M. A. Parker et al. / Bioorg. Med. Chem. 16 (2008) 4661–4669
4667
35 mL of THF was added dropwise via syringe, and the
reaction mixture was heated at reflux for 5.5 h. The mix-
ture was cooled to room temperature, quenched care-
fully by the (initially dropwise) addition of water
(175 mL), acidified with 90 mL of 2 M HCl, and heated
at 80–85 ꢁC for 2 h. After cooling to room temperature,
most of the THF was removed under reduced pressure
and the remaining material was washed once with
Et2O. The aqueous layer was separated, made strongly
alkaline with 10% aqueous NaOH, and extracted three
times with Et2O. The Et2O extracts were dried with
MgSO4, filtered, and evaporated, yielding 1.83 g (77%)
of the crude amine 26 as a yellow oil. 1H NMR (CDCl3)
d 1.13 (d, 3, CH3, J = 6.4 Hz), 1.88 (br s, 2, NH2), 2.60
(dd, 1, ArCH2, J = 7.7, 13.3 Hz), 2.71 (dd, 1, ArCH2,
J = 5.7, 13.3 Hz), 3.21 (sextet, 1, ArCH2CH,
J = 6.3 Hz), 6.86–6.93 (complex m, 2, ArH), 6.98 (dt,
1, ArH, J = 4.5, 8.9 Hz). The amine was converted to
4.1.5.
1-(4-Bromo-2,5-difluorophenyl)-2-aminopropane
hydrochloride (3). A solution of 2 g of NaOH in
10 mL of H2O was added to a solution of 0.500 g of
amide 28 in 40 mL of methanol. The mixture was stir-
red under argon for 24 h at room temperature. The
methanol was removed by rotary evaporation and
the remaining mixture was partitioned between Et2O
and H2O. The Et2O phase was washed with H2O,
dried with MgSO4, filtered, and evaporated. The resi-
due was dissolved in 2 mL of EtOH and acidified with
1 mL of 2 M anhydrous HCl in ethanol. Dilution with
Et2O produced a fine white precipitate of 0.205 g
(50%) of the hydrochloride salt: mp 193–194 ꢁC. 1H
NMR (D2O) d 1.12 (d, 3, CH3, J = 6.7 Hz), 2.75
(dd, 1, ArCH2, J = 7.3, 14.2 Hz), 2.81 (dd, 1, ArCH2,
J = 6.6, 14.2 Hz), 3.47 (sextet, 1, ArCH2CH, J=
6.8 Hz), 7.04 (dd, 1, ArH, J = 6.4, 8.7 Hz), 7.31 (dd,
1, ArH, J = 5.8, 9.0 Hz). Anal. Calcd for
C9H11BrClF2N: C, 37.72; H, 3.87; N, 4.89. Found:
C, 37.63; H, 3.69; N, 4.68.
the
characterization.
trifluoroacetamide
58
without
further
4.1.3. N-Trifluoroacetyl-1-(2,5-difluorophenyl)-2-amino-
propane (27). To a solution of 1.3 g (7.6 mmol) of
crude26 in 100 mL of CH2Cl2 under argon was added
1.26 mL (9.13 mmol) of triethylamine. A solution of
3.27 mL (23.2 mmol) of trifluoroacetic anhydride in
10 mL of CH2Cl2 was added dropwise via syringe with
stirring. The solution was stirred at room temperature
for 15 min, and the volatiles were removed under re-
duced pressure. The residue was partitioned between
Et2O and water. The Et2O phase was dried with MgSO4,
filtered, and evaporated, and the residue (2.06 g) was
recrystallized from EtOAc–hexane, yielding 1.33 g
4.1.6. 1-(9-Anthracenyl)-2-nitropropene (29). A mixture
of 4.0 g of 9-anthraldehyde, 33 mL of nitroethane,
and 2.81 g of piperidinium acetate in a round-bot-
tomed flask under an argon atmosphere was placed
into an oil bath already heated to 90 ꢁC and stirred
for exactly 30 min. The flask was removed from the
oil bath and cooled under running water, then poured
into 200 mL water. The mixture was extracted twice
with CH2Cl2. The organic phases were combined,
washed with water, dried with MgSO4, filtered, and
evaporated, yielding 4.95 g (97%) of 29 as bright or-
ange crystals, quite clean by proton NMR. An analyt-
ical sample was recrystallized from THF/hexane: mp
142–142.5 ꢁC. 1H NMR (CDCl3) d 2.01 (s, 3, CH3),
7.54 (pentet, 4, ArH, J = 7 Hz), 7.90 (d, 2, ArH,
J = 8.5 Hz), 8.07 (d, 2, ArH, J = 7.5 Hz), 8.54 (s, 1,
ArH), 8.79 (s, 1, vinylic H). Anal. Calcd for
C17H13NO2: C, 77.55; H, 4.98; N, 5.32. Found: C,
77.35; H, 4.76; N, 5.15.
