9200 J . Org. Chem., Vol. 62, No. 26, 1997
Brodfuehrer et al.
yield): 1H NMR (DMSO-d6) δ 1.82 (m, 2H), 2.56 (d, 3 H, J )
5.0 Hz), 2.73 (t, 2 H, J ) 7.7 Hz), 3.49 (m, 2 H,), 4.36 (s, 2 H),
4.47 (t, 1 H, J ) 5.2 Hz), 6.78 (q, 1 H, J ) 5.0 Hz), 7.09 (dd, 2
was added 20 (27.73 g, 230 mmol), followed by triethylamine
(28 mL, 200 mmol). The resulting mixture was stirred for 1.5
h at 0-5 °C, at which point conversion to chlorohydrazone 33
was complete (HPLC). The reaction mixture was filtered
through a Celite pad to remove the precipitated triethylamine
hydrochloride, and the pad was washed with BuOAc (80 mL).
Crude 33 could be isolated as a ∼3:1 mixture of isomers by
concentrating the filtrate but generally was carried on directly
to the indolization reaction: 1H NMR of the major isomer
(DMSO-d6) δ 1.60 (m, 2 H), 1.75 (m, 2 H), 2.27 (m, 2 H), 2.51
(d, 3 H, J ) 5.0 Hz), 3.66 (t, 2 H, J ) 6.4 Hz), 4.13 (s, 2 H),
6.82 (m, 3 H), 7.03 (m, 3 H), 9.76 (s, 1 H). The filtrate was
cooled to 0-5 °C and added dropwise to a vigorously stirred
mixture of BuOAc (300 mL) and 6 M H3PO4 (120 mL, 720
mmol) at 105-108 °C in a jacketed reactor equipped with a
bottom drain. The addition was done as fast as possible while
still maintaining a reflux of the reaction mixture. Stirring was
stopped 15 min after completion of the addition, the lower
aqueous H3PO4 phase was drained off, and fresh 6 M H3PO4
(120 mL, 720 mmol) was added. Heating and stirring were
resumed for 30 min, and then the aqueous H3PO4 phase
exchange was done once more. After an additional 45 min-
1.5 h the reaction was complete by HPLC. The phases were
separated, and the BuOAc phase was washed with cold (0-5
°C) water (2 × 200 mL), followed by saturated NaHCO3 (2 ×
200 mL), and then concentrated in vacuo to a volume of ∼100
mL. This solution was seeded with ∼10 mg of crystalline 35
and BuOAc:hexane (1:1, 60 mL) added slowly until a thick
crystal slurry was obtained. Crystallization was completed
by further slow addition of hexane (60 mL). The crystal slurry
was stirred for 1 h at 20 °C, and then the solid was collected
by filtration, washed with BuOAc:hexane (1:4, 50 mL), and
dried to constant weight in vacuo at 20 °C to give 35 as a tan
crystalline solid (44.11 g, 73%). This material assayed at 87%
purity by HPLC vs standard for an isolated activity yield of
64%. An analytical sample was prepared by recrystallization
from EtOAc: mp 102-104 °C; 1H NMR (DMSO-d6) δ 2.12 (m,
2 H), 2.57 (d, 3 H, J ) 5.0 Hz), 2.84 (t, 2 H, J ) 7.2 Hz), 3.71
(t, 2 H, J ) 6.6 Hz), 4.37 (s, 2 H), 6.81 (q, 1 H, J ) 5.0 Hz),
7.12 (dd, 1 H, J ) 8.5, 1.6 Hz), 7.21 (d, 1 H, J ) 1.6 Hz), 7.36
(d, 1 H, J ) 8.5 Hz), 7.56 (s, 1 H), 10.90 (s, 1 H); 13C NMR
(DMSO-d6) δ 22.8, 29.8, 33.6, 46.0, 57.4, 112.1, 113.9, 120.7,
121.6, 124.0, 124.7, 127.9, 136.9; ES- MS m/z 299 (100) M -
H+.
4-(5-Meth oxy-4-p yr im id in yl)-1-[3-[5-[[(m eth yla m in o)-
su lfon yl]m eth yl]-1H-in dol-3-yl]pr opyl]piper azin e (1) fr om
8. To a stirred solution of 8 (4.17 g, 14.8 mmol) in pyridine
(45 mL) under Ar at 0-5 °C were added DMAP (0.18 g, 1.5
mmol) and p-toluenesulfonic anhydride (5.96 g, 17.7 mmol).
