Journal of Medicinal Chemistry
ARTICLE
EtOAc/CH2Cl2 gave 224 (668 mg, 83%) as a pale yellow solid: mp
(MeOH/CH2Cl2/hexane) 220ꢀ221 °C. 1H NMR [(CD3)2SO] δ 8.25
(d, J = 5.8 Hz, 1 H), 8.04 (s, 1 H), 7.33 (d, J = 2.3 Hz, 1 H), 7.11 (dd, J =
5.8, 2.3 Hz, 1 H), 5.44 (m, 1 H), 4.68 (m, 2 H), 4.43 (dd, J = 14.1, 3.2 Hz,
1 H), 4.35 (br d, J = 14.2 Hz, 1 H). Anal. (C11H9ClN4O4) C, H, N.
See the Supporting Information for details of the syntheses of
bromides 221 and 223 from alcohol 135.
(6S)-2-Nitro-6-({2-[4-(trifluoromethoxy)phenyl]-4-pyridinyl}oxy)-
6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (44). Reaction of chloride
224 and 4-(trifluoromethoxy)phenylboronic acid under the Suzuki
coupling conditions described in Procedure U (but using 0.33 equiv
of Pd(dppf)Cl2 for 100 min), followed by chromatography of the
product on silica gel, eluting with 0ꢀ10% EtOAc/CH2Cl2 (foreruns)
and then with 10ꢀ12% EtOAc/CH2Cl2, gave 44 (67%) as a cream solid:
mp (MeOH/CH2Cl2/hexane) 240ꢀ241 °C. 1H NMR [(CD3)2SO] δ
8.53 (d, J = 5.7 Hz, 1 H), 8.25 (br d, J = 8.9 Hz, 2 H), 8.06 (s, 1 H), 7.69
(d, J = 2.3 Hz, 1 H), 7.46 (br d, J = 8.8 Hz, 2 H), 7.10 (dd, J = 5.7, 2.4 Hz,
1 H), 5.55 (m, 1 H), 4.75 (dt, J = 12.5, 2.1 Hz, 1 H), 4.71 (br d, J =
12.8 Hz, 1 H), 4.48 (dd, J = 14.0, 3.2 Hz, 1 H), 4.39 (br d, J = 14.1 Hz,
1 H). Anal. (C18H13F3N4O5) C, H, N.
Pd(dppf)Cl2 (10.4 mg, 0.014 mmol), and aqueous Na2CO3 (2 M,
0.35 mL) were added. The resulting mixture was degassed for 5 min
(vacuum pump), and N2 was added. After being stirred at 90 °C for
60 min, the mixture was cooled, diluted with aqueous NaHCO3
(50 mL), and extracted with CH2Cl2 (4 ꢂ 50 mL). The extracts were
evaporated to dryness, and the residue was chromatographed on silica
gel. Elution with 0ꢀ4% EtOAc/CH2Cl2 first gave foreruns, and then
further elution with 4ꢀ6% EtOAc/CH2Cl2 gave the crude product;
impure fractions were combined and further chromatographed on silica
gel. Elution with 0ꢀ0.25% MeOH/CH2Cl2 first gave foreruns, and then
further elution with 0.25ꢀ0.5% MeOH/CH2Cl2 gave additional pro-
duct; impure fractions were rechromatographed using this method, and
the purified material was combined to give 77 (23 mg, 39%) as a pale
yellow solid: mp (CH2Cl2/pentane) 198ꢀ200 °C. 1H NMR (CDCl3) δ
8.93 (d, J = 1.9 Hz, 1 H), 8.02 (dd, J = 8.1, 1.9 Hz, 1 H), 7.74 (d, J = 8.2
Hz, 1 H), 7.52 (br d, J = 8.2 Hz, 2 H), 7.41 (s, 1 H), 7.28 (br d, J = 8.1 Hz,
2 H), 4.59 (ddd, J = 12.1, 3.5, 2.2 Hz, 1 H), 4.33 (br d, J = 12.7 Hz, 1 H),
4.19 (dd, J = 12.8, 3.8 Hz, 1 H), 4.11 (dt, J = 12.8, 2.4 Hz, 1 H), 4.00 (m,
1 H), 3.65 (dt, J = 8.8, 6.2 Hz, 1 H), 3.55 (dt, J = 8.8, 6.1 Hz, 1 H), 2.74 (t,
J = 7.5 Hz, 2 H), 1.97 (m, 2 H). Anal. (C21H19F3N4O4) C, H, N.
