1428 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 4
Meltzer et al.
3H), 1.68 (m, 2H), 1.39 (m, 2H), 0.94 (t, 3H) was brominated
(general procedure B) to afford 2-bromo-1-(2-tolyl)pentan-1-one
(3r). H NMR δ 7.63 (d, 1H), 7.42 (m, 1H), 7.27 (m, 2H), 5.05
yellow mixture was warmed slowly to room temperature and stirred
for 3 h. The yellow solution was hydrolyzed cautiously with
aqueous Na2CO3 (20% solution) until the pH was 8 and then water
(50 mL) was added, and the solution was allowed to stand overnight.
Neutral organics were extracted from the mixture by the separation
of the CH2Cl2 layer, which was then discarded. The aqueous layer
was acidified to pH 3 with 1 M HCl, most of the water was removed
by rotary evaporation, and the remaining volume of ca. 10 mL was
allowed to cool in the refrigerator. After 3 days, a white solid
separated from the solution and was collected by filtration.
Recrystallization (EtOH/Et2O) afforded pure 1-(3,4-dihydroxy-
phenyl)-2-pyrrolidin-1-yl-pentan-1-one (4v) as its hydrobromide,
an off-white solid (0.60 g, 44%); mp 181-182 °C. 1H NMR
δ 10.42 (s, 1H), 10.1-9.9 (br, 1H), 9.59 (s, 1H), 7.51 (dd, 1H),
7.43 (d, 1H), 6.91 (d, 1H), 5.35-5.25 (br, 1H), 3.75-3.5 (br, 1H),
3.5-3.3 (br, 1H), 3.3-3.15 (br, 1H), 3.0-2.85 (br, 1H), 2.1-1.8
(m, 6H), 1.3-1.0 (m, 2H), 0.80 (t, 3H); 13C NMR δ 194.8, 153.4,
146.4, 126.7, 123.5, 116.0, 115.9, 67.5, 54.5, 52.3, 32.8, 23.2, 17.9,
14.3; APCI MS m/z: 264 (M + 1). Anal. (C15H22BrNO3) C, H, N,
Br.
1-(3,4-Dimethoxyphenyl)-2-pyrrolidin-1-yl-pentan-1-one Hy-
drochloride (4w). 2-Bromo-1-(3,4-dimethoxyphenyl)pentan-1-one
(3w) was obtained together with 2-bromo-1-(2-bromo-4,5-dimethox-
yphenyl)pentan-1-one by using general procedure B. The com-
pounds were separated by flash column chromatography (10%
EtOAc/hexane) to provide 2-bromo-1-(3,4-dimethoxyphenyl)-pen-
tan-1-one (3w): 1H NMR δ 7.66 (dd, 1H), 7.58 (d, 1H), 6.91 (d,
1H), 5.15 (dd, 1H), 3.97 (s, 3H), 3.95 (s, 3H), 2.25-2.05 (m, 2H),
1.7-1.35 (m, 2H), 1.01 (t, 3H) and 2-bromo-1-(2-bromo-4,5-
dimethoxyphenyl)pentan-1-one: 1H NMR δ 7.07 (s, 1H), 7.04 (s,
1H), 5.28 (dd, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 2.3-2.0 (m, 2H),
1.7-1.4 (m, 2H), 1.00 (t, 3H). Compound 4w was then prepared
from 3w as described in general procedure C to provide a solid
(74% yield); mp 177 °C dec. 1H NMR δ 10.5-10.3 (br, 1H), 7.78
(d, 1H), 7.53 (d, 1H), 7.18 (d, 1H), 5.55-5.4 (br, m, 1H), 3.90 (s,
3H), 3.86 (s, 3H), 3.7-3.55 (br, m, 1H), 3.5-3.3 (br, m, 1H), 3.3-
3.15 (br, m, 1H), 3.05-2.9 (br, m, 1H), 2.1-1.8 (m, 6H), 1.3-1.0
(m, 2H), 0.80 (t, 3H); 13C NMR δ 194.7, 154.7, 149.0, 127.2, 124.6,
111.2, 110.5, 66.7, 56.0, 55.7, 53.7, 51.8, 32.1, 22.8, 17.4, 13.7;
APCI MS m/z: 292 (M + 1). Anal. (C17H26ClNO3) C, H, N, Cl.