The reaction mixture was stirred at 0-5 °C for 1 h, at which
point HPLC showed the reaction was complete. The reaction
mixture was concentrated in vacuo, and the residue was
dissolved in CH2Cl2 (100 mL). The organic solution was
washed with 1 N HCl (2 × 30 mL) and water (3 × 30 mL).
The combined aqueous washes were back-extracted with CH2-
Cl2 (30 mL), and the combined organic solution was dried over
MgSO4 and concentrated in vacuo to give tosylindole 39b as a
viscous yellow oil (6.05 g): 1H NMR (CDCl3) δ 2.02 (m, 2 H),
2.43 (s, 3 H), 2.68 (s, 3 H), 2.79 (t, 2 H, J ) 7.1 Hz), 4.05 (t, 2
H, J ) 6.2 Hz), 4.33 (s, 2 H), 6.95 (s, 1 H), 7.17 (d, 1 H, J ) 8.0
Hz), 7.35 (m, 3 H), 7.57 (s, 1 H), 7.78 (d, 2 H, J ) 8.2 Hz), 8.18
(br s, 1 H). This material was used directly in the next step
by dissolving in acetone (42 mL) and N,N-diisopropylethy-
lamine (3.1 mL, 17.7 mmol) and adding 9 (5.74 g, 29.5 mmol).
The reaction mixture was heated at reflux for 2.5 h, at which
point conversion to 1 was complete (HPLC). EtOAc (50 mL)
and water (25 mL) were added, and the phases were separated.
The aqueous phase was extracted with EtOAc (30 mL). The
organic phases were combined and washed with saturated
NaHCO3 and saturated NaCl, dried over MgSO4, and concen-
trated in vacuo to give the crude product as a foam (5.81 g).
This material was purified by flash chromatography on silica
gel (CH2Cl2, MeOH, NH4OH; 95:5:0.5) to give 1 as an off-white
foam (3.59 g, 53% yield). An analytical sample was prepared
by crystallization from anhydrous EtOH: mp 173-174 °C; 1H
NMR (DMSO-d6) δ 1.75 (m, 2 H), 2.29 (t, 2 H, J ) 7.2 Hz),
H, J ) 8.6, 1.8 Hz) 7.33 (d, 1 H, J ) 8.6 Hz), 7.53 (s, 1 H); 13
C
NMR (DMSO-d6) δ 22.0, 29.8, 34.1, 57.5, 61.4, 112.0, 115.5,
120.4, 121.7, 123.6, 124.5, 128.1, 136.9; ES+ MS m/z 283 (21)
MH+, 565 (52) 2M + H+. Three impurities giving another 20%
yield were also isolated from the chromatography. 36: 1H
NMR (DMSO-d6) δ 1.30-1.95 (m, 8 H), 2.55 (d, 3 H, J ) 5.0
Hz), 2.72 (m, 2 H), 3.35 (m, 2 H), 3.70 (m, 2 H), 4.35 (s, 2 H),
4.53 (s, 1 H), 6.80 (m, 1 H), 7.07 (d, 1 H, J ) 8.6 Hz), 7.15 (s,
1 H), 7.27 (d, 1 H, J ) 8.6 Hz), 7.38 (s, 1 H), 7.52 (s, 1 H). 37:
1
mp 118-120 °C; H NMR (DMSO-d6) δ 1.34-1.90 (m, 8 H),
2.32 (d, 3 H, J ) 5.0 Hz), 2.47 (t, 2 H, J ) 7.2 Hz), 3.25 (m, 2
H), 3.49 (m, 1 H), 3.72 (m, 1 H), 4.13 (s, 2 H), 4.23 (br s, 1 H),
5.33 (d, 1 H, J ) 9.5 Hz), 6.54 (m, 1 H), 6.92 (d, 1 H, J ) 8.6
Hz), 7.07 (s, 1 H), 7.27 (d, 1 H, J ) 8.6 Hz), 7.29 (s, 1 H); 13C
NMR (DMSO-d6) δ 21.9, 23.7, 25.7, 29.8, 31.1, 33.8, 57.2, 61.3,
68.0, 83.3, 111.1, 116.2, 121.6, 122.0, 123.5, 125.0, 128.9, 136.6;
ES+ MS m/z 367 (100) MH+. 38: 1H NMR (DMSO-d6) δ 2.03
(m, 4 H), 2.78 (d, 3 H, J ) 5.0 Hz), 2.92 (m, 2 H), 2.98 (m, 2
H), 3.72 (t, 4 H, J ) 6.3 Hz), 4.36 (s, 2 H), 4.57 (s, 2 H), 4.69
(br s, 2 H), 6.99 (q, 1 H, J ) 5.0 Hz), 7.19 (d, 1 H, J ) 8.1 Hz),
7.24 (d, 1 H, J ) 8.6 Hz), 7.30 (d, 1 H, J ) 1.8 Hz), 7.46 (d, 1
H, J ) 8.1 Hz), 7.47 (d, 1 H, J ) 8.1 Hz), 7.67 (s, 1 H), 7.70 (s,
1 H), 10.86 (s, 1 H), 10.93 (s, 1 H); 13C NMR (DMSO-d6) δ 21.1,
22.1, 29.8, 32.8, 34.1, 34.9, 41.1, 61.4, 61.5, 111.2, 112.0, 115.1,
118.7, 120.2, 121.2, 122.6, 123.2, 123.7, 128.2, 129.1, 130.1,
135.9, 136.1, 137.0; ES+ MS m/z 470 (70) MH+.
