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F. Liebner et al. / Tetrahedron 63 (2007) 11817–11821
Computations, as implemented through Spartan Pro 02 by
Wavefunction, Inc., Irvine, CA, USA, were carried out on
geometries pre-optimized by the semi-empirical PM3
method. For full geometry optimization the widely em-
ployed B3LYP hybrid method, which includes a mixture
of HF and DFT exchange terms and the gradient-corrected
correlation functional of Lee, Yang, and Parr16 parametrized
by Becke,17 was used, along with the double-zeta split va-
lence basis sets 6-31+G*,18 which includes diffuse func-
tions. Transition states and minima were confirmed by
analysis of the calculated vibrational spectrum. For all tran-
sition states the number of imaginary frequencies was 1, for
all minimum geometries it was 0.
C5H7NO2: C 53.09, H 6.24, N 12.38. Found C 52.99, H
6.40, N 12.33.
4.1.4. 4-Methyl-3,4-dihydro-2H-[1,4]oxazine (DNMM,
2,3-dehydro-N-methylmorpholine, 5). To a solution of
acylenamine 18 (0.8 g, 7.0 mmol) in diethyl ether (50 mL)
was added LiAlH4 (10.0 mmol) at ꢁ30 ꢀC. The mixture
was stirred at this temperature for 4 h, and warmed to
0 ꢀC. Concentrated aqueous NH4Cl solution was added
and the organic phase separated. The aqueous layer was ex-
tracted three times with diethyl ether (20 mL), and the com-
bined extracts were dried over MgSO4. Removal of the
solvent and microdistillation over CaCO3 at ambient pres-
sure provided DNMM (5) as colorless liquid (548 mg,
79%, n2D0¼1.362, bp¼84–87 ꢀC). For long-term storage,
the substance should be kept at ꢁ20 ꢀC in the dark over basic
alumina to avoid discoloration and polymerization reactions.
1H NMR: 2.44 (s, 3H, N–CH3), 2.98 (dd, 1H, N–CHA,
J¼11.9, 1.9 Hz), 3.08 (dt, 1H, N–CHB, J¼11.0, 2.8 Hz),
3.78 (dd, 1H, O–CHA, J¼11.9, 2.8 Hz), 4.13 (dt, 1H, O–
CHB, J¼11.0, 1.9 Hz), 5.86 (d, 1H, J¼17.4 Hz, N–CH]),
6.24 (d, 1H, J¼17.4 Hz, O–CH]). 13C NMR: d 39.0 (N–
CH3), 58.3 (N–CH2), 60.5 (O–CH2), 112.1 (N–CH]),
122.9 (O–CH]). M¼99.1. Anal. Calcd for C5H9NO: C
60.58, H 9.15, N 14.13. Found C 60.50, H 9.26, N 13.97.
4.1.1. Formmorpholide, 16. A mixture of morpholine
(17.4 g, 0.2 mol), ethyl formate (74 g, 1.0 mol), and toluene-
sulfonic acid (0.05 g) was refluxed (55 ꢀC) for 4 h. Excess
ester was distilled off and the residue was fractionated under
reduced pressure to afford 4-formylmorpholine as viscous
liquid (20.2 g, 88%, nD20¼1.488, bp (5 Torr)¼96–98 ꢀC,
bp¼233–235 ꢀC), which was directly used for further
manipulation.
4.1.2. 3-Methoxy-4-formylmorpholine, 17. A solution of
4-formylmorpholine (3.45 g, 30 mmol) in methanol
(190 mL) and formic acid (concn, 10 mL) was heated to re-
flux, and N-bromosuccinimide (16.0 g, 90 mmol) was added
in portions over 5 h. Refluxing was continued for 3 h, the so-
lution was cooled to rt. The solution was concentrated to
a volume of about 50 mL, methylene chloride (100 mL)
was added, and the mixture was extracted five times with
2 N NaOH (20 mL), washed with brine and dried over
MgSO4 overnight. Removal of the solvent provided a resi-
due, which was distilled under reduced pressure to afford
3-methoxy-4-formylmorpholine as a colorless, viscous liq-
uid (2.70 g, 62%, bp (1 Torr)¼96–98 ꢀC, nD20¼1.33919).
4.2. Hetero-Diels–Alder reaction of DNMM with in situ-
generated ortho-quinone methide (8)
a-Tocopherol (1.00 g, 2.32 mmol) and DNMM (5, 0.50 g,
5.0 mmol) was dissolved in 20 mL of dry n-hexane. Freshly
prepared Ag2O (0.65 g, 2.81 mmol) was added to the to-
copherol solution in four equal charges at intervals of about
5 min. The reaction mixture was stirred for another 10 min
and the solids were filtered off through a layer of Celite.
The solvent was evaporated, and the oily residue was chro-
matographed on silica gel (n-hexane/toluene, v/v¼9:1) to af-
ford tetracycles 9 (683 mg, 55.7%) and 10 (242 mg, 19.8%)
in a molar ratio of 2.8:1.
