Hantzsch-like synthesis of novel bis(hexahydroacridine-1,8-diones),bis(tetrahydrodipyrazolo[3,4- b :4′,3′- e ]pyridines),and bis(pyrimido[4,5- b ]quinolines) incorporating thieno[2,3- b ]thiophenes

Abstract

A novel series of bis(hexahydroacridine-1,8-diones), bis(tetrahydrodipyrazolo[3,4-b:4′,3′-e]pyridines), and bis(pyrimido[4,5-b]quinolines) incorporating a thieno[2,3-b]thiophene core via ether or ester linkages is prepared via a Hantzsch-like reaction.

Introduction

Multicomponent reactions represent a facile and rapid access to varieties of heterocyclic compounds. In addition, they have the advantages of atom-economy and selectivity.^1–20 Moreover, 1,4-dihydropyridines (1,4-DHPs) have gained particular interest as they have major therapeutic effects in the treatment of cardiovascular diseases as a class of calcium-channel modulators. Also, they exhibit pharmacological activities that include antitumor,^21–23 antioxidant,^24–27 and antivasodilator. ²⁸ Furthermore, acridines have attracted considerable attention due to their reported bioactivities.^29–43 In conjunction with these findings, and in continuation of our recent project aimed at the synthesis of novel bis(heterocycles),^44–55 we report herein on the one-pot synthesis of novel bis(acridines), bis(dipyrazolo[3,4-b:4′,3′-e]pyridines), and bis(pyrimido[4,5-b]quinolines) incorporating thieno[2,3-b]thiophenes through ether or ester bridges.

Results and discussion

Bis(aldehydes) linked to a thieno[2,3-b]thiophene core via a phenoxymethyl linker (3a–d) were chosen as precursors for Hantzsch multicomponent reactions for the preparation of novel bis(heterocycles). They were prepared following the literature procedure via the reaction of diethyl 3,4-bis(bromomethyl)thieno[2,3-b]thiophene-2,5-dicarboxylate 1 with the potassium salts of salicylaldehyde (2a), m-hydroxybenzaldehyde (2b), p-hydroxybenzaldehyde (2c), and 4-formylbenzoic acid (2d) in dimethylformamide (DMF) at reflux (Scheme 1).^56–60 The synthetic utility of these bis-aldehydes as building blocks for the synthesis of benzo-fused macrocyclic ligands and bis(thiazoles) was previously investigated.^56,57

Scheme 1.

Synthesis of the bis(aldehydes) 3a–d.

The reactivity of bis(aldehydes) (3a–d) toward different active methylene reagents was then investigated. Thus, the Hantzsch multicomponent reactions of bis(aldehydes) (3a–c) with 4 equiv. of dimedone (4) in the presence of 5 equiv. of ammonium acetate resulted in the formation of a series of bis(hexahydroacridine-1,8-diones) (5a–c), which are linked to a thieno[2,3-b]thiophene unit (Scheme 2). The structures of the target compounds (5a–c) were established based on spectral data. Thus, the infrared (IR) spectrum of compound (5a) as a representative example revealed the absorptions of the NH group at 3376 cm⁻¹ and the carbonyl groups at 1720 and 1635 cm⁻¹. The ¹H NMR spectrum of (5a) indicated the presence of two singlets integrating for 12 protons each at 0.81 and 0.89 ppm assigned to the eight CH₃ groups. In addition, the singlet at 4.87 ppm corresponds to the acridine-H9 protons. Moreover, the NH groups appeared as a broad singlet signal at 8.44 ppm. All the other signals appeared at expected chemical shifts.

Scheme 2.

Synthesis of the bis(hexahydroacridine-1,8-diones) 5a–c.

