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DOI: 10.1055/s-2008-1077970
Synthesis of Novel 3-Oxopiperidin-2-ones from Methyl 2-Alkoxy-5-amino-2-pentenoates
Publikationsverlauf
Publikationsdatum:
15. Juli 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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References and Notes
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.
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).
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.