686 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 4
Sternfeld et al.
CH2Cl2 (gradient 0:100 to 3:97) to give (3R)-N-(tert-butyloxy-
carbonyl)-3-(benzyloxy)pyrrolidine (2.53 g, 76%): 1H NMR (250
MHz, CDCl3) δ 1.46 (9H, s, OC(Me)3), 1.87-2.11 (2H, m, CH2),
3.42-3.50 (4H, m, 2 of CH2), 4.13 (1H, m, CHOCH2Ph), 4.53
(2H, s, OCH2Ph), 7.26-7.39 (5H, m, Ph).
filtered off, washed with ether, and dried in vacuo. The crude
product was dissolved in water, basified with concentrated
aqueous NaOH, and extracted with ethyl acetate (×5). The
combined extracts were dried (MgSO4) and evaporated in
vacuo to afford 10 (0.95 g, 54%): 1H NMR (250 MHz, CDCl3/
MeOH-d4) δ 3.98 (3H, br s, NH and NH2), 6.97 (2H, d, J )
12.0 Hz, 2 of Ar-H), 7.25 (2H, J ) 12.0 Hz, 2 of Ar-H), 8.48
(2H, s, 2 of Ar-H).
Gen er a l P r oced u r e for th e P r ep a r a tion of In d oles
11a ,c,d , a n d 30a -c. (3R)-3-(Ben zyloxy)-1-[2-(5-(1,2,4-tr ia -
zol-4-yl)-1H-in d ol-3-yl)eth yl]p yr r olid in e Hyd r ogen Ox-
a la te Hem ih yd r a te (11a ). A solution of 10 (1.25 g, 7.1 mmol)
and (R)-9a (1.90 g, 6.48 mmol) in 4% H2SO4 (25 mL) was
heated at reflux for 48 h. The mixture was cooled to room
temperature, basified with K2CO3, and extracted into ethyl
acetate (×3). The combined extracts were dried (MgSO4) and
evaporated in vacuo, and the residue was chromatographed
on silica gel, eluting with CH2Cl2/MeOH/NH3 (90:8:1) to give
11a (0.50 g, 22%).The hydrogen oxalate hemihydrate salt was
prepared. 11a : mp 97-98 °C; 1H NMR (360 MHz, DMSO-d6)
δ 1.96-2.22 (2H, m, CH2), 3.02-3.10 (2H, m, CH2), 3.12-3.35
(6H, m, 3 of CH2), 4.27 (1H, m, CHOBn), 4.50 (2H, s, CH2Ph),
7.29-7.38 (7H, m, 7 of Ar-H), 7.52 (1H, d, J ) 8.6 Hz, Ar-
H), 7.88 (1H, d, J ) 1.8 Hz, Ar-H), 9.02 (2H, s, 2 of Ar-H),
11.25 (1H, s, NH); MS m/z 388 [MH]+. Anal. (C23H25N5O‚
C2H2O4‚0.5H2O) C, H, N.
A solution of (3R)-N-(tert-butyloxycarbonyl)-3-(benzyloxy)-
pyrrolidine (5.0 g, 18.0 mmol) in 90% formic acid (150 mL)
was stirred at 0 °C for 0.3 h and then at room temperature
for 2.5 h. The solvent was evaporated in vacuo and the residue
neutralized by addition of saturated potassium carbonate
solution and extracted with n-butanol (2 × 40 mL). The solvent
was evaporated in vacuo and the residue azeotroped with
ethanol (×2) and chromatographed on silica gel eluting with
CH2Cl2/MeOH/NH3 (80:8:1) to give (3R)-N(H)-3-(benzyloxy)-
pyrrolidine (2.62 g, 82%): 1H NMR (250 MHz, CDCl3) δ 1.85-
1.93 (2H, m, CH2), 2.79-2.89 (2H, m, CH2), 3.07-3.17 (2H,
m, CH2), 4.11 (1H, m, CHOCH2Ph), 4.53 (2H, s, OCH2Ph),
7.24-7.38 (5H, m, Ph).
A mixture of (3R)-N(H)-3-(benzyloxy)pyrrolidine (2.60 g, 15.0
mmol), 4-chlorobutanal dimethyl acetal18 (2.29 g, 15.0 mmol),
and potassium carbonate (2.23 g, 16.0 mmol) in THF (40 mL)
was heated at reflux for 48 h. The mixture was cooled to room
temperature, water (70 mL) was added, and the mixture was
extracted with ethyl acetate (3 × 70 mL). The combined
extracts were dried (MgSO4) and evaporated in vacuo and the
residue chromatographed on silica gel eluting with MeOH/CH2-
Cl2 (5:95) to give (R)-9a (1.9 g, 44%): 1H NMR (250 MHz,
CDCl3) δ 1.57-1.67 (4H, m, 2 of CH2), 1.90 (1H, m, CH of CH2),
2.10 (1H, m, CH of CH2), 2.46-2.74 (5H, m, 2 of CH2 and CH
of CH2), 2.89 (1H, dd, J ) 10.3 and 6.1 Hz, CH of CH2), 3.31
(6H, s, CH(OMe)2), 4.14 (1H, m, CHOBn), 4.38 (1H, t, J ) 5.2
Hz, CH(OMe)2), 4.48 (2H, q, J ) 11.9 Hz, OCH2Ph), 7.24-
7.38 (5H, m, Ph).
