T. Grandi et al. / Il Farmaco 54 (1999) 479–485
481
cal results for the indicated elements were within
90.3% of the calculated values.
2 h. The solution was then poured into ice/water,
extracted with chloroform and the solvent was removed
under reduced pressure. The resulting solid was crystal-
lized from methanol to yield 5, m.p. 235°C (dec.) (0.84
g, 66%). IR (KBr, cm−1): 3264 (NH indole), 3180 (NH
UV spectra were recorded on a Perkin–Elmer 550 S
spectrophotometer; IR spectra were recorded on a
1
Perkin–Elmer spectrometer Paragon FT-100. H NMR
1
spectra were taken on Varian Gemini 200 or Bruker
300 spectrometers, using CDCl3 or DMSO-d6 as sol-
vents, with TMS as internal standard.
piperidinone), 1667 (CO). H NMR (DMSO-d6): 10.95
(br s, 1H, H(1%)); 7.84 (br s, 1H, H(1)); 7.30–7.19 (m,
2H, H(4%)+H(7%)); 6.88 (dd, 1H, J1=7.9 Hz, J2=2.0
Hz, H(6%)); 6.17 (s, 1H, H(3%)); 4.68 (br.t 1H, J about 6
Hz, H(6)); 2.35 (s, 3H, CH3); 2.23 (t, 2H, J=6.2 Hz,
H(3)); 2.15–1.62 (m, 4H, H(4)+H(5)). Anal.
(C14H16N2O) C, H, N.
3.1.1. 2-[(5-Methyl-2-nitrophenyl)acetyl]cyclopentanone
(3)
A mixture of 5-methyl-2-nitrophenylacetic acid [6]
(8.00 g, 0.041 mol), thionyl chloride (5.94 g, 0.050 mol),
DMF (1 ml) and anhydrous chloroform (50 ml) was
heated for 4 h at 40°C under magnetic stirring. The
solvent was removed, the residue was dissolved in dry
chloroform and it was slowly added to a solution of
N-(1-cyclopentenyl)morpholine (6.13 g, 0.040 mol) and
triethylamine (6.07 g, 0.060 mol) in anhydrous chloro-
form (50 ml). The mixture was stirred for 2 h at room
temperature (r.t.), then the solvent was removed at
reduced pressure. The resulting oil was stirred overnight
with 37% HCl (15 ml) and water (15 ml). Finally, water
was added (50 ml) and the solution was extracted with
chloroform. After removal of the solvent the viscous oil
was chromatographed on a silica gel column (CHCl3 as
eluent). The first fractions were pooled and evaporated
to afford 3 as a yellow oil which gave a positive colour
test with FeCl3 and was used without further character-
ization (6.30 g, 59%).
3.1.4. 5-Methyl-2-(2-piperidinyl)-1H-indole (6)
A suspension of 5 (0.84 g, 0.0037 mol) in anhydrous
THF (20 ml) was refluxed with LiAlH4 (1.68 g, 0.044
mol) for 2 h. Water was added slowly (3 ml) and the
product was extracted with ether. The organic phases
were evaporated and the white solid was crystallized
from cyclohexane, m.p. 148–150°C (0.56 g, 71%). IR
(KBr, cm−1): 3283 (NH indole), 3143 (NH piperidine).
1H NMR (DMSO-d6): 0.79 (br s, 1H, H(1)); 7.27–7.14
(m, 2H, H(4)+H(7)); 6.84 (dd, 1H, J1=8.0 Hz, J2=
2.0 Hz, H(6)); 6.13 (s, 1H, H(3)); 3.75 (dd, 1H, J1=
10.0 Hz, J2=3.0 Hz, H(2%)); 3.03 (br d, 1H, J=12.8
Hz); 2.79–2.60 (m, 2H); 2.38 (s, 3H, CH3); 2.00–1.87
(m, 1H+NH); 1.79–1.32 (m, 4H). Anal. (C14H18N2) C,
H, N.
3.1.5. 2-(5-Methyl-2(1H)-indolyl)-1-piperidineacetic
acid (7)
3.1.2. 2-(5-Methyl-1H-indol-2-yl)cyclopentanone (4)
Dry hydrogen chloride was bubbled for 30 min into
a solution of 3 (3.40 g, 0.013 mol) and anhydrous
stannous chloride (7.40 g, 0.039 mol) in dry ether (100
ml). The mixture was stirred at r.t. for 1 h, then the
solvent was removed under reduced pressure to give a
yellow residue which, in turn, was treated at 0°C with
15% NaOH solution (70 ml). After 15 min the solution
was extracted with CHCl3, the extracts were dried
(Na2SO4), the solvent was removed and the residue was
purified by chromatography on a silica gel column
(eluent CHCl3). The first fractions gave a solid which
was crystallized from ethanol to give 4, m.p. 147–
148°C (1.20 g, 43%). IR (KBr, cm−1): 3330 (NH), 1726
(CO). 1H NMR (CDCl3): 9.93 (br s, 1H, H(1%)); 7.34 (d,
1H, J=2.0 Hz, H(4%)); 7.25 (d, 1H, J=8.5 Hz, H(7%));
6.97 (dd, 1H, J1=8.5 Hz, J2=2.0 Hz, H(6%)); 6.22 (m,
1H, H(3%)); 3.48 (m, 1H, H(2)); 2.70–1.92 (m, 9H,
H(CH3)+aliphatic protons). Anal. (C14H15NO) C, H,
N.
A solution of 6 (1.00 g, 0.0047 mol), ethyl bromo-
acetate (7.0 ml), N-ethyldicyclohexylamine (7.0 ml) in
methanol (40 ml) was stirred at r.t. for 48 h. The
solution was evaporated to dryness and the residue
treated with benzene/pentane (1:1) to allow the precipi-
tation of the N-ethyldicyclohexylamine hydrobromide.
After filtration, the organic phase was extracted with 1
N HCl and the acid extracts made alkaline with
NH4OH 2 N up to pH 10. Finally, the aqueous phase
was extracted with benzene, the organic phase was
dried (Na2SO4) and evaporated to give an oil which was
dissolved in 7 ml of 20% KOH methanolic solution.
The mixture was stirred at r.t. for 20 h and added with
water (20 ml). The pH value was adjusted to 5.5, the
white solid which precipitated was filtered, washed with
water and finally crystallized from methanol to yield 7,
m.p. 217–219°C (dec.) (0.67 g, 52%). IR (KBr, cm−1):
3600–2600 (very broad, NH indole+ꢀNH+), 1616
1
and 1368 (COO−). H NMR (DMSO-d6, 300 MHz):
10.87 (br s, 1H, H(1%)); 7.23–7.18 (m, 2H, H(4%)+
H(7%)); 6.84 (dd, 1H, J1=8.0 Hz, J2=2.0 Hz, H(6%));
6.18 (d, 1H, J=2.0 Hz, H(3%)); 3.78 (dd, 1H, J1=11.0
Hz, J2=3.0 Hz, H(2)); 3.11–3.04 (m, 1H); 3.10 (d, 1H,
J=16.0 Hz, H(a)); 2.80 (d, 1H, J=16.0 Hz, H(a));
2.65–2.54 (m, 1H); 2.33 (s, 3H, CH3); 1.86–1.30 (m,
3.1.3. 6-(5-Methyl-1H-indol-2-yl)piperidin-2-one (5)
A mixture of 4 (1.2 g, 0.0056 mol), sodium azide
(0.75 g, 0.011 mol) and conc. H2SO4 (10 ml) in chloro-
form (60 ml) and benzene (60 ml) was stirred at 0°C for