Radical Cyclization of R-(Methylthio)acetamides
1-enyl)-N-(3,4-dimethoxybenzyl)-2-chloroacetamide thus ob-
tained was dissolved in EtOH (5 mL) and the solution was
added dropwise to a solution of NaSMe (295 mg, 4 mmol) in
EtOH (10 mL) at 0 °C. The mixture was stirred at room
temperature overnight and the solvent was evaporated off. The
residue was dissolved in water (10 mL) and the mixture was
extracted with AcOEt. The extract was washed with brine,
dried (MgSO4), and concentrated. The residue was chromato-
graphed on silica gel (hexane/AcOEt, 10:1) to give 6a (254 mg,
38%): IR ν 1635 cm-1; 1H NMR δ 1.53-1.74 (m, 4H), 2.03 (m,
4H), 2.26 (s, 3H), 3.28 (s, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 4.56
(br s, 2H), 5.47 (s, 1H), 6.79 (s, 2H), 7.26 (s, 1H); 13C NMR δ
16.3, 21.3, 22.6, 24.6, 28.1, 35.1, 49.1, 55.7, 110.5, 111.7, 120.8,
on e (11). Following the general procedure, compound 8 (94.1
mg, 0.282 mmol) was treated with Mn(OAc)3‚2H2O (772 mg,
2.82 mmol) and Cu(OAc)2 (51.2 mg, 0.282 mmol) in CF3CH2-
OH. After workup, the crude material was chromatographed
on silica gel (hexane/AcOEt, 20:1 to 10:1 to 5:1 to 3:1). The
first fraction gave 9 (26.4 mg, 28%): IR ν 1715 cm-1; 1H NMR
δ 1.81 (quint, J ) 6.3 Hz, 2H), 2.31 (q, J ) 5.5 Hz, 2H), 2.49
(s, 3H), 2.61 (t, J ) 6.3 Hz, 2H), 2.77 (t, J ) 7.6 Hz, 2H), 3.70
(t, J ) 7.6 Hz, 2H), 5.46 (t, J ) 4.8 Hz, 1H), 5.92 (s, 2H), 6.63
(dd, J ) 7.8, 1.8 Hz, 1H), 6.68 (d, J ) 1.3 Hz, 1H), 6.72 (d, J
) 7.9 Hz, 1H); 13C NMR δ 15.3, 23.2, 23.3, 24.3, 34.9, 41.2,
100.8, 108.3, 108.9, 109.3, 121.7, 122.4, 132.5, 138.3, 143.6,
146.1, 147.7, 167.7; HRMS calcd for C18H19NO3S (M+) 329.1085,
found 329.1093. The second fraction gave 10 (25.2 mg, 21%):
128.7, 130.4, 138.0, 148.1, 148.6, 168.7; HRMS calcd for C18H25
-
NO3S (M+) 335.1555, found 335.1559.
1
IR ν 1715 cm-1; H NMR δ 1.81 (quint, J ) 6.3 Hz, 2H), 2.30
N-(1,3-Ben zod ioxol-5-ylm eth yl)-N-(cycloh ex-1-en yl)-2-
(m eth ylth io)a ceta m id e (6b). Using a procedure similar to
that described above for 6a , compound 6b (543 mg, 34%) was
obtained from cyclohexanone (491 mg, 5.00 mmol), piperony-
lamine (756 mg, 5.00 mmol), chloroacetyl chloride (678 mg,
(q, J ) 5.4 Hz, 2H), 2.48 (s, 3H), 2.61 (t, J ) 6.6 Hz, 2H), 2.80
(t, J ) 7.6 Hz, 2H), 3.72 (t, J ) 7.6 Hz, 2H), 3.96 (q, J ) 8.4
Hz, 2H), 5.46 (t, J ) 4.6 Hz, 1H), 6.73 (dd, J ) 7.9, 1.7 Hz,
1H), 6.76 (d, J ) 1.3 Hz, 1H), 6.82 (d, J ) 7.9 Hz, 1H), 6.93 (s,
1H); 13C NMR δ 15.3, 23.2, 23.3, 24.3, 34.9, 41.1, 60.2 (q, J )
36.6 Hz), 77.2, 108.4, 108.7, 109.3, 117.8, 122.5, 133.4, 138.3,
143.5, 144.0, 145.5, 167.7; HRMS calcd for C20H20F3NO4S (M+)
427.1065, found 427.1077. The third fraction gave the starting
material 8 (5.4 mg, 6%). The fourth fraction gave 11 (trace):
6.00 mmol), and NaSMe (738 mg, 10.0 mmol): IR ν 1635 cm-1
;
1H NMR δ 1.25-1.70 (m, 4H), 2.03 (br s, 4H), 2.25 (s, 3H),
3.28 (s, 3H), 4.52 (s, 2H), 5.48 (br s, 1H), 5.92 (s, 2H), 6.71 (s,
2H), 6.81 (s, 1H); 13C NMR δ 16.3, 21.3, 22.6, 24.6, 28.1, 35.1,
49.2, 100.8, 107.7, 109.1, 121.9, 128.8, 131.7, 138.0, 146.6,
147.4, 168.8; HRMS (FAB) calcd for
320.1321, found 320.1327.
