Cycloadditions of 3-Ylidenepiperazine-2,5-diones
J . Org. Chem., Vol. 66, No. 11, 2001 3995
2,3-Dim eth yl-3(E)-styr yl-h exa h yd r op yr r olo[1,2-a ]p yr -
a zin e-1,4-d ion e (41a ), 7,8-Dim eth yl-10-p h en yl-5,8-d ia za -
tr icyclo[5.2.2.01,5]u n d eca n e-6,9-d ion e (44a ), a n d 7,8-Di-
m et h yl-11-p h en yl-5,8-d ia za t r icyclo[5.2.2.01,5]u n d eca n e-
6,9-d ion e (45a ). Entry 1, reaction of 39a and styrene gave a
mixture of 41a , 44a , and 45a after 4.5 h of reflux, which was
separated by 2-fold column chromatography (EtOAc/hexane
9:1, reactant 39a Rf ) 0.23). 41a : yield 12 mg (8.5%); Rf )
0.42; oil; dr ) 87:13, not separable, spectra were recorded from
mixture. Major diastereoisomer: 1H NMR (300 MHz, CDCl3)
δ 1.67 (s, 3H), 1.74 (m, 1H), 1.89-2.00 (m, 2H), 2.33 (m, 1H),
2.98 (s, 3H), 3.50 (m, 2H), 3.95 (m, 1H), 6.00 (d, J ) 16.0 Hz,
1H), 6.20 (d, J ) 16.0 Hz, 1H), 7.09-7.28 (m, 5H); 13C NMR
(75.5 MHz, CDCl3) δ 23.0 (CH2), 23.4 (CH3), 29.7 (CH3), 30.2
(CH2), 46.9 (CH2), 59.0 (CH), 67.4 (C), 127.5 (CH), 127.9 (CH),
129.1 (CH), 129.5 (CH), 129.7 (CH), 137.5 (C), 167.0 (CdO),
170.1 (CdO); HRMS calcd for C17H20N2O2 284.1525, found
284.1525. Anal. Calcd for C17H20N2O2: C, 71.81; H, 7.09; N,
9.85. Found: C, 71.42; H, 7.15; N, 9.59.
(2CH,), 143.9 (C), 148.8 (C), 169.7 (CdO), 171.8 (CdO); HRMS
calcd for C23H23N2O2 359.1760, found 359.1763 (M+ - H).
(3R,8a S)-3-(2,2-Dip h e n ylvin yl)-3-isob u t yl-2-m e t h yl-
h exah ydr opyr r olo[1,2-a ]pyr azin e-1,4-dion e (41c), (3S,8aS)-
3-(2,2-Dip h en ylvin yl)-3-isobu tyl-2-m eth ylh exa h yd r op yr -
r olo[1,2-a ]p yr a zin e-1,4-d ion e (42c), a n d 10,10-Dip h en yl-
7-isobu tyl-8-m eth yl-5,8-d ia za tr icyclo[5.2.2.01,5]u n d eca n e-
6,9-d ion e (44c). Entry 3, reflux, 2 days. Chromatography
