 (s, 1H, pyridine-5-H), 7.90 (d, J = 7.8 Hz, 2H, ArH), 8.15 (d, J = 8.7 Hz, 2H, ArH), 10.32 (s, 1H, NH); MS: m/z (%) 589 (M+). Anal. Calcd For C34H24ClN3O3S: C, 69.20; H, 4.10; N, 7.12; S, 5.43. Found: C, 69.21; H, 4.07; N, 7.11; S, 5.41. %.

General Procedure for the Synthesis of Sodium 2-(4-(3-amino-4-alkyl-6-phenylthieno[2,3-b]pyridine-2-carbonyl)phenoxy)-1-(p-arylamino)ethen-1-olate Derivatives 9a–d

A solution of the suitable 2-(4-(2-((3-cyano-4-alkyl-6-phenylpyridin-2-yl)thio)acetyl)phenoxy)-N-(aryl)acetamide 8a–d (10 mmol) in ethanol (25 mL) containing sodium ethoxide (10 mmol) was heated at reflux for 2 h. The solid was collected on heating to provide 9a–d.

Sodium 2-(4-(3-Amino-4-methyl-6-phenylthieno[2,3-b]pyridine-2-carbonyl)phenoxy)-1-(p-tolylamino)ethen-1-olate (9a)

Yellow powder (83% Yield), mp > 300 °C; IR (cm–1): 3433, 3224 (NH2), 1675 (CO); 1H NMR (DMSO): δ 2.27 (s, 3H, CH3), 2.89 (s, 3H, CH3), 7.05 (d, J = 7.5 Hz, 2H, ArH), 7.09–7.77 (m, 10H, ArH), 7.84 (s, 1H, pyridine-5-H), 7.88(s, 2H, NH2), 8.17 (d, J = 6.6 Hz, 2H, ArH), 8.58 (s, 1H, NH); 13C NMR: δ 20.4, 23.6, 103.4, 113.5, 118.5, 119.6, 123.0, 127.0, 128.8, 129.7, 129.9, 130.4, 130.8, 137.4, 138.8, 146.7, 147.6, 151.6, 157.0, 161.5, 187,6; MS: m/z (%) 529 (M+). Anal. Calcd For C30H24N3NaO3S: C, 68.04; H, 4.57; N, 7.93; S, 6.05. Found: C, 68.02; H, 4.56; N, 7.91; S, 6.05%.

Sodium 2-(4-(3-Amino-4,6-diphenylthieno[2,3-b]pyridine-2-carbonyl)phenoxy)-1-(p-tolylamino)ethen-1-olate (9b)

Orange powder (81% Yield), mp > 300 °C; IR (cm–1): 3425, 3260 (NH2), 1671 (CO); 1H NMR (DMSO): δ 2.27 (s, 3H, CH3), 6.76 (s, 2H, NH2), 7.06 (d, J = 8.7 Hz, 2H, ArH), 7.10–7.63 (m, 13H, ArH), 7.76 (d, J = 8.7 Hz, 2H, ArH), 7.82 (s, 1H, pyridine-5-H), 8.23–8.26 (m, 2H, ArH), 8.61 (s, 1H, NH); MS: m/z (%) 591 (M+). Anal. Calcd For C35H26N3NaO3S: C, 71.05; H, 4.43; N, 7.10; S, 5.42. Found: C, 71.05; H, 4.42; N, 7.11; S, 5.41%.

Sodium 2-(4-(3-Amino-4-methyl-6-phenylthieno[2,3-b]pyridine-2-carbonyl)phenoxy)-1-((4-chlorophenyl)amino)ethen-1-olate (9c)

Yellow powder (83% Yield), mp > 300 °C; IR (cm–1): 3456,3260 (NH2), 1666 (CO); 1H NMR (DMSO): δ 2.89 (s, 3H, CH3), 7.13 (d, J = 8.4 Hz, 2H, ArH), 7.19–7.53 (m, 8H, ArH), 7.78 (d, J = 8.4 Hz, 2H, ArH), 7.83 (s, 1H, pyridine-5-H), 7.92 (s, 2H, NH2), 8.17 (d, J = 7.2 Hz, 2H, ArH), 8.82 (s, 1H, NH); 13C NMR: δ 20.4, 103.4, 113.5, 118.5, 119.6, 123.0, 127.0, 128.8, 129.7, 129.9, 130.4, 130.7, 137.4, 138.8, 146.7, 147.6, 151.6, 157.0, 161.5, 187,6; MS: m/z (%) 549 (M+). Anal. Calcd For C29H21ClN3NaO3S: C, 63.33; H, 3.85; N, 7.64; S, 5.83. Found: C, 63.33; H, 3.83; N, 7.63; S, 5.82%.

