106
N.J. Lawrence et al. / Journal of Fluorine Chemistry 123 (2003) 101–108
(KBr disc) n 3000–2800 (s), 1580, 1140 cmÀ1; H NMR
(300 MHz; CDCl3) dH (ppm) 3.70 [6H, s, (OCH3)2], 3.83
(3H, s, OCH3), 3.95 (3H, s, OCH3), 6.36 (1H, d, J 12.4 Hz,
C¼CH), 6.44 (2H, s, H-20 and H-60), 6.52 (1H, d, J 12.4 Hz,
CH¼C), 6.85 (2H, d, J 9.0 Hz, H-200 and H-600); 13C NMR
(100 MHz; CDCl3) dC (ppm) 56.0, 61.0, 61.9, 103.7, 105.9,
112.7 (2C, dd, JCF 10 Hz and JCF 20 Hz), 127.3, 131.5,
132.2, 135.3, 137.6, 153.1, 155.3 (2C, dd, JCF 250 Hz and
JCF 10 Hz); FABMS m/z (%) 336 [(Mþ), 100%].
in vacuo yielding a pale pink solid. Column chromatography
(SiO2, hexane:EtOAc, 4:1 (v/v)) provided Z-2 as a white
powder (71 mg, 34%), mp 75–78 8C; Analysis: Found C,
68.0; H, 6.3; F, 5.9%. Calculated for C18H19FO4: C, 67.9;
H, 6.0; F, 6.0%; Rf 0.27 (SiO2, hexane:EtOAc, 4:1 (v/v));
IR (KBr disc) n 3000–2860, 2840–2800, 1620 (cis-C¼C),
1
1140–1110 cmÀ1; H NMR (400 MHz; CDCl3) dH (ppm)
1
3.68 [6H, s, (OCH3)2], 3.83 (3H, s, OCH3), 3.84 (3H, s,
OCH3), 6.42 (1H, d, J 12.5 Hz, C¼CH), 6.46 (1H, d, J
12.5 Hz, CH¼C), 6.47 (2H, s, H-20 and H-60), 6.82 (1H, t, J
8.8 Hz, H-500), 6.98 (1H, d, J 8.8 Hz, H-600), 7.03 (1H, dd,
J 12.5 Hz and 2.0 Hz, H-200); 13C NMR (100 MHz; CDCl3)
dC (ppm) 55.8, 56.0, 60.9, 105.8, 112.8, 116.3 (1C, d, JCF
20 Hz), 125.1, 128.3, 129.9, 130.2, 132.2, 137.2, 146.4 (1C,
d, JCF 10 Hz), 151.8 (d, JCF 240 Hz), 152.9; FABMS m/z (%)
318 [(Mþ), 100%].
Further elution provided E-2 as a white powder (71 mg,
34%), mp 173–177 8C; Analysis: Found C, 68.2; H, 5.7; F,
6.4. Calculated for C18H19FO4: C, 67.9; H, 6.0; F, 6.0%;
Rf 0.48 (SiO2, hexane:EtOAc, 4:1 (v/v)); IR (KBr disc) n
3000–2900 (s), 2840–2820, 1580, 1140, 960 cmÀ1; 1H NMR
(300 MHz; CDCl3) dH (ppm) 3.86 (3H, s, OCH3), 3.92 [9H,
s, (OCH3)3], 6.71 (2H, s, H-20 and H-60), 6.90–6.97 (3H, m),
7.18 (1H, d, J 8.3 Hz, H-500), 7.30 (1H, d, J 2.3 Hz, H-200);
13C NMR (100 MHz; CDCl3) dC (ppm) 56.0 (2 Â OCH3),
56.2 (OCH3), 60.9 (OCH3), 103.3 (CH), 113.1 (2 Â CH),
122.8 (CH), 126.4 (CH), 127.8 (CH), 130.7, 132.8, 137.8,
147.1 (1C, d, JCF 20 Hz), 152.5 (1C, d, JCF 250 Hz), 153.3;
FABMS m/z (%) 318 [(Mþ), 100%].
Further elution provided E-1 as a white crystalline solid
(0.22 g, 35%), mp 160–163 8C; Analysis: Found C, 64.5; H,
5.3%. Calculated for C18H18F2O4: C, 64.3; H, 5.3%; Rf 0.49
(SiO2, hexane:EtOAc, 7:1 (v/v)); IR (KBr disc) n 3000–2900
(m), 2860–2840, 1580, 1520–1510, 1130 (s), 960 (s) cmÀ1
;
