11850
S.B. Ho¨fling et al. / Tetrahedron 64 (2008) 11846–11851
Table 5
3.1.5. 2-(Aminomethyl)acrylic acid (15)
Binding data of baclofen analogues (IC50, m
M)19
A solution of acid 19 (245 mg, 1.48 mmol) in 25% aqueous NH3
was stirred for 17 h at room temperature. The solvent was removed
under reduced pressure and the residue was dissolved in 1 N HCl.
After washing with EtOAc, the aqueous phase was evaporated to
dryness to give 15 as a colourless solid along with oligomers
Baclofen analogue
R-(ꢁ)-[H3]-baclofen binding
0.33
>100
>100
0.80
(rac)-Baclofen (27), R¼Cl
28, R¼H
29, R¼OH
24, R¼F
resulting from partial degradation. 1H NMR (250 MHz, D2O)
d 3.82
(s, 2H), 6.11 (s, 1H), 6.51 (s, 1H); 13C NMR (63 MHz, D2OꢁCD3OD)
d
41.4 (CH2), 131.7 (CH2), 134.6 (Cq), 168.0 (Cq).
4-fluorobenzenediazonium tetrafluoroborate (105 mg, 0.50 mmol)
was added in small portions over 15 min and the resulting mixture
was stirred at 40 ꢀC for 20 more minutes. After cooling to room
temperature, the reaction mixture was either extracted with EtOAc
(non-protonable products) or directly concentrated in vacuo (pro-
tonable products). Purification was achieved by silica gel column
chromatography or preparative HPLC.
3.1.6. 2-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)acrylic acid (21)15
To a mixture of acid 19 (900 mg, 5.50 mmol) and K2CO3
(912 mg, 6.60 mmol) in dry CH3CN (12 mL) under argon was
added tetrahydroisoquinoline 20 (1.03 mL, 8.20 mmol). While
stirring at 40 ꢀC, the reaction course is monitored by TLC. Com-
plete consumption of acid 19 was usually observed after 2 h, and
the resulting mixture was then filtered. Concentration of the fil-
trate in vacuo and purification by column chromatography gave 21
(1.07 g, 4.90 mmol, 90%) as a light yellow oil. Rf¼0.5 (CH2Cl2ꢁ
3.1.2. 2-Acetylamino-3-(4-fluorophenyl)propionic acid (11b)20
Preparation according to the general procedure for non-radio-
active fluoroarylation. Purification by preparative HPLC. Rf¼0.8
(nBuOHꢁAcOHꢁEtOHꢁH2O, 4:1:1:1, v/v); 1H NMR (250 MHz,
MeOHꢁAcOH, 66:33:1, v/v); 1H NMR (500 MHz, CDCl3)
d 3.10 (t,
J¼6.0 Hz, 2H), 3.44 (t, J¼6.0 Hz, 2H), 3.86 (s, 2H), 4.28 (s, 2H), 5.72
CDCl3)
d
2.00 (s, 3H), 3.09 (dd, J¼5.6, 14.2 Hz, 1H), 3.21 (dd, J¼5.6,
(s, 1H), 6.43 (s, 1H), 7.22 (m, 4H); 13C NMR
d 29.8 (CH2), 51.8 (CH2),
14.2 Hz, 1H), 4.80–4.88 (m, 1H), 6.12 (d, J¼7.3 Hz, 1H), 6.97 (dd,
JHF¼8.7 Hz, J¼8.7 Hz, 2H), 7.12 (dd, JHF¼5.4 Hz, J¼8.7 Hz, 2H), 9.25
57.0 (CH2), 61.0 (CH2), 121.4 (CH2), 126.7 (CH), 127.3 (CH), 127.5
(CH), 129.6 (CH), 135.4 (Cq), 136.0 (Cq), 166.6 (Cq), one Cq-signal
missing. All analytical data is in agreement with those reported in
Ref. 15
(br s, 1H); 13C NMR (63 MHz, CDCl3)
d 22.9 (CH3), 36.5 (CH2), 53.3
(CH), 115.4 (d, JCF¼21.3 Hz, 2ꢂCH),130.9 (d, JCF¼7.9 Hz, 2ꢂCH), 131.5
(d, JCF¼3.1 Hz, Cq), 170.7 (s, Cq), 174.1 (s, Cq), one Cq-signal missing;
19F NMR (234 MHz, CDCl3)
analytical data is in agreement with those reported in Ref. 20
d
ꢁ116.1; MS (ESI) m/z: 226 (MþþH). All
3.1.7. 2-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-3-(4-
fluorophenyl)propionic acid (22)
Preparation according to the general procedure for non-radio-
active fluoroarylation. Purification by column chromatography.