See the Supporting Information for details of the synthesis of 78
(Table 2) from bromide 153.
See the Supporting Information for details of the syntheses of 45,
46, 48ꢀ51, and 56ꢀ59 (Table 2) from halides 224, 223, and 221,
respectively.
Procedure Y. Methyl (2E)-3-[40-(trifluoromethoxy)[1,10-biphenyl]-4-
yl]-2-propenoate (176a) (Scheme 3C). A mixture of methyl (2E)-3-(4-
bromophenyl)-2-propenoate (174) (0.500 g, 2.07 mmol) and 4-
(trifluoromethoxy)phenylboronic acid (0.612 g, 2.97 mmol) in dioxane
(40 mL) and aqueous K2CO3 (2 M, 10 mL) was purged with N2.
Pd(dppf)Cl2 (0.050 g, 0.07 mmol) was added, and the stirred mixture
was refluxed under N2 for 1 h. The resulting mixture was concentrated
under reduced pressure, and the residue was partitioned between EtOAc
and water. The organic layer was dried and evaporated, and then column
chromatography of the residue on silica gel, eluting with a gradient of
hexanes to CH2Cl2, gave 176a (0.567 g, 85%) as a white solid: mp
134ꢀ136 °C. 1H NMR (CDCl3) δ 7.73 (d, J = 16.0 Hz, 1 H), 7.63ꢀ7.56
(m, 6 H), 7.30 (br d, J = 8.8 Hz, 2 H), 6.48 (d, J = 16.0 Hz, 1 H), 3.82 (s,
3 H). APCI MS m/z 323 [M + H]+.
Procedure W. (6S)-2-Nitro-6-{[60-(trifluoromethyl)[2,30-bipyridin]-
4-yl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (47). A stirred
mixture of chloride 224 (50.2 mg, 0.169 mmol), 6-(trifluoromethyl)-
3-pyridinylboronic acid (70.5 mg, 0.369 mmol), and Pd(dppf)Cl2 (51.5
mg, 0.070 mmol) in DMF (1.5 mL), toluene (1.0 mL), and EtOH
(0.6 mL) was degassed for 6 min (vacuum pump), and then N2 was
added. An aqueous solution of Na2CO3 (0.40 mL of 2 M, 0.80 mmol)
was added by syringe, the stirred mixture was again degassed for 6 min,
and then N2 was added. The resulting mixture was stirred at 90 °C for 5 h
and then cooled, diluted with aqueous NaHCO3 (50 mL), and extracted
with CH2Cl2 (4x 50 mL). The extracts were evaporated to dryness, and
the residue was chromatographed on silica gel. Elution with 0ꢀ0.75%
MeOH/CH2Cl2 first gave foreruns, and then further elution with 0.75%
MeOH/CH2Cl2 gave 47 (50 mg, 73%) as a cream solid: mp (MeOH/
Procedure Z. (2E)-3-[40-(Trifluoromethoxy)[1,10-biphenyl]-4-yl]-2-
propen-1-ol (177a). A solution of DIBAL-H (20% w/w in toluene,
2.0 mL, 2.42 mmol) was added to a slurry of ester 176a (0.396 g, 1.23
mmol) in toluene (12 mL) at ꢀ78 °C. The mixture was warmed to room
temperature, stirred for 1 h, and then poured into ice cold aqueous
NH4Cl (50 mL). The resulting mixture was diluted with CH2Cl2
(100 mL) and filtered through Celite, and then the organic layer was
dried and evaporated. Column chromatography of the residue on silica
gel, eluting with a gradient of 0ꢀ5% EtOAc/CH2Cl2, gave 177a (0.195
g, 54%) as a white solid: mp 86ꢀ90 °C (dec). 1H NMR (CDCl3) δ 7.60
(br d, J = 8.7 Hz, 2 H), 7.53 (br d, J = 8.4 Hz, 2 H), 7.47 (br d, J = 8.4 Hz,
2 H), 7.28 (br d, J = 8.1 Hz, 2 H), 6.66 (br d, J = 15.9 Hz, 1 H), 6.42 (dt,
J = 15.9, 5.7 Hz, 1 H), 4.36 (td, J = 5.8, 1.5 Hz, 2 H), 1.44 (t, J = 5.9 Hz,
1 H). HRAPCIMS calcd for C16H12F3O m/z [M + H ꢀ H2O]+
277.0835, found 277.0832.
