Journal of Medicinal Chemistry
Article
To an ice-cooled solution of 1 M diborane in THF (45 mL, 45
mmol), a solution of (2R)-(+)- or (2S)-(−)-chromane-2-carboxamide
(2.11 g, 11.9 mmol) in anhydrous THF (55 mL) was added dropwise
under an argon atmosphere, and the mixture was stirred at room
temperature overnight. Then, the reaction mixture was refluxed for 1 h
and, after cooling to room temperature, 10% HCl (3.4 mL) was added.
The solvent was evaporated, and the residue was basified to pH 8.5
with aqueous 10% NaOH and extracted with Et2O (6 × 50 mL). The
combined organic layers were dried (Na2SO4) and evaporated. The
residue was purified by column chromatography (dichloromethane/
EtOH, 9:1) to afford the corresponding amines (−)-64 or (+)-64 in
8.11 (d, J = 8.5, 1H, CHAr). 13C NMR (CDCl3) δ 24.4, 25.8, 26.8,
27.4, 38.7, 45.4, 53.8, 54.1 (8CH2), 63.1, 120.9, 126.0, 127.2, 128.9
(5CH), 129.1 (C), 129.2 136.2 (2CH), 147.4 (C), 160.5, 160.7 (C,
CO), 173.8 (CO). Anal. (C20H24N4O2·HCl) C, H, N.
(±)-2-{4-[(3,4-Dihydro-2H-chromen-2-ylmethyl)amino]butyl}-
tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione ((±)-9). Ob-
tained from 42 and racemic amine 64 in 37% yield. Chromatography:
EtOAc/EtOH, 8:2; oil. Rf (dichloromethane/EtOH, 9:1) 0.28. IR
(CHCl3) ν 3405, 1772, 1709. 1H NMR (CDCl3) δ 1.47−1.86 (m, 5H,
(CH2)2, 1/2CH2cyc), 1.91−2.12 (m, 4H, CH2cyc, CH2chrom,), 2.16−2.34
(m, 1H, 1/2CH2cyc), 2.64−2.92 (m, 6H, 2CH2NH, CH2chrom), 3.16−
3.28 (m, 1H, 1/2CH2cyc), 3.48 (t, J = 7.1, 2H, CH2N), 3.66 (dt, J =
11.2, 7.3, 1H, 1/2CH2cyc), 4.05 (dd, J = 9.1, 7.3, 1H, CHcyc), 4.11−4.18
(m, 1H, CHchrom), 6.81 (t, J = 7.6, 2H, 2CHAr), 7.00−7.10 (m, 2H,
2CHAr). 13C NMR (CDCl3) δ 24.6, 25.6, 25.8, 26.9, 27.1, 27.5, 38.7,
45.4, 49.3, 54.1 (10CH2), 63.2, 75.0, 116.7, 120.1 (4CH), 121.9 (C),
127.1, 129.4 (2CH), 154.5 (C), 160.8, 173.9 (2CO). Anal.
(C20H27N3O3·HCl·H2O) C, H, N.
82 and 86% yield, respectively. (−)-64: oil. [α]20 −119.5 (c 1.0,
D
THF) (lit.59 [α]20 −122.8 (c 1.0, THF)). Rf (dichloromethane/
D
1
EtOH, 9:1): 0.35. IR (CHCl3) ν 3387, 1608, 1581, 1489, 1456. H
NMR (CDCl3) δ 1.69−1.97 (m, 2H, CH2CH), 2.70−2.88 (m, 2H,
CH2Ar), 2.92 (d, J = 7.3, 2H, CH2NH2), 3.95 (dtd, J = 10.3, 5.5, 2.4,
1H, CH), 6.81 (m, 2H, 2CHAr), 7.04−7.13 (m, 2H, 2CHAr). 13C NMR
(CDCl3) δ 24.6, 25.0, 46.6 (3CH2), 77.4, 116.6, 120.1 (3CH), 121.9
(C), 127.2, 129.5 (2CH), 154.7 (C). (+)-64: oil. [α]20D +110.5 (c 1.0,
(+)-2-(4-{[(2S)-3,4-Dihydro-2H-chromen-2-ylmethyl]amino}-
THF) (lit.59 [α]20 +128.8 (c 1.0, THF)).
butyl)tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione ((+)-9).
D
Obtained from 42 and enantiopure amine (+)-64 in 38% yield; [α]20
D
General Procedure for the Synthesis of Final Compounds
4−35. To a solution of 4 equiv of the corresponding arylalkylamine
(commercially available or 61−64) in dry acetonitrile (1 mL/mmol), a
solution of 1 equiv of the appropriate bromo- or chloroalkyl derivative
42−60 in dry acetonitrile (4 mL/mmol) was added dropwise and
under an argon atmosphere. The reaction mixture was stirred at 60 °C
overnight. Once at room temperature, the solvent was removed under
reduced pressure and the residue was suspended in an aqueous
solution of 20% K2CO3 and extracted with dichloromethane (3 × 50
mL). The organic layer was dried (Na2SO4), and the solvent was
evaporated to dryness. The residue was purified by column
chromatography using the appropriate eluent, to afford pure 4−35.