EtOAc/hexane, 1:1 (reactant 39b Rf ) 0.11) or EtOAc/hexane,
9:1 (reactant 39b Rf ) 0.29). 41c: yield 29 mg (14.4%); Rf )
1
0.43 (EtOAc/hexane, 9:1); oil; [R]20 ) +25.7 (c 1, CHCl3); H
D
NMR (300 MHz, CDCl3) δ 0.72 (d, J ) 6.6 Hz, 3H), 0.80 (d, J
) 6.6 Hz, 3H), 1.28 (m, 1H), 1.50 (m, 2H), 1.77 (m, 1H), 1.90
(dd, J ) 4.7, 14.4 Hz, 1H), 2.06 (m, 1H), 2.28 (dd, J ) 5.7,
11.0 Hz, 1H), 2.36 (dd, J ) 7.1, 14.4 Hz, 1H), 2.77 (s, 3H),
3.07 (m, 1H), 3.55 (m, 1H), 6.04 (s, 1H), 7.04-7.34 (m, 10H);
13C NMR (75.5 MHz, CDCl3) δ 21.4 (CH2), 23.1 [(CH3)2], 24.2
(CH), 24.3 [(CH3)2], 29.8 (CH3), 30.2 (CH2), 45.0 (CH2), 48.6
(CH2), 58.0 (CH), 67.5 (C), 127.3 (2CH), 128.2 (CH), 128.4 (CH),
128.6 (2CH), 128.8 (2CH), 129.3 (2CH), 130.5 (CH), 138.4 (C),
141.4 (C), 146.1 (C), 165.5 (CdO), 166.3 (CdO); HRMS calcd
for C26H30N2O2 402.2307, found 402.2309. Anal. Calcd for
44a : yield 21 mg (14.8%); Rf ) 0.39; colorless crystals; mp
1
196-197 °C (EtOAc); H NMR (300 MHz, CDCl3) δ 0.98 (m,
1H, NCH2CH2), 1.57 (s, 3H, CH3C), 1.45-1.63 (m, 2H,
NCH2CH2CH2), 1.99 (dd, J ) 14.1, 4.8 Hz, 1H, PhCHCH2),
2.45 (dd, J ) 14.1, 10.3 Hz, 1H, PhCHCH2), 2.54 (m, 1H, NCH2-
CH2CH2), 2.90 (s, 3H, CH3N), 3.04 (dd, J )10.3, 4.8 Hz, 1H,
PhCHCH2), 3.13 (m, 1H, NCH2), 3.30 (m, 1H, NCH2), 7.02 (m,
2H, Ph), 7.24 (m, 3H, Ph); 13C NMR (75.5 MHz, CDCl3) δ 16.7
(CH3C), 23.7 (NCH2CH2), 27.0 (NCH2CH2CH2), 27.2 (CH3N),
42.2 (PhCHCH2), 44.8 (NCH2), 44.9 (PhCHCH2), 62.3 (CH3C),
70.7 (NCH2CH2CH2C), 127.7 (CH, Ph), 128.6 (CH, Ph), 128.8
(CH, Ph), 139.5 (C, Ph), 169.4 (CdO), 172.2 (CdO); HRMS
calcd for C17H20N2O2 284.1525, found 284.1520.
C
26H30N2O2: C, 77.58; H, 7.51; N, 6.96. Found: C, 77.11; H,
7.48; N, 7.04.
42c: yield 29 mg (14.4%); Rf ) 0.48 (EtOAc/hexane, 9:1);