Sodium 2-(4-(3-Amino-4,6-diphenylthieno[2,3-b]pyridine-2-carbonyl)phenoxy)-1-((4-chlorophenyl)amino)ethen-1-olate (9d)

Orange powder (84% Yield), mp > 300 °C; IR (cm–1): 3425,3255 (NH2), 1667 (CO); 1H NMR (DMSO): δ 6.79 (s, 2H, NH2), 7.14 (d, J = 8.7 Hz, 2H, ArH), 7.20–7.63 (m, 13H, ArH), 7.79 (d, J = 8.7 Hz, 2H, ArH), 7.82 (s, 1H, pyridine-5-H), 8.22–8.24 (m, 2H, ArH), 8.88 (s, 1H, NH); MS: m/z (%) 611 (M+). Anal. Calcd For C34H23ClN3NaO3S: C, 66.72; H, 3.79; N, 6.87; S, 5.24. Found: C, 66.71; H, 3.79; N, 6.88; S, 5.21. %.

General Procedure for the Synthesis of 2-(3-Amino-4-alkyl-6-phenylthieno[2,3-b]pyridine-2-carbonyl)phenoxy-N-arylacetamide Derivatives 9′b–d

A solution of the appropriate 2-(4-(2-((3-cyano-4-alkyl-6-phenylpyridin-2-yl)thio)acetyl)phenoxy)-N-(aryl)acetamide 8a–d (10 mmol) in ethanol (25 mL) containing potassium carbonate (10 mmol) was heated at reflux for 2 h. The reaction mixture was then cooled, and the solvent was evaporated in a vacuum. The solid residue was collected and recrystallized from DMF to afford 9a–d.

2-(4-(3-Amino-4,6-diphenylthieno[2,3-b]pyridine-2-carbonyl)phenoxy)-N-(p-tolyl)acetamide (9′b).

Orange powder (77% Yield), mp 226–228 °C; IR (cm–1): 3425, 3253 (NH2), 1671 (CO), 1645 (CO); 1H NMR (DMSO): δ 2.26 (s, 3H, CH3), 4.81 (s, 2H, OCH2), 6.86 (s, 2H, NH2), 7.12–8.25 (m, 19H, ArH, pyridine-5-H), 10.19 (s, 1H, NH); MS: m/z (%) 569 (M+). Anal. Calcd For C35H27N3O3S: C, 73.79; H, 4.78; N, 7.38; S, 5.63. Found: C, 73.77; H, 4.78; N, 7.35; S, 5.60%.

2-(4-(3-Amino-4-methyl-6-phenylthieno[2,3-b]pyridine-2-carbonyl)phenoxy)-N-(4-chlorophenyl)acetamide (9′c)

Yellow powder (76% Yield), mp 240–242 °C; IR (cm–1): 3414,3233 (NH2), 1668 (CO), 1643 (CO); 1H NMR (DMSO): δ 2.89 (s, 3H, CH3), 3.32 (s, 1H, NH DMSO moisture), 4.85 (s, 2H, OCH2), 7.13–7.81 (m, 11H, ArH), 7.85 (s, 1H, pyridine-5-H), 7.92 (s, 2H, NH2), 8.16–8.17 (m, 2H, ArH); MS: m/z (%) 527 (M+). Anal. Calcd For C29H22ClN3O3S: C, 65.97; H, 4.20; N, 7.96; S, 6.07. Found: C, 65.97; H, 4.21; N, 7.93; S, 6.05%.