1
trans-Atropisomer (75%): H NMR: d 3.18 (dt, 1H, N–
CHA), 3.28 (s, 3H, O–CH3), 3.45–3.63 (m, 2H, O–CH2),
3.94–4.08 (m, 2H, O–CH2), 4.07 (dd, 1H, N–CHB), 4.46
(m, 1H, N–CH), 8.21 (s, 1H, CHO). 13C NMR: d 36.1 (5-
C), 54.3 (O–CH3), 65.9 (6-C), 69.7 (2-C), 83.1 (3-C),
160.9 (CHO). cis-Atropisomer (25%): 1H NMR: d 3.28
(dd, 1H, N–CHA), 3.34 (s, 3H, O–CH3), 3.45–3.63 (m, 2H,
O–CH2), 3.59–3.63 (dt, 1H, N–CHB), 3.94–4.08 (m, 2H,
O–CH2), 5.33 (m, 1H, N–CH), 8.20 (s, 1H, CHO). 13C
NMR: d 41.2 (5-C), 55.4 (O–CH3), 66.6 (6-C), 69.1 (2-C),
77.0 (3-C), 162.0 (CHO).
3,5,6,8-Tetramethyl-3-(4,8,12-trimethyltridecyl)-2,3,7a,-
8,9,10,11a,12-octahydro-1H-4,7,11-trioxa-8-aza-benzo[a]
anthracene, 9. 1H NMR: d 0.70–1.89 (m, 38H, 3-CH2,
2a-CH3, and C16H33 chain), 2.11 (s, 3H, 7a-CH3), 2.15 (s,
3H, 8b-CH3), 2.31 (s, 3H, N–Me), 2.34 (m, 1H, N–
CH2A), 2.54–2.60 (m, 2H, 5a-CH2A, N–CH2B), 2.60 (t,
2H, 4-CH2), 2.75 (s, 2H, 5a-CH2B), 3.33 (m, 1H, N–CH),
3
3.60–3.68 (m, 2H, O–CH2), 5.82 (d, 1H, J¼3.7 Hz, O–
4.1.3. 2,3-Dihydro-[1,4]oxazine-4-carbaldehyde (2,3-de-
hydro-formmorpholide, 18). To a solution of 3-methoxy-
4-formylmorpholine (1.45 g, 10 mmol) in chloroform
(60 mL) was added triflic acid (45 mg, 26 mL, 0.03 equiv)
at ꢁ20 ꢀC. The solution was heated to reflux for 30 min
and subsequently cooled to rt. The solvent was removed
and the residue chromatographed on silica gel to provide
acylenamine 18 as colorless liquid (1.04 g, 92%,
CH–O). 13C NMR: d 11.6 (8b-CH3), 12.4 (7a-CH3), 20.3
(4-CH2), 20.8 (5a-CH2), 23.5 (2a-CH3), 32.4 (3-CH2),
39.4 (N–CH3), 54.2 (N–CH2), 62.5 (O–CH2), 68.3 (N–
CH), 74.2 (2-C), 107.9 (O–CH–O), 115.0 (4a-C), 115.5
(5-C), 122.2 (7-C), 123.5 (8-C), 145.3 (6-C), 147.5 (6-C);
isoprenoid side chain: 19.7 (C-4a0), 19.8 (C-8a0), 21.0 (C-
20), 22.67 (C-130), 22.74 (C-12a0), 24.5 (C-60), 24.7 (C-
100), 28.0 (C-120), 32.6 (C-80), 32.7 (C-40), 37.3 (C-70),
37.4 (C-90), 37.5 (C-50), 37.6 (C-30), 39.3 (C-110), 39.7
(C-10). M¼527.8. Anal. Calcd for C34H57NO3: C 77.37,
H 10.88, N 2.65. Found C 77.27, H 11.02, N 2.57.
n2D0¼1.35519). H NMR (2 atropisomers): d 3.68–3.72 (m,
1
1H, N–CHA), 3.98–4.05 (m, 2H, N–CHB, O–CHA), 4.45
(m, 1H, O–CHB), 6.04 and 6.06 (2d, 2ꢂ1H, N–CH]),
6.41 and 6.46 (2d, 2ꢂ1H, O–CH]), 7.86 and 8.08 (2s,
2ꢂ1H, CH]O). 13C NMR (2 atropisomers): d 39.1, 42.4
(5-C), 66.6, 67.3 (6-C), 96.3, 101.2 (3-C), 122.3, 122.5
(2-C), 157.8, 160.3 (CHO). M¼113.1. Anal. Calcd for
3,5,6,11-Tetramethyl-3-(4,8,12-trimethyl-tridecyl)-1,2,3,9,-
10,11,11a,12-octahydro-7aH-4,7,8-trioxa-11-aza-benzo[a]
anthracene, 10. H NMR: d 0.70–1.89 (m, 38H, 3-CH2,
1