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1
(CDCl3) d 20.64, 30.60, 37.72, 42.39, 48.06, 57.97,
126.93, 127.22, 129.90, 137.22, 142.38, 178.51.
CH3OH). H NMR (CDCl3) d 1.71–2.27 (m, 6H, CH2),
2.72 (s, 2H, CH2), 3.30–3.50 (m, 4H, CH2), 7.06–7.47
(m, 4H, Ar-H); 13C NMR (CDCl3) d 20.00, 29.89,
34.20, 44.54, 45.35, 57.56, 126.71, 126.79, 127.05,
129.51, 137.99, 139.26, 164.93. Anal. Calcd for
(C13H17N.C2H2O4): C, 64.96; H, 6.90; N, 5.05. Found:
C, 64.99; H, 6.93; N, 4.96.
2.2.3. 4,4-Diphenylpyrrolidin-2-one. Yield (75%); mp
160–161 ꢁC (CHCl3/petroleum ether). 1H NMR (CDCl3)
d 3.04–3.05 (d, J ¼ 3 Hz, 2H, CH2), 4.01–4.03 (d,
J ¼ 6 Hz, 2H, CH2), 6.92 (br s, 1H, NH), 7.18–7.34 (m,
10H, Ar-H); 13C NMR (CDCl3) d 44.69, 51.64, 54.54,
127.20, 127.35, 129.21, 146.64, 177.46.
2.3.3. 3,3-Diphenylpyrrolidine oxalate (7). Yield (91%);
mp 184–185 ꢁC (EtOAc/CH3OH). 1H NMR (DMSO-d6)
2.2.4. Spiro[10,11-dihydrodibenzo[a,d]cycloheptene-5,40-
pyrrolidin]-20-one. Yield (55%); mp 198–199 ꢁC (CHCl3/
petroleum ether). lit. mp 201–202 ꢁC.7 1H NMR
(CDCl3) d 3.18–3.48 (m, 6H, CH2), 4.15 (s, 2H, CH2),
7.08–7.31 (m, 8H, Ar-H); 13C NMR (CDCl3) d 32.80,
40.44, 44.37, 55.24, 93.06, 125.28, 125.71, 126.79,
127.224, 127.98, 128.29, 129.93, 131.98, 138.88, 142.92,
177.37.
d
2.68–2.72 (t, J ¼ 6 Hz, 2H, CH2), 3.13–3.17(t,
J ¼ 6 Hz, 2H, CH2), 3.92 (s, 2H, CH2), 7.18–7.43 (m,
10H, Ar-H); 13C NMR (DMSO-d6) d 35.98, 43.72,
53.18, 54.86, 126.90, 127.07, 128.99, 144.48, 165.37.
Anal. Calcd for (C16H17N.C2H2O4): C, 68.99; H, 6.11;
N, 4.46. Found: C, 69.07; H, 6.13; N, 4.53.
2.3.4. Spiro(10,11-dihydrodibenzo[a,d]cycloheptene)-5,30-
pyrrolidine fumarate (8). Yield (77%); mp 169–170 ꢁC
Spiro[9,10-dihydroanthracene]-9,50-piperidin-20-
1
2.2.5.
(EtOAc/CH3OH). H NMR(DMSO-d6) d 2.70–2.75 (t,
one. Yield (66%); mp 189–190 ꢁC. (CHCl3/petroleum
J ¼ 7:5 Hz, 2H, CH2), 3.14–3.19 (t, J ¼ 7:5 Hz, 2H,
CH2), 3.29–3.37 (m, 4H, CH2), 3.73 (s, 2H, CH2), 7.07–
7.29 (m, 8H, Ar-H); 13C NMR (DMSO-d6) d 32.74,
38.25, 45.76, 58.14, 125.66, 126.54, 127.35, 131.98,
138.79, 144.67. Anal Calcd for (C19H21N.C4H4O4.1/
4H2O): C, 71.42; H, 6.40; N, 3.78. Found: C, 71.35; H,
6.61; N, 3.65.
