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Synlett 2002(6): 0863-0866
DOI: 10.1055/s-2002-31908
LETTER
© Georg Thieme Verlag Stuttgart · New York

Preparation of Cyclic and Bicyclic β-Amino Acids Derivatives from Methyl 6-Ethoxy-5,6-dihydro-4H-1,2-oxazine-4-carboxylate

Alexander A. Tishkova,b, Hans-Ulrich Reissig*a, Sema L. Ioffeb
a Freie Universität Berlin, Institut für Chemie - Organische Chemie, Takustr. 3, 14195 Berlin, Germany
b N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prosp. 47, 117913 Moscow, Russian Federation
Fax: +49(30)83855367; e-Mail: hans.reissig@chemie.fu-berlin.de;
Further Information

Publication History

Received 6 March 2002
Publication Date:
07 February 2007 (online)

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Abstract

The readily available methyl 6-ethoxy-5,6-dihydro-4H-1,2-oxazine-4-carboxylate (1) was alkylated at C-4 and acylated at the nitrogen atom. 1,2-Oxazine 1 and the resulting new substituted 1,2-oxazines 2 and 3 were suitable precursors for the preparation of derivatives of β-proline, nipecotic acid, as well as indolizine-6- and quinolizine-3-carboxylic acids.

Key words

β-amino acids - 1,2-oxazines - Diels-Alder reaction - alkylation - acylation

    References

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8

General Procedure for Alkylation and Acylation via Deprotonation: 1,2-Oxazine 1 (375 mg, 2.00 mmol) in THF (4 mL) was added to a stirred solution of LiHMDS (2.4 mL of 1 M solution in THF, 2.4 mmol) or KHMDS (4.8 mL
of 0.5 M solution in toluene, 2.4 mmol) in THF (4 mL) at
-78 °C. After being stirred for 10 min the alkyl iodide (3.0 mmol) was added neat via syringe and the reaction mixture was maintained under conditions as indicated in Table 1. Then Et2O and sat. aq NH4Cl solution were added and the organic layer was separated. The water phase was extracted with Et2O and the combined organic layers were washed with H2O and brine, dried over MgSO4 and evaporated in vacuum. The residue was subjected to column chromatography (silica gel, hexane/EtOAc 3:1) to give analytically pure products. Analytical data of 2a, major isomer (higher Rf), colorless oil: 1H NMR (CDCl3, 270 MHz): δ = 7.32 (br s, 1 H, 3-H), 4.97 (ddd, J = 5.1, 3.2, 0.9 Hz, 1 H, 6-H), 3.87 (mc, 1 H, OCH2), 3.72 (s, 3 H, OMe), 3.54 (mc, 1 H, OCH2), 2.49 (dd, J = 13.7, 2.9 Hz, 1 H, 5-H), 1.82 (ddd, J = 13.7, 5.1, 1.0 Hz, 1 H, 5-H), 1.46 (s, 3 H, 4-Me), 1.18 (t, J = 7.1 Hz, 3 H, Me); 13C NMR (CDCl3, 67.9 MHz): δ = 173.5 (s, C=O), 151.0 (d, C-3), 96.6 (d, C-6), 64.8 (t, OCH2), 53.1 (q, MeO), 40.0 (s, C-4), 33.6 (t, C-5), 24.1 (q, 4-Me), 15.5 (q, Me); MS (pos. FAB): m/z (%) = 202(100) [M+ + 1], 69(41), 55(54), 41(53). Anal. Calcd for C9H15NO4 (201.2): C, 53.72; H, 7.51; N, 6.96. Found: C, 53.21; H, 7.30; N, 6.68. Minor isomer (lower Rf), colorless crystals, mp 29-30 °C (Et2O/hexane): 1H NMR (CDCl3, 270 MHz): δ = 7.36 (dd, J = 2.3, 2.0 Hz, 1 H, 3-H), 5.08 (ddd, J = 2.4, 2.3, 2.0 Hz, 1 H, 6-H), 3.73 (mc, 1 H, OCH2), 3.69 (s, 3 H, OMe), 3.47 (mc, 1 H, OCH2), 2.70 (dt, J = 13.7, 2.3 Hz, 1 H, 5-H), 1.70 (dd, J = 13.7, 2.4 Hz, 1 H, 5-H), 1.33 (s, 3 H, 4-Me), 1.09 (t, J = 7.0 Hz, 3 H, Me); 13C NMR (CDCl3, 67.9 MHz): δ = 174.0 (s, C=O), 151.8 (d, C-3), 94.6 (d, C-6), 63.3 (t, OCH2), 52.6 (q, MeO), 36.1 (s, C-4), 33.7 (t, C-5), 24.5 (q, 4-Me), 15.0 (q, Me); MS (pos. FAB): m/z (%) = 202(100) [M+ + 1], 157(21), 69(43), 55(55), 41(48). Anal. Calcd for C9H15NO4 (201.2): C, 53.72; H, 7.51; N, 6.96. Found: C, 53.64; H, 7.45; N, 6.90.