In a similar manner, bis(tetrahydrodipyrazolo[3,4-b:4’,3’-e]pyridines) (7a–c) were prepared via the Hantzsch-like multicomponent reaction of bis(aldehydes) (3a–d) with 4 equiv. of 3-methyl-1H-pyrazol-5(4H)-one (6) and 5 equiv. of ammonium acetate in boiling ethanol (Scheme 3). The structures of compounds (7a–c) were also elucidated based on different spectral tools. Thus, the ¹H NMR spectrum of compound (7a) indicated the presence of a singlet at 4.73 ppm corresponding to H4. It also exhibited two broad singlets at 7.42 and 11.25 ppm related to two different NH groups. The methyl, ester, –CH₂O–, and aromatic protons appeared at their expected positions (see the “Experimental” section).

Scheme 3.

Synthesis of bis(3,5-dimethyl-1,4,7,8-tetrahydrodipyrazolo[3,4-b:4′,3′-e]pyridin-4-yl)phenoxy)alkanes 7a–c.

On the contrary, investigations to synthesize the bis(decahydropyrido[2,3-d:6,5-d′] dipyrimidinetetraones (10) linked to thieno[2,3-b]thiophenes via multicomponent reactions of the bis(aldehydes) (3a–c) with four moles of 6-aminouracil were unsuccessful. Instead, the tetrabis(6-aminopyrimidine-2,4-diones) (9) were obtained in satisfactory yields (Scheme 4). Several attempts to convert compounds (9) into (10) via prolonged heating in AcOH at reflux were unfortunately unsuccessful. The ¹H NMR spectrum of compound (9a) features a singlet at 5.25 ppm for the linking CH group. Also, it showed the presence of the amino groups as a broad singlet integrating for eight protons at 10.46 ppm. In addition, two broad singlets at 10.05 and 10.26 ppm were present for the two different NH groups. All the other protons appear at expected positions.

Scheme 4.

Synthesis of tetrabis(6-aminopyrimidine-2,4-diones) 9.

In an extension to this work to include the unsymmetric Hantzsch reaction, we investigated the reactivity of bis(aldehydes) toward both 6-aminouracil and dimedone. Thus, the reaction of bis(aldehydes) (3b–d) with two moles of both 6-aminouracil (8) and dimedone (4) afforded the corresponding bis(pyrimido[4,5-b]quinolines) (11a–c) (Scheme 5). Trials to isolate the noncyclized adducts 12 were not succeeded (Scheme 5). It is worth mentioning that the two diastereoisomers that are possible for compounds 11 could not be distinguished by NMR. Moreover, the long distance between the chiral carbons may be a good reason for diastereoisomers to show essentially identical NMR spectra. The structure of compound 11a was confirmed based on spectral analysis. The IR spectrum indicated the presence of NH groups with absorption bands at 3394, 3201, and 3059 cm⁻¹. Moreover, it indicated a sharp band at 1720 cm⁻¹ corresponding to the amide CO and a broad band at 1666 cm⁻¹ for the ester carbonyl. The ¹H NMR spectrum of 11a revealed the presence of two singlets at 0.86 and 1.01 ppm due to the four methyl groups. In addition, it showed multiplets at 1.91 to 2.02 ppm for H7 and H9. It also revealed the methylene ether linkage OCH₂ as a multiplet at 5.47 to 5.58 ppm. The singlet at 4.71 ppm is assigned to H5. The aromatic protons appeared as multiplets at 6.41 to 8.79 ppm. The NH protons appeared as three broad signals integrating for six protons at 10.30, 10.74, and 11.94 ppm.

Scheme 5.

Synthesis of bis(pyrimido[4,5-b]quinolines) 11.

Generally, the reaction mechanism for the formation of compounds 11 encompasses the initial acid catalyzed condensation of bis(aldehydes) (3) with two moles of the 6-aminouracil (8) to yield the intermediates 13 that lose two moles of water to afford the unstable bis(ylidene) derivatives (14). The bis(ylidenes) then react with an additional two moles of compound (8) to give the target tetrabis(6-aminopyrimidine-2,4-diones) (9). On the contrary, the reaction of the bis(ylidenes) (14) with two moles of dimedone (4) afforded the nonisolable intermediates 15, which cyclized into 16 that underwent elimination of two moles of water to give the bis(pyrimido[4,5-b]quinolines) (11) (Scheme 6).

