A Facile Stereoselective Domino Approach for the Construction of Novel Bis(spiropiperidone)–Tetrahydrothiophene Hybrid Heterocycles

Abstract

A library of novel bis-spiropiperidone–tetrahydrothiophene hybrid heterocycles have been synthesized via pseudo-three-component domino reaction of (3E,5E)-3,5-bis(arylidene)-1-methyl/benzyl piperidin-4-ones and 1,4-dithiane-2,5-diol in the presence of triethylamine. This transformation presumably proceeds via two annulations each involving the generation of 2-mercaptoacetaldehyde from 1,4-dithiane-2,5-diol–Michael addition–intramolecular aldol sequence which result in the creation of four new bonds in a one-pot operation. The advantages of this protocol are high atom economy, high stereoselectivity, short reaction time, and operational simplicity.

Key words

domino reactions - stereoselectivity - (3E,5E)-3,5-bis(arylidene)-1-methyl/benzylpiperidin-4-ones - 1,4-dithiane-2,5-diol - bis(spiropiperidone)–tetrahydrothiophene hybrids

• References and Notes

• 1 Both authors contributed equally to this work.
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• 37 General Procedure for the Synthesis of 1,8-Bis(aryl)-4,11-dihydroxy-13-methyl/benzyl-2,9-dithia-13-azadispiro[4.1.4⁷.3⁵]tetradecan-6-ones 3a–p A mixture of (3E,5E)-3,5-bis(arylidene)-1-methyl/benzylpiperidin-4-one (1 mmol), 1,4-dithiane-2,5-diol (1 mmol), and Et₃N (0.25 equiv) in CH₂Cl₂ (6 mL) was heated under reflux for 3–4 h. After completion of the reaction (TLC), the solvent was removed and the product was purified by flash column chromatography using a PE–EtOAc mixture (4:1 v/v) as eluent to afford pure compound
• 38 Characterization Data of Representative Compounds 1,8-Bis(4-fluorophenyl)-4,11-dihydroxy-13-methyl-2,9-dithia-13-azadispiro[4.1.4⁷.3⁵]tetradecan-6-one (3a) White solid; yield 88% (0.38 g); mp 215–216 °C. ¹H NMR (300 MHz, CDCl₃ + DMSO-d ₆): δ = 1.64 (d, 2 H, J = 12.3 Hz), 2.22 (s, 3 H, NCH₃), 2.64 (d, 2 H, J = 12.3 Hz), 2.97 (d, 2 H, J = 12.3 Hz), 3.48 (dd, 2 H, J = 12.3, 4.8 Hz), 5.03 (d, 2 H, J = 4.5Hz,), 5.28 (t, 2 H, J = 4.4 Hz), 5.72 (s, 2 H), 6.81–6.87 (m, 4 H, ArH), 7.34–7.44 (m, 4 H, ArH). ¹³C NMR (75 MHz, CDCl₃ + DMSO-d ₆): δ = 36.6, 46.5, 50.7, 57.6, 68.2, 79.4, 114.0 (² J _C,_F = 20.9 Hz), 131.2 (³ J _C,_F = 7.8 Hz), 131.4, 161.5 (¹ J _C,_F = 244.9 Hz), 203.5. Anal. Calcd for C₂₄H₂₅F₂NO₃S₂: C, 60.36; H, 5.28; N, 2.93. Found: C, 60.29; H, 5.24; N, 2.99. ESI-MS: m/z calcd: 477.12; found: 478.07 [M⁺]. 1,8-Bis(4-chlorophenyl)-4,11-dihydroxy-13-methyl-2,9-dithia-13-azadispiro[4.1.4⁷.3⁵]tetradecan-6-one (3b) White solid; yield 85% (0.36 g); mp 225–226 °C. ¹H NMR (300 MHz, CDCl₃ + DMSO-d ₆): δ = 1.62 (d, 2 H, J = 12.0 Hz), 2.22 (s, 3 H, NCH₃), 2.64 (d, 2 H, J = 12.0 Hz), 2.95 (d, 2 H, J =12.3 Hz), 3.49 (dd, 2 H, J = 12.2, 4.4 Hz), 5.10 (d, 2 H, J = 3.9 Hz), 5.27 (t, 2 H, J = 5.9 Hz), 5.67 (s, 2 H), 7.13 (d, 4 H, J = 8.4 Hz, ArH), 7.33 (d, 4 H, J = 8.4 Hz, ArH). ¹³C NMR (75 MHz, CDCl₃ + DMSO-d ₆): δ = 36.0, 45.8, 50.1, 56.7, 67.6, 78.6, 126.7, 130.4, 131.8, 133.8, 202.8. Anal. Calcd for C₂₄H₂₅Cl₂NO₃S₂: C, 56.47; H, 4.94; N, 2.74. Found: C, 56.58; H, 4.88; N, 2.69. ESI-MS: m/z calcd: 509.07; found: 546.16 [M + Cl]. 