2-(4-(3-Amino-4,6-diphenylthieno[2,3-b]pyridine-2-carbonyl)phenoxy)-N-(4-chlorophenyl)acetamide (9′d)

Orange powder (77% Yield), mp 229–231 °C; IR (cm–1): 3430,3253 (NH2), 1667 (CO), 1443 (CO); 1H NMR (DMSO): δ 3.38 (s, 1H, NH DMSO moisture), 4.83 (s, 2H, OCH2), 6.84 (s, 2H, NH2), 7.13–7.82 (m, 16H, ArH), 7.84 (s, 1H, pyridine-5-H), 8.22–8.24 (m, 2H, ArH); 13C NMR: δ 67.0, 103.4, 114.5, 118.5, 119.9, 121.2, 127.3, 128.6, 128.7, 129.0, 129.1, 129.5, 129.6, 130.2, 133.7, 136.2, 137.2, 137.4, 148.9, 149.9, 157.2, 160.2, 162.0, 166.4; 188.0; m/z (%) 589 (M+). Anal. Calcd For C34H24ClN3O3S: C, 69.20; H, 4.10; N, 7.12; S, 5.43. Found: C, 69.21; H, 4.07; N, 7.11; S, 5.41. %.

General Procedure for the Synthesis of 2,2′-((Piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(sulfanediyl))bis(4-alkyl-6-phenylnicotinonitrile) 11a,b

To a solution of the appropriate 1,1′-(piperazine-1,4-diyl)bis(2-chloroethanone) 10 (5 mmol) in ethanol (25 mL) containing 0.2 mL of TEA, the appropriate 2-mercapto-4,6-disubstituted nicotinonitrile 2a or 2b (10 mmol) was added. The reaction mixture was heated at reflux for 3h. The solid obtained upon cooling was filtered off and recrystallized from ethanol/DMF to afford the title compounds 11a,b.

2,2′-((Piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(sulfanediyl))bis(4-methyl-6-phenylnicotinonitrile) (11a)

Colorless powder (79% Yield), mp 178–180 °C; IR (cm–1): 2214 (CN), 1643 (CO); 1H NMR (DMSO): δ 2.47 (s, 6H, CH3), 3.56–3.75 (m, 8H, NCH2), 4.43 (s, 4H, SCH2), 7.46–7.61 (m, 6H, ArH), 7.83 (s, 2H, pyridine-5-H), 8.11 (s, 4H, ArH); MS: m/z (%) 618 (M+). Anal. Calcd For C34H30N6O2S2: C, 66.00; H, 4.89; N, 13.58; S, 10.36. Found: C, 66.02; H, 4.83; N, 13.58; S, 10.37%.

2,2′-((Piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(sulfanediyl))bis(4,6-diphenylnicotinonitrile) (11b)

Off-white powder (74% Yield), mp 198–200 °C; IR (cm–1): 2211 (CN), 1645 (CO); 1H NMR (DMSO): δ 3.49–3.83 (m, 8H, NCH2), 4.53 (s, 4H, SCH2), 7.50–7.78 (m, 16H, ArH), 7.91 (s, 2H, pyridine-5-H), 8.22–8.24 (m, 4H, ArH); MS: m/z (%) 742 (M+). Anal. Calcd For C44H34N6O2S2: C, 71.14; H, 4.61; N, 11.31; S, 8.63. Found: C, 71.13; H, 4.63; N, 11.29; S, 8.60%.

General Procedure for the Synthesis of Piperazine-1,4-diylbis((3-amino-4-alkyl-6-phenylthieno[2,3-b]pyridin-2-yl)methanone) 12a,b

A solution of the appropriate 2,2′-(2,2′-(piperazine-1,4-diyl)bis(2-oxoethane-2,1-diyl))bis(sulfanediyl)bis(4-alkyl-6-phenylnicotinonitrile) 11a,b (5 mmol) in ethanol (25 mL) containing sodium ethoxide (10 mmol) was heated at reflux for 2 h. The reaction mixture was then cooled, and the solvent was evaporated in a vacuum. The solid residue was collected and recrystallized from DMF to afford 12a,b.