Scheme 6.

Suggested mechanism for the synthesis of tetrabis(6-aminopyrimidine-2,4-diones) 9 and bis(pyrimido[4,5-b]quinolines) 11.

Conclusion

We have developed an efficient approach for the synthesis of novel series of bis(hexahydroacridine-1,8-diones), bis(tetrahydrodipyrazolo[3,4-b:4′,3′-e]pyridines), and bis(pyrimido[4,5-b]quinolines), which are linked to a thieno[2,3-b]thiophene core via ether or ester linkages. The target compounds were prepared under mild conditions and were obtained in good yields from inexpensive starting materials.

Experimental

General

Melting points were determined in open glass capillaries with a Gallenkamp apparatus. The IR spectra were recorded as potassium bromide disks on Pye Unicam SP 3-300 and Shimadzu FTIR 8101 PC IR spectrophotometers. NMR spectra were recorded with a Varian Mercury VXR-300 NMR spectrometer at 300 MHz ( ¹ H NMR) and at 75 MHz ( ¹³ C NMR). Mass spectra (EI) were obtained at 70 eV with a Shimadzu GCMQP 1000 EX spectrometer. Analytical thin-layer chromatography was performed using precoated silica gel 60778 plates (Fluka), and the spots were visualized with ultraviolet (UV) light at 254 nm.

General procedure for the synthesis of compounds 5a–c

A mixture of bis(aldehyde) (3a–c) (1 mmol), dimedone (4) (4 mmol), and ammonium acetate (5 mmol) in acetic acid (10 mL) was heated at reflux for 5 h. The resulting crude solid was isolated and recrystallized from the proper solvent.

Diethyl 3,4-Bis((2-(3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8,9,10-decahydroacridin-9yl)phenoxy)methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate (5a)

Yield:(550 mg (53%), AcOH); Colorless crystals; m.p. >300 °C. IR (KBr): 3376 (NH), 1720 (CO), 1635 (CO) cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆): δ 0.81 (s, 12H, 4 CH₃), 0.89 (s, 12H, 4 CH₃), 1.23 (t, J = 7.2 Hz, 6H, 2 CH₃CH₂), 1.86–2.02 (m, 16H, 8 CH₂), 4.30 (q, J = 7.2 Hz, 4H, 2 CH₃ CH₂), 4.87 (s, 2H, acridine-H9), 5.38 (s, 4H, 2 OCH₂), 6.15–7.15 (m, 8H, ArH), 8.44 (s, 2H, 2 NH); MS (ESI): m/z 1039 [M + 1]⁺. Anal. calcd for C₆₀H₆₆N₂O₁₀S₂: C, 69.34; H, 6.40; N, 2.70; found: C, 69.55; H, 6.57; N, 2.67.

Diethyl 3,4-Bis((3-(3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8,9,10-decahydroacridin-9yl)phenoxy)methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate (5b)

Yield:(582 mg (56%), Dioxane); Colorless crystals; m.p. >300 °C. IR (KBr): 3201 (NH), 1712 (CO), 1635 (CO) cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆): δ 0.78 (s, 12H, 4 CH₃), 0.96 (s, 12H, 4 CH₃), 1.23 (t, J = 7.2 Hz, 6H, 2 CH₃CH₂), 1.78-2.42 (m, 16H, 8 CH₂), 4.27 (q, J = 7.2 Hz, 4H, 2 CH₃ CH₂), 4.77 (s, 2H, acridine-H9), 5.45 (s, 4H, 2 OCH₂), 6.33–6.89 (m, 8H, ArH), 8.11 (s, 2H, 2 NH); ¹³C NMR (100 MHz, DMSO-d₆): δ 14.4, 26.8, 29.5, 32.5, 40.7, 47.4, 50.6, 62.1, 111.9, 115.4, 118.8, 121.2, 125.5, 128.8, 134.7, 137.2, 149.1, 149.7, 148.8, 149.9, 157.6, 161.9, 165.8, 194.9. MS (ESI): m/z 1039 [M + 1]⁺. Anal. calcd for C₆₀H₆₆N₂O₁₀S₂: C, 69.34; H, 6.40; N, 2.70; found: C, 69.53; H, 6.14; N, 2.62.

