Diastereo- and Facially Selective Imino-Diels–Alder Cycloaddition of 2-Azeditinone-Tethered 1-Azadiene: Synthesis of Functionalized (2-Oxo-4-styrylazetidin-3-yl)–Pyridine Hybrids

Abstract

Highly diastereo- and π-facially selective imino Diels–Alder cycloadditions of 3-allylideneamino-2-azetidinones having stereocentres at its α- and β-positions, with symmetrical dienophiles leading to the formation of biologically potent (2-oxo-4-styrylazetidin-3-yl)–pyridine hybrids have been reported.

Key words

Diels–Alder reactions - diastereoselectivity - π-facial selectivity - β-lactams - 1-azadiene

• References and Notes

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We have previously reported the π-facially selective Diels–Alder cycloaddition reactions of 3-butadienyl-2-azetidinones with different dienophiles. For further reference to facially selective DA reaction, see:
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• 13 General Procedure for the Preparation of 3-Allylideneamino-2-azetidinones 3To a solution of 3-amino-2-azetidinones 1 (1 equiv) in toluene or xylene was added cinnamaldehyde (2) (1.1 equiv) in the presence of anhydrous Na₂SO₄ (5 equiv). The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered, washed with toluene or xylene, and dried to get 3-allylideneamino-2-azetidinones 3.
• 14 Typical Procedure for the Preparation of 1-[2-Oxo-4-styrylazetidin-3-yl]-1,4,4a,7a-tetrahydropyridines 5 and 7To a stirred solution of 3 was added dienophile 4a, 4b, or 6 in the requisite solvent. The mixture was heated to reflux for 4–6 h, and the progress of the reaction was monitored by TLC. After the completion of reaction, the crude product, so obtained, was purified by flash chromatography on silica gel using a mixture of EtOAc and hexane (2:8) as the eluent system to furnish compounds 5 and 7 as pure products.1-[1-(4-Chlorophenyl)-2-oxo-4-styrylazetidin-3-yl]-4,6-diphenyl-1,4,4a,7a-tetrahydropyrrolo[3,4-b]pyridine-5,7-dione (5a)Pale yellow solid; yield 61%; mp 120–123 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.35 (m, 19 ArH), 6.70 (m, 2 H, H₄ + H₆), 6.18 (m, 2 H, H₃ + H₅), 5.80 (d, J = 7.2 Hz, 1 H, H₁), 4.78 (d, J = 5.4, 7.2 Hz, 1 H, H₂), 3.68 (m, 2 H, H₈ + H₉), 2.34 (d, J = 2.7 Hz, 1 H, H₇). ¹³C NMR (75 MHz, CDCl₃): δ = 27.3, 30.7, 47.1, 59.6, 60.1, 117.3, 118.8, 122.3, 123.7, 125.1, 126.5, 126.9, 127,4, 127.8, 128.5, 128.9, 129.0, 129.3, 132.5, 133.2, 133.7, 135.1, 136.7, 137.9, 147.4, 168.9, 174.5, 175.9. MS: m/z = 585 [M⁺]. Anal. Calcd for C₃₆H₂₈ClN₃O₃: C, 73.78; H, 4.82; N, 7.17. Found: C, 73.84; H, 4.91; N, 7.11.1-(2-Oxo-1-phenyl-4-styrylazetidin-3-yl)-4-phenyl-1,2,3,4-tetrahydropyridine-2,3-dicarboxylic Acid Dimethyl Ester (7b)Pale yellow solid; yield 48%; mp 116–118 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.25 (m, 15 H, ArH), 6.81 (m, 1 H, H₆), 6.55 (m, 2 H, H₄ + H₅), 6.27 (dd, J = 6.0, 15.9 Hz, 1 H, H₃), 5.14 (d, J = 6.6 Hz, 1 H, H₁), 4.33 (d, J = 6.0, 9.0 Hz, 1 H, H₂), 3.79–3.94 (m, 2 H, H₈ + H₉), 3.53 (s, 3 H, OCH₃), 3.48 (s, 3 H, OCH₃), 2.85 (dd, J = 1.2, 3.6 Hz, 1 H, H₇). ¹³C NMR (75 MHz, CDCl₃): δ = 30.7, 43.7, 50.4, 51.1, 57.8, 59.6, 60.1, 63.2, 117.6, 118.2, 122.6, 123.2, 124.3, 125.1, 126.5, 126.9, 127.1, 128.1, 128.6, 129.4, 129.7, 130.1, 132.1, 133.5, 134.2, 135.7, 136.3, 137.2, 147.6, 169.2, 175.6, 176.2. MS: m/z = 522 [M⁺]. Anal. Calcd for C₃₂H₃₀N₂O₅: C, 73.55; H, 5.79; N, 5.36. Found: C, 73.62; H, 5.84; N, 5.31.