Piperazine-1,4-diylbis((3-amino-4-methyl-6-phenylthieno[2,3-b]pyridin-2-yl)methanone) (12a)

Yellow powder (72% Yield), mp 245–247 °C; IR (cm–1): 4415–3260 (NH2), 1633 (CO); 1H NMR (DMSO): δ 2.86 (s, 6H, CH3), 3.75 (s, 8H, NCH2), 6.03 (s, 4H, NH2), 7.49–7.51 (m, 6H, ArH), 7.78 (s, 2H, pyridine-5-H), 8.13–8.16 (m, 4H, ArH); 13C NMR: δ 25.5, 47.7, 116.7, 120.6, 122.7, 124.8, 127.6, 129.0, 130.4, 135.4, 144.4, 151.0, 156.4, 168.0; MS: m/z (%) 618 (M+). Anal. Calcd For C34H30N6O2S2: C, 66.00; H, 4.89; N, 13.58; S, 10.36. Found: C, 66.00; H, 4.83; N, 13.58; S, 10.37%.

Piperazine-1,4-diylbis((3-amino-4,6-diphenylthieno[2,3-b]pyridin-2-yl)methanone) (12b)

Orange powder (70% Yield), mp 288–290 °C; IR (cm–1): 2425–2271 (NH2), 1625 (CO); 1H NMR (DMSO): δ 3.70 (s, 8H, NCH2), 7.01 (s, 4H, NH2), 7.48–7.60 (m, 16H, ArH), 7.78 (s, 2H, pyridine-5-H), 8.20–8.23 (m, 4H, ArH); MS: m/z (%) 742 (M+). Anal. Calcd For C44H34N6O2S2: C, 71.14; H, 4.61; N, 11.31; S, 8.63. Found: C, 71.14; H, 4.64; N, 11.29; S, 8.61%.

General Procedure for the Synthesis of 1,1′-(Piperazine-1,4-diyl)bis(2-acetylphenoxy)ethanone Derivatives 13a,b

2-Hydroxyacetophenone 5a or 4-hydroxyacetophenone 5b (10 mmol) was dissolved in hot ethanolic KOH solution (prepared by dissolving 0.56 g (10 mmol) of KOH in 10 mL of absolute ethanol), and the solvent was then removed in vacuo. The remaining material was dissolved in DMF (10 mL) and 1,1′-(piperazine-1,4-diyl)bis(2-chloroethan-1-one) (10) (5 mmol) was added. The reaction mixture was refluxed for 10 min during which KCl was separated. The solvent was then removed in vacuo, and the remaining materials were poured onto crushed ice. The crude precipitate of 6 was recrystallized from ethanol 13a as off-white crystals and DMF 13b as a white powder.

1,1′-(Piperazine-1,4-diyl)bis(2-(2-acetylphenoxy)ethan-1-one) (13a)

Off-white crystals, (77% yield), mp 260 °C; IR (KBr) 1702 (C=O), 1682 (C=O) cm–1; 1H NMR: δ 2.63 (s, 6H, CH3), 3.50–3.56 (m, 8H, NCH2), 5.06 (s, 4H, OCH2), 7.00–7.58 (m, 8H, ArH); MS: m/z (%) 438 (M+). Anal. Calcd for C24H26N2O6; C, 65.74; H, 5.98; N, 6.39. Found: C, 65.71; H, 5.97; N, 6.38%

1,1′-(Piperazine-1,4-diyl)bis(2-(4-acetylphenoxy)ethan-1-one) (13b)

White crystals, (79% yield), mp 240 °C; IR (KBr) 1698 (C = O), 1677 (C=O) cm–1; 1H NMR: δ 2.51 (s, 6H, CH3), 3.47–3.54 (m, 8H, NCH2), 5.00 (s, 4H, OCH2), 7.02 (d, J = 8.7 Hz, 4H, ArH), 7.91 (d, J = 8.7 Hz, 4H, ArH); MS: m/z (%) 438 (M+). Anal. Calcd for C24H26N2O6; C, 65.74; H, 5.98; N, 6.39. Found: C, 65.71; H, 5.97; N, 6.38%

General Procedure for the Synthesis of 1,1′-(Piperazine-1,4-diyl)bis(2-(2-bromoacetyl)phenoxy)ethanone Derivatives 14a,b

To a stirred solution of the bis(acetophenone) derivatives 13a,b (l0 mmol) and p-TsOH (5.6 g, 20 mmol) in acetonitrile (50 mL) was slowly added NBS (3.6 g, 20 mmol). After NBS was added, the reaction mixture was heated at reflux with stirring for 2–3 h then left to cool to room temperature. The solvent was evaporated in vacuo, and the residue was dissolved in chloroform (50 mL), washed with water (20 mL), and dried over MgSO4. After evaporation of the solvent, the resulting solid was recrystallized from ethyl acetate to afford the bis(α-bromoketone) derivatives 14a,b.

