Synthesis of Novel 3-Oxopiperidin-2-ones from Methyl 2-Alkoxy-5-amino-2-pentenoates

Abstract

Alkylamino-substituted 2-alkoxy-2-pentenoates, obtained through ring transformation of 4-(1-chloro-1-methylethyl)- or 4-(2-halo-1,1-dimethylethyl)azetidin-2-ones upon treatment with sodium methoxide in methanol, have been evaluated as substrates for the cyclization towards pyrrolidines and piperidines. Thus, a convenient approach for the transformation of methyl 2-alkoxy-5-amino-4,4-dimethyl-2-pentenoates into 5,5-dimethyl-3-oxopiperidin-2-ones is described utilizing an excess of concentrated sulfuric acid.

β-lactams - azetidin-2-ones - 3-oxopiperidin-2-ones - ring closure - acid hydrolysis

References and Notes

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8

Representative Procedure; Synthesis of 1-Isopropyl-5,5-dimethylpiperidine-2,3-dione (6c): To (Z)-methyl 5-isopropylamino-2-methoxy-4,4-dimethyl-2-pentenoate (4c; 0.50 g, 2.2 mmol) [7] was added concd sulfuric acid (0.6 mL, 21.6 mmol) dropwise. The resulting homogeneous mixture was stirred at r.t. for 1 h and subsequently cooled to 0 ˚C. NaOH (1 M) was added cautiously dropwise until pH 10, the resulting aqueous phase was extracted with CH₂Cl₂ (3 × 5 mL) and the combined organic phases were dried (MgSO₄). After filtration and evaporation of the solvent, crude 5,5-dimethyl-1-isopropylpiperidine-2,3-dione (6c) was purified by filtration over silica gel using EtOAc.
1-Isopropyl-5,5-dimethylpiperidine-2,3-dione (6c): yield: 50%. ^¹H NMR (270 MHz, CDCl₃): δ = 1.13 (s, 6 H, C_qMe₂), 1.18 (d, J = 6.6 Hz, 6 H, CHMe ₂), 2.54 [s, 2 H, C(O)CH₂], 3.22 (s, 2 H, NCH₂C_q), 4.91 (sept, J = 6.6 Hz, 1 H, CHMe₂). ^¹³C NMR (68 MHz, CDCl₃): δ = 18.94 (CHMe ₂), 26.13 (C_q Me ₂), 32.04 (C _qMe₂), 45.00 (CHMe₂), 51.41 [C(O)CH₂], 52.16 (NCH₂C_q), 156.57, 191.84 (2 × C=O). IR (NaCl): 1726, 1658 (C=O) cm^-¹. MS (70 eV): m/z (%) = 183 (46) [M⁺], 168 (61) [M⁺ - Me], 154 (12), 140 (39), 126 (64), 112 (12), 99 (87), 98 (30), 97 (26), 85 (35), 84 (20), 83 (21), 77 (24), 72 (19), 71 (11), 70 (16), 69 (24), 59 (12), 58 (21), 57 (37), 56 (43), 55 (52). Anal. Calcd for C₁₀H₁₇NO₂: C, 65.54; H, 9.35; N, 7.64. Found: C, 65.43; H, 9.51; N, 7.53.

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14

Methyl 2-Hydroxy-4-isopropylamino-4-methyl-pentanoate (7a): yield: 86%; R _f 0.05 (CH₂Cl₂-MeOH, 19:1). ^¹H NMR (270 MHz, CDCl₃): δ = 1.09, 1.11 (2 × d, J = 6.3 Hz, 6 H, Me ₂CH), 1.19, 1.27 (2 × s, 6 H, C_qMe₂), 1.72 (d, J = 6.6 Hz, 2 H, C_qCH₂), 2.99 (sept, J = 6.3 Hz, 1 H, CHMe₂), 3.75 (s, 3 H, OMe), 4.58 (t, J = 6.6 Hz, 1 H, OCH). ^¹³C NMR (68 MHz, CDCl₃): δ = 24.21, 28.88 (C_q Me ₂), 25.79, 26.35 (CHMe ₂), 42.64 (NCH), 43.11 (CHCH₂), 51.59 (OMe), 54.32 (C _qMe₂), 69.52 (OCH), 174.39 (C=O). IR (NaCl): 3286, 1754 (OH, C=O) cm^-¹. MS (70 eV): m/z
(%) = no [M⁺], 201 (15), 188 (33) [M⁺ - Me], 186 (22), 171 (35), 170 (15), 156 (72), 144 (11), 138 (9), 128 (24), 115 (13), 114 (38), 102 (12), 100 (79), 99 (10), 98 (17), 96 (15), 86 (22), 85 (24), 84 (60), 83 (16), 74 (12), 72 (11), 71 (51), 70 (16), 68 (17), 58 (54), 57 (20), 56 (21), 55 (24).

15

1-Isopropyl-3-methoxy-5,5-dimethylpiperidin-2-one (12): yield: 80%; R _f 0.40 (hexane-EtOAc, 3:2). ^¹H NMR (270 MHz, CDCl₃): δ = 1.02, 1.05 (2 × s, 6 H, C_qMe₂), 1.04, 1.06 (2 × d, J = 6.9 Hz, 6 H, Me ₂CH), 1.62 [dd, J = 7.0, 13.0 Hz, 1 H, C_qCH(H)], 1.88 [dd, J = 8.0, 13.0 Hz, 1 H, C_qCH(H)], 2.79 [d, J = 12.0 Hz, 1 H, NCH(H)], 2.97 [d, J = 12.0 Hz, 1 H, NCH(H)], 3.57 (s, 3 H, OMe), 3.87 (dd, J = 8.0. 13.0 Hz, 1 H, OCH), 4.87 (sept, J = 6.9 Hz, 1 H, CHMe₂). ^¹³C NMR (68 MHz, CDCl₃): δ = 19.19, 19.43 (CHMe ₂), 26.04, 28.84 (C_q Me ₂), 29.92 (C _qCH₂), 40.65 (C_q CH₂), 43.41 (CHMe₂), 51.30 (NCH₂), 58.85 (OMe), 75.96 (OCH), 169.13 (C=O). IR (NaCl): 1646 (C=O) cm^-¹. MS (70 eV): m/z (%) = no [M⁺], 168 (100) [M⁺ - OMe], 155 (13), 153 (93), 140 (26), 139 (92), 138 (11), 125 (13), 123 (15), 112 (28), 111 (11), 98 (22), 97 (23), 85 (12), 84 (26), 83 (19), 82 (23), 81 (10), 80 (21), 72 (18), 70(11), 69 (10), 58 (24), 55 (37). Anal. Calcd for C₁₁H₂₁NO₂: C, 66.29; H, 10.62; N, 7.03. Found: C, 66.13; H, 10.80; N, 6.88.

16 Alcaide B. Almendros P. Cabrero G. Ruiz MP. J. Org. Chem.  2007,  72:  7980