Aerobic ActiVity and QSARs
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 5 1339
128.9, 132.4, 135.7, 145.0, 148.48, 148.50; HRMS (ESMS) calcd
for C15H15ClF3N4O6 [M + HCOO-] 439.0632, found 439.0615.
(R)-6-(4-(Trifluoromethoxy)benzyloxy)-5,6,7,8-tetrahydro-2-
nitroimidazo[1,2-a]pyrimidine (9). A mixture of 8 (300 mg, 0.76
mmol) and DIPEA (0.15 mL, 0.86 mmol) in DMF (3 mL) was
heated under microwave conditions at 150 °C for 30 min. The
reaction mixture was concentrated under vacuum. Chromatography
on preparative TLC (MeOH/CH2Cl2, 1:9) afforded 9 as a yellow
solid (85 mg, 0.24 mmol, 32%). [R]2D0 -12.9 (c 0.39, CHCl3); mp
4.62 (s, 2H), 7.17 (d, J ) 8.1 Hz, 2H), 7.31 (d, J ) 8.7 Hz, 2H),
7.27 (s, 1H); 13C NMR (CDCl3) δ 37.2, 47.5, 50.0, 68.0, 70.1, 116.5,
118.6, 121.0, 122.0, 128.8, 135.8, 145.2, 147.0, 148.8; HRMS
(ESMS) calcd for C15H16F3N4O4 [M + H+] 373.1124, found
1
373.1118. 14: [R]2D0 -26.8 (c 0.52, CHCl3); H NMR (CDCl3) δ
3.58 (dd, J ) 12.0, 6.9 Hz, 1H), 3.68 (dd, J ) 12.0, 3.9 Hz, 1H),
3.88-3.95 (m, 1H), 4.16 (dd, J ) 14.6, 8.0 Hz, 1H), 4.33-4.43
(m, 2H), 4.66 (d, J ) 11.7 Hz, 1H), 7.15 (d, J ) 8.4 Hz, 2H), 7.21
(d, J ) 8.4 Hz, 2H), 7.80 (s, 1H); 13C NMR (CDCl3) δ 41.7, 49.2,
71.5, 76.2, 118.6, 121.1, 121.8, 122.0, 129.3, 132.6, 134.9, 145.6,
149.1; HRMS (ESMS) calcd for C14H12Cl2F3N3O4 [M-] 413.0157,
found 413.0159.
1
) 86-88 °C; H NMR (CDCl3) δ 3.56 (d, J ) 12.9 Hz, 1H),
3.75-3.87 (m, 1H), 3.97-4.11 (m, 3H), 4.57 (d, J ) 12.3 Hz,
1H), 4.72 (d, J ) 12.0 Hz, 1H), 7.17 (d, J ) 8.7 Hz, 2H), 7.34 (d,
J ) 8.7 Hz, 2H), 8.34 (s, 1H); HRMS (ESMS) calcd for
C14H14F3N4O4 [M + H+] 359.0967, found 359.0964.
S-(S)-2-(4-(Trifluoromethoxy)benzyloxy)-3-(2-chloro-4-nitro-
1H-imidazol-1-yl)propyl Ethanethioate (15). To a solution of 6
(850 mg, 1.79 mmol) in DMF (15 mL) was added KSAc (410 mg,
3.59 mmol) at room temperature. The reaction mixture was stirred
at 45 °C for 14 h and quenched with H2O. The crude mixture was
extracted with EtOAc (2×). The combined organic layers were dried
with anhydrous MgSO4, filtered, and concentrated. Chromatography
on silica gel (EtOAc/hexane, 2:1) afforded 15 as a white solid (768
mg, 1.69 mmol, 95%). [R]2D0 -34.1 (c 1.27, CHCl3); mp )
(R)-6-(4-(Trifluoromethoxy)benzyloxy)-6,7-dihydro-2-nitroim-
idazo[1,2-a]pyrimidine-8(5H)-carbaldehyde (10). A mixture of
HCO2H (0.50 mL, 13 mmol) and Ac2O (1.0 mL, 11 mmol) was
heated at 80 °C for 30 min. The reaction mixture was cooled down
to room temperature. A solution of 9 (17 mg, 0.048 mmol) in
CH2Cl2 (3 mL) was added to the reaction mixture at room
temperature. The reaction mixture was stirred at room temperature
for 14 h and then concentrated under vacuum. Chromatography on
preparative TLC (EtOAc/hexane, 5:1) afforded 10 as a yellow oil
(6.2 mg, 0.016 mmol, 33%). [R]2D0 +16.6 (c 0.98, CHCl3); 1H NMR
(CDCl3) δ 3.41 (d, J ) 13.2 Hz, 1H), 4.12-4.32 (m, 3H), 4.52 (d,
J ) 12.0 Hz, 1H), 4.65 (d, J ) 12.0 Hz, 1H), 4.66-4.76 (m, 1H),
7.18 (d, J ) 8.4 Hz, 2H), 7.29 (d, J ) 8.4 Hz, 2H), 7.63 (s, 1H),
9.37 (s, 1H); 13C NMR (CDCl3) δ 77.0, 39.4, 48.5, 66.2, 70.1, 117.2,
118.6, 121.2, 122.0, 129.2, 134.9, 139.2, 145.3, 149.1, 159.8; HRMS
(ESMS) calcd for C15H14F3N4O5 [M + H+] 387.0916, found
387.0912.
