Aza-Annulation of Polarized N,S- and N,N-Ketene Acetals with Itaconic Anhydride: Synthesis of Novel Functionalized 1,2,3,4-Tetrahydro-2-pyridones and Related Azabicycles

Abstract

Synthesis of novel highly functionalized 2-oxo-(1,2,3,4-tetrahydropyridin-3-yl)acetic acids has been described via aza-­annulation of both acyclic and cyclic α-oxo- and α-nitro-N,S- and -N,N-ketene acetals with itaconic anhydride.

Key words

alkaloids - annulation - esters - heterocycles - lactams - Michael addition - nitriles

References

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17

General procedure for the aza-annulation of acyclic and cyclic α-oxo- and α-nitro N,S- and N,N-ketene acetals with itaconic anhydride: A solution of the appropriate N,S- or N,N-ketene acetal (1 mmol) and itaconic anhydride (0.12 g, 1.1 mmol) in anhyd acetonitrile (30 mL) was refluxed under a nitrogen atmosphere for 8-10 h (monitored by TLC). The reaction mixture was concentrated under reduced pressure and the residue was subjected to column chromatography over silica gel using hexane-EtOAc (4:1) (4a-f, 6a,b, 8a-f, 12, 14) as eluent to give pure compounds.
4a. Yield 70%; white solid (CHCl₃-hexane); mp 138-140 °C; R _f 0.5 (EtOAc); IR (KBr): 3032, 2924, 1698, 1668, 1629, 1596 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ = 1.99 (s, 3 H, SCH₃), 2.56 (dd, J = 6.6 Hz, 16.8 Hz, 1 H, CHHCO₂H), 2.57-2.60 (m, 2 H, =CCH ₂CH),2.94 (dd, J = 6.6 Hz, 16.8 Hz, 1 H, CHHCO₂H), 3.17-3.23 (m, 1 H, CHCH₂CO₂H), 4.91 (d, J = 15.0 Hz, 1 H, NCHHPh), 5.41 (d, J = 15.0 Hz, 1 H, NCHHPh), 7.25-7.35 (m, 5 H, ArH), 7.39-7.45 (m, 2 H, ArH), 7.54 (t, J = 7.4 Hz, 1 H, ArH), 7.72 (d, J = 7.6 Hz, 2 H, ArH), 8.91 (br s, 1 H, CO₂H); ¹³C NMR (100 MHz, CDCl₃): δ = 19.0, 29.14, 34.26, 37.22, 46.17, 127.32, 127.43, 128.56, 128.63, 129.05, 133.29, 137.12, 137.58, 137.68, 171.46, 176.98, 195.16; FABMS: m/z (%) = 396 (MH⁺, 100); Anal. Calcd for C₂₂H₂₁NO₄S (395.47): C, 66.82; H, 5.35; N, 3.54. Found: C, 66.65; H, 5.40; N, 3.48.
6a. Yield 80%; yellow solid (CHCl₃-hexane); mp 152-153 °C; R _f 0.20 (hexane-EtOAc 7:3); IR (KBr): 3438, 2962, 2365, 1714, 1567 cm^-1; ¹H NMR (400 MHz, DMSO-d ₆ ): δ = 2.37 (s, 3 H, SCH₃), 2.41-2.54 (m, 2 H, CH ₂CO₂H), 2.68 (dd, J = 5.6 Hz, 16.8 Hz, 1 H, =CCHH), 2.86-2.88 (m, 2 H, CH₂Ph), 3.06-3.12 (m, 1 H, CHCH₂CO₂H), 3.20 (dd, J = 5.9 Hz, 16.1 Hz, 1 H, CHHCO₂H), 3.91-3.98 (m, 1 H, NCHH), 4.37-4.42 (m, 1 H, NCHH), 7.21-7.29 (m, 5 H, ArH), 12.40 (br s, 1 H, CO₂H); ¹³C NMR (100 MHz, DMSO-d ₆ ): d = 17.77, 26.46, 33.41, 34.23, 36.31, 47.96, 126.60, 128.33, 128.95, 137.49, 137.84, 150.07, 171.30, 172.71; FABMS: m/z (%) = 351 (MH⁺, 100); Anal. Calcd for C₁₆H₁₈N₂O₅S (350.39): C, 54.84; H, 5.18; N, 7.99. Found: C, 54.81; H, 5.22; N, 7.94.