1
IR ν 1680, 1735 cm-1; H NMR δ 1.74-1.97 (m, 4H), 1.99 (s,
C
17H22NO3S (MH+)
3H), 2.47 (s, 3H), 2.76-2.89 (m, 2H), 3.27-3.56 (m, 4H), 5.33
(d, J ) 3.0 Hz, 1H), 5.94 (d, J ) 1.3 Hz, 1H), 5.97 (d, J ) 1.3
Hz, 1H), 6.74 (s, 1H), 6.97 (s, 1H).
1,4,5,6-Tet r a h yd r o-1-(3,4-d im et h oxyb en zyl)-3-m et h -
ylth io-2H-in d ol-2-on e (7a ). Following the general procedure,
compound 6a (61.5 mg, 0.183 mmol) was treated with Mn-
(OAc)3‚2H2O (502 mg, 1.83 mmol) and Cu(OAc)2 (33.2 mg,
0.183 mmol) in CF3CH2OH. After workup, the crude material
was chromatographed on silica gel (hexane/AcOEt, 10:1) to give
N-(Cycloh ex-1-en yl)-N-(2-p h en yleth yl)-2-(m eth ylth io)-
a ceta m id e (12). Using a procedure similar to that described
above for 6a , compound 12 (1.21 g, 61%) was obtained from
cyclohexanone (687 mg, 7.00 mmol), 2-phenylethylamine (848
mg, 7.00 mmol), chloroacetyl chloride (949 mg, 8.40 mmol),
1
7a (58.1 mg, 96%): IR ν 1685 cm-1; H NMR δ 1.80 (quint, J
1
and NaSMe (1.03 g, 16.8 mmol): IR ν 1635 cm-1; H NMR δ
) 6.2 Hz, 2H), 2.28 (q, J ) 5.5 Hz, 2H), 2.53 (s, 3H), 2.62 (t, J
) 6.4 Hz, 2H), 3.85 (s, 6H), 4.70 (s, 2H), 5.54 (t, J ) 4.6 Hz,
1H), 6.74-6.87 (m, 3H); 13C NMR δ 15.5, 23.0, 23.3, 24.3, 43.0,
55.8, 55.9, 110.6, 110.7, 111.0, 119.5, 122.1, 129.9, 138.2, 144.5,
148.3, 149.1, 168.1; HRMS calcd for C18H21NOS (M+) 331.1242,
found 331.1244.
1.56-1.73 (m, 4H), 2.08-2.09 (m, 4H), 2.22 (s, 3H), 2.85 (t, J
) 7.9 Hz, 2H), 3.24 (s, 2H), 3.60 (br t, J ) 7.9 Hz, 2H), 5.60
(br s, 1H), 7.18-7.30 (m, 5H); 13C NMR δ 16.2, 21.3, 22.6, 24.5,
27.8, 34.0, 35.1, 47.2, 126.0, 127.9, 128.2, 128.6, 138.5, 138.9,
168.6; HRMS calcd for C17H23NOS (M+) 289.1500, found
289.1494.
1-(1,3-Ben zod ioxol-5-ylm et h yl)-1,4,5,6-t et r a h yd r o-3-
m eth ylth io-2H-in d ol-2-on e (7b). Following the general pro-
cedure, compound 6b (90.6 mg, 0.284 mmol) was treated with
Mn(OAc)3‚2H2O (777 mg, 2.84 mmol) and Cu(OAc)2 (51.6 mg,
0.284 mmol) in CF3CH2OH. After workup, the crude material
was chromatographed on silica gel (hexane/AcOEt, 10:1). The
first fraction gave 7b (66.0 mg, 74%): IR ν 1685 cm-1; 1H NMR
δ 1.80 (quint, J ) 6.1 Hz, 2H), 2.28 (q, J ) 5.5 Hz, 2H), 2.53
(s, 3H), 2.62 (t, J ) 6.4 Hz, 2H), 4.66 (s, 2H), 5.50 (t, J ) 4.8
Hz, 1H), 5.92 (s, 2H), 6.71-6.81 (m, 3H); 13C NMR δ 15.3, 23.0,
23.2, 24.2, 42.8, 101.0, 107.9, 108.1, 109.9, 118.0, 120.4, 131.3,
1,4,5,6-Tetr a h yd r o-3-m eth ylth io-1-(2-p h en yleth yl)-2H-
in d ol-2-on e (13) a n d (7R*,7a R*)-7-Acet oxy-1,4,5,6-t et -
r a h yd r o-7a -h yd r oxy-3-m eth ylth io-1-(2-p h en yleth yl)-2H-
in d ol-2-on e (14). Following the general procedure, compound
12 (55.9 mg, 0.194 mmol) was treated with Mn(OAc)3‚2H2O
(531 mg, 1.94 mmol) and Cu(OAc)2 (35.2 mg, 0.194 mmol) in
CF3CH2OH. After workup, the crude material was chromato-
graphed on silica gel (hexane/AcOEt, 10:1). The first fraction
gave 13 (48.5 mg, 88%): IR ν 1690 cm-1; 1H NMR δ 1.80 (quint,
J ) 6.7 Hz, 2H), 2.28 (q, J ) 5.9 Hz, 2H), 2.50 (s, 3H), 2.57-
2.63 (m, 2H), 2.86 (t, J ) 7.8 Hz, 2H), 3.77 (t, J ) 7.8 Hz, 2H),
5.43 (t, J ) 4.6 Hz, 1H), 7.18-7.31 (m, 5H); 13C NMR δ 15.2,
23.1, 23.2, 24.3, 35.1, 41.0, 108.8, 126.4, 128.4, 128.8, 128.9,
138.2, 138.7, 143.4, 167.6; HRMS calcd for C17H19NOS (M+)
285.1188, found 285.1181. The second fraction gave 14 (8.0
138.1, 144.0, 146.8, 147.9, 167.8; HRMS (FAB) calcd for C17H18
-
NO3S (MH+) 316.1008, found 316.1001. The second fraction
gave the starting meterial 6b (10.0 mg, 11%).
