Alkylation Studies of N-Protected Morpholin-3-ones
J . Org. Chem., Vol. 61, No. 15, 1996 4995
MHz) δ 0.96 (s, 9H), 2.80 (m, 1H), 3.61 (dd, 1H, J ) 11.9 and
7.8 Hz), 3.92 (dd, 1H, J ) 11.9 and 4.2 Hz), 4.06 (d, 1H, J )
16.6 Hz), d, 1H, J ) 16.6 Hz), 6.38 (bs, 1H); 13C NMR (CDCl3,
75 MHz) δ 25.9, 33.2, 60.1, 64.8, 67.5, 170.0; IR (KBr) 3203,
2970, 1674, 1127 cm-1; MS (FD+) m/ z 157 (M)+. Anal. Calcd
for C8H15NO2: C, 61.12; H, 9.62; N, 8.91. Found: C, 61.33;
H, 9.41; N, 8.85.
cm-1; MS (FD+) m/ z 277 (M)+. Anal. Calcd for C16H23NO3:
C, 69.29; H, 8.36; N, 5.05. Found: C, 69.00; H, 8.56; N, 4.81.
(2R,5S)-2-Ben zyl-5-sec-bu tyl-4-(4-m eth oxyben zyl)m or -
p h olin -3-on e (14a ). LDA was prepared at 0 °C from 0.697
mL (4.98 mmol) of diisopropylamine and 3.11 mL (4.98 mmol)
of n-butyllithium (1.6 M in hexane) in 10 mL of THF under a
nitrogen atmosphere. The solution of LDA was then cooled
to -78 °C, and 1.15 g (4.15 mmol) of the N-protected morpho-
lin-3-one 13a in tetrahydrofuran (5 mL) was added dropwise.
The bright yellow solution was stirred at -78 °C for 30 min,
after which 0.592 mL (4.98 mmol) of benzyl bromide was
added. The reaction mixture was allowed to warm to 25 °C
and stirred for an additional 2 h. The reaction mixture was
poured into 1 N HCl and extracted with ethyl acetate (3 × 50
mL). The combined extracts were dried over sodium sulfate
and concentrated in vacuo to give a crude oil, which was
purified by flash chromatography on a silica gel column using
3:1 hexane-ethyl acetate as the eluent. The major fractions
were combined and concentrated in vacuo to give 1.29 g (84%,
8:1 selectivity) of 14a as a clear oil: 1H NMR (CDCl3, 300 MHz)
δ 0.83 (t, 3H, J ) 7.4 Hz), 0.88 (d, 3H, J ) 7.0 Hz), 1.17 (m,
2H), 1.86 (m, 1H), 3.19 (m, 2H), 3.33 (dd, 1H, J ) 14.2 and 3.5
Hz), 3.60-3.85 (m, 3H), 3.79 (s, 3H), 4.41 (dd, 1H, J ) 7.7
and 3.5 Hz), 5.53 (d, 1H, J ) 14.8 Hz), 6.79 (d, 2H, J ) 8.5
Hz), 6.94 (d, 2H, J ) 8.5 Hz), 7.32 (m, 5H); 13C NMR (CDCl3,
75 MHz) δ 12.3, 13.5, 26.3, 34.4, 37.9, 44.8, 55.2, 56.4, 61.9,
77.7, 114.0, 126.5, 128.2, 128.4, 129.2, 130.0, 138.0, 158.9,
169.8; IR (CHCl3) 3031, 2967, 1640, 1513, 1248 cm-1; MS (FD+)
m/ z 367 (M)+. Anal. Calcd for C23H29NO3: C, 75.17; H, 7.95;
N, 3.81. Found: C, 75.46; H, 7.95; N, 3.91.