1
CH2Cl2/hexane) 284ꢀ286 °C. H NMR [(CD3)2SO] δ 9.47 (d, J =
1.9 Hz, 1 H), 8.75 (dd, J = 8.2, 1.7 Hz, 1 H), 8.62 (d, J = 5.8 Hz, 1 H), 8.07
(s, 1 H), 8.02 (d, J = 8.1 Hz, 1 H), 7.89 (d, J = 2.4 Hz, 1 H), 7.22 (dd, J =
5.7, 2.4 Hz, 1 H), 5.57 (m, 1 H), 4.77 (dt, J = 12.4, 2.2 Hz, 1 H), 4.73
(br d, J = 12.4 Hz, 1 H), 4.50 (dd, J = 14.1, 3.2 Hz, 1 H), 4.41 (br d, J =
14.2 Hz, 1 H). Anal. (C17H12F3N5O4) C, H, N.
(6S)-6-[3-(4-Bromophenyl)propoxy]-2-nitro-6,7-dihydro-5H-imidazo-
[2,1-b][1,3]oxazine (153) (Scheme 2A). Reaction of alcohol 135 with
iodide 146 and NaH, using Procedure K for 5.5 h, followed by chro-
matography of the product on silica gel, eluting with CH2Cl2 (foreruns)
and then with 0ꢀ1.5% EtOAc/CH2Cl2, gave 153 (38%) as a pale yellow
solid: mp (CH2Cl2/pentane) 148ꢀ150 °C. 1H NMR (CDCl3) δ 7.40
(s, 1 H), 7.39 (br d, J = 8.4 Hz, 2 H), 7.01 (br d, J = 8.4 Hz, 2 H), 4.55
(ddd, J = 12.1, 3.7, 2.2 Hz, 1 H), 4.31 (dd, J = 12.0, 1.4 Hz, 1 H), 4.16 (dd,
J = 12.7, 3.9 Hz, 1 H), 4.06 (dt, J = 12.8, 2.5 Hz, 1 H), 3.95 (m, 1 H), 3.59
(dt, J = 8.8, 6.2 Hz, 1 H), 3.49 (dt, J = 8.8, 6.1 Hz, 1 H), 2.62 (t, J = 7.4 Hz,
2 H), 1.89 (m, 2 H). Anal. (C15H16BrN3O4) C, H, N.
Procedure AA. 4-[(1E)-3-Bromo-1-propenyl]-40-(trifluoromethoxy)-
1,10-biphenyl (178a). PBr3 (26 μL, 0.28 mmol) was added to a solution
of alcohol 177a (0.159 g, 0.540 mmol) in Et2O (10 mL) at 0 °C. The
mixture was stirred at room temperature for 1 h and then quenched with
ice and extracted with Et2O. The organic layer was dried and evaporated,
and then column chromatography of the residue on silica gel, eluting
with CH2Cl2, gave 178a (0.123 g, 64%) as a white solid: mp 125ꢀ
127 °C. 1H NMR (CDCl3) δ 7.60 (br d, J = 8.8 Hz, 2 H), 7.53 (br d, J =
8.4 Hz, 2 H), 7.46 (br d, J = 8.3 Hz, 2 H), 7.28 (br d, J = 8.8 Hz, 2 H), 6.69
(d, J = 15.6 Hz, 1 H), 6.45 (dt, J = 15.6, 7.8 Hz, 1 H), 4.18 (dd, J = 7.8, 0.9
Hz, 2 H). HRAPCIMS calcd for C16H12F3O m/z [M + H ꢀ HBr]+
277.0835, found 277.0832.
See the Supporting Information for details of the syntheses of 74ꢀ76
(Table 2) from bromide 153.
Procedure X. (6S)-2-Nitro-6-(3-{4-[6-(trifluoromethyl)-3-pyridinyl]-
phenyl}propoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (77)
(Scheme 2C). A stirred mixture of bromide 153 (50.0 mg, 0.131 mmol),
bis(pinacolato)diboron (38.9 mg, 0.153 mmol), KOAc (47 mg, 0.479
mmol), and Pd(dppf)Cl2 (19.3 mg, 0.026 mmol) in anhydrous DMF
(0.8 mL) was degassed for 5 min (vacuum pump), and then N2 was
added. After being stirred at 90 °C for 5 h, the mixture was cooled, and
5-bromo-2-(trifluoromethyl)pyridine (159) (55 mg, 0.243 mmol),
6581
dx.doi.org/10.1021/jm200377r |J. Med. Chem. 2011, 54, 6563–6585