2302 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7
Belliotti et al.
residue was triturated with EtOAc and filtered, and the solid
recrystallized from MeOH/EtOAc/heptane to provide 0.40 g
(49%) of (3S)-aminomethyl-(2S,5)-dimethylhexanoic acid hy-
drochloride 23 as a colorless crystalline solid, mp 167-169
°C: [R]D +12.7 (c 0.22, H2O). 1H NMR (DMSO-d6) δ 12.3 (br s,
1H), 8.00 (br s, 3H), 2.65 (m, 3H), 2.11 (m, 1H), 1.51 (m, 1H),
1.07 (m, 1H), 0.96 (m, 1H), 0.91 (d, J ) 7.1 Hz, 3H), 0.79 (app
t, J ) 6.3 Hz, 6H). Anal. (C9H19NO2‚HCl) C, H, N, Cl.
2,4-Dimethylvaleronitrile 25a. Prepared according to the
procedure outlined for 25b below. Physical and spectroscopic
properties of 25a were identical to those described in the
literature.51
2-Ethyl-4-methylpentanenitrile 25b. A solution of 4-meth-
ylpentanenitrile 24 (10.0 g, 103 mmol) and 2,2′-dipyridyl (1.6
g, 10.2 mmol) in 50 mL of THF was added to a solution of
freshly generated LDA in 100 mL of THF at -78 °C. After 10
min, iodoethane (16.0 mL, 200 mmol) was added and the
mixture stirred at -78 °C for 1 h. The reaction was quenched
by addition of 150 mL of 1.0 N HCl and warmed to room
temperature. The THF was evaporated and the mixture
extracted with Et2O (3 × 50 mL). The combined extracts were
washed with 1.0 N HCl (3 × 50 mL) and sat. NaHCO3 (2 × 50
mL). Drying over Na2SO4 followed by evaporation of the
solvent and atmospheric distillation (bp 170-178 °C) yielded
10.8 g (84%) of 2-ethyl-4-methylpentanenitrile 25b as a
colorless oil: 1H NMR (CDCl3) δ 2.58 (m, 1H), 1.85 (m, 1H),
1.58 (m, 3H), 1.30 (m, 1H), 1.08 (t, J ) 7.3 Hz, 3H), 0.94 (m,
6H).
3-Cyano-3,5-dimethylhexanoic Acid Ethyl Ester 26a.
Prepared as described above for compound 11 using 2,4-
dimethylvaleronitrile 25a. Yield of 26a was 25%: 1H NMR
(CDCl3) δ 4.13 (q, J ) 7.1 Hz, 2H), 2.58 (m, 1H), 2.44 (d, J )
15.4 Hz, 1H), 1.81 (dt, J ) 13.0, 6.6 Hz, 1H), 1.60 (m, 2H),
1.40 (s, 3H), 1.22 (t, J ) 7.1 Hz, 3H), 0.97 (dd, J ) 6.6, 4.6 Hz,
6H).
3-Cyano-3-ethyl-5-methylhexanoic Acid Ethyl Ester
26b. Prepared as described above for compound 11 using
2-ethyl-4-methylpentanenitrile 25b (10.8 g, 86.2 mmol). Yield
of 26b 5.5 g (30%): 1H NMR (CDCl3) δ 4.14 (q, J ) 7.1 Hz,
2H), 2.57 (s, 2H), 1.83 (ddd, J ) 12.6, 6.6, 6.4 Hz, 1H), 1.73 (t,
J ) 7.5 Hz, 2H), 1.60 (m, 1H), 1.52 (m, 1H), 1.24 (t, J ) 7.1
Hz, 3H), 1.01 (ddd, J ) 14.8, 7.3, 7.2 Hz, 9H).
added over 1.5 h. After the addition was complete, the reaction
was quenched with 350 mL of sat. NH4Cl (aq) and concen-
trated to remove THF. The residue was extracted three times
with Et2O, and the combined organic phases washed with sat.
NH4Cl (aq), brine, dried (Na2SO4), and concentrated. The
residue was purified by flash chromatography (3:1 hexanes:
EtOAc) to yield 6.1 g (95%) of 3-isobutyl-2-methyl-5-oxopyr-
rolidine-1-carboxylic acid tert-butyl ester 30a as a colorless
oil: 1H NMR (CDCl3) δ 3.82 (m, 1H), 2.73 (dd, J ) 17.6, 8.4
Hz, 1H), 2.15 (dd, J ) 17.6, 3.6 Hz, 1H), 1.90 (m, 1H), 1.61
(m, 1H), 1.54 (s, 9H), 1.33 (d, J ) 6.5 Hz 3H), 1.31 (m, 2H),
0.90 (m, 6H). Anal. (C14H25NO3) C, H, N.