1,1′-(Piperazine-1,4-diyl)bis(2-(2-(2-bromoacetyl)phenoxy)ethan-1-one) (14a)

Creamy crystals, (69% yield), mp 180 °C; IR (KBr) 1692 (C=O), 1660 (C=O) cm–1; 1H NMR: δ 3.50–3.56 (m, 8H, NCH2), 5.03 (s, 4H, CH2Br), 5.12 (s,4H, OCH2), 7.06–7.67 (m, 8H, ArH); MS: m/z (%) 596 (M+). Anal. Calcd for C24H24Br2N2O6; C, 48.34; H, 4.06; N, 4.70. Found: C, 48.34; H, 4.07; N, 4.67%.

1,1′-(Piperazine-1,4-diyl)bis(2-(4-(2-bromoacetyl)phenoxy)ethan-1-one) (14b)

White powder, (71% yield), mp 136 °C; IR (KBr) 1697 (C=O), 1659 (C=O) cm–1; 1H NMR: δ 3.48–3.55 (m, 8H, NCH2), 4.82 (s, 4H, CH2Br), 5.03 (s,4H, OCH2), 7.05 (d, J = 8.4 Hz, 4H, ArH), 7.96 (d, J = 8.4 Hz, 4H, ArH); MS: m/z (%) 596 (M+). Anal. Calcd for C24H24Br2N2O6; C, 48.34; H, 4.06; N, 4.70. Found: C, 48.33; H, 4.05; N, 4.67%.

General Procedure for the Synthesis of 2,2′-(((((Piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(oxy))bis(n,1-phenylene))bis(2-oxoethane-2,1-diyl))bis(sulfanediyl))bis(4-alkyl-6-phenylnicotinonitrile) 15a–d

To a solution of the appropriate bis-bromoacetyls 14a,b (5 mmol) in ethanol (25 mL) containing 0.2 mL of TEA, the appropriate 2-mercapto-4,6-disubstituted nicotinonitrile 2a or 2b (10 mmol) was added. The reaction mixture was heated at reflux for 3–4 h. The solid product obtained upon cooling was filtered off and recrystallized from ethanol/DMF to afford compounds 15a–d.

2,2′-(((((Piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(oxy))bis(2,1-phenylene))bis(2-oxoethane-2,1-diyl))bis(sulfanediyl))bis(4-methyl-6-phenylnicotinonitrile) (15a)

Yellowish white powder (76% Yield), mp 226–228 °C; IR (cm–1): 2217 (CN), 1690 (CO), 1643 (CO); 1H NMR (DMSO): δ 2.34 (s, 6H, CH3), 3.46–3.54 (m, 8H, NCH2), 4.98 (s, 4H, SCH2), 5.13 (s, 4H, OCH2), 6.99 (t, J = 7.2 Hz, 2H, ArH), 7.23–7.59 (m, 12H, ArH), 7.81 (s, 2H, pyridine-5-H), 7.95 (d, J = 7.8 Hz, 4H, ArH); MS: m/z (%) 886 (M+). Anal. Calcd For C50H42N6O6S2: C, 67.70; H, 4.77; N, 9.47; S, 7.23. Found: C, 67.69; H, 4.75; N, 9.47; S, 7.21%.

