Synthesis of Tropinones by Cyclization of 1,3-Bis-Silyl Enol Ethers with ­Iminium Triflates

Abstract

Tropinone derivatives were prepared by cyclization of 1,3-bis-silyl enol ethers with iminium salts.

cyclizations - iminium salts - Lewis acids - silyl enol ethers - tropinones

References

1a Isomura S. Hofman TZ. Wirsching P. Janda KD. J. Am. Chem. Soc.  1981,  103:  1172 ; and references cited therein

1b Lounasmaa M. Tamminen T. Alkaloids  1993,  44:  1 

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2 Willstätter R. Ber. Dtsch. Chem. Ges.  1901,  34:  129 

For the reaction of silyl enol ethers with 2a, see:

3a Shono T. Matsumura Y. Tsubata K. J. Am. Chem. Soc.  1981,  103:  1172 

3b Hernández AS. Thaler A. Castells J. Rapoport H. J. Org. Chem.  1996,  61:  314 

3c Gauthier I. Royer J. Husson H.-P. J. Org. Chem.  1997,  62:  6704 

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4b Hayakawa Y. Baba Y. Makino S. Noyori R. J. Am. Chem. Soc.  1978,  100:  1786 

4c Rigby JH. Pigge FC. J. Org. Chem.  1995,  60:  7392 

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5 Robinson R. J. Chem. Soc.  1917,  762 

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9a Langer P. Chem.-Eur. J.  2001,  7:  3858 

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10

Synthesis of Methyl 2-(3-Methoxycarbonyl-2-oxo-propyl)-pyrrolidine-1-carboxylate (3a): To a CH₂Cl₂ solution (20 mL) of 2c (0.165 g, 1.04 mmol) was added TMSOTf (0.227 g, 1.25 mmol) at -78 °C. After stirring for 5 min, 1a (0.306 g, 1.25 mmol) was added and the solution was warmed to ambient temperature during 12 h. After stirring for 2 h, an aq solution of HCl acid (10%, 10 mL) was added. The organic and the aq layers were separated and the latter was extracted with Et₂O (3 × 100 mL) and CH₂Cl₂ (100 mL). The combined organic layers were dried (MgSO₄), filtered and concentrated. The residue was purified by chromatography (silica gel, Et₂O) to give 3a as a colorless oil (0.152 g, 65%). ¹H NMR (250 MHz, CDCl₃): δ = 1.59-1.70 (m, 1 H, CH₂), 1.79-1.93 (m, 3 H, CH₂), 2.03-2.17 (m, 1 H, CH₂), 2.53-2.63 (m, 1 H), 3.55-3.58 (m, 4 H, NCH₂, CH ₂CO₂CH₃), 3.65 (s, 3 H, NCO₂CH₃), 3.71 (s, 3 H, OCH₃), 4.12-4.22 (m, 1 H, 2-H). ¹³C NMR (62.9 MHz, CDCl₃): δ = 23.60, 30.96, 36.31, 46.32, 49.15 (CH₂), 52.22, 52.29 (OCH₃), 53.77 (CH), 155.22 (NCO₂CH₃), 167.52 (CO₂CH₃), 201.12 (CO). IR (neat): 2597 (s), 2880 (w), 1750 (s), 1695 (s), 1454 (s), 1383 (s), 1317 (s), 1260 (s), 1189 (s), 1118 (s)cm^-1. MS (EI, 70 eV): m/z (%) = 243 (2) [M⁺], 212 (4), 200 (7), 184 (12), 168 (10), 128 (100). HRMS (EI, 70 eV): m/z [M⁺] calcd for C₁₁H₁₇NO₅ = 243.1107 ± 2 mD. All new compounds gave satisfactory spectroscopic and analytical and/or HRMS data.

Compounds 4a,b were prepared by anodic oxidation:

11a Shono T. Matsumura Y. Tsubata K. Sugihara Y. Yamane S.-I. J. Am. Chem. Soc.  1982,  104:  6697 

11b For the reaction with trimethylallylsilane, see: Shono T. Matsumura Y. Uchida K. Kobayashi H. J. Org. Chem.  1985,  3243 

11c For the reaction with a silyl enol ether, see: Shono T. Matsumura Y. Uchida K. Tagami K. Chem. Lett.  1987,  919 

12

Typical Procedure for the Preparation of Tropinones 5 : To a CH₂Cl₂ solution (15 mL) of 4a (0.567 g, 3.0 mmol) were added 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene (0.520 g, 2.0 mmol) and TMSOTf (0.130 g, 0.6 mmol) at
-78 °C. After warming to r.t. within 16 h, a sat. aq solution of NaHCO₃ was added. The organic and the aqueous layers were separated and the latter was extracted with CH₂Cl₂ (3 × 50 mL). The combined organic layers were dried (Na₂SO₄), filtered and the solvent was removed in vacuo. The residue was purified by column chromatography (silica gel, hexane-Et₂O = 4:1) to give 5a (185 mg, 38%) as a colorless oil. IR (KBr): 3247 (w), 3201 (w), 2956 (s), 1748 (s), 1706 (s), 1673 (s), 1615 (s), 1483 (m), 1448 (s) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.62-1.69 (m, 1 H, CH₂), 1.90 (m, 1 H, CH₂), 1.97-2.05 (m, 1 H, CH₂), 2.07-2.23 (m, 1 H, CH₂), 2.90 (d, J = 19 Hz, 1 H, CH₂), 3.30-3.38 (m, 1 H, CH₂), 3.67-3.70 (2 × s, 3 H, keto-enol, OCH₃), 3.70 (m, 1 H, CH, keto), 3.73-3.77 (2 × s, 3 H, keto-enol, OCH₃), 4.42-4.51 (m, 1 H, CH), 4.97-5.01 (m, 1 H, CH), 10.81 (s, OH, enol). ¹³C NMR (75 MHz, CDCl₃, keto/enol = 2:1): δ = 28.69, 28.70, 29.51, 29.52, 35.28, 36.39 (CH₂), 51.09, 51.10 (OCH₃), 51.49, 51.95 (CH), 52.54, 52.55 (OCH₃), 54.16, 55.78 (CH), 62.92 (CH, keto), 107.86 (C, enol), 153.06, 154.03 (C), 167.72, 167.73 (CO), 173.02 (enol), 203.22 (CO, keto). MS (EI, 70 eV): m/z (%) = 241 (8) [M⁺], 226 (28), 182 (100). Anal. Calcd for C₁₁H₁₅NO₅ (241.24): C, 54.77; H, 6.27; N, 5.80. Found: C, 54.52; H, 6.40; N, 5.66.

13a Brownbridge P. Chan TH. Tetrahedron Lett.  1979,  4437 

13b Lee SD. Chan TH. Tetrahedron  1984,  40:  3611