Synthesis of Novel Isochromene Derivatives by Tandem Ugi Reaction/Nucleophilic Substitution

Abstract

Unprecedented 3-amino-4-amido-1H-isochromenes have been prepared in three steps from protected ortho-(hydroxy­methyl)benzaldehyde, with the introduction of three diversity inputs, through a Ugi reaction followed by intramolecular nucleophilic substitution.

Key words

multicomponent reactions - heterocycles - iso­chromenes - enzymatic acylation - nucleophilic substitutions

References and Notes

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14

The aldehyde derived from oxidation of monoacetate 6 could not be used for the preparation of alcohols 10, because acetyl removal after the Ugi reaction brought about cyclization to the phthalide derivatives with elimination of R^¹NH₂

17

12a and 12b were stable enough to be purified by chromatography and characterized by NMR. However, compound 12a, upon GC-MS analysis, gave a peak corresponding to the cyclized products 13a.

18

Interestingly, treatment of either 11a,b or 12a,b with strong bases (NaH, t-BuOK, LiHMDS) failed to afford any cyclization product. Buffered thermal conditions were needed for this cyclization to occur. In the one-pot procedure (Method A), Et₃NH⁺Cl^- was already present in the crude chloride, whereas, in the two-step process (Method B), a triethylammonium salt had to be added.

19

In compounds 13, the protons of all CH₂ groups, which should be enantiotopic since there are no stereogenic centres, behave as if they were diastereotopic instead. A partial coalescence of these non-isochronous protons was observed only at 130 ˚C. This phenomenon is likely due to restricted rotation around the C4-N bond, which generates axial chirality.

20

Typical experimental procedure: cyclization of 10h to give 13h. A solution of alcohol 10h (0.50 mmol) in anhydrous CH₂Cl₂ (3.5 mL) was cooled to -15 ˚C, and treated with Et₃N (153 µL, 1.1 mmol) and methanesulfonyl chloride (46 µL, 0.60 mmol). After 1 h, the cooling bath was removed and Et₃N (139 µL, 1.0 mmol) was added. After stirring for 1 h at r.t., the solvent was removed under reduced pressure. The residue was taken up in anhydrous DMF (6.5 mL), treated with Et₃N (139 µL, 1.0 mmol) and TBAI (92 mg, 0.25 mmol), and stirred at 100 ˚C for 2 h. After cooling, the mixture was treated with sat. aq NH₄Cl (25 mL) and H₂O (25 mL) and extracted with EtOAc. The organic phases were washed with sat. aq NaCl, evaporated, and purified by chromatography (PE-EtOAc, 85:15) to give pure 13h. R _f = 0.69 (PE-acetone, 70:30). ^¹H NMR (CDCl₃):^¹9 δ = 7.45-7.35 (m, 2 H, ArH), 7.33-7.25 (m, 3 H, ArH), 7.21 (dt, J _d = 1.2 , J _t = 7.5 Hz, 1 H, H-7), 7.02 (d, J = 7.2 Hz, 1 H, H-9), 6.96 (dt, J _d = 0.9, J _t = 7.3 Hz, 1 H, H-8), 6.65 (d, J = 7.8 Hz, 1 H, H-6), 5.62 (d, J = 13.2 Hz, 1 H, CHHPh), 5.03 and 4.90 (AB system, J = 12.6 Hz, 2 H, H-1), 3.71 (d, J = 13.5 Hz, 1 H, CHHPh), 3.39 (d, J = 8.4 Hz, 1 H, HN), 3.03 (dtt, J _t = 4.0, 11.5, J _d = 8.0 Hz, 1 H, CHNH), 2.24 (q, J = 7.2 Hz, 2 H, CH ₂CH₃), 1.75-1.40 (m, 4 H, c-Hex_eq CHH), 1.30 (m, 1 H, eq. CHH of c-Hex), 1.13 (tq, J _t = 3.1 Hz, J _q = 12.9 Hz, 1 H, axial CH₂CHHCH₂), 1.13-1.02 (m, 1 H, axial CH₂CHHCH₂), 1.08 (t, J = 7.2 Hz, 3 H, CH ₃CH₂), 0.94 (tq, J _t = 3.0 Hz, J _q = 12.3 Hz, 1 H, axial CH₂CHHCH₂), 0.71 (dq, J _d = 3.3 Hz, J _q = 11.7 Hz, 1 H, axial CH-CHH-CH₂), 0.22 (dq, J _d = 3.3 Hz, J _q = 11.8 Hz, 1 H, axial CH-CHH-CH₂). ^¹³C NMR (CDCl₃): δ (attribution of signals was made with the aid of HSQC and HMBC experiments) = 177.4 (C=O), 155.1 (C-3), 139.3 (quarternary C of benzyl), 133.0 (C-5), 129.7 (×2), 128.8 (×2), 127.7 (CH of benzyl), 128.8 (C-7), 124.3 (C-10), 123.8 (C-9), 122.5 (C-8), 116.0 (C-6), 93.4 (C-4), 69.2 (C-1), 50.7 (CH₂Ph), 50.7 (CHN), 34.3, 33.1, 25.6, 25.1, 24.9 (c-Hex CH₂), 25.9 (CH₂CH₃), 9.6 (CH₃). HRMS (EI): m/z [M]⁺ calcd for C₂₅H₃₀N₂O₂: 390.2307; found: 390.2235. GC-MS: m/z (%) = 390 (41.1) [M]⁺, 334 (5.9), 333 (8.2), 299 (71.5), 243 (63.1), 207 (10.4), 206 (8.5), 161 (35.9), 144 (27.6), 143 (4.8), 118 (18.6), 117 (14.0), 116 (19.3), 106 (5.1), 91 (100.0), 89 (8.7), 65 (9.6), 57 (20.7), 55 (19.5), 41 (13.6). IR (CHCl₃): 3399, 3012, 2924, 2850, 1625, 1594, 1569, 1447, 1397, 1362, 1347, 1226, 1097, 1073, 917 cm^-¹.