1
oil; [R]20 ) -55.3 (c 1, CHCl3); H NMR (300 MHz, CDCl3) δ
D
0.82 (d, J ) 3.5 Hz, 3H), 0.84 8d, J ) 3.5 Hz, 3H), 0.94 (m,
1H), 1.46 (m, 1H), 1.65 (m, 2H), 1.92 (dd, J ) 5.3, 14.5 Hz,
1H), 1.98 (m, 1H), 2.18 (dd, J ) 6.0, 14.5 Hz, 1H), 2.80 (s, 3H),
3.23 (m, 1H), 3.36 (m, 1H), 3.72 (dd, J )6.0, 11.5 Hz, 1H), 5.99
(s, 1H), 6.95-7.29 (m, 10H); 13C NMR (75.5 MHz, CDCl3) δ
21.2 (CH2), 24.1 (CH), 24.4 [(CH3)2], 24.6 [(CH3)2], 29.2 (CH2),
30.0 (CH3), 45.4 (CH2), 48.9 (CH2), 58.5 (CH), 68.0 (C), 127.4
(2CH), 127.8 (CH), 128.3 (CH), 128.5 (2CH), 128.7 (2CH), 129.3
(2CH), 131.2 (CH), 139.1 (C), 141.9 (C), 145.4 (C), 166.1 (Cd
O), 166.6 (CdO); HRMS calcd for C26H30N2O2 402.2307, found
402.2306. Anal. Calcd for C26H30N2O2: C, 77.58; H, 7.51; N,
6.96. Found: C, 77.30; H, 7.42; N, 6.99.
45a : yield 38 mg (26.8%); Rf ) 0.37; colorless crystals; mp
167-168 °C (EtOAc/hexane); dr )73:27, not separable, spectra
were recorded from the mixture. Major diastereomer: 1H NMR
(300 MHz, CDCl3) δ 1.11 (s, 3H), 1.80 (m, 1H), 1.94 (m, 2H),
2.01 (dd, J ) 13.8, 4.9 Hz, 1H), 2.33 (dd, J ) 13.8, 10.3 Hz,
1H), 2.64 (s, 3H), 2.81 (m, 1H), 2.99 (dd, J ) 10.3, 4.9 Hz, 1H),
3.43 (m, 2H), 6.95 (m, 2H), 7.22 (m, 3H); 13C NMR (75.5 MHz,
CDCl3) δ 15.6 (CH3), 24.4 (CH2), 28.7 (CH3), 29.6 (CH2), 39.2
(CH2), 44.2 (CH2), 48.5 (CH), 65.9 (C), 66.4 (C), 127.5 (CH),
128.1 (CH), 128.7 (CH), 139.4 (C), 169.4 (CdO), 171.9 (CdO).
Minor diastereomer: 1H NMR (300 MHz, CDCl3) (major peaks)
δ 1.13 (s, 3H), 1.76 (dd, J ) 14.2, 6.5 Hz, 1H), 2.42 (dd, J )
14.2, 10.5 Hz, 1H), 2.87 (s, 3H), 3.09 (dd, J ) 10.5, 6.5 Hz,
1H), 3.56 (m, 2H), 6.95 (m, 2H), 7.22 (m, 3H);13C NMR (75.5
MHz, CDCl3) δ 15.8 (CH3), 24.5 (CH2), 27.0 (CH3), 29.8 (CH2),
40.2 (CH2), 44.4 (CH2), 51.0 (CH), 66.1 (C), 66.3 (C), 127.7 (CH),
128.5 (CH), 128.9 (CH), 140.0 (C), 168.0 (CdO), 172.0 (CdO);
HRMS calcd for C17H20N2O2 284.1525, found 284.1522. Anal.
Calcd for C17H20N2O2: C, 71.81; H, 7.09; N, 9.85. Found: C,
71.92; H, 7.11; N, 9.78.
44c: yield 45 mg (22%); Rf ) 0.60 (EtOAc/hexane, 1:1);
amorphous solid; mp 60 °C (EtOAc/hexane); 1H NMR (300
MHz, CDCl3) δ 0.50 (m, 1H), 0.98 (d, J ) 6.6 Hz, 3H), 1.09 (d,
J ) 6.6 Hz, 3H), 1.50 (m, 1H), 1.66 (dd, J ) 4.6, 14.4 Hz, 1H),
1.86 (m, 1H), 1.98 (m, 1H), 2.14 (dd, J ) 4.9, 14.4 Hz, 1H),
2.71 (m, 1H), 2.72 (d, J ) 14.1 Hz, 1H), 2.79 (s, 3H), 2.99 (m,
1H), 3.13 (m, 1H), 3.18 (d, J )14.Hz, 1H), 6.77 (m, 2H), 7.12-
7.23 (m, 8H); 13C NMR (75.5 MHz, CDCl3) δ 23.4 (CH2), 25.1
(CH), 25.7 [(CH3)2], 25.8 [(CH3)2], 28.2 (CH2), 28.4 (CH3), 38.8
(CH2), 44.4 (CH2), 50.2 (CH2), 55.7 (C), 65.5 (C), 72.8 (C), 126.8
(CH), 127.5 (CH), 128.2 (CH), 128.7 (CH), 129.3 (CH), 130.0
(CH), 145.5 (C), 147.9 (C), 170.1 (CdO), 172.7 (CdO); HRMS
calcd for C26H31N2O2 403.2386, found 403.2388 (M+ + H).
(3R,6S)-3-(2,2-Diph en ylvin yl)-3-isobu tyl-1,4,6-tr im eth yl-
2,5-p ip er a zin ed ion e (41d ), (3S,6S)-3-(2,2-Dip h en ylvin yl)-
3-isobu tyl-1,4,6-tr im eth yl-2,5-p ip er a zin ed ion e (42d ), a n d
tr a n s-3-(2,2-Dip h en ylvin yl)-6-isob u t yl-1,3,4-t r im et h yl-
2,5-p ip er a zin ed ion e (47d ). Entry 4, reflux, 7 days. Chroma-
tography EtOAc/hexane 2:1 (reactant 39c Rf ) 0.20) gave three
product fractions. 41d : 118 mg of a crude product (Rf ) 0.37)
were obtained, consisting of 41d , 1,4-dimethyl-6-isobutyl-3-
methylidenepiperazine-2,5-dione (48) and E-isomer (E-39).
