2-Iminopyrrolidines as Inhibitors of hiNOS
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 19 3681
(s, 3H), 1.27-1.63 (m, 8H), 2.64 (d, J ) 17.3 Hz, 1H), 2.70 (d,
J ) 17.3 Hz, 1H), 3.57 (dd, J ) 9.4, 4.0 Hz, 1H). 13C NMR
(D2O, 125 MHz): 16.2, 23.8, 28.6 (CH3’s); 24.7, 28.6, 31.8, 33.8,
46.9 (CH2’s); 42.5 (C), 71.8 (CH), 172.7 (CdNH). Anal.
(C11H20N2‚HCl) C, H, N, Cl.
tr a n s-5-P en tyl-4-(tr iflu or om eth yl)p yr r olid in -2-im in e
Hyd r och lor id e (13). A suspension of ethyl 4,4,4-trifluoro-
crotonate (10.0 g, 59 mmol), 1-nitrohexane (7.86 g, 60 mmol),
K2CO3 (4.1 g), and Aliquat 336 (6 drops) was sonicated for 5
h. To the reaction was added Et2O (200 mL). The reaction
mixture was filtered, extracted with brine, dried over Na2SO4
(anhydrous), filtered, and concentrated under reduced pressure
to give a yellow liquid. The product was purified by column
chromatography to give 13.8 g (77%) of methyl 3-(trifluorom-
ethyl)-4-nitrononanoate.
A solution of methyl 3-(trifluoromethyl)-4-nitrononanoate
(13.0 g) in MeOH was reduced under catalytic hydrogenation
conditions (60 psi, 55 °C) using Raney nickel. The reaction
was heated for 8 h to effect cyclization after reduction of the
nitro group. After concentration of the reaction mixture under
reduced pressure, the residue was purified by column chro-
matography to give 9.0 g of a light-yellow liquid. A second
column was run to separate the cis- and trans-5-pentyl-4-
(trifluoromethyl)pyrrolidin-2-one.
tr a n s-5-P en tyl-4-(tr iflu or om eth yl)p yr r olid in -2-on e: Rf
) 0.5 (silica gel; EA). 1H NMR (CDCl3, 400 MHz): 0.90 (t, J
) 6 Hz, 3H), 1.22-1.41 (m, 6H), 1.53 (m, 1H), 1.65 (m, 1H),
2.49 (dd, J ) 17.5, 6.1 Hz, 1H), 2.62 (dd, J ) 17.5, 10.0 Hz,
1H), 2.75 (dqdd, J ) 10.0, 8.8, 6.1, 4.4 Hz, 1H), 3.75 (dt, J )
7.5, 4.4 Hz, 1H) 6.50 (br s, 1H). 13C NMR (CDCl3, 125 MHz,
was hydrogenated over Pd/C (4%) at 55 °C and 5 psi for 40 h.
The reaction product was purified by column chromatography
to yield 5-benzylpyrrolidin-2-one (0.61 g, 29%).
The 5-benzylpyrrolidin-2-one (0.54 g, 3.1 mmol) was reacted
with trimethyloxonium tetrafluoroborate (550 mg, 3.7 mmol)
according to general procedure A to yield, after chromatogra-
phy, 460 mg of the iminoether. The iminoether (460 mg, 2.4
mmol) was reacted with ammonium chloride (144 mg, 2.7
mmol) according to general procedure B to yield the title
material 15, 310 mg (48%, from the lactam).
1H NMR (D2O,
400 MHz): 1.96 (dddd, J ) 13.2, 9.6, 6.3, 5.1 Hz, 1H), 2.29
(dddd, J ) 13.2, 10.0, 7.9, 6.4 Hz, 1H), 2.63 (ddd, J ) 17.9,
9.6, 6.4 Hz, 1H), 2.77 (ddd, J ) 17.9, 10.0, 6.3 Hz, 1H), 2.91
(dd, J ) 13.9, 6.5 Hz, 1H), 2.95 (dd, J ) 13.9, 6.2 Hz, 1H),
4.32 (dq, J ) 8, 6 Hz, 1H), 7.31 (complex d, J ) 7.5 Hz, 2H),
7.36 (tt, J ) 7, 2 Hz, 1H), 7.42 (complex t, J ) 7.5 Hz, 2H). 13
C
NMR (D2O, 125 MHz): 28.4, 32.5, 43.0 (CH2’s); 64.3 (CH);
129.9, 131.7, 132.5 (dCH’s); 139.9 (dC); 174 (CdN). Anal.