1
84.2-84.5 °C; H NMR (CDCl3) δ 2.36 (s, 3H), 2.95 (dd, J )
14.1, 7.2 Hz, 1H), 3.24 (dd, J ) 14.1, 3.9 Hz, 1H), 3.68-3.78 (m,
1H), 3.99 (dd, J ) 14.4, 8.4 Hz, 1H), 4.17 (dd, J ) 14.4, 3.09 Hz,
1H), 4.38 (d, J ) 11.7 Hz, 1H), 4.64 (d, J ) 11.7 Hz, 1H), 7.10
(d, J ) 8.7 Hz, 2H), 7.18 (d, J ) 8.7 Hz, 2H), 7.75 (s, 1H); 13C
NMR (CDCl3) δ 29.2, 30.4, 50.1, 71.0, 118.5, 120.8, 121.86,
121.92, 129.4, 132.4, 135.2, 145.3, 148.8, 148.9, 194.5; HRMS
(ESMS) calcd for C16H16ClF3N3O5S [M + H+] 454.0451, found
454.0454.
(S)-6-(4-(Trifluoromethoxy)benzyloxy)-6,7-dihydro-2-nitro-
5H-imidazo[2,1-b][1,3]thiazine (16). To a solution of 15 (300 mg,
0.661 mmol) in MeOH (50 mL) was added 3 M NaOH (aq) (0.30
mL, 0.90 mmol) at 0 °C. The reaction mixture was stirred at 0 °C
for 30 min and at room temperature for 17 h and then concentrated
under vacuum. Column chromatography on silica gel (EtOAc/
hexane, 1:1 to 2:1) afforded 16 as a yellow oil (65 mg, 0.17 mmol,
26%). [R]2D0 -62.7 (c 1.00, MeOH); 1H NMR (CDCl3) δ 3.27-3.38
(m, 2H), 4.19 (d, J ) 3.6 Hz, 2H), 4.30 (m, 1H), 4.59 (d, J ) 6.0
Hz, 1H), 4.72 (d, J ) 6.0 Hz, 1H), 7.17 (d, J ) 8. Hz, 2H), 7.34
(d, J ) 8.4 Hz, 2H), 7.67 (s, 1H); 13C NMR (MeOH-d4) δ 28.7,
49.9, 67.4, 70.0, 118.6, 121.0, 122.0, 129.1, 129.2, 135.4, 139.0,
147.2, 148.9; HRMS (ESMS) calcd for C14H13F3N3O4S [M + H+]
376.0579, found 376.0575.
1-((R)-6-(4-(Trifluoromethoxy)benzyloxy)-6,7-dihydro-2-ni-
troimidazo[1,2-a]pyrimidin-8(5H)-yl)ethanone (11). To a solution
of 9 (50 mg, 0.14 mmol) and Et3N (0.030 mL, 0.22 mmol) in
CH2Cl2 was added AcCl (0.015 mL, 0.21 mmol) at 0 °C. The
reaction mixture was stirred at room temperature for 2 h and was
concentrated under vacuum. Chromatography on preparative TLC
(EtOAc/hexane, 5:1) afforded 11 as a yellow oil (13 mg, 0.032
1
mmol, 23%). [R]2D0 -25.7 (c 0.65, CHCl3); H NMR (CDCl3) δ
2.70 (s, 3H), 3.41 (d, J ) 14.1 Hz, 1H), 4.13-4.21 (m, 3H), 4.50
(d, J ) 11.9 Hz, 1H), 4.66 (d, J ) 11.9 Hz, 1H), 4.97 (dd, J )
14.1, 3.9 Hz, 1H), 7.19 (d, J ) 8.4 Hz, 2H), 7.30 (d, J ) 8.4 Hz,
2H), 7.60 (s, 1H); 13C NMR (CDCl3) δ 25.0, 41.7, 49.7, 67.1, 70.1,
116.9, 118.7, 121.2, 122.1, 129.2, 135.2, 140.1, 145.0, 149.1, 170.4;
LC-MS (ESMS) 401.0 [M + H+], 423.1 [M + Na+].
17 and 18. To a solution of 16 (60 mg, 0.16 mmol) in CH2Cl2
(6 mL) was added 77% mCPBA (107 mg, 0.48 mmol) at 0 °C.
