PAPER
A New Method for the Synthesis of a-Hydroxyoxime Derivatives
3103
1H NMR (300 MHz, CDCl3): d = 0.24 (s, 9 H, 13-CH3), 1.31 (s, 3
H, 6-CH3), 1.50 (br s, 3 H, 7-CH3), 1.73 (dd, J = 12.9, 4.8 Hz, 1 H,
4-CHHa), 1.98 (t, J = 12.9 Hz, 1 H, 4-CHHb), 3.75 (br d, J = 11.0
Hz, 1 H, 3-CH), 3.80 (s, 3 H, 12-CH3), 3.93 (br s, 1 H, 1-CHHa),
4.98 (br s, 1 H, 1-CHHb), 6.87 (d, J = 8.8 Hz, 2 H, 10-CH), 7.19 (d,
J = 8.8 Hz, 2 H, 9-CH).
13C NMR (75 MHz, CDCl3): d = –0.7 (13-CH3), 28.9 and 31.5 (6-
CH3, 7-CH3), 42.0 and 43.7 (3-CH, 4-CH2), 55.2 (12-CH3), 76.8 (5-
C), 96.9 (1-CH2), 113.8 (10-CH), 129.7 (9-CH), 158.4 (11-C). Sig-
nals of 8-C and 2-C could not be unambiguously identified due to
low intensity and broadening because of dynamic processes.1
for 30 min and the solvent was removed in vacuo to give a brown
oil.
rel-[(4S,6S)-6-Methoxy-4-(4-methoxyphenyl)-6-methyl-5,6-di-
hydro-4H-1,2-oxazin-3-yl]methyl 2,2,2-Trifluoroacetate (9a)
1H NMR (300 MHz, CDCl3): d = 1.50 (s, 3 H, 7-CH3), 1.96 (t,
J = 13.0 Hz, 1 H, 4-CHHax), 2.32 (dd, J = 13.0, 7.7 Hz, 1 H, 4-
CHHeq), 3.32 (s, 3 H, 6-CH3), 3.73 (dd, J = 13.0, 7.7 Hz, 1 H, 3-
CH), 3.80 (s, 3 H, 12-CH3), 4.64–4.73 (m, 2 H, 1-CH2), 6.89 (d,
J = 8.4 Hz, 2 H, 10-CH), 7.11 (d, J = 8.4 Hz, 2 H, 9-CH).
13C NMR (75 MHz, CDCl3): d = 21.0 (7-CH3), 36.3 and 38.1 (3-
CH, 4-CH2), 49.5 (6-CH3), 55.2 (12-CH3), 66.2 (1-CH2), 98.7 (5-C),
114.8 (10-CH), 129.4 (9-CH), 129.5 (8-C), 155.4 (2-C), 159.3 (11-
C).
rel-(4S,6S)-(E)-6-Ethoxy-3-ethylidene-4-(4-methoxyphenyl)-2-
(trimethylsiloxy)-1,2-oxazinane (2h)
Oil; yield: 98%. Mixture of two conformers in a 3:1 ratio (NMR).
rel-[(4S,6S)-6-Methoxy-6-methyl-4-phenyl-5,6-dihydro-4H-1,2-
oxazin-3-yl]methyl 2,2,2-Trifluoroacetate (9b)
Major Conformer
1H NMR (300 MHz, CDCl3): d = 0.27 (s, 9 H, 13-CH3), 1.17 (t,
J = 6.8 Hz, 3 H, 7-CH3), 1.35 (d, J = 7.2 Hz, 3 H, 14-CH3), 2.09–
2.21 (m, 1 H, 4-CHHa), 2.31 (ddd, J = 13.1, 8.5, 5.3 Hz, 1 H, 4-
CHHb), 3.35 (dq, J = 9.2, 7.2 Hz, 1 H, 6-CHHa), 3.78 (s, 3 H, 12-
CH3), 3.90 (dq, J = 9.2, 7.2 Hz, 1 H, 6-CHHb), 4.05 (br s, 1 H, 3-
CH), 4.61 (dd, J = 8.2, 6.2 Hz, 1 H, 5-CH), 5.51 (q, J = 7.2 Hz, 1 H,
1-CH), 6.81 (d, J = 8.8 Hz, 2 H, 10-CH), 7.33 (d, J = 8.8 Hz, 2 H,
9-CH).