(C11H14N2‚HCl) C, H, N, Cl.
t r a n s-5-Be n zyl-4-(t r iflu or om e t h yl)p yr r olid in -2-im -
in e Hyd r och lor id e (17) a n d cis-5-Ben zyl-4-(tr iflu or om -
eth yl)p yr r olid in -2-im in e Hyd r och lor id e (18). The ethyl
4,4,4-(trifluoromethyl)crotonate (5.5 g, 33 mmol) and â-nitro-
ethylbenzene19 (5.0 g, 33 mmol) were reacted with potassium
carbonate (4.6 g, 33 mmol) and Aliquat 336 (10 drops), in a
manner similar to the method described in 11. Purification
by chromatography on silica gel yielded the methyl 3-(trifluo-
romethyl)-4-nitrobenzenepentanoate (4.4 g, 42%).
The methyl 3-(trifluoromethyl)-4-nitrobenzenepentanoate
(4.3 g, 13.5 mmol) in absolute MeOH was hydrogenated over
RaNi at 55 °C and 60 psi for 16 h. The reaction product was
purified by column chromatography to yield cis,trans-5-benzyl-
4-(trifluoromethyl)pyrrolidin-2-one (2.33 g, 71%) as a mixture
of diastereomers.
HETCOR): 13.8 (C-11), 22.3 (C-10), 25.0 (C-8), 30.3 (q, J CF
)
3 Hz, C-3), 31.3 (C-9), 36.7 (C-7), 43.6 (q, J CF ) 29 Hz, C-4),
54.2 (C-5), 126.7 (q, J CF ) 277 Hz, C-6), 174.8 (C-2). Anal.
(C10H16NOF3‚0.1EA) C, H, N.
The cis,trans-5-benzyl-4-(trifluoromethyl)pyrrolidin-2-one
(0.74 g, 3 mmol) was treated with trimethyloxonium tetrafluo-
roborate (0.54 g, 3.7 mmol) in DCM (20 mL) by general method
A, to yield the iminoether (0.58 g, 76%) as a mixture of
diastereomers. A solution of the iminoethers (0.58 g, 2.3 mmol)
in MeOH (20 mL) was reacted with ammonium chloride (134
mg, 2.3 mmol) by general method B, followed by chromatog-
raphy on reverse-phase HPLC to generate the cis and trans
title materials, trans-5-benzyl-4-(trifluoromethyl)pyrrolidin-2-
imine (240 mg) and cis-5-benzyl-4-(trifluoromethyl)pyrrolidin-
2-imine (250 mg).
tr a n s-5-Ben zyl-4-(t r iflu or om et h yl)p yr r olid in -2-im i-
n e (17): 1H NMR (D2O, 400 MHz) 2.93 (dd, J ) 18.6, 9.6 Hz,
1H), 3.00 (dd, J ) 14.0, 6.6 Hz, 1H), 3.02 (dd, J ) 18.6, 4.5
Hz, 1H), 3.12 (dd, J ) 14.0, 5.3 Hz, 1H), 3.28 (m, 1H), 4.58
(m, 1H), 7.32 (complex d, 2H), 7.38 (complex t, 1H), 7.43
(complex t, 2H). 13C NMR (D2O, 125 MHz): 32.8, 42.4, 45.0
(q, J CF ) 29 Hz), 63.9, 129.1 (q, J CF ) 277 Hz), 130.4, 131.9,
132.7, 138.2, 171.3. Anal. (C12H13N2F3‚1HCl‚1.1NH4Cl‚
0.67H2O) C, H, N.
cis-5-P en tyl-4-(tr iflu or om eth yl)p yr r olid in -2-on e: Rf )
0.4 (silica gel; EA). 1H NMR (CDCl3, 400 MHz): 0.90 (t, J )
6, 3H), 1.22-1.45 (m, 6H), 1.54 (m, 1H), 1.66 (m, 1H), 2.50
(dd, J ) 17.0, 9.1 Hz, 1H), 2.57 (dd, J ) 17.0, 9.1 Hz, 1H),
3.20 (qtd, J ) 9.4, 9.1, 7.6 Hz, 1H), 3.79 (ddd, J ) 10.7, 7.6,
3.4 Hz, 1H) 6.48 (br s, 1H). 13C NMR (CDCl3, 125 MHz,
HETCOR): 13.9 (C-11), 22.4 (C-10), 26.2 (C-8), 30.2 (q, J CF
2 Hz, C-3), 30.7 (q, J CF ) 2 Hz, C-7), 31.5 (C-9), 42.1 (q, J CF
)
)
29 Hz, C-4), 54.5 (C-5), 126.0 (q, J CF ) 278 Hz, C-6), 174.7
(C-2). Anal. (C10H16NOF3) C, H, N.
