LETTER
Preparation of Cyclic and Bicyclic -Amino Acids Derivatives
865
30 °C (Et2O/hexane): 1H NMR (CDCl3, 270 MHz): = 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):
= 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.
Acknowledgement
We are very grateful to the Deutsche Akademische Austauschdienst
for a fellowship for A.A.T. We also thank the Fonds der Chemi-
schen Industrie and Schering AG for generous support and Dr. I. M.
Lyapkalo for help during preparation of the manuscript.
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, B. W.
(9) General Procedures for Acylation with Na2CO3 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
Tetrahedron Lett. 1998, 39, 8563.
(2) Preparation of 1: Ioffe, S. L.; Lyapkalo, I. M.; Tishkov, A.
A.; Danilenko, V. M.; Strelenko, Y. A.; Tartakovsky, V. A.
Tetrahedron 1997, 53, 13085.
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): = 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):
= 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): = 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):
= 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): = 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.
(3) (a) Ioffe, S. L.; Lyapkalo, I. M.; Makarenkova, L. M. Russ.
J. Org. Chem. 1998, 34, 1141; Russ. J. Org. Chem. (Engl.
Transl.), 1998, 34, 1085. (b) Tartakovsky, V. A.; Ioffe, S.
L.; Dilman, A. D.; Tishkov, A. A. Russ. Chem. Bull. 2001,
1850; Russ. Chem. Bull. (Engl. Transl.), 2001, 1936.
(4) (a) Gilchrist, T. L. Chem. Soc. Rev. 1983, 12, 53.
(b) Hippeli, C.; Reissig, H.-U. Liebigs Ann. Chem. 1990,
217.
(5) (a) Chrystal, E. J. T.; Gilchrist, T. L.; Stretch, W. J. Chem.
Res., Synop. 1987, 180. (b) Chrystal, E. J. T.; Gilchrist, T.
L.; Stretch, W. J. Chem. Res., Miniprint 1987, 1563.
(c) Henning, R.; Lerch, U.; Urbach, H. Synthesis 1989, 265.
(d) Hippeli, C.; Reissig, H.-U. Liebigs Ann. Chem. 1990,
475.
(6) (a) Shatzmiller, S.; Shalom, E. Liebigs Ann. Chem. 1983,
897. (b) Faragher, R.; Gilchrist, T. L. J. Chem. Soc., Perkin
Trans. 1 1979, 258.
(7) Recent advances in the chemistry of 1-azabutadienes are
surveyed in the following publications: (a) Tietze, L. F.;
Kettschau, G. Top. Curr. Chem. 1997, 189, 1. (b) Ishar, M.
P. S.; Jayakumar, S.; Mahajan, M. P. 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 Rf), colorless oil: 1H NMR (CDCl3, 270
MHz): = 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): = 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–
Synlett 2002, No. 6, 863–866 ISSN 0936-5214 © Thieme Stuttgart · New York