9

General Procedures for Acylation with Na 2 CO 3 as a Base: The acyl chloride (1.3 equiv) was added at 0 °C to a stirred suspension of dry Na2CO3 (3 equiv) in a solution of 1,2-oxazine (1 equiv) in CH2Cl2 (5 mL to 1 mmol of oxazine). After being stirred for 10 min at 0 °C, the temperature was increased to ambient, the reaction mixture was stirred for additional 30 min and filtered. The filtrate was evaporated in vacuum to remove the excess of acyl chloride and subjected to column chromatography (silica gel, hexane/EtOAc 3:1) to give analytically pure products. Analytical data of 3c, colorless oil: 1H NMR (CDCl3, 270 MHz): δ = 8.18 (br s, 1 H, 3-H), 5.73 (ddt, J = 17.0, 10.1,
6.5 Hz, 1 H, =CH), 5.08 (t, J = 3.6 Hz, 1 H, 6-H), 4.95 (dq, J = 17.0, 1.4 Hz, 1 H, =CH2), 4.89 (dq, J = 10.1, 1.5 Hz, 1 H, =CH2), 3.76 (mc, 1 H, OCH2), 3.61 (s, 3 H, OMe), 3.57 (mc, 1 H, OCH2), 2.55 (mc, 3 H, 5-H, CH2), 2.39 (ddd, J = 17.2, 3.1, 1.3 Hz, 1 H, 5-H), 2.30 (q, J = 6.5 Hz, 2 H, CH2), 1.12 (t, J = 7.1 Hz, 3 H, Me); 13C NMR (CDCl3, 67.9 MHz): δ = 169.3, 166.7 (2 s, 2 C=O), 136.8 (d, =CH), 129.4 (d, C-3), 115.8 (t, =CH2), 104.2 (s, C-4), 100.2 (d, C-6), 65.6 (t, OCH2), 51.7 (q, MeO), 31.7 (t, CH2), 28.6 (t, C-5), 28.1 (t, CH2), 15.1 (q, Me); MS (EI, 80 eV): m/z (%) = 269(42) [M+], 187(100) [M+ - CH2=CHCH2CH=C=O], 155(71), 141(24), 83(19). Anal. Calcd for C13H19NO5 (269.3): C, 57.98; H, 7.11; N, 5.20. Found: C, 58.29; H, 6.96; N, 5.07.

10

General Procedure for Reduction with Raney-nickel: A commercially available 50% water suspension of Raney-nickel (ca. 7 mL to 1 mmol of 1,2-oxazine) was washed 3 times with methanol, fresh methanol (10 mL to 1 mmol of 1,2-oxazine) was placed in the flask and Boc2O (1.2 equiv) was added. After H2 was bubbled for 20 min through the resulting suspension, a solution of 1,2-oxazine (1 equiv) in methanol (3 mL to 1 mmol of 1,2-oxazine) was added and the mixture was stirred under H2 atmosphere for 24 h at ambient temperature. Then the catalyst was filtered off through Celite, the filtrate was evaporated and the residue was subjected to column chromatography (silica gel, hexane/EtOAc 3 1) to give analytically pure products. Analytical data of 4b, colorless oil: 1H NMR (C6D5CD3, 500 MHz, 363 K): δ = 4.03 (d, J = 11.0 Hz, 1 H, 2-H), 3.58 (mc, 1 H, 5-H), 3.57 (s, 3 H, OMe), 3.51 (mc, 1 H, 5-H), 3.34 (d, J = 11.0 Hz, 1 H, 2-H), 2.33 (mc, 1 H, 4-H), 1.67 (s, 9 H, CMe3), 1.62 (ddd, J = 12.5, 6.0, 1.3 Hz, 1 H, 4-H), 1.31 (s, 3 H, 3-Me); 13C NMR (C6D5CD3, 125.8 MHz, 363 K): δ = 175.5 (s, 3-C=O), 154.4 (s, 1-C=O), 79.0, 28.9 (s, q, OCMe3), 55.9 (t, C-2), 51.6 (q, OMe), 48.8 (s, C-3), 45.4 (t, C-5), 36.2 (t, C-4), 22.5 (q, 3-Me); IR (Film): ν = 2975 (C-H), 2955 (C-H), 2930 (C-H), 1735 (C=O), 1700 (C=O), 1455, 1400, 1165, 1140, 1100 cm-1; MS (EI, 80 eV): m/z (%) = 243(3) [M+], 186(19) [M+ - CMe3], 170(11) [M+ - Me3CO], 142(21), 128(12), 115(11), 84(14), 57(100), 43(45). Anal. calcd for C12H21NO4 (243.3): C, 59.24; H, 8.70; N, 5.76. Found: C, 59.34; H, 8.62; N, 5.60.