(S)-5-sec-Bu t yl-4-(4-m et h oxyb en zyl)m or p h olin -3-on e
(13a ). A solution containing 1.00 g of the morpholin-3-one 12a
(6.36 mmol) in 50 mL of DMF was stirred at 25 °C under a
nitrogen atmosphere as 305 mg (7.63 mmol, 60% in mineral
oil) of sodium hydride was added. The reaction was stirred
at 25 °C for 30 min, after which 1.03 mL (7.63 mmol) of
p-methoxybenzyl chloride was added dropwise over 5 min. The
resulting solution was stirred at 25 °C for 4 h and then poured
into 1 N HCl. The mixture was extracted with ethyl acetate
(3 × 100 mL), and the combined extracts were washed twice
with brine, dried over sodium sulfate, and concentrated in
vacuo to give a brown oil. This crude material was purified
by flash chromatography on a silica gel column using 50% ethyl
acetate-hexane as the eluent. The major fraction was col-
lected and concentrated in vacuo to give 1.61 g (91%) of 13a
as a clear oil: [R]25D ) -83.4 (c 1.0, CH3OH); 1H NMR (CDCl3,
300 MHz) δ 0.93 (t, 3H, J ) 7.4 Hz), 1.00 (d, 3H, J ) 7.0 Hz),
1.32 (m, 2H), 1.96 (m, 1H), 3.15 (m, 1H), 3.61 (dd, 1H, J )
12.1 and 3.6 Hz), 3.83 (s, 3H), 3.85 (d, 1H, J ) 14.7 Hz), 3.95
(dd, 1H, J ) 12.1 and 2.5 Hz), 4.20 (d, 1H, J ) 16.7 Hz), 4.28
(d, 1H, J ) 16.7 Hz), 5.50 (d, 1H, J ) 14.7 Hz), 6.89 (d, 2H, J
) 8.4 Hz), 7.21 (d 2H, J ) 8.4 Hz); 13C NMR (CDCl3, 75 MHz)
δ 12.4, 14.4, 26.6, 35.2, 45.3, 55.3, 56.2, 64.5, 67.7, 114.1, 128.6,
159.1, 167.9; IR (CHCl3) 3010, 2967, 1640, 1513, 1247 cm-1
;
(2R,5S)-5-sec-Bu tyl-2-(cycloh exylm eth yl)-4-(4-m eth oxy-
ben zyl)-m or p h olin -3-on e (14b). 14b was prepared accord-
ing to the procedure for 14a , by quenching the enolate of 13a
with cyclohexylmethyl bromide. 14b (65%, 7:1 selectivity): 1H
NMR (CDCl3, 300 MHz) δ 0.80-1.10 (m, 8H), 1.10-1.38 (m,
5H), 1.40-1.60 (m, 1H), 1.60-1.77 (m, 5H), 1.78-2.10 (m, 3H)
3.25 (m, 1H), 3.43-4.18 (m, 3H), 3.80 (s, 3H), 4.21 (dd, 1H, J
) 9.2 and 3.0 Hz), 5.50 (d, 1H, J ) 14.7 Hz), 6.86 (d, 2H, J )
8.5 Hz), 7.15 (d, 2H, J ) 8.5 Hz); 13C NMR (CDCl3, 75 MHz)
δ 12.62, 14.16, 27.26, 27.43, 27.53, 27.65, 33.12, 35.18, 35.37,
35.99, 39.75, 46.26, 55.69, 58.25, 61.50, 75.52, 115.12, 129.83,
130.38, 160.69, 173.62; IR (CHCl3) 2926, 1632, 1513, 1248,
MS (FD+) m/ z 277 (M)+. Anal. Calcd for C16H23NO3: C, 69.29;
H, 8.36; N, 5.05. Found: C, 69.18; H, 8.35; N, 4.95.
13b-e were prepared according to the procedure for 13a .