1-(4-Furan-2-ylphenyl)-2-pyrrolidin-1-yl-pentan-1-one Hy-
drochloride (4x). This compound was prepared using a procedure
analogous to that described later for the preparation of 4z, except
that commercially available 2-tributylstannyl furan was employed
as a starting material, and chromatography was not performed on
the crude free base. The crude hydrochloride was recrystallized
from hot EtOH to give pure 4x as a colorless crystalline solid: (59%
yield); mp 236 °C dec. 1H NMR (DMSO-d6 + 6 drops of CD3OD)
δ 8.14 (d, 2H), 7.95 (d, 2H), 7.90 (d, 1H), 7.29 (d, 1H), 6.71 (dd,
1H), 5.51 (m, 1H), 3.7-3.6 (br, m, 1H), 3.6-3.45 (br, m, 1H),
3.35-3.2 (br, m, 1H), 3.15-3.0 (br, m, 1H), 2.15-1.85 (br, m,
6H), 1.35-1.15 (m, 1H), 1.15-1.0 (m, 1H), 0.81 (t, 3H); 13C NMR
δ 195.7, 151.8, 145.1, 136.0, 132.6, 130.0, 123.8, 112.9, 109.9,
67.8, 54.2, 52.0, 32.0, 22.9, 17.3, 13.7; APCI MS m/z: 298 (M +
1). Anal. (C19H24ClNO2) C, H, N, Cl.
1
(dd, 1H), 2.50 (s, 3H), 2.25-2.0 (m, 2H), 1.65-1.35 (m, 2H), 0.99
(t, 3H). Compound 4r was prepared from 3r as described in general
procedure C (39% yield). 1H NMR δ 10.9-10.7 (br, 1H), 8.12 (d,
1H), 7.58 (t, 1H), 7.44 (t, 2H), 5.56 (m, 1H), 3.7-3.5 (br, 2H),
3.35-3.1 (br, m, 2H), 2.46 (s, 3H), 2.1-1.7 (br, m, 6H), 1.4-1.2
(m, 1H), 1.1-0.9 (m, 1H), 0.76 (t, 3H); 13C NMR δ 199.1, 138.8,
134.4, 133.2, 132.3, 130.0, 126.2, 68.9, 53.5, 51.8, 31.4, 23.0, 20.7,
17.5, 13.7; APCI MS m/z: 246 (M + 1). Anal. (C16H24ClNO‚H2O)
C, H, N, Cl.
1-(3-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one Hydro-
chloride (4s). 1-(3-Methylphenyl)pentan-1-one (2s) obtained in 98%
yield from 3-methylbenzonitrile (general procedure A) and purified
by distillation (bp 64-68 °C, 0.1 mmHg): 1H NMR δ 7.86 (d,
2H), 7.26 (d, 2H), 2.94 (t, 2H), 2.41 (s, 3H), 1.71 (m, 2H), 1.41
(m, 2H), 0.95 (t, 3H) was brominated (general procedure B) to
1
provide 2-bromo-1-(3-methylphenyl)pentan-1-one 3s. H NMR δ
7.81 (m, 2H), 7.40 (m, 2H), 5.15 (dd, 1H), 2.43 (s, 3H), 2.25-
2.05 (m, 2H), 1.7-1.35 (m, 2H), 0.99 (t, 3H). Compound 4s was
prepared from 3s as described in general procedure C (53% yield);
mp 166 °C dec. 1H NMR δ 10.8-10.6 (br, 1H), 7.90 (d, 2H), 7.65-
7.5 (m, 2H), 5.57 (m, 1H), 3.7-3.55 (br, 1H), 3.55-3.4 (br, 1H),
3.3-3.15 (br, m, 1H), 3.15-3.0 (br, m, 1H), 2.42 (s, 3H), 2.1-1.8
(br, m, 6H), 1.35-1.15 (m, 1H), 1.15-0.95 (m, 1H), 0.78 (t, 3H);
13C NMR δ 196.7, 138.8, 135.6, 134.5, 129.1, 126.1, 67.4, 53.6,
51.9, 31.7, 22.9, 20.8, 17.3, 13.7; APCI MS m/z: 246 (M + 1).
Anal. (C16H24ClNO) C, H, N, Cl.
1-Naphthalen-2-yl-2-pyrrolidin-1-yl-pentan-1-one Hydrochlo-
ride (4t). 1-Naphthalen-2-yl-pentan-1-one (2t) prepared in 95%
yield from naphthalene-2-carbonitrile (general procedure A): 1H
NMR δ 8.48 (s, 1H), 8.04 (dd, 1H), 7.97 (d, 1H), 7.90 (m, 2H),
7.57 (m, 2H), 3.11 (t, 2H), 1.79 (m, 2H), 1.44 (m, 2H), 0.98 (t,
3H) was brominated (general procedure B) to afford 2-bromo-1-
1
naphthalen-2-yl-pentan-1-one (3t). H NMR δ 8.55 (s, 1H), 8.1-
7.85 (m, 4H), 7.60 (m, 2H), 5.33 (dd, 1H), 2.3-2.1 (m, 2H), 1.7-
1.4 (m, 2H), 1.01 (t, 3H). Compound 4t was prepared from 3t as
described in general procedure C (51% yield); mp 221-223 °C
1
dec; H NMR δ 10.8-10.6 (br, 1H), 8.92 (s, 1H), 8.2-8.0 (m,
4H), 7.75 (dt, 2H), 5.73 (m, 1H), 3.75-3.6 (br, 1H), 3.6-3.4 (br,
m, 1H), 3.35-3.1 (br, m, 2H), 2.2-1.8 (m, 6H), 1.4-1.2 (m, 1H),
1.2-1.0 (m, 1H), 0.78 (t, 3H); 13C NMR δ 196.6, 135.7, 132.0,
131.8, 131.7, 129.9, 129.7, 129.0, 127.8, 127.5, 123.4, 67.3, 53.6,
52.0. 31.9, 22.9, 17.4, 13.7; APCI MS m/z: 282 (M + 1). Anal.
