Synthesis of Tetrahydroisoquinolin-1-ones
J . Org. Chem., Vol. 66, No. 6, 2001 1997
as the hydrobromide, [R]25
) 9.5 (c ) 0.21, CH
Cl
), which
sec-Bu Li/TMEDA Meta la tion . Gen er a l P r oced u r e. A
solution of 7b (140 mg, 0.60 mmol) in dry THF (3 mL) was
added to a stirred solution of sec-BuLi (1.00 mmol) and
TMEDA (1.00 mmol) in THF (2 mL) at -78 °C under argon.
After 1 h, a solution of the imine 2 (1.00 mmol) in dry THF (2
mL) was added, and the reaction mixture was allowed to warm
D
2
2
was recrystallized from CH
2 2
Cl /hexanes 4:1 to give suitable
crystals. X-ray analysis of 5‚HBr: C16
H
18NBr, M ) 304.22,
r
crystal size 0.1 × 0.3 × 0.4 mm, orthorhombic, space group
P2(1)2(1)2(1), a ) 11.61(3) Å, b ) 17.25(5) Å, c ) 18.05(5) Å,
3
R, â, γ ) 90°, V ) 3613(18) Å , T ) 296 K, Z ) 8, λ ) 0.710 73,
2
0
4172 independent reflexes, 8392 refined parameters, R1 )
.0761, wR2 ) 0.1845.
to rt. A solution of saturated NH
the mixture was concentrated in vacuo. The aqueous phase
was extracted with Et
O (3 × 20 mL), and the combined
organic layer was washed with H
O (2 × 15 mL) and with
brine (15 mL). The organic phase was dried (Na SO ) and
4
Cl (1 mL) was added, and
(
()-N-Meth yl-4-m eth yl-3-p h en yltetr a h yd r oisoqu in oli-
2
2
n on e (8a ,b). According to the general procedures above, the
reaction of 7c (22 mg, 0.1 mmol) with 2a yielded, after flash
chromatography (hexanes/ethyl acetate 3:1), 9 mg (36%) of 8a
2
4
concentrated in vacuo, and the crude product was purified by
flash chromatography with hexanes/ethyl acetate 3:1 as
solvent.
sec-Bu Li/(-)-sp a r t ein e Met a la t ion . Gen er a l P r oce-
d u r e. To a solution of 7b (35 Mg, 0.15 mmol) in dry toluene
(R
f
) 0.13) as a colorless solid (98% by GC, mp 132-133 °C)
and 3 mg (12%) of 8b (R ) 0.08) as a colorless oil (93% by
GC). 8a . IR (KBr) ν: 3061, 2959, 1647, 1255 cm . H NMR
300 MHz, CDCl
f
-
1
1
(
7
7
CH
3
) δ: 8.19-8.16 (m, 1H), 7.37-7.20 (m, 5H),
.06-6.98 (m, 3H, arom CH), 4.50 (s, 1H, 3-H), 3.16 (q, J )
.1 Hz, 1H, 4-H), 3.15 (s, 3H, NCH
(2 mL) was added a freshly prepared, precooled solution of sec-
BuLi (0.20 mmol) and (-)-sparteine (0.20 mmol) in toluene (2
mL) at -78 °C under argon via syringe. After 1 h, a solution
of the imine 2 (0.22 mmol) in dry toluene (1 mL) was added
slowly via syringe, and the reaction mixture was allowed to
3
), 1.52 (d, J ) 7.1 Hz, 3H,
) δ: 164.3, 141.0, 140.1, 128.6,
1
3
3
). C NMR (75 MHz, CDCl
3
1
2
32.0, 128.6, 127.9, 127.5, 127.2, 127.0, 125.9, 68.8, 41.0, 34.9,
3.7 ppm. MS (EI) m/z: 251 (5) [M ], 236 (5), 174 (14), 165
+
warm to rt. A solution of saturated NH
and the mixture was concentrated in vacuo. The aqueous phase
was extracted with Et
O (3 × 20 mL), and the combined
organic layer was washed with H
O (2 × 15 mL) and with
brine (15 mL). The organic phase was dried (Na SO ) and
4
Cl (1 mL) was added,
(
8), 159 (3), 144 (3), 132 (100), 118 (30), 104 (64). HRMS: calcd
for C17 17NO 251.1310, found 251.1301. X-ray analysis of 8a :
) 251.32, crystal size 0.2 × 0.3 × 0.4 mm, monoclinic, space
group P2(1)/n, a ) 8.792(3) Å, b ) 11.590(4) Å, c ) 13.546(5)
H
2
M
r
2
3
-3
2
4
Å, â ) 101.459(7)°, V ) 1352.8(8) Å , Fcalcd ) 1.234 Mg m , T
296 K, Z ) 4, λ ) 0.71073, 9210 independent reflexes, 3219
refined parameters, R1 ) 0.0820, wR2 ) 0.2114. 8b. IR (NaCl)
concentrated in vacuo, and the crude product was purified by
flash chromatography with hexanes/ethyl acetate 3:1 as
solvent.