Diethyl 3,4-Bis((4-(3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8,9,10-decahydroacridin-9yl)phenoxy)methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate (5c)

Yield:(581 mg (56%), AcOH); Colorless crystals; m.p. >300 °C. IR (KBr): 3379 (NH), 1720 (CO), 1635 (CO) cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆): δ 0.86 (s, 12H, 4 CH₃), 1.00 (s, 12H, 4 CH₃), 1.25 (t, J = 7.2 Hz, 6H, 2 CH₃CH₂), 1.97–2.49 (m, 16H, 8 CH₂), 4.27 (q, J = 7.2 Hz, 4H, 2 CH₃ CH₂), 4.75 (s, 2H, acridine-H9), 5.57 (s, 4H, 2 OCH₂), 6.70 (d, J = 8.1 Hz, 4H, ArH), 7.02 (d, J = 8.1 Hz, 4H, ArH), 9.21 (s, 2H, 2 NH); ¹³C NMR (75 MHz, DMSO-d₆): δ 13.7, 26.4, 28.8, 31.6, 31.9, 50.1, 61.5, 111.4, 113.9, 120.7, 120.8, 128.3, 134.2, 136.9, 140.0, 149.1, 155.5, 161.1, 194.3. MS (ESI): m/z 1038 [M + 1]⁺. Anal. calcd for C₆₀H₆₆N₂O₁₀S₂: C, 69.34; H, 6.40; N, 2.70; found: C, 69.58; H, 6.17; N, 2.68.

General procedure for the synthesis of compounds 7a–c

A mixture of bis(aldehyde) 3a, 3c, or 3d (1 mmol), 5-methyl-2,4-dihydro-3H-pyrazol-3-one (6) (4 mmol), and ammonium acetate (5 mmol) in acetic acid (10 mL) was heated at reflux for 5 h. The crude solid was isolated and recrystallized from the acetic acid.

Diethyl 3,4-Bis((2-(3,5-dimethyl-1,4,7,8-tetrahydrodipyrazolo[3,4-b:4′,3′-e]pyridin-4yl)phenoxy)methyl)thieno[2,3-b] (7a)

Yield: (436 mg, 50%); Colorless crystals; m.p. 295–297 °C. IR (KBr): 3387 (NH), 3217 (NH), 1712 (CO) cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆): δ 1.26 (t, J = 7.2 Hz, 6H, 2 CH₃CH₂), 1.53 (s, 12H, 4 CH₃), 4.30 (q, J = 7.2 Hz, 4H, 2 CH₃ CH₂), 4.73 (s, 2H, dihydrpyridine-H4), 4.95 (s, 4H, 2 OCH₂), 6.25–6.71 (m, 8H, ArH), 7.42 (s, 2H, 2 NH), 11.25 (br, 4H, 2 NH). MS (ESI): m/z 871 [M + 1]⁺. Anal. calcd for C₄₄H₄₂N₁₀O₆S₂: C, 60.68; H, 4.86; N, 16.08; found: C, 60.84; H, 4.98; N, 16.20.