1H NMR (300 MHz, CDCl3): d = 1.50 (s, 3 H, 7-CH3), 1.98 (t,
J = 13.0 Hz, 1 H, 4-CHHax), 2.35 (dd, J = 13.0, 7.7 Hz, 1 H, 4-
CHHeq), 3.32 (s, 3 H, 6-CH3), 3.77 (dd, J = 13.0, 7.7 Hz, 1 H, 3-
CH), 4.64–4.73 (m, 2 H, 1-CH2), 7.18–7.38 (m, 5 H, 9-CH, 10-CH,
11-CH).
13C NMR (75 MHz, CDCl3): d = 21.0 (7-CH3), 37.1 and 38.0 (3-
CH, 4-CH2), 49.5 (6-CH3), 66.2 (1-CH2), 98.5 (5-C), 128.0 (11-
CH), 128.3 and 129.3 (9-CH, 10-CH), 137.8 (8-C), 154.9 (2-C).
13C NMR (75 MHz, CDCl3): d = –1.1 (13-CH3), 11.9 (14-CH3),
14.8 (7-CH3), 34.0 (4-CH2), 38.3 (3-CH), 55.1 (12-CH3), 63.4 (6-
CH2), 99.7 (5-CH), 108.3 (1-CH), 113.6 (10-CH), 129.1 (9-CH),
134.6 (8-C), 148.7 (2-C), 157.9 (11-C).
(6,6-Dimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazin-3-yl)meth-
yl 2,2,2-Trifluoroacetate (9c)
1H NMR (300 MHz, CDCl3): d = 1.32 and 1.41 (both s, both 3 H, 6-
CH3, 7-CH3), 1.96 (dd, J = 13.7, 11.7 Hz, 1 H, 4-CHHax), 2.15 (dd,
J = 13.7, 7.7 Hz, 1 H, 4-CHHeq), 3.55 (dd, J = 11.7, 7.7 Hz, 1 H, 3-
CH), 4.64–4.75 (m, 2 H, 1-CH2), 7.17–7.38 (m, 5 H, 9-CH, 10-CH,
11-CH).
29Si NMR (60 MHz, CDCl3): d = 23.8.
Minor Conformer
1H NMR (300 MHz, CDCl3): d = 0.24 (s, 9 H, 13-CH3), 1.17 (t,
J = 6.8 Hz, 3 H, 7-CH3), 1.55 (d, J = 7.2 Hz, 3 H, 14-CH3), 2.09–
2.20 (m, 2 H, 4-CH2), 3.44–3.54 (m, 1 H, 6-CHHa), 3.78 (s, 3 H, 12-
CH3), 3.90 (dq, J = 9.2, 7.2 Hz, 1 H, 6-CHHb), 4.16 (br s, 1 H, 3-
CH), 4.95 (br t, J = 5.5 Hz, 1 H, 5-CH), 5.80 (q, J = 7.2 Hz, 1 H, 1-
CH), 6.85 (d, J = 8.6 Hz, 2 H, 10-CH), 7.27 (d, J = 8.6 Hz, 2 H, 9-
CH).
13C NMR (75 MHz, CDCl3): d = 22.6 and 28.1 (6-CH3, 7-CH3),
37.8 and 39.4 (3-CH, 4-CH2), 66.6 (1-CH2), 76.1 (5-C), 128.0 (11-
CH), 128.1 and 129.4 (9-CH, 10-CH), 138.0 (8-C), 152.5 (2-C).
