F. Karimi, B. Langström
FULL PAPER
Table 4. Data for the synthesis of amides 8e,[20] 9, 10؊11b,[21] 13,[22] 38, 45؊47[23] and 7
1
13C NMR, δ [ppm]
Yield [%]
GC-MS
H NMR, δ [ppm]
8
9
e
88
97
194, 164
361, 98
Ϫ
Ϫ
7.39 (s, 1 H), 6.50 (br, 1 H), 3.73Ϫ3.90
163.9, 152.2, 131.2, 129.3, 123.8,
62.5, 62.3, 53.4, 48.0, 40.6, 27.9, 22.6, 13.5
(
(
(
m, 7 H), 3.10Ϫ3.33 (m, 2 H), 2.60Ϫ2.90
m, 2 H), 2.22 (m, 2 H), 1.90 (m, 1 H), 1.70
m, 3 H), 1.08 (t, 3 H)
10
89
185, 155
8.20 (m, 1 H), 7.81 (m, 2 H), 7.82Ϫ7.31
m, 4 H), 6.37 (br, 1 H), 2.93 (s, 3 H)
170.2, 134.3, 133.4, 130.2, 129.9, 128.1, 126.8,
126.2, 125.3, 124.7, 125.5, 26.6
(
1
1
1
4
1a
1b
3
95
97
85
98
149, 119
169, 139
213, 106
247, 156
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
5
7.32 (m, 5 H), 4.13 (q, 2 H), 3.48 (s, 2 H),
175.2, 138.3, 129.0, 128.1, 126.9, 63.2, 60.2,
52.8, 41.1, 26.2, 14.1
2
1
.85 (td, 2 H), 2.28 (tt, 1 H), 2.08 (dt, 2 H),
.85 (m, 4 H), 1.25 (t, 3 H)
4
4
6
7
78
97
339, 248
341, 326
7.29 (m, 5 H), 6.99 (m, 3 H), 3.86 (s, 3 H),
206.6, 152.6, 146.8, 138.3, 134.4, 128.9, 128.0,
126.8, 124.2, 120.1, 114.6, 63.1, 61.6, 55.8, 53.1,
48.1, 28.0
152.3, 146.3, 138.2, 136.5, 129.1, 128.0, 126.8,
123.8, 119.6, 111.2, 74.1, 63.2, 60.7, 55.5, 53.5,
42.8, 28.6
3
2
.84 (s, 3 H), 3.49 (s, 2 H), 3.07 (tt, 1 H),
.87 (dt, 2 H), 2.05 (m, 2 H), 1.80 (m, 4 H)
7.28 (m, 5 H), 7.02 (t, 1 H), 6.82 (d, 1 H),
6
3
1
1
.80 (d, 1 H), 4.61 (d, 1 H), 3.86 (s, 6 H),
.46 (s, 2 H), 2.70Ϫ3.0 (m, 2 H), 2.15 (s, 1 H),
.80Ϫ1.94 (m, 3 H), 1.64 (m, 1 H),
.13Ϫ1.55 (m, 2 H)
3
8[a]
76
79
252, 220
7.00 (t, 1 H), 6.88 (d, 1 H), 6.82 (d, 1 H),
152.4, 146.3, 136.3, 123.9, 119.6, 111.3, 74.1,
60.8, 55.6, 42.8
4
2
1
.61 (d, 1 H), 3.84 (s, 6 H), 3.15 (m, 4 H),
.52 (m, 2 H), 2.01 (m, 1 H), 1.75 (m, 1 H),
.15Ϫ2.45 (m, 3 H)
7[b]
Ϫ
7.1Ϫ6.8 (m, 7 H), 4.60 (m, 2 H), 3.89Ϫ3.72
m, 7 H), 3.62 (d, 2 H), 2.90Ϫ2.40 (m, 3 H),
.10Ϫ1.00 (m, 5 H)
169.0, 152.3, 135.8, 130.9, 130.1, 124.0, 119.2,
115.3, 111.3, 73.5, 73.1, 60.7, 55.6, 46.1, 42.1,
41.9, 39.9, 28.7, 27.9
(
2
[
a]
Racemic alcohol 47 (0.50 g, 1.48 mmol), ammonium formate (1.13 g, 17.92 mmol) and palladium on activated carbon (10%, 0.59 g)
were dissolved in methanol (18 mL) under argon. The reaction mixture was heated under reflux for 45 min, cooled to room temperature
and filtered through Celite. The filtrate was concentrated in vacuo. The residue was treated with NaOH solution (1 , 300 mL) and
extracted with EtOAc (3 ϫ 100 mL). The combined organic layers were dried over MgSO
4
and the solvents were evaporated under
ϩ
reduced pressure. Column chromatography (CH Cl /MeOH, 2:1) yielded 38 as a white solid (0.28 g, 76%). LC-MS (ESI , solvent A/B):
2
2
ϩ
[b]
m/z ϭ 252 [M ϩ H] . Under argon, 4-fluorophenylacetyl chloride (0.29 mL, 2.1 mmol) was added to a solution of 38 (0.50 g, 2.0 mmol)
in anhydrous THF (10 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h then at 40 °C for 2 h. The volatile