The free amine was characterized (yield, Rf, IR, NMR), dissolved in
anhydrous Et2O (6 mL/mmol), and a commercial 1 M HCl(g)/Et2O
solution (3 mL/mmol) was added. The hydrochloride salt was isolated
by filtration or evaporation, washed with anhydrous Et2O, dried under
high vacuum, and characterized (mp, elemental analysis).
1
+65 (c 0.5, CHCl3). IR, H, and 13C NMR spectra were consistent
with those reported for racemic 9. Anal. (C20H27N3O3·HCl·3H2O) C,
H, N.
(−)-2-(4-{[(2R)-3,4-Dihydro-2H-chromen-2-ylmethyl]amino}-
butyl)tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione
((−)-9). Obtained from 42 and enantiopure amine (−)-64 in 35%
1
yield; [α]20 −77 (c 0.5, CHCl3). IR, H, and 13C NMR spectra were
D
consistent with those reported for racemic 9. Anal. (C20H27N3O3·HCl)
C, H, N.
2-[4-(Benzylamino)butyl]tetrahydro-1H-pyrrolo[1,2-c]imidazole-
1,3(2H)-dione (10). Obtained from 42 and benzylamine in 45% yield.
Chromatography: EtOAc.
2-{4-[(2-Phenylethyl)amino]butyl}tetrahydro-1H-pyrrolo[1,2-c]-
imidazole-1,3(2H)-dione (11). Obtained from 42 and 2-phenylethyl-
amine in 48% yield. Chromatography: EtOAc.
2-{4-[(2-Furylmethyl)amino]butyl}tetrahydro-1H-pyrrolo[1,2-c]-
imidazole-1,3(2H)-dione (12). Obtained from 42 and 2-furylmethyl-
amine in 38% yield. Chromatography: EtOAc; mp 135−136 °C
(hexane/Et2O). Rf (EtOAc/EtOH, 8:2) 0.32. IR (CHCl3) ν 3462,
1771, 1709. 1H NMR (CDCl3) δ 1.38−1.71 (m, 5H, (CH2)2, 1/
2CH2cyc), 1.98−2.22 (m, 3H, 3/2CH2cyc), 2.55 (t, J = 7.3, 2H,
CH2NH), 3.19 (ddd, J = 11.7, 7.4, 5.4, 1H, 1/2CH2cyc), 3.39 (t, J = 6.9,
2H, CH2N), 3.58 (dt, J = 11.2, 7.4, 1H, 1/2CH2cyc), 3.70 (s, 2H,
CH2Ar), 3.99 (dd, J = 8.4, 7.4, 1H, CHcyc), 6.07 (d, J = 3.1, 1H, CHAr),
2-{4-[(1-Naphthylmethyl)amino]butyl}tetrahydro-1H-pyrrolo-
[1,2-c]imidazole-1,3(2H)-dione (4). Obtained from 42 and 1-
naphthylmethylamine in 42% yield. Chromatography: EtOAc; mp
150−153 °C (chloroform/hexane). IR (CHCl3) ν 3500, 3300, 1770,
1
1708. H NMR (CDCl3) δ 1.48−1.71 (m, 5H, (CH2)2, 1/2CH2cyc),
1.99−2.08 (m, 2H, CH2cyc), 2.16−2.24 (m, 1H, 1/2CH2cyc), 2.74 (t, J
= 6.9, 2H, CH2NH), 3.16−3.24 (m, 1H, 1/2CH2cyc), 3.47 (t, J = 6.9,
2H, CH2N), 3.64 (dt, J = 11.1, 7.8, 1H, 1/2CH2cyc), 4.02 (dd, J = 9.3,
7.8, 1H, CHcyc), 4.20 (s, 2H, CH2Ar), 7.37−7.54 (m, 4H, 4CHAr), 7.74
(d, J = 7.2, 1H, CHAr), 7.82−7.85 (m, 1H, CHAr), 8.08 (d, J = 8.4, 1H,
CHAr). 13C NMR (CDCl3) δ 25.9, 27.0, 27.2, 27.5, 38.8, 45.5, 49.3,
51.6 (8CH2), 63.3, 123.6, 125.4, 125.6, 125.9, 126.1, 127.7, 128.7
(8CH), 131.8, 133.9, 136.0 (3C), 160.9, 173.9 (2CO). Anal.
(C21H25N3O2·HCl) C, H, N.
6.24 (dd, J = 3.6, 1.9, 1H, CHAr), 7.28 (dd, J = 1.8, 0.8, 1H, CHAr). 13
C
NMR (CDCl3) δ 25.6, 26.8, 26.9, 27.4, 38.6, 45.3, 45.9, 48.3, (8CH2),
63.1, 106.6, 109.9, 141.6 (4CH), 153.7 (C), 160.6, 173.8 (2CO). Anal.