2,2′-(((((Piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(oxy))bis(2,1-phenylene))bis(2-oxoethane-2,1-diyl))bis(sulfanediyl))bis(4,6-diphenylnicotinonitrile) (15b)

Yellow powder (77% Yield), mp 233–235 °C; IR (cm–1): 2223(CN), 1698 (CO), 1651 (CO); 1H NMR (DMSO): δ 3.48–3.56 (m, 8H, NCH2), 5.06 (s, 4H, SCH2), 5.15 (s, 4H, OCH2), 7.01 (t, J = 7.5 Hz, 2H, ArH), 7.25–7.75 (m, 22H, ArH), 7.87 (s, 2H, pyridine-5-H), 8.05 (d, J = 7.8 Hz, 4H, ArH); 13C NMR: δ 35.8, 42.0, 66.2, 102.5, 113.7, 115.7, 116.0, 121.0, 126.5, 127.5, 128.6, 128.8, 130.1, 130.6, 134.1, 135.6, 136.2, 154.1, 157.3, 157.8, 162.1, 165.6;, 194.7; MS: m/z (%) 1010 (M+). Anal. Calcd For C60H46N6O6S2: C, 71.27; H, 4.59; N, 8.31; S, 6.34. Found: C, 71.26; H, 4.59; N, 8.29; S, 6.36%.

2,2′-(((((Piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(oxy))bis(4,1-phenylene))bis(2-oxoethane-2,1-diyl))bis(sulfanediyl))bis(4-methyl-6-phenylnicotinonitrile) (15c)

Yellow powder (78% Yield), mp 198–200 °C; IR (cm–1): 2214 (CN), 1695 (CO), 1650 (CO); 1H NMR (DMSO): δ 2.51 (s, 6H, CH3), 3.52–3.59 (m, 8H, NCH2), 4.92 (s, 4H, SCH2), 5.07 (s, 4H, OCH2), 7.09 (d, J = 8.4 Hz, 4H, ArH), 7.22–7.80(m, 10H, ArH), 7.82 (s, 2H, pyridine-5-H), 8.07 (d, J = 8.4 Hz, 4H, ArH); MS: m/z (%) 886 (M+). Anal. Calcd For C50H42N6O6S2: C, 67.70; H, 4.77; N, 9.47; S, 7.23. Found: C, 67.70; H, 4.76; N, 9.45; S, 7.22%.

2,2′-(((((Piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(oxy))bis(4,1-phenylene))bis(2-oxoethane-2,1-diyl))bis(sulfanediyl))bis(4,6-diphenylnicotinonitrile) (15d)

Yellow powder (77% Yield), mp 239–241 °C; IR (cm–1): 2217(CN), 1691 (CO), 1644 (CO); 1H NMR (DMSO): δ 3.53–3.61 (m, 8H, NCH2), 4.99 (s, 4H, SCH2), 5.09 (s, 4H, OCH2), 7.12 (d, J = 8.1 Hz, 4H, ArH), 7.22–7.85 (m, 16H, ArH), 7.86 (s, 2H, pyridine-5-H), 7.91 (d, J = 7.8 Hz, 4H, ArH), 8.10 (d, J = 8.1 Hz, 4H, ArH); MS: m/z (%) 1010 (M+). Anal. Calcd For C60H46N6O6S2: C, 71.27; H, 4.59; N, 8.31; S, 6.34. Found: C, 71.26; H, 4.57; N, 8.30; S, 6.34%.

General Procedure for the Synthesis of 1,1′-(Piperazine-1,4-diyl)bis(2-(n-(3-amino-4-alkyl-6-phenylthieno[2,3-b]pyridine-2-carbonyl)phenoxy)ethanone) (16a, 16b, and 18)

A solution of the appropriate 2,2′-(((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(oxy))bis(n,1-phenylene))bis(2-oxoethane-2,1-diyl))bis(sulfanediyl))bis(4-alkyl-6-phenylnicotinonitriles) 15a, 15b, and 15d (5 mmol) in ethanol (25 mL) containing sodium ethoxide (10 mmol) was heated at reflux for 2 h. The reaction mixture was then cooled, and the solvent was evaporated in a vacuum. The solid residue was collected and recrystallized from DMF to afford 16a, 16b, and 18.