(C19H24ClNO) C, H, N, Cl.
1-(3,4-Dichlorophenyl)-2-pyrrolidin-1-yl-pentan-1-one Hy-
drochloride (4u). 1-(3,4-Dichlorophenyl)pentan-1-one (2u) pre-
pared in 93% yield from 3,4-dichlorobenzonitrile (general procedure
A) and used crude in the next step of the reaction: 1H NMR δ
8.03 (d, 1H), 7.78 (dd, 1H), 7.54 (d, 1H), 2.92 (t, 2H), 1.71 (m,
2H), 1.39 (m, 2H), 0.94 (t, 3H) was brominated (general procedure
B) to afford 2-bromo-1-(3,4-dichlorophenyl)pentan-1-one (3u). 1H
NMR δ 8.09 (d, 1H), 7.84 (dd, 1H), 7.55 (d, 1H), 5.02 (dd, 1H),
2.25-2.05 (m, 2H), 1.65-1.35 (m, 2H), 0.99 (t, 3H). Compound
4u was prepared from 3u as described in general procedure C (32%
2-Pyrrolidin-1-yl-1-(4-thiophen-2-yl-phenyl)pentan-1-one Hy-
drochloride (4y). This compound was prepared using a procedure
analogous to that described later for the preparation of 4z, except
that commercially available 2-tributylstannyl thiophene was em-
ployed as a starting material, and chromatography was not
performed on the crude free base. The crude hydrochloride was
readily obtained by the treatment of the crude free base with 2 M
ethereal HCl. Recrystallization from hot EtOH gave pure 4v as a
1
yield); mp 195 °C dec; H NMR δ 10.8-10.6 (br, 1H), 8.35 (d,
1H), 8.04 (dd, 1H), 7.94 (d, 1H), 5.58 (m, 1H), 3.7-3.6 (br, 1H),
3.6-3.45 (br, m, 1H), 3.3-3.05 (br, m, 2H), 2.15-2.85 (br, m,
6H), 1.35-1.15 (m, 1H), 1.15-0.95 (m, 1H), 0.79 (t, 3H); 13C NMR
δ 195.0, 137.8, 134.5, 132.3, 131.6, 130.8, 128.8, 67.5, 53.7, 51.9,
31.4, 22.9, 17.2, 13.6; APCI MS m/z: 300, 302, 304 (M + 1). Anal.
(C15H20Cl3NO) C, H, N, Cl.
1
1-(3,4-Dihydroxyphenyl)-2-pyrrolidin-1-yl-pentan-1-one Hy-
drobromide (4v). 1-(3,4-Dimethoxyphenyl)-2-pyrrolidin-1-yl-pen-
tan-1-one (4w) (1.50 g, 4.6 mmol) was freed from its hydrochloride
salt by treatment with aqueous Na2CO3 and extraction into CH2-
Cl2. The organics were dried (MgSO4), filtered, and reduced to a
pale-yellow oil in vacuo. The oil was taken up in CH2Cl2 (10 mL)
and cooled to -78 °C, whereon BBr3 (46 mL, 1.0 M solution in
CH2Cl2, 46 mmol) was added dropwise over 0.5 h. The resulting
colorless crystalline solid (61% yield); mp 220 °C dec. H NMR
(DMSO-d6 + 12 drops of CD3OD) δ 8.12 (d, 2H), 7.93 (d, 2H),
7.77 (dd, 1H), 7.72 (dd, 1H), 7.23 (dd, 1H), 5.5-5.4 (br, 1H), 3.7-
3.45 (br, m, 2H), 3.3-3.2 (br, m, 1H), 3.1-3.0 (br, m, 1H), 2.2-
1.9 (br, m, 6H), 1.35-1.2 (m, 1H), 1.2-1.0 (m, 1H), 0.83 (t, 3H);
13C NMR δ 195.9, 141.8, 140.3, 132.9, 130.3, 129.3, 128.6, 126.6,
126.0, 68.1, 54.5, 52.1, 32.2, 23.1, 17.4, 13.8; APCI MS m/z: 314
(M + 1). Anal. (C19H24ClNOS) C, H, N, Cl.