The reaction mixture was stirred at 0 °C for 30 min and at room
temperature for 1 h and then concentrated under vacuum. Column
chromatography on silica gel (EtOAc/hexane, 5:1) afforded 17 as
a colorless oil (16 mg, 0.042 mmol, 26%) and 18 as a white solid
(38 mg, 0.094 mmol, 59%). 17: [R]2D0 -112.9 (c 0.82, MeOH); 1H
NMR (MeOH-d4) δ 3.66-3.71 (m, 1H), 3.81-3.91 (m, 1H),
4.27-4.35 (m, 1H), 4.66-4.82 (m, 4H), 7.26 (d, J ) 8.1 Hz, 2H),
7.46 (d, J ) 8.7 Hz, 2H), 8.30 (s, 1H); 13C NMR (MeOH-d4) δ
51.3, 51.6, 68.8, 71.8, 120.4, 122.3, 123.2, 124.2, 130.7, 138.1,
143.8, 149.2, 150.3; HRMS (ESMS) calcd for C14H13F3N3O5S [M
+ H+] 392.0528, found 392.0522. 18: [R]2D0 -26.5 (c 1.12, MeOH);
1-((S)-2-(4-(Trifluoromethoxy)benzyloxy)-3-iodopropyl)-2-
chloro-4-nitro-1H-imidazole (12). A solution of 6 (850 mg, 1.79
mmol) and NaI (1.18 g, 7.87 mmol) in acetone (10 mL) was
refluxed for 6 h. The reaction mixture was filtered and concentrated
under vacuum. Chromatography on silica gel (EtOAc/hexane, 2:1)
afforded 12 as a colorless oil (824 mg, 1.63 mmol, 91%). [R]D20
1
-20.7 (c 0.80, CHCl3); H NMR (CDCl3) δ 3.23 (dd, J ) 10.8,
7.2 Hz, 1H), 3.36 (dd, J ) 10.8, 3.6 Hz, 1H), 3.62-3.69 (m, 1H),
4.10 (dd, J ) 14.4, 8.4 Hz, 1H), 4.34 (d, J ) 11.7 Hz, 1H), 4.38
(dd, J ) 14.4, 3.0 Hz, 1H), 4.65 (d, J ) 11.7 Hz, 1H), 7.16 (d, J
) 8.7 Hz, 2H), 7.22 (d, J ) 8.7 Hz, 2H), 7.79 (s, 1H); 13C NMR
(CDCl3) δ 2.7, 51.4, 71.2, 75.7, 118.6, 121.1, 121.7, 122.0, 129.4,
132.6, 134.8, 145.6, 149.17, 149.20; LC-MS (ESMS) 506.2 [M
+ H+].
1
mp ) 71.5-72.7 °C; H NMR (MeOH-d4) δ 4.04 (dd, J ) 14.7,
2.1 Hz, 1H), 4.25 (dd, J ) 14.7, 6.6 Hz, 1H), 4.58-4.72 (m, 5H),
7.20 (d, J ) 8.7 Hz, 2H), 7.43 (d, J ) 8.7 Hz, 2H), 8.24 (s, 1H);
13C NMR (MeOH-d4) δ 52.0, 55.3, 71.3, 71.7, 120.3, 122.1, 123.2,
123.7, 130.9, 137., 143.5, 148.0, 150.28, 150.30; HRMS (ESMS)
calcd for C14H13F3N3O6S [M + H+] 408.0477, found 408.0471.
(R)-6,7-Dihydro-2-nitro-5H-imidazo[2,1-b][1,3]oxazin-6-yl meth-
anesulfonate (21). MsCl (0.78 mL, 10.0 mmol) was added to a
stirred solution of 20 (0.93 g, 5.0 mmol) and Et3N (2.1 mL, 15.0
mmol) in DMF (40 mL) at 0 °C. The reaction mixture was then
further stirred at 0 °C for 1 h. The solvent and excess reagents
were removed under reduced pressure. H2O (50 mL) was added to
the light-brown residue. The mixture was then filtered and the solid
was washed with H2O (50 mL) to give 21 as a yellow/white solid
(R)-6-(4-(Trifluoromethoxy)benzyloxy)-5,6,7,8-tetrahydro-8-
methyl-2-nitroimidazo[1,2-a]pyrimidine (13) and 1-((S)-2-(4-
(Trifluoromethoxy)benzyloxy)-3-chloropropyl)-2-chloro-4-nitro-
1H-imidazole (14). A mixture of 12 (245 mg, 0.485 mmol), 2.0
M MeNH2 (1.5 mL, 3.0 mmol) in THF, and DIPEA (0.10 mL,
0.57 mmol) in DMF (2 mL) was heated under microwave conditions
at 200 °C for 20 min. The reaction mixture was concentrated under
vacuum. Chromatography on preparative TLC (MeOH/CH2Cl2,
1:15) afforded 13 as a yellow solid (94 mg, 0.25 mmol, 52%) in
addition to 14 (72 mg, 0.17 mmol, 35%) as a colorless oil. 13:
1
[R]2D0 -35.3 (c 1.12, MeOH); mp ) 116.0-117.3 °C; H NMR
(CDCl3) δ 3.06 (s, 3H), 3.32-3.47 (m, 2H), 3.96-4.13 (m, 3H),