Rapid Access to Tricyclic Ring System Containing Isoindolone by Novel Diastereoselective Intramolecular Aldol-Type Cyclization of N-Substituted Phthalimides

Abstract

The cyclization of N-substituted phthalimide to 3-hydroxy­isoindolone derivatives has been successfully carried out by the base-promoted aldol-type reaction. The new morpholine and thiomorpholine derivatives have been synthesized and characterized.

Key words

isoindolones - phthalimide derivatives - aldol reactions - cyclization - diastereoselectivity

References and Notes

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7

The nucleophilic center of linear cyano group is too far from the strong alkoxide anion for any relation of sodium cation with both centers. Ab initio molecular calculation for isomeric cis -2a and trans-2a anions (in gas phase) show a very small gap -ΔE _{cis - trans}  = 0.22 kJ/mol that is in opposition to the observed high diastereoselectivity. That means that the steric effects in solution determine the selectivity of cyclization.

8

Procedure I (for 2a-i)
Compound 1a-i (0.5 mmol),⁹ NaH (1 mmol), and anhyd DMF (100 mL) were stirred for 15 h at -38 ˚C. The reaction mixture was neutralized with AcOH, and DMF was evaporated on a rotary evaporator. The products were purified with the flash-preparative chromatography technique and recrystallized.
Isolation and Purification for cis -2h
The precipitate obtained after addition of H₂O to the product of procedure I was recrystallized from EtOH.
Isolation and Purification for trans -2h, cis -2i, trans -2i
The mixture of trans- and cis-isomers (product of procedure I) was separated with column chromatography on silica gel (60-120 mesh; trans-2h: CHCl₃-MeOH, 30:1; cis-2i: hexane-CHCl₃-MeOH, 100:200:5; trans-2i: CHCl₃-MeOH, 10:1) to give the product.
Procedure II (for 3a-c, f, h, i)
Compounds 2a-c,f,h,i (0.5 mmol) were stirred in CHCl₃ (10 mL) with three drops of TFA at 55 ˚C. When the reaction was completed (TLC control), the solvent was evaporated, and the product was recrystallized from EtOH.
Spectroscopic and Analytical Data for Selected Products