1
(66%) of 27 as beige crystals: mp 90–92 ꢁC. H NMR
(CDCl3) d 1.27 (d, 3, CH3, J = 6.8 Hz), 2.87 (d, 2,
ArCH2, J = 6.9 Hz), 4.29 (septet, 1, ArCH2CH,
7.1 Hz), 6.23 (br s, 1, NH), 6.87–6.95 (complex m, 2,
ArH), 7.02 (dt, 1, ArH, J = 4.4, 9.3 Hz). Anal. Calcd
for C11H10F5NO: C, 49.45; H, 3.77; N, 5.24. Found:
C, 49.17; H, 3.52; N, 5.01.
4.1.4. N-Trifluoroacetyl-1-(4-bromo-2,5-difluorophenyl)-
2-aminopropane (28). To 3.66 g of water in a 100 mL
round-bottomed flask was added 41.6 g of 98% sulfuric
acid. To the warm stirred solution was added 1.22 g of
crystalline 27. When all the solid had dissolved, the flask
was cooled to room temperature, and 0.76 g of elemen-
tal bromine was added, followed by 0.76 g of silver sul-
fate. The mixture was stirred 1 h at room temperature
and then poured carefully over ice. The quenched mix-
ture was partitioned between Et2O and H2O, and the
Et2O phase was washed three times with H2O and twice
(carefully) with saturated aqueous NaHCO3, dried with
MgSO4, filtered, and evaporated. The solid residue
(2.35 g) was dissolved in 1.2 mL of hot EtOAc and di-
luted with 160 mL of warm hexane. On cooling,
0.694 g (44%) of 28 precipitated as white crystals: mp
128–130 ꢁC. 1H NMR (CDCl3) d 1.27 (d, 3, CH3,
J = 6.7 Hz), 2.85 (d, 2, ArCH2, J = 6.7 Hz), 4.28 (septet,
1, ArCH2CH, J = 7.1 Hz), 6.13 (br s, 1, NH), 6.97 (dd,
1, ArH, J = 6.2, 8.3 Hz), 7.29 (dd, 1, ArH, J = 5.6,
8.7 Hz). Anal. Calcd for C11H9BrF5NO: C, 38.17; H,
2.62; N, 4.05. Found: C, 37.99; H, 2.49; N, 3.82.
4.1.7. 1-(9-Anthracenyl)-2-aminopropane (30). A solu-
tion of 4.55 g of 29 in 160 mL of anhydrous THF
was added dropwise under argon to a stirred suspen-
sion of 4.00 g of LiAlH4 in 160 mL of anhydrous
THF. The mixture was stirred and heated at reflux
for 42 h. The mixture was cooled to room temperature
and slowly quenched, sequentially, with 4.5 mL of 2-
propanol, 4.5 mL of 15% aqueous NaOH, and
16 mL of water. The resulting solids were filtered off
and the filtrate was evaporated. The residue was par-
titioned between 200 mL of Et2O and 200 mL of
0.5 M HCl. The aqueous phase was washed twice with
Et2O and basified with aqueous NaOH, then extracted
3· with Et2O. The Et2O extracts were dried with
MgSO4, filtered, and evaporated, yielding 1.90 g
(47%) of the crude free amine 30 as a viscous tan
oil. 1H NMR (CDCl3)
d
1.28 (d, 3, CH3,
J = 6.2 Hz), 3.54 (sextet, 1, ArCH2CH, 6.7 Hz), 3.66
(dd, 1, ArCH2, J = 7.6, 14.2 Hz), 3.71 (dd, 1, ArCH2,
J = 6.0, 14.2 Hz), 7.47 (t, 2, ArH, J = 7.5 Hz), 7.51 (t,
2, ArH, J = 7.5 Hz), 8.01 (d, 2, ArH, J = 8 Hz), 8.33
(d, 2, ArH, J = 9 Hz), 8.37 (s, 1, ArH). This product