ACCEPTED MANUSCRIPT
0.1 M pH 10 / MeOH, 8:2): tR (3e) = 2.0 min, tR (2e) = 4.9 min. Method 3
(mobile phase: aq. NH4OH 0.1 M pH 10 / MeOH, 7:3): tR (3f) = 1.6 min, tR
(2f) = 3.8 min, tR (3g) = 2.9 min, tR (2g) = 6.9 min, tR (3h) = 2.5 min, tR
(2h) = 6.1 min, tR (3i) = 3.6 min, tR (2i) = 8.8 min, tR (3n) = 2.9 min, tR
(2n) = 7.0 min, tR (3o) = 3.3 min, tR (2o) = 8.8 min, tR (3p) = 3.9 min, tR
(2p) = 9.3 min. Method 4 (mobile phase: aq. NH4OH 0.1 M pH 10 / MeOH, 6:4):
tR (3k) = 3.1 min, tR (2k) = 7.4 min, tR (3l) = 3.5 min, tR (2l) = 8.1 min,
tR (3m) = 4.4 min, tR (2m) = 10.5 min. Response factors were measured and
taken into account in the calculation of the conversions (a: 2.3, b: 2.7,
c: 2.7, d: 2.8, e: 2.2, f: 2.1, g: 2.0, h: 1.4, i: 1.4, j: 2.9, k: 2.2, l:
2.2, m: 2.2, n: 2.4, o: 2.4, p: 2.4).
The enantiomeric excess values of L-3a-p were measured on a reverse-phase
Crownpak CR(+) column (150 mm × 4 mm × 3.5 µm, Daicel). Flow rate 1.0 mL
min–1, temperature 40°C, detection wavelength 210 nm. Method 1 (mobile
phase: aq. HClO4 1.14% w/v / MeOH 96:4): tR (D-3a) = 5.1 min, tR (L-3a) =
7.9 min, tR (D-3b) = 6.9 min, tR (L-3b) = 9.2 min, tR (D-3c) = 7.6 min, tR
(L-3c) = 10.9 min, tR (D-3d) = 8.0 min, tR (L-3d) = 9.9 min, tR (D-3j) =
10.9 min, tR (L-3j) = 13.2 min. Method 2 (mobile phase: aq. HClO4 1.14% w/v
/ MeOH 86:14): tR (D-3e) = 10.2 min, tR (L-3e) = 13.0 min; tR (D-3f) = 17.1
min, tR (L-3f) = 20.9 min; tR (D-3g) = 13.9 min, tR (L-3g) = 17.6 min; tR
(D-3h) = 13.6 min, tR (L-3h) = 16.4 min; tR (D-3i) = 18.2 min, tR (L-3i) =
23.7 min; tR (D-3k) = 33.4 min, tR (L-3k) = 42.1 min; tR (D-3l) = 46.9 min,
tR (L-3l) = 63.8 min; tR (D-3m) = 48.2 min, tR (L-3m) = 61.6 min; tR (D-3n)
= 12.6 min, tR (L-3n) = 14.7 min; tR (D-3o) = 17.0 min, tR (L-3o) = 22.8
min; tR (D-3p) = 17.2 min, tR (L-3p) = 21.5 min.
4.3 Knoevenagel-Doebner condensation for the synthesis of cinnamic acids
The suitable aldehyde (10 mmol), malonic acid (30 mmol, 3.12 g) and
piperidine (0.5 mL) were dissolved in pyridine (20 mL) and the mixture was
heated under reflux for 4 h. The solution was cooled to room temperature
and poured in ice-cold aqueous HCl (100 mL, 3 M). The white solid
precipitate was filtered, washed with water (3 × 50 mL), aqueous NaHCO3 (20
mL, 5% w/v), then again with water (2 × 50 mL) and dried in an oven (60°C).
If required, the crude solid was recrystallysed from EtOH/H2O.
4.3.1 (E)-3-(3,4-difluorophenyl)acrylic acid (2j). Yield: 1.70 g (92%). 1H
NMR (DMSO-d6, 400 MHz), δ: 7.85-7.91 (m, 1H), 7.55-7.57 (m, 1H), 7.56
(d, J=16.0 Hz, 1H), 7.43-7.50 (m, 1H), 6.57 (d, J=16.0 Hz, 1H). 13C
1
2
NMR (DMSO-d6, 101 MHz), δ: 167.30, 150.35 (dd, JCF=248 Hz, JCF=13
1
2
3
Hz), 149.64 (dd, JCF=244 Hz, JCF=13 Hz), 141.64, 132.03 (dd, JCF=6
4
3
4
Hz, JCF=4 Hz), 125.82 (dd, JCF=7 Hz, JCF=3 Hz), 120.68, 117.88 (d,
2JCF=17 Hz), 116.65 (d, 2JCF=18 Hz).
4.3.2 (E)-3-(2,4-dichlorophenyl)acrylic acid (2k). Yield: 2.04 g (94%). 1H
NMR (DMSO-d6, 400 MHz), δ: 7.92-7.97 (m, 1H), 7.79 (d, J=15.6 Hz,
1H), 7.69-7.72 (m, 1H), 7.44-7.49 (m, 1H), 6.63 (d, J=15.6 Hz, 1H).
13C NMR (DMSO-d6, 101 MHz), δ: 166.96, 137.44, 135.24, 134.32, 130.93,
129.48, 129.36, 127.94, 122.99.
4.3.3 (E)-3-(3,4-dichlorophenyl)acrylic acid (2l). Yield: 1.99 g (92%). 1H
NMR (DMSO-d6, 400 MHz), δ: 7.92-7.97 (m, 1H), 7.79 (d, J=16.3 Hz,
1H), 7.69-7.73 (m, 1H), 7.42-7.49 (m, 1H), 6.63 (d, J=16.3 Hz, 1H).
13C NMR (DMSO-d6, 101 MHz), δ: 167.21, 141.20, 135.12, 132.35, 131.70,
130.91, 129.95, 128.10, 121.57.
4.3.4 (E)-3-(2-chloro-4-fluorophenyl)acrylic acid (2n). Yield: 1.87 g
(93%). 1H NMR (DMSO-d6, 400 MHz), δ: 7.98-8.03 (m, 1H), 7.80 (d,
J=16.0 Hz, 1H), 7.51-7.58 (m, 1H), 7.24-7.32 (m, 1H), 6.59 (d,
13
J=16.0 Hz, 1H). C NMR (DMSO-d6, 101 MHz), δ: 167.08, 162.64 (d,
3
3
1JCF=253 Hz), 137.56, 134.50 (d, JCF=11 Hz), 129.99 (d, JCF=9 Hz),
4
2
128.62 (d, JCF=3 Hz), 122.18, 117.14 (d, JCF=25 Hz), 115.29 (d,
2JCF=21 Hz).
13