8b. Yield 86%; white solid (CHCl₃-hexane); mp 203-204 °C; R _f 0.49 (EtOAc); IR (KBr): 1732, 1691, 1637, 1504 cm^-1; ¹H NMR (400 MHz, DMSO-d ₆ ): d = 2.39 (dd, J = 7.0 Hz, 16.9 Hz, 1 H, CHHCO₂H), 2.55-2.78 (m, 3 H, =CCH₂ and CHHCO₂H), 2.83-2.91 (m, 1 H, CHCH₂CO₂H), 3.76-3.86 (m, 3 H, HNCH ₂ and NCHH), 3.94-4.02 (m, 1 H, NCHH), 7.35-7.42 (m, 5 H, ArH), 9.50 (br s, 1 H, CO₂H), 12.50 (br s, 1 H, NH); ¹³C NMR (100 MHz, DMSO-d ₆ ): d = 27.71, 33.79, 38.36, 41.60, 42.50, 83.99, 126.48, 127.49, 128.71, 141.0, 156.19, 169.82, 172.73, 189.38; FABMS: m/z (%) = 301 (MH⁺, 100); Anal. Calcd for C₁₆H₁₆N₂O₄ (300.31): C, 63.99; H, 5.37; N, 9.33. Found: C, 63.76; H, 5.46; N, 9.17.
8d. Yield 57%; white solid (CHCl₃-hexane); mp 196-197 °C; R _f 0.52 (EtOAc); IR (KBr): 2975, 1732, 1618, 1501 cm^-1; ¹H NMR (400 MHz, DMSO-d ₆ ): d = 2.52 (dd, J = 6.4 Hz, 17.0 Hz, 1 H, CHHCO₂H), 2.64-2.75 (m, 2 H, =CCH₂), 3.01-3.07 (dd, J = 6.4 Hz, 17.0 Hz, 1 H, CHHCO₂H), 3.09-3.19 (m, 1 H, CHCH₂CO₂H), 3.24 (t, J = 7.7 Hz, 2 H, SCH₂), 3.90-3.96 (m, 1 H, NCHH), 4.27-4.33 (m, 1 H, NCHH), 12.41 (br s, 1 H, CO₂H); ¹³C NMR (100 MHz, DMSO-d ₆ ): d = 26.57, 28.56, 33.78, 36.32, 49.21, 121.83, 157.89, 168.67, 172.56; FABMS: (m/z) = 258 (MH⁺, 45); Anal. Calcd for C₉H₁₀N₂O₅S (258.25): C, 41.86; H, 3.90; N, 10.85. Found: C, 41.65; H, 4.02; N, 10.68.
12. Yield 90%; white crystalline solid (CHCl₃-hexane); mp 172-174 °C; R _f 0.55 (EtOAc); IR (KBr): 3059, 2982, 1712, 1667, 1598 cm^-1; ¹H NMR (400 MHz, CDCl₃): d = 1.90 (d, J = 7.1 Hz, 3 H, CH ₃CH), 1.94 (s, 3 H, SCH₃), 2.49-2.67 (m, 3 H, =CCH ₂CH and CHHCO₂H), 2.92 (dd, J = 6.4 Hz, 17.1 Hz, 1 H, CHHCO₂H), 3.11-3.16 (m, 1 H, CH₂CHCH₂CO₂H), 5.96-6.06 (m, 1 H, CHCH₃), 7.21-7.57 (m, 8 H, ArH), 7.69-7.71 (m, 2 H, ArH), 10.20 (br s, 1 H, CO₂H); ¹³C NMR (100 MHz, CDCl₃): d = 7.77, 20.02, 29.39, 34.24, 37.93, 53.55, 126.76, 126.98, 128.21, 128.55, 129.17, 130.83, 133.31, 136.53, 137.92, 140.55, 171.41, 176.96, 195.05; FABMS: m/z (%) = 410 (M + 1, 50); Anal. Calcd for C₂₃H₂₃NO₄S (409.50): C, 67.46; H, 5.66; N, 3.42. Found: C, 67.29; H, 5.80; N, 3.31.
14. Yield 71% (0.35 g); white solid (CHCl₃-hexane); mp 136-137 °C; R _f 0.55 (EtOAc); IR (KBr): 2933, 2546, 1693, 1549, 1418 cm^-1; ¹H NMR (400 MHz, DMSO-d ₆ ): δ = 2.50 (dd, J = 7.6 Hz, 17.1 Hz, 1 H, =CCHH), 2.59 (dd, J = 7.6 Hz, 17.1 Hz, 1 H, =CCHH), 2.66 (s, 3 H, SCH₃), 2.88 (dd, J = 6.8 Hz, 15.6 Hz, 1 H, CHHCO₂H), 2.98 (dd, J = 6.8 Hz, 15.6 Hz, 1 H, CHHCO₂H), 3.06-3.13 (m, 1 H, CHCH₂CO₂H), 3.35 (br s, 1 H, NH), 12.45 (br s, 1 H, CO₂H); ¹³C NMR (100 MHz, DMSO-d ₆ ): d = 14.42, 24.30, 34.84, 38.51, 151.05, 153.13, 172.67, 174.16; FABMS: m/z (%) = 247 (M + 1⁺, 70); Anal. Calcd for C₈H₁₀N₂O₅S (246.24): C, 39.02; H, 4.09; N, 11.38. Found: C, 39.19; H, 3.97; N, 11.52.