Diethyl 3,4-Bis((4-(3,5-dimethyl-1,4,7,8-tetrahydrodipyrazolo[3,4-b:4′,3′-e]pyridin-4yl)phenoxy)methyl)thieno[2,3-b] (7b)

Yield: (505 mg, 58%); Orange crystals; m.p. 264–269 °C. IR (KBr): 3857 (NH), 3101 (NH), 1705 (CO) cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆): δ 1.27 (t, J = 7.2 Hz, 6H, CH₃CH₂), 2.03 (s, 12H, CH₃), 3.57 (s, 2H, NH), 4.32 (q, J = 7.2 Hz, 4H, CH₃ CH₂), 4.74 (s, 2H, dihydrpyridine-H4), 5.64 (s, 4H, OCH₂), 6.77 (d, J = 8.7 Hz, 4H, ArH), 6.98 (d, J = 8.7 Hz, 4H, ArH), 11.32 (br, 4H, NH); MS (ESI): m/z 871 [M + 1]⁺. Anal. calcd for C₄₄H₄₂N₁₀O₆S₂: C, 60.68; H, 4.86; N, 16.08; found: C, 60.90; H, 5.01; N, 16.23.

Diethyl 3,4-Bis(((4-(3,5-dimethyl-4,7a-dihydrodipyrazolo[3,4-b:4′,3′-e]pyridin-4yl)benzoyl)oxy)methyl)thieno[2,3-b] (7c)

Yield: (572 mg, 62%); Colorless crystals; m.p. 248–251°C. IR (KBr): 3866 (NH), 3110 (NH), 1604 (CO) cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆): δ 1.29 (t, J = 7.2 Hz, 6H, 2 CH₃CH₂), 2.05 (s, 12H, 4 CH₃), 3.45 (br, 6H, NH), 4.32 (q, J = 7.2 Hz, 4H, 2 CH₃ CH₂), 4.88 (s, 2H, dihydrpyridine-H4), 5.87 (s, 4H, 2 OCH₂), 7.22 (d, J = 6.1 Hz, 4H, ArH), 7.78 (d, J = 6.1 Hz, 4H, ArH); ¹³C NMR (75 MHz, DMSO-d₆): δ 10.8, 14.4, 21.5, 33.4, 40.8, 58.0, 62.1, 126.8, 128.4, 129.3, 135.3, 135.9, 145.4, 145.8, 150.0, 161.5, 165.7, 172.5. MS (ESI): m/z 922 [M + 1]⁺. Anal. calcd for C₄₆H₄₂N₁₀O₈S₂: C, 59.60; H, 4.57; N, 15.11; found: C, 59.79; H, 4.28; N, 15.12.

General procedure for the synthesis of compounds 9a–c

A mixture of bis(aldehyde) (3a–c) (1 mmol) and 6-aminopyrimidine-2,4-diones (8) (4 mmol) in acetic acid (10 mL) was heated at reflux for 5 h. The crude solid was isolated and recrystallized from acetic acid.

Diethyl 3,4-Bis((3-(bis(6-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5yl)methyl)phenoxy)methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate (9a)

Yield: (717 mg, 70%); Colorless crystals; m.p. >300 °C. IR (KBr): 3356 (NH₂), 3170 (NH), 1712 (CO), 1627 (CO), 1604 (CO) cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆): δ 1.28 (t, J = 7.2 Hz, 6H, 2 CH₃CH₂), 4.31 (q, J = 7.2 Hz, 4H, 2 CH₃ CH₂), 5.25 (s, 2H, 2 CH), 5.55 (s, 4H, 2 OCH₂), 6.17–7.02 (m, 16H, ArH, and 4 NH₂), 10.08 (brs, 4H, 4 NH), 10.46 (s, 4H, 4 NH). MS (ESI): m/z 1024 [M + 1]⁺. Anal. calcd for C₄₄H₄₀N₁₂O₁₄S₂: C, 51.56; H, 3.93; N, 16.40; found: C, 51.69; H, 4.08; N, 16.56.