^¹H NMR (400 MHz, CDCl₃), ^¹³C NMR (100 MHz, CDCl₃, TMS as internal standard unless otherwise noted), IR (KBr), Raman (λ = 532 nm), MS (EI, 40 eV). The assignments of quaternary C, CH, CH₂, and CH₃ were made with the aid of DEPT spectra, and the assignments of H_a, H_b, H_c, and H_d for aromatic protons of compounds 2a-i and 3a-c,f,h,i were done according to Figure  [4] .
(1 R *,10b S *)-Methyl 10b-Hydroxy-1,3,4,10b-tetrahydro[1,4]oxazino-6-oxo[3,4- a ]isoindole-1-carboxylate (2a)
^¹H NMR (200 MHz): δ = 7.69 (d, 1 H_d, J _cd = 7.5 Hz), 7.66 (d, 1 H_a, J _ab = 7.5 Hz), 7.58 (td, 1 H_c, J _cd = J _bc = 7.5 Hz, J _ac = 1.0 Hz), 7.50 (td, 1 H_b, J _ab = J _bc = 7.5 Hz, J _bd = 1.0 Hz), 4.51 (s, 1 H, OH), 4.13 (dd, 1 H, J = 12.0, 3.8 Hz, CH₂O), 4.00 (dd, 1 H, J = 12.0, 2.0 Hz, CH₂O), 3.93 (s, 3 H, OCH₃), 3.87 (s, 1 H, OCH), 3.45-3.35 (m, 2 H, J = 12.0, 2.0 Hz, NCH₂). ^¹³C NMR (50 MHz): δ = 167.7 (C), 165.3 (C), 143.3 (C), 132.2 (CH), 131.1 (C), 130.4 (CH), 124.5 (CH), 123.5 (CH), 85.0 (C), 81.5 (CH), 66.8 (CH₂), 52.8 (CH₃), 36.1 (CH₂). IR: 3264 (OH), 1764 (C=O), 1735, 1671 cm^-¹. Anal. Calcd for C₁₃H₁₃NO₅: C, 59.31; H, 4.98; N, 5.32. Found: C, 59.21; H, 4.68; N, 5.35. Mp 206-207 ˚C. The crystallographic data (structure CCDB 276311) can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdb.cam.ac.uk/data_request/cif.
(1 R *,10b S *)-Benzyl 10b-Hydroxy-1,3,4,10b-tetrahydro[1,4]oxazino-6-oxo[3,4- a ]isoindole-1-carboxylate (2d)
^¹H NMR (500 MHz): δ = 7.80 (m, 1 H_d), 7.50 (m, 1 H_a), 7.44-7.38 (m, 6 H, C₆H₅, H_c), 7.32 (m, 1 H_b), 5.42 (d_AB, 1 H, J = 12.0 Hz, OCH₂C₆H₅), 5.31 (d_AB, 1 H, J = 12.0 Hz, OCH₂C₆H₅), 4.22-4.13 (m, 3 H, CH₂O, OH), 3.90 (s, 1 H, OCHCOO), 3.49 (m, 2 H, NCH₂). ^¹³C NMR (125 MHz): δ = 167.4 (C), 165.0 (C), 143.9 (C), 134.6 (C), 132.1 (CH), 131.5 (C), 130.4 (CH), 128.9 (CH), 128.8 (CH), 128.7 (CH), 124.2 (CH), 123.7 (CH), 84.9 (C), 81.6 (CH), 67.8 (CH₂) 67.0 (CH₂), 36.1 (CH₂). IR: 3232 (OH), 1732 (C=O), 1668 cm^-¹. Anal. Calcd for C₁₉H₁₇NO₅: C, 67.25; H, 5.05; N, 4.13; O, 23.57. Found: C, 66.98; H, 5.10; N, 4.14. Mp 179-180 ˚C.
(1 R *,10b S *)-Ethyl 10b-Hydroxy-1-methyl-1,3,4,10b-tetrahydro[1,4]oxazino-6-oxo[3,4- a ]isoindole-1-carboxylate (2e)