(S)-5-Isob u t yl-4-(4-m et h oxyb en zyl)m or p h olin -3-on e
(13b) (85%): 1H NMR (CDCl3, 300 MHz) δ 0.89 (d, 3H, J )
6.4 Hz), 1.00 (d, 3H, J ) 6.5 Hz), 1.45 (m, 1H), 1.62 (m, 1H),
1.90 (m, 1H), 3.15 (m, 1H), 3.61 (m, 1H), 3.78 (d, 1H, J ) 14.7
Hz), 3.85 (s, 3H), 3.88 (d, 1H, J ) 14.7 Hz), 4.23 (d, 1H, J )
16.7 Hz), 4.33 (d, 1H, J ) 16.7 Hz), 5.46 (d, 1H, J ) 14.7 Hz),
6.91 (d, 2H, J ) 8.6 Hz), 7.24 (d, 2H, J ) 8.6 Hz); 13C NMR
(CDCl3, 75 MHz) δ 21.5, 23.8, 25.1, 38.8, 45.9, 52.1, 55.3, 66.3,
67.9, 114.1, 128.8, 129.6, 159.2, 166.8; IR (CHCl3) 3010, 2962,
1641, 1513, 1247 cm-1; MS (FD+) m/ z 277 (M)+. Anal. Calcd
for C16H23NO3: C, 69.29; H, 8.36; N, 5.05. Found: C, 69.23;
H, 8.45; N, 5.03.
1036 cm-1; MS (FD+) m/ z 373 (M)+. Anal. Calcd for C23H35
-
NO3: C, 73.96; H, 9.45; N, 3.75. Found: C, 74.24; H, 9.46; N,
3.96.
(2R,5S)-5-sec-Bu t yl-4-(4-m et h oxyb en zyl)-2-(2-p h en yl-
eth yl)m or p h olin -3-on e (14c). 14c was prepared according
to the procedure for 14a , by quenching the enolate of 13a with
2-phenylethyl bromide. 14c (66%, 3:1 selectivity): 1H NMR
(CDCl3, 300 MHz) δ 0.80-1.10 (m, 6H), 1.18-1.40 (m, 2H),
1.92 (m, 1H), 2.10 (m, 1H), 2.35 (m, 1H), 2.78 (m, 2H), 3.30
(m, 1H), 3.48-4.10 (m, 3H), 3.79 (s, 3H), 4.11 (dd, 1H, J ) 9.2
and 3.0 Hz), 5.52 (d, 1H, J ) 14.9 Hz), 6.85 (d, 2H, J ) 8.1
Hz), 7.14-7.45 (m, 7H); IR (CHCl3) 3033, 2968, 1639, 1513,
(S)-5-Meth yl-4-(4-m eth oxyben zyl)m or ph olin -3-on e (13c)
(62%, 2 steps): [R]25 ) -112.5 (c 1.0, CH3OH); 1H NMR
D
(CDCl3, 300 MHz) δ 1.32 (d, 3H, J ) 6.5 Hz), 3.35 (m, 1H),
3.67 (dd, 1H, J ) 11.7 and 3.0 Hz), 3.75 (dd, 1H, J ) 11.7 and
3.2 Hz), 3.84 (s, 3H), 3.92 (d, 1H, J ) 14.8 Hz), 4.24 (d, 1H, J
) 16.6 Hz), 4.33 (d, 1H, J ) 16.6 Hz), 5.37 (d, 1H, J ) 14.8
Hz), 6.90 (d, 2H, J ) 8.5 Hz), 7.23 (d, 2H, J ) 8.5 Hz); 13C
NMR (CDCl3, 75 MHz) δ 16.7, 45.7, 49.6, 55.3, 68.1, 69.5,
114.1, 128.7, 129.5, 159.1, 166.9; IR (CHCl3) 3010, 2980, 1643,
1513 cm-1; MS (FD+) m/ z 235 (M)+.
1248 cm-1; MS (FD+) m/ z 381 (M)+. Anal. Calcd for C24H31
-
NO3: C, 75.55; H, 8.19; N, 3.67. Found: C, 75.31; H, 8.12; N,
3.74.