21

A pure dry sample of 13a (87.5 mg) was left for 5 days in an open flask on the bench at r.t. After this time, TLC showed that it had completely decomposed, giving a new main spot on the TLC plate. This was isolated by chromatography (PE-acetone, 85:15→70:30). R _f = 0.46 (PE-acetone, 75:25). Yield: 45.5 mg (48%). ^¹H NMR (CDCl₃): δ = 7.54-7.43 (m, 2 H), 7.41-7.30 (m, 2 H), 5.22 (s, 2 H, CH ₂O), 4.72 (br t, 1 H, NH), 3.58 (d, J = 7.5 Hz, 2 H, CH ₂-iPr), 3.16 (q, J = 6.7 Hz, 2 H, CH ₂NH), 2.44 (q, J = 7.4 Hz, 2 H, O=CCH ₂CH₃), 2.00 [nonuplet, J = 6.8 Hz, 1 H, CH(CH₃)₂], 1.48 (quint., J = 7.0 Hz, 2 H, NCH₂CH ₂), 1.38-1.24 (m, 4 H, CH ₂CH ₂CH₃), 1.05 (t, J = 7.4 Hz, 3 H, CH ₃CH₂), 0.89 [t (covered by the d at 0.88), J = 7.2 Hz, 3 H, CH ₃CH₂CH₂], 0.88 [d, J = 6.8 Hz, 6 H, (CH ₃)₂CH]. ^¹³C NMR (CDCL₃): δ (attribution was made also by HSQC and HMBC) = 177.9 (O=CCH₂), 173.3 (CCON), 155.9 (OCON), 135.7, 135.2 (C-1, C-2), 131.0, 129.7, 128.1, 127.6 (C-3, C-4, C-5, C-6), 63.9 (CH₂O), 52.7 (CH₂ of isobutyl), 41.1 (NHCH₂), 32.0 (O=CCH₂CH₃), 29.6 (NCH₂ CH₂), 28.8 (NCH₂CH₂ CH₂), 28.2 [CH(CH₃)₂], 22.3 (CCH₂CH₃), 20.2 [(CH₃)₂CH], 14.0 (CH₃CH₂C), 9.7 (CH₃CH₂CO). HMRS (EI): m/z [M]⁺ C₂₁H₃₂N₂O₄: 376.2362; found: 376.2375. GC-MS: m/z (%) = 376 (0.3) [M]⁺, 347 (5.6), 232 (11.4), 189 (4.0), 146 (19.5), 135 (100.0), 134 (60.1), 133 (9.9), 130 (16.3), 118 (24.4), 105 (6.8), 91 (6.7), 90 (8.3), 86 (12.4), 77 (5.9), 74 (10.5), 57 (25.6), 56 (13.0), 43 (9.9), 41 (9.4). IR (CHCl₃): 3445, 2952, 2867, 1709 (s), 1654 (s), 1602, 1461, 1359, 1326, 1183, 1117, 1047 cm^-¹.