100 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 1
Webber et al.
2-Im in o-4,6-d im eth ylp ip er id in e Acetic Acid Sa lt (8).
Use of 2-amino-4,6-dimethylpyridine afforded 8 by the ap-
plication of general procedure B. 1H NMR (D2O): 3.48-3.40
(m, 1H), 2.52-2.40 (m, 1H), 2.071.95 (m, 1H), 1.85-1.75 (m,
2H), 1.75 (s, 3H), 1.12 (d, J ) 6 Hz, 3H), 1.02-0.92 (m, 1H),
0.86 (d, J ) 6 Hz, 3H). MS: 127 (M + H). Anal. (C12H24N2O2)
C, H, N.
(14.2 g, 100 mmol), 1-iodopropane (17 g, 100 mmol), and
potassium carbonate (10 g) in 100 mL of DMF was stirred
under N2 at 50 °C for 16 h. Removal of the solvent in vacuo
left a residue which was partitioned between EtOAc and water.
The EtOAc layer was separated, washed with water and brine,
and dried over MgSO4. Concentration in vacuo afforded
2-(carboxymethyl)-2-propylcyclopentanone.
2-Im in o-4-(tr iflu or om eth yl)p ip er id in e Hyd r och lor id e
(9). 2-Chloro-4-(trifluoromethyl)pyridine was converted by the
application of general procedure C to afford 2-amino-4-(trif-
luoromethyl)pyridine as a white solid. Catalytic hydrogena-
tion by application of general procedure B afforded 9. 1H NMR
(D2O): 3.45-3.35 (m, 1H), 3.30-3.20 (m, 1H), 2.85-2.55 (m,
3H), 2.10-2.00 (m, 1H), 1.80-1.60 (m, 1H). MS: 167 (M +
H). Anal. (C6H10F3N2Cl1) C, H, N.
2-Im in o-6-(tr iflu or om eth yl)p ip er id in e Hyd r och lor id e
(10). 2-Chloro-6-(trifluoromethyl)pyridine was converted by
application of general procedure C to afford 2-amino-6-(trif-
luoromethyl)pyridine. Catalytic hydrogenation by application
of general procedure B afforded 10. 1H NMR (D2O): 4.20-
4.00 (m, 1H), 2.60-2.50 (m, 2H), 2.05-1.50 (m, 4H), 1.80 (s,
3H). MS: 167 (M + H). Anal. (C6H10F3N2Cl1) C, H, N.
2-Im in o-6-cycloh exylp ip er id in e Hyd r och lor id e (11).
2-Phenylpyridine was converted by application of general
procedure D to afford 2-amino-6-phenylpyridine as a white
solid (3.6 g, 73% yield). Catalytic hydrogenation was carried
out as in general procedure B except that the reaction was
run at 55 °C to afford 11. 1H NMR (D2O): 3.30-3.15 (m, 1H),
2.50-2.30 (m, 2H), 1.85-1.68 (m, 2H), 1.65-1.20 (m, 8H),
1.20-0.80 (m, 5H). MS: 181 (M + H). Anal. (C13H21F3N2O2‚3/
4H2O) C, H, N.
2-Im in o-6-b en zylp ip er id in e H yd r och lor id e (12).
2-Amino-6-benzylpyridine was converted by application of
general procedure D to afford 2-amino-6-benzylpyridine as a
white solid (3.6 g, 73% yield). Catalytic hydrogenation by
application of general procedure B afforded 12. 1H NMR
(D2O): 7.35-7.10 (m, 5H), 3.70-3.60 (m, 1H), 2.75 (d, J ) 7
Hz, 2H), 2.50-2.30 (m, 2H), 1.82-1.62 (m, 2H), 1.60-1.30 (m,
2H). MS: 189 (M + H). Anal. (C12H17F3N2Cl1‚H2O) C, H, N.
2-Im in o-6-(cycloh exylm eth yl)p ip er id in e Hyd r och lo-
r id e (13). 2-Amino-6-benzylpyridine from the synthesis of 12
was catalytically hydrogenated by application of general
procedure B except that platinum oxide was used as the
catalyst to afford 13. 1H NMR (CDCl3): 9.60 (s, 1H), 8.90 (s,
1H), 8.70 (s, 1H), 3.60-3.40 (m, 1H), 2.90-2.70 (m, 1H), 2.70-
2.50 (m, 1H), 2.10-1.80 (m, 2H), 1.80-1.00 (m, 13H), 1.00-
0.80 (m, 2H). MS: 195 (M + H). Anal. (C12H23N2Cl1‚1/5H2O)
C, H, N.
P r ep a r a tion of 2-P r op ylcyclop en ta n on e. A mixture of
2-(carboxymethyl)-2-propylcyclopentanone (10 g, 54 mmol),
sodium cyanide (2.9 g, 60 mmol), and DMSO (100 mL) was
stirred at 160 °C for 3 h under N2. After cooling, the reaction
mixture was poured into ice water and extracted with a
mixture of ether/hexanes (300 mL, 1/1). The organic layer was
removed, washed with brine (2×), dried over MgSO4, and
concentrated in vacuo. The residue was purified by chroma-
tography on silica gel eluting with EtOAc/hexanes (3/7) to
afford 5.5 g (83%) of 2-propylcyclopentanone.
P r ep a r a tion of 2-P r op ylcylop en ta n on e Oxim e. A solu-
tion of 10 g (43 mmol) of 2-propylcyclopentanone in 75 mL of
EtOH was added to a solution of 5.8 g (83 mmol) of hydroxy-
lamine hydrochloride and 8.2 g (100 mmol) of sodium acetate
in 50 mL of water. This mixture was stirred for 4 h at reflux
and then for 18 h at 25 °C. The reaction mixture was
concentrated to a reduced volume, diluted with EtOAc, washed
with three 200-mL portions of aqueous NaCl, dried (MgSO4),
filtered, and concentrated to afford 10 g of the 2-propylcyclo-
pentanone oxime as a colorless oil.