1H NMR (300 MHz; CDCl3) dH (ppm) 3.85 (3H, s, OCH3),
3.89[6H, s, (OCH3)2], 3.99(3H, t,JHF 1.0 Hz, 400-OCH3),6.68
(2H, s, H-20 and H-60), 6.85 (1H, d, J 16.2 Hz, C¼CH), 6.95
(1H, d, J 16.2 Hz, CH¼C), 7.05 (2H, d, J 9.8 Hz, H-200 and
H-600); 13C NMR (100 MHz; CDCl3) dC (ppm) 56.1
(2 Â OCH3), 61.0 (OCH3), 61.9 (OCH3), 103.6, 109.9 (2C,
d, JCF 20 Hz), 125.7, 129.9, 132.2, 132.6 (1C, t, JCF 10 Hz),
135.7 (1C, t, JCF 10 Hz), 138.3, 153.4, 155.8 (2C, dd, JCF
250 Hz and JCF 10 Hz); FABMS m/z (%) 336 [(Mþ), 100%].
3.6. Preparation of 3-fluoro-4-methoxybenzaldehyde (11)
A stirring solution of 2-fluoroanisole (12) (4.46 cm3,
39.7 mmol)andhexamethylenetetramine(5.57 g,39.7 mmol)
in TFA (35 cm3) was heated at reflux under argon overnight.
On cooling to room temperature the solvent was evaporated in
vacuo and the crude residue dissolved in DCM (75 cm3). The
mixture was washed with an aqueous solution (saturated) of
NaHCO3 (2 Â 30 cm3), dried (MgSO4) and evaporated in
vacuo to afford the aldehyde 11 as a pale yellow solid
(3.32 g, 54%), mp 30–31 8C [24] [mp 29–30 8C]; Analysis:
Found C, 62.3; H, 4.6%. Calculated for C8H7O2F: C, 62.0; H,
3.8. Preparation of 1,2-difluoro-3-methoxybenzene (14)
Freshly ground K2CO3 (4.04 g, 28.8 mmol) was added to a
solution of 2,3-difluorophenol (13) (2.5 g, 19.23 mmol) in
DMSO (5 cm3), followed by MeI (2.39 cm3, 38.5 mmol). The
resulting pale green solution was stirred for 30 min at RTafter
which time the solution appeared yellow in colour. Water
(25 cm3) was added and the mixture extracted with DCM
(3 Â 30 cm3). The combined organic extracts were thor-
oughly washed with water (5 Â 50 cm3), dried (MgSO4)
andconcentratedinvacuotoyieldapaleyellowoil. Kugelrohr
distillation (bp 50 8C at 2 mmHg) gave the ether 14 [25] as an
oil (2.17 g, 78%), Rf 0.81 (SiO2, hexane:EtOAc, 3:1 (v/v)); IR
1
4.5%; H NMR (300 MHz, CDCl3) dH (ppm) 3.98 (3H, s,
OCH3), 7.08 (1H, t, JHF,HH 8.0 Hz, H-5), 7.55–7.65 (2H, m,
H-2 and H-6), 9.87 (1H, d, JHF 5.0 Hz, CHO).
3.7. Preparation of (Z)-1-(30,40,50-trimethoxyphenyl)-
2-(300-fluoro-400-methoxyphenyl)ethene (Z-2) and
(E)-1-(30,40,50-trimethoxyphenyl)-2-(300-fluoro-
400-methoxyphenyl)ethene (E-2)
(Neat) n 3020–2900, 1240 cmÀ1 1H NMR (400 MHz;
;
CDCl3) dH (ppm) 3.93 (3H, s, OMe), 6.75–6.82 (2H, m, H-
1 and H-5), 6.99–7.05 (1H, m, H-6); 13C NMR (100 MHz;
CDCl3) dC (ppm) 56.4 (OMe), 108.4 (d, JCF 2 Hz), 108.8 (d,
JCF 8 Hz), 123.1 (dd, JCF 9 Hz and 5 Hz), 141.1 (dd, JCF 247
and 15 Hz), 149.2 (dd, JCF 8 Hz and 4 Hz), 151.3 (dd, JCF 245
and9 Hz);EIMSm/z(%)129[(MÀMe)þ,90%],101(100%).
Potassium tert-butoxide (175 mg, 1.56 mmol) in EtOH
(4 cm3) was added to the phosphonium chloride 8 (622 mg,
1.3 mmol) and 3-fluoro-p-anisaldehyde (11) (100 mg,
0.65 mmol) in anhydrous EtOH (5 cm3) at À78 8C. The
resulting clear pink solution was stirred for a further 20 min
at À78 8C before being allowed to slowly warm to room
temperature. A pink precipitate quickly formed and the
mixture was stirred overnight. Water (10 cm3) was added
causing the precipitate to redissolve and the resulting
mixture was extracted with DCM (3 Â 30 cm3). The com-
bined organic extracts were dried (MgSO4) and concentrated
3.9. Preparation of 2,3-difluoro-4-
methoxybenzaldehyde (15)
Using the method developed by Scarpati et al. [26] TiCl4
(2.74 cm3, 25 mmol) in DCM (5 cm3) was added dropwise