1,8-Bis(4-bromophenyl)-4,11-dihydroxy-13-methyl-2,9-dithia-13-azadispiro[4.1.4⁷.3⁵]tetradecan-6-one (3c) White solid; yield 83% (0.33 g); mp 227–228 °C. ¹H NMR (300 MHz, CDCl₃ + DMSO-d ₆): δ = 1.64 (d, 2 H, J = 12.0 Hz), 2.22 (s, 3 H, NCH₃), 2.63 (d, 2 H, J = 12.0 Hz,), 2.99 (d, 2 H, J = 12.3 Hz), 3.48 (dd, 2 H, J = 12.3, 4.8 Hz), 4.99 (d, 2 H, J = 4.5 Hz), 5.26 (t, 2 H, J = 4.4 Hz), 5.69 (s, 2 H), 7.24–7.30 (m, 6 H, ArH), 7.42–7.43(m, 2 H, ArH). ¹³C NMR (75 MHz, CDCl₃ + DMSO-d ₆): δ = 36.5, 46.2, 50.7, 57.2, 68.0, 79.2, 120.7, 130.2, 131.2, 134.7, 203.3. Anal. Calcd for C₂₄H₂₅Br₂NO₃S₂: C, 48.09; H, 4.20; N, 2.34. Found: C, 48.12; H, 4.28; N, 2.30. ESI-MS: m/z calcd: 598.96; found: 634.16 [M + Cl]
• 39 General Procedure for the Synthesis of 3-[(E)-4-arylidene]-1-methyl-5-[(E)-4-arylidene]piperidin-4-ones 1q,r The synthesis of (E)-1-methyl-3-(arylidene)piperidin-4-ones was performed from our earlier reported procedure.⁴² Unsymmetrically substituted 3-[(E)-4-arylidene]-1-methyl-5-[(E)-4-arylidene]piperidin-4-one were synthesized from previous reports⁴³ with simple modification. A mixture of (E)-1-methyl-3-(arylidene)piperidin-4-ones (1 mmol) and Ba(OH)₂·8H₂O (1 mmol) in EtOH was reacted under stirring conditions for 5 min. Then aromatic aldehyde (1 mmol) was dissolved in EtOH and was added dropwise. After completion of the addition the resulting mixture was stirred for further 3 h. After completion of the reaction with evident TLC, the precipitated solid was filtered and washed with cold EtOH that afforded pure 1q and 1r.
• 40 Characterization Data of Unsymmetrically Substituted Di­arylidines 3-[(E)-benzylidene]-1-methyl-5-[(E)-4-methylbenzylid­ene]piperidin-4-one (1q) Yellow solid; yield 88% (0.39 g); mp 185–186 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.40 (s, 3 H, NCH₃), 2.48 (s, 3 H), 3.79 (s, 4 H), 7.22–7.32 (m, 7 H, ArH), 7.41–7.43 (m, 2 H, ArH), 7.81(s, 2 H, ArH). ¹³C NMR (75 MHz, CDCl₃): δ = 21.4, 45.8, 57.1, 129.3, 130.5, 132.4, 132.5, 136.4, 139.3, 186.9. Anal. Calcd for C₂₁H₂₁NO: C, 83.13; H, 6.98; N, 4.62. Found: C, 83.05; H, 6.86; N, 4.69. 1-Methyl-3-[(E)-4-methylbenzylidene]-5-[(E)-4-nitrobenz­ylidene]piperidin-4-one (1r) Yellow solid; yield 90% (0.46 g); mp 164–165 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.40 (s, 3 H, NCH₃), 2.48 (s, 3 H), 3.73 (s, 2 H), 3.79 (s, 2 H), 7.25, (d, 2 H, J = 8.4 Hz, ArH), 7.32 (d, 2 H, J = 8.1 Hz, ArH), 7.53 (d, 2 H, J = 8.7 Hz, ArH), 7.79 (s, 1 H), 7.81 (s, 1 H), 8.28 (d, 2 H, J = 8.7 Hz, ArH). ¹³C NMR (75 MHz, CDCl₃): δ = 21.3, 45.7, 56.6, 57.0, 123.5, 129.3, 130.5, 130.6, 131.7, 131.9, 132.7, 136.2, 137.2, 139.7, 141.6, 147.2, 186.1. Anal. Calcd for C₂₁H₂₀N₂O₃: C, 72.40; H, 5.79; N, 8.04. Found: C, 72.46; H, 5.71; N, 8.16. ESI-MS: m/z calcd: 348.15; found: 349.18 [M⁺]
• 41 Crystallographic data (excluding structure factors) for compound 3b in this letter have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 999878. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone] or e-mail: [e-mail]].
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