Diethyl3,4-Bis((4-(bis(6-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5yl)methyl)phenoxy)methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate (9b)

Yield: (768 mg, 75% yield); Yellow crystals; m.p. >300°C. IR (KBr): 3410 (NH₂), 3170 (NH), 1712 (CO), 1627 (CO), 1504 (CO) cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆): δ 1.24 (t, J = 7.2 Hz, 6H, 2 CH₃CH₂), 4.30 (q, J = 7.2 Hz, 4H, 2 CH₃ CH₂), 5.22 (s, 2H, 2 CH), 5.65 (s, 4H, 2 OCH₂), 6.68 (br, 8H, 4 NH₂), 6.70–6.93 (m, 8H, ArH), 10.25 (br, 4H, 4 NH), 10.39 (s, 4H, 4 NH); MS (ESI): m/z 1024 [M + 1]⁺. Anal. calcd for C₄₄H₄₀N₁₂O₁₄S₂: C, 51.56; H, 3.93; N, 16.40; found: C, 51.72; H, 4.09; N, 16.55.

Diethyl 3,4-Bis(((4-(bis(6-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5yl)methyl)benzoyl)oxy)methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate (9c)

Yield: (864 mg, 80% yield); Colorless crystals; m.p. >300°C. IR (KBr): 3410 (NH₂), 3194 (NH), 1720 (CO), 1627 (CO), 1527 (CO) cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆): δ 1.30 (t, J = 7.2 Hz, 6H, 2 CH₃CH₂), 4.34 (q, J = 7.2 Hz, 4H, 2 CH₃ CH₂), 5.33 (s, 2H, 2 CH), 5.89 (s, 4H, 2 OCH₂), 6.68 (br, 8H, 4 NH₂), 7.18 (d, J = 6.1 Hz, 4H, ArH), 7.77 (d, J = 6.1 Hz, 4H, ArH), 10.33 (br, 4H, 4 NH), 10.53 (s, 4H, 4 NH); ¹³C NMR (75 MHz, DMSO-d₆): δ 14.4, 33.3, 56.5, 62.1, 74.6, 126.4, 127.5, 129.2, 135.3, 135.9, 146.8, 150.2, 151.4, 155.6, 161.5, 164.8, 165.7, 172.5. MS (ESI): m/z 1080 [M + 1]⁺. Anal. calcd for C₄₆H₄₀N₁₂O₁₆S₂: C, 51.11; H, 3.73; N, 15.55; found: C, 51.25; H, 3.68; N, 15.70.

General procedure for the synthesis of compounds 11a–c

A mixture of bis(aldehyde) (3b–d) (1 mmol), dimedone (4) (2 mmol), and 6-aminopyrimidine-2,4-diones (8) (2 mmol) in acetic acid (10 mL) was heated at reflux for 5 h. The formed solid was filtered off, washed with ethanol, and recrystallized from acetic acid.

Diethyl 3,4-Bis((3-(8,8-dimethyl-2,4,6-trioxo-1,2,3,4,5,6,7,8,9,10-decahydropyrimido[4,5-b]quinolin-5-yl)phenoxy)methyl)thieno[2,3-b] (11a)

Yield: (740 mg, 73% yield); Colorless crystals; m.p. >300 °C. IR (KBr): 3394 (NH), 3201 (NH), 3059 (NH), 1720 (CO), 1666 (CO), 1527 (CO) cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆): δ 0.86 (s, 6H, 2 CH₃), 1.01 (s, 6H, 2 CH₃), 1.26 (t, J = 7.2 Hz, 6H, 2 CH₃CH₂), 2.02-2.45 (m, 8H, 4 CH₂), 4.31 (q, J = 7.2 Hz, 4H, 2 CH₃ CH₂), 4.71 (s, 2H, 2 CH), 5.44–5.58 (m, 4H, 2 OCH₂), 6.41–6.88 (m, 8H, ArH), 8.90 (brs, 2H, 2 NH), 10.71 (s, 2H, 2 NH), 11.88 (brs, 2H, 2 NH). MS (ESI): m/z 1014 [M + 1]⁺. Anal. calcd for C₅₂H₅₀N₆O₁₂S₂: C, 61.53; H, 4.96; N, 8.28; found: C, 61.70; H, 5.15; N, 8.45.