(S)-5-Ben zyl-4-(4-m eth oxyben zyl)m or ph olin -3-on e (23d)
1
(79%): [R]25 ) -54.8 (c 1.0, CH3OH); H NMR (CDCl3, 300
(2R,5S)-2-Allyl-5-sec-b u t yl-4-(4-m et h oxyb en zyl)m or -
p h olin -3-on e (14d ). 14d was prepared according to the
procedure for 14a , by quenching the enolate of 13a with allyl
bromide. 14d (85%, 6:1 selectivity): 1H NMR (CDCl3, 300
MHz) δ 0.80-1.10 (m, 6H), 1.16-1.38 (m, 2H), 1.90 (m, 1H),
2.63 (m, 1H), 2.7-2.9 (m, 1H), 3.29 (m, 1H), 3.63-4.05 (m,
3H), 3.80 (s, 3H), 4.20 (dd, 1H, J ) 8.3 and 3.6 Hz), 5.10-5.25
(m, 2H), 5.52 (d, 1H, J ) 14.8 Hz), 5.90 (m, 1H) 6.86 (d, 2H, J
) 8.6 Hz), 7.16 (d, 2H, J ) 8.6 Hz); 13C NMR (CDCl3, 75 MHz)
δ 12.60, 13.93, 27.33, 35.78, 37.26, 46.18, 55.69, 58.20, 62.37,
77.51, 115.10, 118.07, 129.62, 130.45, 135.47, 160.07, 172.33;
IR (CHCl3) 3011, 2969, 1640, 1513, 1464, 1247, 1176, 1036
cm-1; MS (FD+) m/ z 317 (M)+. Anal. Calcd for C19H27NO3:
C, 71.89; H, 8.58; N, 4.41. Found: C, 71.79; H, 8.68; N, 4.20.
(2R,5S)-5-sec-Bu tyl-2-n -h exyl-4-(4-m eth oxyben zyl)m or -
p h olin -3-on e (14e). 14e was prepared according to the
procedure for 14a , by quenching the enolate of 13a with
n-hexyl iodide. 14e (75%, 6:1 selectivity): 1H NMR (CDCl3,
300 MHz) δ 0.80-1.10 (m, 9H), 1.16-1.60 (m, 10H), 1.61-
D
MHz) δ 2.99 (dd, 1H, J ) 13.3 and 10.3 Hz), 3.12 (dd, 1H, J )
13.3 and 4.0 Hz), 3.32 (m, 1H), 3.47 (dd, 1H, J ) 11.7 and 1.6
Hz), 3.74 (d, 1H, J ) 11.7 Hz), 3.85 (s, 3H), 3.90 (d, 1H, J )
14.8 Hz), 4.26 (d, 1H, J ) 16.7 Hz), 4.40 (d, 1H, J ) 16.7 Hz),
5.48 (d, 1H, J ) 14.8 Hz), 6.92 (d, 2H, J ) 8.3 Hz), 7.17 (d,
2H, J ) 7.4 Hz), 7.29-7.37 (m, 5H); 13C NMR (CDCl3, 75 MHz)
δ 36.6, 46.6, 55.3, 55.6, 65.6, 68.0, 114.2, 126.8, 128.6, 128.8,
129.3, 129.7, 137.5, 159.3, 166.9; IR (CHCl3) 3013, 2935, 1644,
1513, 1248 cm-1; MS (FD+) m/ z 311 (M)+.
(S )-5-t er t -B u t yl-4-(4-m e t h o xy b e n zyl)m o r p h olin -3-
on e (13e) (82%): [R]25 ) -77.4 (c 1.0, CH3OH); 1H NMR
D
(CDCl3, 300 MHz) δ 1.15 (s, 9H,), 2.89 (d, 1H, J ) 1.5 Hz),
3.42 (dd, 1H, J ) 12.0 and 2.7 Hz), 3.84 (s, 3H), 3.87 (d, 1H,
J ) 14.7 Hz), 4.14 (d, 1H, J ) 12.0 Hz), 4.26 (d, 1H, J ) 17.2
Hz), 4.33 (d, 1H, J ) 17.2 Hz), 5.77 (d, 1H, J ) 14.7 Hz), 6.90
(d, 2H, J ) 8.5 Hz), 7.21 (d, 2H, J ) 8.5 Hz); 13C NMR (CDCl3,
75 MHz) δ 28.9, 36.7, 49.8, 55.3, 61.6, 66.5, 67.0, 114.1, 128.8,
129.6, 159.1, 168.5; IR (CHCl3) 3010, 2967, 1639, 1513, 1249