2-Methyl-5-oxo-3-propylpyrrolidine-1-carboxylic Acid
tert-Butyl Ester 30b. Prepared in 59% yield using n-propyl-
magnesium chloride as described above for the 3-isobutyl
derivative 30a: 1H NMR (CDCl3) δ 3.80 (m, 1H), 2.69 (dd, J
) 17.6, 8.5 Hz, 1H), 2.12 (dd, J ) 17.8, 3.7 Hz, 1H), 1.78 (m,
1H), 1.49 (s, 9H), 1.44 (m, 1H), 1.28 (d, J ) 6.3 Hz 3H), 1.31
(m, 3H), 0.88 (app t, J ) 7.1 Hz, 3H).
3-Butyl-2-methyl-5-oxopyrrolidine-1-carboxylic Acid
tert-Butyl Ester 30c. Prepared in 39% yield using n-butyl-
magnesium chloride as described above for the 3-isobutyl
derivative 30a: 1H NMR (CDCl3) δ 3.81 (m, 1H), 2.69 (dd, J
) 17.8, 8.5 Hz, 1H), 2.13 (dd, J ) 17.8, 3.7 Hz, 1H), 1.75 (m,
1H), 1.49 (s, 9H), 1.45 (m, 1H), 1.28 (d, J ) 6.4 Hz 3H), 1.23
(m, 5H), 0.86 (app t, J ) 6.8 Hz, 3H).
3-(1-Amino-ethyl)-5-methylhexanoic Acid 31a. To 3-iso-
butyl-2-methyl-5-oxopyrrolidine-1-carboxylic acid tert-butyl
ester 30a (4.45 g, 17.4 mmol) was added 350 mL of 6 N HCl
(aq), and the mixture was heated to reflux for 30 h, cooled,
and concentrated. The residue was triturated several times
with Et2O, and the remaining solid residue was recrystallized
from acetonitrile to afford 1.18 g (32%) of 3-(1-aminoethyl)-5-
methylhexanoic acid 31a as a white solid, mp 136.5-138.5
°C: 1H NMR (DMSO-d6) δ 3.20 (m, 1H), 2.19 (m, 2H), 2.06
(m, 1H), 1.51 (m, 1H), 1.23 (m, 1H), 1.06 (d, J ) 6.6 Hz 3H),
1.00 (m, 1H), 0.81 (m, 3H). MS (m/z) 174 (M + 1). Anal. (C9H19-
NO2‚HCl) C, H, N, Cl.
3-(1-Amino-ethyl)hexanoic Acid 31b. Prepared in 55%
yield from 2-methyl-5-oxo-3-propylpyrrolidine-1-carboxylic acid
tert-butyl ester 30b as described above for the isobutyl
derivative 31a. Obtained as a white solid, mp 129-131 °C:
1H NMR (DMSO-d6) δ 3.25 (m, 1H), 2.27 (m, 2H), 2.06 (m,
1H), 1.45 (m, 1H), 1.34 (m, 1H), 1.27 (m, 1H), 1.13 (m, 1H),
1.12 (d, J ) 6.8 Hz 3H), 0.87 (app t, J ) 7.2 Hz, 3H). MS (m/z)
160 (M + 1). Anal. (C8H17NO2‚HCl) C, H, N, Cl.
4-Methyl-4-isobutylpyrrolidin-2-one 27a. Prepared as
described above for 4-(1-ethyl-propyl)pyrrolidin-2-one 7, using
3-cyano-3,5-dimethylhexanoic acid ethyl ester 26a (1.95 g, 9.9
mmol). Yield of 27a 1.0 g (65%): mp ) 59-61 °C.
4-Ethyl-4-isobutylpyrrolidin-2-one 27b. Prepared as
described above for 4-(1-ethyl-propyl)pyrrolidin-2-one 7, using
3-cyano-3-ethyl-5-methylhexanoic acid ethyl ester 26b (3.0 g,
14.2 mmol). Yield of 27b 2.2 g (95%): 1H NMR (CDCl3) δ 5.87
(s, 1H), 3.10 (s, 2H), 2.12 (m, 2H), 1.66 (dt, J ) 12.9, 6.5 Hz,
1H), 1.49 (q, J ) 7.2 Hz, 2H), 1.35 (s, 2H), 0.86 (m, 9H).