compounds were removed in vacuo and the residue was partitioned between saturated sodium bicarbonate and dichloromethane. The
aqueous layer was extracted with dichloromethane (3 ϫ 20 mL). The combined organic phases were dried (MgSO
4
) and the solvents
evaporated under reduced pressure. The crude product was purified by flash column chromatography on silica gel. Elution with ether
ϩ
ϩ
yielded 7 (0.52 g, 79%) as a colourless oil that solidified. LC-MS (ESI , solvent A/B): m/z ϭ 387 [M ϩ H] .
µmol) dissolved in DMSO (50 µL) and anhydrous dioxane (150
µL). The reaction mixture was treated as described in Method A.
Labelling Experiments
Method A: [Tetrakis(triphenylphosphane)palladium] (ca. 3 µmol)
and halide (ca. 9 µmol) were placed in a vial (1 mL). The vial was
flushed with nitrogen gas and dry THF (250 µL) was added. The
resulting mixture was heated to 70 °C for 1 min and kept at room
temperature for 10Ϫ15 min. Amine (ca. 50 µmol) was added and
the reaction mixture was shaken just before injection into the
micro-autoclave that was pre-charged with [ C]carbon monoxide.
The mixture was heated at the desired temperature for 5 min. The
crude product was transferred to a vial (3 mL) under reduced press-
ure. The micro-autoclave was washed with THF (250 µL) and the
solvents were combined in the vial. The radioactivity was measured
before and after purging with nitrogen. The solvent volume was
reduced to 0.1 mL by heating at 80 °C and flushing with nitrogen.
The crude mixture was dissolved in acetonitrile/water and injected
onto a semi-preparative LC. The identity and radiochemical purity
of the collected fraction was analysed by LC and LC-MS.
Method C: A capped vial (1 mL) containing a solution of [tetrakis-
(
triphenylphosphane)palladium] (ca. 3 µmol) and halide (ca. 7
µmol) in dry THF (125 µL) was flushed with nitrogen. The reaction
mixture was heated at 70 °C for 1 min and kept at room tempera-
ture for 10Ϫ15 min. Another capped vial (1 mL) was flushed with
nitrogen and charged with the amine (ca. 50 µmol) in anhydrous
THF (100 µL) and pempidine (25 µL, 138 µmol), and then it was
shaken and kept at room temperature for 10Ϫ15 min. The reaction
mixture in the first vial was transferred to the vial containing the
amine just before injection into the micro-autoclave that was pre-
11
11
charged with [ C]carbon monoxide. The micro-autoclave was
heated at 150 °C for 5 minutes. The crude product was treated as
for Method A.
Method D: A vial (1 mL) was charged with [tetrakis(triphenylphos-
phane)palladium] (ca. 3 µmol), substrate (ca. 17 µmol) and THF
Method B: Halide (ca. 9 µmol) and [tetrakis(triphenylphosphane)-
palladium] (ca. 3 µmol) were dissolved in anhydrous 1,4 dioxane (225 µL). The solution was heated to 70 °C for 1 min and kept at
50 µL). Another vial (1 mL) was charged with the amine (ca. 50 room temperature for 10Ϫ15 min. Pempidine (25 µL, 138 µmol)
(
2136
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2132Ϫ2137