Diethyl 3,4-Bis((4-(8,8-dimethyl-2,4,6-trioxo-1,2,3,4,5,6,7,8,9,10-decahydropyrimido[4,5-b]quinolin-5-yl)phenoxy)methyl)thieno[2,3-b] (11b)

Yield: (659 mg, 65%); Yellow crystals; m.p. 284–287°C. IR (KBr): 3309 (NH), 3209 (NH), 3055 (NH), 1712 (CO), 1666 (CO) cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆): δ 0.88 (s, 6H, 2 CH₃), 1.01 (s, 6H, 2 CH₃), 1.28 (t, J = 7.2 Hz, 6H, 2 CH₃CH₂), 2.02-2.45 (m, 8H, 4 CH₂), 4.31 (q, J = 7.2 Hz, 4H, 2 CH₃ CH₂), 4.71 (s, 2H, 2 CH), 5.55 (m, 4H, 2 OCH₂), 6.73 (d, J = 6.1 Hz, 4H, ArH), 7.06 (d, J = 6.1 Hz, 4H, ArH), 8.89 (br, 2H, 2 NH), 10.65 (s, 2H, 2 NH), 11.85 (br, 2H, 2 NH). MS (ESI): m/z 1014 [M + 1]⁺. Anal. calcd for C₅₂H₅₀N₆O₁₂S₂: C, 61.53; H, 4.96; N, 8.28; found: C, 61.73; H, 5.18; N, 8.44.

Diethyl 3,4-Bis(((4-(8,8-dimethyl-2,4,6-trioxo-1,2,3,4,5,6,7,8,9,10-decahydropyrimido[4,5-b]quinolin-5-yl)benzoyl)oxy)methyl)thieno[2,3-b] (11c)

Yield: (728 mg, 68%); Colorless crystals; m.p. >300 °C. IR (KBr): 3394 (NH), 3289 (NH), 3240 (NH), 1720 (CO), 1666 (CO) cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆): δ 0.85 (s, 6H, 2 CH₃), 1.00 (s, 6H, 2 CH₃), 1.28 (t, J = 7.2 Hz, 6H, 2 CH₃CH₂), 1.97–2.51 (m, 8H, 4 CH₂), 4.33 (q, 4H, 2 CH₃ CH₂, J = 7.2 Hz), 4.80 (s, 2H, 2 CH), 5.85 (s, 4H, 2 OCH2), 7.30 (d, J = 6.1 Hz, 4H, ArH), 7.75 (d, J = 6.1 Hz, 4H, ArH), 8.55 (br, 2H, 2 NH), 10.60 (br, 2H, 2 NH), 11.95 (br, 2H, 2 NH). MS (ESI): m/z 1071 [M + 1]⁺. Anal. calcd for C₅₄H₅₀N₆O₁₄S₂: C, 60.55; H, 4.71; N, 7.85; found: C, 60.73; H, 4.91; N, 7.66.

Supplemental Material

SI – Supplemental material for Hantzsch-like synthesis of novel bis(hexahydroacridine-1,8-diones), bis(tetrahydrodipyrazolo[3,4-b:4′,3′-e]pyridines), and bis(pyrimido[4,5-b]quinolines) incorporating thieno[2,3-b]thiophenes

Supplemental material, SI for Hantzsch-like synthesis of novel bis(hexahydroacridine-1,8-diones), bis(tetrahydrodipyrazolo[3,4-b:4′,3′-e]pyridines), and bis(pyrimido[4,5-b]quinolines) incorporating thieno[2,3-b]thiophenes by Elshimaa M Eid, Huwaida M E Hassaneen, Ahmed H M Elwahy and Ismail A Abdelhamid in Journal of Chemical Research