(R)-9b: 1H NMR (250 MHz, DMSO-d6) δ 1.24-1.56 (6H, m,
3 of CH2), 1.82 (1H, m, CH), 2.21-2.55 (6H, m, 3 of CH2), 3.20
(6H, s, CH(OMe)2), 3.30 (2H, d, J ) 7.1 Hz, CH2OBn), 4.34
(1H, t, J ) 5.3 Hz, CH(OMe)2), 4.45 (2H, s, OCH2Ph), 7.24-
7.39 (5H, m, Ph).
29b: prepared from Boc-D-prolinol; 1H NMR (250 MHz,
CDCl3) δ 1.56-1.90 (8H, m, 4 of CH2), 2.17-2.30 (2H, m, 2 of
CH), 2.64 (1H, m, CH), 2.86 (1H, m, CH), 3.15 (1H, m, CH),
3.31 (6H, s, CH(OMe)2), 3.36 (1H, m, CH), 3.49 (1H, m, CH),
4.37 (1H, t, J ) 5.4 Hz, CH(OMe)2), 4.53 (2H, t, J ) 12.2 Hz,
CH2Ph), 7.25-7.35 (5H, m, Ph).
4′-(Tr ia zol-4-yl)p h en ylh yd r a zin e (10). A mixture of 4′-
aminoacetanilide (3.52 g, 23.4 mmol), N,N-dimethylformamide
azine37(3.33 g, 23.4 mmol), and p-toluenesulfonic acid mono-
hydrate (0.223 g, 1.17 mmol) in anhydrous toluene (100 mL)
was heated at reflux for 17 h. The beige-colored precipitate
was filtered off, washed with toluene and dichloromethane,
and dried in vacuo to give 4′-(1,2,4-triazol-4-yl)acetanilide (4.29
g, 91%): 1H NMR (250 MHz, MeOH-d4/DMSO-d6) δ 2.14 (3H,
s, Me), 7.60 (2H, d, J ) 8.8 Hz, 2 of Ar-H), 7.78 (2H, d, J )
8.8 Hz, 2 of Ar-H), 8.96 (2H, s, 2 of Ar-H).
A solution of 4′-(1,2,4-triazol-4-yl)acetanilide (4.91 g, 24.3
mmol) in 5 N HCl (100 mL) was heated at 125 °C for 1.5 h.
The mixture was cooled to 0 °C, basified with concentrated
aqueous NaOH solution, and extracted with dichloromethane
(×5). The combined extracts were dried (MgSO4) and evapo-
rated in vacuo, and the residue was chromatographed on silica
gel, eluting with CH2Cl2/MeOH/NH3 (80:8:1) to give 4′-(1,2,4-
triazol-4-yl)aniline (2.94 g, 76%): 1H NMR (250 MHz, CDCl3)
δ 3.80 (2H, s, NH2), 6.71 (2H, d, J ) 8.8 Hz, 2 of Ar-H), 7.08
(2H, d, J ) 8.8 Hz, 2 of Ar-H), 8.36 (2H, s, 2 of Ar-H).
A solution of sodium nitrite (0.69 g, 9.99 mmol) in water (8
mL) was added to a cooled (-21 °C) solution of 4′-(1,2,4-triazol-
4-yl)aniline (1.60 g, 9.99 mmol) in concentrated HCl/H2O (23
and 3 mL, respectively), at such a rate that the temperature
did not exceed -10 °C. The mixture was stirred for 0.3 h and
then filtered rapidly through a sinter, under vacuum. The
filtrate was added to a cooled (-20 °C) solution of tin(II)
chloride dihydrate (9.02 g, 40.0 mmol) in concentrated HCl
(17 mL). The mixture was stirred at -20 °C for 0.25 h and
then at room temperature for 1.25 h. The resulting solid was
The following indoles were prepared using the general
procedure.