Oxazines 10a–f and Isoxazoles 10o,p; General Procedure
A soln of enamine 2 (2 mmol) in CH2Cl2 (4 mL) was added drop-
wise to a stirred soln of TFAA (0.31 mL, 2.2 mmol) in CH2Cl2 (4
mL) at –78 °C under an argon atmosphere. The mixture was stirred
for 1 h and then allowed to warm to r.t. Then MeOH (4 mL) and
K2CO3 (0.5 g) were added and the mixture was stirred for 1 h and
poured into a mixture of EtOAc (70 mL) and brine (50 mL). The or-
ganic layer was washed with brine (50 mL) [for 10o additional ex-
traction from the aqueous layer with EtOAc (50 mL) and addition
of solid NaCl was needed] and dried (Na2SO4). The solvents were
removed in vacuo. The residue was subjected to column chromatog-
raphy (hexane–EtOAc, 5:1, 1:1, 1:2) to give target derivatives 10 as
colorless oils. For yields see Table 2.
13C NMR (75 MHz, CDCl3): d = –0.8 (13-CH3), 11.8 (14-CH3),
14.0 (7-CH3), 35.9 (4-CH2), 36.3 (3-CH), 55.1 (12-CH3), 64.3 (6-
CH2), 98.2 (5-CH), 110.5 (1-CH), 113.5 (10-CH), 128.6 (9-CH),
134.6 (8-C), 148.7 (2-C), 157.9 (11-C).
29Si NMR (60 MHz, CDCl3): d = 23.8.
Enamines 2n–p; General Procedure
Nitronates 1n,o were prepared by the literature procedure.26 1p was
synthesized by a procedure analogous to that described for 1o.26
(Yield: 74%, spectroscopic data are identical to those previously re-
ported.27)
rel-[(4S,6S)-6-Methoxy-4-(4-methoxyphenyl)-6-methyl-5,6-di-
hydro-4H-1,2-oxazin-3-yl]methanol (10a)
Mp 100–101 °C (EtOAc); Rf = 0.25 (hexane–EtOAc, 1:1).
Et3N (0.50 mL, 3.6 mmol, 1.2 equiv) was added to stirred soln of
nitronate 1 (3 mmol) in CH2Cl2 (6 mL) at –78 °C. Then TMSBr
(0.44 mL, 1.1 equiv, 3.3 mmol) was added. The mixture was main-
tained at the same temperature for 24 h, diluted with hexane (15
mL) and poured into a mixture of hexane (30 mL) and aq NaHSO4
soln (0.5 g in 30 mL of H2O). The organic layer was washed with
H2O (30 mL) and brine (2 × 30 mL) and dried (Na2SO4). The sol-
vents were removed in vacuo to give enamines 2n–p as colorless
oils, which were used in the next step without additional purifica-
tion. Yields of crude products: 2n: 74%, 2o: 69%, 2p: 71%.
1H NMR (300 MHz, CDCl3): d = 1.49 (s, 3 H, 7-CH3), 1.93 (dd,
J = 13.5, 12.5 Hz, 1 H, 4-CHHax), 2.26 (dd, J = 13.5, 7.7 Hz, 1 H, 4-
CHHeq), 2.75 (br s, 1 H, 13-OH), 3.31 (s, 3 H, 6-CH3), 3.63 (dd,
J = 12.5, 7.7 Hz, 1 H, 3-CH), 3.80 (s, 3 H, 12-CH3), 3.94 (s, 2 H, 1-
CH2), 6.87 (d, J = 8.4 Hz, 2 H, 10-CH), 7.11 (d, J = 8.4 Hz, 2 H, 9-
CH).
13C NMR (75 MHz, CDCl3): d = 21.3 (7-CH3), 35.9 (3-CH), 38.4
(4-CH2), 49.3 (6-CH3), 55.1 (12-CH3), 62.1 (1-CH2), 97.8 (5-C),
114.3 (10-CH), 129.2 (9-CH), 130.6 (8-C), 158.8 (2-C), 159.2 (11-
C).
Trifluoroacetates 9a–c; General Procedure
Soln of enamine 2 (0.3 mmol) in CH2Cl2 (0.5 mL) was added drop-
wise to a stirring soln of TFAA (50 mL, 0.35 mmol) in CH2Cl2 (0.5
mL) at –78 °C under an argon atmosphere. The mixture was stirred
Synthesis 2009, No. 18, 3099–3105 © Thieme Stuttgart · New York