trans-5-Pentyl-4-methylpyrrolidin-2-one (1.05 g, 4.7 mmol)
was reacted with trimethyloxonium tetrafluoroborate (770 mg,
5.2 mmol) according to general procedure A to yield, after
chromatography, 1.12 g of the iminoether. The iminoether
(1.12 g, 4.64 mmol) was reacted with ammonium chloride (250
mg, 4.64 mmol) according to general procedure B to yield the
title material 13, 410 mg (34%, from the lactam). 1H NMR
(D2O, 300 MHz): 0.9 (t, J ) 6 Hz, 3H), 1.15-1.7 (m, 6H), 1.95
(dd, J ) 16, 7.5 Hz, 1H), 2.40-2.83 (m, 3H), 3.72 (m, 1H). Anal.
(C10H16NOF3‚HCl) C, H, N, Cl.
cis-5-Be n zyl-4-(t r iflu or om e t h yl)p yr r olid in -2-im in e
(18): 1H NMR (D2O, 400 MHz) 2.91 (br t, J ) 13 Hz, 1H),
3.22 (br dd, J ) 14, 2 Hz, 1H), 3.28 (dd, J ) 18, 9 Hz, 1H),
3.36 (dd, J ) 18, 8.5 Hz, 1H), 3.72 (heptet, J ) 8 Hz, 1H), 4.60
(m, 1H), 7.34 (complex d, J ) 8 Hz, 2H), 7.37 (complex t, J )
7 Hz, 1H), 7.44 (complex t, J ) 8.5 Hz, 2H). 13C NMR (D2O,
125 MHz): 33.0, 38.4, 44.4 (q, J CF ) 29 Hz), 63.9, 128.6 (q,
J CF ) 278 Hz), 131.9, 132.0, 132.2, 139.7, 171. Anal.
(C12H13N2F3‚1HCl‚0.1AcOH) C, H, N, Cl.
4,4-Dim eth yl-5-ben zylp yr r olid in -2-im in e Hyd r och lo-
r id e (19). Ethyl dimethyl acrylate (10.75 g, 84 mmol) was
mixed with â-nitroethylbenzene19 (12.68 g, 84 mmol) in tetra-
n-butylammonium fluoride in THF (84 mL, 1 M) and heated
at 40 °C. When the reaction, monitored by GC, was complete,
the mixture was treated with brine (saturated) and the
aqueous phase was extracted with ether. Purification by
chromatography on silica gel yielded the product ethyl 3,3-
dimethyl-4-nitrobenzenepentanoate (9.04 g, 34%). Anal.
(C15H21NO4).
cis-5-P en tyl-4-(tr iflu or om eth yl)p yr r olid in -2-im in e Hy-
d r och lor id e (14). cis-5-Pentyl-4-(trifluoromethyl)pyrrolidin-
2-one (500 mg, 5 mmol) was reacted with trimethyloxonium
tetrafluoroborate (890 mg, 6 mmol) according to general
procedure A to yield, after chromatography, 610 mg of the
iminoether. The iminoether (610 mg, 5 mmol) was reacted
with ammonium chloride (200 mg, 4 mmol) according to
general procedure B to yield the title material 14, 500 mg (70%,
from the lactam). 1H NMR (DMSO-d6, 400 MHz): 0.88 (t, J
) 6 Hz, 3H), 1.20-1.65 (m, 6H), 3.01 (dd, J ) 17, 7 Hz, 1H),
3.17 (dd, J ) 17, 9 Hz, 1H), 3.74 (m, 1H), 4.12 (apparent q, J
) 7 Hz, 1H). Anal. (C10H17N2F3‚1HCl‚0.15NH4Cl) C, H, N,
Cl.
5-Ben zylp yr r olid in -2-im in e Hyd r och lor id e (15). The
methyl acrylate (2.84 g, 33 mmol) was mixed with â-nitroeth-
ylbenzene19 (5.0 g, 33 mmol), potassium carbonate (4.6 g, 33
mmol), and Aliquat 336 (10 drops), in a manner similar to the
method described in 11. Purification by chromatography on
silica gel yielded methyl 4-nitrobenzenepentanoate (4.0 g,
55%). The methyl 4-nitrobenzenepentanoate (4.0 g, 18 mmol)
The above product (3.5 g, 12.5 mmol) in absolute MeOH was