1352
A. Stehl et al. / Tetrahedron 58 ,2002) 1343±1354
procedure fromenol ether ,S)-12 )502 mg, 2.34 mmol) and
tetrazine 7a )222 mg, 2.71 mmol). Yield: 350 mg )64%),
at room temperature. The mixture was re¯uxed under an
atmosphere of argon for 8 h before a second portion of 7a
)300 mg, 1.38 mmol) was added to the reaction mixture at
roomtemperature. Stirring at re¯ux was continued for 16 h
)reaction was monitored by TLC: silica gel, eluant: ethyl-
acetate/cyclohexane1:2). The solvent was evaporated in
vacuo and the oily residue )1.47 g) puri®ed by ¯ash-
chromatography )silica gel, 30£3 cm2, eluant: ethyl-
acetate/cyclohexane, 1:3; Rf0.61). Removal of the solvent
in vacuo yielded pyridazine )S)-23a )1.05 g, 72%) as a
20
[a]D 228.68 )c 0.44, trichloromethane). Further analyti-
cal data of the enantiomers correspond to those of the
racemate.
4.1.16. ꢀS)-2-Formyl-piperidine-1-carboxylic acid-tert-
butyl ester ꢀS-21). Using the same procedure as described
for alcohol )RS)-10, aldehyde )S)-21 )1.91 g, 87%) was
obtained within 4.5 h at roomtemperature from)
S)-20
20
)2.22 g, 10.3 mmol) and 2-Iodoxybenzoic acid )4.52 g,
16.1 mmol). Puri®cation was accomplished by ¯ash-
chromatography )silica gel, 25£3 cm2, eluant: ethyl-
colorless solid, mp 50±538C. [a]D 245.38 )c 1.23,
trichloromethane); IR )neat): n3058, 2945, 1704, 1654,
1
1401, 1167 cm21; H NMR )500 MHz, CDCl3) d: 1.18 )s,
20
acetate/cyclohexane, 1:1; Rf0.69). [a]D20277.98
9H, OC)CH3)3), 1.56±1.65 )m, 3H), 1.77±1.83 )m, 2H),
2.07 )m, 1H), 3.57 )m, 1H), 3.81 )m, 1H), 5.07 )m, 1H),
7.84 )s, 1H); 13C NMR )125 MHz, CDCl3) d: 19.22, 22.94,
27.96 )q, OC)CH3)3), 30.90, 42.20, 52.76, 81.53 )s,
)c1.49, trichloromethane), literature:12 [a]D 277.48
)c1.4, trichloromethane); 1H NMR )500 MHz, CDCl3,
rotamers) d: 1.20 )m, 1H), 1.40 )bs, 9H, OC)CH3)3), 1.52
)m, 1H), 1.60±1.65 )m, 3H), 2.11 )m, 1H), 2.79 and 2.90
)bs, 1H), 3.83 and 3.97 )bs, 1H), 4.45 and 4.55 )bs, 1H), 9.52
)s, 1H, CHO); 13C NMR )125 MHz, CDCl3, rotamers): d:
20.99, 23.68, 24.80, 28.38 )q, OC)CH3)3), 41.87 and 43.02,
60.60 and 61.53, 80.46 )s, OC)CH3)3), 155.65 and 155.73 )s,
Boc-CvO), 201.39 )d, CHO); MS )70 eV) m/z )%) 213
)0.1, M1), 184 )52, M12CHO).
1
OC)CH3)3), 120.46 )q, JCF275.1 Hz, CF3), 121.91 )q,
2
1JCF273.8 Hz, CF3), 122.02, 147.97, 149.75 )q, JCF
2
33.4 Hz, C-3 or C-6), 153.51 )q, JCF34.3 Hz, C-3 or
C-6), 155.28 )s, Boc-CvO); MS )70 eV) m/z )%)399
)0.8, M1), 344 )22, M12C4H7); HRMS calcd for
C16H19N3O2F6 )399.34) )M1): 399.1381. Found: 399.1375.
4.1.19. ꢀS)-2-ꢀ30,60-Bis-methoxycarbonyl-pyridazine-40-
yl)-piperidine-1-carboxylic acid-tert-butyl ester ꢀS)-
4.1.17. E- and Z-ꢀS)-2-ꢀ20-Methoxyethenyl)-piperidine-1-
carboxylic acid-tert-butyl ester E- and Z-ꢀS)-ꢀ22). Using
the same procedure as described for aldehyde )RS)-11,
1.70 g )83%) enol ether )S)-22 was obtained as an insepar-
able mixture of E- and Z-isomers with the ratio 68:32 from
1.81 g )8.49 mmol) )S)-21, 6.54 g )19.1 mmol) )methoxy-
methyl)-triphenyl-phosphonium-chloride and 2.14 g )19.1
mmol) potassium tert-butanolate. Puri®cation was accom-
plished by ¯ash-chromatography )silica gel, 27£5.5 cm2,
eluant: ethylacetate/cyclohexane, 1:5; Rf0.53, 0.60).