(C15H21N3O3·HCl·H2O) C, H, N.
2-(4-{[2-(2-Furyl)ethyl]amino}butyl)tetrahydro-1H-pyrrolo[1,2-c]-
imidazole-1,3(2H)-dione (13). Obtained from 42 and 2-(2-furyl)-
ethylamine in 36% yield. Chromatography: EtOAc.
2-(4-{[2-(1-Naphthyl)ethyl]amino}butyl)tetrahydro-1H-pyrrolo-
[1,2-c]imidazole-1,3(2H)-dione (5). Obtained from 42 and amine 61
in 35% yield. Chromatography: EtOAc/EtOH, 1:1.
2-{4-[(Thien-2-ylmethyl)amino]butyl}tetrahydro-1H-pyrrolo[1,2-
c]imidazole-1,3(2H)-dione (14). Obtained from 42 and thien-2-
ylmethylamine in 40% yield. Chromatography: EtOAc.
2-{4-[(2-Naphthylmethyl)amino]butyl}tetrahydro-1H-pyrrolo-
[1,2-c]imidazole-1,3(2H)-dione (6). Obtained from 42 and 2-
naphthylmethylamine in 44% yield. Chromatography: dichloro-
methane/EtOH, 95:5.
2-(4-{[2-(2-Naphthyl)ethyl]amino}butyl)tetrahydro-1H-pyrrolo-
[1,2-c]imidazole-1,3(2H)-dione (7). Obtained from 42 and amine 62
in 35% yield. Chromatography: EtOAc/EtOH, 9:1.
2-{4-[(2-Thien-2-ylethyl)amino]butyl}tetrahydro-1H-pyrrolo[1,2-
c]imidazole-1,3(2H)-dione (15). Obtained from 42 and 2-(thien-2-
yl)ethylamine in 35% yield. Chromatography: EtOAc.
2-{4-[(Pyridin-2-ylmethyl)amino]butyl}tetrahydro-1H-pyrrolo-
[1,2-c]imidazole-1,3(2H)-dione (16). Obtained from 42 and pyridin-
2-ylmethylamine in 37% yield. Chromatography: EtOAc; oil. Rf
1
(EtOAc) 0.05. IR (CHCl3) ν 3385, 1771, 1709. H NMR (CDCl3)
δ 1.49−1.84 (m, 5H, (CH2)2, 1/2CH2cyc), 1.95−2.32 (m, 3H, 3/
2CH2cyc), 2.67 (t, J = 7.1, 2H, CH2NH), 3.23 (ddd, J = 11.4, 7.3, 5.4,
1H, 1/2CH2cyc), 3.48 (t, J = 6.8, 2H, CH2N), 3.67 (dt, J = 11.2, 7.6,
1H, 1/2CH2cyc), 3.89 (s, 2H, CH2Ar), 4.06 (dd, J = 8.8, 7.6, 1H,
CHcyc), 7.16 (dd, J = 6.7, 5.0, 1H, CHAr), 7.26−7.31 (m, 1H, CHAr),
7.64 (td, J = 7.6, 1.5, 1H, CHAr), 8.54 (d, J = 4.6, 1H, CHAr). 13C NMR
(CDCl3) δ 25.9, 27.0, 27.2, 27.6, 38.8, 45.5, 49.0, 55.2 (8CH2), 63.3,
121.9, 122.3, 136.4, 149.3 (5CH), 163.3 (C), 164.2, 175.9 (2CO).
Anal. (C16H22N4O2·2HCl·5H2O) C, H, N.
2-{4-[(Quinolin-2-ylmethyl)amino]butyl}tetrahydro-1H-pyrrolo-
[1,2-c]imidazole-1,3(2H)-dione (8). Obtained from 42 and amine 63
in 40% yield. Chromatography: EtOAc/EtOH, 7:3; mp 126−127 °C
(EtOAc). Rf (EtOAc/EtOH, 7:3) 0.21. IR (CHCl3) ν 3362, 1770,
1
1708. H NMR (CDCl3) δ 1.52−1.67 (m, 5H, (CH2)2, 1/2CH2cyc),
1.90−2.27 (m, 3H, 3/2CH2cyc), 2.50 (t, J = 6.3, 2H, CH2NH), 3.01−
3.24 (m, 1H, 1/2CH2cyc), 3.42 (t, J = 6.8, 2H, CH2N), 3.53−3.69 (m,
1H, 1/2CH2cyc), 3.91−4.00 (m, 3H, CH2Ar, CHcyc), 7.47 (t, J = 7.1,
1H, CHAr), 7.62−7.77 (m, 3H, 3CHAr), 8.02 (d, J = 8.3, 1H, CHAr),
7994
dx.doi.org/10.1021/jm2007886 | J. Med. Chem. 2011, 54, 7986−7999