N-Met h yl-3-(3′-b r om op r op yl)-1H -in d olyl-5-m et h a n e-
su lfon a m id e (34). To a stirred hazy solution of the HCl salt
of 6 (10.07 g, 40.0 mmol) in EtOH (100 mL)/water (50 mL)
under Ar at 20 °C was added 17 (10.13 g, 48.0 mmol) dropwise
during 1-2 min. The resulting mixture was stirred for 1 h as
the pH dropped from 2.2 to 1.1. The pH was adjusted to 4.0
with 50% NaOH, and after 15 min conversion to bromohydra-
zone 32 was complete (HPLC). The reaction mixture was
clarified by filtration through a Celite pad, which was washed
with EtOH (25 mL). The filtrate was concentrated in vacuo
to remove EtOH, and the aqueous residue was extracted with
BuOAc (3 × 100 mL). The combined BuOAc phase was
washed with saturated NaCl, dried over MgSO4, and filtered
through a Celite pad, which was washed with BuOAc (25 mL).
Crude 32 could be isolated as a ∼3:1 mixture of isomers by
concentrating to a residue but was generally carried on to the
indolization step without isolation. 1H NMR of the major
isomer (DMSO-d6): δ 1.60 (m, 2 H), 1.85 (m, 2 H), 2.25 (m, 2
H), 2.50 (d, 3 H, J ) 4.0 Hz), 3.54 (m, 2H), 4.13 (s, 2 H), 6.83
(m, 3 H), 7.10 (m, 3 H), 9.77 (br s, 1 H). The filtrate was added
to 6 M H3PO4 (24 mL, 144 mmol) in a jacketed reactor
equipped with a bottom drain. The resulting two-phase
mixture was stirred vigorously and heated at reflux (jacket
temperature of 110 °C) for 30 min. Stirring was stopped, the
lower aqueous H3PO4 phase was drained off, and fresh 6 M
H3PO4 (24 mL, 144 mmol) was added. Heating and stirring
were resumed for an additional 30 min. Stirring was stopped,
and the H3PO4 phase exchange was done once more. Heating
and stirring were continued an additional 30 min, at which
point no 32 remained (HPLC). The reaction mixture was
cooled to 20 °C, and the phases were separated. The BuOAc
phase was washed with saturated NaHCO3 and saturated
NaCl, dried over Na2SO4, and concentrated in vacuo to give
34 as a pale orange crystalline solid (9.35 g). This material
assayed at 87% purity by HPLC vs a standard for an overall
activity yield of 59%. An analytical sample was prepared by
recrystallization from BuOAc: mp 108-109 °C; 1H NMR
(DMSO-d6) δ 2.39 (m, 2 H), 2.77 (d, 3 H, J ) 5.0 Hz), 3.05 (t,
2 H, J ) 7.2 Hz), 3.79 (t, 2 H, J ) 6.6 Hz), 4.57 (s, 2 H), 6.99
(q, 1 H, J ) 5.0 Hz), 7.31 (dd, 1 H, J ) 8.5, 1.6 Hz), 7.40 (d, 1
H, J ) 1.6 Hz), 7.55 (d, 1 H, J ) 8.5 Hz), 7.75 (s, 1 H); 13C
NMR (DMSO-d6) δ 24.0, 29.8, 33.8, 35.8, 57.4, 112.1, 113.8,
120.7, 121.6, 124.0, 124.7, 127.9, 136.9; ES- MS m/z 343 (100)
M - H+.
N-Met h yl-3-(3′-ch lor op r op yl)-1H -in d olyl-5-m et h a n e-
su lfon a m id e (35). To a stirred slurry of the HCl salt of 6
(50.34 g, 200 mmol) in BuOAc (500 mL) under Ar at 0-5 °C