1,1′-(Piperazine-1,4-diyl)bis(2-(4-(3-amino-4-methyl-6-phenylthieno[2,3-b]pyridine-2-carbonyl)phenoxy)ethan-1-one) (16a)

Yellow powder (68% Yield), mp > 300 °C; IR (cm–1): 3420, 3315 (NH2), 1695 (CO), 1650 (CO); 1H NMR (DMSO): δ 2.89 (s, 6H, CH3), 3.53–3.59 (m, 8H, NCH2), 5.02 (s, 4H, OCH2), 7.09 (d, J = 8.7 Hz, 4H, ArH), 7.50–7.82 (m, 10H, ArH), 7.85 (s, 2H, pyridine-5-H), 7.99 (s, 4H, NH2), 8.07 (d, J = 6.3 Hz, 4H, ArH); MS: m/z (%) 886 (M+). Anal. Calcd For C50H42N6O6S2: C, 67.70; H, 4.77; N, 9.47; S, 7.23. Found: C, 67.70; H, 4.76; N, 9.45; S, 7.22%.

1,1′-(Piperazine-1,4-diyl)bis(2-(4-(3-amino-4,6-diphenylthieno[2,3-b]pyridine-2-carbonyl)phenoxy)ethan-1-one) (16b)

Yellow powder (69% Yield), mp > 300 °C; IR (cm–1): 3425, 3326 (NH2), 1677 (CO), 1648 (CO); 1H NMR (DMSO): δ 3.53–3.60 (m, 8H, NCH2), 5.03 (s, 4H, OCH2), 6.85 (s, 4H, NH2), 7.22–7.85 (m, 30H, ArH, pyridine-5-H); MS: m/z (%) 1010 (M+). Anal. Calcd For C60H46N6O6S2: C, 71.27; H, 4.59; N, 8.31; S, 6.34. Found: C, 71.26; H, 4.57; N, 8.30; S, 6.34%.

2-((Benzofuran-3-ylmethyl)thio)-4,6-diphenylnicotinonitrile (18)

Yellow powder (77% Yield), mp 233–235 °C; IR (cm–1): 2223(CN), 1698 (CO), 1651 (CO); 1H NMR (DMSO): δ 7.45–7.56 (m, 10H, NH2, ArH), 7.72–7.81 (m, 5H, ArH, pyridine-5-H), 8.02 (d, J = 7.8 Hz, 1H, ArH), 8.24 (d, J = 7.2 Hz, 2H, ArH); MS: m/z (%) 418 (M+). Anal. Calcd For C27H18N2OS: C, 77.49; H, 4.34; N, 6.69; S, 7.66. Found: C, 77.47; H, 4.33; N, 6.68; S, 7.64%.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.3c06653.

  • 1H NMR spectrum of compound 3a; 13C NMR spectrum of compound 3a; 1H NMR spectrum of compound 3b; 1H NMR spectrum of compound 3c; 13C NMR spectrum of compound 3c; 1H NMR spectrum of compound 3d; 1H NMR spectrum of compound 4a; 13C NMR spectrum of compound 4a; 1H NMR spectrum of compound 4b; 1H NMR spectrum of compound 4c; 13C NMR spectrum of compound 4c; 1H NMR spectrum of compound 4d; 1H NMR spectrum of compound 8a; 1H NMR spectrum of compound 8b; 1H NMR spectrum of compound 8c; 1H NMR spectrum of compound 8d; 1H NMR spectrum of compound 9a; 13C NMR spectrum of compound 9a; 1H NMR spectrum of compound 9b; 1H NMR spectrum of compound 9c; 13C NMR spectrum of compound 9c; 1H NMR spectrum of compound 9d; 1H NMR spectrum of compound 9′b; 1H NMR spectrum of compound 9′c; 1H NMR spectrum of compound 9′d; 13C NMR spectrum of compound 9′d; 1H NMR spectrum of compound 11a; 1H NMR spectrum of compound 11b; 1H NMR spectrum of compound 12a; 13C NMR spectrum of compound 12a; 1H NMR spectrum of compound 12b; 1H NMR spectrum of compound 13a; 1H NMR spectrum of compound 13b; 1H NMR spectrum of compound 14a; 1H NMR spectrum of compound 14b; 1H NMR spectrum of compound 15a; 1H NMR spectrum of compound 15b; 13C NMR spectrum of compound 15b; 1H NMR spectrum of compound 15c; 1H NMR spectrum of compound 15d; 1H NMR spectrum of compound ′6a; 1H NMR spectrum of compound 16b; and 1H NMR spectrum of compound 18 (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao3c06653_si_001.pdf (4.4MB, pdf)

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