)
-
1
1
ν ) 2925, 1646, 1455 cm
3
. H NMR (300 MHz, CDCl ) δ:
(
()-N ,N -Diisop r op yl-t r a n s-[o-(2-N -p h e n yla m in o)-2-
p h en yl-1-m eth yl]ben za m id e (10c). Flash chromatography
hexanes/ethyl acetate 15:1) yielded 179 mg (0.43 mmol, 72%)
of 10c (R ) 0.10) as a colorless solid (99% by GC, 81% de, mp
62-164 °C). 10c: [R]25
: 5.4 (c (10c‚HCl) ) 0.13, CH Cl2, 98%
ee determined by Chiracel-OD-HPLC column, hexanes/ PrOH
8
6
.21-8.18 (m, 1H), 7.46-6.89 (m, 8H, arom CH), 4.48 (d, J )
.2 Hz, 3-H), 3.87 (dd, J ) 6.2/7.1 Hz, 1H, 4-H), 3.16 (s, 3H,
(
NCH
(
3
), 1.22 (d, J ) 7.1 Hz, 3H, 1′-H). GC-MS (CI) m/z: 251
+
f
30) [M ], 236 (51), 207 (22), 174 (24), 132 (100), 104 (55), 78
35).
()-N-Meth yl-tr a n s-3-p h en yl-4-tr im eth ylsilyltetr a h y-
1
D
2
(
i
(
9
1
2:8, flow: 0.4 mL/min). IR (KBr) ν: 3312, 3022, 2960, 1610,
d r oisoqu in olin on e (9a ). To a freshly prepared solution of
LDA (1.20 mmol of n-BuLi was added dropwise to diisopro-
pylamine (1.20 mmol) in dry THF (4 mL) at 0 °C) was added
a solution of 1e (205 mg, 1.00 mmol) in dry THF (2 mL)
dropwise by syringe at -78 °C under argon. After 10 min of
stirring, a solution of 2a (1.20 mmol) in THF (2 mL) was added.
The reaction mixture was stirred at -78 °C for 20 min and
allowed to warm to -50 °C over 2 h. TMSCl (1.50 mmol) was
added in one portion, and the reaction mixture was allowed
-1
1
3
600, 1342, 1138, 1032, 743 cm . H NMR (300 MHz, CDCl )
δ: 7.51-7.47 (m, 3H), 7.30-7.14 (m, 4H), 6.99 (t, J ) 7.1 Hz,
2
1
H), 6.45-6.38 (m, 3H, NH, arom CH), 4.17 (d, J ) 10.3 Hz,
H, 2′-H), 3.87, 3.67 (dq, J ) 6.6, 6.6 Hz, 2H, CH(CH ), 3.03
3 2
)
(
dd, J ) 6.7, 10.3 Hz, 1H, 1′-H), 1.73, 1.69 (d, J ) 6.6 Hz, 6H,
CH(CH ), 1.19 (d, J ) 6.7 Hz, 3H, CH ), 1.08, 1.06 (d, J )
). C NMR (75 MHz, CDCl ) δ: 171.7,
3
)
2
3
13
6
1
1
2
3
.6 Hz, 6H, CH(CH
3
)
2
3
48.5, 144.7, 141.2, 137.8, 129.5, 128.9, 128.8, 127.9, 127.4,
26.9, 126.4, 124.5, 115.7, 112.8, 65.5, 51.5, 46.5, 43.3, 21.3,
to warm to rt. Et
was washed with H
Na SO ) and concentrated in vacuo to give the crude product.
2
O (20 mL) was added, and the organic phase
+
1.1, 20.9, 20.9, 19.3. GC-MS (CI) m/z 415 (100) [M + 1],
2
O (5 mL). The organic phase was dried
+
22 (72) [M - NHPh], 233 (31), 204 (32), 182 (31), 77(36)
(
2
4
+
[Ph ]. HRMS: calcd for C28
H
34
N
2
O 414.2671, found 414.2661.
Flash chromatography (hexanes/ethyl acetate 3:1) yielded 146
mg (0.62 mmol, 62%) of 3a (99% by GC) and 24 mg (0.8 mmol,
+
1
2
1c. GC-MS (EI) m/z: 415 (9) [M + 1], 322 (61), 313 (30),
80 (79), 256 (4), 236 (6), 102 (100), 93 (4), 77 (12).