Further chromatography with acetone/CHCl3 (1:8) afforded a
mixture (15 mg, 14%, Rf ) 0.54) of 48 and E-39 and pure 44d
(102 mg, 52%, Rf ) 0.63): [R]20D ) +45.1 (c 1, CHCl3); colorless
crystals, mp 136-138 °C (CH2Cl2/hexane); 1H NMR (300 MHz,
CDCl3) δ 0.79 (d, J ) 4.9 Hz, 3H), 0.82 (d, J ) 4.9 Hz, 3H),
1.26 (d, J ) 7.0 Hz, 3H), 1.38 (m, 1H), 1.86 (dd, J ) 5.1, 14.4
Hz, 1H), 2.27 (dd, J ) 6.1, 14.4 Hz, 1H), 2.61 (s, 3H), 2.73 (s,
3H), 2.76 (q, J ) 7.0 Hz, 1H), 6.03 (s, 1H), 6.95 (m, 2H), 7.08-
7.31 (m, 8H); 13C NMR (75.5 MHz, CDCl3) δ 19.3 (CH3), 23.6
[(CH3)2], 23.8 [(CH3)2], 23.9 (CH), 29.6 (CH3), 32.1 (CH3), 48.1
(CH2), 56.1 (CH), 65.6 (C), 127.0 (CH), 127.8 (CH), 128.0 (CH),
128.2 (CH), 128.3 (CH), 128.6 (CH), 131.0 (CH), 138.0 (C),
141.1 (C), 145.0 (C), 165.7 (CdO), 166.5 (CdO); HRMS calcd
for C25H30N2O2 390.2307, found 390.2312.
(3R,8a S)-2,3-Dim et h yl-3-(2,2-d ip h en ylvin yl)h exa h y-
d r op yr r olo[1,2-a ]p yr a zin e-1,4-d ion e (41b) a n d 7,8-Di-
m e t h y l-11,11-d ip h e n y l-5,8-d ia za t r ic y c lo [5.2.2.01 ,5 ]-
u n d eca n e-6,9-d ion e (45b). Entry2, 3 h reflux, chromatography
acetone/CHCl3/hexane 1:2 (reactant 39a Rf ) 0.17). 41b: yield
111 mg (61%); Rf ) 0.24; [R]20 ) +75.6° (c 0.5, CHCl3);
D
amorphous solid; mp 170-177 °C (EtOAc/hexane); 1H NMR
(300 MHz, CDCl3) δ 1.54 (m, 1H), 1.66 (s, 3H), 1.62-1.80 (m,
2H), 2.13 (m), 2.77 (s, 3H), 3.09 (m, 1H), 3.10 (dd, J ) 6.3,
10.1 Hz, 1H), 3.99 (m, 1H), 6.00 (s, 1H), 7.02-7.32 (m, 10H);
13C NMR (75,5 MHz, CDCl3) δ 21.7 (CH2), 26.0 (CH3), 28.7
(CH3), 29.3 (CH2), 45.1 (CH2), 58.0 (CH), 64.5 (C), 126.9 (CH),
127.8 (C), 128.0 (CH), 128.2 (CH), 129.1 (CH), 137.5 (C), 141.2
(C), 144.8 (C), 165.7 (CdO), 167.4 (CdO); HRMS calcd for
C
23H24N2O2 360.1838, found 360.1841.
45b: yield 38 mg (21%); Rf ) 0.45; amorphous solid; mp 90
°C (EtOAc/hexane); 1H NMR (300 MHz, CDCl3)δ 1.50 (s, 3H),
1.69 (m, 1H), 1.98 (m, 2H), 2.24 (s, 3H), 2.32 (d, J ) 14.1 Hz,
1H), 2.84 (m, 1H), 3.09 (d, J ) 14.1 Hz, 1H), 3.30 (m, 1H),
3.57 (m, 1H), 6.91 (m, 2H), 7.11-7.26 (m, 8H); 13C NMR (75.5
MHz, CDCl3) δ 14.3 (CH3), 24.3 (CH2), 28.2 (CH3), 29.8 (CH2),
44.5 (CH2), 49.4 (CH2), 58.4 (C), 66.2 (C), 68.3 (C), 126.0 (CH),
127.1 (CH), 127.5 (2CH), 128.3 (2CH), 128.4 (2CH), 130.3