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

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.

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

References

1 Commercially available 3-nitro propionic acid can be quantitatively converted into its methyl ester by treatment with Me₂C(OMe)₂ in MeOH in the presence of Me₃SiCl (10 mol%): Rodriguez A. Nomen M. Spur BW. Tetrahedron Lett.  1998,  39:  8563 

2 Preparation of 1: Ioffe SL. Lyapkalo IM. Tishkov AA. Danilenko VM. Strelenko YA. Tartakovsky VA. Tetrahedron  1997,  53:  13085 

3a Ioffe SL. Lyapkalo IM. Makarenkova LM. Russ. J. Org. Chem.  1998,  34:  1141 ; Russ. J. Org. Chem. (Engl. Transl.), 1998, 34, 1085

3b Tartakovsky VA. Ioffe SL. Dilman AD. Tishkov AA. Russ. Chem. Bull.  2001,  1850 ; Russ. Chem. Bull. (Engl. Transl.), 2001, 1936

4a Gilchrist TL. Chem. Soc. Rev.  1983,  12:  53 

4b Hippeli C. Reissig H.-U. Liebigs Ann. Chem.  1990,  217 

5a Chrystal EJT. Gilchrist TL. Stretch W. J. Chem. Res., Synop.  1987,  180 

5b Chrystal EJT. Gilchrist TL. Stretch W. J. Chem. Res., Miniprint  1987,  1563 

5c Henning R. Lerch U. Urbach H. Synthesis  1989,  265 

5d Hippeli C. Reissig H.-U. Liebigs Ann. Chem.  1990,  475 

6a Shatzmiller S. Shalom E. Liebigs Ann. Chem.  1983,  897 

6b Faragher R. Gilchrist TL. J. Chem. Soc., Perkin Trans. 1  1979,  258 

Recent advances in the chemistry of 1-azabutadienes are surveyed in the following publications:

7a Tietze LF. Kettschau G. Top. Curr. Chem.  1997,  189:  1 

7b Ishar MPS. Jayakumar S. Mahajan MP. Tetrahedron  2002,  58:  379 

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 R_f), 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 (m_c, 1 H, OCH₂), 3.72 (s, 3 H, OMe), 3.54 (m_c, 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 R_f), 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 (m_c, 1 H, OCH₂), 3.69 (s, 3 H, OMe), 3.47 (m_c, 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 (m_c, 1 H, OCH₂), 3.61 (s, 3 H, OMe), 3.57 (m_c, 1 H, OCH₂), 2.55 (m_c, 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 (m_c, 1 H, 5-H), 3.57 (s, 3 H, OMe), 3.51 (m_c, 1 H, 5-H), 3.34 (d, J = 11.0 Hz, 1 H, 2-H), 2.33 (m_c, 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.

The [4+2]-cycloreversion of 1,2-oxazines of compounds which are structurally similar to 3 is known:

11a Goldberg I. Saad D. Shalom E. Shatzmiller S. J. Org. Chem.  1982,  47:  2192 

11b

see also ref. [2] [6a]

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 (m_c, 2 H, OCH₂), 2.38, 2.05 (2 m_c, 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 (m_c, 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.

15a Michael JP. Nat. Prod. Rep.  1994,  11:  17 

15b Howard AS. Michael JP. In The Alkaloids   Vol. 28:  Brossi A. Academic Press; New York: 1986.  p.183 

A similar approach to the synthesis of indolizines and quinolizines by intramolecular trapping of 1-aza-1,3-butadienes has been previously applied:

16a Jung ME. Choi YM. J. Org. Chem.  1991,  56:  6729 

16b Cheng Y.-S. Fowler FW. Lupo AT. J. Am. Chem. Soc.  1981,  103:  2090 

16c Uyehara T. Suzuki I. Yamamoto Y. Tetrahedron Lett.  1990,  31:  3753 

16d Potts D. Stevenson PJ. Thompson N. Tetrahedron Lett.  2000,  41:  275 

16e Hwang YC. Fowler FW. J. Org. Chem.  1985,  50:  2719 

16f Motorina IA. Grierson DS. Tetrahedron Lett.  1999,  40:  7215