^¹H NMR: δ = 7.89 (d, 1 H_d, J _cd = 7.6 Hz), 7.67 (d, 1 H_a, J _ab = 7.6 Hz), 7.57 (td, 1 H_c, J _bc = J _cd = 7.6 Hz, J _ac = 1.2 Hz), 7.47 (td, 1 H_b, J _ab = J _bc = 7.6 Hz, J _bd = 1.2 Hz), 4.43 (m, 2 H, OCH₂CH₃), 4.26 (s, 1 H, OH), 3.98 (m, 2 H, CH₂O), 3.76 (m, 1 H, NCH₂), 3.40 (m, 1 H, NCH₂), 1.43 (t, 3 H, J = 7.2 Hz, OCH₂CH₃), 1.07 (s, 3 H, CCH₃). ^¹³C NMR: δ = 171.1 (C), 165.8 (C), 144.0 (C), 132.2 (CH), 131.4 (C), 130.0 (CH), 124.6 (CH), 123.3 (CH), 88.0 (C), 81.9 (C), 62.5 (CH₂), 59.9 (CH₂), 35.3 (CH₂), 17.4 (CH₃), 14.2 (CH₃). IR: 3300 (OH), 1728 (C=O), 1691 cm^-¹. Anal. Calcd for C₁₅H₁₇NO₅: C, 61.85; H, 5.88; N, 4.81. Found: C, 61.90; H, 6.11; N, 4.81. Mp 175-176 ˚C.
(1 R *,10b S *)-Ethyl 10b-Hydroxy-1-methyl-1,3,4,10b-tetrahydro[1,4]thiazino-6-oxo-[3,4- a ]isoindole-1-carboxylate (2g)
^¹H NMR (acetone-d ₆): δ = 7.75 (d, 1 H_d, J _cd = 7.4 Hz), 7.69 (dt, 1 H_a, J _ab = 7.4 Hz, J _ac = J _ad = 1.0 Hz), 7.57 (td, 1 H_c, J _bc = J _cd = 7.4 Hz, J _ac = 1.0 Hz), 7.52 (td, 1 H_b, J _ab = J _bc = 7.4 Hz, J _bd = 1.0 Hz), 5.72 (s, 1 H, OH), 4.50 (dt, 1 H, J = 13.0, 3.2 Hz, NCH₂), 3.71 (qd, 1 H, J = 10.8, 7.0 Hz, OCH₂CH₃), 3.56 (qd, 1 H, J = 10.8, 7.0 Hz, OCH₂CH₃), 3.42 (td, 1 H, J = 13.2, 3.2 Hz, NCH₂), 3.26 (td, 1 H, J = 13.2, 3.2 Hz, CH₂S), 2.53 (dt, 1 H, J = 13.0, 3.2 Hz, CH₂S), 1.79 (s, 1 H, CH₃), 0.83 (t, 3 H, J = 7.2 Hz, OCH₂CH₃). ^¹³C NMR: δ = 170.87 (C), 165,42 (C), 146.35 (C), 133.89 (C), 132.30 (C), 130.47 (CH), 124.15 (CH), 123.42 (CH), 86.36 (C), 61.51 (CH₂), 52.15 (C), 36.16 (CH₂), 27.16 (CH₂), 20.56 (CH₃), 13.73 (CH₃). IR: 3216 (OH), 1724 (C=O), 1664 cm^-¹. Anal. Calcd for C₁₅H₁₇NO₄S: C, 58.62; H, 5.58; N, 4.56. Found: C, 58.58; H, 5.61; N, 4.50. Mp 159-162 ˚C.
(1 R *,10b S *)-10b-Hydroxy-6-oxo-3,4,6,10b-tetrahydro-[1,4]oxazino[3,4- a ]isoindole-1-carbonitrile ( cis-2h)
^¹H NMR (acetone-d ₆): δ = 7.83 (d, 1 H_d, J _cd = 7.5 Hz), 7.78 (m, 2 H_a,c, J _ab = J _cd = J _bc = 7.5 Hz, J _ca = 1.0 Hz), 7.69 (td, 1 H_b, J _ab = J _bc = 7.5 Hz, J _bd = 1.0 Hz), 6.48 (s, 1 H, OH), 4.55 (s, 1 H, OCHCN), 4.10 (d, 1 H, J = 3.2 Hz, CH₂O), 4.09 (d, 1 H, J = 3.2 Hz, CH₂O), 3.57 (td, 1 H, J = 11.0, 2.5 Hz, NCH₂), 3.47 (td, 1 H, J = 11.0, 2.5 Hz, NCH₂). ^¹³C NMR (acetone-d ₆): δ = 164.8 (C), 144.1 (C), 133.3 (C), 132.7 (CH), 131.5 (CH), 124.2 (CH), 123.7 (CH), 116.4 (CN), 84.3 (C), 72.8 (CH), 67.4 (CH₂), 36.6 (CH₂). IR: 3408, 3204, 2972, 2884, 1672, 1472, 1432, 1072, 984, 748 cm^-¹. Raman: 3051.19, 3002.49, 2994.09, 2973.32, 2958.17, 2884.34, 2241.55 (CN), 1658.63, 1614.21, 1017.71, 681.26 cm^-¹. Anal. Calcd for C₁₂H₁₀N₂O₃: C, 62.60; H, 4.38; N, 12.17. Found: C, 62.42; H, 4.61, N, 12.00. Mp 203-205 ˚C.
