1
position at 285 °C; H NMR (400 MHz, DMSO-d6, CF3-
3.1(m, 3H), 3.53 (d, J ) 13 Hz, 2H), 3.81 (d, J ) 13 Hz,
2H), 7.08 (dd, J ) 3, 8 Hz, 1H), 7.15 (dd, J ) 3, 10 Hz,
1H).
CO2H) δ 2.94 (s, 3Η), 3.20 (t, J ) 12.0 Hz, 2H), 3.32 (t, J
) 11.1 Hz, 2H), 3.62 (d, J ) 12.0 Hz, 2H), 3.90 (d, J )
13.0 Hz, 2H), 6.93 (s, 1H), 7.31 (dd, J ) 8.0, 3.0 Hz, 1H),
7.38 (dd, J ) 10.4, 3.0 Hz, 1H); 13C NMR (100.6 MHz,
DMSO-d6) δ 42.6, 47.5, 52.9, 102.0 (JC-F ) 24.1 Hz), 111.7
(JC-F ) 27.9 Hz), 112.8, 125.9 (JC-F ) 9.0 Hz), 142.8 (JC-F
) 9.0 Hz), 145.5, 153.1, 159.8 (JC-F ) 244.9 Hz), 161.8,
177.7 (JC-F ) 2.3 Hz); FTIR (KBr, cm-1) 3434, 1627, 1488,
1461, 1376, 1325, 1131, 982.
Isolation of Acetophenone 5. The vessels required for
the amination stage were carefully dried, and processing was
carried out under a nitrogen atmosphere. To a mixture of
tris(dibenzylideneacetone)dipalladium (1.16 g, 0.02 mol
equiv), rac-BINAP (1.58 g, 0.04 mol equiv), and anisole (200
mL) was added cesium carbonate (28.95 g, 1.40 mol equiv).
The mixture was heated to 125 °C, and a solution of
bromoester 1b (20.0 g, 1.00 mol equiv) and N-methylpip-
erazine (6.99 g, 1.10 mol equiv) in anisole (90 mL)
maintained at 45 °C was added in six portions over 90 min;
this was followed by an anisole (10 mL) line wash. The
resulting mixture was maintained at 125 °C for an additional
3 h, cooled to 20 °C, and diluted with water (120 mL); 47%
w/w sodium hydroxide solution (11.88 g, 2.20 mol equiv)
was added, and the mixture was stirred at 20 °C for 0.75 h.
After allowing the filtrate to settle, the aqueous layer was
separated and filtered through Celite. Tetrahydrofuran (30
mL) and methanol (30 mL) were added to the filtrate, and
the pH was adjusted to 7. The solid piperazine acid 2b was
filtered off, and the mother liquor was freeze-dried to give
an orange-brown solid. This solid was subjected to chroma-
tography on silica (acetonitrile/methanol, 10/00 to 9/1),
Procedure B (Acidic Hydrolysis). The vessels required
for the amination stage were carefully dried, and processing
was carried out under a nitrogen atmosphere. To a mixture
of tris(dibenzylideneacetone)dipalladium (1.16 g, 0.02 mol
equiv), rac-BINAP (1.58 g, 0.04 mol equiv), and anisole (200
mL) was added cesium carbonate (28.95 g, 1.40 mol equiv).
The mixture was heated to 125 °C, and a solution of
bromoester 1b (20.0 g, 1.00 mol equiv) and N-methylpip-
erazine (6.99 g, 1.10 mol equiv) in anisole (90 mL)
maintained at 45 °C was added in six portions over 90 min;
this was followed by an anisole (10 mL) line wash. The
resulting mixture was maintained at 125 °C for an additional
3 h, cooled to 75 °C, and diluted with water (200 mL). A
solution of concentrated sulphuric acid (55.4 g, 8.8 mol
equiv) in water (100 mL) was added at 75 °C, and the
mixture was heated at 96 °C for 4 h. The mixture was cooled
to 75 °C, and the layers were separated. Anisole (100 mL)
and 47% w/w sodium hydroxide solution (37.75 g, 6.99 mol
equiv) were added to the hot aqueous layer, and the mixture
was cooled to 20 °C. The pH was adjusted to 7 by adding
47% w/w sodium hydroxide solution (39.26 g, 7.29 mol
equiv), and the precipitated solid was filtered off, washed
with a mixture of tetrahydrofuran (30 mL), methanol (30
mL) and water (30 mL), and then dried at 40 °C under
vacuum. The yield of piperazine acid 2b was 14.2 g (73%).