(3R)-3-(Ben zyloxym et h yl)-1-[2-(5-(1,2,4-t r ia zol-4-yl)-
1H-in d ol-3-yl)eth yl]p yr r olid in e h yd r ogen oxa la te h em i-
1
h yd r a te (11d ): mp 145 °C; H NMR (360 MHz, DMSO-d6) δ
1.71 (1H, m, CH of CH2), 2.10 (1H, m, CH of CH2), 2.66 (1H,
m, CH), 3.04-3.50 (10H, m, 5 of CH2), 4.49 (2H, s, OCH2Ph),
7.27-7.40 (7H, m, 7 of Ar-H), 7.52 (1H, d, J ) 8.6 Hz, Ar-
H), 7.90 (1H, d, J ) 2.0 Hz, Ar-H), 9.04 (2H, s, 2 of Ar-H),
11.30 (1H, s, NH); MS m/z 402 [MH]+. Anal. (C24H27N5O‚
C2H2O4‚0.6H2O) C, H, N.
(2R)-2-(Ben zyloxym et h yl)-1-{2-[5-(1,2,4-t r ia zol-4-yl)-
1H-in d ol-3-yl]eth yl}p yr r olid in e sesqu ioxa la te (30b): mp
1
114-116 °C; H NMR (360 MHz, D2O) δ 1.79 (1H, m, CH of
CH2), 2.03 (1H, m, CH of CH2), 2.12-2.32 (2H, m, 2 of CH of
CH2), 3.10-3.44 (4H, m, 4 of CH), 3.67 (1H, m, CH), 3.77-
3.82 (4H, m, 4 of CH), 4.32 (1H, d, J ) 11.8 Hz, 1 of CH2Ph),
4.36 (1H, d, J ) 11.7 Hz, 1 of CH2Ph), 7.10-7.17 (5H, m, Ph),
7.27 (1H, dd, J ) 8.6 and 2.1 Hz, Ar-H), 7.38 (1H, s, Ar-H),
7.55 (1H, d, J ) 1.9 Hz, Ar-H), 7.61 (1H, d, J ) 8.7 Hz, Ar-
H), 8.72 (2H, s, 2 of Ar-H); MS m/z 402 [MH]+. Anal.
(C24H27N5O‚1.4(C2H2O4)‚0.1H2O) C, H, N. Optical purity 96.8%
ee (measured on a Chiralpak AD column eluting with 30%
EtOH in hexane/0.5% DEA at 1 mL/min; retention time of 30b
5.4 min, retention time of 30a 4.7 min).
(2S)-2-[(N-Ben zyl-N-m eth ylam in o)m eth yl]-1-{2-[5-(1,2,4-
tr ia zol-4-yl)-1H-in d ol-3-yl]eth yl}p yr r olid in e sesqu isu c-
cin a te sesqu ih yd r a te (30c): mp 70-72 °C; 1H NMR (360
MHz, D2O) δ 1.74 (1H, m, CH of CH2), 1.89 (1H, m, CH of
CH2), 2.12 (1H, m, CH of CH2), 2.22 (3H, s, Me), 2.28 (1H, m,
CH of CH2), 2.68-2.79 (2H, m, CH2), 3.12-3.76 (9H, m, CH
and 4 of CH2), 7.01-7.03 (2H, m, 2 of Ar-H), 7.15-7.21 (3H,
m, 3 of Ar-H), 7.32 (1H, dd, J ) 8.6 and 2.1 Hz, Ar-H), 7.47
(1H, s, Ar-H), 7.64 (1H, d, J ) 2.1 Hz, Ar-H), 7.67 (1H, d, J
) 8.6 Hz, Ar-H), 8.70 (2H, s, 2 of Ar-H); MS m/z 415 [MH]+.
Anal. (C25H30N6‚1.5(C4H6O4)‚1.5H2O) C, H, N.
Gen er a l P r oced u r e for th e P r ep a r a tion of In d oles
11b,e. (3R)-3-Hyd r oxy-1-{2-[5-(1,2,4-tr ia zol-4-yl)-1H-in d ol-
3-yl]eth yl}p yr r olid in e Hyd r ogen Oxa la te Hyd r a te (11b).
A mixture of 11a (90 mg, 0.23 mmol), ammonium formate (81
mg, 1.3 mmol), and 10% palladium/carbon (90 mg) in methanol
(10 mL) was heated at 60-65 °C for 6.5 h. The mixture was
cooled to room temperature and filtered through Hyflo and
the solvent evaporated in vacuo. The residue was chromato-
graphed on silica gel, eluting with CH2Cl2/MeOH/NH3 (60:8:
1) to give 11b (62 mg, 86%). The hydrogen oxalate salt was
1
prepared. 11b: mp 110-112 °C; H NMR (360 MHz, D2O) δ
1.96-2.44 (2H, m, CH2), 3.17-3.90 (8H, m, 4 of CH2), 4.65 (1H,