(1 R *,10b R *)-10b-Hydroxy-6-oxo-3,4,6,10b-tetrahydro-[1,4]oxazino[3,4- a ]isoindole-1-carbonitrile ( trans -2h)
^¹H NMR (500 MHz, acetone-d ₆): δ = 7.80 (t, 2 H_a,d, J = 9.5 Hz), 7.73 (td, 1 H_c, J _cd = J _bc = 7.3 Hz, J _ac = 1.1 Hz), 7.67 (td, 1 H_b, J _ab = J _bc = 7.3 Hz, J _bd = 1.1 Hz), 6.12 (s, 1 H, OCHCN), 5.56 (s, 1 H, OH), 4.16 (dd, 1 H, J = 12.8, 3.2 Hz, CH₂O), 4.05 (dd, 1 H, J = 12.8, 4.6 Hz, CH₂O), 3.75 (td, 1 H, J = 12.2, 3.4 Hz, NCH₂), 3.53 (td, 1 H, J = 12.2, 4.6 Hz, NCH₂). ^¹³C NMR (acetone-d ₆): δ = 164.85 (C), 144.69 (C), 134.02 (CH), 133.34 (CH), 131.57 (CH), 124.12 (CH), 123.60 (CH), 115.09 (CN), 72.01 (CH), 67.37 (C), 63.02 (CH₂), 36.21 (CH₃). IR: 3252, 2936, 2868, 1680, 1468, 1420, 1084, 1008, 764 cm^-¹. Raman: 3092.65, 3064.30, 2996.36, 2946.16, 2926.05, 2879.35, 2253.97 (CN), 1663.58, 1614.90, 1442.67, 1191.88 cm^-¹. Anal. Calcd for C₁₂H₁₀N₂O₃: C, 62.60, H, 4.38; N, 12.17. Found: C, 62.61; H, 4.44; N, 12.19. Mp 216-217 ˚C. The crystallographic data (structure CCDC 665666) can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdb.cam.ac.uk/data_request/cif.
Methyl 3,4-Dihydro[1,4]oxazino-6-oxo[3,4- a ]isoindole-1-carboxylate (3a) ^¹H NMR: δ = 8.72 (dt, 1 H_d, J _cd = 7.6 Hz, J _bd = J _ad = 1.0 Hz), 7.90 (dt, 1 H_a, J _ab = 7.6 Hz, J _ac = J _ad = 1.0 Hz), 7.63 (td, 1 H_c, J _bc = J _cd = 7.6 Hz, J _ac = 1.0 Hz), 7.55 (td, 1 H_b, J _ab = J _bc = 7.6 Hz, J _bd = 1.0 Hz), 4.33 (t, 2 H, J = 4.8 Hz, CH₂O), 4.01-3.98 (t, 2 H, J = 4.8 Hz, NCH₂), 1.56 (s, 3 H, OCH₃). ^¹³C NMR: δ = 164.4 (C), 162.7 (C), 132.9 (C), 132.7 (CH), 129.6 (CH), 129.2 (C), 128.8 (C), 127.1 (C), 126.2 (CH), 123.4 (CH), 64.8 (CH₂), 52.5 (CH₃), 38.1 (CH₂). IR: 1719 (C=O), 1711, 1696, 1607 (C=C) cm^-¹. MS: m/z (%) = 186 (100), 245 (70) [M]⁺, 130 (44), 102 (27), 187 (13), 103 (12), 246 (10), 158 (10), 129 (9). Anal. Calcd for C₁₃H₁₁NO₄: C, 63.67; H, 4.52; N, 5.71. Found: C, 63.51; H, 4.68; N, 5.55. Mp 190-191 ˚C. Ethyl 3,4-Dihydro[1,4]thiazino-6-oxo[3,4- a ]isoindole-1-carboxylate (3f)