Preparation of Hydrated Species 4. The vessels required
for the amination stage were carefully dried, and processing
was carried out under a nitrogen atmosphere. To a mixture
of tris(dibenzylideneacetone)dipalladium (1.16 g, 0.02 mol
equiv), racemic-BINAP (1.58 g, 0.04 mol equiv), and anisole
(200 mL) was added cesium carbonate (28.95 g, 1.40 mol
equiv). The mixture was heated to 125 °C, and a solution of
bromoester 1b (20.0 g, 1.00 mol equiv) and N-methylpip-
erazine (6.99 g, 1.10 mol equiv) in anisole (90 mL)
maintained at 45 °C was added in six portions over 90 min;
this was followed by an anisole (10 mL) line wash. The
resulting mixture was maintained at 125 °C for an additional
3 h, cooled to 20 °C, and diluted with water (120 mL); 47%
w/w sodium hydroxide solution (17.83 g, 3.30 mol equiv)
was added in four portions, and the mixture was stirred at
20 °C for 2 h. After allowing the filtrate to settle, the aqueous
layer was separated and acidified to pH 3 with concentrated
hydrochloric acid at 20 °C. The precipitated pale-yellow solid
was filtered off, washed with a mixture of tetrahydrofuran
(30 mL) and methanol (30 mL), and then dried at 60 °C
under vacuum. The yield of compound 4 was 1.6 g (8%).
Mp: decomposition at 285 °C; 1H NMR (400 MHz, DMSO-
d6, CF3CO2H) δ 2.89 (s, 3H), 2.96 (m, 3H), 3.21 (m, 3H),
1
yielding acetophenone 5 (0.72 g, 5%). Mp: 92-94 °C; H
NMR (400 MHz, CDCl3) δ 2.54 (s, 3H), 2.61 (s, 3H), 2.89
(br s, 4H), 3.30 (br s, 4H), 6.84 (dd, J ) 3, 10 Hz, 1H), 7.07
(dd, J ) 3, 8.5 Hz, 1H).
First Synthetic Route to Bromoester 1b. Alkene 6.
Dimethyl acetylenedicarboxylate (91.3 kg, 1.12 mol equiv)
was added to a stirred solution of 2-bromo-4-fluorophenol
(110.0 kg, 1.00 mol equiv) and triethylamine (0.58 kg, 0.01
mol equiv) in 2-propanol (110 L) over 2 h whilst maintaining
the batch temperature at 20-25 °C; this was followed by a
line wash of 2-propanol (22 L). The mixture was adjusted
to 40-45 °C, and a solution of sodium hydroxide (57.2 kg,
2.48 mol equiv) in water (440 L) was added over 1 h; ester
hydrolysis was complete after an additional 4 h at 40-45
°C. The solution was concentrated (to 440 L) under reduced
pressure at <40 °C, diluted with water (220 L), and again
concentrated (to 440 L). The residual solution was cooled
to 20-25 °C, diluted with tert-butyl methyl ether (440 L),
and adjusted to pH 1 with 6 N hydrochloric acid (280 L)
over 60 min. The temperature of the mixture was adjusted
to 28-33 °C, and the layers were separated. The aqueous
phase was extracted with more tert-butyl methyl ether (440
L) at 28-33 °C. The extracts were combined and washed
with water (220 L) at 28-33 °C and then concentrated (to
660 L) at atmospheric pressure. More tert-butyl methyl ether
(440 L) was added to the residue and the distillation repeated
to ensure removal of water. The solution was further
concentrated (to 440 L) under reduced pressure at <40 °C.
Heptane (440 L) was added over 60 min and the resulting
suspension concentrated (to 660 L) under reduced pressure
at 20-25 °C. The resulting slurry was diluted with more
heptane (660 L) over 1 h (the solvent contained <29 mol %
tert-butyl methyl ether). The slurry was stirred for 1 h at
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