3-Aminomethyl-3,5-dimethylhexanoic Acid 28a. Pre-
pared as described above for compound 13 using 4-isobutyl-
4-methylpyrrolidin-2-one 27a (1.0 g, 6.4 mmol). Yield of 28a
0.27 g (24%), mp 144-146 °C (dec): 1H NMR (DMSO-d6) δ
7.87 (m, 2H), 3.57 (s, 1H), 2.89 (m, 1H), 2.40 (s, 1H), 2.3 (s,
1H), 1.64 (m, 1H), 1.26 (m, 2H), 0.98 (s, 3H), 0.87 (m, 6H). MS
(m/z) M+ ) 174. Anal. (C9H19NO2-0.15 H2O) C, H, N.
3-Aminomethyl-3-ethyl-5-methylhexanoic Acid Hydro-
chloride 28b. Prepared as described above for compound 13
using 4-ethyl-4-isobutylpyrrolidin-2-one 27b (2.2 g, 12.9 mmol).
Yield of 28b 27%, mp 133-135 °C: 1H NMR (DMSO-d6) δ 7.69
(s, 2H), 2.89 (d, J ) 13.7 Hz, 1H), 2.78 (d, J ) 13.7 Hz, 1H),
2.27 (s, 2H), 1.61 (s, 1H), 1.36 (s, 2H), 1.22 (s, 2H), 0.85 (m,
6H), 0.73 (d, J ) 7.3 Hz, 3H). MS (m/z) M+ ) 188. Anal.
(C10H21NO2‚1.1HCl) C, H, N, Cl.
3-(1-Amino-ethyl)heptanoic Acid 31c. Prepared in 61%
yield from 3-butyl-2-methyl-5-oxopyrrolidine-1-carboxylic acid
tert-butyl ester 30c as described above for the isobutyl deriva-
tive 31a. Obtained as a white solid, mp 107-109 °C: 1H NMR
(DMSO-d6) δ 3.19 (m, 1H), 2.21 (m, 2H), 1.96 (m, 1H), 1.42
(m, 1H), 1.20 (m, 4H), 1.12 (m, 1H), 1.06 (d, J ) 6.6 Hz 3H),
0.81 (app t, J ) 6.8 Hz, 3H). MS (m/z) 174 (M + 1). Anal.
(C9H19NO2‚HCl) C, H, N, Cl.
5-Methylhex-2-enoic Acid Ethyl Ester 33. Sodium hy-
dride (60% dispersion in mineral oil, 16.0 g, 0.41 mol) was
washed with hexane and then taken up in DME (250 mL) and
cooled to 0 °C. To the slurry was added triethylphosphonoac-
etate (80 mL, 0.4 mol) in 50 mL of DME slowly over 25 min.
After the addition was complete, the ice bath was removed
and a solution of isovaleraldehyde 32 (129 mL, 1.2 mol) in 100
mL of DME was added. The mixture was refluxed 16 h and
then concentrated. The residue was partitioned between
hexanes and water, the aqueous phase was extracted with
hexanes, and the combined organic phases were washed twice
with brine, dried (Na2SO4), and concentrated to afford 68 g
(∼100%) of crude 5-methylhex-2-enoic acid ethyl ester 33 as a
colorless oil: 1H NMR (CDCl3) δ 4.21 (m, 1H), 2.55 (m, 1H),
2.41 (m, 1H), 2.13 (m, 1H), 1.60 (m, 1H), 1.49 (s, 9H), 1.28 (d,
J ) 6.3 Hz, 3H).
3-Isobutyl-2-methyl-5-oxopyrrolidine-1-carboxylic Acid
tert-Butyl Ester 30a. To a suspension of copper(I) bromide-
dimethyl sulfide complex (5.14 g, 25 mmol) in 150 mL of THF
at -10 °C was added isobutylmagnesium bromide (2.0 M soln.
in Et2O, 25 mL, 50 mmol). The mixture was cooled to -40 °C
at which time a solution of 2-methyl-5-oxo-2,5-dihydropyrrole-
1-carboxylic acid tert-butyl ester 2942 (4.93 g, 25 mmol) was
5-Methyl-3-(1-nitroethyl)hexanoic Acid Ethyl Ester 34.
To 5-methylhex-2-enoic acid ethyl ester 33 (66 g, 0.42 mol) in
200 mL of acetonitrile were added DBU (63.9 g, 0.42 mol) and
nitroethane (157.5 g, 2.1 mol). The mixture was heated to 60