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Synlett 2008(13): 1961-1964  
DOI: 10.1055/s-2008-1077970
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Yves Dejaegher, Matthias D’hooghe, Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
Fax: +32(9)2646243; e-Mail: norbert.dekimpe@UGent.be;
Further Information

Publication History

Received 5 May 2008
Publication Date:
15 July 2008 (online)

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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.

Keywords

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

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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, CqMe2), 1.18 (d, J = 6.6 Hz, 6 H, CHMe 2), 2.54 [s, 2 H, C(O)CH2], 3.22 (s, 2 H, NCH2Cq), 4.91 (sept, J = 6.6 Hz, 1 H, CHMe2). ¹³C NMR (68 MHz, CDCl3): δ = 18.94 (CHMe 2), 26.13 (Cq Me 2), 32.04 (C qMe2), 45.00 (CHMe2), 51.41 [C(O)CH2], 52.16 (NCH2Cq), 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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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, CqMe2), 1.72 (d, J = 6.6 Hz, 2 H, CqCH2), 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 (Cq 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).

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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, CqMe2), 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, CqCH(H)], 1.88 [dd, J = 8.0, 13.0 Hz, 1 H, CqCH(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 (Cq Me 2), 29.92 (C qCH2), 40.65 (Cq 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.