ꢀ23b). To
a suspension of tetrazine 7b )738 mg,
3.72 mmol) in anhydrous toluene )15 mL) was added a
solution of S-enol ether )S)-22 )691 mg, 2.86 mmol) in
anhydrous toluene )10 mL) at room temperature. The
mixture was re¯uxed under an atmosphere of argon for
28 h )reaction was monitored by TLC: silica gel, eluant:
ethylacetate/cyclohexane1:3). The solvent was removed
in vacuo and the oily residue )1.53 g) puri®ed by ¯ash-
chromatography )silica gel, 31£4 cm2, eluant: ethyl-
acetate/cyclohexane, 1:1; Rf0.48). Removal of the solvent
in vacuo yielded pyridazine )S)-23b )880 mg, 81%) as
20
[a]D 246.38 )c 1.17, trichloromethane); IR )neat):
1
n2937, 1696, 1650, 1454, 1272, 1208, 1139 cm21; H
20
NMR )500 MHz, CDCl3, E-isomer) d: 1.25 )m, 1H), 1.31
)s, 9H, OC)CH3)3), 1.40±1.44 )m, 4H), 1.56 )m, 1H), 2.68
)td, J2.7 Hz, J13.1 Hz, 1H), 3.38 )s, 3H, OCH3), 3.76
colorless oil. [a]D 251.08 )c 1.11, trichloromethane);
IR )neat): n3342, 2870, 1726, 1692, 1258 cm21
;
1H
NMR )500 MHz, CDCl3) d: 1.29 )s, 9H, OC)CH3)3), 1.40
)m, 1H), 1.58±1.71 )m, 3H), 1.80±1.87 )m, 1H), 2.04 )m,
1H), 3.14 )td, J10.9 Hz, J2.7 Hz, 1H), 3.96 )m, 1H),
4.02 )s, 3H, CO2CH3), 4.08 )s, 3H, CO2CH3), 5.51 )t,
J5.6 Hz, 1H), 8.09 )s, 1H); 13C NMR )125 MHz, CDCl3)
d: 19.18, 23.51, 28.22 )q, OC)CH3)3), 28.74, 41.64, 51.87,
53.48 )q, CO2CH3), 53.70 )q, CO2CH3), 80.91 )s,
OC)CH3)3), 125.72, 151.61, 153.20, 153.68, 155.01 )s,
Boc-CvO), 164.04 )s, CO2CH3), 165.00 )s, CO2CH3); MS
)70 eV) m/z )%)379 )0.4, M1), 279 )M12C4H8±CO2);
HRMS calcd for C18H25N3O6 )379.41) )M1): 379.1743.
Found: 379.1754.
3
3
0
0
0
)m, 1H), 4.60 )m, 1H), 4.77 )dd, JH-1 , H-2 12.6 Hz, JH-1 ,
3
7.6 Hz, 1H, 10-H), 6.29 )d, JH-1 ,
12.6 Hz, 1H,
0
0
H-2
H-2
20-H); 13C NMR )125 MHz, CDCl3) d: 19.28, 25.51,
28.44 )q, OC)CH3)3), 30.43, 39.35, 49.26, 55.95 )q,
OCH3), 79.11 )s, OC)CH3)3), 100.55 )d, C-10), 149.38 )d,
1
C-20), 154.92 )s, Boc-CvO); H NMR )500 MHz, CDCl3,
Z-isomer) d: 1.25 )m, 1H), 1.30 )s, 9H, OC)CH3)3),
1.40±1.44 )m, 4H), 1.56 )m, 1H), 2.64 )td, J2.5,
12.9 Hz; 1H), 3.44 )s, 3H, OCH3), 3.76 )m, 1H), 4.39 )dd,
3
3
JH-1 , H-2 6.5 Hz, JH-1 , H-26.8 Hz; 1H, 10-H), 5.00 )m,
0
0
0
3
4
0
0
0
1H, 2-H), 5.73 )dd, JH-1 , H-2 6.5 Hz, JH-2 , H-21.5 Hz,
1H, 20-H); 13C NMR )125 MHz, CDCl3) d: 19.69, 25.57,
28.40 )q, OC)CH3)3), 30.30, 39.55, 46.83, 59.65 )q, OCH3),
78.79 )s, OC)CH3)3), 104.50 )d, C-10), 146.39 )d, C-20),
154.92 )s, Boc-CvO); MS )70 eV) m/z )%) 241 )6, M1),
185 )81, M12C4H8); HRMS calcd for C13H23NO3 )241.33)
)M1), 241.1678. Found: 241.1673.
4.1.20. ꢀS)-2-ꢀPyridazin-40-yl)-piperidine-1-carboxylic
acid-tert-butyl ester ꢀS)-ꢀ23c). To a solution of S-enol
ether )S)-22 )757 mg, 3.14 mmol) in anhydrous trichloro-
methane )10 mL) was added a solution of tetrazine 7c
)947 mg, 11.5 mmol) in anhydrous trichloromethane at
roomtemperature. The deep red solution was re¯uxed
under an atmosphere of argon for 30 h )reaction was
monitored by TLC: silica gel, eluant: ethylacetate/cyclo-
hexane1:3). After removal of solvent in vacuo the sirupy
residue )1.03 g) was puri®ed by ¯ash-chromatography
)silica gel, 24.5£3 cm2, eluant: ethylacetate; Rf0.41)
4.1.18. ꢀS)-2-ꢀ30,60-Bis-tri¯uoromethyl-pyridazine-40-yl)-
piperidine-1-carboxylic acid-tert-butyl ester ꢀS)-ꢀ23a).
To a solution of S-enol ether )S)-22 )880 mg, 3.65 mmol)
in anhydrous toluene )12 mL) was added a solution of tetra-
zine 7a )795 mg, 3.65 mmol) in anhydrous toluene )17 mL)