12

General Procedure for Intermolecular Trapping of 1-Azabutadiene A: A solution of 1,2-oxazines (1.00 mmol) and n-butyl vinyl ether (1.94 mL, 15.0 mmol) in toluene (50 mL) was refluxed for 1.5 h (for 3a) or 4 h (for 3b), cooled down to ambient temperature and evaporated. The residue was subjected to column chromatography (silica gel, hexane/EtOAc 3:1) to give analytically pure products. Analytical data of 6a, colorless oil: 1H NMR (CDCl3, 270 MHz): δ = 7.69 (br s, 1 H, 2-H), 5.83 (br s, 1 H, 6-H), 3.73 (s, 3 H, OMe), 3.50 (mc, 2 H, OCH2), 2.38, 2.05 (2 mc, 4 H, 4-H, 5-H), 2.30 (s, 3 H, 1-Ac), 1.59-1.20 (m, 4 H, 2 CH2), 0.85 (t, J = 7.3 Hz, 3 H, Me); 13C NMR (CDCl3, 67.9 MHz): δ = 170.1, 167.9 (2 s, C=O), 133.7 (d, C-2), 110.8 (s, C-3), 76.4 (d, C-6), 68.7 (t, OCH2), 51.9 (q, MeO), 32.0, 25.8 (2 t, C-4, C-5), 22.1 (q, 1-Me), 19.6, 16.9 (2 t, 2 CH2), 14.1 (q, 6-Me); MS (EI, 80 eV): m/z (%) = 255(42) [M+], 212(79) [M+ - Ac], 156(37), 140(100), 139(89), 138(48), 124(63). Anal. Calcd for C13H21NO4 (255.3): C, 61.16; H, 8.29; N, 5.49; Found: C, 60.98; H, 8.04; N, 5.57.

13

General Procedure for Intramolecular Trapping of 1-Azabutadiene A: A solution of 1,2-oxazines 3c,d (0.50 mmol) in toluene (18 mL) was refluxed for 40 min, cooled down to r.t. and evaporated in vacuum. The residue was subjected to chromatography (silica gel, hexane/EtOAc 1:2) and additionally recrystallized from hexane/toluene to give pure products. Analytical data of 7a, colorless crystals [mp 142-143 °C (hexane/toluene)]: 1H NMR (CDCl3, 270 MHz): δ = 7.91 (br s, 1 H, 5-H), 3.72 (s, 3 H, OMe), 3.68 (mc, 1 H, 8a-H), 2.67-2.14 (m, 6 H, 7-H, 8-H, 9-H, 10-H), 1.81-1.61, 1.51-1.32 (2 m, 2 H, 9-H, 8-H); 13C NMR (CDCl3, 67.9 MHz): δ = 172.9, 168.1 (2 s, C=O), 130.7 (d, C-5), 110.9 (s, C-6), 55.7 (d, C-8a), 51.7 (q, MeO), 31.7 (t, C-2), 28.0, 26.8, 22.3 (3 t, C-1, C-7, C-8); MS (EI, 80 eV): m/z (%) = 195(100) [M+], 164(64) [M+ - MeO], 140(42), 136(52), 108(17). Anal. Calcd for C10H13NO3 (195.2): C, 61.53; H, 6.71; N, 7.17. Found: C, 61.39; H, 6.71; N, 7.03.

14

Even very slow addition of the diluted solution of 3e into a large volume of boiling toluene did not lead to formation of a detectable amount of the expected bicyclic compound 7c; instead, unidentifiable products of high molecular mass were isolated.