P r ep a r a tion of 6-P r op ylva ler ola cta m . A solution of 5.6
g (40 mmol) of 2-propylcyclopentanone oxime in 50 mL of
acetone was treated with 44 mL (44 mmol) of 1 N NaOH at 0
°C. To this stirred mixture was added 7.4 g (42 mmol) of
benzenesulfonyl chloride dropwise. The resulting mixture was
stirred for 18 h at 25 °C. The reaction mixture was poured
into water and extracted with EtOAc. The organic layer was
separated, washed with aqueous NaCl, dried (MgSO4), filtered,
and concentrated to afford a yellow oil. Chromatography (C-
18, 10% acetonitrile/water to 70% acetonitrile/water) on 2 g of
the yellow oil afforded 1 g of a mixture of the 6-propylvalero-
lactam and 3-propylvalerolactam. Chromatography (silica gel,
8/3 hexane/EtOAc) of this 1 g of yellow oil afforded 0.4 g of
the 6-propylvalerolactam.
2-Im in o-6-(1-p r op yl)p ip er id in e Tr iflu or oa cetic Acid
Sa lt (16). To a solution of 0.63 g (4.3 mmol) of trimethyloxo-
nium tetrafluoroborate in 15 mL of CH2Cl2 was added 0.4 g
(2.8 mmol) of 6-propylvalerolactam. This mixture was stirred
for 2 days at 25 °C. The reaction mixture was then diluted
with EtOAc, washed with dilute potassium carbonate, dried
(MgSO4), filtered through a patty of silica gel, and concentrated
to afford 0.5 g of the imino ether as a yellow oil. This oil was
dissolved in 50 mL of MeOH, and 1 g (19 mmol) of ammonium
chloride was added. After stirring at reflux for 4 h the mixture
was stirred at 25 °C for 18 h. The reaction mixture was then
concentrated to remove solvents. The residue was dissolved
in water and extracted with EtOAc. The aqueous layer was
lyophilized to afford 2-imino-6-(1-propyl)piperidine hydrochlo-
ride salt as a white solid. A final purification by reverse-phase
C-18 chromatography (0-50% acetonitrile/H2O, 30 min) af-
forded 0.3 g of 2-imino-6-(1-propyl)piperidine trifluoroacetate
as a white semisolid. 1H NMR (D2O): 3.4-3.3 (m, 1H), 2.50-
2.38 (m, 2H), 1.88-1.15 (m, 8H), 0.78-0.70 (t, 3H). MS: 141
(M + H). Anal. (C10H17N2O2F3‚1/2 H2O) C, H, N.
1-Met h yl-2-im in op ip er id in e Hyd r oiod id e Sa lt (14).18
Use of N-methylthiovalerolactam and ammonia by application
of general procedure A afforded 0.8 g of 14 as a white solid.
Mp: 157-158 °C. 1H NMR (D2O): 1.6-1.7 (m, 2H), 1.7-1.8
(m, 2H), 2.5 (t, 2H), 2.95 (s, 3H), 3.38 (t, 2H). MS: 113 (M +
H). Anal. (C6H13N2I1) C, H, N.
P r ep a r a tion of Th iova ler ola cta m . A mixture of 100 g
(230 mmol) of P4S10 and 24 g (230 mmol) of Na2CO3 in 1.5 L of
anhydrous THF was stirred vigorously with a mechanical
stirrer for 30 min. To this stirred mixture was added 19 g
(190 mmol) of valerolactam. After stirring for 3 h, the reaction
solution was diluted with 1 L of 10% aqueous Na3PO4, 750
mL of EtOAc, and 750 mL of hexanes. The organic layer was
separated and the aqueous layer extracted with an additional
500 mL of EtOAc. The organic extracts were combined, dried
(MgSO4), filtered through silica gel, and concentrated to afford
a white semisolid. Trituration with a mixture of hexanes and
ether afforded 9.7 g of thiovalerolactam as a white solid. Mp:
85-88 °C.
P r ep a r a tion of 4,4-Dim eth ylp ip er id in -2-on e. A solu-
tion of 3,3-dimethylglutaric anhydride (10 g, 70 mmol) in
concentrated ammonium hydroxide (30 mL) was hydrogenated
over Pd/Al2O3 at 1600 psi and 250 °C for 3 h. After the mixture
cooled to room temperature, brine (75 mL) was added, and the
contents were extracted with CH2Cl2 (150 mL), dried over Na2-
SO4, and concentrated in vacuo to yield a solid. The solid was
purified by chromatography on silica gel to give 4,4-dimeth-
ylpiperidin-2-one (1.4 g, 16% yield).
2-Im in o-4,4-d im et h ylp ip er id in e H yd r och lor id e Sa lt
(17). A mixture of 4,4-dimethylpiperidin-2-one (0.64 g, 5
mmol) and trimethyloxonium tetrafluoroborate (0.89 g, 6
mmol) in CH2Cl2 (20 mL) was stirred overnight. The contents
2-(Meth ylim in o)p ip er id in e Hyd r oiod id e Sa lt (15).19
Use of thiovalerolactam and methylamine by application of
general procedure A afforded 15. 1H NMR (D2O): 1.6-1.7 (m,
4H), 2.45 (t, 2H), 2.7 (s, 3H), 3.3 (t, 2H). MS: 113 (M + H).
Anal. (C6H13N2I1) C, H, N.
P r ep a r a tion of 2-(Ca r boxym eth yl)-2-p r op ylcyclop en -
ta n on e. A solution of methyl 1-oxocyclopentane-2-carboxylate