Rf¼0.85 (CH2Cl2ꢁMeOHꢁAcOH, 8:2:1, v/v); 1H NMR (250 MHz,
3.1.3. 2-(Hydroxymethyl)acrylic acid ethyl ester (18)21
A suspension of paraformaldehyde (3.30 g, 110 mmol) and
phosphorous acid (1 N, 0.4 mL) in water (10 mL) was heated for
90 min to 90 ꢀC under continuous stirring. The resulting clear
solution was cooled to room temperature and is then treated with
THF (10 mL), ethyl acrylate (10.9 mL, 100 mmol) and 1,4-diaza-
bicyclo[2.2.2]octane (1.10 g, 10.0 mmol). After stirring for 36 h at
room temperature, solid NaCl (3.50 g) and Et2O were added, and
the organic phase was separated. Together with the organic phases
obtained from further extraction with Et2O (3ꢂ30 mL), the com-
bined solutions were washed with satd aqueous NaCl and dried
over Na2SO4. Removal of the solvent in vacuo and distillation under
reduced pressure gave 18 (9.10 g, 69.6 mmol, 70%) as a colourless
CDCl3)
d
2.77–3.29 (m, 3H), 3.76 (t, J¼5.9 Hz, 2H), 3.63 (t, J¼5.9 Hz,
2H), 3.58 (s, 2H), 4.09 (m, 2H), 6.87–7.14 (m, 8H), 11.48 (s, 1H); 13C
NMR (360 MHz, CDCl3) 25.8 (CH2), 35.2 (CH2), 43.4 (CH), 49.2
d
(CH2), 53.5 (CH2), 56.7 (CH2), 115.3 (d, JCF¼21.2 Hz, 2ꢂCH), 125.6
(CH), 126.5 (CH), 126.7 (CH), 127.3 (CH), 130.3 (d, JCF¼7.9 Hz, 2ꢂCH),
131.8 (Cq), 133.9 (Cq), 134.3 (d, JCF¼3.2 Hz, Cq), 162.8 (d,
JCF¼244.4 Hz, Cq), 174.8 (Cq); 19F NMR (234 MHz, CDCl3þCFCl3)
d
ꢁ117.2; MS (ESI) m/z: 314 (MþþH); HRMS (ESI) calcd for
C19H21FNO2 [MþþH] 314.1556, found 314.1555.
3.1.8. (E)-4-Bromobut-2-enoic acid (26)23
oil. 1H NMR (250 MHz, CDCl3)
J¼7.1 Hz, 2H), 4.32 (d, J¼0.7 Hz, 2H), 5.82 (m, 1H), 6.24 (d, J¼0.7 Hz,
1H); 13C NMR (63 MHz, CDCl3)
22.9 14.1 (CH3), 60.8 (CH2), 62.5
d
1.31 (t, J¼7.1 Hz, 3H), 4.23 (q,
A suspension of crotonic acid (8.60 g, 100 mmol), N-bromo-
succinimide (21.4 g, 120 mmol) and AIBN (500 mg, 3.05 mmol) in
CCl4 (200 mL) was heated to 95–100 ꢀC. Heating was stopped when
all undissolved material had moved from bottom to the top of the
solution (ca. 6 h). The resulting mixture was cooled in an ice-bath,
filtered and evaporated to dryness to give crude 26, which was used
for the next step without further purification. 1H NMR (250 MHz,
d
(CH2), 125.5 (CH2), 139.5 (Cq), 166.3 (Cq). All analytical data is in
agreement with those reported in Ref. 21
3.1.4. 2-(Bromomethyl)acrylic acid (19)22
A solution of hydroxyester 18 (5.20 g, 39.9 mmol) in 48%
aqueous HBr (previously degassed with argon) under argon is
heated to 125 ꢀC for 10 min. The resulting mixture is cooled to
ꢁ78 ꢀC (acetone–dry ice) until precipitation of a colourless solid
starts. The reactions vessel is then warmed to 0 ꢀC by immersion in
an ice-bath. The precipitated solid was collected by filtration and
dissolved in a 1:1 mixture of CH2Cl2 and 1 N HCl (2ꢂ30 mL). The
combined organic phases obtained also from further extraction of
the acidic aqueous phase with CH2Cl2 (3ꢂ30 mL) were washed
with satd aqueous NaCl and dried over Na2SO4. Evaporation of the
solvent in vacuo gave 19 (3.70 g, 22.4 mmol, 56%) as a colourless
CDCl3)
d
4.03 (dd, J¼1.3, 7.3 Hz, 2H), 6.04 (td, J¼1.3, 15.3 Hz,1H), 7.11
(td, J¼7.3, 15.3 Hz, 1H); 13C NMR (63 MHz, CD3OD)
d 30.4 (CH2),
124.5 (CH), 145.3 (CH), 170.5 (Cq). All analytical data is in agreement
with those reported in Ref. 23
3.1.9. (E)-4-Aminobut-2-enoic acid (23)24
A solution of crude bromide 26 (7.80 g, 47.3 mmol) in 25%
aqueous NH3 was stirred for 20 h at room temperature. The solvent
was removed in vacuo and the residue was dissolved in MeOH.
After stirring for 1 h, the mixture was kept at 5 ꢀC for 15 h. Filtration
and drying in vacuo gave 23 (1.47 g, 14.5 mmol, 31%) as an ochre-
solid. 1H NMR (250 MHz, CDCl3)
d
4.17 (d, J¼0.8 Hz, 2H), 6.11 (dd,
coloured solid. 1H NMR (250 MHz, D2O)
d
3.55 (dd, J¼1.1, 6.0 Hz,
J¼0.4, 0.8 Hz, 1H), 6.50 (d, J¼0.4 Hz, 1H), 9.00 (br s, 1H); 13C NMR
2H), 5.90 (td, J¼1.1, 15.8 Hz, 1H), 6.34 (td, J¼6.0, 15.8 Hz, 1H); 13C
(63 MHz, CDCl3)
d
28.4 (CH2), 131.7 (CH2), 136.8 (Cq), 170.5 (Cq); MS
NMR (63 MHz, D2OþCD3OD)
d 40.8 (CH2), 132.3 (CH), 133.9 (CH),
(EI) m/z (rel int.): 164 (100, Mþ), 147 (68), 119 (37), 85 (70). All
174.7 (Cq). All analytical data is in agreement with those reported in
Ref. 24
analytical data is in agreement with those reported in Ref. 22