N-[2-(1,3-Ben zod ioxol-5-yl)eth yl]-N-(cycloh ex-1-en yl)-
2-(m eth ylth io)a ceta m id e (8). Using a procedure similar to
that described above for 6a , compound 8 (807 mg, 41%) was
prepared from cyclohexanone (580 mg, 5.91 mmol), 3,4-
(methylenedioxyphenyl)ethylamine (977 mg, 5.91 mmol), chlo-
roacetyl chloride (801 mg, 7.09 mmol), and NaSMe (431 mg,
mg, 11%): IR ν 1740, 1695 cm-1 1H NMR δ 1.43-1.61 (m,
;
2H), 1.75-1.90 (m, 2H), 1.93 (s, 3H), 2.24 (td, J ) 13.4, 5.6
Hz, 1H), 2.52 (s, 3H), 2.74-2.88 (m, 2H), 3.03-3.28 (m, 2H),
3.58 (ddd, J ) 13.9, 8.5, 4.7 Hz, 1H), 5.23 (br s, 1H), 7.17-
7.32 (m, 5H); 13C NMR δ 15.8, 20.9, 21.2, 24.3, 26.1, 34.4, 41.2,
71.3, 77.2, 87.5, 126.6, 128.7, 129.0, 139.4, 155.6, 168.5, 169.5;
HRMS calcd for C19H23NO4S (M+) 361.1348, found 361.1353.
1
5.84 mmol): IR ν 1635 cm-1; H NMR δ 1.55-1.77 (m, 4H),
2.04-2.13 (m, 4H), 2.23 (s, 3H), 2.77 (t, J ) 7.9 Hz, 2H), 3.24
(s, 2H), 3.55 (br t, J ) 7.9 Hz, 2H), 5.63 (br s, 1H), 5.91 (s,
2H), 6.66-6.74 (m, 3H); 13C NMR δ 16.3, 21.4, 22.7, 24.7, 27.9,
33.9, 35.2, 47.6, 100.7, 108.1, 109.2, 121.6, 128.0, 132.8, 130.6,
145.9, 147.5, 168.7; HRMS (FAB) calcd for C18H24NO3S (MH+)
334.1477, found 334.1474.
Attem p ted Cycliza tion of 16. Following the general
procedure, compound 169 (86.9 mg, 0.290 mmol) was treated
with Mn(OAc)3‚2H2O (318 mg, 1.16 mmol) and Cu(OAc)2 (52.7
mg, 0.290 mmol) in CF3CH2OH for 6 h. After workup, the crude
material was chromatographed on silica gel (hexane/AcOEt,
2:1) to give recovered 16 (69.0 mg, 79%): 1H NMR δ 1.74-
1.84 (m, 2H), 2.24-2.31 (m, 2H), 2.57-2.63 (m, 2H), 2.77-
2.84 (m, 2H), 3.70-3.76 (m, 2H), 3.85 (s, 6H), 5.47 (br t, J )
4.6 Hz, 1H), 5.74 (s, 1H), 6.70-6.81 (m, 3H).
1-[2-(1,3-Ben zod ioxol-5-yl)eth yl]-1,4,5,6-tetr a h yd r o-3-
m eth ylth io-2H-in d ol-2-on e (9), 1-{2-[2-(2,2,2-Tr iflu or oet-
h oxy)-1,3-b en zod ioxol-5-yl]et h yl}-1,4,5,6-t et r a h yd r o-3-
m eth ylth io-2H-in d ol-2-on e (10), a n d (4R*,5S*)-4-Acetoxy-
15,16-m e t h yle n e d ioxy-7-(m e t h ylt h io)e r yt h r in -6-e n -8-
J . Org. Chem, Vol. 68, No. 2, 2003 317