^¹H NMR: δ = 8.40 (d, 1 H_d, J _cd = 8.0 Hz), 7.85 (dt, 1 H_a, J _ab = 6.8 Hz, J _ac = 1.2 Hz, J _ad = 0.8 Hz), 7.58 (td, 1 H_c, J _bc = J _cd = 8.0 Hz, J _ac = 1.2 Hz), 7.50 (td, 1 H_b, J _ab = J _bc = 7.6 Hz, J _bd = 1.2 Hz), 4.40 (q, 2 H, J = 7.2 Hz, OCH₂CH₃), 4.17 (m, 2 H, NCH₂), 3.11 (m, 2 H, CH₂S), 1.41 (t, 3 H, J = 7.2 Hz, OCH₂CH₃). ^¹³C NMR: δ = 166.11 (C), 164.29 (C), 136.18 (C), 133.65 (C), 132.68 (CH), 129.65 (CH), 128.42 (CH), 125.49 (CH), 123.02 (CH), 114.30 (C), 62.14 (CH₂), 39.68 (CH₂), 25.68 (CH₂), 14.14 (CH₃). IR: 1704 (C=O), 1592 (C=C) cm^-¹. Anal. Calcd for C₁₄H₁₃NO₃S: C, 61.07; H, 4.76; N, 5.09. Found: C, 60.93; H, 4.68; N, 5.03. Mp 96-98 ˚C.
1-Cyano-3,4-dihydro[1,4]oxazino[3,4a]isoindolo-6-one (3h)
^¹H NMR: δ = 8.03 (d, 1 H_d, J _cd = 7.6 Hz), 7.90 (d, 1 H_a, J _ab = 7.6 Hz), 7.67 (td, 1 H_c, J _bc = J _cd = 7.6 Hz, J _ac = 0.8 Hz), 7.58 (t, 1 H_b, J _ab = J _bc = 7.6 Hz), 4.32 (t, 2 H, J = 4.8 Hz, CH₂O), 3.99 (t, 2 H, J = 4.8 Hz, NCH₂). ^¹³C NMR: δ = 165.45 (C), 132.93 (C), 132.34 (CH), 130.43 (C), 129.66 (CH), 128.65 (CH), 124.2 (CH), 121.44 (C), 114.0 (C), 110.42 (C), 65.87 (CH₂), 38.16 (CH₂). IR: 2220 (CºN), 1692 (C=O), 1656 (C=C), 1216 (C-O) cm^-¹. Anal. Calcd for C₁₂H₈N₂O₂: C, 67.94, H, 3.80, N, 13.20. Found: C, 67.84; H, 3.61; N, 13.05. Mp 133-134 ˚C.
1-Cyano-3,4-dihydro[1,4]thiazino[3,4a]isoindolo-6-one (3i)
^¹H NMR: δ = 8.35 (dt, 1 H_d, J _cd = 7.4 Hz, J _bd = J _ad = 0.8 Hz), 7.88 (dt, 1 H_a, J _cd = 7.4 Hz, J _bd = J _ad = 0.8 Hz), 7.67 (td, 1 H_c, J _bc = J _cd = 7.4 Hz, J _ac = 0.8 Hz), 7.58 (t, 1 H_b, J _ab = J _bc = 7.4 Hz), 4.32 (t, 2 H, J = 4.8 Hz, NCH₂), 3.99 (t, 2 H, J = 4.8 Hz, CH₂S). ^¹³C NMR: δ = 165.38 (C), 133.46 (C), 132.89 (CH), 130.87 (C), 130.46 (CH), 125.46 (CH), 123.78 (CH), 122.56 (C), 116.00 (C), 74.42 (C), 39.56 (CH₂), 26.17 (CH₂). IR: 2208 (CºN), 1708 (C=O), 1596 (C=C) cm^-¹. Anal. Calcd for C₁₂H₈N₂OS: C, 63.14; H, 3.53; N, 12.27. Found: C, 63.21; H, 3.61; N, 12.14. Mp 142-144 ˚C.

9

The synthesis of precursors 1a-i will be described separately, see: Wostowski, M.; Jańczewski, D.; Czarnocka, S.; Synoradzki, L. in preparation.