1
ether). H NMR (CDCl3) d 2.04–2.18 (m, 4H, CH2),
3.93–4.25 (m, 4H, CH2), 7.31–7.61 (m, 8H, Ar-H); 13C
NMR (CDCl3) d 30.25, 31.36, 37.32, 41.22, 49.16,
124.89, 127.33, 129.04, 137.34, 141.36, 172.60.
2.3. General method for the reduction of the spiropyrrol-
idin-2-ones to spiro pyrrolidines
2.3.5. Spiro[9,10-dihydroanthracene]-9,30-piperidine oxal-
ate (9). Yield (77%); mp 193–194 ꢁC (EtOAc/CH3OH).
1H NMR (CDCl3) d 1.72–1.81 (t, J ¼ 3 Hz, 2H, CH2),
2.09–2.18 (m, 2H, CH2), 2.94–2.98 (m, 2H, CH2), 3.45
(s, 2H, CH2), 4.00–4.06 (d, J ¼ 18 Hz, 1H, CH2), 4.10–
4.16 (d, J ¼ 18 Hz, 1H, CH2), 7.19–7.89 (m, 8H, Ar-H);
13C NMR (CDCl3) d 24.79, 33.45, 38.07, 42.18, 47.60,
54.09, 126.23, 123.32, 123.61, 128.69, 138.18, 144.57.
Anal. Calcd for (C18H19N.C2H2O4): C, 70.77; H, 6.23;
N, 4.12. Found: C, 70.93; H, 6.19; N, 4.05.
A 1.0 M solution of BH3–THF complex (7.00 mol) was
added at 0 ꢁC to a well stirred solution of 4-spiro-pyr-
rolidin-2-ones (1.40 mmol) in anhydrous THF (2 mL).
The solution was brought to room temperature and then
heated at reflux (8 h) and cooled. HCl (4 mL) of 6.0 M
solution was added cautiously to the reaction mixture,
heated at reflux (1 h), cooled, and the solvent was
removed under reduced pressure, resulting in a white
suspension. Water (20 mL) was added and extracted
with EtOAc (20 mL). The aqueous phase was made
basic with 10% NaOH and extracted with CH2Cl2
(3 · 25 mL). The combined CH2Cl2 extracts were washed
with water, brine, dried (MgSO4), and the solvent was
removed under reduced pressure to give the respective
amines as oils.
2.3.6. Affinity determinations. Radioligand binding
assays using [3H]-ketanserin and cloned 5HT2A recep-
tors were performed as previously described. Data were
analyzed with the LIGAND program as previously
detailed.13;14
2.3.1. Spiro[9,10-dihydroanthracene]-9,30-pyrrolidine fum-
arate (4). Yield (94%); mp 190.5–191.5 ꢁC (EtOAc/
Acknowledgements
CH3OH). 1H NMR (DMSO-d6)
d 2.25–2.30 (t,
J ¼ 7:5 Hz, 2H, CH2), 3.21–3.26 (t, J ¼ 7:5 Hz, 2H,
CH2), 3.55 (s, 2H, CH2), 4.06 (s, 2H, CH2), 6.44 (s, 1H),
7.20–7.56 (m, 8H, Ar-H); 13C NMR (DMSO-d6) d 36.22,
36.67, 45.18, 51.09, 54.10, 124.43, 126.69, 126.76,
128.17, 135.84, 137.08, 141.44, 168.96. Anal. Calcd for
(C17H17N.1/2C4H4O4): C, 77.79; H, 6.52; N, 4.77.
Found: C, 77.12; H, 6.56; N, 4.78.
This was supported by United States Public Health
Service Grant MH57969 (R.B.W.) and the NIMH Psy-
choactive Drug Screening Program NO280005 (B.L.R.).
References and notes
1. Westkaemper, R. B.; Runyon, S. P.; Bondarev, M. L.;
Savage, J. E.; Roth, B. L.; Glennon, R. A. Eur. J.
Pharmacol. 1999, 380, R5.
2.3.2. Spiro[1,2,3,4-tetrahydronaphthalenyl)-1,30-pyrrol-
idine oxalate (6). Yield (80%); mp 197–198 ꢁC (EtOAc/