8
9
%) of 9a (R
9-100 °C. IR (KBr) ν: 2925, 1644, 1245 cm . H NMR (300
) δ: 8.14 (dd, J ) 1.0, 7.5 Hz, 1H), 7.31-7.17 (m,
H), 7.04 (dd, J ) 2.0, 7.9 Hz, 1H), 6.79 (dd, J ) 0.5, 7.5 Hz,
H, arom CH), 4.72 (s, 3-H), 3.12 (NCH ), 2.55 (s, 4-H), 0.08
). C NMR (75 MHz, CDCl ) δ: 165.0, 141.8
f
) 0.38) as a colorless solid (97% by GC). Mp:
(
()-N,N-Diisopr opyl-tr a n s-[o-(2-N-ben zylam in o)-2-ph en -
yl-1-m eth yl]ben zam ide (10h ). Flash chromatography yielded
39 mg (0.32 mmol, 54%) of 10h (R
93% by GC, 90% de). 10h : IR (KBr) ν: 3328, 3061, 2967, 1628,
-
1 1
MHz, CDCl
6
1
3
1
(
1
7
f
) 0.10) as a colorless oil
3
-1
1
453, 1337, 1032, 701 cm
.47-7.03 (m, 15H, NH, arom CH), 3.88-3.66 (m, 2H,
, CH Ph*), 3.61-3.47 (m, 2H, CH(CH , 2′-H), 3.36,
.28* (d, J ) 14.5, 1H, CH Ph*), 3.09-2.97 (m, 1H, 1′-H),
.72-1.57 (m, 6H, CH(CH *), 1.31-1.02 (m, 6H, CH(CH *),
*). C NMR (75 MHz,
3
. H NMR (300 MHz, CDCl ) δ:
1
3
(s, 9H, Si(CH
3
)
3
3
1
6
38.2, 127.9, 131.5, 128.6, 127.8, 127.4, 127.1, 125.5, 125.4,
CH(CH
3
)
2
a
3 2
)
3.3, 39.8, 34.6, -2.9. MS (CI) m/z: 310 (100) [M+ + 1],0.238
3
1
0
b
(13), 232 (27), 160 (10), 149 (17), 135 (10), 123 (16), 111 (29).
3
)
2
3 2
)
HRMS: calcd for C19
()-N-Meth yl-tr a n s-4-a llyl-3-p h en yltetr a h yd r oisoqu in -
olin on e (9b). Flash chromatography (hexanes/ethyl acetate
H
23NOSi 309.1549, found 309.1567.
13
.98, 0.93* (d, J ) 7.8 Hz, 3H, CH
3
(
CDCl ) δ: 170.8, 169.9*, 141.3*, 139.1, 138.8*, 138.5, 128.8,
3
128.4, 128.2, 128.0, 128.0, 127.8*, 127.3*, 126.9, 126.6, 126.4*,
126.1, 125.0, 124.4, 67.2, 51.6*, 51.1*, 50.7, 50.3, 45.8, 44.2*,
42.4, 42.2, 21.0*, 20.7, 20.6, 19.6 (rotamers are marked with
3
4
:1) yielded 175 mg (0.74 mmol, 74%) of 3a (96% by GC) and
0 mg (0.14 mmol, 14%) of 9b (R ) 0.33) as a colorless oil
f
-
1
1
+
(
97% by GC). IR (NaCl) ν: 3066, 2923, 1646, 1265 cm . H
*). MS (CI) m/z: 429 (100) [M + 1], 322 (15), 234 (34), 196
NMR (300 MHz, CDCl ) δ: 8.19-8.16 (m, 1H), 7.37-7.18 (m,
3
(61), 148 (3), 132 (9), 111 (19), 106 (26). HRMS (FAB): calcd
5
5
3
H), 7.02-6.97 (m, 3H, arom CH), 5.92-5.86 (m, 1H, 2′-H),
36 2
for C29H N O 428.2828, found 428.2806. 11h : GC-MS (CI)
.23-5.11 (m, 2H, 3′-H), 4.65 (s, 1H, 3-H), 3.14 (s, 3H, NCH3
3
),
m/z: 429 (100), 362 (10), 337 (27), 322 (57), 196 (71).
(()-N,N-Diisop r op yl-tr a n s-[o-(2-N-ben zyla m in o)-2-(4-
ch lor op h en yl)-1-m eth yl]ben za m id e (10i). Flash chroma-
.05 (dd, J ) 6.6, 8.2 Hz, 4-H), 2.56-2.48 (m, 2H, 1′-H). 1
C
NMR (75 MHz, CDCl
3
) δ: 163.2, 140.0, 139.1, 127.9, 140.0,
1
4
2
39.1, 135.4, 131.9, 128.6, 127.5, 127.3, 126.0, 118.3, 64.9, 46.2,
f
tography yielded 108 mg (0.23 mmol, 39%) of 10i (R ) 0.06)
+
1.5, 34.6 ppm. MS (EI) m/z: 277 (4) [M ], 248 (14), 236 (100),
21 (7), 200 (15), 195 (23), 178 (31), 165 (21), 158 (73), 147
as a pale yellow solid (94% by GC, 88% de, mp. 52-54 °C).
10i: IR (KBr) ν: 3295, 3061, 2961, 1618, 1453, 1339, 1090
-
1 1
(23), 129 (61), 118 (57). HRMS: calcd for C19
H
19NO 277.1467,
cm . H NMR (300 MHz, CDCl
3
) δ: 7.38-7.10 (m, 12H), 7.04-
found 277.1461.
7.01 (m, 1H), 6.93-6.89 (m, 1H, arom CH, NH), 3.86-3.66 (m,